Milestones, Muscle, and Missing the Bar
Week Of February 28 - March 6, 2026
Zealand and Roche reported positive Phase 2 results for petrelintide - a pure amylin analog with tolerability comparable to placebo - but analysts are already asking whether 10.7% weight loss clears the bar set by Lilly. Speaking of Lilly, retatrutide hit two milestones this week: the first Phase 3 T2D trial completed and the 10,000-patient cardiovascular outcomes study closed enrollment. I go into the sheer scale of that program in this week’s Trial Spotlight. The Mechanism Explained tackles a question that’s increasingly front-of-mind: when patients lose weight on GLP-1s, roughly a quarter of it is muscle. SARMs and anti-activin antibodies are two very different approaches that are showing promise in addressing that challenge.
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.
💡 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.
🔬 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.
🆕 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.
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