As Eli Lilly (NYSE: LLY) and Novo Nordisk (Nasdaq Copenhagen: NOVO-B) scramble to bring an oral glucagon-like peptide 1 (GLP-1) receptor agonist to market for obesity, a much smaller potential rival spotlighted positive mid-stage clinical data that captivated investors enough to send its share price more than doubling this past week.
Structure Therapeutics (NASDAQ: GPCR) shares soared 102% after it reported positive data from its Phase II ACCESS clinical program assessing its oral GLP-1 candidate aleniglipron in people with obesity and/or overweight with at least one weight-related co-morbidity. Aleniglipron (formerly GSBR-1290) is designed to be a biased G protein-coupled receptor (GPCR) agonist, which selectively activates the G-protein signaling pathway.
If approved, Structure would compete with oral GLP-1s for weight management by the leading obesity drug developers, whose candidates could both win FDA approval in the new year.
Novo Nordisk’s once-daily oral 7.2 mg Wegovy® (semaglutide) is the subject of a supplemental New Drug Application under FDA review, with positive data from the Phase III OASIS 4 trial (NCT05564117) released over the past year. In data published in The New England Journal of Medicine, Novo Nordisk reported trial participants receiving oral semaglutide showed a mean change in body weight from baseline to week 64 of -13.6% compared with -2.2% for placebo.
Lilly’s orfoglipron is in Phase III trials with data due in 2026. Orfoglipron dazzled investors in August with data showing patients taking the pill lowered their weight by an average of 10.5% (22.9 lbs) vs. 2.2% (5.1 lbs) with placebo. Analysts have projected more than $10 billion in annual sales for orfoglipron.
Last month, the FDA awarded two of its Commissioner’s National Priority Vouchers to orfoglipron and oral Wegovy, under a pilot program that grants the vouchers to products whose developers have agreed to increase affordability, manufacture the product in the United States as a national security issue, or address an unmet public health need. The vouchers entitle developers to have their drugs reviewed within 1–2 months following a one-day “tumor board style” meeting consisting of team-based review by a multidisciplinary group of physicians and scientists.
Up to 15% mean weight loss
Structure announced data showing that at 36 weeks, treatment with the 120 mg dose of aleniglipron led to a placebo-adjusted mean weight loss of 11.3% (27.3 lbs) in the core Phase IIb ACCESS trial (NCT06693843), whose active arms had a 10.4% adverse event (AE)-related treatment discontinuation rate.
Mean weight loss rose to 15.3% (35.5 lbs) in patients treated with 240 mg of aleniglipron in the Phase II ACCESS II trial (NCT06703021), where the discontinuation rate related to adverse treatment events averaged 10.4% across all three doses studied (120 mg, 180 mg, and 240 mg).
“For the higher doses, the observed weight loss data at 36 weeks with no weight loss plateau is potentially best-in-class for oral small molecule GLP1s,” Structure Therapeutics CEO Raymond Stevens, PhD, said in a statement.
One analyst stops short of agreeing with Stevens, while opining that aleniglipron could make its way to market following orfoglipron.
“While it is premature to declare aleniglipron as best-in-class based on the available data, we are reiterating our Outperform rating given the large market opportunity and aleniglipron’s potential to be the second oral small-molecule GLP-1 receptor agonist to be approved after orforglipron,” Andy T. Hsieh, PhD, a partner and biotechnology analyst with William Blair, wrote in a research note.
Hsieh, however, acknowledged that aleniglipron’s data was comparable to that of orfoglipron: Thirty-six weeks of treatment with aleniglipron led to weight loss of 8.2% among participants dosed at 45 mg, 9.8% at 90 mg, and 11.3% at 120 mg—a notch above the 11.2% weight loss of 36 mg orfoglipron in a Phase II trial, and a notch below the roughly 11% measured visually in the Phase III ACHIEVE-1 trial (NCT05971940).
More frequent vomiting
One concerning set of data was the higher frequency of vomiting in Structure’s Phase IIb ACCESS trial vs. Lilly’s ATTAIN-2 trial of orforglipron.
Structure reported vomiting in 18 (40%) of 45 mg aleniglipron participants (of which 6.7% were severe cases), 29 (44.6%) of 65 90 mg participants (including 3.1% severe cases), and 20 (31.7%) of 63 20 mg patients (including 1.6% severe cases), compared with 5.4% and no severe cases among placebo patients
Lilly, by contrast, reported its highest vomiting percentage as 23.1% of patients treated with 36 mg orforglipron in the ATTAIN-2 trial (NCT05872620), with the percentages dropping to 20.2% of patients taking the 12 mg dose and 12.8% of 6 mg participants—compared with 3.8% of placebo patients.
