The release of early-stage data on three oral weight loss drug candidates hints at which companies have the strongest hand, but the comparisons are rife with confounding variables, leaving analysts unsure about where to place their bets.
Novo Nordisk, Roche and Terns Pharmaceuticals used last week’s European Association for the Study of Diabetes annual meeting to present new data on their oral obesity candidates. After four weeks of dosing, the placebo-adjusted weight loss figures were 4% for Novo’s amycretin, 4.9% for Terns’ TERN-601 and 6.1% for Roche’s CT-996.
Slotting the three candidates into a ranking of oral obesity drug candidates by placebo-adjusted weight loss after four weeks enables an early attempt to order the molecules and rival drugs by efficacy. In earlier data drops, the comparable figures were 3.2% for Viking Therapeutics’ VK2735, 3.9% for Eli Lilly’s orforglipron, 4.9% for Structure Therapeutics’ GSBR-1290 and 5.2% for Pfizer’s danuglipron. Based on the figures, Roche and Pfizer hold the top two spots, with Structure and Terns tied for third.
However, it is unclear whether the figures reflect differences between the molecules or the trial designs, analysts warned, noting that these early cross-trial assessments always introduce factors that can confound attempts to compare efficacy.
Roche’s Tolerability Data Disappoint
While Roche saw the most weight loss, Jefferies analysts said in a note to investors that the competitive result “appears driven by rapid titration.” The fast speed at which Roche increased the doses may explain both the strong efficacy and high rates of adverse events seen in the study.
Taken at face value, the data suggest CT-996 is more efficacious and less tolerable than the competition. Yet, the Jefferies analysts said the molecule’s “true competitive profile” will not be known until Roche runs larger Phase II trials, which could dial down efficacy and side effects using lower starting doses and smaller or less frequent dose increases.
For now, the tolerability data are overshadowing the promising efficacy, with Roche reporting rates of nausea, diarrhea and vomiting of 83.3%, 50.0% and 33.3%, respectively, even in the less rapidly titrated cohort. BMO analysts gave their take on the figures and data on Roche’s injectable obesity candidate in a note to investors.
“While Ph 1 results slightly underperformed expectations this week on tolerability, Roche is likely to remain a relevant player in obesity development, even if they are a step behind leaders like Lilly and Novo,” the analysts said.
Novo Faces Manufacturing Questions
Truist analysts said in a note to investors that Novo’s tolerability update on its oral amycretin “was a bit underwhelming” but that reflected the lack of positive differentiation rather than a downside versus other oral GLP-1 drugs. In addition to GLP-1, the molecule engages amylin, enabling it to act on glucose control and appetite via a different pathway than rival drug candidates, BMO analysts described.
“Amylin was one of the hottest topics of the conference, with a number of presenters highlighting the importance of optionality when you are looking to treat [a] heterogeneous disease like obesity,” BMO analysts wrote. “The target offers benefits separate from and synergistic to what we have seen from the GLP-1 class.”
The analysts said the molecule’s efficacy is potentially best in class but added that “given amycretin is a peptide, we would like to hear more from Novo on manufacturing.” Jefferies analysts expanded on why manufacturing could be a problem for Novo.
“Based on conservative Phase I titration info, even our $5bn amycretin WW peak sales may require >30 tonnes of API p.a. if the oral route is prioritized, suggesting reformulation for greater bioavailability through tweaking SNAC technology is critical,” the analysts said.
Terns’ Novel Approach Catches Attention
Terns’ results were in line with the Jefferies analysts’ bull case, with the company reporting weight loss at the upper end of the spectrum achieved by rivals. Gastrointestinal side effects were common, with 88% of people reporting nausea on one dose, but more than 85% of treatment-emergent adverse events were mild. The Jefferies analysts spotted details that could differentiate Terns.
“Here’s what surprised us – we think there’s a possibility [Terns] could have a dose that could thread the needle in larger trial by showing tolerability that could approach [Lilly’s orforglipron] (but too soon to say) despite a less than ideal PK/PD profile with competitive 10-15% 52 week [weight loss],” the analysts said. “Interestingly, [Terns] is taking an approach we have not seen with other oral GLP-1s so far.”
The analysts said the high plasma protein binding, low solubility and high gut permeability of Terns’ drug candidate means the “oral-GLP-1 is accumulating in the gut in a manner that meaningfully extends its effective exposure, pretty similar to a long-acting oral.” The profile could allow Terns to give relatively high doses to maximize weight loss without causing intolerable side effects, the analysts said.
However, the downsides are that the approach requires people to take lots of tablets and high doses with potential variability, the analysts said. Like its rivals, Terns needs to generate Phase II data to start to clear up the questions about its candidate.
