🔥 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.

For the Trial Spotlight and Mechanism Explained, I focused on CR059 — a circular RNA candidate encoding exenatide from a Chinese academic center. It’s an early Phase 1 with just nine participants, so not a trial that will move markets. But circRNA is a genuinely different platform than the peptide injections or small molecules we usually cover, and CR059 appears to be the first circRNA application targeting metabolic disease. The broader circRNA field is still nascent — the first circRNA drug (non-vaccine) to reach patients was CirCode’s HM2002 for heart disease in 2024, and only a handful of programs have entered clinical trials globally. The idea is that the closed-loop RNA structure resists degradation 2-5x better than linear mRNA (like the COVID vaccines), potentially enabling sustained protein expression from a single dose. Whether this “genetic medicine” approach offers meaningful advantages in durability or convenience is an open question, but it’s worth tracking as an alternative delivery paradigm.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Viking completes enrollment for Phase 3 obesity trial of VK2735.

  Viking Therapeutics announced the publication of its Phase 2 VENTURE trial results for the dual GLP-1/GIP agonist VK2735 in the journal Obesity. After 13 weekly doses, participants demonstrated statistically significant reductions in mean body weight from baseline of up to 14.7%, with no plateau observed. VK2735 is currently being evaluated in the VANQUISH Phase 3 registrational program for obesity.

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

🆕 NEWLY REGISTERED TRIALS (3 in last week)

• Exenatide circular RNA (CR059) Early Phase 1 single ascending dose study in Chinese subjects with type 2 diabetes (First Affiliated Hospital of Henan University..., n=9)

  [New Indications]

  Trials: NCT07347080 (CR059101) | Mechanism: GLP-1 receptor agonist

• AMAZE 1 Phase III investigating NNC0487-0111, a new medicine for weight loss in people with excess body weight (Novo Nordisk, n=1150)

  [Weight Loss/Efficacy]

  Trials: NCT07339423 (AMAZE 1) | Mechanism: GLP-1 + amylin combination (amycretin)

• Petrelintide Phase I pharmacokinetic study testing different drug concentrations of the long-acting amylin analog for weight management (Zealand Pharma, n=48)

  [Weight Loss/Efficacy]

  Trials: NCT07338214 | Mechanism: Amylin receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

A Single-Center, Open-Label, Single Ascending Dose Study of Exenatide Circular RNA-Lipid Nanoparticle Injection (CR059) in Chinese Subjects With Type 2 Diabetes Mellitus (CR059101)

This Early Phase 1, open-label study is designed to evaluate the safety and pharmacokinetics of CR059, a novel circular RNA (circRNA) candidate, in nine participants with Type 2 Diabetes Mellitus. Encapsulated in lipid nanoparticles, CR059 encodes exenatide—a GLP-1 receptor agonist—but leverages the unique closed-loop structure of circRNA to resist enzymatic degradation. This structural stability aims to prolong protein expression, potentially addressing the durability limitations often associated with linear mRNA and traditional peptide therapies. As an initial clinical test initiated by The First Affiliated Hospital of Henan University of Science and Technology, this trial serves as a strategic proof-of-concept for determining whether circRNA technology can successfully deliver sustained metabolic control in a human setting.

ClinicalTrials.gov: NCT07347080 (CR059101)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

GLP-1 receptor agonist with a unique delivery mechanism (Example drug: CR059/Exenatide circRNA)

CR059 represents a “genetic medicine” approach to GLP-1 therapy, utilizing circular RNA (circRNA) encapsulated in lipid nanoparticles (LNPs) rather than injecting the therapeutic peptide directly. Upon injection, the LNPs deliver the circRNA payload into the patient’s cells, where it serves as a durable template for the continuous intracellular production and secretion of exenatide (exendin-4). Unlike linear mRNA, circRNA forms a closed loop that evades degradation by exonucleases, significantly extending its intracellular stability and allowing for sustained protein expression over days or weeks. This mechanism potentially offers a “bio-factory” effect, reducing dosing frequency beyond what is possible with standard peptide injections or linear mRNA.

Why it matters:

• Modality Shift: Moves beyond simple peptide replacement to instructing the body to manufacture its own drug, a key differentiator in a crowded market.

• Durability: The stable circRNA platform enables prolonged protein production, potentially achieving ultra-long-acting profiles that could allow for less frequent dosing than standard peptide injections.

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.

GLP-1 Tracker Dashboard

I’ve been building something alongside this newsletter and wanted to share it: a dashboard that tracks the GLP-1 clinical trial landscape in one place. It continuously monitors ClinicalTrials.gov to surface what actually changes day-to-day – from emerging mechanisms and new trial results to quiet timeline delays that don’t make the press releases.

You can explore the live dashboard for free here: glp1.bio1up.com

It’s designed to give you the picture quickly. I’ve also included a Plus tier for those who need deeper views, including upcoming readout tracking and export capabilities. I’d love to hear how it fits into your workflow. What do you want to track?

