22.5%, Table Stakes, and the Gila Monster
Week Of January 24 – January 30, 2026
The headline this week is Roche/Genentech’s CT-388 Phase II readout — 22.5% placebo-adjusted weight loss at 48 weeks, with the curve still not plateauing. That’s competitive with tirzepatide’s SURMOUNT data, and they’re moving to Phase III this quarter. Regeneron also signaled it’s advancing olatorepatide to Phase 3, making the dual GLP-1/GIP agonist space increasingly crowded.
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.
🔬 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.
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