Oral Bets and Multi-Target Comparisons
Week Of December 6 – December 12, 2025
This week, the GLP-1 landscape reflects two distinct tracks: pushing efficacy ceilings and scaling up.
On the clinical side, we are seeing higher limits tested. The EU panel backed a 7.2 mg dose of Wegovy, and Lilly’s triple-agonist retatrutide delivered impressive numbers in Phase 3. However, the oral market drew the most attention. We saw clinical validation for Structure Therapeutics’ oral candidate, followed closely by Lilly announcing a $6 billion investment in a facility dedicated to orforglipron. It is a significant indicator that the industry is preparing for a future where pills play a central role alongside injectables.
For the Trial Spotlight, I wanted to highlight the head-to-head comparison between CagriSema and tirzepatide. I find this study interesting because it tests two distinct biological approaches -- GLP-1 plus amylin versus GLP-1 plus GIP. To get into that in more depth, I’ve used the Mechanism Explained section to focus on DACRAs to explain what the amylin component brings to the equation.
🔥 THIS WEEK’S KEY DEVELOPMENTS
EU panel recommends approval for higher-dose Wegovy.
The European Medicines Agency’s (EMA) CHMP issued a positive opinion for a new 7.2 mg dose of Wegovy® for individuals with obesity. In the STEP UP trial, people with obesity taking the 7.2 mg dose lost an average of 20.7% body weight at 72 weeks, with one in three participants achieving 25% or more weight loss. The new dose is also under review in the US following a November 2025 submission to the FDA.
Press | Trials: NCT05646706 | Mechanism: GLP-1 agonist
Positive Phase 2b data advances obesity drug aleniglipron to Phase 3.
Structure Therapeutics announced positive topline data from its Phase 2b ACCESS study for its once-daily oral GLP-1 receptor agonist, aleniglipron. At 36 weeks, the 120 mg dose achieved a clinically meaningful and statistically significant placebo-adjusted mean weight loss of 11.3% (27.3 lbs), with a 10.4% adverse event-related treatment discontinuation rate across active arms. An exploratory ACCESS II study showed a placebo-adjusted mean weight loss of up to 15.3% (35.5 lbs) with a 240 mg dose at 36 weeks, and the company plans to advance to a Phase 3 program by mid-2026.
Press | Trials: NCT06693843 | NCT06703021 | Mechanism: GLP-1 agonist
📰 PRESS RELEASES
Lilly’s retatrutide reduces weight and knee pain in Phase 3 trial.
Press | Mechanism: triple agonist
Lilly invests $6B in Alabama plant for oral GLP-1 orforglipron.
Press | Mechanism: oral GLP-1
Pfizer licenses YaoPharma’s GLP-1 for weight management.
Press | Mechanism: glucagon-like peptide 1 (GLP-1) receptor agonist
Novo Nordisk completes acquisition of Akero for MASH drug efruxifermin.
🆕 NEWLY REGISTERED TRIALS (4 in last week)
iGlarLixi vs. iGlar Phase 4 trial investigating the effect on liver fat in patients with type 2 diabetes and MASLD (Nanjing Drum Tower Hospital, n=36)
[New Indications]
Trials: NCT07274644 | Mechanism: GLP-1 with novel mechanism
WAIT Study Phase 4 investigating whether semaglutide before catheter ablation improves arrhythmia-free survival in patients with atrial fibrillation and obesity (Emma Svennberg, n=200)
[New Indications]
Trials: NCT07275697 (WAIT) | Mechanism: GLP-1 receptor agonist
Oral Semaglutide Phase 3 comparing the safety and efficacy of two different formulations in Japanese adults with Type 2 Diabetes (Novo Nordisk, n=264)
[Oral Formulations]
Trials: NCT07271251 | Mechanism: GLP-1 receptor agonist
Semaglutide Phase 4 trial comparing its effects versus energy restriction for managing Type 2 Diabetes (Second Affiliated Hospital of Nanchang University, n=100)
[New Indications]
Trials: NCT07272343 | Mechanism: GLP-1 receptor agonist
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
A Research Study to See How Well CagriSema Compared to Tirzepatide Helps People With Obesity Lose Weight
This Phase 3 head-to-head trial evaluates the efficacy of Novo Nordisk’s investigational fixed-dose combination, CagriSema, directly against Eli Lilly’s tirzepatide in 809 adults with obesity. While the comparator tirzepatide functions as a dual GIP/GLP-1 receptor agonist, CagriSema employs a distinct synergistic approach by combining the GLP-1 receptor agonist semaglutide with cagrilintide, a long-acting amylin analogue. The study tests the hypothesis that simultaneously targeting amylin and GLP-1 pathways can surpass the weight-loss efficacy of dual incretin agonism. As the obesity treatment landscape shifts toward multi-mechanism therapies, this trial is strategically significant for determining whether combining non-overlapping hormonal targets can establish a new benchmark for weight reduction.
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
DACRA (Example drug: Cagrilintide)
Cagrilintide functions as a long-acting Dual Amylin and Calcitonin Receptor Agonist (DACRA), designed to mimic the physiological effects of native amylin, a hormone co-secreted with insulin. By activating amylin and calcitonin receptors—primarily in the hindbrain—it induces satiety and delays gastric emptying through pathways distinct from the incretin system. This non-overlapping mechanism is strategically critical, as it allows for synergistic pairing with GLP-1 agonists (such as semaglutide in CagriSema) to surmount therapeutic plateaus often reached with mono-therapies. As the obesity sector pursues efficacy rivaling bariatric surgery, DACRAs represent a vital evolutionary step, enabling deeper weight loss by attacking metabolic dysregulation from multiple biological angles.
This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.