🔥 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 readout for any GLP-1/glucagon dual agonist (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: 16.6% Sets a Phase 3 Floor for GLP-1/Glucagon Dual Agonists

Boehringer Ingelheim and Zealand Pharma have unveiled the first Phase 3 results for a GLP-1/glucagon dual receptor agonist, setting a new benchmark in the evolving obesity treatment landscape. 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

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.

Separately, GLP-1 drugs and pancreatitis risk came up in the news this week. The evidence is murky. Two good reads: a Nature news feature on new regulatory warnings, and a JCI review that puts the evidence in perspective.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• CagriSema fails to match tirzepatide in Phase 3 obesity trial.

  In the open-label, head-to-head REDEFINE 4 trial, CagriSema (cagrilintide 2.4 mg/semaglutide 2.4 mg) did not meet its primary endpoint of demonstrating non-inferiority on weight loss compared to tirzepatide 15 mg at 84 weeks. People treated with CagriSema achieved a 23.0% weight loss, compared to 25.5% for those treated with tirzepatide. Novo Nordisk reported that CagriSema appeared to have a safe and well-tolerated profile, consistent with the GLP-1 receptor agonist class.

  Press | Trials: NCT06131437 | Mechanism: GLP-1 receptor agonist + amylin receptor agonist

• Orforglipron outperforms oral semaglutide in Phase 3 diabetes trial.

  In the Phase 3 ACHIEVE-3 trial for type 2 diabetes, Eli Lilly’s orforglipron 36 mg demonstrated superiority over oral semaglutide 14 mg, lowering A1C by 2.2% versus 1.4% at 52 weeks. For a key secondary endpoint, orforglipron led to a weight loss of 19.7 lbs (9.2%) compared to 11.0 lbs (5.3%) for oral semaglutide. Lilly has submitted orforglipron to regulators in over 40 countries and anticipates potential U.S. action for obesity in Q2 2026.

  Press | Lancet | Trials: NCT06045221 | Mechanism: oral GLP-1

📰 PRESS RELEASES

• Structure Therapeutics plans to advance oral GLP-1 aleniglipron into Phase 3 in H2 2026.

  Press | Mechanism: GLP-1 receptor agonist

• Novo Nordisk partners with Vivtex in $2.1B deal for oral obesity and diabetes drugs.

  Press | Mechanism: oral formulation of peptides

• Pfizer strikes $495M deal to market Sciwind’s China-approved GLP-1 obesity drug in China.

  Press | Mechanism: GLP-1 receptor agonist

• Novo Nordisk cuts U.S. list prices for Wegovy, Ozempic, and Rybelsus.

  Press | Mechanism: GLP-1s

• UBT251 shows 19.7% weight loss in Phase 2 obesity trial.

  Press | Mechanism: triple agonist of the receptors for GLP-1, GIP and glucagon

• Zepbound now available in multi-dose KwikPen.

  Press | Mechanism: Dual GLP-1/GIP agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

The First Semaglutide Implant Enters the Clinic: SLIM-1 Tests a Radical New Delivery Approach

The cleverly named SLIM-1 trial (NCT07430059) is a pioneering Phase 1 study by Vivani Medical evaluating the first-ever sustained-release semaglutide subcutaneous implant against a comparator arm of standard weekly Wegovy injections. Slated to begin in April 2026, the trial will enroll 20 participants with obesity or overweight to assess the novel device’s safety, tolerability, and pharmacokinetics. The device uses Vivani’s proprietary NanoPortal™ technology — a miniaturized titanium nanotube reservoir with no moving parts — designed to release semaglutide steadily for up to six months or longer from a single subdermal insertion. By avoiding the pharmacokinetic peak-and-trough cycling typical of frequent dosing, an implantable approach could theoretically minimize gastrointestinal side effects while fundamentally solving the challenge of long-term patient adherence. Strategically, SLIM-1 represents a fascinating leap in the broader metabolic drug delivery race, pushing the field’s evolution beyond standard weekly injectables, investigational monthly shots like MariTide, and experimental daily pills like orforglipron, toward the frontier of ultra-long-acting implantable therapies.

