Here are five oral obesity candidates that, according to Mizuho’s Graig Suvannavejh, could change the weight loss game.
Highly anticipated Phase III data for Eli Lilly’s next-generation oral GLP-1 therapy, orforglipron, dropped last week, adding new energy to an already hot weight-loss space.
In the Phase III ATTAIN-1 study, orforglipron elicited 12.4% average weight reduction at 72 weeks, versus 0.9% in placebo comparators. Nearly 60% of patients on the drug’s highest dose lost 10% of their body weight.
While Lilly claimed a late-stage victory for orforglipron, analysts weren’t as effusive. Writing to investors on Aug. 7, Truist Securities noted that the pharma’s readout “leaves room for competition.”
William Blair agreed. “In what we view as a once-in-a-blue-moon occasion in the biopharma sector, Eli Lilly’s obesity franchise underperformed” compared with the consensus expectation that orforglipron could deliver efficacy matching injectable drugs, analysts wrote on Aug. 7, adding that ATTAIN-1’s data present a chip in Lilly’s “otherwise impenetrable obesity franchise.”
Still, despite the underwhelming readout, orforglipron stands out in the increasingly crowded obesity space because it comes in the form of a poppable pill, as opposed to an injection.
In an email to BioSpace ahead of the ATTAIN-1 readout, Andy Hsieh, a healthcare research analyst at William Blair, characterized orforglipron as “the de facto leader” in the industry’s oral obesity push, as a “first-in-class compound in this therapeutic category.”
While flagging safety concerns, such as nausea, vomiting and constipation, Hsieh said William Blair still sees orforglipron as “positioned to potentially expand the market,” opening obesity treatments up to patients who are “extremely needle-phobic” and those who simply prefer pills to injections.
Graig Suvannavejh, managing director of Equity Research at Mizuho Securities, agreed. Oral obesity therapies “will be a ‘game changer’” for the space, he told BioSpace in an email.
Unlike injections, “orals have less of a learning curve for patients to self-apply,” he explained. Doctors also typically prefer prescribing orals, which patients can pick up at pharmacies, over injectables, for which they have to see specialists. From the companies’ perspective, Suvannavejh argued that oral small-molecule drugs are easier to manufacture, which in turn could “increase accessibility and lower prices.”
Like Hsieh, Suvannavejh said he sees orforglipron as “the most advanced oral GLP-1 in clinical development,” noting that the drug is well-positioned for commercial success. “Having first mover to the market status will likely mean a lot,” he said, adding that orforglipron will also benefit heavily from Lilly’s “commercial machinery.”
Still, Suvannavejh noted there will still be space for other oral obesity therapies, not to mention an opening to overtake Lilly in the market. “Recall that Pfizer’s Lipitor was not the first statin approved by the FDA, but ultimately it by far became the dominant statin product of choice,” he said.
Here, BioSpace looks at the lay of the oral obesity land, paying particular attention to those candidates with readouts or milestones in the coming months.
Novo Leads Oral Amylin Push With Amycretin
Arguably the most closely watched asset on this list is Novo Nordisk’s amycretin, in part because it leads a novel and likewise closely watched drug class: oral amylin analogs. The pharma is developing amycretin as both a subcutaneous injection, currently in mid-stage development, and a pill, which is still in early-stage studies.
Whereas the two leading obesity drugs on the market right now—Novo’s Wegovy and Lilly’s Zepbound—target the GLP-1 receptor, amycretin additionally mimics amylin, a hormone in the pancreas that, like GLP-1, helps control appetite and blood sugar levels. In a December 3 note to investors, Leerink analysts highlighted amylin as “the hottest new mechanism for obesity.”
That mechanism, Suvannavejh noted, is potentially complementary to current GLP-1s.
A lot rests on amycretin’s fate. Novo is looking to succeed semaglutide with CagriSema, an injectable weight loss therapy that, like amycretin, targets both GLP-1 and amylin. But CagriSema’s results haven’t been encouraging: A disappointing December 2024 readout triggered a selloff that slashed some $72 billion off the Danish drugmaker’s market cap.
In January, Phase Ib/IIa data showed that a 20 mg subcutaneous dose of amycretin cut weight by up to 22% after 20 weeks. At the American Diabetes Association meeting, follow-on data demonstrated that weight loss improved slightly to 23.9% at 36 weeks. Meanwhile, the oral formulation is still in Phase I development, with results showing it was overall safe and well-tolerated, and could reduce body weight by 13.1% on average after 12 weeks.
Novo last month unveiled plans to take both subcutaneous and oral amycretin into late-stage development for obesity and diabetes, though it did not provide a timeline for when it expects to begin Phase III studies.
Viking Rushes Forward With Oral GLP-1/GIP Analog
Following in Lilly’s footsteps is Viking Therapeutics with VK2735, which targets both the GLP-1 and GIP receptors—the same mechanism employed by Lilly’s blockbuster drug Zepbound.
While VK2735 is more mature as a subcutaneous injection, Viking is also developing an oral formulation of the drug. Phase I data released in March 2024 showed that a 40 mg pill elicited a 3.3% mean reduction in body weight versus placebo over 28 days. The biotech followed this up with data at ObesityWeek 2024 last November, touting an 8.2% average weight loss after 28 days at the highest dose level of 100 mg.
Viking is moving rapidly with both versions of VK2735. The biotech launched the Phase II VENTURE-Oral Dosing study in January and wrapped up enrollment in March, ultimately recruiting 280 patients. The mid-stage trial will test a once-daily dose of VK2735, but its clinicatrials.gov page doesn’t list a dose strength.
