Approvals, Pills, and Brain Rewards
Week Of March 14 – March 20, 2026
The FDA approved Wegovy HD (semaglutide 7.2 mg) this week, Novo’s higher dose that showed 20.7% weight loss in STEP UP. On the data front, Lilly’s triple agonist retatrutide posted its first Phase 3 diabetes readout (TRANSCEND-T2D-1), with 16.8% weight loss as a secondary endpoint. But the story I find most interesting this week is Structure Therapeutics. Their oral small molecule GLP-1, aleniglipron, posted 16% weight loss in ACCESS II with no plateau at 44 weeks. I go into what makes this data competitively notable in the Trial Spotlight. The Mechanism Explained focuses on something different: GLP-1 receptors aren’t just in the gut and appetite centers - they’re in the brain’s reward circuits too. Over two dozen clinical trials are now testing whether drugs like semaglutide can treat addiction. Separately, as competition in the US heats up, the New York Times reported on the growing availability of generic semaglutide in India, China, and Canada. This is worth reading and a reminder that global access to these drugs is on a very different trajectory than US market dynamics.
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.
🆕 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.
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