This week, following last week's FDA approval, Novo Nordisk was quick in getting oral Wegovy into the market with a notable $149/month self-pay option for the starting dose, including at Costco and CVS. The speed of rollout and aggressive pricing suggest they’re aiming to capture patients who’ve been hesitant about injections. That said, the strict dosing requirements (empty stomach, 4 oz water, 30-minute wait) are a potential hurdle. Meanwhile, Viking completed enrollment in a maintenance dosing study exploring whether monthly subcutaneous or weekly/daily oral regimens can sustain weight loss after an initial treatment period. It’s an important question, especially as more people hit their goal weights.

For the Trial Spotlight, I picked a DDI (drug-drug interaction) study for HDM1002, an oral small molecule GLP-1 from Hangzhou Zhongmei Huadong. These interaction studies aren’t flashy, but they’re essential. Patients on GLP-1s typically take metformin, blood pressure meds, and anticoagulants, so characterizing these interactions is a prerequisite for later phases. The Mechanism Explained section covers triple agonism (GLP-1/GIP/glucagon). Retatrutide’s approach of adding glucagon to the mix represents one of the more ambitious attempts to push beyond the efficacy ceiling of current dual agonists.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Novo Nordisk launches oral Wegovy for weight loss in the US.

  Novo Nordisk announced its Wegovy® (semaglutide) pill, the first oral GLP-1 for weight loss, is now broadly available in the US. In the OASIS 4 trial, the 25 mg dose demonstrated an average weight loss of ~17% (trial product estimand) and ~14% (treatment policy estimand) at 64 weeks. The company is offering the starting dose for $149 per month via a self-pay offer.

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

• Viking completes enrollment for VK2735 obesity maintenance study.

  Viking Therapeutics announced it has completed enrollment in its Phase 1 exploratory maintenance dosing study of VK2735, its dual GLP-1/GIP agonist, in approximately 180 adults with obesity. The trial is evaluating the safety, tolerability, and pharmacokinetics of various maintenance regimens, including monthly subcutaneous, weekly oral, and daily oral dosing, following an initial 19-week treatment period. Exploratory endpoints will assess change in body weight through Week 31, with results expected later in the year.

  Press | Mechanism: GLP-1 / GIP dual agonist (oral and subcutaneous)

• Zepbound plus Taltz shows positive Phase 3 results in psoriatic arthritis.

  Eli Lilly announced its Phase 3b TOGETHER-PsA trial of Taltz (ixekizumab) and Zepbound (tirzepatide) met its primary endpoint at 36 weeks in adults with active psoriatic arthritis and obesity. In the study, 31.7% of patients on the combination therapy achieved ACR50 plus at least 10% weight reduction, compared to 0.8% of patients on Taltz monotherapy (p<.001). The trial also met a key secondary endpoint, with 33.5% of patients on the combination achieving ACR50 versus 20.4% for Taltz alone (p<.05).

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

📰 PRESS RELEASES

• Pemvidutide receives FDA Breakthrough Therapy Designation for MASH.

  Press | Press | NCT05989711 | Mechanism: glucagon/GLP-1 dual receptor agonist

🆕 NEWLY REGISTERED TRIALS (7 in last week)

• HDM1002 Phase 1 study investigating drug-drug interactions with five common medications including metformin and warfarin (Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd., n=111)

  [Weight Loss/Efficacy | Oral Formulations]

  Trials: NCT07331389 | Mechanism: GLP-1 receptor agonist (oral)

• TQF3250 Phase 1 first-in-human trial assessing the safety and tolerability of the new compound in healthy adult volunteers (Chia Tai Tianqing, n=66)

  [Oral Formulations]

  Trials: NCT07327281 | Mechanism: GLP-1 receptor agonist (oral)

• Tirzepatide Phase 4 investigating effects on reproductive function and metabolic health in women with PCOS (University of Bonn, n=198)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07326111 (PERIODS) | Mechanism: Dual GLP-1/GIP agonist

• Incretin Microdosing Phase 2 trial evaluating if low doses can improve cardiometabolic health in people with HIV (UT Health Science Center, Houston, n=30)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07325500 (REINFORCE) | Mechanism: GLP-1 receptor agonist

• Comparing the effects of semaglutide vs. tirzepatide, both combined with exercise, in adults with obesity (Istanbul Galata University, n=48)

  [Weight Loss/Efficacy]

  Trials: NCT07319975 | Mechanism: Dual GLP-1/GIP agonist

• GLP-1 Receptor Agonists Phase 1 trial investigating their role in menstrual irregularities in adolescent females with Type 1 Diabetes (Ain Shams University, n=50)

  [New Indications]

  Trials: NCT07319286 | Mechanism: GLP-1 receptor agonist

• A head-to-head trial comparing a novel surgical procedure, side-to-side duodeno-ileostomy, to semaglutide in adults with obesity and type 2 diabetes (GT Metabolic Solutions, n=20)

  [Weight Loss/Efficacy]

