Some interesting things I was reading recently pointed to how quickly the GLP-1 market is broadening across both access and product form. This New York Times piece on older adults as Medicare coverage expands was a useful reminder that wider access brings a different set of clinical questions around muscle loss, dehydration, and long-term use, while Fierce Pharma’s oral GLP-1 tracker is a good way to watch the shift from injections to pills, an early race in which Lilly’s Foundayo is off to a muted start. I also found Endpoints’ report on BrightGene’s obesity shot nearing approval in China interesting as another sign that the next wave of GLP-1 competition may be increasingly global, a shift echoed in this week’s Press section, where Hengrui’s oral GLP-1 cleared its Phase 3 weight-loss goals in China.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Dr. Reddy’s pauses generic semaglutide supply over an API specification failure

  Dr. Reddy’s announced it will delay commercial supplies of its generic semaglutide, which has launched in India and Canada. The delay is due to an issue with the active pharmaceutical ingredient (API) that caused some batches to be “out of specification.” The company stated there is no impact on patient safety or on the product’s existing global regulatory filings.

  Press | Mechanism: GLP-1 receptor agonist

• Novo Nordisk partners with Vivani Medical on long-acting GLP-1 implant NPM-139

  Novo Nordisk has entered into an agreement with Vivani Medical to evaluate NPM-139, a miniature, ultra long-acting semaglutide implant for chronic weight management. Vivani is set to initiate a first-in-human Phase 1 study of the implant in the coming weeks, using Wegovy injections as an active comparator. The agreement, which utilizes Vivani’s NanoPortal platform technology, has no exclusivity provisions for Novo Nordisk.

  Press | Mechanism: GLP-1

• Kalohexis files for IPO to advance GLP-1 obesity challenger.

  Kalohexis, a spinout from Endevica Bio, announced on July 7 that it has confidentially submitted IPO documents to the Securities and Exchange Commission to support its obesity and cancer cachexia treatments. The company’s lead assets are 710GO, an oral dual MC3R/MC4R agonist in Phase 1 development for weight loss, and mifomelatide, an injectable dual MC3R/MC4R antagonist in Phase 2 for cancer cachexia.

  Press | Mechanism: MC3R/MC4R agonist

📰 PRESS

• Hengrui’s oral GLP-1 meets Phase 3 weight loss goals in China.

  Press | Mechanism: GLP-1 receptor agonist

• MindRank raises $52M for Phase 3 oral GLP-1 drug.

  Press | Mechanism: GLP-1 receptor agonist

• Ascletis submits two FDA INDs for once-monthly obesity drugs.

  Press | Mechanism: amylin receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

A GLP-1 Drug That Isn’t Chasing Weight Loss: Inside Lilly’s RENEW Program

Eli Lilly’s brenipatide (LY3537031) is an internally discovered, unimolecular dual agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, but unlike its class sibling tirzepatide, it is being directed almost entirely outside of obesity. Engineered for once-monthly subcutaneous injection rather than weekly dosing, the molecule is advancing through a coordinated clinical program named RENEW that targets neuropsychiatry, addiction, gastrointestinal, and respiratory indications. The program recently signaled a clear escalation toward pivotal execution when six RENEW trials added approximately 190 clinical sites in a single week, supporting Phase 3 studies in major depressive disorder and alcohol use disorder alongside Phase 2 trials for schizophrenia, bipolar disorder, smoking, opioid use disorder, irritable bowel syndrome, and asthma. While brenipatide is being tested in healthy volunteers with overweight or obesity, these are strictly Phase 1 clinical pharmacology and multiple-ascending-dose studies serving as routine safety, tolerability, and dose-finding anchors required for any incretin development, with no Phase 2 or Phase 3 weight-loss trials underway.

Although Lilly has not publicly explained this strategy, the most credible analytical inference is portfolio diversification into GLP-1 brain and immune biology, given that Lilly already possesses a saturated obesity pipeline featuring tirzepatide, the oral pill orforglipron, and the triple agonist retatrutide, whereas a monthly dosing schedule could plausibly benefit adherence-challenged chronic populations. Reinforcing this strategic shift into immunology and inflammation, Lilly Chief Scientific Officer Dan Skovronsky highlighted brenipatide in the context of a Phase 2 asthma study during a February 2026 earnings call, framing the molecule as an expansion of the mechanism into new therapeutic domains ahead of initial clinical readouts expected around 2027.

ClinicalTrials.gov: NCT07412756 (RENEW-MDD 1, Phase 3 major depressive disorder) | NCT07219966 (RENEW-ALC-1, Phase 3 alcohol use disorder) | NCT07219173 (Phase 2 asthma) | NCT07476118 (Phase 1b obesity pharmacology)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Beyond the Pancreas: Why the Tirzepatide Receptor Class Is Being Tested for Depression, Asthma, and Addiction (Example drugs: Brenipatide)

While glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones best known for stimulating insulin and suppressing appetite, their receptors are expressed far beyond the pancreas and hypothalamic appetite centers, anchoring the expansion of dual agonists like Eli Lilly’s brenipatide into current trials for depression, addiction, irritable bowel syndrome, and asthma. In the brain, GLP-1 receptors populate the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, and amygdala, while GIP receptors are co-expressed in the hypothalamus. Preclinical models show that agonism dampens dopamine signaling in the ventral tegmental area to nucleus accumbens reward pathway, reducing seeking across alcohol, nicotine, cocaine, and opioid models to provide the rationale for alcohol use disorder, smoking, and opioid use disorder trials. This central activity also attenuates neuroinflammation and oxidative stress, enhances hippocampal neurogenesis and neuroplasticity, and modulates serotonergic and noradrenergic signaling, forming the biological basis for depression, bipolar, and schizophrenia trials.

Peripherally, the GLP-1 receptor sits on immune cells including macrophages, monocytes, eosinophils, and lymphocytes to inhibit nuclear factor kappa B signaling and lower pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin 6, acting partly through a gut-to-brain axis that suppresses peripheral inflammation. In mucosal tissues, its expression on pulmonary epithelial cells regulates airway inflammation, while its presence within the enteric nervous system and myenteric plexus on vagal afferent nerves modulates gut motility and secretion, providing the mechanistic rationale for asthma and irritable bowel syndrome trials. The unifying idea is that the exact same biology that suppresses appetite also touches reward, mood, inflammation, and gut and airway physiology, explaining why a single receptor class is spreading across neuropsychiatry, addiction, immunology, and gastroenterology at once. However, human clinical proof in these non-metabolic indications does not yet exist, and ongoing trials with readouts expected around 2027 will ultimately determine if this preclinical receptor pharmacology translates into established clinical benefit.

🆕 NEWLY REGISTERED TRIALS (7 in last week)

• BI 3034701 Phase I evaluating safety and tolerability in Japanese healthy volunteers and individuals with obesity or overweight (Boehringer Ingelheim, n=48)

  [Weight Loss/Efficacy]

  Trials: NCT07693231 | Mechanism: Triple GLP-1/GIP/Y2 agonist

• Efsubaglutide Alfa Phase Ib trial investigating the injection as a potential treatment for obese adolescents (Shanghai Yinnuo Pharmaceutical Technology, n=36)

  [Weight Loss/Efficacy]

  Trials: NCT07693426 | Mechanism: GLP-1 receptor agonist

• HRS-4729 Phase 2 trial investigating the efficacy and safety of the injection for treating obesity (Fujian Shengdi Pharmaceutical, n=252)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07690826 | Mechanism: Triple GLP-1/GIP/glucagon agonist

• MARITIME-1-EXTENSION Phase 3 long-term extension trial evaluating the safety and efficacy of Maridebart Cafraglutide for obesity (Amgen, n=3200)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07684235 | Mechanism: GLP-1 agonist / GIP antagonist

• MARITIME-2-EXTENSION Phase 3 long-term extension study of Maridebart Cafraglutide, assessing continued safety and efficacy in obesity (Amgen, n=950)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07684144 | Mechanism: GLP-1 agonist / GIP antagonist

• Petrelintide Phase 1 studying pharmacokinetics in participants with impaired hepatic function (Zealand Pharma, n=36)

  [Safety/Tolerability]

  Trials: NCT07682818 | Mechanism: Amylin receptor agonist

• Olatorepatide Phase 2 trial evaluating the drug in adults with overweight or obesity who do not have diabetes (Regeneron Pharmaceuticals, n=360)

  [Weight Loss/Efficacy]

  Trials: NCT07685808 | Mechanism: Dual GLP-1/GIP agonist

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com, browse the GLP-1 Field Guides for explainers on each mechanism class, or see the new GLP-1 Verdict, the obesity-drug scoreboard.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Novo Nordisk launches $50 monthly Medicare access program for Wegovy

  Novo Nordisk announced that Wegovy® (semaglutide) injection and pill are now accessible to eligible Medicare beneficiaries with obesity through the Medicare GLP-1 Bridge program. This new pathway provides access for a $50 monthly copay and runs through the end of 2027. The company also stated that the Wegovy® pill has reached 3 million prescriptions since its launch in January 2026.

  Press | Mechanism: GLP-1

• Novo’s amycretin enters Phase 3 recruitment in heart failure, standing up a roughly 900-site global trial

  Novo Nordisk’s amycretin (NNC0487-0111), its next-generation GLP-1/amylin dual agonist, moved its Phase 3 HF-POLARIS trial (NCT07567001) from not-yet-recruiting to recruiting this week, activating roughly 900 clinical sites across more than two dozen countries for a 5,610-patient study in people with obesity and heart failure. The scale signals Novo’s conviction in taking amycretin beyond weight loss into a hard cardiometabolic indication, the same heart-failure-with-obesity territory where semaglutide and tirzepatide have already shown benefit. It also mirrors Amgen, whose competing MariTide trial (MARITIME-HF, NCT07037459, roughly 5,000 patients) added dozens of sites the same week, putting two next-generation incretin programs into heart failure at once.

  ClinicalTrials.gov: NCT07567001 (HF-POLARIS) | Mechanism: GLP-1 / amylin dual agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Semaglutide Without the Needle: A Dissolving Microarray Patch Enters the Clinic

Terrestrial Bio (formerly Vaxess Technologies) dosed the first patients on July 1, 2026, in a Phase 1 trial (NCT07673900) evaluating VX-201, a needle-free microarray patch branded as Tacterra that delivers the established GLP-1 receptor agonist semaglutide. Conducted with the clinical research organization Celerion, the head-to-head study enrolls 62 healthy overweight or obese adults to compare standard subcutaneous injection against the patch, which uses a spring-loaded applicator to deposit dissolving microneedles epi-intradermally into the skin within five minutes. Because the drug molecule is already proven, the developmental risk centers on pharmacokinetics and skin tolerability, aiming to show that human exposure matches the bioavailability previously seen in preclinical minipig models.

A December 2025 human factors study indicated that 95 percent of participants preferred this room-temperature, self-applied system over standard injection pens, suggesting a potential adherence benefit for people who find injections uncomfortable or hard to sustain. Expected to complete its primary endpoint around February 2027, the trial reflects a broader strategic shift in the obesity market, where alternative delivery methods like patches, oral pills, and subcutaneous implants are becoming key battlegrounds for competitive differentiation ahead of eventual losses of exclusivity.

ClinicalTrials.gov: NCT07673900 (VX-201 semaglutide microarray patch vs subcutaneous)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Getting a Peptide Through Skin: How Dissolving Microneedle Patches Deliver a GLP-1 (Example drugs: Semaglutide via VX-201)

With Terrestrial Bio bringing its VX-201 microarray patch into the clinic this week, the glucagon-like peptide-1 (GLP-1) delivery landscape is expanding to overcome a fundamental biological challenge. Peptides like semaglutide are large and water-loving (hydrophilic), meaning they cannot passively cross the skin’s outermost barrier known as the stratum corneum, which is the key distinction from the many over-the-counter “GLP-1 patches” sold online that are not drug products and do not deliver any peptide. To bypass that barrier, a microarray patch uses micron-scale needles that painlessly penetrate just past the stratum corneum into the epidermis and upper dermis, avoiding the deeper nerve endings and blood vessels that make conventional injections hurt. In the VX-201 design, a spring-loaded applicator seats the patch, after which the base dissolves within minutes to leave an epi-intradermal deposit of drug-loaded needle tips that then dissolve in the skin’s interstitial fluid. Because the peptide is released directly into well-perfused tissue with rich capillary and lymphatic networks, preclinical studies in Göttingen minipigs show semaglutide microarray patches reaching bioavailability comparable to subcutaneous injection, far above the roughly 1 percent bioavailability of oral pills that depend on absorption enhancers and strict fasting.

The appeal is real: room-temperature stability that removes the cold-chain requirement, no sharps waste, and fast self-application that could improve adherence. So are the constraints. Dose is limited by how much drug fits in the tiny tips, which suits potent, low-dose peptides but makes higher-dose regimens harder to formulate, and manufacturing dissolving arrays at commercial scale is nontrivial. Patches now join a crowded delivery menu alongside weekly injections, oral pills, and multi-month subcutaneous implants, and the race to crack peptide delivery runs deep across all of them: in February 2026 Novo Nordisk struck a partnership worth up to roughly 2.1 billion dollars with Vivtex, a startup from Robert Langer’s laboratory at the Massachusetts Institute of Technology, to make metabolic peptides orally absorbable.

🆕 NEWLY REGISTERED TRIALS (3 in last week)

• PG-102(MG12) Phase II investigating a switch from dulaglutide in patients with type 2 diabetes mellitus (ProGen. Co., Ltd., n=60)

  [Weight Loss/Efficacy]

  Trials: NCT07677891 | Mechanism: GLP-1/GLP-2 dual agonist

• CLARA Trial Phase 2 investigating the biological impact of GLP-1/GIP receptor agonists in patients with breast cancer (Universitaire Ziekenhuizen KU Leuven, n=168)

  [New Indications]

  Trials: NCT07676331 (CLARA) | Mechanism: Dual GLP-1/GIP agonist

• Semaglutide microarray patch (VX-201) Phase 1 comparing epi-intradermal delivery to standard subcutaneous injection in healthy overweight and obese participants (Terrestrial Bio, n=62)

  [Novel Delivery]

  Trials: NCT07673900 | Mechanism: GLP-1 receptor agonist

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com, or browse the GLP-1 Field Guides for explainers on each mechanism class.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Lilly creates Medicare bridge program for Zepbound and Foundayo.

  Eli Lilly announced the Medicare GLP-1 Bridge program, effective July 1, 2026, which will provide eligible Medicare Part D patients access to Foundayo (orforglipron) or Zepbound (tirzepatide) for weight management for $50 per month. The program will run through December 31, 2027, for patients with a Body Mass Index (BMI) of 35 or higher, or a BMI of 27 or higher with certain weight-related medical conditions.

  Press | Trials: NCT05869903 | NCT05872620 | Mechanism: GLP-1 (orforglipron) and GLP-1/GIP (tirzepatide)

• Viking Initiates Phase 1 Trial of Weight Loss Drug VK3019.

  Viking Therapeutics has initiated a Phase 1 single ascending dose (SAD) clinical trial of VK3019, an investigational dual amylin and calcitonin receptor agonist (DACRA) for weight loss. The randomized, double-blind, placebo-controlled study will evaluate the safety, tolerability, and pharmacokinetics of single subcutaneous doses in healthy adults with a BMI ≥30. The trial will also include exploratory assessments of changes in body weight after a single dose.

  Press | Mechanism: dual amylin and calcitonin receptor agonist

• iBio advances obesity drug IBIO-600 into Phase 1 trial.

  iBio has initiated a Phase 1 clinical trial for its lead obesity asset, IBIO-600, a long-acting myostatin antibody designed to support lean mass preservation. The company is developing IBIO-600 for potential dosing of two to four times per year and notes it could potentially be used alongside current GLP-1 therapies. iBio’s pipeline also includes IBO-610, a monoclonal antibody designed to block Activin E to drive fat loss after GLP-1 discontinuation.

  Press | Mechanism: myostatin antibody

📰 PRESS

• Lilly plans 2026/2027 European launch for oral obesity pill.

  Press | Mechanism: oral obesity treatment

• Corxel’s oral GLP-1 CX11 shows 11.5% weight loss in Phase 2

  Press | Mechanism: GLP-1

• CVS expands GLP-1 support to lower costs and improve access.

  Press | Mechanism: GLP-1

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Two Speeds, One Molecule: A China-Born Triple Agonist Races Into Phase 3 While Novo Optimizes Abroad

UBT251 has become the second GLP-1/GIP/glucagon triple receptor agonist to reach Phase 3, after Eli Lilly’s retatrutide. The once-weekly peptide was discovered by United Biotechnology, a subsidiary of Hong Kong-listed The United Laboratories International Holdings, and licensed to Novo Nordisk for rights outside Greater China in a 2025 deal worth up to about $2 billion, with $200 million paid upfront. Novo placed that bet on early Phase 1b data of roughly 15 percent mean weight loss; a China Phase 2 readout in February 2026 then reported up to 19.7 percent at 24 weeks. This month the originator registered three Chinese pivotal trials, an obesity study (600 patients) plus two type 2 diabetes studies, UNIGUIDE-1 and UNIGUIDE-2, the latter testing UBT251 head-to-head against semaglutide, all with primary completions from September 2027 to February 2028. Novo’s own global program, by contrast, is still in Phase 2 dose-ranging for both obesity and diabetes. That gap creates a two-speed split: the Chinese developer is sprinting toward pivotal data at home while its partner optimizes dosing abroad, leaving Novo a hedge in a triple-agonist race that Lilly currently leads.

ClinicalTrials.gov: NCT07648225 (UBT251 Phase 3, obesity) | NCT07659574 (UNIGUIDE-1, Phase 3 T2D) | NCT07653477 (UNIGUIDE-2, Phase 3 T2D vs semaglutide) | NCT07395687 (Novo global Phase 2 obesity)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

The Other Satiety Receptor: Why Obesity Triples Are Starting to Add Y2 (NPY2R) (Example drugs: BI 3034701, NNC0165-1875)

The Y2 receptor (NPY2R) is the target of PYY3-36, a fragment of the gut hormone peptide YY that the intestine’s L-cells release after a meal, the same cells that release GLP-1. Acting on Y2 receptors, peptide YY curbs appetite through a route separate from GLP-1: it quiets the appetite-driving NPY/AgRP neurons in the brain’s arcuate nucleus and signals fullness along gut-to-brain vagal nerves. On its own, Y2 agonism has delivered only modest weight loss and tends to cause nausea, so developers are now pairing it with incretins rather than using it alone. This week Boehringer Ingelheim registered a 300-patient Phase 2 obesity trial (NCT07662122) for BI 3034701, a single-molecule triple agonist, built on Gubra’s peptide platform, that combines GLP-1 and GIP agonism with Y2 activation. That sets it apart from the GLP-1/GIP/glucagon triples such as retatrutide and UBT251, which use the glucagon receptor to raise energy expenditure; BI 3034701 instead stacks a second satiety signal onto its incretin backbone. Novo Nordisk has tested a standalone PYY analog (NNC0165-1875), but building Y2 directly into an incretin triple is the newer bet now reaching the clinic.

🆕 NEWLY REGISTERED TRIALS (15 in last week)

• HRS9531 Phase 3 trial investigating the efficacy and safety of the oral tablet for overweight or obesity (Hengrui, n=425)

  [Weight Loss/Efficacy | Oral Formulations | Safety/Tolerability]

  Trials: NCT07670884 | Mechanism: Dual GLP-1/GIP agonist

• AMAZE 13 Phase III investigating zenagamtide (amycretin) for weight loss in an Asian population with excess body weight (Novo Nordisk, n=400)

  [Weight Loss/Efficacy]

  Trials: NCT07668401 (AMAZE 13) | Mechanism: GLP-1 + amylin combination

• Elecoglipron Phase 3 master protocol investigating efficacy and safety in adults with obesity or overweight, with or without T2DM (AstraZeneca, n=4500)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07667803 (Embold) | Mechanism: GLP-1 receptor agonist

• BGM0504 Phase 2 trial evaluating an oral tablet for weight management in adults with overweight or obesity without diabetes (BrightGene Bio-Medical, n=200)

  [Weight Loss/Efficacy | Oral Formulations | Safety/Tolerability]

  Trials: NCT07658560 | Mechanism: Dual GLP-1/GIP agonist

• Orforglipron Phase 3 trial comparing the oral GLP-1 agonist to dulaglutide in pediatric patients with Type 2 Diabetes (Eli Lilly, n=170)

  [New Indications]

  Trials: NCT07668336 (ACHIEVE-PEDS) | Mechanism: GLP-1 receptor agonist

• Zenagamtide (amycretin) Phase 3 head-to-head trial comparing its weight loss efficacy against semaglutide in adults with excess body weight (Novo Nordisk, n=650)

  [Weight Loss/Efficacy]

  Trials: NCT07668414 (AMAZE 7) | Mechanism: GLP-1 + amylin combination

• UBT251 Phase 2 dose-ranging study evaluating blood sugar reduction in people with Type 2 Diabetes (Novo Nordisk, n=300)

  [New Indications]

  Trials: NCT07668388 | Mechanism: Triple GLP-1/GIP/glucagon agonist

• Elecoglipron Phase III trial evaluating its efficacy and safety as an add-on to insulin for adults with Type 2 Diabetes (AstraZeneca, n=600)

  [Safety/Tolerability]

  Trials: NCT07664553 (Eluminate-3) | Mechanism: GLP-1 receptor agonist

• BI 3034701 Phase 2 trial investigating its potential for weight loss in adults with obesity or overweight (Boehringer Ingelheim, n=300)

  [Weight Loss/Efficacy]

  Trials: NCT07662122 | Mechanism: GLP-1/GIP/NPY2 (Y2) triple agonist

• Eloralintide Phase 1 study investigating an amylin receptor agonist in participants with overweight or obesity (Eli Lilly, n=115)

  [Weight Loss/Efficacy]

  Trials: NCT07665879 | Mechanism: Amylin receptor agonist

• Elecoglipron/Dapagliflozin Phase III study evaluating the combination therapy for adults with Type 2 Diabetes Mellitus (AstraZeneca, n=2000)

  [Safety/Tolerability]

  Trials: NCT07662109 (Eluminate-5) | Mechanism: GLP-1 receptor agonist

• Elecoglipron Phase 3 investigating efficacy and safety in adults with Type 2 Diabetes and impaired renal function as an add-on to dapagliflozin (AstraZeneca, n=900).