Structure noted, however, that it effectively mitigated vomiting and other gastrointestinal adverse events in its first two treatment cycles by starting patients on a lower 2.5 mg dose in its two additional Phase II studies for aleniglipron. Structure saw no discontinuations of treatment related to adverse events in a 71-participant body composition study (NCT07169942) designed to assess aleniglipron’s effects on body composition in participants with obesity. Participants began with 2.5 mg for the first four weeks (instead of the 5 mg used in ACCESS and ACCESS II.
Structure is also evaluating aleniglipron in an open-label extension study (within NCT06693843) in which ACCESS participants who received placebo were transitioned to aleniglipron starting at 2.5 mg, titrating monthly to a target dose of 120 mg. Initial results showed weight loss in all dose cohorts out to 44 weeks, with no evidence of a weight loss plateau.
Data was positive enough across the ACCESS studies, Structure said, that it plans to ask the FDA to hold a Type B End-of-Phase II meeting in the first half of next year to finalize the design of the Phase III program it expects to begin in mid-2026. Current plans are for a starting titration dose of 2.5 mg, with the aim of evaluating multiple doses up to 240 mg.
Raising sales forecasts
Hsieh cited the positive data in raising William Blair’s peak sales estimate for aleniglipron in the United States and Europe by 53%, from $3.8 billion to $5.8 billion, as well as his firm’s estimate of the probability of success from 55% to 65%.
Jefferies analyst Roger Song, MD, went even higher, laying out a “base case” or most probable scenario for aleniglipron of $6 billion in risk-adjusted peak sales in obesity with a 75% probability of success. The forecast jumps to $7.9 billion with a 100% probability of success in Jefferies’ “best case” scenario.
“GSBR-1290 has the potential to capture meaningful market share in obesity and diabetes,” Song wrote in a research note.
At Morgan Stanley, pharma and biotech analyst Terence Flynn is projecting annual sales for aleniglipron that are better than Jefferies’ base case, modeling worldwide unadjusted sales of $6.3B in 2040 following a U.S. launch in 2028, as reported by TipRanks.
As StockWatch reported in September, analysts have projected Lilly’s orfoglipron to have even higher sales that range from about $10 billion (HSBC), to $13.5 billion (Leerink Partners), $15.5 billion (consensus of analysts cited by MarketWatch), and $25 billion (Jefferies).
A second Jefferies analyst, Akash Tewari, said Lilly’s orfoglipron remains tops among oral GLP-1 candidates for obesity despite data from Structure and a second oral GLP-1 drug developer, Chinese-based Ascletis Pharma.
On December 8, Ascletis announced positive topline data from a 13-week Phase II trial (NCT07002905) assessing three dosages of its oral once-daily GLP-1 ASC30 for obesity. Treatment with ASC30 led to placebo-adjusted mean body weight reductions of 5.4% for the 20 mg dose, 7.0% for 40 mg, and 7.7% 60 mg. Vomiting rates for those doses were 22%, 25%, and 30%, respectively.
“We think these datasets are important for the oral GLP-1 space as: a) both aleniglipron & ASC30 look like viable assets, [and] b) data support the ability to modify tx [therapeutic] profile by adjusting dosing/titration schedules,” Tewari observed in a research note. “We don’t see aleniglipron or ASC30 as differentiated & remain skeptical that either will show an improved profile vs Orfo in a global obesity Ph3 (which could be increasingly harder to run given geographical variability.
“Overall, we continue to believe Orfo is the best-in-class oral small molecule GLP-1,” Tewari concluded.”
94% one-week gain
Rising sales forecasts on top of strong data and Structure’s plans to advance aleniglipron into Phase III studies explain in part the 102% leap in Structure’s share price on December 8, from $34.56 to $69.98.
Shares yo-yoed the rest of the week, falling nearly 5% to $66.74 Tuesday, then rebounding 3% to $68.94 Wednesday, before heading back down 2% to $67.44 Thursday and finishing the week on Friday, dipping 0.6% to $67.06, for a 94% one-week gain.
Structure shares year-over-year have more than doubled, roaring 111% from $31.71 on December 12, 2024. Over the past six months, shares have more than tripled, zooming 202% from $22.22 on June 12.
Why such a strong surge for Structure? Turns out there may be more than the data and rising sales forecasts.