ClinicalTrials.gov: NCT07430059

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

The GLP-1/GIP Dual Agonist Race: How 15 Challengers Are Trying to Beat Tirzepatide at Its Own Game (Example drugs: CT-388, VK2735, KAI-9531, Olatorepatide)

Dual GLP-1/GIP receptor agonism, the mechanism behind tirzepatide (Mounjaro/Zepbound), represents a powerful therapeutic strategy for metabolic disease by simultaneously activating two key incretin hormone pathways. This co-activation produces synergistic effects, amplifying glucose-dependent insulin secretion, enhancing appetite suppression in the brain, and improving fat metabolism beyond what targeting either the GLP-1 or GIP receptor alone can achieve. As the most crowded class in obesity drug development, this space has attracted a wave of competitors from the US, Europe, and China, all vying to challenge tirzepatide’s lead. Challengers are differentiating through varied strategies: Roche’s CT-388, which reported a 22.5% placebo-adjusted weight loss at 48 weeks, employs biased agonism with minimal ß-arrestin recruitment, potentially improving tolerability. Viking Therapeutics is advancing both injectable and oral versions of VK2735 into Phase 3 trials, while Kailera has launched three Phase 3 trials for KAI-9531 (ribupatide), enrolling 4,700 patients. Meanwhile, Regeneron, having licensed olatorepatide from China’s Hansoh Pharma, is exploring a cardiovascular combination approach by pairing it with the PCSK9 inhibitor Praluent. The critical question remains whether any challenger can leverage these differentiators—be it superior efficacy, better tolerability, greater convenience, or lower price—to capture a meaningful share of the market from the well-entrenched tirzepatide.

🆕 NEWLY REGISTERED TRIALS (8 in last week)

• XW003 Phase 3 trial evaluating its effect in obese participants with obstructive sleep apnea (OSA) receiving positive airway pressure therapy (Hangzhou Sciwind Biosciences, n=140).

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07434050 | Mechanism: GLP-1 receptor agonist

• AMG 133 Phase 1 assessing the effect of kidney impairment on its pharmacokinetics (Amgen, n=44)

  [Safety/Tolerability]

  Trials: NCT07429045 | Mechanism: GLP-1 agonist / GIP antagonist (antibody-peptide conjugate)

• AMG 133 Phase 1 study investigating the drug’s effect on gastric emptying in healthy volunteers (Amgen, n=57)

  [Safety/Tolerability]

  Trials: NCT07429032 | Mechanism: GLP-1 agonist / GIP antagonist (antibody-peptide conjugate)

• Olatorepatide Phase 2 trial for adults living with overweight or obesity in the US (Regeneron Pharmaceuticals, n=120)

  [Weight Loss/Efficacy]

  Trials: NCT07431086 | Mechanism: Dual GLP-1/GIP agonist

• GLP-1 RA therapy Phase 3 trial investigating its impact on osteosarcopenia in older women with diabetes (Emory University, n=20)

  [New Indications]

  Trials: NCT07428746 (GLOW) | Mechanism: GLP-1 receptor agonist

• GLP-1 RA for Stage 1 Type 1 Diabetes Phase II trial investigating if a GLP-1 receptor agonist can delay or prevent the onset of clinical T1D (Children’s Hospital Medical Center, Cincinnati, n=15)

  [New Indications]

  Trials: NCT07430332 | Mechanism: GLP-1 receptor agonist

• Semaglutide implant Phase 1 evaluating the safety, tolerability, and pharmacokinetics of a new subcutaneous delivery system (Vivani Medical, n=20)

  [Safety/Tolerability | Novel Delivery]

  Trials: NCT07430059 (SLIM-1) | Mechanism: GLP-1 receptor agonist

• AMG 133 Phase 1 study evaluating its pharmacokinetics and safety in participants with varying degrees of hepatic impairment (Amgen, n=36)

  [Safety/Tolerability]

  Trials: NCT07428525 | Mechanism: GLP-1 agonist / GIP antagonist (antibody-peptide conjugate)

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

• European Commission approves higher, more effective dose of Wegovy.

  On February 17, 2026, Novo Nordisk announced that the European Commission approved a new 7.2 mg once-weekly maintenance dose of Wegovy® (semaglutide injection) for adults with obesity. The approval was based on the STEP UP trial, which showed adults with obesity taking the 7.2 mg dose lost an average of 21.1% of their body weight after 68 weeks, compared to a 2.5% loss for those on placebo. In the trial, 95% of participants on the 7.2 mg dose achieved weight loss of 5% or more, versus 29% for placebo.

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

• Zepbound/Taltz combo improves skin clearance and weight loss in psoriasis.

  Eli Lilly announced that its Phase 3b TOGETHER-PsO trial evaluating Zepbound (tirzepatide) with Taltz (ixekizumab) in adults with psoriasis and obesity met its primary endpoint at 36 weeks. In the study, 27.1% of patients receiving the combination therapy achieved complete skin clearance (PASI 100) and at least 10% weight loss, compared to 5.8% of patients on Taltz alone (p<0.001). A key secondary endpoint showed that 40.6% of patients on the combination achieved PASI 100 versus 29.0% for those taking Taltz alone (p<0.05).

  Press | Trials: NCT06588283 | Mechanism: dual GIP and GLP-1 receptor agonist

• Zealand Pharma outlines 2026 milestones for petrelintide and survodutide.

