Pills, Implants, and Price Cuts
Week Of February 21 – February 27, 2026
This week brought two significant head-to-head results: CagriSema fell short of tirzepatide in the REDEFINE 4 trial (23% vs. 25.5% weight loss), while Lilly’s oral orforglipron beat oral semaglutide on both A1C and weight in ACHIEVE-3. Novo responded to competitive pressure by cutting U.S. list prices for Ozempic, Wegovy, and Rybelsus, and signed a $2.1B deal with Vivtex to bolster its oral delivery pipeline. I find the Vivtex approach fascinating — they use intact porcine gut tissue mounted on robotic microwell plates to screen thousands of oral formulations per day, essentially a gut-on-a-chip. Meanwhile, the first-ever semaglutide implant entered the clinic — I go into the titanium nanotube technology behind it in this week’s Trial Spotlight. The Mechanism Explained maps the increasingly crowded GLP-1/GIP dual agonist race, where 15 challengers are trying to beat tirzepatide at its own game.
Separately, GLP-1 drugs and pancreatitis risk came up in the news this week. The evidence is murky. Two good reads: a Nature news feature on new regulatory warnings, and a JCI review that puts the evidence in perspective.
🔥 THIS WEEK’S KEY DEVELOPMENTS
CagriSema fails to match tirzepatide in Phase 3 obesity trial.
In the open-label, head-to-head REDEFINE 4 trial, CagriSema (cagrilintide 2.4 mg/semaglutide 2.4 mg) did not meet its primary endpoint of demonstrating non-inferiority on weight loss compared to tirzepatide 15 mg at 84 weeks. People treated with CagriSema achieved a 23.0% weight loss, compared to 25.5% for those treated with tirzepatide. Novo Nordisk reported that CagriSema appeared to have a safe and well-tolerated profile, consistent with the GLP-1 receptor agonist class.
Press | Trials: NCT06131437 | Mechanism: GLP-1 receptor agonist + amylin receptor agonist
Orforglipron outperforms oral semaglutide in Phase 3 diabetes trial.
In the Phase 3 ACHIEVE-3 trial for type 2 diabetes, Eli Lilly’s orforglipron 36 mg demonstrated superiority over oral semaglutide 14 mg, lowering A1C by 2.2% versus 1.4% at 52 weeks. For a key secondary endpoint, orforglipron led to a weight loss of 19.7 lbs (9.2%) compared to 11.0 lbs (5.3%) for oral semaglutide. Lilly has submitted orforglipron to regulators in over 40 countries and anticipates potential U.S. action for obesity in Q2 2026.
Press | Lancet | Trials: NCT06045221 | Mechanism: oral GLP-1
📰 PRESS RELEASES
Structure Therapeutics plans to advance oral GLP-1 aleniglipron into Phase 3 in H2 2026.
Press | Mechanism: GLP-1 receptor agonist
Novo Nordisk partners with Vivtex in $2.1B deal for oral obesity and diabetes drugs.
Press | Mechanism: oral formulation of peptides
Pfizer strikes $495M deal to market Sciwind’s China-approved GLP-1 obesity drug in China.
Press | Mechanism: GLP-1 receptor agonist
Novo Nordisk cuts U.S. list prices for Wegovy, Ozempic, and Rybelsus.
Press | Mechanism: GLP-1s
UBT251 shows 19.7% weight loss in Phase 2 obesity trial.
Press | Mechanism: triple agonist of the receptors for GLP-1, GIP and glucagon
Zepbound now available in multi-dose KwikPen.
Press | Mechanism: Dual GLP-1/GIP agonist
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
The First Semaglutide Implant Enters the Clinic: SLIM-1 Tests a Radical New Delivery Approach
The cleverly named SLIM-1 trial (NCT07430059) is a pioneering Phase 1 study by Vivani Medical evaluating the first-ever sustained-release semaglutide subcutaneous implant against a comparator arm of standard weekly Wegovy injections. Slated to begin in April 2026, the trial will enroll 20 participants with obesity or overweight to assess the novel device’s safety, tolerability, and pharmacokinetics. The device uses Vivani’s proprietary NanoPortal™ technology — a miniaturized titanium nanotube reservoir with no moving parts — designed to release semaglutide steadily for up to six months or longer from a single subdermal insertion. By avoiding the pharmacokinetic peak-and-trough cycling typical of frequent dosing, an implantable approach could theoretically minimize gastrointestinal side effects while fundamentally solving the challenge of long-term patient adherence. Strategically, SLIM-1 represents a fascinating leap in the broader metabolic drug delivery race, pushing the field’s evolution beyond standard weekly injectables, investigational monthly shots like MariTide, and experimental daily pills like orforglipron, toward the frontier of ultra-long-acting implantable therapies.