  [New Indications | Safety/Tolerability]

  Trials: NCT07662135 (Eluminate-4) | Mechanism: GLP-1 receptor agonist

• UNIGUIDE-1 Phase III evaluating UBT251 injection in patients with type 2 diabetes inadequately controlled by diet and exercise alone (The United Bio-Technology, n=360)

  [New Indications]

  Trials: NCT07659574 (UNIGUIDE-1) | Mechanism: Triple GLP-1/GIP/glucagon agonist

• Elecoglipron Phase 3 trial evaluating the oral GLP-1 receptor agonist alone or combined with dapagliflozin in adults with type 2 diabetes (AstraZeneca, n=800)

  [Safety/Tolerability]

  Trials: NCT07662044 (Eluminate-1) | Mechanism: GLP-1 receptor agonist

• Elecoglipron Phase 3 head-to-head trial comparing its efficacy against semaglutide in adults with type 2 diabetes mellitus (AstraZeneca, n=1200)

  [New Indications]

  Trials: NCT07662213 (Eluminate-2) | Mechanism: GLP-1 receptor agonist

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com, or browse the GLP-1 Field Guides for explainers on each mechanism class.

I also launched GLP-1 Field Guides this week, free, accessible explainers on how each class of these drugs works and where it’s headed, built on the same daily tracker behind this newsletter so they keep up as the field moves. The mono-agonist guide covers the oral race above, from Foundayo to aleniglipron, if you want to go deeper.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Novo Nordisk’s oral Wegovy outpaces Eli Lilly’s Foundayo in early uptake.

  According to IQVIA data from its 22nd week on the market, oral Wegovy attracted 159,000 prescriptions in the most recent weekly period, compared to 19,879 for Eli Lilly’s Foundayo in its ninth week. Novo Nordisk also reported that since its January 5 launch, the Wegovy pill has garnered more than 3 million total prescriptions. A Spherix Global Insights survey of 100 physicians suggests the stronger launch is due to physician “familiarity” with the semaglutide compound.

  Press | Mechanism: GLP-1

• Gan & Lee’s bofanglutide posts 18.5% weight loss in its Phase 3 China obesity trial (GRADUAL-1).

  Gan & Lee Pharmaceuticals reported positive topline results from the Phase 3 GRADUAL-1 study (NCT06728124) of bofanglutide, a GLP-1 receptor agonist, in adults with overweight or obesity. Over 52 weeks, the 48 mg dose drove a mean weight reduction of 18.54% and the 24 mg dose 15.12%, versus 1.11% for placebo. These are company-announced topline figures, not yet peer-reviewed.

  Press | Trials: NCT06728124 (GRADUAL-1) | Mechanism: GLP-1 receptor agonist

• Amylyx nears Phase 3 readout for GLP-1 antagonist avexitide.

  Amylyx expects topline results from its pivotal study of avexitide, a GLP-1 receptor antagonist, for post-bariatric hypoglycemia (PBH) in the third quarter. The company estimates PBH affects around 160,000 people in the U.S. If the results are positive, Amylyx plans to submit an NDA as soon as possible and launch the drug next year.

  Press | Mechanism: GLP-1 receptor antagonist

• Rhythm’s Imcivree shows positive Phase 2 weight loss in Prader-Willi.

  Rhythm Pharmaceuticals announced six-month data from its Phase 2 study of Imcivree (setmelanotide) in patients with Prader-Willi syndrome. Patients treated with Imcivree saw a 3.06% mean decrease in body mass index (BMI), with body scans showing a 4.19% reduction in fat mass and a 0.74% increase in lean mass. The company also reported “clinically meaningful” improvements in hyperphagia based on the Hyperphagia Questionnaire for Clinical Trials score.

  Press | Mechanism: MC4 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

From Analyst Favorite to Pivotal Risk: Structure’s Oral GLP-1 Commits to Phase 3

Just last week, the impressive Phase 2 weight-loss data from Structure Therapeutics’ aleniglipron served as the benchmark analysts used to deem a competitor’s results “underwhelming.” This week, Structure moved from a favorable talking point to a company taking a significant risk, registering two pivotal Phase 3 trials for its once-daily oral GLP-1 agonist. The newly unveiled ACCOMPLISH program commits roughly 4,700 patients to determine the future of a promising, but early, small-molecule contender in the competitive obesity market. This move shifts the focus from promising mid-stage data to the immense operational and financial challenge of late-stage development, especially for a smaller biotech.

The program’s design signals a broad strategic ambition, splitting the target population into two distinct, large-scale trials. ACCOMPLISH-1 (NCT07654361) is the larger of the two, enrolling 3,600 adults with obesity or overweight to support a chronic weight management indication. The second trial, ACCOMPLISH-2 (NCT07654374), will enroll 1,100 patients who also have type 2 diabetes, aiming to secure a label in that critical metabolic sub-population. This two-pronged approach separates the populations to maximize the potential label, acknowledging the different efficacy hurdles in each group.

Aleniglipron enters this late-stage race on the back of eye-catching but early Phase 2 results. In its small ACCESS II dose-ranging study (n=85), it posted roughly 16% mean weight loss at 44 weeks with a curve that had not plateaued, which worked out to about 15% placebo-adjusted weight loss at 36 weeks at the top dose. That looks competitive on paper, but it is chasing an established leader: Eli Lilly’s oral orforglipron (Foundayo) was approved earlier this year and is already on the market. And cross-trial weight-loss comparisons are notoriously difficult, since trials differ in length, dose, and how the numbers are reported.

Ultimately, registering these trials transforms the narrative from scientific promise to executional reality. A global 4,700-patient program is a massive undertaking that tests a company’s capital reserves and operational discipline as much as its science. The key questions now are whether aleniglipron’s standout Phase 2 efficacy and tolerability will hold up at a much larger scale and over a longer duration, and whether a focused biotech can execute a program of this magnitude against entrenched pharmaceutical giants.

ClinicalTrials.gov: NCT07654361 (ACCOMPLISH-1, obesity) | NCT07654374 (ACCOMPLISH-2, obesity + type 2 diabetes)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Obesity’s Master Switch: Why the MC4R Pathway Explains the Disease but Resists the Drug (Example drugs: Setmelanotide, Bremelanotide)

This week at ENDO 2026, Rhythm Pharmaceuticals reported positive interim Phase 2 data for setmelanotide in Prader-Willi syndrome: roughly a 3% mean BMI reduction at six months, with meaningful improvement in extreme hunger. It is a useful window into the melanocortin-4 receptor, or MC4R, the brain’s master switch for appetite. This is the homeostatic hunger circuit in the hypothalamus, a separate system from the reward circuits we covered in March. Deep in that circuit, two opposing sets of neurons fight over one shared thermostat: POMC neurons release a signal called alpha-MSH that turns MC4R on and suppresses appetite, while AgRP neurons do the opposite, dialing it down to drive hunger. The main upstream input is leptin, the hormone fat tissue releases in proportion to fat stores, which raises MC4R tone to tell a well-fed body it can stop eating. When you lose weight, leptin falls and MC4R tone drops, and that withdrawal of the “stop eating” signal is part of why the body defends its set point, the regain biology we covered on April 3.

The genetics of obesity point straight at this junction. MC4R loss-of-function mutations are the single most common single-gene cause of severe, early-onset obesity, and the receptor is also one of the most reliably replicated common-variant signals in the genome, in the same tier as FTO (the fat-mass-and-obesity-associated gene, the best-known common obesity-risk gene). The causality even runs both ways: loss-of-function variants raise weight, while rare gain-of-function variants lower it and protect carriers against type 2 diabetes and heart disease. Yet the modern drugs mostly target the hormones that feed into this switch rather than the switch itself. Leptin truly requires the melanocortin pathway, and amylin largely depends on it as well, even though it enters through the brainstem (covered in May). GLP-1 is the exception. It nudges POMC neurons but works through parallel, MC4R-independent circuits, and the proof is direct: tirzepatide produces nearly the same weight loss in people who carry MC4R mutations as in people who do not.

So why not just drug the master switch directly? Because MC4R does not only control appetite. It also sits on the nerves that set sympathetic “fight-or-flight” tone, so activating it to curb hunger also raises blood pressure and heart rate, and older MC4R agonists aimed at common obesity were abandoned partly for this cardiovascular liability. The paradox is striking: people who lack a working MC4R are obese yet protected from high blood pressure, while giving an MC4R agonist does the reverse and pushes blood pressure up. The same receptor runs both appetite and blood pressure. That is why setmelanotide is cleared only for rare conditions, where it restores a broken upstream pathway rather than forcing an intact one, and why it still carries blood-pressure monitoring even there. The one mainstream attempt routes around the problem entirely: Palatin Therapeutics tested its MC4R agonist bremelanotide on top of tirzepatide, with positive early-2025 Phase 2 data, while a handful of next-generation “biased” agonists are in early development trying to split the weight benefit from the blood-pressure cost. Safely turning the body’s master appetite switch for everyone is still out of reach.

🆕 NEWLY REGISTERED TRIALS (5 in last week)

• Mazdutide Phase 4 investigating its effect on coronary plaque in overweight or obese patients with coronary atherosclerosis (China National Center for Cardiovascular Diseases, n=116)

  [New Indications]

  Trials: NCT07657676 | Mechanism: Dual GLP-1/glucagon agonist

• LY4174794 Phase 1 trial investigating a new drug for obesity or overweight in otherwise healthy participants (Eli Lilly and Company, n=108)

  [Weight Loss/Efficacy]

  Trials: NCT07654972 | Mechanism: Mechanism not disclosed

• ACCOMPLISH-2 Phase 3 evaluating Aleniglipron in adults with obesity or overweight and type 2 diabetes (Structure Therapeutics, n=1100)

  [Weight Loss/Efficacy]

  Trials: NCT07654374 | Mechanism: GLP-1 receptor agonist

• ACCOMPLISH-1 Phase 3 trial of Aleniglipron for obesity or overweight with weight-related comorbidities (Structure Therapeutics, n=3600)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07654361 | Mechanism: GLP-1 receptor agonist

• UNIGUIDE-2 Phase 3 trial of UBT251 injection for type 2 diabetes inadequately controlled on metformin and other common therapies (United Bio-Technology, n=956)

  [New Indications]

  Trials: NCT07653477 (UNIGUIDE-2) | Mechanism: Triple GLP-1/GIP/glucagon agonist

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Novo Nordisk’s CagriSema meets primary endpoints across Phase 3 REIMAGINE trials.

  Novo Nordisk announced that its investigational drug CagriSema met primary endpoints across three Phase 3 trials in the REIMAGINE program for adults with type 2 diabetes. In the 68-week REIMAGINE 2 trial, CagriSema 2.4 mg/2.4 mg demonstrated a statistically significant 1.91% reduction in HbA1c and a 14.2% reduction in bodyweight, compared to a 1.75% HbA1c reduction and 10.2% weight reduction for semaglutide 2.4 mg. The REIMAGINE 1 and 3 trials also showed significant reductions versus placebo, with the 2.4 mg/2.4 mg dose achieving HbA1c reductions of 1.8% and 2.33% and bodyweight reductions of 13.8% and 12.0%, respectively.

  Press | Trials: NCT06323174 | NCT06065540 | NCT06323161 | Mechanism: GLP-1 + amylin combination

• Retatrutide’s detailed TRIUMPH-1 data add knee OA pain and sleep apnea benefits beyond weight loss.

  Eli Lilly announced detailed Phase 3 results for retatrutide from the TRIUMPH-1 trial, where participants on the 12 mg dose lost an average of 28.3% of their body weight (70.3 lbs) over 80 weeks, with 65.3% achieving a BMI below 30. In the TRANSCEND-T2D-1 trial for type 2 diabetes, retatrutide achieved A1C reductions of up to 2.0% and weight loss of up to 16.8% (36.6 lbs) at 40 weeks.

  Press | Trials: NCT05929066 | NCT06354660 | Mechanism: triple agonist

• Boehringer’s Phase 3 survodutide data reveals 63% liver fat reduction.

  In a pre-specified analysis from a sub-study of the Phase III SYNCHRONIZE-1 trial, Boehringer Ingelheim’s survodutide achieved up to a 34% reduction in visceral fat and up to a 63.1% reduction in liver fat after 76 weeks. The main 76-week trial met its primary endpoints, showing up to 16.6% weight loss from baseline, while lean mass loss accounted for no more than 10.8% of the change in total tissue mass at the highest dose.

  Press | Trials: NCT06066515 | NCT06309992 | Mechanism: glucagon/GLP-1 dual agonist

📰 PRESS

• Novo Nordisk secures UK approval for daily oral Wegovy pill.

  Press | Mechanism: GLP-1

• Pfizer’s monthly berobenatide posts up to 15.9% weight loss, heads toward 10 Phase 3 trials.

  Press | Trials: NCT07575932 | Mechanism: GLP-1 receptor agonist

• Gan & Lee’s bofanglutide meets endpoints in a China Phase 3 obesity study and a US Phase 2.

  Press | Trials: NCT06737042 | Mechanism: GLP-1 RA

• Lilly’s oral orforglipron tops Novo’s oral semaglutide in first head-to-head diabetes trial.

  Press | Mechanism: GLP-1

• Kailera presents positive ribupatide bridging data at ADA.

  Press | Mechanism: GLP-1/GIP dual agonist

• Tolerability stands out in Roche and Zealand’s amylin obesity prospect petrelintide.

  Press | Mechanism: amylin analog

• Study: Semaglutide 2 mg matches tirzepatide on blood sugar, tops on weight loss.

  Press | Mechanism: GLP-1 agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Met Every Endpoint, Still Called ‘Underwhelming’: How to Read AstraZeneca’s Oral GLP-1 Data

AstraZeneca’s once-daily oral GLP-1 receptor agonist, elecoglipron, delivered a clean, positive, yet context-dependent result in its Phase 2b program, prompting a move to Phase 3. In the 310-patient VISTA trial for obesity, the small-molecule pill achieved a solid 11.8% average weight loss at 36 weeks (versus about 0.3% on placebo), with a curve that had not yet plateaued, suggesting further benefit was possible. The 406-patient SOLSTICE trial in type 2 diabetes also succeeded, showing a strong 1.9% reduction in HbA1c and 7.7% weight loss. The lower weight-loss figure in the diabetes cohort is an expected outcome of incretin biology, a phenomenon detailed in this week’s Mechanism Explained. Safety and tolerability were consistent with the GLP-1 class: about 93% of participants completed the study, and gastrointestinal-driven discontinuations stayed low at roughly 2 to 4%.

The strategic debate ignited at the ADA 2026 conference, where these data were presented, hinges entirely on the choice of comparator. Judged in isolation, elecoglipron’s performance was a clear success, meeting all endpoints. However, at the same meeting, rival Structure Therapeutics reported that its oral GLP-1, aleniglipron, achieved roughly 15% placebo-adjusted weight loss at 36 weeks, creating a challenging side-by-side comparison that led some analysts to label AstraZeneca’s results “relatively underwhelming.” This highlights a crucial lesson in trial interpretation: while headlines often carelessly compare weight-loss percentages, factors like trial duration are critical. Comparing elecoglipron’s 36-week, non-plateaued result to the longer, 64-to-72-week registrational data for drugs like oral semaglutide or orforglipron is misleading.

AstraZeneca’s decision to advance elecoglipron from the back of the current oral-pill pack is a strategic bet, not on a best-in-class Phase 2 number, but on future potential. The company is likely banking on the signal that more weight loss may be achievable with longer dosing and an optimized titration schedule in Phase 3. This positions the program as a long-term platform play, potentially for combinations within AstraZeneca’s broad cardiometabolic portfolio, rather than a sprint to win on monotherapy efficacy alone. The key question is whether this hopeful signal can translate into competitive registrational data in a crowded field.

ClinicalTrials.gov: NCT06579092 (VISTA, obesity) | NCT06579105 (SOLSTICE, type 2 diabetes)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Why Diabetes Blunts the Scale: The Glucosuria Offset Behind Smaller Weight Loss (Example drugs: Elecoglipron, Semaglutide, Tirzepatide)

A consistent pattern on display at ADA 2026 and in historical data is that people with type 2 diabetes (T2D) lose less weight on incretin drugs than people with obesity but without diabetes. This was seen again this week with AstraZeneca’s oral GLP-1, elecoglipron, which drove 10.5% weight loss in the VISTA obesity trial but 7.7% in the SOLSTICE T2D trial at the same dose. This isn’t a sign of drug failure but an expected, mechanistically understood difference that makes direct cross-trial comparisons misleading. The pattern holds for every major incretin: semaglutide produced about 15% loss in obesity (STEP-1) versus about 10% in T2D (STEP-2), and tirzepatide showed a similar gap between its SURMOUNT-1 (about 21-22%) and SURMOUNT-2 (about 15%) trials.

The primary driver of this weight-loss gap is a phenomenon called the glucosuria offset. In poorly controlled T2D, high blood sugar overwhelms the kidneys’ ability to reabsorb glucose, causing calories to be spilled into the urine, a process known as glucosuria that passively removes energy from the body. When an incretin drug effectively lowers blood glucose toward normal levels, this urinary calorie-spilling stops. The body begins retaining those calories that were previously being lost, and this retained energy partially counteracts the weight loss caused by the drug’s primary effect on appetite. Since people without diabetes do not have glucosuria to begin with, they experience the full, unblunted weight-loss effect of the drug.

This physiological offset is multifactorial, with other elements contributing to the observed difference. Patients in T2D trials are often on background medications that can promote weight gain, such as insulin or sulfonylureas, which are absent from obesity-only trials. Factors like longer disease duration and different baseline metabolic profiles in the T2D population are also recognized as smaller contributors to the attenuated weight-loss response. Understanding this context is important for reading clinical data accurately. The smaller weight loss in a diabetes trial does not mean the drug is less effective; it reflects a different physiological starting point, where patients gain a profound glycemic benefit alongside still-meaningful weight reduction.

🆕 NEWLY REGISTERED TRIALS (1 in last week)

• NNC0662-0419 Phase 2 trial comparing different dose-escalation strategies in participants with obesity (Novo Nordisk, n=230)

  [Weight Loss/Efficacy]

  Trials: NCT07639021 | Mechanism: Triple GLP-1/GIP/glucagon agonist

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

One interesting thing I was reading this week: this New York Times piece on China’s rising role in drug development is about cancer drugs rather than GLP-1s, but it fits this week’s theme closely. The oncology deals it describes are the leading edge of the same shift now happening in the obesity and metabolic pipeline, where Chinese assets, and the deal activity around them, are an increasingly large part of the story.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Wegovy pill launches in the United Arab Emirates.

  Novo Nordisk has launched the Wegovy pill (semaglutide tablets) in the United Arab Emirates, the first country outside the United States to make the oral therapy available. The approval is based on the OASIS 4 trial, where the 25 mg once-daily dose demonstrated a mean weight loss of approximately 17%. The Wegovy pill is also approved to reduce the risk of major adverse cardiovascular events (MACE) in adults with established cardiovascular disease and obesity or overweight.

  Press | Trials: NCT05564117 | Mechanism: GLP-1 receptor agonist

• Lilly, Novo, and rivals head to ADA 2026 with their headline obesity data.