  Zealand Pharma expects to report 42-week topline data from the Phase 2 ZUPREME-1 trial of its amylin analog, petrelintide, in the first quarter of 2026. The company and its partner Roche plan to advance petrelintide into a Phase 3 program in the second half of 2026. Additionally, topline data from the Phase 3 SYNCHRONIZE™-1 trial of survodutide, partnered with Boehringer Ingelheim, are expected in the first half of 2026, with results from all key trials in the program anticipated throughout the year.

  Press | Trials: NCT06926842 (petrelintide) | Mechanism: amylin analog

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

The First ‘Add-On to Incretin’ Mega-Trial Goes Live: ENLIGHTEN-6 Targets Persistent Obesity

Eli Lilly’s ENLIGHTEN-6 trial (NCT07392190) marks a potential paradigm shift in metabolic medicine by formally defining “persistent obesity” not as a failure of monotherapy, but as a distinct clinical indication suitable for combination treatment. This Phase 3 study of 900 participants evaluates eloralintide, a selective amylin receptor agonist that promotes satiety through neural pathways complementary to—but distinct from—GLP-1 mechanisms, specifically in patients who have plateaued on standard weekly incretins. Operational execution has been notably aggressive, with 178 trial sites activated within a single week of the February 2026 launch, signaling high confidence that adding an amylin analogue can unlock further weight loss where incretins alone plateau. Strategically, this approach mirrors oncology’s evolution toward layered regimens, moving beyond the “one-drug-fits-all” model to address the significant subset of patients who remain clinically obese despite current best-in-class therapies. If successful by its 2028 completion, ENLIGHTEN-6 could establish amylin agonism as the standard “add-on” to overcome therapeutic ceilings.

ClinicalTrials.gov: NCT07392190

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Beyond Monotherapy: Why ‘Persistent Obesity’ Is Driving the Next Wave of Combination Trials (Example drug: Eloralintide)

The remarkable success of incretin monotherapies like GLP-1 agonists is tempered by the reality of ‘persistent obesity,’ where a significant subset of patients either fail to achieve meaningful weight loss or, more commonly, hit a weight-loss plateau. This plateau isn’t a failure of willpower but a predictable biological defense; as fat mass decreases, the body fights back by lowering levels of the satiety hormone leptin, increasing the hunger hormone ghrelin, and reducing metabolic rate through adaptive thermogenesis. To break through this physiological stalemate, the field is shifting toward a combination therapy paradigm, exemplified by Eli Lilly’s new ENLIGHTEN-6 trial for eloralintide. This study specifically recruits patients with persistent obesity who are already on a stable incretin regimen, aiming to add a drug with a distinct and complementary mechanism.

Eloralintide is a selective agonist for the amylin receptor, engaging a different set of neural pathways for satiety than GLP-1 agonists. While GLP-1 agonists primarily act on the hypothalamus, amylin signaling is concentrated in the area postrema of the brainstem, providing a separate, powerful brake on food intake. By adding an amylin-based therapy on top of an incretin, the strategy is to counteract the body’s counter-regulatory measures from multiple angles, much like combination chemotherapy targets various pathways to overcome cancer resistance. This add-on strategy — keeping patients on their existing incretin while layering in a complementary mechanism — positions eloralintide alongside competitors like Novo Nordisk’s CagriSema and Amgen’s MariTide in a broader race to move beyond monotherapy and define the next standard of care for patients who plateau.

🆕 NEWLY REGISTERED TRIALS (6 in last week)

• Tirzepatide (Spartina) Phase 4 trial evaluating its use for obesity in kidney transplant recipients (Shahid Beheshti University of Medical Sciences, n=30)

  [New Indications]

  Trials: NCT07423247 | Mechanism: Dual GLP-1/GIP agonist

• HDM1005 Phase 3 trial for type 2 diabetes inadequately controlled on metformin, with or without an SGLT2 inhibitor (Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd., n=912)

  [Weight Loss/Efficacy]

  Trials: NCT07417306 | Mechanism: Dual GLP-1/GIP agonist

• ABBV-295 Phase 1 assessing its effect on oral contraceptives in healthy women with overweight or obesity (AbbVie, n=20)

  [Safety/Tolerability]

  Trials: NCT07414784 | Mechanism: Dual amylin/calcitonin receptor agonist

• Survodutide Phase 1 comparing two delivery methods, a pre-filled syringe vs. a pen injector, in healthy adults or those with overweight/obesity (Boehringer Ingelheim, n=56)

  [Weight Loss/Efficacy]

  Trials: NCT07413913 | Mechanism: Dual GLP-1/glucagon agonist

• GIP + Amylin combination Phase 1 trial investigating if the combination reduces gastrointestinal side effects in people with overweight or obesity (Novo Nordisk, n=100).

