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iStock, RudyBalasko While Eli Lilly’s orforglipron is top of mind heading into the European Association for the Study of Diabetes meeting this week, experts told BioSpace the conference will also provide important insights into the therapeutic benefits of incretin therapies beyond weight loss. This year’s annual meeting of the European Association for the Study of Diabetes comes at a pivotal time. Over the last month, several high-pro have shaken up the cardiometabolic space, particularly in obesity. Eli Lilly’s orforglipron, which many analysts regard as the leading oral weight loss pill in development, fumbled in late-stage assessments. While the candidate outperformed placebo at reducing body weight in patients with overweight or obesity—regardless of the presence of type 2 diabetes—analysts broadly agree that orforglipron’s Phase III performance has left the door open for competitors. But even the challengers have come up short. While Viking Therapeutics reported a 10.9% placebo-adjusted weight reduction for its investigational pill at 13 weeks, tolerability issues turned investors off. Phase II data for VK2735 pointed to a relatively high rate of study dropouts due to adverse events, as well as an excess of gastrointestinal side effects. Meanwhile, Novo Nordisk appears to have quietly emerged as the new frontrunner , as it anticipates approval of an oral version of its blockbuster GLP-1 Wegovy by year’s end. Against this backdrop, EASD will convene Sept. 15 to 19 in Vienna, Austria. Unlike at the American Diabetes Association congress in June , however, “nothing splashy” seems to be lined up for this year’s EASD meeting, Graig Suvannavejh, senior biotechnology and biopharmaceuticals analyst at Mizuho Securities, told BioSpace in an email. For Suvannavejh—who also has his eye on orforglipron—the EASD will provide attendees with the opportunity to dig into these recent readouts, with a particular focus on safety data. “The space is evolving in terms of trying to find more effective and safer/better tolerated treatments,” he said. The conference will also look ahead—past the current focus on obesity and toward other potential areas of application for these promising therapies. “EASD will probably recognize obesity as a chronic, treatable disease,” Mihail Zilbermint, associate professor of Clinical Medicine at the Johns Hopkins School of Medicine, told BioSpace in an email. Aside from the spotlight on obesity, he said, there will also be a “breadth of sessions” tackling other, less trendy topics such as devices and digital health, artificial intelligence and nutrition. “I believe the meeting will help advance both the science and the public health conversation around obesity and diabetes care,” Zilbermint added. Here, BioSpace looks at some of these key topics, and how they could change the broader cardiometabolic space moving forward. Safety Under the Spotlight Suvannavejh, along with much of the field, is anticipating Lilly’s presentation of further data from the Phase III ATTAIN-1 trial at EASD. For Suvannavejh, the initial negative reaction to orforglipron’s 72-week data from the ATTAIN-1 was due not to underwhelming efficacy but the “surprisingly high levels of adverse events.” According to data provided by Suvannavejh, placebo-adjusted nausea rates were at 11%, 16% and 14% for the 6-mg, 12-mg and 36-mg doses of orforglipron at 40 weeks, respectively. These frequencies then jumped to 18%, 25.5% and 23.3% at 72 weeks. Similarly, Mizuho flagged an increase in the rate of vomiting over time. “Usually the side effects for GLP-1s occur in the earlier stages of taking the drug,” Suvannavejh explained, whereas Phase III data suggest that orforglipron’s toxicities occur later in its treatment course. This “wouldn’t be ideal if the goal was to take the pill as a maintenance therapy for the rest of your life,” he added. Suvannavejh expects Lilly’s EASD presentation to provide “more clarity” regarding the safety and tolerability pro orforglipron, particularly the point during the 72-week treatment period that patients experienced nausea or vomiting. Such data will help investors and analysts better gauge the role that orforglipron could play in a weight-loss treatment regimen, he said. Aside from orforglipron, Suvannavejh is also keeping an eye on two other presentations that could provide additional granularity on the safety findings of two previous readouts. The first, on Sept. 16, is for Novo Nordisk’s amycretin, an analog of the amylin hormone. Like the currently dominant GLP-1 therapies, amycretin works by suppressing appetite and controlling blood sugar levels. Novo is developing both oral and subcutaneous formulations of amycretin. Phase Ib/IIa data released in June showed that a 60-mg subcutaneous dose of amycretin can lower body weight by 24.3% at 36 weeks. Safety data at the time were sparse, however, with Novo announcing only that adverse events were “ mild or moderate in severity ,” occurring in a dose-dependent manner. Suvannavejh is also looking out for additional safety details on Zealand Pharma’s dapiglutide, a subcutaneous GLP-1 and GLP-2 dual agonist. Dapiglutide elicited 11.6% weight reduction at 28 weeks in a Phase Ib trial , with analysts predicting the potential for more. As in the case of amycretin, safety data for dapiglutide were wanting: Zealand revealed only that there were no serious or severe treatment-emergent adverse events, with two study dropouts. Suvannavejh concedes that such additional safety data from Novo and Zealand could be “unlikely” but nevertheless notes that they would be timely, “given that safety/tolerability appears to be at the forefront of current discussions.” Beyond Obesity While experts anticipate obesity to be the main attention-grabber at EASD, the conference is also expected to look beyond weight loss, probing the other clinical upsides of incretin therapies. Zilbermint pointed to Novo’s SOUL trial on oral semaglutide and cardiovascular outcomes as being particularly important, as it provides further evidence of the benefits of GLP-1 therapies outside of glycemic control and weight loss. Findings from SOUL could, he added, set the stage for GLP-1s to provide “long-term cardiometabolic protection in pill form.” SOUL is testing the effects of Rybelsus, an earlier oral brand of semaglutide, on major adverse cardiovascular events (MACE), such as stroke and heart attack, in more than 9,600 patients with type 2 diabetes. Novo published data from this trial in March, touting a significant reduction in MACE . At the time, analysts at BMO Capital Markets were left unconvinced, writing in a March 31 note that SOUL’s data were “complicated” and pointed to an “inconsistent benefit” of oral semaglutide across the different components of MACE. EASD, which will see a handful of presentations on SOUL , could help clear that up. As Zilbermint suggests, SOUL is part of a broader push by the industry to describe the cardiovascular benefits of GLP-1 therapies. Earlier this month, for instance, Novo released a readout from its Phase III STEER trial, which compared injectable semaglutide directly against Lilly’s tirzepatide in patients with overweight or obesity who had established cardiovascular disease but not diabetes. Data leaned in Novo’s favor, showing a 57% drop in MACE risk versus tirzepatide. “Over the past year, incretin-based therapies have redefined what is possible, with benefits extending to weight loss, cardiometabolic risk reduction and more,” Zilbermint said. “We keep discovering new benefits.”