  At the ADA 2026 Scientific Sessions, Eli Lilly will present Phase 3 data for its triple-G agonist retatrutide, which previously demonstrated 28.3% weight loss over 80 weeks in the TRIUMPH-1 study. Novo Nordisk will present Phase 3 data for CagriSema, which showed 23% average weight loss at 84 weeks in the head-to-head REDEFINE-4 study. Other companies presenting data include Boehringer Ingelheim for survodutide (16.6% weight loss at 76 weeks) and Roche for CT-388 (22.5% placebo-adjusted reduction at 48 weeks).

  Press | Mechanism: Multiple

• Lilly, Boehringer scale back German investments over budget cuts.

  Citing planned cuts to healthcare spending in Germany, Eli Lilly is halving its €2.3 billion investment in a new manufacturing plant for its GLP-1 drugs, Zepbound and Mounjaro. The facility will open as planned in 2027 but will operate at half the intended capacity and headcount. Boehringer Ingelheim also dropped its plans to invest €900 million in German infrastructure expansion for the same reason.

  Press | Mechanism: GLP-1/GIP dual agonist

📰 PRESS

• Biomea Fusion to evaluate icovamenib with semaglutide in obesity.

  Press | Mechanism: menin inhibitor + GLP-1 RA

• Biohaven targets obesity with muscle-preserving taldefgrobep alfa.

  Press | Mechanism: myostatin blocker

💡 TRIAL SPOTLIGHT

China’s GLP-1/GIP Dual Goes for the Hardest Endpoint: Inside HRS9531’s 9,262-Patient Cardiovascular Trial

A landmark in the globalization of the obesity drug race began this week as a pivotal cardiovascular outcomes trial for a Chinese-origin GLP-1/GIP agonist officially started recruiting. The 9,262-patient, placebo-controlled trial (NCT07551492) will test whether HRS9531 can reduce major adverse cardiovascular events (MACE) in adults with established atherosclerotic cardiovascular disease. This is a massive, long-term bet for sponsors Jiangsu Hengrui and its ex-China partner Kailera Therapeutics, with treatment lasting up to five years and a final readout not expected until 2031. Committing to a MACE-endpoint CVOT, the most expensive and highest-stakes trial in metabolic medicine, signals a strategic shift for China-developed assets; it’s a clear play to compete directly with Western incumbents on the ultimate value proposition for obesity drugs. After all, proving a therapy prevents heart attacks and strokes is what elevates it from a weight-loss agent to essential cardiovascular medicine, and as we made the full case for why these mega-trials are table stakes back in January, this is the evidence payers and guidelines require for broad reimbursement. While separate Phase 3 data from China showed the drug, a dual agonist like tirzepatide, produced Zepbound-class weight loss of around 18%, this event-driven outcomes trial takes on the harder question of cardiovascular benefit, still unanswered for this drug. The move places HRS9531 (known as ribupatide ex-China) in the same arena as ongoing CVOTs for Lilly’s orforglipron and retatrutide and Amgen’s MariTide, representing the leading edge of a much larger wave of China-origin incretins aiming for the global market, a trend explored in this week’s Mechanism Explained.

ClinicalTrials.gov: NCT07551492 (HRS9531 ASCVD cardiovascular outcomes trial)

🔬 MECHANISM EXPLAINED

From Fast-Follower to Licensing Engine: How China Became a Source of the West’s Next Obesity Drugs (Example drugs: Ribupatide (HRS9531), UBT251, Mazdutide)

A decade ago, China primarily licensed Western drugs for its domestic market; today, it has become a primary source of next-generation obesity assets for Western pharma. This strategic reversal is powered by a combination of clinical speed, cost advantages, and inventive deal structures that are reshaping the global incretin pipeline. The scale of this outbound wave is striking, marked by multi-billion-dollar pacts like Novo Nordisk licensing a triple agonist from United Laboratories for up to $2 billion, Regeneron acquiring rights to a Hansoh dual agonist for a similar amount, and Madrigal buying into a CSPC oral GLP-1. The template was set by Hengrui’s deal for its dual agonist ribupatide, featured in this week’s Trial Spotlight; it licensed the asset to a new venture-backed company, Kailera, for up to $6 billion in milestones plus a 20 percent equity stake, a structure validated by Kailera’s record-setting $625 million IPO. This “NewCo” model fuses licensing with venture capital, letting Chinese firms generate compelling human proof-of-concept data quickly and cheaply, and de-risking the asset for Western partners willing to pay premium prices for clinically advanced molecules.

That machine carries real caveats. In obesity specifically, the work is still more differentiated fast-following than first-in-class invention; several China-origin orals are open derivatives of established mechanisms, and the novel-target breakthroughs in obesity remain largely Western. The model also faces headwinds, from geopolitical tension to proposed US legislation that could limit the FDA’s acceptance of China-generated clinical data for American approvals.

But reading “fast-follower” as a permanent label would be its own mistake, because the trajectory points up-market. The bargain era is closing fast: the average upfront on a Chinese licensing deal climbed by nearly 40% in a single year, and analysts have started saying plainly that China is no longer the bargain basement. The deal structures are maturing too. Pfizer’s recent oncology pact with Innovent left the Chinese company with US and European co-commercialization and profit-share rights on a third of the programs, an arrangement analysts are calling a new model rather than a simple sale of ex-China rights. China’s first-in-class evidence is still led by oncology rather than obesity, but it is mounting, and in obesity China granted the world’s first approval of a GLP-1/glucagon dual for weight management, mazdutide. The safer assumption is not that China stays a discount source of me-too molecules, but that it keeps climbing from supplier of de-risked fast-follows toward co-developer and originator.

🆕 NEWLY REGISTERED TRIALS (5 in last week)

• BALANCE-DM2 Phase 3 study of Bofanglutide in adults with Type 2 Diabetes (Carnot Laboratories, n=374)

  Trials: NCT07628985 | Mechanism: GLP-1 receptor agonist

• HRS-7535 Phase III evaluating a novel oral small-molecule GLP-1RA for renal efficacy and safety in patients with Chronic Kidney Disease (Shandong Suncadia Medicine, n=3690).

  [Oral Formulations | New Indications | Safety/Tolerability]

  Trials: NCT07625774 (RENEW-CKD) | Mechanism: GLP-1 receptor agonist

• Oral VRB-103 and Ecnoglutide Phase 1 trial investigating oral VRB-103 alone or combined with oral ecnoglutide (VRB-101) in adults with obesity or overweight (Verdiva Bio Dev Limited, n=336)

  [Weight Loss/Efficacy | Oral Formulations]

  Trials: NCT07628127 | Mechanism: oral amylin agonist (VRB-103), alone or with oral GLP-1 (ecnoglutide)

• Semaglutide observational study tracking real-world weight loss outcomes in a massive cohort of adults (Novo Nordisk, n=35000)

  [Weight Loss/Efficacy]

  Trials: NCT07627074 (Observational) | Mechanism: GLP-1 receptor agonist

• BALANCE-OBS Phase 3 head-to-head study comparing Bofanglutide (GZR18) to Semaglutide for overweight/obesity in Latin American adults (Carnot Laboratories, n=352)

  [Weight Loss/Efficacy]

  Trials: NCT07622810 | Mechanism: GLP-1 receptor agonist

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Eli Lilly secures PBM coverage for Zepbound and Foundayo.

  Eli Lilly announced that its obesity portfolio, including Zepbound and Foundayo, is now covered by all three of the largest U.S. pharmacy benefit managers (PBMs). CVS Caremark will begin covering Foundayo on June 1 and will broaden access for Zepbound across its template plans by October 1. Eligible patients with commercial insurance may pay as low as $25 a month for either medicine.

  Press | Mechanism: GLP-1/GIP (Zepbound) + oral GLP-1 (Foundayo)

• Efsubaglutide alfa Phase IIb data supports advancement to Phase III.

  Innogen announced that its Phase IIb ENLIGHT study of Efsubaglutide alfa in 200 Chinese overweight and obese adults without diabetes met its primary endpoint. After 18 weeks of treatment, participants achieved weight reductions of 10.58% (QW) and 9.70% (Q2W), along with a 46.9% decrease in liver fat content. The company also reported a 45.3% increase in the muscle-to-fat ratio, with no hypoglycemic events occurring during the trial.

  Press | Mechanism: GLP-1 receptor agonist

📰 PRESS

• Kailera walks path paved by Lilly in post-IPO ‘catalyst-rich period’

  Press | Mechanism: GLP-1/GIP dual agonist

• Lilly wins challenge over Noom’s GLP-1 dosing claims.

  Press | Mechanism: GLP-1

• CordenPharma acquires AmbioPharm to expand GLP-1 manufacturing.

  Press | Mechanism: peptide

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

A Plan B for GLP-1 Intolerance: Novo Tests Cagrilintide on Its Own

Novo Nordisk’s new Phase 1 trial of cagrilintide is small, but it sends a strategic signal well out of proportion to its size. The study (NCT07607587) will enroll 114 adults with obesity and no diabetes who share one specific history: they were treated with a GLP-1 drug, stopped because of gastrointestinal side effects, and are not good candidates to start one again. Nausea, vomiting, and constipation are the most common real-world reasons people come off GLP-1 therapy, and a meaningful share of those who start never reach a full dose. By building a trial exclusively around this group, Novo is testing a clear commercial thesis: that an amylin agonist can serve people the incretin wave has not been able to keep on treatment.

The pharmacological rationale is that amylin works through a different route than GLP-1. It signals satiety largely through the area postrema in the brainstem and slows gastric emptying less aggressively, which is the basis for the bet that it can be tolerated where a GLP-1 could not. The clearest indication of Novo’s intent is the trial’s primary endpoint. It is not weight loss, which amylin is already known to deliver, but the percentage of participants who can reach and hold a standard or higher dose over 26 weeks. The question is not how well cagrilintide works, but whether this particular group can stay on it.

A few caveats keep this in perspective. It is Phase 1, not yet recruiting, and built around tolerability rather than efficacy, so meaningful data are a long way off. However, the positioning makes it worth watching. Studying cagrilintide on its own, separate from the CagriSema combination where it usually appears, suggests Novo sees a standalone amylin franchise aimed at a large population that current obesity drugs do not reach.

ClinicalTrials.gov: NCT07607587 (cagrilintide in GLP-1-intolerant adults)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

The Liver Is Glucagon’s Home Turf: Why GLP-1 / Glucagon Duals Are Posting Fibrosis Wins (Example drugs: Pemvidutide, Zabopegdutide, Survodutide)

This week’s MASH data wave at the EASL 2026 congress is repositioning GLP-1/glucagon dual agonists as liver-focused therapies, a story rooted in the specific action of glucagon. While pure GLP-1 drugs like semaglutide treat metabolic dysfunction-associated steatohepatitis (MASH) largely by driving weight loss (recent work also finds GLP-1 receptors on liver endothelial and immune cells, hinting at a smaller direct effect), the dual-agonist class adds a second hepatic lever that works directly on the fat-storing liver cells themselves. The glucagon component acts on receptors dense in the liver to stimulate fatty acid oxidation, reduce new fat synthesis, and increase energy expenditure. This mechanism directly coaxes liver cells to burn stored fat, an effect distinct from the indirect benefit of systemic weight loss and a key reason these drugs are posting compelling anti-fibrotic signals.

Adding a typically glucose-raising hormone like glucagon to a metabolic drug seems counterintuitive, but the design is elegant. The GLP-1 component simultaneously stimulates insulin secretion, which effectively neutralizes glucagon’s hyperglycemic potential. This lets the drug harness glucagon’s direct fat-burning effects in the liver without elevating blood sugar. Companies deliberately engineer the activity ratio between the two targets; Altimmune’s pemvidutide, for instance, is a balanced 1:1 dual agonist. The strategy is not a fringe bet: survodutide (Boehringer Ingelheim and Zealand) is the most advanced of these duals, already in Phase 3 for MASH, and retatrutide’s triple agonist layers this same glucagon lever on top of GIP.

The EASL readouts provide fresh evidence for this liver-centric mechanism. D&D Pharmatech’s zabopegdutide showed statistically significant fibrosis improvement on 48-week biopsies, with about half of patients on the high dose achieving at least a one-stage improvement without MASH worsening. Altimmune’s pemvidutide demonstrated fibrosis regression at 24 weeks via AI-based digital pathology and showed broad metabolic benefits at 48 weeks, including a nearly 24% drop in triglycerides. MetaVia’s early-phase DA-1726 posted 9.1% weight loss by day 54, with exploratory FibroScan data hinting at early liver improvements.

Still, the path forward requires navigating real trade-offs. The clinical evidence varies in quality, from gold-standard biopsy histology for zabopegdutide, albeit in a small Phase 2, to digital pathology and non-invasive measures for the others. Glucagon’s known risks, like increased heart rate, remain a dose-limiting concern that requires careful management of the agonist ratio. And in a crowded field with approved agents like Rezdiffra and semaglutide, these dual agonists must ultimately prove that their direct hepatic action delivers anti-fibrotic outcomes beyond what weight loss alone can achieve.

ClinicalTrials.gov: NCT05989711 (pemvidutide IMPACT, MASH) | NCT06410924 (zabopegdutide / DD01, MASH) | NCT06632444 (survodutide LIVERAGE Phase 3, MASH)

🆕 NEWLY REGISTERED TRIALS (industry programs from 5 registered in last week)

• Cagrilintide Phase 1 investigating its tolerability in patients who previously stopped GLP-1 therapies due to GI side effects (Novo Nordisk, n=114)

  [Safety/Tolerability]

  Trials: NCT07607587 | Mechanism: Dual amylin/calcitonin receptor agonist

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

Some interesting things I saw this week: this Wall Street Journal report on early signals that weight-loss drugs may help slow some cancers (paywalled) points to a intriguing, if still observational/preliminary, extension beyond metabolic disease; and the New York Times coverage of new retatrutide data was in line with the big readout of the week (covered below), and also mentioned Lilly’s ongoing suit against the FDA over reclassifying retatrutide as a biologic.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Wegovy pill recommended for approval in the European Union.

  Novo Nordisk announced that the EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the Wegovy® pill (once-daily oral semaglutide 25 mg) for weight management in the EU. The recommendation is based on the OASIS 4 trial, where the drug demonstrated a 16.6% mean weight loss, and also includes SELECT data showing a reduction in the risk of major adverse cardiovascular events (MACE). Novo Nordisk plans to launch the pill in select markets outside the US in the second half of 2026.

  Press | Trials: NCT05564117 | NCT03574597 | Mechanism: oral GLP-1

• Lilly’s retatrutide achieves 28.3% weight loss in Phase 3 trial.

  In the Phase 3 TRIUMPH-1 trial, Eli Lilly’s retatrutide met its primary and key secondary endpoints for obesity. At 80 weeks, participants taking the 12 mg dose achieved an average weight loss of 28.3% (70.3 lbs), with 45.3% of participants achieving ≥30% weight loss. Lower doses also delivered strong results, with 25.9% loss at 9 mg and 19% at 4 mg. In a pre-specified extension to 104 weeks, participants with a baseline BMI ≥35 who continued on the 12 mg dose lost an average of 30.3% (85.0 lbs). See the Trial Spotlight below for the full dose-response picture.

  Press | Trials: NCT05929066 | Mechanism: GIP, GLP-1, and glucagon triple receptor agonist

📰 PRESS

• Mounjaro and Zepbound sales drive Lilly’s 56% Q1 revenue surge.

  Press | Mechanism: tirzepatide era

• FDA warns Chinese supplier over illegal GLP-1 imports.

  Press | Mechanism: GLP-1 receptor agonist

• Vincentage oral GLP-1 shows 12.4% weight loss in Phase 3.

  Press | Mechanism: oral GLP-1 agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

The 28% Drug, Now With a Dial: What TRIUMPH-1 Confirms and What It Costs

Eli Lilly recently reported eighty-week data from the flagship Phase 3 TRIUMPH-1 trial evaluating retatrutide, a once-weekly investigational GIP, GLP-1, and glucagon triple receptor agonist, across 2,300 adults with obesity or overweight and at least one weight-related comorbidity but without type 2 diabetes. The reason retatrutide can reach efficacy numbers that dual agonists cannot is this novel third lever of glucagon receptor agonism added on top of GIP and GLP-1. Readers should reference this week’s Mechanism Explained for how those three pathways combine.

TRIUMPH-1 confirmed a bariatric-surgery-like 28.3% weight loss at the top 12 mg dose, but its real strategic significance lies in revealing a highly titratable dose-response curve. An intermediate 9 mg dose dropped 25.9%, and a single-step 4 mg dose achieved nearly 20% weight reductions (about 47 pounds) with an adverse event discontinuation rate that actually fell below placebo. This dose ladder reframes the molecule from the “powerful but rough” reputation it acquired after the smaller TRIUMPH-4 osteoarthritis readout late last year, which saw top-dose discontinuation rates hover around 18%, into a much more flexible clinical tool that allows physicians to scale from a highly tolerable tirzepatide-like floor to a maximal-loss ceiling. Comparisons across distinct trial populations are directional rather than a clean head-to-head.

Pushing to that 12 mg ceiling still brings a notable side-effect burden, most distinctly a 12.5% incidence of dysesthesia, the dose-dependent burning or pins-and-needles skin sensitivity signal that remains a class-defining hurdle to watch. This specific rate is notably softer than the 21% incidence reported previously in the TRIUMPH-4 population.

A pre-specified 104-week extension showed even deeper weight loss for patients with a baseline body mass index of 35 or higher. Additional pre-specified analyses highlighted broad cardiovascular risk factor improvements and a substantial share of top-dose participants dropping below the obesity threshold, entirely absent multiplicity control. This primary cohort anchors a massive pipeline program that includes the upcoming TRIUMPH-2 diabetes and TRIUMPH-3 cardiovascular trials scheduled to read out later this year.

ClinicalTrials.gov: NCT05929066 (TRIUMPH-1, retatrutide flagship obesity) | NCT05929079 (TRIUMPH-2, obesity + type 2 diabetes) | NCT05882045 (TRIUMPH-3, established cardiovascular disease) | Lilly press release

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Three Levers at Once: Why GLP-1 / GIP / Glucagon Triple Agonists Reach 28% (Example drugs: Retatrutide, UBT251)

Anchored by this week’s TRIUMPH-1 readout, the clinical profile of retatrutide illustrates why triple hormone receptor agonists can achieve weight loss approaching 28%, pushing past the 16 to 21% ceiling where the best dual agonists currently plateau. They succeed by pairing the well documented energy-in suppression of GLP-1 and GIP with a completely distinct energy-out mechanism driven by the glucagon receptor.

The GLP-1 component functions as the foundational lever to slow gastric emptying and signal satiety to the brain. The GIP component acts synergistically to amplify postprandial insulin release while softening nausea via brainstem pathways. Adding a glucagon receptor target initially sounds biologically backwards, because the hormone natively raises blood sugar to prevent hypoglycemia. But the simultaneous insulin stimulation from both GLP-1 and GIP neutralizes this hyperglycemic risk.

With the glucose-raising effect counterbalanced by parallel insulin pathways, the glucagon component is free to act as a metabolic engine that elevates whole-body resting energy expenditure and directly stimulates hepatic fat oxidation, pulling lipid stores out of liver cells. That yielded the 82% hepatic fat reduction observed during the 24-week Phase 2 trials of retatrutide. Coupling this expenditure and fat mobilization mechanism with appetite suppression explains the efficacy jump, and defines a distinct competitive strategy compared to subtractive dual agonist approaches. Drugs like tirzepatide drop the glucagon lever entirely to simplify development, and alternatives like survodutide, mazdutide, and pemvidutide sacrifice the tolerability buffering of GIP.

Incorporating a third target demands a difficult pharmacological balancing act to optimize the activity ratios so that fat burns without unmasking diabetes, and it introduces extra clinical questions. These are evidenced by glucagon-linked heart rate elevations and a novel, dose-dependent dysesthesia skin sensation, the pins-and-needles burning that surfaced in the retatrutide Phase 3 safety data. Because navigating these trade-offs is complex, the late-stage pipeline remains thin, leaving retatrutide as the solitary Phase 3 asset. A sparse group of followers, notably UBT251 with its roughly 19.7% weight loss at 24 weeks in Phase 2, alongside Hanmi candidates efocipegtrutide for liver disease and HM15275 for diabetes, are attempting to replicate the receptor calibration required to combine intake reduction with enhanced metabolic output.

ClinicalTrials.gov: NCT05929066 (TRIUMPH-1, retatrutide)

🆕 NEWLY REGISTERED TRIALS (6 in last week)

• HRS9531 Phase 2 trial investigating the efficacy and safety of the oral tablet in participants with type 2 diabetes (Fujian Shengdi Pharmaceutical, n=240).