  [Weight Loss/Efficacy]

  Trials: NCT07411560 | Mechanism: GIP agonist + amylin analog (cagrilintide)

• NNC0662-0419 Phase 2 dose-finding study evaluating blood sugar reduction in people with type 2 diabetes (Novo Nordisk, n=270)

  [Weight Loss/Efficacy]

  Trials: NCT07415954 | Mechanism: Triple GLP-1/GIP/glucagon 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

• Viking to Advance Oral Obesity Drug VK2735 into Phase 3

  Viking Therapeutics plans to advance its oral GLP-1/GIP agonist, VK2735, into Phase 3 development for obesity in 3Q26, following feedback from the FDA. The Phase 3 VANQUISH program for subcutaneous VK2735 is ongoing, with the VANQUISH-1 study having completed enrollment of over 4,500 patients and the VANQUISH-2 study expected to complete enrollment in 1Q26. Additionally, a fully enrolled maintenance dosing study for VK2735 is expected to report results in 3Q26.

  Press | Trials: NCT07104383 | NCT07104500 | NCT06068946 | Mechanism: dual agonist of the GLP-1 and GIP receptors

• Novo Nordisk sues Hims & Hers over knock-off Wegovy and Ozempic.

  Novo Nordisk announced it has filed a lawsuit against telehealth company Hims & Hers for infringing US Patent 8,129,343 with its compounded semaglutide products, which Novo Nordisk calls unapproved knock-off versions of Wegovy® and Ozempic®. The company is asking the court to permanently ban Hims from selling these products and is seeking to recover damages. Novo Nordisk stated its testing found impurities of up to 86% in compounded injectable semaglutide drugs and as high as 75% in compounded oral versions.

  Press | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

From Acquisition to Phase 3 in Record Time: Pfizer’s PF-08653944 Enters Late-Stage Development

Following a rapid strategic pivot after its late-2025 acquisition of Metsera — and the earlier discontinuation of its own oral GLP-1 candidate, danuglipron, due to liver safety signals — Pfizer has aggressively advanced PF-08653944 (formerly MET097) into pivotal development by simultaneously registering a Phase 3 efficacy trial in patients with Type 2 diabetes and a Phase 1 pharmacokinetic study. The drug is distinct as a “fully-biased” GLP-1 receptor agonist, engineered to preferentially activate cAMP signaling while limiting beta-arrestin recruitment, a mechanism hypothesized to maintain weight-loss potency while minimizing gastrointestinal side effects. This biochemical profile also supports an ultra-long-acting duration, allowing Pfizer to target a competitive monthly dosing schedule that differentiates the therapy from current weekly standards. The immediate transition from a Phase 2b readout to Phase 3 registration highlights a parallel processing strategy, where formulation optimization and efficacy validation occur concurrently to accelerate the drug’s timeline in a crowded obesity market.

ClinicalTrials.gov: NCT07400653 | NCT07400679

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Antibody-Peptide Conjugates: How MariTide Achieves Monthly Dosing and a Contrarian GIP Bet (Example drug: Maridebart cafraglutide / AMG 133)

Amgen’s maridebart cafraglutide (MariTide) showcases the power of the antibody-peptide conjugate (APC) platform to create a differentiated therapeutic for obesity. This modality fuses a GLP-1 receptor agonist peptide to a monoclonal antibody, where the antibody serves two critical functions: it dramatically extends the drug’s half-life to enable monthly or less frequent dosing, and it is engineered to act as a GIP receptor antagonist. This dual mechanism of GLP-1 agonism for appetite suppression and GIP antagonism to potentially reduce fat storage positions MariTide uniquely in a competitive landscape dominated by dual GLP-1/GIP agonists like tirzepatide. The robust Phase 2 weight loss data for MariTide suggests that GIP antagonism is a clinically viable strategy, fueling a key scientific debate over the optimal way to modulate the GIP pathway in metabolic disease. With Amgen adding over 80 new trial sites to the MARITIME-CV and MARITIME-HF Phase 3 programs this week alone, the aggressive clinical expansion signals high confidence in this unique “agonist-antagonist” mechanism and its potential to offer a major advantage in patient convenience and long-term adherence.