Viking expects to report data from VENTURE-Oral Dosing in the back half of the year, according to the company’s second-quarter report last month. But given the pace at which VK2735 has been moving, Hsieh said the study “might read out as soon as next month.”
Roche’s Carmot-Acquired Asset Set to Enter Phase II in 2025
In December 2023, Roche made a serious commitment to the obesity space with the $2.7 billion acquisition of Carmot Therapeutics.
The purchase gave Roche three clinical-stage GLP-1 assets that the pharma at the time said had “best-in-class potential” for obesity, including two subcutaneous injections—the late-stage CT-388 and the mid-stage CT-868—and the once-daily oral candidate CT-996.
Like other GLP-1 analogs, CT-966 promotes the secretion of insulin in response to blood sugar levels, while also slowing down gastric emptying. Uniquely, however, the drug candidate is biased toward a specific cellular pathway, which, according to Genentech’s website, could boost its efficacy while also improving its safety profile. Phase Ib data released in July 2024 demonstrated a 7.3% reduction in body weight after 4 weeks of CT-996 treatment, versus 1.2% in placebo counterparts.
“We are seeing best-in-class efficacy” for CT-996, Suvannavejh said, however noting that Mizuho would still like to see longer-term data from the molecule, as well as confirmation of these early effects in late-stage programs.
Also in July 2024, during the pharma’s Q2 earnings report, CEO Thomas Schinecker told investors it was putting its obesity assets—including CT-996—on the fast track, allowing Roche to bring these molecules “much faster to the market than what’s currently being assumed.” Schinecker called CT-966 a “very good molecule,” noting that Roche is well-positioned to scale its production up using its existing manufacturing network for small-molecule drugs.
A few months later, however, in September, CT-996 hit a speedbump when a readout presented at the 2024 meeting of the European Association for the Study of Diabetes hinted at safety concerns in patients whose doses were rapidly up-titrated. Nausea developed in 85% of these patients. Other gastrointestinal side effects, such as vomiting, constipation and abdominal distension, were likewise common. Gradual dose escalation showed better tolerability.
In Roche’s Q2 report last month, the pharma revealed that it expects to report additional Phase I data for CT-996 in the coming months. A Phase II study for the drug in obesity with or without diabetes is likewise slated for later this year.
Terns Joins Oral GLP-1 Rumble With TERN-601
Adding another contender to the already crowded oral GLP-1 race is Terns Pharmaceuticals, which is developing TERN-601.
While the GLP-1 pill doesn’t open up a novel pathway for treating obesity, Terns hopes to differentiate its molecule in terms of clinical profile. Using its proprietary 3D model of the GLP-1 receptor, Terns has optimized TERN-601’s metabolic stability and pharmacokinetic profile, additionally biasing the asset toward a specific pathway that can combat weight gain.
Phase I data, released in September 2024, showed that patients treated with 740 mg TERN-601 once daily saw a 4.9% placebo-adjusted weight loss over 28 days. At this top dose, 67% of patients lost at least 5% of their body weight. Terns presented additional early-stage results for TERN-601 at ADA in June, touting weight reduction of up to 5.5% over 28 days. Pharmacokinetic findings identified an effective half-life of 9–10 hours, allowing for 24-hour therapeutic coverage with once-daily dosing.
Terns also hopes to stand out in terms of convenience. TERN-601 has the “simplest dose titration amongst GLP1-RA therapies,” the biotech noted in a June news release, adding that the drug can be given with or without food and can be taken alongside other therapies.
Terns is running the Phase II FALCON study, which recently finished enrollment. Topline data are expected by the end of the year. Last week, the biotech revealed that it is seeking a partner for TERN-601 as it shifts its focus to cancer amid an oversaturated obesity market.
Rhythm Targets Alternate Pathway With Bivamelagon
Of all the assets on this list, Rhythm Pharmaceuticals’ bivamelagon targets arguably the least explored pathway for obesity.
Whereas the majority of weight loss therapies mimic incretin hormones or leverage the amylin approach, bivamelagon activates the melanocortin-4 receptor (MC4R), which according to the company’s website is involved in regulating hunger, caloric intake and energy expenditure. Dysfunctions in MC4R can lead to rare diseases that are characterized by severe obesity and hyperphagia, an abnormally strong and insatiable hunger.
Phase II data released last month point to the potential clinical benefit of bivamelagon’s MC4R-activating action. At a 400 mg dose level, bivamelagon treatment resulted in a 7.7% reduction in body mass index (BMI) over 14 weeks of follow-up among patients with acquired hypothalamic obesity, a rare condition that develops after the hypothalamic region of the brain is damaged.
The higher 600 mg dose lowered BMI by 9.3%. In comparison, over the same time span, placebo comparators lost 2.2% BMI.
Suvannavejh called bivamelagon a differentiated asset that works “with a very unique mechanism of action . . . for a niche disease.” The molecule has promising efficacy, he added, which could potentially set it up for combination regimens down the line. However, “its adverse event profile . . . could potentially limit its uptake,” Suvannavejh said. Indeed, Rhythm’s mid-stage study found one serious complication, rectal bleeding, that led to discontinuation. Some patients also reported localized hyperpigmentation.
Reacting to this mid-stage readout, analysts at Stifel in a July 9 note called bivamelagon’s data strong, adding their belief that the asset is derisked based on efficacy and “mostly derisked on safety, barring something surprising coming up” in late-stage development, though they deem this unlikely.
Following these results, Rhythm now plans to engage with U.S. and EU regulators to plot out a Phase III path for bivamelagon in hypothalamic obesity. The company has yet to provide a target timeline for initiating late-stage studies.
