Plateaus, Psoriasis, and Persistent Obesity
Week Of February 14 – February 20, 2026
The theme this week is what happens when GLP-1 monotherapy isn’t enough. Lilly launched ENLIGHTEN-6, a 900-patient Phase 3 that’s the first trial designed specifically for patients with “persistent obesity” who’ve plateaued on incretins, and ramped up 178 trial sites in a single week. I go into both the trial and the biology behind weight loss plateaus in this week’s Spotlight and Mechanism Explained. Meanwhile, Europe approved Wegovy’s higher 7.2 mg dose (21% weight loss in STEP UP), and Lilly showed that pairing Zepbound with its psoriasis drug Taltz can clear skin and cut weight simultaneously. On the other end of the spectrum from persistent obesity, STAT News and the New York Times both ran pieces this week on the opposite concern — patients who don’t want to stop taking GLP-1s and drugs that may work too well — a reminder that the field is complex and that efficacy can’t be reduced to a single narrative.
🔥 THIS WEEK’S KEY DEVELOPMENTS
European Commission approves higher, more effective dose of Wegovy.
On February 17, 2026, Novo Nordisk announced that the European Commission approved a new 7.2 mg once-weekly maintenance dose of Wegovy® (semaglutide injection) for adults with obesity. The approval was based on the STEP UP trial, which showed adults with obesity taking the 7.2 mg dose lost an average of 21.1% of their body weight after 68 weeks, compared to a 2.5% loss for those on placebo. In the trial, 95% of participants on the 7.2 mg dose achieved weight loss of 5% or more, versus 29% for placebo.
Press | Trials: NCT05646706 | Mechanism: GLP-1 agonist
Zepbound/Taltz combo improves skin clearance and weight loss in psoriasis.
Eli Lilly announced that its Phase 3b TOGETHER-PsO trial evaluating Zepbound (tirzepatide) with Taltz (ixekizumab) in adults with psoriasis and obesity met its primary endpoint at 36 weeks. In the study, 27.1% of patients receiving the combination therapy achieved complete skin clearance (PASI 100) and at least 10% weight loss, compared to 5.8% of patients on Taltz alone (p<0.001). A key secondary endpoint showed that 40.6% of patients on the combination achieved PASI 100 versus 29.0% for those taking Taltz alone (p<0.05).
Press | Trials: NCT06588283 | Mechanism: dual GIP and GLP-1 receptor agonist
Zealand Pharma outlines 2026 milestones for petrelintide and survodutide.
Zealand Pharma expects to report 42-week topline data from the Phase 2 ZUPREME-1 trial of its amylin analog, petrelintide, in the first quarter of 2026. The company and its partner Roche plan to advance petrelintide into a Phase 3 program in the second half of 2026. Additionally, topline data from the Phase 3 SYNCHRONIZE™-1 trial of survodutide, partnered with Boehringer Ingelheim, are expected in the first half of 2026, with results from all key trials in the program anticipated throughout the year.
Press | Trials: NCT06926842 (petrelintide) | Mechanism: amylin analog
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
The First ‘Add-On to Incretin’ Mega-Trial Goes Live: ENLIGHTEN-6 Targets Persistent Obesity
Eli Lilly’s ENLIGHTEN-6 trial (NCT07392190) marks a potential paradigm shift in metabolic medicine by formally defining “persistent obesity” not as a failure of monotherapy, but as a distinct clinical indication suitable for combination treatment. This Phase 3 study of 900 participants evaluates eloralintide, a selective amylin receptor agonist that promotes satiety through neural pathways complementary to—but distinct from—GLP-1 mechanisms, specifically in patients who have plateaued on standard weekly incretins. Operational execution has been notably aggressive, with 178 trial sites activated within a single week of the February 2026 launch, signaling high confidence that adding an amylin analogue can unlock further weight loss where incretins alone plateau. Strategically, this approach mirrors oncology’s evolution toward layered regimens, moving beyond the “one-drug-fits-all” model to address the significant subset of patients who remain clinically obese despite current best-in-class therapies. If successful by its 2028 completion, ENLIGHTEN-6 could establish amylin agonism as the standard “add-on” to overcome therapeutic ceilings.
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
Beyond Monotherapy: Why ‘Persistent Obesity’ Is Driving the Next Wave of Combination Trials (Example drug: Eloralintide)
The remarkable success of incretin monotherapies like GLP-1 agonists is tempered by the reality of ‘persistent obesity,’ where a significant subset of patients either fail to achieve meaningful weight loss or, more commonly, hit a weight-loss plateau. This plateau isn’t a failure of willpower but a predictable biological defense; as fat mass decreases, the body fights back by lowering levels of the satiety hormone leptin, increasing the hunger hormone ghrelin, and reducing metabolic rate through adaptive thermogenesis. To break through this physiological stalemate, the field is shifting toward a combination therapy paradigm, exemplified by Eli Lilly’s new ENLIGHTEN-6 trial for eloralintide. This study specifically recruits patients with persistent obesity who are already on a stable incretin regimen, aiming to add a drug with a distinct and complementary mechanism.
Eloralintide is a selective agonist for the amylin receptor, engaging a different set of neural pathways for satiety than GLP-1 agonists. While GLP-1 agonists primarily act on the hypothalamus, amylin signaling is concentrated in the area postrema of the brainstem, providing a separate, powerful brake on food intake. By adding an amylin-based therapy on top of an incretin, the strategy is to counteract the body’s counter-regulatory measures from multiple angles, much like combination chemotherapy targets various pathways to overcome cancer resistance. This add-on strategy — keeping patients on their existing incretin while layering in a complementary mechanism — positions eloralintide alongside competitors like Novo Nordisk’s CagriSema and Amgen’s MariTide in a broader race to move beyond monotherapy and define the next standard of care for patients who plateau.
🆕 NEWLY REGISTERED TRIALS (6 in last week)
Tirzepatide (Spartina) Phase 4 trial evaluating its use for obesity in kidney transplant recipients (Shahid Beheshti University of Medical Sciences, n=30)
[New Indications]
Trials: NCT07423247 | Mechanism: Dual GLP-1/GIP agonist
HDM1005 Phase 3 trial for type 2 diabetes inadequately controlled on metformin, with or without an SGLT2 inhibitor (Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd., n=912)
[Weight Loss/Efficacy]
Trials: NCT07417306 | Mechanism: Dual GLP-1/GIP agonist
ABBV-295 Phase 1 assessing its effect on oral contraceptives in healthy women with overweight or obesity (AbbVie, n=20)
[Safety/Tolerability]
Trials: NCT07414784 | Mechanism: Dual amylin/calcitonin receptor agonist
Survodutide Phase 1 comparing two delivery methods, a pre-filled syringe vs. a pen injector, in healthy adults or those with overweight/obesity (Boehringer Ingelheim, n=56)
[Weight Loss/Efficacy]
Trials: NCT07413913 | Mechanism: Dual GLP-1/glucagon agonist
GIP + Amylin combination Phase 1 trial investigating if the combination reduces gastrointestinal side effects in people with overweight or obesity (Novo Nordisk, n=100).
[Weight Loss/Efficacy]
Trials: NCT07411560 | Mechanism: GIP agonist + amylin analog (cagrilintide)
NNC0662-0419 Phase 2 dose-finding study evaluating blood sugar reduction in people with type 2 diabetes (Novo Nordisk, n=270)
[Weight Loss/Efficacy]
Trials: NCT07415954 | Mechanism: Triple GLP-1/GIP/glucagon agonist
This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.
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