ClinicalTrials.gov: NCT07037433 | NCT07037459

🆕 NEWLY REGISTERED TRIALS (6 in last week)

• Semaglutide Phase 4 trial evaluating its effect on clinical outcomes and metabolic inflammation in patients with psoriasis (Hospital Universitario Dr. Jose E. Gonzalez, n=62)

  [New Indications]

  Trials: NCT07401992 (SEMAPSO) | Mechanism: GLP-1 receptor agonist

• PF-08653944 Phase 1 pharmacokinetics study in adults with overweight or obesity (Pfizer, n=54)

  [Weight Loss/Efficacy]

  Trials: NCT07400679 | Mechanism: GLP-1 receptor agonist

• Aleniglipron Phase 2 evaluating the oral GLP-1 receptor agonist in adults with Type 2 Diabetes (Structure Therapeutics, n=50)

  [Weight Loss/Efficacy]

  Trials: NCT07400588 (GSBR-1290) | Mechanism: GLP-1 receptor agonist

• PF-08653944 Phase 3 investigating the study drug in adults with obesity or overweight and Type 2 Diabetes (Pfizer, n=999)

  [Weight Loss/Efficacy]

  Trials: NCT07400653 | Mechanism: GLP-1 receptor agonist

• AMAZE 8 Phase 3 trial comparing NNC0487-0111 to semaglutide for weight loss in adults with excess weight and Type 2 Diabetes (Novo Nordisk A/S, n=1000)

  [Weight Loss/Efficacy]

  Trials: NCT07400107 (AMAZE 8) | Mechanism: GLP-1 + amylin combination

• UBT251 Phase 2 dose-ranging study for adults living with overweight or obesity (Novo Nordisk A/S, n=333)

  [Weight Loss/Efficacy]

  Trials: NCT07395687 | Mechanism: Triple GLP-1/GIP/glucagon 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.

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🔥 THIS WEEK’S KEY DEVELOPMENTS

• CagriSema shows superior blood sugar, weight loss in Phase 3 trial.

  In the Phase 3 REIMAGINE 2 trial, Novo Nordisk’s once-weekly CagriSema demonstrated superior HbA1c reduction and weight loss versus semaglutide in adults with type 2 diabetes. At 68 weeks, CagriSema 2.4 mg/2.4 mg achieved a 1.91%-point HbA1c reduction and 14.2% weight loss, compared to a 1.76%-point HbA1c reduction and 10.2% weight loss for semaglutide 2.4 mg. The company reported that CagriSema appeared to have a safe and well-tolerated profile consistent with incretin and amylin-based therapies.

  Press | Trial: NCT06065540 (REIMAGINE 2) | Mechanism: GLP-1 receptor agonist + amylin receptor agonist

• Novo Nordisk threatens legal action over Hims & Hers’ compounded semaglutide.

  On February 5, 2026, Novo Nordisk issued a statement regarding Hims & Hers’ announcement to market a compounded semaglutide pill. Novo Nordisk described the Hims & Hers product as an “unlawfully mass-marketed, unapproved, inauthentic, and untested knockoff.” The company stated it is the sole manufacturer of the FDA-approved Wegovy® pill, which is available in all doses and in full supply nationwide in the US.

  Press | Mechanism: GLP-1

• Lilly reports strong Q4 driven by Mounjaro and Zepbound.

  Eli Lilly reported Q4 2025 revenue increased 43% to $19.3 billion, driven by Mounjaro sales of $7.4 billion and Zepbound sales of $4.2 billion. The company announced positive Phase 3 results for retatrutide in obesity and knee osteoarthritis, which delivered weight loss of up to an average of 71.2 lbs. Lilly also submitted its oral GLP-1, orforglipron, for obesity approval to regulatory authorities in the U.S. and Japan.

  Press | Mechanism: GLP-1 receptor agonists (injectable and oral)

📰 PRESS RELEASES

• Pfizer’s danuglipron (PF-07976016), acquired via Metsera (formerly MET097), shows robust Phase 2b weight loss.

  Press | Press | Mechanism: GLP-1 receptor agonist

• Amgen Q4 results highlight MariTide Phase 2 data: sustained weight loss and T2D benefits.

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

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Two New Trials, One Hypothesis: Can GLP-1 Drugs Improve Atrial Fibrillation Ablation Outcomes?

The recent, simultaneous registration of two independent academic trials, SPICE-AF in Germany and TREAT-AF in Taiwan, signals a strategic convergence in cardiology research, as both aim to determine if incretin-based drugs can improve outcomes for atrial fibrillation (AF) patients undergoing catheter ablation. The mechanistic rationale is compelling: by targeting obesity, a key driver of AF, GLP-1 agonists like semaglutide (SPICE-AF) and the dual GLP-1/GIP agonist tirzepatide (TREAT-AF) may reduce the pro-inflammatory epicardial fat that promotes the arrhythmia. These studies join a growing landscape of approximately 10 trials investigating the role of GLP-1s in AF, reflecting rising confidence in this therapeutic hypothesis. This parallel investigation by separate research groups underscores a pivotal moment for incretins, potentially expanding their use beyond metabolic disease to improving the success of cardiovascular procedures.