  Trials: NCT07317115 (MAGvMED) | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

A Drug-Drug Interaction Study of HDM1002 and Metformin, Empagliflozin, Midazolam, Valsartan, and Warfarin

This Phase 1 trial evaluates HDM1002, an investigational oral small molecule GLP-1 receptor agonist developed by Hangzhou Zhongmei Huadong Pharmaceutical, for potential drug-drug interactions. Unlike approved peptide-based GLP-1 therapies (such as semaglutide) that typically require injection, HDM1002 is a small molecule designed for oral administration, positioning it in a highly competitive class of next-generation metabolic treatments. The study enrolls 111 participants to determine if HDM1002 alters the pharmacokinetics of five specific co-administered agents: metformin, empagliflozin, valsartan, warfarin, and the metabolic probe midazolam. Verifying these interactions is a critical safety milestone, as the target patient population—those with obesity or Type 2 diabetes—frequently manages comorbidities with these exact maintenance medications. Successful characterization of this safety profile is a necessary step to advance HDM1002 into larger, late-stage global efficacy trials.

ClinicalTrials.gov: NCT07331389

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

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

Retatrutide is a unimolecular peptide that simultaneously activates receptors for GLP-1, GIP, and glucagon (GCGR), effectively hitting three distinct metabolic levers in a single therapeutic. While the GLP-1 and GIP components drive satiety and improve insulin sensitivity—building on the foundation laid by dual agonists like tirzepatide—the addition of GCGR agonism acts as a metabolic accelerator by increasing energy expenditure and promoting hepatic lipolysis. This mechanism is critical because it aims to breach the efficacy ceiling of current incretin therapies, offering the potential for bariatric-surgery-level weight loss through combined appetite suppression and increased calorie burning. Furthermore, the glucagon component’s direct impact on liver fat mobilization uniquely positions triple agonists as leading contenders in the high-stakes race to treat metabolic dysfunction-associated steatohepatitis (MASH).

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.

For the Mechanism Explained section this week, I wanted to explore Amgen’s approach with maridebart cafraglutide (AMG 133), which takes the opposite tack from tirzepatide on GIP - blocking the receptor rather than activating it. The genetic data supporting GIP antagonism is interesting, and it’ll be worth watching whether this “push-pull” design provides meaningfully different outcomes than the dual agonist approach.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• China’s Supreme Court upholds Novo Nordisk’s semaglutide patent.

  On December 31, 2025, Novo Nordisk announced that China’s Supreme People’s Court upheld the validity of its semaglutide compound patent, confirming a previous ruling by the Beijing IP Court. The company stated this decision does not alter its previous communication that the patent expiry in certain countries is expected to have a negative low-single-digit impact on global sales growth in 2026.

  Press | Mechanism: glucagon-like peptide-1 (GLP-1) receptor agonist

🆕 NEWLY REGISTERED TRIALS (7 in last week)

• Maridebart cafraglutide (AMG 133) Phase I bioavailability study comparing two different subcutaneous presentations of the obesity drug candidate (Amgen, n=340)

  [Weight Loss/Efficacy]

  Trials: NCT07313761 | Mechanism: GLP-1 Agonism + GIP Receptor Antagonism

• MET097 Phase 3 investigating the efficacy and safety of the once-weekly therapy in people with overweight or obesity (Metsera, n=3500)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07311850 (VESPER-4) | Mechanism: GLP-1 receptor agonist

• GLP-1 RAs Phase 4 trial investigating effects on inflammatory and endothelial biomarkers in patients with type 2 diabetes (Federico II University, n=80)

  [New Indications]

  Trials: NCT07314684 (STABLE-GLP1) | Mechanism: GLP-1 receptor agonist

• Dulaglutide Phase 1 studying the impact of fasting and drug withholding on gastric retention in patients with Type 2 Diabetes (Eli Lilly, n=20)

  [New Indications]

  Trials: NCT07313813 (GBGT) | Mechanism: GLP-1 receptor agonist

• AMG 133 Phase 1 completed drug-drug interaction study with anti-nausea medication in adults with obesity or overweight (Amgen, n=59).

  [Weight Loss/Efficacy]

  Trials: NCT07310563 | Mechanism: GLP-1 with novel mechanism

• ZT006 Phase 1 dose-escalation and food effect study in healthy, overweight, and obese participants (Beijing QL Biopharmaceutical, n=94)

  [Weight Loss/Efficacy, Oral Formulations]

  Trials: NCT07307638 | Mechanism: GLP-1 receptor agonist (oral)

• iGlarLixi Phase 4 real-world study versus standard of care in Chinese adults with uncontrolled type 2 diabetes on oral agents (Shanghai Zhongshan Hospital, n=1316)

  [Oral Formulations | Safety/Tolerability]

  Trials: NCT07307235 | Mechanism: GLP-1 agonist + basal insulin combination

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Efficacy and Safety of MET097 Once-Weekly in People With Overweight or Obesity (VESPER-4)