  [Oral Formulations | Safety/Tolerability]

  Trials: NCT07599410 | Mechanism: Dual GLP-1/GIP agonist

• Berobenatide Phase 3 trial evaluating the efficacy and safety of the drug in adults with overweight or obesity (Pfizer, n=954)

  [Weight Loss/Efficacy]

  Trials: NCT07595549 | Mechanism: GLP-1 receptor agonist

• HDM1002 Phase 1 thorough QT study assessing the drug’s effect on cardiac repolarization in healthy subjects (Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd., n=72)

  [Safety/Tolerability]

  Trials: NCT07594847 | Mechanism: GLP-1 receptor agonist

• Cagrilintide Phase 1 trial comparing blood levels of different formulations in adults with overweight or obesity (Novo Nordisk, n=234)

  [Novel Delivery]

  Trials: NCT07597018 | Mechanism: Long-acting amylin analog (DACRA)

• REGN20934 Phase 1 assessing safety and drug concentrations in adults with overweight or obesity (Regeneron Pharmaceuticals, n=90)

  [Safety/Tolerability]

  Trials: NCT07594093 | Mechanism: Mechanism not disclosed

• Vascular and Neurocognitive Effects of Weight Loss Phase 4 trial investigating the impact of weight loss on blood vessel and brain health (Alain Dagher, n=240)

  [Weight Loss/Efficacy]

  Trials: NCT07592546 (THRIVE) | Mechanism: GLP-1 receptor agonist

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

Some interesting things I saw this week: on the basic science side, this Nature paper on a brain reward circuit affected by next-generation weight-loss drugs adds a mechanistic angle to how these newer agents may be working beyond a simple appetite-suppression story; and if you enjoy knowing some of the more than 40-year history behind GLP-1s, this EASD video piece with some of the main researchers at the core of the discoveries is fascinating.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Wegovy demonstrates weight loss and heart protection across all menopause stages

  Novo Nordisk presented data at ECO 2026 showing that Wegovy (semaglutide) 7.2 mg achieved average weight loss of 22.6% in premenopausal women and approximately 19.8% in perimenopausal and postmenopausal women over 72 weeks in the STEP UP trial. Post-hoc analysis of the SELECT trial demonstrated cardiovascular risk reductions of 42% in perimenopausal and 13% in postmenopausal women compared to placebo. Additionally, real-world evidence associated Wegovy with a 42–45% lower risk of migraine and a 25% lower risk of depression compared to those using menopausal hormone therapy alone.

  Press | Trials: NCT05646706 | NCT03574597 | Mechanism: GLP-1 receptor agonist (semaglutide)

• High-dose Wegovy demonstrates 28% weight loss in early responders

  Novo Nordisk presented sub-analyses from the Phase 3b STEP UP trial at the 2026 European Congress on Obesity, showing that semaglutide 7.2 mg (Wegovy) achieved a mean weight loss of 20.7% at week 72 compared to 17.5% for the 2.4 mg dose. Among early responders who lost at least 15% of their weight by week 24, those on the 7.2 mg dose reached an average weight loss of 27.7% by the end of the trial. Body composition data further indicated that 84% of the total weight loss across both semaglutide doses was attributed to fat mass reduction while maintaining functional muscle strength.

  Press | Trials: NCT05646706 | Mechanism: GLP-1 receptor agonist (semaglutide)

• Lilly reports SURMOUNT-MAINTAIN and ATTAIN-MAINTAIN maintenance results at ECO 2026

  In SURMOUNT-MAINTAIN, participants continuing Zepbound (tirzepatide) at maximum tolerated dose held their prior weight loss over 52 weeks; those stepping down to a 5 mg dose regained 5.6 kg on average. In ATTAIN-MAINTAIN, participants switching from injectable Wegovy or Zepbound to oral Foundayo (orforglipron) regained 0.9 kg and 5.0 kg respectively. Both trials had placebo arms, which regained substantially more. The Trial Spotlight below discusses what these trials tested and did not test.

  Press | Trials: NCT06584916 | NCT06047548 | Mechanism: GLP-1/GIP dual agonist (tirzepatide); GLP-1 receptor agonist (orforglipron)

📰 PRESS

• FDA halts Aardvark’s ARD-101 and ARD-201 over cardiac safety concerns

  Press | Mechanism: TAS2R (bitter taste receptor) agonist

• Apotex launches generic Ozempic (Apo-Semaglutide) in Canada

  Press | Mechanism: GLP-1 receptor agonist (semaglutide)

• Wegovy pill achieves 21.6% weight loss and improved mobility in early responders (OASIS 4)

  Press | Trials: NCT05564117 | Mechanism: GLP-1 receptor agonist (oral semaglutide 25 mg)

• Endoscopic sleeve gastroplasty outperforms oral semaglutide in head-to-head weight-loss study at ESGE 2026 (12.7% vs 8.7% at 6 months)

  Press | Mechanism: GLP-1 receptor agonist (oral semaglutide) vs endoscopic procedure

• Hims reports $33 million impact from GLP-1 medication pivot

  Press

• Eli Lilly pauses India obesity campaign following regulatory scrutiny

  Press | Mechanism: GLP-1 receptor agonist

• Hepta’s AI blood test predicts patient response to GLP-1 medications

  Press | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Less Drug, Still Drug: What Lilly’s Two Maintenance Trials Actually Tested

At the ECO 2026 conference, Eli Lilly presented data from two maintenance trials, SURMOUNT-MAINTAIN and ATTAIN-MAINTAIN, framed as showing patients can switch therapies and maintain weight loss. However, a closer look at the trial designs reveals a more nuanced story about chronic disease management rather than treatment cessation. SURMOUNT-MAINTAIN tested a dose reduction, not a switch, randomizing patients who had lost approximately 20% of their body weight on a 60-week open-label lead-in of maximum-tolerated Zepbound (tirzepatide) to either continue that dose, step down to a 5 mg dose, or take a placebo. While the maximum dose group maintained 100% of their loss, the 5 mg step-down arm regained an average of 5.6 kg, demonstrating that even a lower dose of the same drug allows for partial weight regain compared to the induction dose.

The ATTAIN-MAINTAIN trial evaluated switching from injectable Zepbound or Wegovy to oral Foundayo (orforglipron) versus placebo, but critically, not versus continuing the original injectable. The results showed that switching from dual-agonist Zepbound to the single-agonist Foundayo resulted in a 5.0 kg average regain, a predictable outcome when stepping down the mechanism of action, whereas the same-mechanism switch from Wegovy to Foundayo led to only a 0.9 kg regain. Both trials confirm that a lower-intensity incretin regimen is superior to stopping treatment altogether, where placebo arms saw substantial weight rebound.

Ultimately, these studies reinforce the view of obesity as a chronic condition requiring continuous therapy, much like statins for cardiovascular risk. They introduce commercially significant, potentially more tolerable or convenient maintenance options like lower-dose injectables or oral agents. What they do not demonstrate is that patients can stop incretin therapy and sustain their weight loss. The central question of whether an exit ramp from this drug class exists remains unanswered, with all current data suggesting that discontinuation leads to significant weight regain over time. The operating assumption for now remains lifelong treatment, with these trials mapping out the first options for a less intensive, long-term therapeutic journey.

ClinicalTrials.gov: NCT06047548 (SURMOUNT-MAINTAIN, tirzepatide step-down) | NCT06584916 (ATTAIN-MAINTAIN, orforglipron switch) | NCT05822830 (SURMOUNT-5, the run-in parent trial) | Lilly press release

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Beyond the Headline Number: How ‘Early Responder’ Segmentation Is Becoming Pharma’s New Fighting Axis (Example drugs: Semaglutide, Tirzepatide, Orforglipron)

As headline weight-loss numbers saturate across the maturing obesity pipeline with semaglutide at 15% and tirzepatide at 21%, the competitive battleground has shifted from trial-wide averages to early-responder segmentation, a transition vividly illustrated by Novo Nordisk’s ECO 2026 sub-analyses demonstrating that patients hitting specific early milestones achieve dramatically higher final numbers. By stratifying completed Phase 3 trials, Novo revealed that early responders, defined as hitting a 5% milestone on the 25 mg oral Wegovy in OASIS 4, achieved an impressive 21.6% weight loss at 64 weeks compared to the 16% trial average while driving clinical mobility improvements for 80% of functionally impaired participants. Those hitting a steeper 15% threshold by week 24 on the high-dose 7.2 mg injectable in STEP UP ultimately reached a striking 27.7% reduction at 72 weeks with 84% of that loss attributed to fat mass rather than lean tissue.

This clinical heuristic operates on the biological premise that a productive initial trajectory predicts long-term receptor responsiveness and tolerability, a concept further reinforced by demographic slicing that showed premenopausal women hitting 22.6% loss on the 7.2 mg dose and perimenopausal SELECT participants seeing a 42% cardiovascular event reduction alongside major real-world drops in migraine and depression risk versus hormone therapy alone. Much like the early 2000s statin market evolved past baseline lipid-lowering into risk-stratified high and moderate-intensity regimens, slicing data by responder status gives companies a rhetorically powerful tool to position assets, assert superiority over competitors like orforglipron or Viking’s oral VK2735 (which itself showed 80% of patients hitting a 10% benchmark at 13 weeks), and pinpoint the ideal candidates for the step-down maintenance protocols currently being operationalized in Lilly’s SURMOUNT-MAINTAIN and ATTAIN-MAINTAIN trials.

However, these segmentation figures remain hypothesis-generating, post-hoc selections from mature trials utilizing inconsistent definitions across the landscape, varying from 5% to 15% milestones depending on the study design, which invites critical questions regarding the exact proportion of patients who actually qualify as early responders and what alternative mechanisms those left behind might require. While pharmaceutical developers are advancing this profiling to guide future sequencing and maintenance paradigms, payers and regulators have not yet adopted responder-based criteria, meaning commercial coverage and formulary placement will continue to operate on flat label-level efficacy averages until this clinical framing catches up with policy over the next 12 to 24 months.

ClinicalTrials.gov: NCT05564117 (OASIS 4, oral sema 25 mg) | NCT05646706 (STEP UP, high-dose sema 7.2 mg) | NCT03574597 (SELECT, semaglutide CVOT) | NCT05822830 (SURMOUNT-5, tirzepatide vs semaglutide) | NCT05869903 (ATTAIN-1, orforglipron Phase 3)

🆕 NEWLY REGISTERED TRIALS (industry programs from 9 registered in last week)

• Macupatide and Eloralintide Phase II evaluating the efficacy of these novel agents alone or in combination for weight management in adults with obesity or overweight (Eli Lilly, n=400)

  [Weight Loss/Efficacy]

  Trials: NCT07589608 | Mechanism: GIP receptor agonist + amylin receptor agonist (no GLP-1 component)

• Petrelintide with Enicepatide (RO7795068) Phase II dose-finding study evaluating the safety and efficacy of this combination therapy for weight management in adults with obesity or overweight (Hoffmann-La Roche, n=486)

  [Weight Loss/Efficacy]

  Trials: NCT07589686 (ZYNERGY) | Mechanism: Amylin receptor agonist (petrelintide) + biased GLP-1/GIP dual agonist (enicepatide/CT-388)

• NNC0487-0111 Phase I evaluating pharmacokinetics and tolerability in participants with reduced liver function compared to those with normal liver function (Novo Nordisk, n=35)

  [Weight Loss/Efficacy]

  Trials: NCT07587710 | Mechanism: Unimolecular GLP-1/amylin co-agonist (amycretin)

• NNC0497-0040 Phase I evaluating safety and effect in healthy participants and individuals with overweight or obesity, including those with Type 1 Diabetes (Novo Nordisk, n=146)

  [Weight Loss/Efficacy]

  Trials: NCT07578584 | Mechanism: Mechanism not disclosed

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• BGM0504 achieves 19.3% weight loss in Phase 3 obesity trial.

  Bright Gene Bio-Pharm announced that its dual GLP-1/GIP receptor agonist BGM0504 met the primary endpoint and all key secondary endpoints in a Phase 3 obesity trial in Chinese adults, achieving a 19.3% mean weight reduction. Additional results included a 16.5 cm waist circumference decrease, blood pressure improvements (-22.9/-12.9 mmHg), and a 70.7 µmol/L uric acid reduction. The data positions BGM0504 between semaglutide (~15% in STEP) and tirzepatide (~21% in SURMOUNT-1), and adds another Chinese-origin GLP-1/GIP dual to a growing field that includes HRS9531 (Hengrui/Kailera), VK2735 (Viking), and HDM1005 (Hangzhou Zhongmei Huadong).

  Press | Mechanism: Dual GLP-1/GIP agonist

• SEMALCO Phase 2: semaglutide cuts heavy drinking days in adults with alcohol use disorder and comorbid obesity.

  The Phase 2 SEMALCO trial (Psychiatric Centre Rigshospitalet, Copenhagen, n=108) reported that once-weekly semaglutide reduced heavy drinking days by 13.7 percentage points vs placebo (95% CI -22.0 to -5.4; p=0.0015) in adults with moderate-to-severe alcohol use disorder and comorbid obesity, meeting the primary endpoint. Adverse events were generally mild-to-moderate gastrointestinal effects, more common in the semaglutide arm. The randomized Phase 2 result adds to a growing investigational area for GLP-1 receptor agonists, complementing the brain reward circuit biology covered in this newsletter’s March 20 Mechanism Explained (”From Appetite to Addiction”) and joining ongoing Phase 3 work including a 438-patient VA-sponsored semaglutide AUD study.

  Trial: NCT05895643 | Mechanism: GLP-1 receptor agonist

• Novo Nordisk Q1 2026: CagriSema co-formulation project terminated; launch device shifts to dual-chamber pen.

  In its Q1 2026 results, Novo Nordisk disclosed it has terminated the CagriSema co-formulation project “due to portfolio considerations,” shifting the planned launch device from a single-chamber pen (where semaglutide and cagrilintide would have been pre-mixed in solution) to a dual-chamber pen that keeps the two molecules separate until injection. CEO Mike Doustdar reaffirmed that launch timing remains unchanged, with US approval expected in Q4 2026 and global launch in early 2027. Separately, Novo’s Q1 obesity care sales grew 22% at constant exchange rates, and Wegovy pill (oral semaglutide 25 mg) reached over 2 million total prescriptions since its January 2026 US launch. See the Trial Spotlight below for what the device shift means in the broader GLP-1 + amylin combo architecture landscape.

  Press | Mechanism: GLP-1 + amylin combination

• GSK pens up to $1B deal for SiranBio’s ALK7 oligonucleotide for obesity.

  GSK signed a licensing agreement with Chinese siRNA specialist SiranBio for SA030, an oligonucleotide drug that targets activin receptor-like kinase 7 (ALK7) and is designed to reduce visceral and abdominal fat. The deal is potentially worth up to $1 billion in upfront and milestone payments. SA030 represents a non-incretin approach to obesity, joining a growing class of next-generation candidates that include amylin analogs, GIP antagonists, and tri-agonists. The deal extends GSK’s reach into Chinese-origin metabolic assets, mirroring a broader industry trend of Western biopharma licensing China-developed GLP-1-adjacent candidates.

  Press | Mechanism: ALK7-targeting siRNA / oligonucleotide

📰 PRESS

• Wegovy access expanded for Medicare beneficiaries via the Medicare GLP-1 Bridge program starting July 1, 2026.

  Press | Mechanism: GLP-1

• Lilly commits an additional $4.5B across Indiana manufacturing sites.

  Press | Mechanism: GLP-1 / GLP-1-GIP

• Wegovy pill (oral semaglutide 25 mg) reaches 1 million patients with $355M in Q1 sales.

  Press | Mechanism: oral GLP-1

• France fines Novo Nordisk and Eli Lilly over misleading obesity drug promotions.

  Press | Mechanism: GLP-1

• Lilly dismisses liver safety concern for Foundayo as analysts shrug.

  Press | Mechanism: oral non-peptide GLP-1 receptor agonist

• Neurocrine initiates Phase 1 of NBIP-2118, a non-incretin CRF2 receptor agonist for obesity.

  Press | Mechanism: corticotropin-releasing factor type 2 (CRF2) receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Three Ways to Build a GLP-1 + Amylin Combo: Amycretin’s Phase 3 Reveal Lands Alongside Pfizer’s First Post-Metsera Combo

Following last week’s focus in the newsletter on amylin receptor selectivity, the simultaneous registration of pivotal GLP-1 and amylin combination trials by Novo Nordisk and Pfizer this week shifts the competitive lens to a defining new axis: the underlying molecular architecture of these dual therapies. Novo Nordisk just unveiled a massive five-indication Phase 3 program for amycretin (NNC0487-0111), registering the 5,610-patient HF-POLARIS heart failure trial alongside new AMAZE studies in sleep apnea to anchor its bet on a “unimolecular co-agonist” architecture, which uses a single engineered peptide to bind both targets, trading independent dosing flexibility for a locked activity ratio and a highly streamlined single-API manufacturing supply chain. In sharp contrast, Pfizer’s newly registered 872-patient Phase 2 SOLIS-1 trial adopts a “co-administered separates” architecture for its first post-Metsera obesity program, delivering its fully biased GLP-1 (MET-097) and its selective amylin receptor agonist (MET-233) as two separate subcutaneous injections, with primary completion targeted for August 2027. This separate-injection approach allows Pfizer to independently titrate two uniquely specialized molecules that sit on the extreme tolerability frontier of their respective classes, reflecting a clinical bet that the optimal ratio depends heavily on the individual patient and should not be locked in.

Meanwhile, Novo Nordisk is hedging its bets by advancing a third distinct architecture via its CagriSema program: two molecules paired in a single device at a fixed ratio. The newly registered 2,500-patient Phase 3 dose study (NCT07564414) this week tests whether the right semaglutide-cagrilintide dose pairing can overcome the pharmacokinetic decoupling risks that may have contributed to its REIMAGINE 2 miss in February 2026. Ultimately, the dual advancement of both unimolecular (amycretin) and single-device-paired (CagriSema) programs by Novo Nordisk, contrasted against Pfizer’s pure two-injection separates approach, illustrates how the structural choice between engineered integration, independent titration flexibility, and packaged convenience is rapidly becoming one of the most consequential strategic wagers in metabolic drug development.

NCT07567001 (HF-POLARIS, amycretin in HF) | NCT07571005 (AMAZE 3, OSA) | NCT07571109 (AMAZE 4, OSA on PAP) | NCT07503210 (AMAZE 12, weight maintenance) | NCT07533175 (AMAZE 2, T2D) | NCT07575932 (SOLIS-1, Pfizer combo) | NCT07564414 (new CagriSema dose study) | NCT06862791 (ASCEND, AstraZeneca combo)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

HFpEF: Why Obesity Drugs Are Crowding Into a Specific Cardiac Phenotype (Example drugs: Tirzepatide, Maridebart Cafraglutide, Amycretin)

This week’s registration of Novo Nordisk’s 5,610-patient HF-POLARIS Phase 3 trial evaluating amycretin and Amgen’s rapid addition of 54 clinical sites to the 5,056-patient MARITIME-HF study evaluating maridebart cafraglutide establish heart failure with preserved ejection fraction (HFpEF) as the premier cardiac target for next-generation obesity therapeutics, following the precedent set by Eli Lilly’s SUMMIT trial. Unlike classical heart failure with reduced ejection fraction where a weakened myocardium struggles to pump blood and requires standard neurohormonal blockade, HFpEF presents a distinct biological challenge: the ventricle maintains a normal pumping fraction but becomes stiff, fibrotic, and unable to adequately relax or fill during diastole. This pathology accounts for roughly half of all heart failure cases yet had essentially no disease-modifying treatments until SGLT2 inhibitors, and now obesity drugs, entered the field. The restrictive diastolic dysfunction is heavily driven by the obesity phenotype found in roughly 80 percent of HFpEF patients, specifically mediated by epicardial adipose tissue, a visceral fat layer in direct contact with the myocardium and coronary arteries that mechanically constricts the ventricle while simultaneously functioning as an inflammatory endocrine organ secreting cytokines like TNF-alpha and leptin to drive microvascular dysfunction. In other words, the fat acts as both a physical straitjacket and a biochemical toxin.

Incretin and amylin therapies are uniquely suited to address this specific pathology. GLP-1 receptor agonism triggers a proportionally larger reduction in epicardial adipose tissue volume than overall subcutaneous fat loss, while simultaneously exerting direct, tissue-specific anti-inflammatory effects that reduce macrophage infiltration. The partner mechanisms (GIP modulation in tirzepatide and MariTide, amylin agonism in amycretin) layer on complementary appetite-regulating and metabolic effects, even if their direct cardiac signaling is less well-characterized than GLP-1’s. Researchers are now isolating those effects from generalized weight loss in a newly recruiting Phase 4 University of Virginia mechanistic study focused on epicardial adipose tissue composition. With tirzepatide’s GLP-1/GIP dual agonism having already shown in SUMMIT that targeting this obesity-driven HFpEF phenotype reduces clinical heart failure events and improves patient exercise capacity, these massive new Phase 3 programs represent a high-stakes mechanistic horse race to determine whether the distinct tissue-specific pathways of amycretin or MariTide can drive even greater reductions in epicardial inflammation, potentially forcing payers to recognize HFpEF as a distinctly covered cardiometabolic indication ahead of broader obesity coverage.

