Combos, CagriSema, and Heart Failure
Week Of May 2 – May 8, 2026
Two GLP-1+amylin combination programs registered new pivotal trials in the same week. Novo’s amycretin (zenagamtide) Phase 3 program came into full view, and Pfizer registered its first Phase 2 obesity trial since the Metsera deal. The Trial Spotlight goes into the three combo architectures that companies are now betting on for pairing GLP-1 with amylin, and what each choice implies. Also, both Novo and Amgen made big HFpEF (heart failure with preserved ejection fraction) moves this week, motivating the Mechanism Explained section on why obesity drugs are increasingly being tested with this increasingly common (now more than 50% of heart failure) condition.
🔥 THIS WEEK’S KEY DEVELOPMENTS
BGM0504 achieves 19.3% weight loss in Phase 3 obesity trial.
Bright Gene Bio-Pharm announced that its dual GLP-1/GIP receptor agonist BGM0504 met the primary endpoint and all key secondary endpoints in a Phase 3 obesity trial in Chinese adults, achieving a 19.3% mean weight reduction. Additional results included a 16.5 cm waist circumference decrease, blood pressure improvements (-22.9/-12.9 mmHg), and a 70.7 µmol/L uric acid reduction. The data positions BGM0504 between semaglutide (~15% in STEP) and tirzepatide (~21% in SURMOUNT-1), and adds another Chinese-origin GLP-1/GIP dual to a growing field that includes HRS9531 (Hengrui/Kailera), VK2735 (Viking), and HDM1005 (Hangzhou Zhongmei Huadong).
Press | Mechanism: Dual GLP-1/GIP agonist
SEMALCO Phase 2: semaglutide cuts heavy drinking days in adults with alcohol use disorder and comorbid obesity.
The Phase 2 SEMALCO trial (Psychiatric Centre Rigshospitalet, Copenhagen, n=108) reported that once-weekly semaglutide reduced heavy drinking days by 13.7 percentage points vs placebo (95% CI -22.0 to -5.4; p=0.0015) in adults with moderate-to-severe alcohol use disorder and comorbid obesity, meeting the primary endpoint. Adverse events were generally mild-to-moderate gastrointestinal effects, more common in the semaglutide arm. The randomized Phase 2 result adds to a growing investigational area for GLP-1 receptor agonists, complementing the brain reward circuit biology covered in this newsletter’s March 20 Mechanism Explained (”From Appetite to Addiction”) and joining ongoing Phase 3 work including a 438-patient VA-sponsored semaglutide AUD study.
Trial: NCT05895643 | Mechanism: GLP-1 receptor agonist
Novo Nordisk Q1 2026: CagriSema co-formulation project terminated; launch device shifts to dual-chamber pen.
In its Q1 2026 results, Novo Nordisk disclosed it has terminated the CagriSema co-formulation project “due to portfolio considerations,” shifting the planned launch device from a single-chamber pen (where semaglutide and cagrilintide would have been pre-mixed in solution) to a dual-chamber pen that keeps the two molecules separate until injection. CEO Mike Doustdar reaffirmed that launch timing remains unchanged, with US approval expected in Q4 2026 and global launch in early 2027. Separately, Novo’s Q1 obesity care sales grew 22% at constant exchange rates, and Wegovy pill (oral semaglutide 25 mg) reached over 2 million total prescriptions since its January 2026 US launch. See the Trial Spotlight below for what the device shift means in the broader GLP-1 + amylin combo architecture landscape.
Press | Mechanism: GLP-1 + amylin combination
GSK pens up to $1B deal for SiranBio’s ALK7 oligonucleotide for obesity.
GSK signed a licensing agreement with Chinese siRNA specialist SiranBio for SA030, an oligonucleotide drug that targets activin receptor-like kinase 7 (ALK7) and is designed to reduce visceral and abdominal fat. The deal is potentially worth up to $1 billion in upfront and milestone payments. SA030 represents a non-incretin approach to obesity, joining a growing class of next-generation candidates that include amylin analogs, GIP antagonists, and tri-agonists. The deal extends GSK’s reach into Chinese-origin metabolic assets, mirroring a broader industry trend of Western biopharma licensing China-developed GLP-1-adjacent candidates.
Press | Mechanism: ALK7-targeting siRNA / oligonucleotide
📰 PRESS
Wegovy access expanded for Medicare beneficiaries via the Medicare GLP-1 Bridge program starting July 1, 2026.
Press | Mechanism: GLP-1
Lilly commits an additional $4.5B across Indiana manufacturing sites.
Press | Mechanism: GLP-1 / GLP-1-GIP
Wegovy pill (oral semaglutide 25 mg) reaches 1 million patients with $355M in Q1 sales.