This Phase 3 pivotal trial evaluates MET097, a novel ultra-long-acting GLP-1 receptor agonist, in 3,500 participants managing overweight or obesity. Distinguished by its proprietary HALO™ lipidation technology, MET097 is engineered for an extended half-life (approximately 15 days) and “fully biased” receptor engagement, a mechanism designed to maintain potent weight-loss efficacy while potentially reducing gastrointestinal side effects like nausea. While the molecule’s durability theoretically supports once-monthly dosing, this specific study assesses a once-weekly regimen, likely to optimize therapeutic exposure and establish a competitive efficacy profile against established daily or weekly agents. The trial is strategically significant as the flagship late-stage effort for Metsera (recently acquired by Pfizer), marking a major bid to introduce a “next-generation” mono-agonist with best-in-class tolerability into the global obesity market.

ClinicalTrials.gov: NCT07311850 (VESPER-4)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

GLP-1 Agonism with GIP Receptor Antagonism (Example: Maridebart Cafraglutide (AMG 133))

Maridebart cafraglutide represents a novel antibody-peptide conjugate design, linking a monoclonal antibody that inhibits the glucose-dependent insulinotropic polypeptide (GIP) receptor to two peptides that activate the GLP-1 receptor. While GLP-1 activation drives established benefits like satiety and insulin secretion, the decision to block rather than activate GIP distinguishes this mechanism from co-agonists like tirzepatide. This approach is grounded in human genetic data showing that loss-of-function variants in the GIP receptor are associated with lower body mass index and protection against obesity. Physiologically, GIP is known to promote lipid storage in adipose tissue; therefore, antagonizing this receptor may limit fat accumulation while GLP-1 promotes weight loss. This “push-pull” synergy—driving satiety while preventing fat storage—aims to deepen weight loss efficacy and potentially improve durability compared to GLP-1 mono-agonism.

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

🔥 THIS WEEK’S KEY DEVELOPMENTS

• FDA approves oral Wegovy for weight management.

  Novo Nordisk announced that the US FDA has approved the Wegovy® pill (once-daily oral semaglutide 25 mg) to reduce excess body weight, maintain weight reduction, and reduce the risk of major adverse cardiovascular events. The approval, which marks the first oral GLP-1 therapy for weight management, was based on the OASIS trial program, where the OASIS 4 trial demonstrated a 16.6% mean weight loss. Novo Nordisk expects to launch the Wegovy® pill in the US in early January 2026.

  Press | Trials: NCT05564117 | NCT03574597 | Mechanism: glucagon-like peptide-1 (GLP-1) receptor agonist

🆕 NEWLY REGISTERED TRIALS (5 in last week)

• Metabolic correction with GLP-1 drugs to improve cardiovascular disease diagnosis and treatment in Kazakhstan (Nazarbayev University, n=120)

  [New Indications]

  Trials: NCT07303556 (ICDDTKZ26) | Mechanism: Dual GLP-1/GIP agonist

• Liraglutide Phase 4 real-world study evaluating the drug alone and combined with Orlistat for weight loss in overweight/obese patients (The Fourth Affiliated Hospital of Zhejiang University School of Medicine, n=120)

  [Weight Loss/Efficacy]

  Trials: NCT07301437 | Mechanism: GLP-1 RA

• Tirzepatide Phase 1 study to determine how fasting and withholding the drug affects stomach emptying in adults with T2D or obesity (Eli Lilly, n=40)

  [Weight Loss/Efficacy]

  Trials: NCT07299084 | Mechanism: Dual GLP-1/GIP agonist

• EXER-MED Phase 3 comparing exercise versus tirzepatide on weight and health outcomes (University of Virginia, n=24)

  [Weight Loss/Efficacy]

  Trials: NCT07298915 (EXER-MED) | Mechanism: Dual GLP-1/GIP agonist

• Exploratory trial investigating GLP-1’s effect on intestinal barrier function in patients with Short Bowel Syndrome with Intestinal Failure (SBS-IF) (Jinling Hospital, n=20)

  [New Indications]

  Trials: NCT07297238 | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

A Study to Evaluate the Effect of Fasting Duration and Tirzepatide Withholding on the Amount of Food and Fluid in the Stomach in Participants With Type 2 Diabetes Mellitus and Participants With Overweight or Obesity Without Type 2 Diabetes Mellitus

In response to growing concerns about perioperative safety, Eli Lilly has designed a crucial Phase 1 study (NCT07299084) to generate data on gastric emptying in patients taking tirzepatide. As a dual GLP-1/GIP agonist, tirzepatide’s mechanism inherently slows the passage of food from the stomach, which has led to debate among anesthesiologists about the risk of aspiration during procedures. This open-label trial will enroll 40 participants with type 2 diabetes or obesity to directly measure stomach contents after test meals, evaluating different fasting durations and withholding the drug. The study, set to begin recruiting in early 2026, is strategically significant as it aims to provide the first direct clinical evidence to inform and refine preoperative fasting guidelines for this major drug class, addressing a critical knowledge gap highlighted by medical societies.

