GLP-1s in MASH and Sleep Apnea
Week Of November 8 – November 14, 2025
Last week’s happenings included the liver-focused conference AASLD. GLP-1s have become important in liver disease based on their ability to impact metabolic dysfunction-associated steatohepatitis (MASH), a condition in which fatty infiltration and inflammation of the liver can lead to liver cell damage and fibrosis, with longer-term chances of liver cancer or liver failure. MASH is difficult to treat and represents a significant unmet need. GLP-1s seem to reduce liver inflammation through some combination of their metabolic effects and direct antiinflammatory effects (exact balance unknown). With an estimated total global addressable market of around 8 billion USD currently, MASH has been a growing area of focus for pharma. I’ve mentioned FGF21 analogs, an approach to MASH that is competitive with GLP-1s, previously in the newsletter (see Novo Nordisk’s acquisition of Akero and Roche’s acquisition of 89Bio).
Some MASH-related highlights, including the publication of 24-week data from the IMPACT Phase 2b trial for pemvidutide in The Lancet, are mentioned below in Key Developments.
New trials from Amgen studying maredibart cafraglutide (MariTide, AMG 133) for obstructive sleep apnea (OSA) are now in the trial registry. Given that this is a relative recent focus for GLP-1s and that the drug has a novel mechanism, I’ve chosen this drug and one of the trials for the Mechanism Explained and Trial Spotlight sections.
🔥 THIS WEEK’S KEY DEVELOPMENTS
Wegovy reduces liver injury in MASH, independent of weight loss.
At the AASLD 2025 meeting, Novo Nordisk presented a post hoc analysis of the phase 3 ESSENCE trial for Wegovy® (semaglutide 2.4 mg) in adults with MASH and liver scarring. The analysis showed that semaglutide was associated with resolution in liver injury even at low levels of weight loss (≤2%). In this subgroup, 48.4% of patients receiving semaglutide showed resolution of liver injury compared to 25.8% on placebo, while improvements in liver scarring trended in favor of semaglutide.
Press | Trials: NCT04822181 | Mechanism: GLP-1 receptor agonist
Altimmune publishes pemvidutide Phase 2b MASH data in The Lancet.
Altimmune announced 24-week results from its IMPACT Phase 2b trial of pemvidutide in patients with MASH, published in The Lancet. The trial met its primary endpoint, with 52% of patients on the 1.8 mg dose achieving MASH resolution without worsening of fibrosis, compared to 20% for placebo (p<0.0001). Secondary endpoints included a mean body weight reduction of 5.8% for the 1.8 mg dose versus 0.5% for placebo. Final data is expected in Q4 2025. Also note the interpretation from The Lancet02114-2/abstract) of “Pemvidutide treatment met the primary endpoint of MASH resolution without worsening of fibrosis at 24 weeks but did not meet the other primary endpoint of fibrosis improvement without worsening of MASH at this timepoint.”
Press | Trials: NCT05989711 | Mechanism: glucagon/GLP-1 agonist
🆕 NEWLY REGISTERED TRIALS (5 in last week)
Repurposing Semaglutide Phase II for the treatment of cocaine use disorder (The University of Texas Health Science Center, Houston, n=75)
[New Indications]
Trials: NCT07227948 | Mechanism: GLP-1 receptor agonist
Liraglutide/Semaglutide Phase 1 study assessing how fasting and temporary drug holds affect residual gastric contents in users (Novo Nordisk, n=75)
[Weight Loss/Efficacy]
Trials: NCT07225816 | Mechanism: GLP-1 receptor agonist
Maridebart Cafraglutide Phase 3 trial evaluating the drug for obstructive sleep apnea in adults not on positive airway pressure (PAP) therapy (Amgen, n=250)
[New Indications]
Trials: NCT07226765 | Mechanism: unimolecular antibody-peptide conjugate that acts as a GLP-1 receptor agonist and a GIP receptor antagonist
Maridebart Cafraglutide (AMG 133) Phase 1 comparing the bioavailability of two different subcutaneous presentations of the weight loss drug candidate (Amgen, n=340).
[Weight Loss/Efficacy]
Trials: NCT07226778 | Mechanism: unimolecular antibody-peptide conjugate that acts as a GLP-1 receptor agonist and a GIP receptor antagonist
Maridebart Cafraglutide Phase III trial evaluating the drug in adults with obstructive sleep apnea already on positive airway pressure (PAP) therapy (Amgen, n=250)
[Weight Loss/Efficacy | New Indications]
Trials: NCT07225686 (MARITIME-OSA-1) | Mechanism: unimolecular antibody-peptide conjugate that acts as a GLP-1 receptor agonist and a GIP receptor antagonist
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
Maridebart Cafraglutide Versus Placebo in Adult Participants With Obstructive Sleep Apnea Not on Positive Airway Pressure (PAP) Therapy
Amgen’s Phase 3 MARITIME-OSA-2 trial (NCT07226765) is a randomized, double-blind study evaluating maridebart cafraglutide against a placebo in 250 adults with obstructive sleep apnea (OSA) who are not using PAP therapy. The trial investigates a novel mechanism of action, as maridebart cafraglutide is an antibody-peptide conjugate that simultaneously activates the GLP-1 receptor to suppress appetite and blocks the GIP receptor, which may reduce fat storage. While not yet recruiting, the study is part of a broader Phase 3 program for the drug, with similar Amgen trials in OSA slated to begin as early as December 2025. Strategically, this trial positions Amgen to enter the expanding market for metabolic drugs in OSA, a field recently validated by the FDA’s approval of the dual GLP-1/GIP agonist Zepbound for the same condition. This study will explore if maridebart cafraglutide’s unique GIP receptor blockade can offer a competitive advantage in treating OSA, which is strongly linked to obesity.
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
GLP-1 with novel mechanism (Example drug: Maridebart Cafraglutide)
Maridebart cafraglutide represents a novel approach in metabolic medicine, functioning as a unimolecular antibody-peptide conjugate with a dual mechanism. It simultaneously activates the glucagon-like peptide-1 (GLP-1) receptor while antagonizing the glucose-dependent insulinotropic polypeptide (GIP) receptor. The GLP-1 agonism drives weight loss through established pathways of appetite suppression and improved glycemic control, similar to drugs like semaglutide. Uniquely, this therapeutic intentionally blocks the GIP receptor, a strategy supported by genetic data suggesting that reduced GIP signaling is associated with lower BMI and may decrease fat storage. This contrarian approach —- inhibiting GIP while activating GLP-1 —- aims to produce a synergistic and potentially more durable weight loss effect compared to GLP-1 agonism alone. In a competitive landscape dominated by GLP-1 agonists and dual GLP-1/GIP agonists (like tirzepatide), maridebart cafraglutide’s distinct mechanism and antibody structure, which allows for monthly dosing, positions it as a potentially powerful and convenient future option.
This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.