ClinicalTrials.gov: NCT04847557 (SUMMIT, tirzepatide HFpEF) | NCT07037459 (MARITIME-HF, maridebart cafraglutide) | NCT07567001 (HF-POLARIS, amycretin in HF + obesity) | NCT07178145 (UVA EAT composition + HFpEF)

🆕 NEWLY REGISTERED TRIALS (10 in last week)

• NNC0487-0111 Phase 3 trial evaluating efficacy in people with heart failure and obesity (Novo Nordisk, n=5610)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07567001 (HF-POLARIS) | Mechanism: GLP-1 + amylin combination

• SOLIS-1 Phase 2 investigating the combination of PF-08653945 (MET-233, selective amylin) and PF-08653944 (MET-097, biased GLP-1) as two separate subcutaneous injections in adults with overweight or obesity (Pfizer, n=872)

  [Weight Loss/Efficacy]

  Trials: NCT07575932 (SOLIS-1) | Mechanism: biased GLP-1 receptor agonist + selective amylin receptor agonist (co-administered combo)

• Tirzepatide Phase 2 trial assessing metabolic health in patients with Mild Autonomous Cortisol Secretion following adrenalectomy (Alaa Sada, n=34)

  [New Indications]

  Trials: NCT07573163 | Mechanism: Dual GLP-1/GIP agonist

• MARITIME-SWITCH Phase 3 evaluating Maridebart Cafraglutide in adults with obesity or overweight who are switching from other GLP-1RA therapies (Amgen, n=300)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07575399 | Mechanism: GLP-1 receptor agonist + GIP receptor antagonist (antibody-peptide conjugate)

• Tirzepatide trial investigating a modified titration schedule to reduce side effects in adults with obesity (Dasman Diabetes Institute, n=68)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07574723 (TiTRE) | Mechanism: Dual GLP-1/GIP agonist

• AMAZE 4 Phase 3 trial of NNC0487-0111 for weight loss and sleep apnea improvement in patients with obesity and obstructive sleep apnea (Novo Nordisk, n=300)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07571109 (AMAZE 4) | Mechanism: GLP-1 + amylin combination

• AMAZE 3 Phase 3 evaluating NNC0487-0111 for weight loss and obstructive sleep apnea in adults not treated with PAP therapy (Novo Nordisk A/S, n=300)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07571005 (AMAZE 3) | Mechanism: GLP-1 + amylin combination

• NNC0113-5840 Phase 1 investigating a new medicine for people with overweight or obesity (Novo Nordisk, n=48)

  [Safety/Tolerability]

  Trials: NCT07566390 | Mechanism: Undisclosed

• Semaglutide Depot Phase 1 assessing a new long-acting formulation for type 2 diabetes (Mapi Pharma Ltd., n=24)

  [Safety/Tolerability]

  Trials: NCT07563699 | Mechanism: GLP-1 receptor agonist

• CagriSema Phase 3 trial evaluating two doses against Semaglutide for weight loss in adults with obesity, with or without type 2 diabetes (Novo Nordisk, n=2500)

  [Weight Loss/Efficacy]

  Trials: NCT07564414 | Mechanism: GLP-1 + amylin combination

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

Some interesting things I was reading this week highlight the wide range of the GLP-1 story: a new Lancet trial of semaglutide in patients with alcohol use disorder and obesity suggests the class may have meaningful effects beyond weight and glycemic control, while this NEJM perspective on GLP-1 receptor agonists and eating disorders (paywalled) focuses on a risk area that may draw more scrutiny as use expands. I also found this Scientific American piece on the anti-inflammatory effects of GLP-1 drugs decent as a broader framing for why the category continues to generate interest well beyond obesity treatment.

I’ve also opened up a Weekly Updates tab on the dashboard for readers who prefer a more structured view of the week’s trial changes and results without the editorial framing or educational sections I add here. It surfaces the week’s trial changes and results, with a look at the kind of drill-down details available in the full dashboard.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Survodutide achieves 16.6% weight loss in Phase 3 SYNCHRONIZE-1

  Boehringer Ingelheim and Zealand Pharma announced that survodutide, an unimolecular GLP-1/glucagon receptor dual agonist, met co-primary endpoints in the Phase 3 SYNCHRONIZE-1 trial in adults with obesity or overweight without type 2 diabetes. Participants achieved a statistically significant average weight loss of 16.6% (17.8 kg) at 76 weeks compared to 3.2% for placebo, with 85.1% reaching at least 5% weight reduction (vs 38.8% for placebo). The trial also met its key secondary endpoint for waist circumference reduction. Safety findings showed mild-to-moderate gastrointestinal events consistent with the GLP-1 class. Full data are scheduled for the American Diabetes Association’s 2026 Scientific Sessions. This is the first Phase 3 obesity readout for a globally developed GLP-1/glucagon dual agonist; Innovent's mazdutide read out Phase 3 obesity data in China earlier (see Trial Spotlight below for context across the class).

  Press | Trial: NCT06066515 | Mechanism: GLP-1/glucagon dual agonist

📰 PRESS

• FDA proposes excluding semaglutide, tirzepatide, and liraglutide from 503B bulks list

  Press | Mechanism: incretin receptor agonists (GLP-1 and GLP-1/GIP)

• Zealand and Roche announce plans to advance petrelintide into Phase 3 for chronic weight management (no Phase 3 trials registered yet)

  Press | Mechanism: amylin analog

• Lilly Q1 2026: revenue +56%, raised full-year guidance, Foundayo (orforglipron) approved and launched in the US

  Press | Mechanism: oral GLP-1 (orforglipron)

• Novo Nordisk to present 52 abstracts at ECO 2026, including STEP UP, OASIS 4, and REDEFINE 1 post hoc analyses

  Press | Mechanism: GLP-1 receptor agonist (Wegovy, oral semaglutide); GLP-1 + amylin combination (CagriSema)

• Amgen positions MariTide as potential “best monthly” obesity drug at Q1 2026

  Press | Mechanism: GLP-1 agonist + GIP antagonist (antibody-peptide conjugate)

• Canada approves first generic semaglutide (Dr. Reddy’s), a “test case for the world”

  Press | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Survodutide Reads Out at 16.6%: the First Global Phase 3 for a GLP-1/Glucagon Dual

Boehringer Ingelheim and Zealand Pharma have unveiled the first Phase 3 obesity results for a globally developed GLP-1/glucagon dual receptor agonist. Innovent's mazdutide, developed in China, read out Phase 3 obesity data earlier, and GLORY-2 reported a higher 18.55% weight loss. In the SYNCHRONIZE-1 trial, which enrolled adults with overweight or obesity but not type 2 diabetes, survodutide demonstrated a placebo-adjusted mean weight loss of 16.6% after 76 weeks of treatment. This unimolecular dual agonist combines the appetite-suppressing effects of GLP-1 with the potential metabolic benefits of glucagon, which is thought to increase energy expenditure and fat metabolism in the liver. The result positions survodutide’s efficacy above the GLP-1 monotherapy semaglutide (~15%) but below the dual GLP-1/GIP agonist tirzepatide (~21%), suggesting the addition of glucagon offers a meaningful but not class-leading boost in weight reduction.

The SYNCHRONIZE-1 readout provides a crucial, if mixed, signal for the broader class of GLP-1/glucagon agonists in development, which includes Innovent’s China-approved mazdutide, Altimmune’s pemvidutide, Merck’s efinopegdutide, and AstraZeneca’s AZD9550 (now in the ASCEND combo trial). While the 16.6% weight loss is a strong result likely sufficient for regulatory approval, it tempers expectations that glucagon co-agonism would dramatically outperform existing dual-incretin therapies. The strategic focus for survodutide may now sharpen around its potential as a treatment for metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease. Survodutide has already received a Breakthrough Therapy Designation from the FDA for MASH, and its liver-targeted mechanism could carve out a significant niche, even if its obesity data doesn’t top the charts. The full picture will become clearer when detailed data, including discontinuation rates, are presented at a future medical congress, which will help clarify the therapy’s overall tolerability.

ClinicalTrials.gov: NCT06066515 (SYNCHRONIZE-1) | NCT06066528 (SYNCHRONIZE-2, T2D) | NCT06077864 (SYNCHRONIZE-CVOT) | Boehringer press release

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

What “Biased Agonism” Actually Means: Inside Orforglipron, MET-097, and Aleniglipron’s Molecular Designs (Example drugs: Orforglipron, MET-097, Aleniglipron)

The recent launch of Eli Lilly’s Foundayo (orforglipron) puts a clinical spotlight back on biased agonism, a receptor design strategy reshaping the incretin landscape. The GLP-1 receptor is a class B G-protein-coupled receptor that signals through two distinct pathways: G-protein activation, which drives cAMP production and satiety, and beta-arrestin recruitment, which scaffolds the receptor for internalization, desensitization, and degradation. Balanced agonists like semaglutide activate both pathways, meaning that acute beta-arrestin signaling in vagal afferents can trigger dose-limiting nausea before the receptor is pulled inside the cell. Biased agonists preferentially trigger the G-protein pathway, keeping the receptor on the cell surface longer while minimizing nausea-inducing beta-arrestin spikes. Orforglipron applies a unique twist to this concept as a non-peptide small molecule that is both G-protein biased and a partial agonist. While fully biased full agonists rely entirely on skewed pathway ratios to widen the therapeutic window, orforglipron’s partial agonism naturally caps peak signaling even at receptor saturation, compounding the tolerability benefits of its bias and allowing Lilly to push oral dosing high enough to achieve the 12.4% weight loss seen in the ATTAIN-1 trial.

This molecular strategy is particularly vital for oral drugs, which require massive doses to overcome low bioavailability. However, the “biased” label is applied loosely across press releases, with companies relying on wildly varying cAMP-to-arrestin ratios and cell-based assays to make their claims. Structure Therapeutics engineered its oral small molecule aleniglipron (GSBR-1290) for a more extreme bias than orforglipron, claiming zero measurable beta-arrestin recruitment alongside a 16.3% placebo-adjusted weight loss in its Phase 2 ACCESS-II study. Pfizer is applying this concept to injectables with MET-097, a fully biased peptide layering ultra-long-acting pharmacokinetics over reduced beta-arrestin signaling as it initiates the Phase 3 VESPER-4 trial. Even tirzepatide exhibits inherent G-protein bias at the GLP-1 receptor, a molecular quirk published in 2020 that partially explains its superior tolerability profile. As we explored last November with the oral peptide ecnoglutide, which just registered a new Phase 2 weight maintenance trial (NCT07553299), manipulating these signaling pathways is a global development trend. While early clinical data show impressively low discontinuation rates, head-to-head clinical experience against standard incretins will ultimately reveal whether these varied biased and partial-agonist designs translate into distinct real-world advantages.

ClinicalTrials.gov: NCT05869903 (ATTAIN-1, orforglipron) | NCT06703021 (ACCESS-II, aleniglipron) | NCT07311850 (VESPER-4, MET-097) | NCT07553299 (Ecnoglutide weight maintenance)

🆕 NEWLY REGISTERED TRIALS (9 in last week)

• HRS9531 Phase 3 evaluating efficacy and safety in participants with atherosclerotic cardiovascular disease (Fujian Shengdi Pharmaceutical / Hengrui; licensed ex-China to Kailera as KAI-9531, n=9,262)

  [New Indications]

  Trials: NCT07551492 | Mechanism: Dual GLP-1/GIP agonist

• Cagrilintide Phase 1 investigating the influence on food intake and appetite in individuals with overweight or obesity (Novo Nordisk, n=120)

  [Weight Loss/Efficacy]

  Trials: NCT07557953 | Mechanism: Dual amylin/calcitonin receptor agonist

• HRS9531 Phase 1 evaluating safety, tolerability, and pharmacokinetics in adolescents with obesity (Fujian Shengdi Pharmaceutical, n=48)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07559136 | Mechanism: Dual GLP-1/GIP agonist

• Tirzepatide Phase 1 evaluating dopaminergic effects and reward processing in individuals with Alcohol Use Disorder (NIAAA, n=176)

  [New Indications]

  Trials: NCT07559500 | Mechanism: Dual GLP-1/GIP agonist

• SRSD384 Phase 1 evaluating the safety, tolerability, and pharmacokinetics of this novel agent in overweight or obese participants (Sirius Therapeutics, n=78)

  [Safety/Tolerability]

  Trials: NCT07557355 | Mechanism: Other metabolic mechanism

• AIM-MAINTAIN Phase 4 comparing AI-assisted multi-domain lifestyle intervention versus tirzepatide for weight loss maintenance in adults with type 2 diabetes (Huazhong University of Science and Technology, n=400)

  [Weight Loss/Efficacy]

  Trials: NCT07555730 | Mechanism: Dual GLP-1/GIP agonist

• Ecnoglutide (VRB-101) Phase 2 evaluating a weekly oral dose for weight maintenance in adults with obesity or overweight and weight-related comorbidities (Verdiva, n=120)

  [Weight Loss/Efficacy | Oral Formulations]

  Trials: NCT07553299 | Mechanism: Biased GLP-1 receptor agonist

• Incretin Therapies Phase 4 investigating the clinical impact of incretin-based treatments on patients with obesity-related heart failure with preserved ejection fraction (Columbia University, n=50)

  [New Indications]

  Trials: NCT07554638 | Mechanism: Dual GLP-1/GIP agonist

• Combatting Muscle Loss in Obese Adult Patients on GLP-1 Medications Phase 4 evaluating if a 12-week exercise and nutrition program can mitigate muscle and bone loss during GLP-1 treatment (William Marsh Rice University, n=20)

  [Weight Loss/Efficacy]

  Trials: NCT07554417 | Mechanism: GLP-1 receptor agonist

Correction (July 10, 2026): This post originally called SYNCHRONIZE-1 the first Phase 3 readout for any GLP-1/glucagon dual agonist. That is wrong. Innovent’s mazdutide, also a GLP-1/glucagon dual, reported Phase 3 obesity data in China earlier: GLORY-1 topline in January 2024, and GLORY-2 at 18.55% weight loss over 60 weeks in November 2025. Survodutide is the first such dual to read out Phase 3 obesity data in a global (non-China) development program, not the first overall. The relevant sentences above have been updated.

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com or at glp1.bio1up.com/weekly-updates for a structured view of weekly updates and the ability to drill down on details.

Separately, Novo’s oral semaglutide met its Phase 3 endpoint in adolescents with T2D (PIONEER TEENS). CMS (Centers for Medicare & Medicaid Services) delayed its Part D GLP-1 pilot to 2027 after insurers declined to participate. Roche used its Q1 earnings to reframe petrelintide as a tolerability-first option rather than a direct competitor to tirzepatide, which is more of a positioning shift than new data since the Phase 2 results were released in March. And Novo’s Phase 3 CagriSema vs tirzepatide trial in T2D (NCT06221969) completed this week, the T2D counterpart to February’s REDEFINE 4 obesity trial where CagriSema missed non-inferiority. The readout is one to watch.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Roche CEO reframes petrelintide as a tolerability-first amylin at Q1 earnings.

  In Q1 2026 earnings commentary, Roche CEO Thomas Schinecker positioned petrelintide (its long-acting amylin analog co-developed with Zealand Pharma) as a high-tolerability alternative for maintenance use and for patients who cannot tolerate incretin-based therapies, rather than as a head-to-head competitor to GLP-1/GIP dual agonists on efficacy. The underlying Phase 2 ZUPREME-1 data (up to 10.7% weight loss at week 42 with placebo-like tolerability) was originally reported in March, so the new element is the positioning rather than the data.

  BioSpace context | Mechanism: amylin analog (AMYR + CTR agonist)

• Oral semaglutide meets Phase 3 endpoint in adolescents with type 2 diabetes.

  Novo Nordisk announced positive topline results from the PIONEER TEENS Phase 3a trial evaluating oral semaglutide in children and adolescents aged 10-17 with type 2 diabetes. The trial met its primary endpoint with a statistically significant 0.83% HbA1c reduction vs placebo at 26 weeks. Novo plans to file for a label expansion in the US and EU in the second half of 2026, positioning oral semaglutide as potentially the first oral GLP-1 RA approved for this pediatric population.

  Press | Trials: NCT04596631 | Mechanism: oral GLP-1 receptor agonist

• CMS delays Part D GLP-1 pilot (BALANCE) to 2027 after insurers refuse to participate.

  The Centers for Medicare and Medicaid Services has indefinitely postponed its BALANCE financing model for Medicare Part D, which was designed to make GLP-1 weight-loss drugs more affordable for seniors. Insurers including CVS and UnitedHealth declined to participate, citing concerns about financial risk and lack of utilization data. CMS will continue the parallel Medicaid program and extend a bridge model to maintain interim beneficiary access. Lilly and Novo Nordisk stocks dipped on the news given the potential revenue impact.

  BioSpace | FiercePharma | Mechanism: policy

📰 PRESS

• FDA issues warning letter after a GLP-1 manufacturer refuses inspectors access to its facility.

  FDA letter (New Life Pharma) | BioSpace | Mechanism: regulatory / manufacturing

• Roche CEO outlines why the company is sitting out the current Big Pharma M&A wave, citing enicepatide and petrelintide as internal growth drivers.

  FierceBiotech | Mechanism: strategy

• Altimmune prices $225 million public offering to fund Phase 3 MASH trial of pemvidutide.

  Altimmune IR | Mechanism: GLP-1 / glucagon dual agonist

• Oral GLP-1 tracker: Lilly’s Foundayo launch continues to trail Novo’s Wegovy pill in early scripts.

  FiercePharma | Mechanism: oral GLP-1

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

The Phase 3 Geographic Arms Race: 500 Sites Added in a Week Across MET097, Orforglipron, and MariTide CVOTs

Between April 18 and 24, 2026, five late-stage cardiometabolic trials added approximately 500 new clinical sites to their ClinicalTrials.gov registrations. The timing signals that the post-Foundayo obesity race has moved from pipeline dealmaking into operational execution. New-site postings lag actual activations by a few weeks, but a surge of this magnitude reflects real, committed infrastructure coming online. The ramp was led by Pfizer’s VESPER-4 obesity trial for MET097, an ultra-long-acting, fully-biased GLP-1 mono-agonist, which added 191 locations (n=3,500, primary completion September 2027) just as its Phase 2 wrapped the same week. Eli Lilly’s ATTAIN-Outcomes trial followed with 151 new sites (n=7,140, primary completion August 2031), pursuing ASCVD and chronic kidney disease label expansions for its newly approved oral Foundayo (orforglipron). Amgen’s MARITIME-CV activated 119 sites for maridebart cafraglutide (MariTide), its GLP-1 agonist / GIP antagonist antibody-peptide conjugate; at 12,800 patients it is the largest of the three.

This rapid mobilization is not isolated to cardiovascular outcomes; Lilly concurrently expanded its 4,500-patient SYNERGY-Outcomes MASLD master protocol by 89 sites while scaling its Phase 3 eloralintide programs across sleep apnea and osteoarthritis. What makes this operational footprint strategically vital is the evolving biology of incretins: because GLP-1 effects on MACE, heart failure, and renal decline extend beyond mere weight loss to systemic improvements in inflammation and vascular function, broad cardiometabolic labeling requires massive, multi-year outcomes trials. With Foundayo’s approval proving that the industry has successfully developed the requisite next-generation molecules, the new competitive moat in obesity is sheer infrastructure. The clinical site footprint is now the ultimate proxy for execution, determining whether a company can recruit and run a 12,000-patient trial faster than its peers to capture critical label expansions.

ClinicalTrials.gov: NCT07311850 (VESPER-4, MET097) | NCT07241390 (ATTAIN-Outcomes, orforglipron) | NCT07037433 (MARITIME-CV, maridebart cafraglutide) | NCT07165028 (SYNERGY-Outcomes MASLD)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Amycretin and the Amylin Selectivity Problem (Example drugs: Amycretin, Cagrilintide, Eloralintide, Petrelintide)

Novo Nordisk’s aggressive clinical strategy for amycretin, underscored this week by a new Phase 1 study on insulin regulation (NCT07535307), forces a closer look at the increasingly complex “GLP-1 plus amylin” landscape. Amycretin’s core distinction is its structure: it is a single, unimolecular co-agonist engineered to activate both GLP-1 and amylin receptors. This contrasts sharply with Novo’s other late-stage combination, CagriSema, which is a co-formulation of two separate drugs: the GLP-1 agonist semaglutide and the amylin analog cagrilintide. The unimolecular design offers a unified pharmacokinetic profile and manufacturing simplicity but locks the ratio of GLP-1 to amylin activity. The new mechanism study likely aims to dissect the amylin component’s specific contribution to restoring normal postprandial glucagon suppression, a key physiological role of amylin that is impaired in type 2 diabetes.