ClinicalTrials.gov: NCT07299084

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Oral Peptide Delivery & The “SNAC” Shield (Example: Oral Wegovy (semaglutide))

The FDA’s approval of oral Wegovy (semaglutide) relies on a clever formulation trick to bypass the stomach’s natural defenses, which typically destroy peptide drugs like GLP-1s. The pill co-formulates semaglutide with an absorption enhancer called SNAC (salcaprozate sodium), which acts as a local buffer to neutralize stomach acid immediately around the dissolving tablet. This creates a transient, pH-neutral “bubble” that protects the peptide from enzymatic breakdown and fluidizes the stomach lining, allowing the large molecule to slip into the bloodstream intact.

This delicate chemical choreography explains the strict dosing requirements: patients must take it on an empty stomach because food or excess water disrupts that protective pH bubble, destroying the drug before it absorbs. In contrast, emerging competitors like orforglipron are non-peptide “small molecules” chemically designed to survive digestion naturally, promising similar efficacy without the rigid fasting rules—positioning oral Wegovy as a bridge between today’s injectables and the next generation of more convenient oral therapies.

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

For the Trial Spotlight, I chose Lilly’s eloralintide ENLIGHTEN-2 study -- a selective amylin agonist that represents Lilly’s bet on a GLP-1-sparing approach. The Mechanism Explained section covers the scientific rationale of combining amylin with GIP activation, a pairing that could offer an alternative for patients. The reality is that people respond differently to different weight loss drugs and so having alternatives that are potentially better tolerated may be important.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• Novo Nordisk submits CagriSema to FDA for weight management approval.

  Novo Nordisk has submitted a New Drug Application (NDA) to the U.S. FDA for once-weekly CagriSema (cagrilintide 2.4 mg and semaglutide 2.4 mg) for long-term weight management in adults with obesity or overweight. The submission is based on the REDEFINE clinical program, including the REDEFINE 1 phase 3 trial, where CagriSema demonstrated an average body weight loss of 23%. The FDA is expected to review the application in 2026.

  Press | Trials: NCT05394519 | NCT05567796 | NCT05669755 | Mechanism: GLP‑1 and amylin combination

• Lilly submits oral weight loss drug orforglipron to FDA.

  In the Phase 3 ATTAIN-MAINTAIN trial, Lilly’s once-daily oral orforglipron met its primary and all key secondary endpoints for weight maintenance versus placebo at 52 weeks. The study evaluated participants who switched to orforglipron after achieving weight loss on injectable Wegovy or Zepbound. At 52 weeks, participants switching from Wegovy maintained all but 0.9 kg of their previously achieved weight loss on average, while those switching from Zepbound had an average difference of 5.0 kg. Lilly has submitted orforglipron to the U.S. FDA for the treatment of obesity.

  Press | NCT06584916 | Mechanism: oral GLP-1 receptor agonist

• Positive MASH data advances Altimmune’s pemvidutide to Phase 3.

  Altimmune announced positive 48-week topline results from its IMPACT Phase 2b trial of pemvidutide in patients with MASH. The 1.8 mg dose achieved a mean reduction in Liver Stiffness Measurement (LSM) of -3.97 (p<0.001) and a mean weight loss of 7.5% (p<0.0001), compared to -0.03 and 0.2% for placebo, respectively. The discontinuation rate due to adverse events was 1.2% for the 1.8 mg dose versus 3.5% for placebo, and the company plans to initiate a Phase 3 program in 2026.

  Press | Trials: NCT05989711 | Mechanism: glucagon/GLP-1 dual receptor agonist

📰 PRESS RELEASES

• Structure Therapeutics begins Phase 1 trial for oral obesity drug ACCG-2671.

  Press | Mechanism: amylin receptor agonist

🆕 NEWLY REGISTERED TRIALS (16 in last week)

• Eloralintide Phase 3 investigating its use in adults with obesity or overweight and type 2 diabetes (Eli Lilly, n=1035)

  [Weight Loss/Efficacy | Oral Formulations]

  Trials: NCT07282600 (ENLIGHTEN-2) | Mechanism: Amylin receptor agonist

• KAI-7535 Phase 1 investigating the effect of a low-fat meal and evening dosing in participants with obesity or overweight (Kailera, n=18)

  [Weight Loss/Efficacy]

  Trials: NCT07294898 | Mechanism: GLP-1 receptor agonist

• GZR18 Injection Phase 3 extension study evaluating long-term safety and efficacy for weight loss in participants from a prior trial (Gan & Lee Pharmaceuticals, n=500)

  [Weight Loss/Efficacy]

  Trials: NCT07292441 (GZR18-BWM-303) Mechanism: GLP-1 receptor agonist

• Tirzepatide Phase 2 trial investigating the drug plus cognitive-behavioural therapy (CBT) for Alcohol Use Disorder in adults with obesity (South West Sydney Local Health District, n=46)