Hsieh said another likely reason is the expectation by investors and other market watchers that Structure will find itself a takeover target, the way another obesity drug developer, Metsera, sparked a bidding war. Pfizer’s up-to-$10 billion offer bested that of Novo Nordisk, which pulled out after President Donald Trump signaled that Washington favored the U.S. pharma giant.
“We assume that GPCR partners aleniglipron, but it is possible that there could be strategic interest in acquiring the company, which drives stock upside beyond our price target,” David Risinger, a senior managing director and senior research analyst covering diversified biopharmaceuticals with Leerink Partners, wrote in a research note.
In that note, Risinger more than doubled Leerink’s 12-month price target on Structure shares 105% from $44 to $90, citing the positive data from ACCESS and ACCESS II.
Also raising their price targets on Structure:
- Stifel (Annabel Samimy)—Up 80% from $50 to $90, maintaining “Buy” rating
- Citigroup (Samantha Semenkow, PhD)—Up 67% from $60 to $100, maintaining “Buy” rating.
- Clear Street (Kaveri Pohlman, PhD)—Up 62% from $61 to $99, maintaining “Buy” rating
- Citizens Capital Markets (Jonathan Wolleben)—Up 38% from $87 to $120, maintaining “Market Outperform” rating
- Morgan Stanley (Terence Flynn, PhD)—Up 4% from $120 to $125, maintaining “Overweight” rating
Novo Nordisk and Lilly have been bolstering their metabolic and cardiovascular pipelines via acquisitions. Novo Nordisk committing up to $5.2 billion to acquire Akero Therapeutics (NASDAQ: AKRO) and its Phase III fibroblast growth factor 21 (FGF21) analogue efruxifermin for metabolic dysfunction-associated steatohepatitis (MASH), while Lilly bought Verve Therapeutics and its gene edited cardio therapy pipeline led by PCSK9-targeting VERVE-102 for up to $1.3 billion.
Leaders and laggards
- Abivax Société Anonyme (Euronext Paris and NASDAQ: ABVX) shares climbed 16% this past week on speculation among investors that the company may be acquired by Eli Lilly (NYSE: LLY). Shares began the week rising 1% from €93.30 ($109.50) to €94.30 ($110.67) on December 8, jumped 9.5% Wednesday from €105 ($123.23) to €115 ($134.97), and inched up another 0.7% Thursday to €115.80 ($135.91) before sliding 6% Friday to €108.20 ($126.99). Similar speculation posted on the website Betaville led to jumps in the price of Abivax’s American depositary shares in September and November. The takeover talk was touched off by Abivax announcing dazzling Phase III data for its lead pipeline candidate, the oral ulcerative colitis (UC) drug obefazimod. That news caused Abivax’s shares to catapult an eye-popping 586% from €8.90 ($10.44) to €54.30 ($63.73) on July 23.
- LENZ Therapeutics (NASDAQ: LENZ) shares tumbled 26% from $24.50 to $18.14 Friday after the company said in a regulatory filing it was aware of an adverse event report submitted to the FDA Adverse Event Reporting System (FAERS) describing a retinal tear in a patient using VIZZ™ (aceclidine ophthalmic solution) 1.44%. “Several days after starting treatment, but on a non-dosing day, the patient observed a change in vision and was subsequently diagnosed with a retinal tear, and received laser retinopexy. The patient is recovering well,” LENZ stated, adding: “Independent retina specialists consulted as part of our assessment noted that the patient had multiple pre-existing risk factors that make spontaneous retinal events more likely, and therefore a causal relationship to VIZZ remains uncertain.” The patient’s history included bilateral lattice degeneration, prior peripheral laser treatment, and a previous retinal tear, LENZ added.
- Wave Life Sciences (NASDAQ: WVE) shares more than doubled, rocketing 147% from $7.49 to $18.52 on December 8 after the company announced positive interim data from the ongoing first-in-human Phase I INLIGHT trial (NCT06842186) assessing its obesity candidate WVE-007, an Inhibin subunit beta E (INHBE) GalNAc-conjugated siRNA that incorporates Wave’s oligonucleotide chemistry and stereopure interfering nucleic acid (SpiNA) next-generation siRNA design. Wave said a single 240 mg dose of WVE-007 improved body composition and led to a 9.4% reduction in visceral fat, a 4.5% reduction in total body fat (3.5 lbs), and a 3.2% increase in lean mass (4.0 lbs) as measured by DEXA scan at Day 85. WVE-007 also showed a favorable safety profile as well as durable reductions in serum Activin E that support potential once or twice-yearly dosing, Wave added.