ClinicalTrials.gov: NCT07389941 | NCT07382024

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

From Diabetes Drug to Sleep Medicine: How GLP-1 Agonists Treat Obstructive Sleep Apnea (Example drugs: Tirzepatide, Ecnoglutide (XW003))

GLP-1 receptor agonists treat obstructive sleep apnea (OSA) primarily by inducing significant weight loss, which directly addresses the anatomical causes of the condition. Obesity, a major risk factor for OSA, leads to fat deposition in the tongue and pharyngeal walls, narrowing the upper airway and increasing its collapsibility during sleep. By promoting weight reduction of 15-25%, these drugs reduce the fat that physically constricts the airway and also lessen abdominal fat, which improves lung volumes and the “tracheal tug” that helps keep the airway open. Eli Lilly’s tirzepatide validated this approach in the SURMOUNT-OSA trial, demonstrating a nearly 50% reduction in apnea-hypopnea events and securing FDA approval, a landmark for a condition historically managed by devices. This success has transformed OSA into a major therapeutic battleground, attracting numerous competitors and fueling at least 12 active late-stage trials for similar metabolic drugs, including dual agonists, antibody-drug conjugates, and even amylin agonists. The rapid evolution from a novel concept to a crowded, approved indication underscores the massive unmet need for effective, non-device-based OSA treatments.

ClinicalTrials.gov: NCT07387094

🆕 NEWLY REGISTERED TRIALS (6 in last week)

• Eloralintide Phase 3 study investigating the drug as an add-on therapy for persistent obesity in patients already being treated with a weekly incretin (Eli Lilly and Company, n=900).

  [Weight Loss/Efficacy]

  Trials: NCT07392190 (ENLIGHTEN-6) | Mechanism: Amylin receptor agonist

• Phase 1 pharmacokinetic study assessing the impact of renal insufficiency on an investigational drug’s exposure (Sun Pharmaceutical, n=40)

  [Safety/Tolerability]

  Trials: NCT07385547 | Mechanism: GLP-1 receptor agonist

• SPICE-AF Phase IV investigating if semaglutide prior to catheter ablation improves outcomes in patients with atrial fibrillation (University of Luebeck, n=240)

  [New Indications]

  Trials: NCT07389941 (SPICE-AF) | Mechanism: GLP-1 receptor agonist

• Oral semaglutide trial investigating its effect on chronic kidney disease in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) (Institute of Liver and Biliary Sciences, India, n=90).

  [Oral Formulations | New Indications]

  Trials: NCT07391267 | Mechanism: GLP-1 receptor agonist

• XW003 Phase 3 trial in obese participants with obstructive sleep apnea who are not receiving positive airway pressure therapy (Hangzhou Sciwind Biosciences, n=140)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07387094 | Mechanism: GLP-1 receptor agonist

• Tirzepatide to Reduce rEcurrence And Burden After Ablation of Atrial Fibrillation (TREAT-AF) trial investigating if tirzepatide can prevent AFib recurrence post-ablation (National Taiwan University Hospital, n=200)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07382024 (TREAT-AF) | 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.

For the Trial Spotlight, I wanted to look at the bigger picture: why are companies now running 10,000+ patient cardiovascular outcomes trials for obesity drugs? Amgen’s MariTide CVOT and Lilly’s TRIUMPH-Outcomes for retatrutide are both recruiting. These are massive, expensive bets that have become table stakes after semaglutide’s SELECT trial proved these drugs can reduce heart attacks and strokes. For the Mechanism Explained, I chose a different angle. With Hanmi registering a new Phase 3 for efpeglenatide this week, I look at how next-gen GLP-1 mono-agonists are differentiating from semaglutide through molecular engineering — exendin backbones, biased signaling, and oral delivery.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Roche/Genentech reports positive Phase II results for obesity drug CT-388, advancing to Phase III.

  Roche/Genentech announced positive topline Phase II results for its dual GLP-1/GIP receptor agonist, CT-388, in people with obesity. The once-weekly injection achieved a placebo-adjusted weight loss of 22.5% at 48 weeks at the highest dose (24 mg), without reaching a weight loss plateau. At that dose, 47.8% of participants achieved ≥20% weight loss, 26.1% achieved ≥30%, and 54% achieved resolution of obesity (BMI <30 kg/m²), with a 5.9% discontinuation rate due to adverse events. The company expects to start the Phase III program (Enith1 and Enith2) this quarter.

  Press (Roche) | Press (Genentech) | Trials: NCT06525935 | Mechanism: dual GLP-1/GIP receptor agonist

• Regeneron advances obesity drug olatorepatide to Phase 3.

  Regeneron plans to initiate a Phase 3 program in 2026 for its investigational GLP-1/GIP receptor agonist, olatorepatide, in obesity for patients with and without Type 2 diabetes. The company also expects to begin a clinical program for olatorepatide in combination with Praluent in 2026. Additionally, Regeneron will report more data from its Phase 2 study of semaglutide in combination with trevogrumab in obesity during 2026.

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

📰 PRESS RELEASES

• Altimmune raises $75M for pemvidutide Phase 3 MASH trial.