This structural choice occurs against a backdrop of active debate over amylin pharmacology itself, centered on receptor selectivity. Native amylin acts on both the amylin receptor (AMYR) and the calcitonin receptor (CTR). While AMYR activation drives the desired effects of satiety and slowed gastric emptying, CTR activation is linked to dose-limiting nausea. This has split the field: some companies are developing dual amylin and calcitonin receptor agonists (DACRAs), like Novo’s cagrilintide, Zealand/Roche’s petrelintide, and AbbVie’s GUB014295 (ABBV-295), betting that broad agonism is optimal. Others are engineering selective amylin receptor agonists (SARAs) to isolate the benefits while minimizing side effects, a strategy pursued by Eli Lilly with eloralintide and AstraZeneca with AZD6234. Ascletis has added a third axis of differentiation with ASC39, an oral small-molecule amylin agonist being co-developed alongside its oral GLP-1 ASC30. Amycretin’s unique unimolecular GLP-1/amylin profile represents yet another largely uncharted path. Novo’s decision to run four Phase 3 trials and at least two parallel Phase 1 mechanism studies reflects the high stakes and scientific uncertainty of pioneering a class where the fundamental rules of pharmacology are still being explored.

ClinicalTrials.gov: NCT07535307 (NNC0487-0111 insulin PoC) | NCT07533175 (AMAZE 2, T2D) | NCT07503210 (AMAZE 12, maintenance) | NCT07508020 (appetite/food intake PoC) | NCT07353931 (Eloralintide OA knee pain)

🆕 NEWLY REGISTERED TRIALS (2 in last week)

• HRS9531 Phase 1 evaluating pharmacokinetics in participants with mild to moderate hepatic impairment compared to normal hepatic function (Fujian Shengdi Pharmaceutical / Hengrui; licensed to Kailera as KAI-9531, n=24)

  [Safety/Tolerability]

  Trials: NCT07540754 | Mechanism: GLP-1/GIP dual agonist

• DWRX5003 Phase 1 first-in-human study assessing safety and bioavailability of a semaglutide microneedle patch relative to two other formulations in healthy adults (Daewoong Pharmaceutical, n=72)

  [Safety/Tolerability | Novel Delivery]

  Trials: NCT07539415 | Mechanism: GLP-1 receptor agonist (microneedle patch formulation)

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

Separately, PrecisionLife and Ovation announced a pharmacogenomic GLP-1 response test launching in H2 2026 as both a physician-ordered LDT and a consumer DNA product. This follows last week’s 23andMe Nature paper on genetic predictors of GLP-1 response. Whether any of it is clinically actionable yet is an open question, but it’s worth noting that commercial pharmacogenomic stratification is arriving before we have robust clinical guidance.

Some interesting things I was reading this week touched on the breadth of the GLP-1 story. The New York Times piece on how GLP-1 experimentation is outrunning the evidence base was a useful reminder of how quickly these drugs are diffusing into adjacent use cases; I also revisited Daniel Drucker and Maria Gonzalez-Rellan’s review on the expanding benefits of GLP-1 medicines as a helpful frame for how wide the therapeutic conversation has already become.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Lilly’s Foundayo meets CV primary endpoint in Phase 3 ACHIEVE-4 with 57% mortality reduction.

  In the Phase 3 ACHIEVE-4 trial, Eli Lilly’s Foundayo (orforglipron) met its primary endpoint of non-inferiority to insulin glargine for major adverse cardiovascular events (MACE-4) in 2,749 adults with type 2 diabetes and elevated cardiovascular risk, with a 16% lower risk numerically (HR 0.84, 95% CI 0.59-1.20). A pre-planned analysis showed a 57% lower risk of all-cause death vs insulin glargine (HR 0.43, 95% CI 0.25-0.75, nominal p=0.002), sustained through 104 weeks alongside superior A1C and body weight reductions. Lilly plans to submit to the FDA for the T2D indication by end of Q2.

  Press | Trials: NCT05803421 | Mechanism: oral non-peptide GLP-1 receptor agonist

• FDA requests post-marketing safety study on Foundayo obesity indication.

  Following the April 1 approval of Foundayo for weight management, the FDA has requested Lilly conduct a postmarketing clinical trial to further assess “serious” cardiovascular and liver safety signals, including unexpected MACE events and drug-induced liver injury (DILI). Lilly will submit the final report from the ongoing ACHIEVE-4 trial, now also assessing for DILI, by July. The request illustrates the tension running through this week: ACHIEVE-4 provides new favorable cardiovascular data, but the FDA’s obesity-indication concern predates ACHIEVE-4 and will take time to fully resolve.

  Press | FiercePharma | Mechanism: oral non-peptide GLP-1 receptor agonist

• Kailera closes $625M IPO, new benchmark for biotech IPOs.

  Kailera Therapeutics closed its IPO at $625 million, the largest biotech IPO of 2026 and a new benchmark for obesity-focused offerings. Proceeds fund Kailera’s quartet of Chinese-origin obesity assets, led by GLP-1/GIP dual agonist ribupatide (KAI-9531, formerly HRS9531, licensed from Hengrui). The IPO tripled its originally targeted ~$200 million raise, reflecting strong investor demand for obesity pipeline exposure and continuing the trend of Chinese-origin metabolic assets entering the Western market.

  Press | Mechanism: GLP-1/GIP dual agonist

📰 PRESS

• Preprint claims semaglutide has muscle-sparing edge over tirzepatide.

  Press | Mechanism: GLP-1 vs GLP-1/GIP dual

• Foundayo launches with 1,390 prescriptions in first week, trailing Novo’s oral Wegovy launch pace.

  Press | Mechanism: oral GLP-1

• Inventors of tirzepatide and tri-agonists propose GIP+glucagon approach that drops GLP-1 entirely.

  Richard DiMarchi and Matthias Tschop, the researchers behind semaglutide, tirzepatide, and the tri-agonist concept, published a peer-reviewed draft paper describing a GIP-receptor / glucagon-receptor co-agonist that excludes GLP-1 activity. In rodent and monkey studies, the molecule matched GLP-1-based weight loss while reportedly avoiding the nausea and vomiting profile typical of incretins. A preclinical result, but notable given the authors.

  STAT News

• Novo Nordisk and OpenAI partner on AI for R&D, manufacturing, and corporate functions.

  Press | Mechanism: AI/drug discovery

• PrecisionLife and Ovation to launch GLP-1 pharmacogenomic stratification test in H2 2026.

  A physician-ordered LDT and consumer DNA product aimed at predicting individual response to GLP-1 therapies. Builds on last week’s 23andMe Nature paper on genetic predictors of response.

  Press | Mechanism: pharmacogenomics

• Q1 2026 obesity-sector dealmaking already exceeds full-year 2025 total.

  Press | Mechanism: market dynamics

• FDA Pharmacy Compounding Advisory Committee to consider broader access to certain peptides (meeting Feb 2027).

  Press | Mechanism: regulatory

• USP adds Trulicity (dulaglutide) to vulnerable drug list over supply risks.

  Press | Mechanism: supply chain

• Lilly investing billions to prepare for overseas oral Foundayo launches.

  Press | Mechanism: oral GLP-1

• FDA issues 15+ warning letters to online pharmacies and compounding sites for unlawful sale of compounded semaglutide and tirzepatide.

  Targets included Hims & Hers (Hers brand), Remedy Meds, SemaBio, and others. Published this week although dated 9/9/2025.

  Example FDA letter | Mechanism: enforcement

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Four Tri-Agonists, Two from Novo: Why the Post-Retatrutide Landscape Is More Crowded Than It Looks

Novo Nordisk’s initiation of a 45-patient Phase 1 drug-drug interaction study (NCT07525791) evaluating NNC0662-0419 alongside oral contraceptives is a meaningful structural signal that the company is preparing for broad Phase 3 populations, highlighting how fiercely contested the GLP-1 / GIP / glucagon tri-agonist race has become. By layering glucagon receptor agonism onto the established dual GLP-1 / GIP mechanism, these unimolecular compounds aim to drive higher weight loss via increased energy expenditure and hepatic lipid oxidation, though developers must carefully calibrate dosing to balance the thermogenic upside against glucagon’s tendency to raise hepatic glucose output. Eli Lilly’s retatrutide proved the viability of this biology by achieving up to 24.2% weight loss at 48 weeks in Phase 2, and the compound is now years ahead with over 13 active Phase 3 trials, including the massive 10,000-patient TRIUMPH-Outcomes study completing in early 2029.

What makes the current landscape strategically fascinating is Novo Nordisk’s deliberate decision to pursue a dual-track hedge to catch up; alongside NNC0662-0419’s expanding Phase 2 obesity and type 2 diabetes program, Novo is simultaneously advancing UBT251, a licensed tri-agonist that recently beat semaglutide on HbA1c reductions in a Chinese Phase 2 trial. With other competitors like Hanmi Pharmaceutical also launching concurrent mid-stage trials for their own candidate, HM15275, the tri-agonist class has rapidly evolved in under 18 months from a differentiated moonshot into a crowded space where companies are aggressively hedging their pipelines to secure the next frontier of twenty-percent-plus weight loss.

ClinicalTrials.gov: NCT07525791 (NNC0662-0419 DDI) | NCT07184632 (NNC0662-0419 Phase 2 Obesity) | NCT07395687 (UBT251 Phase 2 Obesity) | NCT06383390 (TRIUMPH-Outcomes) | NCT07527650 (HM15275 Phase 2 T2D)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Lean Mass and GLP-1s: Sorting Signal from Narrative (Example drugs: Cagrilintide, Bimagrumab, Enobosarm)

The profound weight loss achieved with GLP-1 receptor agonists has surfaced a critical secondary concern: 25 to 40% of the total weight lost is typically fat-free lean mass, including skeletal muscle. A March 2026 meta-analysis in Diabetes, Obesity and Metabolism (20 RCTs, ~15,800 patients) was clarifying: incretins don’t cause disproportionate muscle wasting versus lifestyle-induced weight loss of similar magnitude. The absolute muscle loss is simply larger because GLP-1 drugs produce much more total weight loss. The real differentiator is exercise; resistance training cut lean mass loss to 17.5% of total weight lost, versus roughly 26% for both drugs and diet alone. Clinically, the concern is not the raw DEXA number but functional capacity, particularly in older patients and in those already at risk of obesity-related sarcopenia.

The pharmacological response is organized around two strategies. The first is amylin-based co-therapy: cagrilintide (in CagriSema) and Amgen’s maridebart cafraglutide are thought to spare muscle by regulating central appetite without the same degree of gut-motility-driven protein intake suppression seen with GLP-1 monotherapy. To formally test this “amylin signature” hypothesis, Novo Nordisk registered the Phase 1 RASMUS study this week, directly comparing CagriSema to its individual components. The second strategy targets muscle-anabolic pathways directly: Lilly’s bimagrumab (acquired via Versanis) is an activin type II receptor antagonist blocking myostatin and activin A signaling to drive muscle growth; Veru’s enobosarm is a selective androgen receptor modulator, now in the PLATEAU Phase 2 after the QUALITY Phase 2 completed last year; and Roche’s anti-myostatin emugrobart continues in obesity after discontinuing last month for spinal muscular atrophy. A preprint this week drew “Novo muscle advantage” headlines by reporting that semaglutide patients retained more lean mass than tirzepatide patients, though that observational comparison is confounded by the substantially larger weight loss under tirzepatide. Whether any amylin analog is intrinsically muscle-sparing or just benefits from lower overall weight loss, and whether expensive anti-myostatin monoclonals can justify their cost against plain resistance training, are the outstanding questions that these muscle-focused trials will need to answer.

ClinicalTrials.gov: NCT07527195 (RASMUS) | NCT06643728 (Bimagrumab + Tirzepatide) | NCT07446998 (Enobosarm PLATEAU) | Novo muscle preprint coverage

🆕 NEWLY REGISTERED TRIALS (10 in last week)

• Elecoglipron Phase 1 drug-drug interaction study assessing its effect on rosuvastatin and atorvastatin in healthy participants (AstraZeneca, n=40)

  [Safety/Tolerability]

  Trials: NCT07534592 | Mechanism: oral non-peptide GLP-1 receptor agonist

• AMAZE 2 Phase 3 investigating NNC0487-0111 (amycretin) for weight loss in adults with excess body weight and type 2 diabetes (Novo Nordisk, n=630)

  [Weight Loss/Efficacy]

  Trials: NCT07533175 (AMAZE 2) | Mechanism: GLP-1 + amylin combination

• SYH2082 Phase 1 first-in-human single ascending dose study in healthy participants (CSPC ZhongQi Pharmaceutical, n=44)

  [Safety/Tolerability]

  Trials: NCT07532655 | Mechanism: Dual GLP-1/GIP agonist

• NNC0662-0419 Phase 1 drug-drug interaction study assessing oral contraceptives and gastric emptying in women with excess body weight (Novo Nordisk, n=45)

  [Safety/Tolerability]

  Trials: NCT07525791 | Mechanism: GLP-1 / GIP / glucagon tri-agonist

• HM15275 Phase 2 evaluating the drug in patients with type 2 diabetes (Hanmi Pharmaceutical, n=180)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07527650 | Mechanism: GLP-1 / GIP / glucagon tri-agonist

• Maridebart cafraglutide Phase 1 drug-drug interaction study assessing absorption of oral contraceptives in postmenopausal women with overweight or obesity (Amgen, n=45)

  [Safety/Tolerability]

  Trials: NCT07523711 | Mechanism: GLP-1 agonist + GIP antagonist (antibody-peptide conjugate)

• HDM1005 Phase 2 head-to-head trial versus tirzepatide in adults with obesity without diabetes (Hangzhou Zhongmei Huadong Pharmaceutical, n=372)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07521631 | Mechanism: Dual GLP-1/GIP agonist

• ALN-PNP Phase 2a evaluating the drug alone and in combination with a GLP-1R agonist in patients with homozygous PNPLA3-related MASLD (Regeneron/Alnylam, n=204)

  [New Indications]

  Trials: NCT07527910 | Mechanism: RNAi therapeutic (PNPLA3 silencing), with GLP-1 combination arm

• HASHTAG Phase 2 evaluating semaglutide in adults with Cannabis Use Disorder (Rigshospitalet / University of Copenhagen, n=100)

  [New Indications]

  Trials: NCT07523633 (HASHTAG) | Mechanism: GLP-1 receptor agonist

• RASMUS Phase 1 evaluating CagriSema vs individual components (cagrilintide and semaglutide) on muscle health (Novo Nordisk, n=100)

  [Safety/Tolerability]

  Trials: NCT07527195 (RASMUS) | Mechanism: GLP-1 + amylin combination

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Foundayo (orforglipron) now available in the US.

  Eli Lilly’s once-daily oral GLP-1, Foundayo (orforglipron), is now available in the U.S. for adults with obesity or overweight with weight-related medical problems, following FDA approval on April 1. In the ATTAIN-1 trial, patients on the highest dose lost an average of 27.3 pounds (12.4%) at 72 weeks vs 2.2 pounds (0.9%) for placebo. Available through LillyDirect, telemedicine providers, and retail pharmacies.

  Press | Trials: NCT05869903 | Mechanism: oral non-peptide GLP-1 receptor agonist

• FDA warns of counterfeit Ozempic in US supply chain and clarifies compounding policies.

  The FDA issued a warning about counterfeit Ozempic (semaglutide) found in the US drug supply, urging consumers to verify their sources. Separately, the agency clarified compounding policies as national GLP-1 supply stabilizes, and issued warning letters to multiple compounding pharmacies (PekCura Labs, Mile High Compounds, Gram Peptides, Pink Pony Peptides) over unapproved semaglutide and tirzepatide products.

• Wegovy HD now available nationwide; EU approves 48-hour room-temperature storage.

  Novo Nordisk launched higher-dose Wegovy HD nationwide in the US. Separately, Wegovy became the first GLP-1 weight-loss treatment approved for 48-hour controlled-temperature delivery in the EU, easing cold-chain requirements for patients.

📰 PRESS

• MetaVia doses first patient in higher-dose Phase 1 of DA-1726, a GLP-1/glucagon dual agonist for obesity.

  Press | Mechanism: GLP-1/glucagon dual agonist

• 23andMe finds genetic changes appear to help predict response to GLP-1 drugs for weight loss.

  Nature

• Gan & Lee licenses GLP-1 agonist bofanglutide to JW Pharmaceutical for South Korean market.

  Press | Mechanism: GLP-1 receptor agonist

• Vivtex expands beyond its $2.1B Novo Nordisk deal for oral drug delivery technology.

  Press | Mechanism: oral drug delivery

• Vanda initiates study of motion sickness drug Nereus in GLP-1 users.

  Press

• Ascletis announces fixed-dose combination of ASC30 (oral GLP-1) and ASC39 (oral amylin agonist) for clinical development.

  Press | Mechanism: GLP-1 + amylin combination

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

ASCEND: Inside AstraZeneca’s Quiet Bet on a Multi-Mechanism Obesity Combination

AstraZeneca’s ASCEND trial (NCT06862791) is an active Phase 2 study of 377 patients set to read out in May 2026, offering the first major look at an expansive, under-the-radar obesity pipeline hiding in plain sight. The trial evaluates the co-administration of two distinct injectables against placebo and each component alone: AZD9550, a unimolecular GLP-1/glucagon dual agonist, and AZD6234, a novel long-acting selective amylin receptor agonist (SARA) engineered to avoid the calcitonin-mediated aversion associated with broader amylin drugs. Because the components are delivered as separate injections rather than a fixed co-formulation like Novo Nordisk’s CagriSema, ASCEND allows for independent dose optimization of what is effectively a de facto triple-pathway metabolic intervention. This aggressive combination serves as the centerpiece of AstraZeneca’s quietly assembled obesity portfolio, which spans over 20 trials and includes the oral GLP-1 elecoglipron as well as the newly registered, undisclosed-mechanism AZD1043. It signals a major strategic pivot for a company not historically known for obesity drug development. While combining multiple metabolic mechanisms inherently increases tolerability risks and clinical complexity, a successful ASCEND readout could allow AstraZeneca to leapfrog competitors by establishing a highly differentiated, next-generation approach to weight loss.

ClinicalTrials.gov: NCT06862791 (ASCEND) | NCT06579092 (VISTA - Elecoglipron) | NCT06579105 (SOLSTICE - Elecoglipron)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Beyond Weekly: The Engineering Race to Build Monthly and Quarterly GLP-1 Therapies (Example drugs: PF-08653944, Efsubaglutide, CR059)

As the obesity landscape pushes beyond the weekly dosing standard set by semaglutide’s acylation-driven albumin-binding approach, drug designers are turning to increasingly creative molecular engineering to push toward monthly or even quarterly dosing. Rather than relying solely on fatty acid side chains that eventually hit a clearance ceiling, next-generation candidates utilize Fc domain fusion to hijack the IgG endosomal recycling pathway - effectively tricking the body into preserving the drug the way it preserves its own antibodies (efsubaglutide), increase hydrodynamic radius through PEGylation (loxenatide), encapsulate existing drugs in slow-release matrices (NEX-22A), or feature fundamentally redesigned ultra-long-acting peptides (Pfizer/Metsera’s PF-08653944). More radical moonshots, like CirCode Bio’s CR059, bypass protein half-life limitations entirely by utilizing circular RNA lipid nanoparticles to turn the patient’s own cells into long-term drug factories. While extending dosing intervals promises to drastically improve real-world adherence and enable convenient multi-target regimens like monthly amylin combinations, it introduces complex pharmacokinetic trade-offs, including slower dose titration, delayed steady-state efficacy, and prolonged washout periods if severe adverse events occur. With PF-08653944 and efsubaglutide registering new clinical trials this week alongside promising quarterly dosing data from Ascletis (ASC30), the competitive frontier of incretin therapeutics has officially evolved from maximizing raw weight loss to engineering ultimate pharmacokinetic endurance.

