Structure Takes the Next Step, Novo’s Pill Pulls Ahead
Week Of June 13 - June 19, 2026
The oral pill race continues to move along. Structure Therapeutics is the small biotech whose Phase 2 numbers analysts used just last week to call AstraZeneca’s pill “underwhelming.” This week it committed to two large Phase 3 trials of its own. In the Trial Spotlight, I go into what it means when a company takes on the cost and risk of moving into pivotal trials, and where Structure’s drug sits behind Lilly’s already-approved orforglipron. In the Mechanism Explained, I cover the MC4R pathway, the brain’s master appetite switch that comes up in obesity genetics, and why the same receptor that could curb hunger also raises blood pressure, which is the reason why it resists broader druggability. Also this week: Novo’s oral Wegovy is outpacing Lilly’s Foundayo on early scripts, Amylyx nears a readout for a GLP-1 antagonist (very different than agonists) in a post-surgery complication, and the triple agonist UBT251 enters Phase 3.
I also launched GLP-1 Field Guides this week, free, accessible explainers on how each class of these drugs works and where it’s headed, built on the same daily tracker behind this newsletter so they keep up as the field moves. The mono-agonist guide covers the oral race above, from Foundayo to aleniglipron, if you want to go deeper.
🔥 THIS WEEK’S KEY DEVELOPMENTS
Novo Nordisk’s oral Wegovy outpaces Eli Lilly’s Foundayo in early uptake.
According to IQVIA data from its 22nd week on the market, oral Wegovy attracted 159,000 prescriptions in the most recent weekly period, compared to 19,879 for Eli Lilly’s Foundayo in its ninth week. Novo Nordisk also reported that since its January 5 launch, the Wegovy pill has garnered more than 3 million total prescriptions. A Spherix Global Insights survey of 100 physicians suggests the stronger launch is due to physician “familiarity” with the semaglutide compound.
Press | Mechanism: GLP-1
Gan & Lee’s bofanglutide posts 18.5% weight loss in its Phase 3 China obesity trial (GRADUAL-1).
Gan & Lee Pharmaceuticals reported positive topline results from the Phase 3 GRADUAL-1 study (NCT06728124) of bofanglutide, a GLP-1 receptor agonist, in adults with overweight or obesity. Over 52 weeks, the 48 mg dose drove a mean weight reduction of 18.54% and the 24 mg dose 15.12%, versus 1.11% for placebo. These are company-announced topline figures, not yet peer-reviewed.
Press | Trials: NCT06728124 (GRADUAL-1) | Mechanism: GLP-1 receptor agonist
Amylyx nears Phase 3 readout for GLP-1 antagonist avexitide.
Amylyx expects topline results from its pivotal study of avexitide, a GLP-1 receptor antagonist, for post-bariatric hypoglycemia (PBH) in the third quarter. The company estimates PBH affects around 160,000 people in the U.S. If the results are positive, Amylyx plans to submit an NDA as soon as possible and launch the drug next year.
Press | Mechanism: GLP-1 receptor antagonist
Rhythm’s Imcivree shows positive Phase 2 weight loss in Prader-Willi.
Rhythm Pharmaceuticals announced six-month data from its Phase 2 study of Imcivree (setmelanotide) in patients with Prader-Willi syndrome. Patients treated with Imcivree saw a 3.06% mean decrease in body mass index (BMI), with body scans showing a 4.19% reduction in fat mass and a 0.74% increase in lean mass. The company also reported “clinically meaningful” improvements in hyperphagia based on the Hyperphagia Questionnaire for Clinical Trials score.
Press | Mechanism: MC4 receptor agonist
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
From Analyst Favorite to Pivotal Risk: Structure’s Oral GLP-1 Commits to Phase 3
Just last week, the impressive Phase 2 weight-loss data from Structure Therapeutics’ aleniglipron served as the benchmark analysts used to deem a competitor’s results “underwhelming.” This week, Structure moved from a favorable talking point to a company taking a significant risk, registering two pivotal Phase 3 trials for its once-daily oral GLP-1 agonist. The newly unveiled ACCOMPLISH program commits roughly 4,700 patients to determine the future of a promising, but early, small-molecule contender in the competitive obesity market. This move shifts the focus from promising mid-stage data to the immense operational and financial challenge of late-stage development, especially for a smaller biotech.
The program’s design signals a broad strategic ambition, splitting the target population into two distinct, large-scale trials. ACCOMPLISH-1 (NCT07654361) is the larger of the two, enrolling 3,600 adults with obesity or overweight to support a chronic weight management indication. The second trial, ACCOMPLISH-2 (NCT07654374), will enroll 1,100 patients who also have type 2 diabetes, aiming to secure a label in that critical metabolic sub-population. This two-pronged approach separates the populations to maximize the potential label, acknowledging the different efficacy hurdles in each group.
Aleniglipron enters this late-stage race on the back of eye-catching but early Phase 2 results. In its small ACCESS II dose-ranging study (n=85), it posted roughly 16% mean weight loss at 44 weeks with a curve that had not plateaued, which worked out to about 15% placebo-adjusted weight loss at 36 weeks at the top dose. That looks competitive on paper, but it is chasing an established leader: Eli Lilly’s oral orforglipron (Foundayo) was approved earlier this year and is already on the market. And cross-trial weight-loss comparisons are notoriously difficult, since trials differ in length, dose, and how the numbers are reported.