  [Weight Loss/Efficacy]

  Trials: NCT07292519 | Mechanism: Dual GLP-1/GIP agonist

• GALACTUS Trial Phase 3 investigating the effect of GLP-1 and SGLT2 inhibitors on inflammation following myocardial infarction (Instituto Mexicano del Seguro Social, n=44)

  [New Indications]

  Trials: NCT07295223 (GALACTUS) | Mechanism: GLP-1 RA as comparison

• Semaglutide and Tirzepatide trial investigating their effect on genetic aging delay in adults with obesity (Second Affiliated Hospital, Zhejiang University, n=66)

  [Weight Loss/Efficacy]

  Trials: NCT07293325 | Mechanism: GLP-1 / GIP dual and GLP-1 receptor agonist

• Semaglutide Phase 3 studying the cardiometabolic and physiological effects after patients stop taking the drug (Mount Sinai Hospital, Canada, n=98)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07294950 (REST) | Mechanism: GLP-1 receptor agonist cessation

• KAI-9531 Phase 3 trial investigating a new drug for weight management in adults with obesity or overweight who do not have diabetes (Kailera, n=1800)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07284875 | Mechanism: Dual GLP-1/GIP agonist

• KAI-9531 Phase 3 trial evaluating the once-weekly drug in participants with both obesity/overweight and diabetes (Kailera, n=1700)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07284901 | Mechanism: Dual GLP-1/GIP agonist

• KAI-9531 Phase 3 trial investigating the once-weekly drug against semaglutide and placebo for adults with obesity without diabetes (Kailera, n=1200)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07284979 | Mechanism: Dual GLP-1/GIP agonist

• Tirzepatide Phase 2 trial investigating its use to improve automated glycemic control in adults with Type 1 Diabetes (Melissa-Rosina Pasqua, n=105)

  [New Indications]

  Trials: NCT07284511 (TZP) | Mechanism: Dual GLP-1/GIP agonist

• Ecnoglutide (VRB-101) Phase 2 trial evaluating a weekly oral formulation for adults with obesity or overweight (Verdiva Bio Dev Limited, n=200)

  [Weight Loss/Efficacy | Oral Formulations]

  Trials: NCT07281937 (EVOLVE-2) | Mechanism: GLP-1 agonist

• Semaglutide (Wegovy) Phase 2 pilot study investigating the popular GLP-1 agonist for trichotillomania, an impulse control disorder (University of Chicago, n=10)

  [New Indications]

  Trials: NCT07282769 | Mechanism: GLP-1 receptor agonist

• HRS9531 Phase 3 head-to-head study comparing efficacy and safety against semaglutide for obesity (Fujian Shengdi Pharmaceutical, n=750)

  [Weight Loss/Efficacy | Safety/Tolerability]

  Trials: NCT07285902 | Mechanism: Dual GLP-1/GIP agonist

• CagriSema Phase 3 trial investigating its effect on blood sugar and body weight in children and adolescents with Type 2 Diabetes (Novo Nordisk A/S, n=80)

  [Weight Loss/Efficacy]

  Trials: NCT07282613 (REIMAGINEYOUNG) | Mechanism: GLP-1/amylin combo

• Dulaglutide Phase 2 trial investigating the GLP-1 RA’s effect on severe intracranial atherosclerosis (National University of Singapore, n=130)

  [New Indications]

  Trials: NCT07282041 (RADIANT) | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

A Study of Eloralintide (LY3841136) in Participants With Obesity or Overweight, and Type 2 Diabetes (ENLIGHTEN-2)

This Phase 3 trial (NCT07282600), known as ENLIGHTEN-2, evaluates Eli Lilly’s eloralintide in 1,035 participants with type 2 diabetes and obesity or overweight. Eloralintide operates via a novel mechanism distinct from GLP-1 agonists; it is a selective amylin receptor agonist (preferentially targeting AMY1R) designed to induce satiety and weight loss while potentially minimizing the gastrointestinal side effects associated with non-selective amylin analogs. The ~75-week, randomized, placebo-controlled study will assess the drug’s efficacy in weight reduction, a crucial endpoint given that weight loss is often harder to achieve in patients with type 2 diabetes compared to those without. Strategically, this trial positions Lilly to compete directly with other emerging amylin-based therapies (such as Novo Nordisk’s cagrilintide) and diversifies the company’s obesity portfolio beyond incretin-based treatments like Zepbound (tirzepatide), offering a potential alternative for patients who may not tolerate or respond adequately to GLP-1 therapies.