ClinicalTrials.gov: NCT07519135 (PF-08653944) | NCT07518121 (Efsubaglutide) | NCT07347080 (CR059)

🆕 NEWLY REGISTERED TRIALS (7 in last week)

• PF-08653944 Phase 1 study evaluating the drug in participants with and without impaired liver function (Pfizer, n=26)

  [Safety/Tolerability]

  Trials: NCT07519135 | Mechanism: GLP-1 receptor agonist

• ASCEND-1 evaluating lifestyle intervention plus mazdutide for weight management in a hospital-sponsored study (Shanghai Zhongshan Hospital, n=420)

  [Weight Loss/Efficacy]

  Trials: NCT07517042 | Mechanism: Dual GLP-1/glucagon agonist

• Efsubaglutide Alfa Phase I bridging study evaluating the drug in healthy adults in Brazil (Shanghai Yinnuo Pharmaceutical Technology Co., Ltd., n=48)

  [Safety/Tolerability]

  Trials: NCT07518121 (BRIDGE-BR) | Mechanism: GLP-1 receptor agonist

• ABBV-295 Phase 1 assessing safety and pharmacokinetics in healthy Japanese adults with overweight or obesity (AbbVie, n=24)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07514260 | Mechanism: Dual amylin/calcitonin receptor agonist

• AZD1043 Phase 1 trial evaluating the safety and tolerability of a new potential treatment for adults with overweight or obesity (AstraZeneca, n=112)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07511205 | Mechanism: Mechanism not disclosed

• Low-dose semaglutide Phase 4 trial investigating weight loss in obese, non-diabetic Pakistani adults (Asian Institute Of Medical Sciences, n=60)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07513168 | Mechanism: GLP-1 receptor agonist

• GLP-1 Receptor Agonists Phase 2 trial investigating improved outcomes in patients undergoing endovascular thrombectomy for stroke (Population Health Research Institute, n=100)

  [New Indications]

  Trials: NCT07511543 (LEAST) | Mechanism: GLP-1 receptor agonist

This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

TIER 1: White Hot

1. Retatrutide (Eli Lilly) — GLP-1/GIP/Glucagon Triple Agonist

• Program: TRIUMPH (7+ Phase 3 studies), TRANSCEND
• Why #1: Best-in-class 28.7% weight loss at 68 weeks (TRIUMPH-4). Only triple agonist in Phase 3. TRANSCEND-T2D-1 just reported positive topline (Mar 19) - up to 16.8% weight loss + 2.0% A1C reduction. TRIUMPH-1 pivotal obesity readout expected H1 2026.
• In our DB: TRIUMPH-Outcomes CVOT has 10,000 patients enrolled (active, not recruiting). Seven TRIUMPH readouts expected throughout 2026.
• Watch for: A dysesthesia safety signal flagged in trial data.

2. Survodutide (Boehringer Ingelheim / Zealand) — GLP-1/Glucagon Dual Agonist

• Program: SYNCHRONIZE
• Why it’s hot: Single most anticipated dataset from a non-Lilly/Novo company. Phase 2 showed ~18.7% weight loss. SYNCHRONIZE-1 topline could drop any day (H1 2026). Also has FDA Breakthrough Therapy for MASH.
• In our DB: SYNCHRONIZE-CVOT shows 5,531 patients, active not recruiting.
• Bear case: 24.6% Phase 2 discontinuation from GI side effects - tolerability will make or break it.

3. CagriSema (Novo Nordisk) — Cagrilintide (Amylin) + Semaglutide

• Status: NDA filed Dec 2025, PDUFA ~October 2026
• The problem: REDEFINE 4 (reported Feb 23 in our DB) - CagriSema failed non-inferiority vs Zepbound. REDEFINE 1 showed 22.7% vs placebo. In the head-to-head REDEFINE 4, CagriSema came in at 23.0% vs tirzepatide’s 25.5%. Novo now planning high-dose CagriSema Phase 3 to close the gap.
• In our DB: REDEFINE 3 has 7,101 patients (active, not recruiting). REIMAGINE 4 (CagriSema vs tirzepatide in T2D, 1,000 patients) had a minor date push to April 2026.

TIER 2: Very High Heat

4. Amycretin / Zenagamtide (Novo Nordisk) — Unimolecular GLP-1/Amylin

• 22% weight loss at just 36 weeks (Phase 1b/2a) - highest single-molecule early data. Oral version showed 13.1% at 12 weeks. Phase 3 enrollment began Q1 2026.
• Novo’s most important next-gen asset. Single molecule vs CagriSema’s two-component mix.

5. CT-388 (Roche/Carmot) — Signal-Biased GLP-1/GIP Dual Agonist

• 22.5% weight loss at 48 weeks (Phase 2, Jan 2026). Phase 3 ENITH-1/2 initiating. Combo Phase 2 with petrelintide starting H1 2026.
• Validated Roche’s $2.7B Carmot acquisition. The petrelintide combo could yield >30% weight loss.

6. PF-08653944 / MET-097 (Pfizer/Metsera) — Monthly GLP-1

• In our DB: 3,500 patients enrolling, primary completion Sep 2027.
• 12.3% weight loss at 28 weeks with monthly dosing (VESPER-3 Phase 2b). Full data at ADA June 2026. Massive 10-trial Phase 3 program (VESPER) ramping up.
• Only monthly-dosed GLP-1 in Phase 3. Backs Pfizer’s >$10B Metsera acquisition.

7. Petrelintide (Zealand / Roche) — Long-Acting Amylin Analog

• In our DB: ZUPREME positive Phase 2 reported Mar 5 - 10.7% weight loss with near-zero GI side effects (0% vomiting at max dose).
• Phase 3 mono and combo (with CT-388) both initiating 2026. The tolerability profile makes it the ideal combination backbone.

TIER 3: High Heat

8. VK2735 (Viking Therapeutics) — GLP-1/GIP Dual Agonist

• Just happened in our DB: VANQUISH-2 (1,100 patients) moved from RECRUITING → ACTIVE_NOT_RECRUITING on Apr 7 - enrollment complete!
• SC Phase 2: 14.7% at just 13 weeks. VANQUISH-1 (4,500 patients) data expected H2 2026/early 2027. Frequent acquisition target speculation.

9. MariTide / Maridebart Cafraglutide (Amgen) — Monthly GLP-1 Agonist / GIP Antagonist

• In our DB: MARITIME-CV is one of the largest trials we track at 12,800 patients (recruiting). MARITIME-HF at 5,056.
• Up to 20% weight loss at 52 weeks (Phase 2). Unique mechanism - GIP antagonism (opposite of tirzepatide). ADA June 2026 presentations expected.

10. Aleniglipron / GSBR-1290 (Structure Therapeutics) — Oral Small-Molecule GLP-1

• In our DB: ACCESS data updated Mar 16 - 16.3% weight loss at 44 weeks (180 mg). Advancing to Phase 3.
• Highest oral GLP-1 weight loss data reported. Competitive with some injectables.

11. Eloralintide + Tirzepatide (Eli Lilly) — Amylin + GLP-1/GIP Combo

• In our DB: 1,980 patients recruiting, primary completion Mar 2028.
• Combo showed 11.3% at just 12 weeks. Lilly’s answer to CagriSema.

Recently Approved (Landscape Shifters)

• Orforglipron / Foundayo (Lilly): FDA approved Apr 1 - first oral small-molecule GLP-1. ACHIEVE-3 in our DB (Feb 26) showed it beat oral semaglutide.
• Oral Wegovy 25 mg (Novo): Approved Jan 2026 at $149/month.
• Wegovy HD 7.2 mg (Novo): Approved Mar 19 - 20.7% weight loss, closing the tirzepatide gap.

Five Themes Shaping the Landscape

1. Amylin is the mechanism of the moment - CagriSema, amycretin, eloralintide, petrelintide, ABBV-295 all leverage amylin signaling. The thesis: amylin + GLP-1 combos push past 25-30% weight loss.
2. The oral convenience war is heating up - Orforglipron (approved), oral Wegovy (approved), aleniglipron (16.3%), VK2735 oral, elecoglipron. ATTAIN-MAINTAIN data reframes orals as maintenance therapy after injectable-driven loss.
3. Monthly dosing enters Phase 3 - Pfizer’s PF-08653944 and Amgen’s MariTide differentiate on dosing convenience.
4. Triple agonism’s defining year - Retatrutide’s TRIUMPH readouts will determine whether GLP-1/GIP/glucagon is truly best-in-class. 28.7% is the number to beat.
5. Quality of weight loss emerges - Regeneron’s COURAGE (anti-myostatin preserving 92.6% fat-only loss), bimagrumab + semaglutide (Nature Medicine, Mar 2), pemvidutide (78% fat loss). Lean mass preservation is becoming a competitive axis.

This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• FDA approves Lilly’s Foundayo (orforglipron), the first oral non-peptide GLP-1 for weight loss.

  The FDA has approved Eli Lilly’s Foundayo (orforglipron), a once-daily oral non-peptide GLP-1 receptor agonist, for adults with obesity or overweight with weight-related medical problems. The approval was the first new molecular entity under the FDA’s National Priority Voucher program, completed in just 50 days. In the ATTAIN-1 trial, individuals taking the highest dose of Foundayo lost an average of 27.3 pounds (12.4%) compared to 2.2 pounds (0.9%) with placebo. Unlike oral semaglutide, the pill can be taken at any time of day without food or water restrictions.

  FDA | Press | Trials: NCT05869903 | Mechanism: oral non-peptide GLP-1 receptor agonist

📰 PRESS

• Novo Nordisk claims Wegovy pill beats orforglipron in indirect comparison.

  Press | Mechanism: oral semaglutide

• Taltz/Zepbound combo improves psoriatic arthritis and promotes weight loss.

  Press | Trials: NCT06588296 | Mechanism: dual GLP-1/GIP receptor agonist

• Lilly and Baseline investigate GLP-1s for substance use disorders.

  Press | Mechanism: GLP-1 receptor agonist

• Ambrosia raises $100M Series B for next-generation oral GLP-1s.

  Press | Mechanism: oral small molecule GLP-1 receptor agonist

• UK cost watchdog recommends Wegovy for cardiovascular risk reduction.

  Press | Mechanism: GLP-1 receptor agonist

• Kailera files for IPO to fund obesity drug ribupatide pipeline.

  Press | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Foundayo Arrives: Orforglipron Becomes the First Oral Non-Peptide GLP-1 - But the Race Is Just Starting

The FDA’s 50-day priority voucher approval of Eli Lilly’s orforglipron (Foundayo) on April 1, 2026, the fastest for a new molecular entity since 2002, marks a critical milestone as the first daily oral, non-peptide GLP-1 receptor agonist for weight management. Unlike peptide-based alternatives like oral semaglutide that require permeation enhancers and strict fasting, this small molecule partial agonist utilizes biased G protein signaling to enable convenient dosing at any time without food or water restrictions. The drug’s expansive clinical program provides a robust foundation for broad utilization, highlighted by the ATTAIN-1 obesity trial demonstrating 12.4% weight loss at 72 weeks, ATTAIN-MAINTAIN establishing a novel “injectable-to-oral step-down” paradigm, and ACHIEVE-3 proving superiority over oral semaglutide in diabetes. However, Foundayo’s launch merely fires the opening shot in a rapidly intensifying oral metabolic race, as prescribers now navigate between Lilly and Novo Nordisk’s offerings while tracking over 20 distinct programs advancing through a crowded pipeline. With Pfizer acquiring Metsera for $10 billion to reboot its pipeline and next-generation candidates like Structure Therapeutics’ aleniglipron already posting 16.3% placebo-adjusted weight loss with low discontinuation rates in Phase 2, the competitive landscape of oral incretins is poised for dramatic evolution over the next several years.

ClinicalTrials.gov: NCT05869903 (ATTAIN-1) | NCT06045221 (ACHIEVE-3) | Eli Lilly Press Release

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Why Weight Comes Back: The Biology of Regain After GLP-1 Therapy - And the Race to Solve It

Weight regain after stopping GLP-1 receptor agonists is a coordinated biological defense, not a return to old habits. Three converging forces drive it. First, hormonal counter-regulation: appetite hormones like ghrelin remain elevated and satiety signals like leptin and PYY remain suppressed for over a year after weight loss. GLP-1 drugs mask these changes during treatment but do not reset them, so the full force of this hormonal defense reasserts itself when the drug is removed. Second, metabolic adaptation compounds the problem. Total energy expenditure drops beyond what reduced body mass alone would predict, and because 25-40% of weight lost on GLP-1 drugs is lean muscle, patients end treatment with a lower metabolic rate but the same appetite drive. Third, emerging neuroscience reveals that the brain’s reward circuitry adapts to the drug itself. A 2025 Science paper found that ventral tegmental area (VTA) dopamine neurons recovered their responsiveness to palatable food even during ongoing semaglutide treatment, suggesting the hedonic system begins working around the drug before it is ever stopped.

The often-cited narrative that “you regain everything” is being revised. A March 2026 meta-regression in eClinicalMedicine found that regain follows a decelerating curve, plateauing at roughly 75% of weight lost. About 25% of the loss appears durably retained. Real-world data from a Cleveland Clinic study of 8,000 patients paints an even more favorable picture, largely because patients in practice restart medications rather than going cold turkey as withdrawal trial designs require. The field is now pivoting from maximizing acute weight loss to solving the maintenance problem. Lilly’s ATTAIN-MAINTAIN trial showed orforglipron maintained weight within 0.9 kg after switching from injectable semaglutide. Novo Nordisk registered AMAZE 12 this week, a Phase 3 amycretin trial specifically targeting weight maintenance. And non-incretin approaches like LX9851, which prevented weight regain after semaglutide discontinuation in preclinical studies, alongside muscle-preserving agents like bimagrumab, are attacking the problem from entirely different biological angles.

🆕 NEWLY REGISTERED TRIALS (4 in last week)

• NNC0487-0111 Phase 1 trial assessing effects on food intake, appetite, and post-meal metabolism in people with obesity (Novo Nordisk, n=120)

  [Weight Loss/Efficacy]

  Trials: NCT07508020 | Mechanism: GLP-1 + amylin combination

• MIST Phase 2 trial investigating a THR-β agonist in combination with semaglutide for metabolic disease (Eccogene, n=160)

  [Weight Loss/Efficacy]

  Trials: NCT07505303 | Mechanism: GLP-1 + THR-β combination

• AMAZE 12 Phase 3 investigating NNC0487-0111 for weight loss maintenance in people with excess body weight (Novo Nordisk, n=600)

  [Weight Loss/Efficacy]

  Trials: NCT07503210 (AMAZE 12) | Mechanism: GLP-1 + amylin combination

• RO7795081 Phase 1 investigating multiple oral doses in Chinese adults with obesity or overweight (Hoffmann-La Roche, n=30)

  [Weight Loss/Efficacy | Oral Formulations]

  Trials: NCT07499050 | Mechanism: GLP-1 receptor agonist

This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

Novo Nordisk just started a Phase 1 for something that isn’t a GLP-1 agonist. LX9851, licensed from Lexicon Pharmaceuticals in a deal worth up to $1 billion, inhibits an enzyme called ACSL5 to block fat absorption and trigger the gut’s own satiety signaling. Preclinical data showed it prevented weight regain after semaglutide was stopped, which is one of the biggest unsolved problems in the space. I go into the biology in both the Trial Spotlight and Mechanism Explained. Elsewhere, Viking completed enrollment for its Phase 3 VANQUISH-2 trial of VK2735, BrightGene’s oral dual agonist posted up to 8% weight loss at just 8 weeks, and Novo’s triple agonist UBT251 beat semaglutide on HbA1c in a Phase 2 study. On the cautionary side, Aardvark paused its entire pipeline after cardiac signals emerged with its bitter taste receptor approach. Novel mechanisms carry novel risks.

Separately, a new meta-analysis in Diabetes, Obesity and Metabolism (20 RCTs, ~15,800 patients) found that incretins don’t cause disproportionate lean mass loss compared to lifestyle interventions achieving similar weight reduction - challenging a persistent narrative. Resistance training was the real differentiator, cutting lean mass loss to 17.5% of total weight lost versus ~26% for both drugs and diet alone. Worth thinking about as muscle-sparing drugs like enobosarm and bimagrumab enter trials alongside GLP-1s: are they additive with exercise, or a substitute for it?

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Viking Completes Enrollment for Phase 3 Obesity Trial of VK2735.

  Viking Therapeutics has completed patient enrollment for its Phase 3 VANQUISH-2 trial of subcutaneous VK2735, a dual GLP-1/GIP receptor agonist. The 78-week study enrolled approximately 1,000 adults with obesity or overweight and type 2 diabetes. The trial’s primary endpoint is the percent change in body weight from baseline compared to placebo after 78 weeks of treatment.

  Press | Trial: NCT07104383 | Mechanism: dual GLP-1/GIP agonist

• BrightGene’s oral dual agonist BGM0504 shows up to 8% weight loss at 8 weeks.

  China-based BrightGene reported early data from two Phase 1 studies of oral BGM0504, a dual GLP-1/GIP agonist. In the U.S. study (80 patients, doses 20-80 mg), cohorts saw weight loss between 2.7% and 8.2% after five to eight weeks of daily dosing. A China study (75 participants, 10-80 mg) showed 1-5.6% weight loss at four weeks. GI side effects were mostly mild and transient. These are preliminary analyses of ongoing studies, with detailed results reserved for a future conference. BrightGene’s subcutaneous BGM0504 is further ahead, already in Phase 3 trials including a head-to-head against Zepbound.

  Press | Mechanism: dual GLP-1/GIP agonist

• Novo Nordisk’s triple agonist UBT251 outperforms semaglutide in Phase 2 diabetes trial.

  Novo Nordisk’s GLP-1/GIP/glucagon triple agonist UBT251 beat semaglutide in a Phase 2 trial in Chinese patients with type 2 diabetes. After 24 weeks, UBT251 achieved HbA1c reductions of up to 2.16% compared to 1.77% for semaglutide. Novo plans to initiate a global Phase 2 trial this year. Triple agonists like UBT251 target all three metabolic hormone receptors simultaneously, potentially offering greater efficacy than dual agonists like tirzepatide.

  Press | Mechanism: triple agonist (GLP-1/GIP/glucagon)

📰 PRESS

• Wave’s higher-dose obesity drug WVE-007 disappoints, stock halved.

  Press | Mechanism: RNA interference (siRNA)

• Oral Wegovy launch gains traction, but access remains a challenge.

  Press | Mechanism: GLP-1

• Aardvark pauses entire pipeline over cardiac safety concerns.

  Press | Mechanism: bitter taste receptor (TAS2R) agonist

• Lexicon and Novo Nordisk begin Phase 1 trial for obesity drug LX9851.

  Press | Mechanism: ACSL5 inhibitor (non-incretin)

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

LX9851 - Novo Nordisk Bets on a Non-Incretin Obesity Mechanism

Novo Nordisk has initiated a Phase 1 trial for LX9851, a first-in-class oral obesity candidate licensed from Lexicon Pharmaceuticals for up to $1 billion. The study is evaluating the safety, tolerability, and pharmacology of single and multiple ascending doses in 96 individuals with overweight or obesity, with completion expected in the first quarter of 2027. LX9851 is a potent inhibitor of Acyl-CoA Synthetase 5 (ACSL5), a novel non-incretin target involved in fat accumulation, and may also promote satiety by activating the “ileal brake” mechanism. This trial initiation, which triggered a $10 million milestone payment to Lexicon, is strategically significant as it signals the obesity market leader’s investment in next-generation, oral combination therapies. Preclinical data showed that LX9851 not only enhanced weight loss when combined with semaglutide but also mitigated weight regain after the GLP-1 agonist was stopped. However, the pursuit of novel non-incretin mechanisms carries inherent risks, underscored by this week’s pause of Aardvark Therapeutics’ entire bitter taste receptor agonist pipeline (ARD-101/ARD-201) due to cardiac signals in a healthy volunteer study, a finding potentially linked to on-target effects in cardiac tissue.

GlobeNewsWire: Lexicon and Novo Nordisk Announce Phase 1 Initiation

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

ACSL5 Inhibition and the Ileal Brake - A New Path Beyond Incretin Agonism (LX9851)

Novo Nordisk and Lexicon Pharmaceuticals have initiated a Phase 1 trial for LX9851, a first-in-class oral obesity candidate that introduces a novel, non-incretin mechanism to the metabolic disease landscape. LX9851 inhibits Acyl-CoA Synthetase 5 (ACSL5), an intestinal enzyme crucial for activating long-chain fatty acids for absorption and subsequent metabolic processing. By blocking ACSL5, the drug is thought to work through a dual mechanism: it directly reduces the body’s uptake of dietary fats and indirectly triggers the “ileal brake,” a natural feedback loop. This brake is engaged when unabsorbed fats reach the distal ileum, stimulating gut L-cells to release endogenous satiety hormones like GLP-1 and PYY, which in turn slow gastric emptying and suppress appetite. This approach fundamentally differs from current incretin mimetics by amplifying the body’s own physiological signaling rather than supplying exogenous agonists. Because its mechanism does not overlap with GLP-1 receptor agonists, ACSL5 inhibition is highly attractive for combination therapy, with preclinical data showing that LX9851 combined with semaglutide produced greater weight loss and, notably, mitigated weight regain after semaglutide was discontinued.