Press | Mechanism: oral GLP-1
France fines Novo Nordisk and Eli Lilly over misleading obesity drug promotions.
Press | Mechanism: GLP-1
Lilly dismisses liver safety concern for Foundayo as analysts shrug.
Press | Mechanism: oral non-peptide GLP-1 receptor agonist
Neurocrine initiates Phase 1 of NBIP-2118, a non-incretin CRF2 receptor agonist for obesity.
Press | Mechanism: corticotropin-releasing factor type 2 (CRF2) receptor agonist
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
Three Ways to Build a GLP-1 + Amylin Combo: Amycretin’s Phase 3 Reveal Lands Alongside Pfizer’s First Post-Metsera Combo
Following last week’s focus in the newsletter on amylin receptor selectivity, the simultaneous registration of pivotal GLP-1 and amylin combination trials by Novo Nordisk and Pfizer this week shifts the competitive lens to a defining new axis: the underlying molecular architecture of these dual therapies. Novo Nordisk just unveiled a massive five-indication Phase 3 program for amycretin (NNC0487-0111), registering the 5,610-patient HF-POLARIS heart failure trial alongside new AMAZE studies in sleep apnea to anchor its bet on a “unimolecular co-agonist” architecture, which uses a single engineered peptide to bind both targets, trading independent dosing flexibility for a locked activity ratio and a highly streamlined single-API manufacturing supply chain. In sharp contrast, Pfizer’s newly registered 872-patient Phase 2 SOLIS-1 trial adopts a “co-administered separates” architecture for its first post-Metsera obesity program, delivering its fully biased GLP-1 (MET-097) and its selective amylin receptor agonist (MET-233) as two separate subcutaneous injections, with primary completion targeted for August 2027. This separate-injection approach allows Pfizer to independently titrate two uniquely specialized molecules that sit on the extreme tolerability frontier of their respective classes, reflecting a clinical bet that the optimal ratio depends heavily on the individual patient and should not be locked in.
Meanwhile, Novo Nordisk is hedging its bets by advancing a third distinct architecture via its CagriSema program: two molecules paired in a single device at a fixed ratio. The newly registered 2,500-patient Phase 3 dose study (NCT07564414) this week tests whether the right semaglutide-cagrilintide dose pairing can overcome the pharmacokinetic decoupling risks that may have contributed to its REIMAGINE 2 miss in February 2026. Ultimately, the dual advancement of both unimolecular (amycretin) and single-device-paired (CagriSema) programs by Novo Nordisk, contrasted against Pfizer’s pure two-injection separates approach, illustrates how the structural choice between engineered integration, independent titration flexibility, and packaged convenience is rapidly becoming one of the most consequential strategic wagers in metabolic drug development.
NCT07567001 (HF-POLARIS, amycretin in HF) | NCT07571005 (AMAZE 3, OSA) | NCT07571109 (AMAZE 4, OSA on PAP) | NCT07503210 (AMAZE 12, weight maintenance) | NCT07533175 (AMAZE 2, T2D) | NCT07575932 (SOLIS-1, Pfizer combo) | NCT07564414 (new CagriSema dose study) | NCT06862791 (ASCEND, AstraZeneca combo)
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
HFpEF: Why Obesity Drugs Are Crowding Into a Specific Cardiac Phenotype (Example drugs: Tirzepatide, Maridebart Cafraglutide, Amycretin)
This week’s registration of Novo Nordisk’s 5,610-patient HF-POLARIS Phase 3 trial evaluating amycretin and Amgen’s rapid addition of 54 clinical sites to the 5,056-patient MARITIME-HF study evaluating maridebart cafraglutide establish heart failure with preserved ejection fraction (HFpEF) as the premier cardiac target for next-generation obesity therapeutics, following the precedent set by Eli Lilly’s SUMMIT trial. Unlike classical heart failure with reduced ejection fraction where a weakened myocardium struggles to pump blood and requires standard neurohormonal blockade, HFpEF presents a distinct biological challenge: the ventricle maintains a normal pumping fraction but becomes stiff, fibrotic, and unable to adequately relax or fill during diastole. This pathology accounts for roughly half of all heart failure cases yet had essentially no disease-modifying treatments until SGLT2 inhibitors, and now obesity drugs, entered the field. The restrictive diastolic dysfunction is heavily driven by the obesity phenotype found in roughly 80 percent of HFpEF patients, specifically mediated by epicardial adipose tissue, a visceral fat layer in direct contact with the myocardium and coronary arteries that mechanically constricts the ventricle while simultaneously functioning as an inflammatory endocrine organ secreting cytokines like TNF-alpha and leptin to drive microvascular dysfunction. In other words, the fat acts as both a physical straitjacket and a biochemical toxin.