ClinicalTrials.gov: NCT07282600 (ENLIGHTEN-2)

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Amylin + GIPR Combination (Example: Eloralintide + Macupatide)

This therapeutic approach represents a strategic evolution in the obesity landscape by testing a “GLP-1-sparing” combination of eloralintide, a selective amylin receptor agonist, and macupatide, a selective GIP receptor agonist. Eloralintide mimics the hormone amylin (normally co-secreted with insulin) to centrally signal satiety and physically slow gastric emptying, targeting the same pathway as the “Cagri” component of Novo Nordisk’s CagriSema. Macupatide complements this by isolating the GIP pathway—the key metabolic differentiator of Lilly’s own tirzepatide—to enhance insulin sensitivity and lipid metabolism without direct GLP-1 receptor activation. By decoupling these mechanisms from the standard GLP-1 backbone, this fixed-dose combination aims to determine if targeting neuroendocrine satiety (Amylin) and metabolic efficiency (GIP) together can drive profound weight loss with a potentially differentiated tolerability profile.

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

On the clinical side, we are seeing higher limits tested. The EU panel backed a 7.2 mg dose of Wegovy, and Lilly’s triple-agonist retatrutide delivered impressive numbers in Phase 3. However, the oral market drew the most attention. We saw clinical validation for Structure Therapeutics’ oral candidate, followed closely by Lilly announcing a $6 billion investment in a facility dedicated to orforglipron. It is a significant indicator that the industry is preparing for a future where pills play a central role alongside injectables.

For the Trial Spotlight, I wanted to highlight the head-to-head comparison between CagriSema and tirzepatide. I find this study interesting because it tests two distinct biological approaches -- GLP-1 plus amylin versus GLP-1 plus GIP. To get into that in more depth, I’ve used the Mechanism Explained section to focus on DACRAs to explain what the amylin component brings to the equation.

🔥 THIS WEEK’S KEY DEVELOPMENTS

• EU panel recommends approval for higher-dose Wegovy.

  The European Medicines Agency’s (EMA) CHMP issued a positive opinion for a new 7.2 mg dose of Wegovy® for individuals with obesity. In the STEP UP trial, people with obesity taking the 7.2 mg dose lost an average of 20.7% body weight at 72 weeks, with one in three participants achieving 25% or more weight loss. The new dose is also under review in the US following a November 2025 submission to the FDA.

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

• Positive Phase 2b data advances obesity drug aleniglipron to Phase 3.

  Structure Therapeutics announced positive topline data from its Phase 2b ACCESS study for its once-daily oral GLP-1 receptor agonist, aleniglipron. At 36 weeks, the 120 mg dose achieved a clinically meaningful and statistically significant placebo-adjusted mean weight loss of 11.3% (27.3 lbs), with a 10.4% adverse event-related treatment discontinuation rate across active arms. An exploratory ACCESS II study showed a placebo-adjusted mean weight loss of up to 15.3% (35.5 lbs) with a 240 mg dose at 36 weeks, and the company plans to advance to a Phase 3 program by mid-2026.

  Press | Trials: NCT06693843 | NCT06703021 | Mechanism: GLP-1 agonist

📰 PRESS RELEASES

• Lilly’s retatrutide reduces weight and knee pain in Phase 3 trial.

  Press | Mechanism: triple agonist

• Lilly invests $6B in Alabama plant for oral GLP-1 orforglipron.

  Press | Mechanism: oral GLP-1

• Pfizer licenses YaoPharma’s GLP-1 for weight management.

  Press | Mechanism: glucagon-like peptide 1 (GLP-1) receptor agonist

• Novo Nordisk completes acquisition of Akero for MASH drug efruxifermin.

  Press

🆕 NEWLY REGISTERED TRIALS (4 in last week)

• iGlarLixi vs. iGlar Phase 4 trial investigating the effect on liver fat in patients with type 2 diabetes and MASLD (Nanjing Drum Tower Hospital, n=36)

  [New Indications]

  Trials: NCT07274644 | Mechanism: GLP-1 with novel mechanism

• WAIT Study Phase 4 investigating whether semaglutide before catheter ablation improves arrhythmia-free survival in patients with atrial fibrillation and obesity (Emma Svennberg, n=200)

  [New Indications]

  Trials: NCT07275697 (WAIT) | Mechanism: GLP-1 receptor agonist

• Oral Semaglutide Phase 3 comparing the safety and efficacy of two different formulations in Japanese adults with Type 2 Diabetes (Novo Nordisk, n=264)

  [Oral Formulations]

  Trials: NCT07271251 | Mechanism: GLP-1 receptor agonist

• Semaglutide Phase 4 trial comparing its effects versus energy restriction for managing Type 2 Diabetes (Second Affiliated Hospital of Nanchang University, n=100)

  [New Indications]

  Trials: NCT07272343 | Mechanism: GLP-1 receptor agonist

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

A Research Study to See How Well CagriSema Compared to Tirzepatide Helps People With Obesity Lose Weight

This Phase 3 head-to-head trial evaluates the efficacy of Novo Nordisk’s investigational fixed-dose combination, CagriSema, directly against Eli Lilly’s tirzepatide in 809 adults with obesity. While the comparator tirzepatide functions as a dual GIP/GLP-1 receptor agonist, CagriSema employs a distinct synergistic approach by combining the GLP-1 receptor agonist semaglutide with cagrilintide, a long-acting amylin analogue. The study tests the hypothesis that simultaneously targeting amylin and GLP-1 pathways can surpass the weight-loss efficacy of dual incretin agonism. As the obesity treatment landscape shifts toward multi-mechanism therapies, this trial is strategically significant for determining whether combining non-overlapping hormonal targets can establish a new benchmark for weight reduction.