  Press | Mechanism: balanced glucagon/GLP-1 dual agonist

🆕 NEWLY REGISTERED TRIALS (7 in last week)

• HM11260C Phase 3 trial evaluating its use for Type 2 Diabetes in patients inadequately controlled with metformin and dapagliflozin (Hanmi Pharmaceutical, n=118)

  Trials: NCT07379333 | Mechanism: GLP-1 receptor agonist

• Investigator-led study using a GLP-1 receptor antagonist (exendin 9-39) to test how endogenous GLP-1 affects glucagon secretion in adults with Type 1 Diabetes (Asger Lund, MD, n=12)

  [New Indications]

  Trials: NCT07373236 (EX-HYPO) | Mechanism: GLP-1 receptor antagonist (research tool)

• Tirzepatide Phase N/A investigating its effect on muscle mass and function during weight loss in adults with obesity (University Medical Centre Ljubljana, n=30)

  Trials: NCT07373834 (TIRMO) | Mechanism: Dual GLP-1/GIP agonist

• Liraglutide Phase 4 trial studying the optimal timing of therapy for patients with obesity following metabolic surgery (The Affiliated Nanjing Drum Tower Hospital..., n=100)

  [Weight Loss/Efficacy]

  Trials: NCT07374445 | Mechanism: GLP-1 receptor agonist

• Triple Hypoglycemic Regimens Phase 1 evaluating triple therapy (semaglutide + sitagliptin + metformin) as an initial treatment for newly diagnosed type 2 diabetes (Second Affiliated Hospital of Guangzhou Medical University, n=240)

  Trials: NCT07374328 (TRED) | Mechanism: GLP-1 receptor agonist + DPP-4 inhibitor

• Eloralintide Phase 3 trial evaluating the drug in adults with obstructive sleep apnea and obesity or overweight (Eli Lilly, n=800)

  [New Indications]

  Trials: NCT07369011 (ENLIGHTEN-3) | Mechanism: Amylin receptor agonist

• GLP-1 Receptor Agonist Phase 2 trial investigating diabetes management in children and adolescents with transfusion-dependent thalassemia (Ain Shams University, n=80).

  [New Indications]

  Trials: NCT07370922 | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Cardiovascular Outcomes Trials: Why 10,000-Patient Mega-Trials Are Now Table Stakes for Anti-Obesity Drugs

Following the precedent set by semaglutide’s SELECT trial, cardiovascular outcomes trials (CVOTs) have become essential milestones to validate anti-obesity drugs as systemic health interventions rather than cosmetic treatments. To meet this new standard, developers must run massive, multi-year studies proving their agents reduce major adverse cardiovascular events (MACE) in addition to lowering weight. Amgen’s 12,800-patient trial for MariTide explores a novel mechanistic bet, testing whether GIP antagonism combined with GLP-1 can deliver cardiovascular protection. Conversely, Eli Lilly’s TRIUMPH-Outcomes trial evaluates retatrutide, a triple-agonist, to see if stimulating GLP-1, GIP, and glucagon receptors simultaneously improves both heart and kidney outcomes. These high-stakes trials are designed not just for regulatory approval, but to secure the payer coverage necessary for broad patient access.

ClinicalTrials.gov: NCT07037433 | NCT06383390

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

GLP-1 Mono-Agonist Differentiation (Example drugs: Efpeglenatide, MET097, Ecnoglutide)

While first-generation GLP-1 agonists like semaglutide are analogs of the human hormone, next-generation mono-agonists are differentiating themselves through novel molecular engineering to capture a slice of the massive metabolic disease market. Some, like Hanmi’s efpeglenatide, are built on an exendin-4 backbone derived from Gila monster venom, which alters receptor binding kinetics and signaling. Others, such as Metsera/Pfizer’s MET097 and Sciwind’s ecnoglutide, are designed as “biased agonists” that preferentially activate the desired cAMP signaling pathway over the β-arrestin pathway, a strategy that may reduce the gastrointestinal side effects common to the class. This pursuit of differentiation matters because it creates therapeutics with potentially improved tolerability, varied efficacy profiles for different patient populations, or more convenient oral delivery routes as seen with ecnoglutide. Hanmi’s recent initiation of a new Phase 3 trial for efpeglenatide, which has already demonstrated a 9.75% weight loss in obesity trials, underscores that even without multi-agonist activity, there is a significant opportunity for improved and varied GLP-1 mono-agonists.

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.

No major company press releases this week, so instead a few items that caught my eye. A NYT piece cites a financial services analysis estimating the four largest U.S. carriers could save up to $580 million per year on fuel as passengers lose weight on GLP-1s. A study in the Journal of Marketing Research found that households with a GLP-1 user reduce grocery spending by 5.3% within six months, with an 8% decline at fast-food chains and coffee shops. Separately, Daniel Drucker published a review in Nature Medicine that’s worth reading if you want a comprehensive look at where the field stands scientifically.

