With results from highly anticipated trials of Eli Lilly’s orforglipron and Viking Therapeutics’ VK2735 “underwhelming” investors, William Blair’s Andy Hsieh predicts weight loss pills will play a bigger role in low- and middle-income countries than in the U.S.
Oral weight loss therapy results are here—and they’re not what Wall Street expected. Weight loss pills are projected to capture 25% of the anti-obesity medication market by 2030. But with shares of both Eli Lilly and Viking Therapeutics tumbling after reporting efficacy results for their respective candidates inferior to those generated by weight loss jabs, just how game-changing will these pills be?
“Especially in the U.S., I think the majority of the market share will still be within the injected peptides,” Andy Hsieh, an analyst at William Blair, told BioSpace. “In the U.S., we just want to get the best out there, maximum weight loss, and then kind of go from there.”
In fact, William Blair, which covers Viking, projects that 80% to 90% of the potential revenue from VK2735 will come from its subcutaneous formulation, with the remainder generated by the pill version, Hsieh said.
Where oral weight loss therapies could really make their mark is in low- and middle-income countries, “where the healthcare infrastructure is not as robust,” Hsieh said. In these nations, “the oral, small molecule option could be very, very interesting,” because refrigeration is not required. “That’s huge.”
The generally accepted efficacy benchmark that Lilly’s orforglipron missed—sending the company’s stock down more than 14% on Aug. 7—is the 12% to 13% placebo-adjusted weight loss established by Novo Nordisk’s subcutaneous Wegovy (semaglutide). Against this standard, orforglipron paled, generating 9.1% placebo-adjusted weight loss at 72 weeks, according to an Aug. 7 note from William Blair. Meanwhile, 50 mgs of oral Wegovy led to 12.7% weight loss at 68 weeks in the OASIS-1 trial, while a 25-mg dose generated a 11.4% reduction in the 64-week OASIS-4 trial, per Truist Securities.
Tolerability is another key factor. While oral VK2735 showed efficacy close to a best-case scenario, according to some analysts, eliciting 10.9% placebo-adjusted weight loss after just 13 weeks, a greater percentage of trial participants dropped out of the Phase II trial.
“The aspirational goal [for oral therapies] is to replicate the efficacy . . . the maximum weight loss relative to the injectables,” Hsieh said. “So far, we have not seen that, at least in the context of equaling weight loss while at the same time providing acceptable tolerability profile.”
Apples to Oranges
So far, in the oral weight loss space, Novo, Lilly and Viking have generated the biggest headlines, with Structure Therapeutics set to read out results from two Phase IIb trials of its oral GLP-1 aleniglipron in obesity by the end of this year.
Comparison between orforglipron, Wegovy and oral VK2735, however, is not apples to apples. It’s small molecules to peptides. Orforglipron is a small molecule, while both oral Wegovy and oral VK2735 are peptides.
This difference in modality could have implications when it comes to manufacturing, analysts have noted.
While BMO Capital Markets analyst Evan David Seigerman and colleagues had previously suggested that orforglipron’s manufacturing advantages as a small molecule could be potentially influential in the battle for market share, he recently changed his tune after spending time with Novo and investors.
“Small molecule manufacturing will always be cheaper than peptides, but Novo says they have supply for a launch,” Seigerman told BioSpace earlier this month. “Clinical profile is going to drive the narrative and market share.”
Novo CEO Maziar Mike Doustdar expressed this confidence in a statement emailed to BioSpace. “Our data have demonstrated that Wegovy in a pill has an average 16.6% reduction in body weight, and we will be laser-focused on getting this product to patients without supply constraints in the U.S.,” he said.
But Hsieh noted another convenience factor to consider between peptides and small molecules. For peptides, “there is a concern when it comes to food effect,” he said, adding that Novo’s Rybelsus for type 2 diabetes needs to be taken on an empty stomach, ideally with no more than four ounces of water, followed by a 30-minute fasting period. “With orforglipron, you don’t have that. Having that small molecule provides that freedom away from this food effect.”
Truist analysts in a note published Aug. 19 highlighted another key difference between the oral VK2735 readout and that of its larger competitors: length of the treatment period. To make comparisons between oral VK2735’s weight loss at 13 weeks and orforglipron’s 72-week data and oral semaglutide 25mg’s 64-week data would be a “gross mischaracterization” of the candidate’s efficacy, given that weight loss doesn’t typically plateau until 30 weeks or later. As Lilly has yet to share weight loss trend data over time, Truist said the best comparison is 25 mg oral Wegovy, which showed around 4% placebo-adjusted weight loss at week 12. “Against that backdrop, oral VK2735’s 30 mg, 60 mg, 90 mg and 120 look numerically superior.”
Hsieh, for one, is eager to see “the weight loss curve” when Lilly reveals full data from orforglipron’s Phase III ATTAIN-1 trial at the European Association for the Study of Diabetes (EASD) annual meeting next month in Vienna, Austria.
At the American Diabetes Association’s annual conference in Chicago earlier this year, orforglipron’s efficacy appeared to plateau early, Hsieh said. “It’ll have implications potentially to other small molecule orals in the market if you’re seeing this early plateauing effect.”
The Real World
With all of this to consider, it remains to be seen how patients and physicians will react to the rollout of the first oral weight loss drug. Market watchers may not have to wait long to find out—Novo submitted a new drug application to the FDA for oral Wegovy in May and expects a decision by the end of this year.
Eli Lilly is up next, with Ken Custer, president of Lilly Cardiometabolic Health, telling analysts on the company’s second-quarter earnings call that despite the efficacy miss, a regulatory submission is planned for orforglipron by the end of the year.
As for Viking, the company said on a post-readout call that it plans to discuss with the FDA the path forward for oral VK2735—which could mean either a Phase IIb trial or moving straight to Phase III, according to Hsieh. If Viking were to begin a two-year Phase III study in 2026, Hsieh said the drug could hit the market between 2029 and 2030.
As it currently stands, Novo—which has seen its market cap plummet by around $430 billion since its heyday in June 2024 and has been largely bested by Lilly in the obesity space with injectables—appears to be well-positioned in the oral weight loss game. In addition to its likely first-to-market advantage for oral Wegovy, which has demonstrated superior efficacy to orforglipron, Novo also announced plans in June to take its oral amylin analog amycretin, as well as a subcutaneous form of the drug, into Phase III development for obesity in the first quarter of 2026.
Following the lower-than-expected weight loss generated by orforglipron in ATTAIN-1, Seigerman and his BMO colleagues wrote to investors that Novo’s semaglutide “is the new favorite in the oral segment.”