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
The GLP-1/GIP Dual Agonist Race: How 15 Challengers Are Trying to Beat Tirzepatide at Its Own Game (Example drugs: CT-388, VK2735, KAI-9531, Olatorepatide)
Dual GLP-1/GIP receptor agonism, the mechanism behind tirzepatide (Mounjaro/Zepbound), represents a powerful therapeutic strategy for metabolic disease by simultaneously activating two key incretin hormone pathways. This co-activation produces synergistic effects, amplifying glucose-dependent insulin secretion, enhancing appetite suppression in the brain, and improving fat metabolism beyond what targeting either the GLP-1 or GIP receptor alone can achieve. As the most crowded class in obesity drug development, this space has attracted a wave of competitors from the US, Europe, and China, all vying to challenge tirzepatide’s lead. Challengers are differentiating through varied strategies: Roche’s CT-388, which reported a 22.5% placebo-adjusted weight loss at 48 weeks, employs biased agonism with minimal ß-arrestin recruitment, potentially improving tolerability. Viking Therapeutics is advancing both injectable and oral versions of VK2735 into Phase 3 trials, while Kailera has launched three Phase 3 trials for KAI-9531 (ribupatide), enrolling 4,700 patients. Meanwhile, Regeneron, having licensed olatorepatide from China’s Hansoh Pharma, is exploring a cardiovascular combination approach by pairing it with the PCSK9 inhibitor Praluent. The critical question remains whether any challenger can leverage these differentiators—be it superior efficacy, better tolerability, greater convenience, or lower price—to capture a meaningful share of the market from the well-entrenched tirzepatide.
🆕 NEWLY REGISTERED TRIALS (8 in last week)
XW003 Phase 3 trial evaluating its effect in obese participants with obstructive sleep apnea (OSA) receiving positive airway pressure therapy (Hangzhou Sciwind Biosciences, n=140).
[Weight Loss/Efficacy | New Indications]
Trials: NCT07434050 | Mechanism: GLP-1 receptor agonist
AMG 133 Phase 1 assessing the effect of kidney impairment on its pharmacokinetics (Amgen, n=44)
[Safety/Tolerability]
Trials: NCT07429045 | Mechanism: GLP-1 agonist / GIP antagonist (antibody-peptide conjugate)
AMG 133 Phase 1 study investigating the drug’s effect on gastric emptying in healthy volunteers (Amgen, n=57)
[Safety/Tolerability]
Trials: NCT07429032 | Mechanism: GLP-1 agonist / GIP antagonist (antibody-peptide conjugate)
Olatorepatide Phase 2 trial for adults living with overweight or obesity in the US (Regeneron Pharmaceuticals, n=120)
[Weight Loss/Efficacy]
Trials: NCT07431086 | Mechanism: Dual GLP-1/GIP agonist
GLP-1 RA therapy Phase 3 trial investigating its impact on osteosarcopenia in older women with diabetes (Emory University, n=20)
[New Indications]
Trials: NCT07428746 (GLOW) | Mechanism: GLP-1 receptor agonist
GLP-1 RA for Stage 1 Type 1 Diabetes Phase II trial investigating if a GLP-1 receptor agonist can delay or prevent the onset of clinical T1D (Children’s Hospital Medical Center, Cincinnati, n=15)
[New Indications]
Trials: NCT07430332 | Mechanism: GLP-1 receptor agonist
Semaglutide implant Phase 1 evaluating the safety, tolerability, and pharmacokinetics of a new subcutaneous delivery system (Vivani Medical, n=20)
[Safety/Tolerability | Novel Delivery]
Trials: NCT07430059 (SLIM-1) | Mechanism: GLP-1 receptor agonist
AMG 133 Phase 1 study evaluating its pharmacokinetics and safety in participants with varying degrees of hepatic impairment (Amgen, n=36)
[Safety/Tolerability]
Trials: NCT07428525 | Mechanism: GLP-1 agonist / GIP antagonist (antibody-peptide conjugate)
This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.
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