ClinicalTrials.gov: NCT06131437

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

DACRA (Example drug: Cagrilintide)

Cagrilintide functions as a long-acting Dual Amylin and Calcitonin Receptor Agonist (DACRA), designed to mimic the physiological effects of native amylin, a hormone co-secreted with insulin. By activating amylin and calcitonin receptors—primarily in the hindbrain—it induces satiety and delays gastric emptying through pathways distinct from the incretin system. This non-overlapping mechanism is strategically critical, as it allows for synergistic pairing with GLP-1 agonists (such as semaglutide in CagriSema) to surmount therapeutic plateaus often reached with mono-therapies. As the obesity sector pursues efficacy rivaling bariatric surgery, DACRAs represent a vital evolutionary step, enabling deeper weight loss by attacking metabolic dysregulation from multiple biological angles.

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

🌍 GLOBAL HEALTH POLICY

• WHO issues first global guideline recommending GLP-1s for obesity treatment — The World Health Organization formally recognized obesity as a treatable chronic disease and issued its first guidance endorsing GLP-1 therapies (semaglutide, liraglutide, tirzepatide) for long-term weight management. The recommendation is conditional, citing limited long-term safety data and calling for combination with behavioral interventions. WHO highlighted a stark access gap: even with expanded production, fewer than 10% of those who could benefit will have access by 2030.

  [Policy Milestone]

  Sources: WHO | JAMA

🆕 NEWLY REGISTERED TRIALS (1 in last week)

• Tirzepatide Phase IV trial investigating its role in postmenopausal HR+ breast cancer survivors (Weill Medical College of Cornell University, n=30)

  [Weight Loss/Efficacy | New Indications]

  Trials: NCT07257484 | Mechanism: Dual GLP-1/GIP agonist

📋 PIPELINE UPDATES

• Novo Nordisk amycretin Phase 2 completes — Dose-finding study (n=448) for NNC0487-0111 in type 2 diabetes finished enrollment. Next-gen GLP-1/amylin dual agonist showed 22% weight loss in earlier obesity trials.

  [Completed] NCT06542874

• Semaglutide depression trial now recruiting — Danish study exploring whether semaglutide improves depressive symptoms in patients with MDD and overweight/obesity (n=116).

  [Now Recruiting] NCT07136714

• Lilly’s LY3537021 begins enrollment — Phase 2 trial for chemotherapy-induced nausea/vomiting now recruiting, representing potential expansion of GLP-1 mechanisms into supportive oncology care.

  [Now Recruiting] NCT07169851

💡 TRIAL SPOTLIGHT

Educational spotlight selected by editors

Amycretin (NNC0487-0111) in Type 2 Diabetes

This Phase 2 dose-finding study evaluated “amycretin” (NNC0487-0111), a single molecule engineered to activate both GLP-1 and amylin receptors simultaneously. Unlike combination therapies that mix two separate drugs, amycretin is a unimolecular co-agonist designed to leverage the complementary effects of GLP-1 (insulin secretion, appetite suppression) and amylin (satiety, gastric emptying regulation) for potent glycemic control and weight management. Enrolling 448 participants with Type 2 diabetes, the trial investigated whether this dual-mechanism approach could outperform standard care in lowering HbA1c and body weight. The successful completion of this study is strategically critical for Novo Nordisk, as it sets the stage for Phase 3 development of a potential “next-generation” successor to semaglutide. By targeting the amylin pathway alongside GLP-1, this asset aims to break efficacy ceilings seen with mono-agonists, offering a more comprehensive metabolic intervention for patients requiring significant weight loss alongside glucose regulation.

ClinicalTrials.gov: NCT06542874

🔬 MECHANISM EXPLAINED

Understanding the science behind the therapeutics

Dual GLP-1/GIP agonist (Example drug: Tirzepatide)

Tirzepatide represents a pivotal evolution in incretin therapy as a unimolecular dual agonist that simultaneously engages both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. While the GLP-1 component drives satiety and glucose-dependent insulin secretion, the addition of GIP signaling works synergistically to amplify metabolic regulation and lipid handling, potentially through direct modulation of adipose tissue. Uniquely, tirzepatide exhibits biased agonism at the GLP-1 receptor—favoring cAMP generation over β-arrestin recruitment—which may enhance tolerability while maximizing the therapeutic window compared to selective mono-agonists. This “twincretin” strategy not only resets the efficacy benchmark for weight loss and glycemic control but also validates the broader industry shift toward multi-receptor modalities as the future standard of care in metabolic disease. (The diagram below omits indirect effects, for example those on the liver and on skeletal muscle).

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