🆕 NEWLY REGISTERED TRIALS (3 in last week)

• Oral KAI-7535 Phase 2 trial evaluating efficacy and safety in adults with obesity or overweight with at least one comorbidity (Kailera, n=320)

  [Weight Loss/Efficacy | Oral Formulations | Safety/Tolerability]

  Trials: NCT07497880 | Mechanism: GLP-1 receptor agonist

• Targeting Agonists of Glucagon-like Peptide-1 Receptor for Multiple Sclerosis Phase 2 investigating the potential of this drug class, typically used for diabetes, in treating MS (Johns Hopkins University, n=120)

  [New Indications]

  Trials: NCT07497399 (TAG-MS) | Mechanism: GLP-1 receptor agonist

• QLG1090 Phase III trial comparing its efficacy and safety against Rybelsus as an add-on to metformin for adults with Type 2 Diabetes (Qilu Pharmaceutical, n=478).

  [Safety/Tolerability]

  Trials: NCT07487103 | Mechanism: GLP-1 receptor agonist

This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

In a fun and interesting longer term bet, Lilly’s partner Fauna announced an obesity target related to hibernating squirrels. See the Press section and the link there for more.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• FDA approves higher-dose Wegovy showing 20.7% weight loss.

  Novo Nordisk announced the US FDA has approved Wegovy HD (semaglutide 7.2 mg) for long-term weight management. In the STEP UP trial, Wegovy HD demonstrated a 20.7% mean weight loss in participants with obesity, with approximately one-third of patients achieving 25% or greater weight loss. Novo Nordisk expects to launch the product in the US in April 2026. The approval was the fourth product under the FDA’s National Priority Voucher Program.

  Press | Trials: NCT05646706 | Mechanism: GLP-1 receptor agonist

• Lilly’s retatrutide shows significant weight loss in first Phase 3 diabetes trial.

  Eli Lilly announced positive topline results from the Phase 3 TRANSCEND-T2D-1 trial for its triple agonist, retatrutide, in adults with type 2 diabetes. At 40 weeks, retatrutide met its primary endpoint by lowering A1C by an average of up to 2.0%. For a key secondary endpoint, participants taking the 12 mg dose lost an average of 36.6 lbs (16.8%), with weight loss continuing through the end of the treatment period.

  Press | Trials: NCT06354660 | Mechanism: Triple GLP-1/GIP/glucagon agonist

• Structure reports positive Phase 2 data for oral GLP-1 aleniglipron.

  Structure Therapeutics announced that its once-daily oral GLP-1 receptor agonist, aleniglipron, achieved statistically significant placebo-adjusted mean weight loss of 16.3% (180 mg dose) and 16.0% (240 mg dose) at 44 weeks in the Phase 2 ACCESS II trial. In an open-label extension study, the 120 mg dose showed continued weight loss up to 16.2% at 56 weeks. The company plans an End-of-Phase 2 meeting with the FDA in Q2 2026 and anticipates initiating a Phase 3 program in the second half of 2026.

  Press | Trials: NCT06693843 | Mechanism: Oral small molecule GLP-1 receptor agonist

📰 PRESS

• Rhythm gets FDA approval for rare obesity, but Phase 3 trial fails in related indications.

  The FDA approved Rhythm Pharmaceuticals’ Imcivree (setmelanotide) for acquired hypothalamic obesity in patients aged four and older, supported by Phase 3 TRANSCEND trial data. The same week, Rhythm’s Phase 3 EMANATE basket trial failed to meet its primary endpoint across four other rare genetic obesity sub-populations.

  Press (approval) | Press (trial failure) | Mechanism: Melanocortin-4 receptor (MC4R) agonist

• Roche drops muscular atrophy indications for emugrobart, continues obesity development.

  Roche discontinued its anti-myostatin therapy emugrobart for spinal muscular atrophy and facioscapulohumeral muscular dystrophy due to underwhelming muscle growth data, but confirmed that development for obesity remains active with a mid-stage study ongoing and a potential regulatory filing in 2028.

  Press | Mechanism: Anti-myostatin antibody

• Lilly’s obesity discovery partner Fauna Bio sees weight loss potential in hibernating mammals.

  Fauna Bio, Lilly’s obesity research collaborator, is exploring novel targets derived from the biology of hibernating mammals, which naturally cycle through extreme fat accumulation and mobilization without metabolic harm.

  Press | Mechanism: Novel target (hibernation biology)

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Structure’s Aleniglipron Posts 16% Weight Loss in ACCESS II, Setting a New Bar for Oral GLP-1 Efficacy

Structure Therapeutics’ Phase 2 ACCESS II trial evaluated aleniglipron (formerly GSBR-1290), an investigational oral small molecule GLP-1 agonist, in 82 participants with obesity or overweight and related comorbidities. Unlike traditional peptide-based therapeutics, aleniglipron functions as an allosteric Gs-biased agonist that selectively activates the cAMP signaling pathway without inducing beta-arrestin recruitment, a distinct binding mode designed to optimize cellular responses. Topline results demonstrated up to 16.3% placebo-adjusted weight loss over 44 weeks with no evidence of an efficacy plateau, paving the way for an End-of-Phase 2 FDA meeting in Q2 2026 and pivotal Phase 3 trials in the second half of the year. Crucially, the trial showed that utilizing a lower starting dose of 2.5 mg significantly improved the drug’s tolerability profile, dropping adverse event-related discontinuation rates to between 2.0% and 3.4%. As the oral incretin pipeline grows increasingly crowded, aleniglipron’s ability to pair this optimized tolerability with efficacy data that compares favorably against benchmarks from Eli Lilly’s orforglipron and Novo Nordisk’s oral semaglutide positions the therapy as a highly differentiated contender in the race for a best-in-class once-daily obesity pill.

ClinicalTrials.gov: NCT06703021 (ACCESS II) | NCT06693843 (ACCESS) | Structure Therapeutics Press Release

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

From Appetite to Addiction: How GLP-1 Receptors in Brain Reward Circuits Are Opening a New Therapeutic Frontier (Example drugs: Semaglutide, Tirzepatide)

The therapeutic frontier for GLP-1 receptor agonists is rapidly expanding beyond metabolic disease into addiction, highlighted this week by the initiation of a new trial (NCT07227948) evaluating semaglutide for cocaine use disorder. Instead of merely regulating appetite, these agents act directly on GLP-1 receptors expressed in the ventral tegmental area and nucleus accumbens - key nodes of the mesolimbic reward pathway - to dampen the dopamine surges triggered by addictive substances without inducing anhedonia. This neurobiological decoupling of reward from consumption has sparked a serious clinical bet, with our database now tracking over two dozen trials across six different substance categories testing various incretins, including semaglutide, tirzepatide, mazdutide, and pemvidutide. Alcohol use disorder currently leads the development pack, anchored by a 438-patient VA-sponsored Phase 3 semaglutide study (NCT07218354) and promising Phase 2 data showing meaningful reductions in heavy drinking days. While epidemiological and preclinical signals are remarkably strong, the critical open question for developers is whether currently approved metabolic doses achieve sufficient central target engagement, or if next-generation, highly brain-penetrant formulations will be necessary to fully optimize efficacy in these neural circuits.

ClinicalTrials.gov: NCT07227948 | NCT07218354

🆕 NEWLY REGISTERED TRIALS (4 in last week)

• NNC0487-0111 Phase 3 trial investigating weight loss and pain reduction in adults with excess body weight and knee osteoarthritis (Novo Nordisk, n=400)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07481630 (AMAZE 5) | Mechanism: GLP-1 + amylin combination

• SURMOUNT-1 Phase 3 evaluating once-weekly tirzepatide for weight management in adults with obesity or overweight and related comorbidities (Hudson Biotech [China], n=2539)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07481747 (SURMOUNT-1) | Mechanism: Dual GLP-1/GIP agonist

• DECODE Phase 4 pilot studies comparing the hemodynamic effects of semaglutide versus tirzepatide (Cambridge University Hospitals NHS Foundation Trust, n=112)

  [New Indications]

  Trials: NCT07483801 (DECODE) | Mechanism: GLP-1 receptor agonist / Dual GLP-1/GIP agonist

• Brenipatide Phase 1 study investigating safety and tolerability in healthy participants with overweight or obesity (Eli Lilly, n=150)

  [Safety/Tolerability]

  Trials: NCT07476118 | Mechanism: Dual GLP-1/GIP agonist

This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Novo Nordisk to supply Ozempic, Wegovy through Hims & Hers.

  Novo Nordisk announced an agreement with telehealth company Hims & Hers to expand US patient access to its FDA-approved semaglutide medicines. Under the agreement, which takes effect in March 2026, Hims & Hers will offer Ozempic® and Wegovy® injectables, as well as Wegovy® tablets, at Novo Nordisk’s self-pay prices. As part of this shift, Hims & Hers will no longer advertise compounded GLP-1 offerings, and Novo Nordisk is dismissing its patent infringement lawsuit against the company.

  Press | Mechanism: GLP-1 receptor agonist

• Pfizer, Lilly advance GLP-1 obesity drugs in China.

  Chinese authorities have approved Sciwind Biosciences’ injectable GLP-1, ecnoglutide, for the treatment of obesity. In a 48-week trial, patients on the highest dose of ecnoglutide achieved an average weight loss of 15.4% from baseline. Pfizer will market the drug, which is also indicated for Type 2 diabetes, in China. Separately, Lilly committed $3B to expand manufacturing capacity in China through local CDMO partnerships, focused on scaling production of its oral GLP-1 candidate orforglipron.

  Press | Press | Mechanism: GLP-1 receptor agonist

📰 PRESS

• Regeneron’s olatorepatide shows positive Phase 3 results in obesity.

  Press | Mechanism: Dual GLP-1/GIP receptor agonist

• AbbVie reports positive Phase 1 data for amylin obesity candidate.

  Press | Mechanism: Amylin analog

• FDA issues warning letter to Novo Nordisk over Ozempic safety reporting.

  Press | Mechanism: GLP-1 receptor agonist

• Lilly warns of impurities in compounded tirzepatide.

  Press | Mechanism: Dual GLP-1/GIP receptor agonist

• Lilly invests $126M to expand Japan manufacturing for obesity drugs.

  Press | Mechanism: Dual GLP-1/GIP receptor agonist

• Novo Holdings reports 34% drop in assets for 2025.

  Press | Mechanism: GLP-1 receptor agonist

• Ascletis eyes quarterly GLP-1 dosing after Phase 2 obesity data.

  Press | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Lilly’s COMMIT Program: First Trials to Test Whether Treating IBD and Obesity Together Works Better Than Either Alone

Eli Lilly’s COMMIT program represents a significant strategic and conceptual shift in treating inflammatory bowel disease (IBD) by addressing the interconnected pathways of inflammation and metabolic disease. The program consists of two matched Phase 3b trials, COMMIT-UC and COMMIT-CD, which are the first to formally test the co-administration of an IL-23 inhibitor, mirikizumab (Omvoh), with a dual GLP-1/GIP receptor agonist, tirzepatide (Mounjaro/Zepbound). The biological rationale is compelling: obesity, a pro-inflammatory state, can exacerbate IBD and even blunt the efficacy of standard biologic therapies. Simultaneously targeting gut inflammation with mirikizumab and the underlying metabolic dysfunction with tirzepatide may lead to improved outcomes on both fronts. Enrolling a combined 640 patients with either ulcerative colitis or Crohn’s disease who are also overweight or obese across 24 countries, the global trials began recruiting in June 2025, with a rapid recent expansion of 93 new sites this week pushing toward an expected primary completion in spring 2028. As the sole owner of both drugs, Eli Lilly is uniquely positioned to investigate this synergy — signaling a potential new paradigm where IBD is managed holistically, treating the patient’s systemic inflammatory and metabolic profile rather than just their gut-specific symptoms.

ClinicalTrials.gov: NCT06937086 | NCT06937099

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

RNA Interference Enters the Obesity Race: How Silencing a Single Gene in Fat Cells Could Complement GLP-1 Drugs (Example drugs: ALN-2232, ARO-ALK7)

While existing obesity blockbusters like semaglutide and MariTide modulate appetite circuits in the brain, a new therapeutic modality is taking aim directly at the source: the fat cell itself. Alnylam Pharmaceuticals’ ALN-2232 is an RNA interference (RNAi) therapeutic that silences ACVR1C, the gene encoding the ALK7 receptor, which is highly expressed in adipose tissue. This receptor acts as a metabolic brake, suppressing the breakdown of fat (lipolysis) and promoting catecholamine resistance, a hallmark of obesity. By silencing this gene, ALN-2232 effectively removes these brakes, forcing fat cells to increase fatty acid oxidation and mobilize stored energy — a mechanism supported by human genetic data linking loss-of-function ACVR1C variants to healthier fat distribution and reduced diabetes risk. This direct-to-adipocyte, gene-silencing approach represents a fundamental departure from receptor-based drugs, offering a potentially complementary mechanism that could be paired with brain-acting agents like GLP-1s and dosed as infrequently as quarterly. Alnylam is entering a space where competitor Arrowhead Pharmaceuticals has already shown early clinical promise with a similar ALK7-targeting siRNA, ARO-ALK7. Because this tissue-specific approach works entirely independently of central satiety signaling, it is positioned as a logical, non-overlapping combination partner for existing GLP-1 therapies.

ClinicalTrials.gov: NCT07463846

🆕 NEWLY REGISTERED TRIALS (5 in last week)

• LY3437943 Phase 2 trial investigating the drug in participants with obesity or who are overweight (Hudson Biotech, n=300)

  [Weight Loss/Efficacy]

  Trials: NCT07467447 (GZBF) | Mechanism: Triple GLP-1/GIP/glucagon agonist

• ALN-2232 Phase 1 evaluating an investigational RNAi therapeutic targeting ACVR1C/ALK7 in adipose tissue for obesity (Alnylam Pharmaceuticals, n=156)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07463846 | Mechanism: RNAi (ACVR1C/ALK7 gene silencing)

• Tirzepatide Phase 2 trial for the treatment of cannabis use disorder (National Institute on Drug Abuse (NIDA), n=100)

  [New Indications]

  Trials: NCT07468552 | Mechanism: Dual GLP-1/GIP receptor agonist

• Semaglutide Nasal Spray Phase 1 study of a novel formulation for adults who are overweight or obese (Shanghai World Leader Pharmaceutical, n=60)

  [Weight Loss/Efficacy | Novel Delivery]

  Trials: NCT07465965 | Mechanism: GLP-1 receptor agonist

• KAI-9531 Phase 2 trial evaluating a once-weekly treatment for adults with obesity who do not have diabetes (Kailera, n=250)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07458269 | Mechanism: Dual GLP-1/GIP receptor agonist

This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.

Separately, two new publications highlight the weight loss maintenance challenge from different angles: a Lancet eClinicalMedicine study quantifying regain after stopping GLP-1s, and research showing that every-other-week dosing may sustain weight loss during maintenance. The latter is a different and maybe less costly approach compared to the monthly and depot formulations already in development.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Zealand Pharma / Roche report positive Phase 2 results for petrelintide.

  Zealand Pharma and partner Roche announced positive topline results from the Phase 2 ZUPREME-1 trial for their amylin analog, petrelintide, which achieved up to a 10.7% mean body weight reduction at week 42 compared to 1.7% with placebo (p<0.001). The drug demonstrated a tolerability profile comparable to placebo, with a 4.8% discontinuation rate due to adverse events versus 4.9% for placebo - and notably, no cases of vomiting and no GI-related treatment discontinuations at the maximally effective dose. The companies plan to advance petrelintide into Phase 3.

  Press | Trials: NCT06662539 (ZUPREME-1) | Mechanism: amylin analog

📰 PRESS

• BioSpace analysis: Petrelintide Phase 2 weight loss falls short of Lilly’s bar.

  Press | Mechanism: amylin analog

• Aardvark pauses Phase 3 ARD-101 trial over cardiac safety signals.

  Press | Mechanism: TAS2R pan-agonist

• Lilly launches direct-to-employer platform for Zepbound obesity coverage.

  Press | Mechanism: GLP-1/GIP dual agonist

• FDA sends 30 warning letters to telehealth firms over compounded GLP-1s.

  Press | Mechanism: GLP-1 receptor agonist

• FDA warns Novo Nordisk over misleading Ozempic ad.

  Press | Mechanism: GLP-1 receptor agonist

• Novo Nordisk invests €400M+ to expand Irish facility for oral Wegovy production.

  Press | Mechanism: GLP-1 receptor agonist

• Amgen, Roche build North Carolina hub for obesity drug production.

  Press

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Retatrutide’s Quiet Milestone Week: First T2D Trial Completes as 10,000-Patient Outcomes Study Closes Enrollment

While recent attention has centered on the CagriSema versus tirzepatide rivalry, Eli Lilly’s retatrutide is quietly achieving significant milestones that underscore the breadth of its development program. As a first-in-class unimolecular triple agonist targeting GLP-1, GIP, and glucagon receptors, retatrutide is designed to enhance appetite suppression, glycemic control, and energy expenditure. This past week highlighted the program’s momentum, with the completion of TRANSCEND-T2D-1 - a 537-patient Phase 3 trial in type 2 diabetes - suggesting topline data may be on the horizon. Simultaneously, the massive 10,000-patient TRIUMPH-Outcomes trial, assessing cardiovascular and kidney outcomes in adults with obesity, completed its rapid enrollment in under two years, signaling both operational excellence and high patient demand. These events are part of the broadest clinical program for any next-generation obesity drug, encompassing 13 Phase 3 trials and over 20,000 patients, and its strategic importance is further emphasized by TRANSCEND-T2D-2, an ongoing 1,250-patient head-to-head trial against semaglutide that will directly benchmark competitive efficacy.

ClinicalTrials.gov: NCT06354660 | NCT06383390

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Beyond Weight Loss: How SARMs and Anti-Activin Antibodies Are Redefining What ‘Quality’ Weight Loss Means (Example drugs: Enobosarm, Bimagrumab)

As the use of highly effective GLP-1 receptor agonists for weight loss expands, a critical issue has emerged: an estimated 25-40% of the weight lost is lean muscle mass, not just fat, raising concerns about sarcopenia and metabolic decline. This has spurred the development of a new class of “muscle-preserving” therapies that reframe the goal from the quantity of weight loss to the quality of body composition. Two distinct mechanisms are leading this charge. The first approach involves Selective Androgen Receptor Modulators (SARMs) like Veru’s enobosarm, which directly stimulate muscle protein synthesis through tissue-selective activation of the androgen receptor, an anabolic strategy to build muscle and enhance fat loss. In contrast, antibodies like Eli Lilly’s bimagrumab employ an anti-catabolic mechanism by blocking activin type II receptors, which prevents signaling from myostatin and activin that would otherwise cause muscle degradation. Clinical data has validated both strategies: a trial combining enobosarm with semaglutide showed a 71% relative reduction in lean mass loss, while the BELIEVE trial (recently published in Nature Medicine) showed that adding bimagrumab to semaglutide achieved 22.1% body weight loss at 72 weeks - with 92.8% of the weight lost being fat mass, compared to 71.8% for semaglutide alone. This focus on body composition marks a pivotal shift in the competitive obesity landscape, creating a new therapeutic category aimed at ensuring weight loss is healthy and sustainable.

ClinicalTrials.gov: NCT07446998 | NCT05616013

🆕 NEWLY REGISTERED TRIALS (6 in last week)

• Enobosarm Phase 2 evaluating the SARM as an add-on to GLP-1 agonists, aiming to improve physical function and quality of weight loss (Veru Inc., n=200)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07446998 (PLATEAU) | Mechanism: Selective androgen receptor modulator (SARM)

• NNC6989-0001 Phase 1 safety study in healthy people living with overweight or obesity (Novo Nordisk, n=unknown)

  [Safety/Tolerability]

  Trials: NCT07437079 | Mechanism: Undisclosed

• Maridebart cafraglutide (MariTide) Phase 2 evaluating efficacy and safety in adults with elevated liver fat and obesity or overweight (Amgen, n=unknown)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07441252 | Mechanism: GLP-1 agonist / GIP antagonist (antibody-peptide conjugate)

• Tirzepatide Phase 4 study in adult participants in India with either type 2 diabetes or obesity (Eli Lilly, n=unknown)

  [Weight Loss/Efficacy]

  Trials: NCT07438444 | Mechanism: GLP-1/GIP dual agonist

• AZD5004 Phase 1 drug-drug interaction study assessing its effect on mitiglinide and pioglitazone in healthy volunteers (AstraZeneca, n=32)

  [Safety/Tolerability]

  Trials: NCT07444424 | Mechanism: GLP-1 receptor agonist (oral)

• Trial combining a biologic with an anti-obesity medication for patients with psoriatic arthritis (NHS Greater Glasgow and Clyde, n=45)

  [New Indications]

  Trials: NCT07443956 (COMBAT-PsA) | Mechanism: GLP-1/GIP dual agonist (anti-obesity component)

This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.

Get in touch: Reply to this email, leave a comment on the post, or find me on X @GLP1observer. Explore the GLP-1 dashboard at glp1.bio1up.com.