For the Trial Spotlight, I picked Lilly’s eloralintide ENLIGHTEN-4 study — an amylin agonist targeting osteoarthritis knee pain in people with obesity, which represents the “metabolic pain therapy” concept functioning outside the GLP-1/GIP pathways. The Mechanism Explained covers retatrutide’s triple agonist approach and why Lilly is now running dose optimization studies.

🆕 NEWLY REGISTERED TRIALS (8 in last week)

• IMPACT-MACS comparing adrenalectomy vs. semaglutide for metabolic outcomes in Mild Autonomous Cortisol Secretion (University of Texas Southwestern Medical Center, n=75)

  [New Indications]

  Trials: NCT07361874 (IMPACT-MACS) | Mechanism: GLP-1 receptor agonist

• Feasibility study of tirzepatide-induced weight loss vs. standard care for treating obesity-related hypertension in young adults (Cambridge University Hospitals, n=60)

  [Weight Loss/Efficacy]

  Trials: NCT07364175 (SOLUTION-Pilot) | Mechanism: Dual GLP-1/GIP agonist

• Retatrutide Phase 3 evaluating the drug in adults with obesity or overweight, but without type 2 diabetes (Eli Lilly, n=600)

  [Weight Loss/Efficacy]

  Trials: NCT07357415 (TRIUMPH-9) | Mechanism: Triple GLP-1/GIP/glucagon agonist

• CagriSema Phase 2 comparing two different injectable formulations in people with type 2 diabetes (Novo Nordisk, n=400)

  [New Indications]

  Trials: NCT07357740 | Mechanism: GLP-1 / Amylin combination

• CagriSema Phase III comparing different injectable versions against placebo in people with excess body weight (Novo Nordisk, n=1400)

  [Weight Loss/Efficacy]

  Trials: NCT07357766 | Mechanism: GLP-1 / Amylin combination

• Eloralintide Phase 3 trial investigating treatment for osteoarthritis knee pain in participants with obesity or overweight (Eli Lilly, n=900)

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

  Trials: NCT07353931 (ENLIGHTEN-4) | Mechanism: Amylin receptor agonist

• Tirzepatide Phase 4 study investigating cardiovascular and metabolic effects in obese adults with congenital heart disease (University Medical Centre Ljubljana, n=30)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07354880 (TEACH) | Mechanism: Dual GLP-1/GIP agonist

• Tirzepatide plus progestin IUD Phase II trial evaluating a weight-loss intervention to treat endometrial hyperplasia and early-stage endometrial cancer (NCI, n=55)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07349641 | Mechanism: Dual GLP-1/GIP agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Efficacy and Safety of Eloralintide (LY3841136) in Participants With Osteoarthritis Knee Pain and Obesity or Overweight (ENLIGHTEN-4)

Eloralintide (LY3841136) is an investigational, long-acting amylin receptor agonist designed to promote satiety and slow gastric emptying, offering a novel non-incretin (non-GLP-1) mechanism for weight management. This Phase 3, randomized, double-blind, placebo-controlled trial (part of the ENLIGHTEN-4 master protocol) will enroll approximately 900 participants to evaluate the drug’s efficacy in treating osteoarthritis (OA) knee pain in adults with obesity or overweight. Participants will undergo treatment for approximately 75 weeks, a duration sufficient to assess both substantial weight reduction and its secondary benefits on structural or symptomatic joint improvements. Strategically, this study aims to replicate the success seen with other weight-loss agents in reducing OA pain while validating a new class of “metabolic” pain therapies that function independently of the GLP-1/GIP pathways.

ClinicalTrials.gov: NCT07353931 (ENLIGHTEN-4)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Triple GLP-1/GIP/glucagon agonist (Example drug: Retatrutide (LY3437943))

Retatrutide functions as a triple agonist (”triple G”), simultaneously activating receptors for GLP-1, GIP, and glucagon, distinguishing it from dual agonists like tirzepatide (GLP-1/GIP) and mono-agonists like semaglutide. While the GLP-1 and GIP components drive satiety and improve insulin sensitivity, the addition of glucagon receptor agonism is the critical differentiator; it increases energy expenditure and enhances lipid metabolism, potentially stripping liver fat more aggressively than existing therapies. This mechanism matters because it aims to break the “efficacy ceiling” of current weight-loss drugs, targeting roughly 25% or greater body weight loss in clinical data to date. This week’s newly registered TRIUMPH-9 (NCT07357415) is a Phase 3b study launching in early 2026 to optimize dose escalation schemes, a strategic move by Eli Lilly to improve tolerability and speed of titration for this potent therapeutic profile.

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.