Incretin and amylin therapies are uniquely suited to address this specific pathology. GLP-1 receptor agonism triggers a proportionally larger reduction in epicardial adipose tissue volume than overall subcutaneous fat loss, while simultaneously exerting direct, tissue-specific anti-inflammatory effects that reduce macrophage infiltration. The partner mechanisms (GIP modulation in tirzepatide and MariTide, amylin agonism in amycretin) layer on complementary appetite-regulating and metabolic effects, even if their direct cardiac signaling is less well-characterized than GLP-1’s. Researchers are now isolating those effects from generalized weight loss in a newly recruiting Phase 4 University of Virginia mechanistic study focused on epicardial adipose tissue composition. With tirzepatide’s GLP-1/GIP dual agonism having already shown in SUMMIT that targeting this obesity-driven HFpEF phenotype reduces clinical heart failure events and improves patient exercise capacity, these massive new Phase 3 programs represent a high-stakes mechanistic horse race to determine whether the distinct tissue-specific pathways of amycretin or MariTide can drive even greater reductions in epicardial inflammation, potentially forcing payers to recognize HFpEF as a distinctly covered cardiometabolic indication ahead of broader obesity coverage.
ClinicalTrials.gov: NCT04847557 (SUMMIT, tirzepatide HFpEF) | NCT07037459 (MARITIME-HF, maridebart cafraglutide) | NCT07567001 (HF-POLARIS, amycretin in HF + obesity) | NCT07178145 (UVA EAT composition + HFpEF)
🆕 NEWLY REGISTERED TRIALS (10 in last week)
NNC0487-0111 Phase 3 trial evaluating efficacy in people with heart failure and obesity (Novo Nordisk, n=5610)
[Weight Loss/Efficacy | New Indications]
Trials: NCT07567001 (HF-POLARIS) | Mechanism: GLP-1 + amylin combination
SOLIS-1 Phase 2 investigating the combination of PF-08653945 (MET-233, selective amylin) and PF-08653944 (MET-097, biased GLP-1) as two separate subcutaneous injections in adults with overweight or obesity (Pfizer, n=872)
[Weight Loss/Efficacy]
Trials: NCT07575932 (SOLIS-1) | Mechanism: biased GLP-1 receptor agonist + selective amylin receptor agonist (co-administered combo)
Tirzepatide Phase 2 trial assessing metabolic health in patients with Mild Autonomous Cortisol Secretion following adrenalectomy (Alaa Sada, n=34)
[New Indications]
Trials: NCT07573163 | Mechanism: Dual GLP-1/GIP agonist
MARITIME-SWITCH Phase 3 evaluating Maridebart Cafraglutide in adults with obesity or overweight who are switching from other GLP-1RA therapies (Amgen, n=300)
[Weight Loss/Efficacy | Safety/Tolerability]
Trials: NCT07575399 | Mechanism: GLP-1 receptor agonist + GIP receptor antagonist (antibody-peptide conjugate)
Tirzepatide trial investigating a modified titration schedule to reduce side effects in adults with obesity (Dasman Diabetes Institute, n=68)
[Weight Loss/Efficacy | Safety/Tolerability]
Trials: NCT07574723 (TiTRE) | Mechanism: Dual GLP-1/GIP agonist
AMAZE 4 Phase 3 trial of NNC0487-0111 for weight loss and sleep apnea improvement in patients with obesity and obstructive sleep apnea (Novo Nordisk, n=300)
[Weight Loss/Efficacy | New Indications]
Trials: NCT07571109 (AMAZE 4) | Mechanism: GLP-1 + amylin combination
AMAZE 3 Phase 3 evaluating NNC0487-0111 for weight loss and obstructive sleep apnea in adults not treated with PAP therapy (Novo Nordisk A/S, n=300)
[Weight Loss/Efficacy | New Indications]
Trials: NCT07571005 (AMAZE 3) | Mechanism: GLP-1 + amylin combination
NNC0113-5840 Phase 1 investigating a new medicine for people with overweight or obesity (Novo Nordisk, n=48)
[Safety/Tolerability]
Trials: NCT07566390 | Mechanism: Undisclosed
Semaglutide Depot Phase 1 assessing a new long-acting formulation for type 2 diabetes (Mapi Pharma Ltd., n=24)
[Safety/Tolerability]
Trials: NCT07563699 | Mechanism: GLP-1 receptor agonist
CagriSema Phase 3 trial evaluating two doses against Semaglutide for weight loss in adults with obesity, with or without type 2 diabetes (Novo Nordisk, n=2500)
[Weight Loss/Efficacy]
Trials: NCT07564414 | Mechanism: GLP-1 + amylin combination
This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.
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