Ultimately, registering these trials transforms the narrative from scientific promise to executional reality. A global 4,700-patient program is a massive undertaking that tests a company’s capital reserves and operational discipline as much as its science. The key questions now are whether aleniglipron’s standout Phase 2 efficacy and tolerability will hold up at a much larger scale and over a longer duration, and whether a focused biotech can execute a program of this magnitude against entrenched pharmaceutical giants.
ClinicalTrials.gov: NCT07654361 (ACCOMPLISH-1, obesity) | NCT07654374 (ACCOMPLISH-2, obesity + type 2 diabetes)
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
Obesity’s Master Switch: Why the MC4R Pathway Explains the Disease but Resists the Drug (Example drugs: Setmelanotide, Bremelanotide)
This week at ENDO 2026, Rhythm Pharmaceuticals reported positive interim Phase 2 data for setmelanotide in Prader-Willi syndrome: roughly a 3% mean BMI reduction at six months, with meaningful improvement in extreme hunger. It is a useful window into the melanocortin-4 receptor, or MC4R, the brain’s master switch for appetite. This is the homeostatic hunger circuit in the hypothalamus, a separate system from the reward circuits we covered in March. Deep in that circuit, two opposing sets of neurons fight over one shared thermostat: POMC neurons release a signal called alpha-MSH that turns MC4R on and suppresses appetite, while AgRP neurons do the opposite, dialing it down to drive hunger. The main upstream input is leptin, the hormone fat tissue releases in proportion to fat stores, which raises MC4R tone to tell a well-fed body it can stop eating. When you lose weight, leptin falls and MC4R tone drops, and that withdrawal of the “stop eating” signal is part of why the body defends its set point, the regain biology we covered on April 3.
The genetics of obesity point straight at this junction. MC4R loss-of-function mutations are the single most common single-gene cause of severe, early-onset obesity, and the receptor is also one of the most reliably replicated common-variant signals in the genome, in the same tier as FTO (the fat-mass-and-obesity-associated gene, the best-known common obesity-risk gene). The causality even runs both ways: loss-of-function variants raise weight, while rare gain-of-function variants lower it and protect carriers against type 2 diabetes and heart disease. Yet the modern drugs mostly target the hormones that feed into this switch rather than the switch itself. Leptin truly requires the melanocortin pathway, and amylin largely depends on it as well, even though it enters through the brainstem (covered in May). GLP-1 is the exception. It nudges POMC neurons but works through parallel, MC4R-independent circuits, and the proof is direct: tirzepatide produces nearly the same weight loss in people who carry MC4R mutations as in people who do not.
So why not just drug the master switch directly? Because MC4R does not only control appetite. It also sits on the nerves that set sympathetic “fight-or-flight” tone, so activating it to curb hunger also raises blood pressure and heart rate, and older MC4R agonists aimed at common obesity were abandoned partly for this cardiovascular liability. The paradox is striking: people who lack a working MC4R are obese yet protected from high blood pressure, while giving an MC4R agonist does the reverse and pushes blood pressure up. The same receptor runs both appetite and blood pressure. That is why setmelanotide is cleared only for rare conditions, where it restores a broken upstream pathway rather than forcing an intact one, and why it still carries blood-pressure monitoring even there. The one mainstream attempt routes around the problem entirely: Palatin Therapeutics tested its MC4R agonist bremelanotide on top of tirzepatide, with positive early-2025 Phase 2 data, while a handful of next-generation “biased” agonists are in early development trying to split the weight benefit from the blood-pressure cost. Safely turning the body’s master appetite switch for everyone is still out of reach.
🆕 NEWLY REGISTERED TRIALS (5 in last week)
Mazdutide Phase 4 investigating its effect on coronary plaque in overweight or obese patients with coronary atherosclerosis (China National Center for Cardiovascular Diseases, n=116)
[New Indications]
Trials: NCT07657676 | Mechanism: Dual GLP-1/glucagon agonist
LY4174794 Phase 1 trial investigating a new drug for obesity or overweight in otherwise healthy participants (Eli Lilly and Company, n=108)
[Weight Loss/Efficacy]
Trials: NCT07654972 | Mechanism: Mechanism not disclosed
ACCOMPLISH-2 Phase 3 evaluating Aleniglipron in adults with obesity or overweight and type 2 diabetes (Structure Therapeutics, n=1100)
[Weight Loss/Efficacy]
Trials: NCT07654374 | Mechanism: GLP-1 receptor agonist
ACCOMPLISH-1 Phase 3 trial of Aleniglipron for obesity or overweight with weight-related comorbidities (Structure Therapeutics, n=3600)
[Weight Loss/Efficacy | Safety/Tolerability]
Trials: NCT07654361 | Mechanism: GLP-1 receptor agonist
UNIGUIDE-2 Phase 3 trial of UBT251 injection for type 2 diabetes inadequately controlled on metformin and other common therapies (United Bio-Technology, n=956)
[New Indications]
Trials: NCT07653477 (UNIGUIDE-2) | Mechanism: Triple GLP-1/GIP/glucagon agonist
This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.
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