Dive Brief:An experimental RNA editing medicine from Wave Life Sciences helped study participants with a rare liver and lung disease produce a protein their bodies cant make, but wasnt as effective in testing as investors had anticipated.Last year, Wave revealed promising results from the first two volunteers with alpha-1 antitrypsin deficiency to receive a single dose of its therapy in a clinical trial. On Wednesday, it said therapeutically relevant protein levels were observed in patients whod received several doses, and similar results were seen in patients who received a single, higher dose.Wave said the findings support monthly or less frequent dosing and added that there were no serious adverse events or study discontinuations. Still, the amount of so-called AAT protein expressed in people whod received that higher dose or multiple administrations of a lower dose wasnt much greater than what was seen in those who got one low dose. Wave shares lost nearly a fifth of their value Wednesday.Dive Insight:Waves treatment, WVE-006, was the first of its kind to reach human testing.WVE-006 edits RNA, the messenger molecules that turn DNA into proteins. That approach is seen as a potentially safer and more flexible alternative to DNA editing and, accordingly, has drawn interest from an array of investors and drugmakers. But RNA editing is also far less proven, making each study update from Wave a referendum on the concept.Wave last year reported that, after receiving a single, 200 milligram dose of WVE-007, the first two patients in its trial began producing the wild-type AAT protein their bodies normally cant. The total levels of AAT protein including that important wild-type version reached, on average, about 11 micromolars in blood plasma concentration within 15 days. That result surpassed investor expectations and met a threshold set by regulators for approval of AAT augmentation therapies.Investors were hoping to see more powerful effects in Waves latest update, which involved eight patients who received a 400 mg dose and eight whod gotten a series of twice-monthly injections at the lower dose. According to Wave, the former group hit about 12.8 micromolars of total AAT protein, on average, while the latter got to 11.9 micromolars. Wave said all side effects were deemed mild to moderate, and that there were no notable elevations in liver enzyme levels, which can be a sign of organ damage.Wave also said a single patient spiked to over 20 micromolars during an acute response to the type of exacerbation that can damage the lungs of people with AATD. That finding suggests WVE-006 can help patients produce protective protein when needed, CEO Paul Bolno told analysts on a conference call.The data show the therapy can rise to meet the occasion, wherever it is, to drive down and protect during exacerbations, he said. That is the functional cure.Despite that apparent promise, Wave shares fell as much as 22%. Protein levels for the multidose group narrowly hit what Jefferies analysts projected as a positive result, while the higher dose data missed the firms mark, wrote Roger Song. Excluding the one patient with an acute response, the single dose group achieved a mean 11.8 micromolars of AAT protein, roughly the same result as the multidose group. The findings require a bit more digestion than WVE-006s last readout, added Mizuho Securities Salim Syed.Still, multiple analysts came to Waves defense. The share sell-off reflects outdated investor expectations, wrote Leerink Partners Joseph Schwartz, as the findings show higher levels of AAT protein do not appear to be required to drive efficacy and protection in AATD. Song and Syed added that all study groups hit the mark set by regulators, even if not by much.The results are still clinically meaningful, Syed wrote.Wave is testing monthly administrations of the higher dose and expects to deliver results in early 2026. Korro Bio, meanwhile, will share early results for a rival RNA editing drug for AATD later this year.GSK has global rights to Waves AATD medicine under a broad partnership the companies signed in 2022. '

Armed with positive late-stage data, BioXcel Therapeutics plans to seek in the first quarter of next year an expanded label for Igalmi (dexmedetomidine) — its agitation therapy for adults with schizophrenia or bipolar I or II disorder — that would permit use in the home setting without medical supervision.The company said Wednesday that the SERENITY At-Home study of BXCL501, a sublingual film formulation of the alpha-2 adrenergic receptor agonist, met its primary endpoint of being well tolerated when self-administered during agitation episodes in people with schizophrenia or bipolar disorder. Financing overhangDespite the upbeat results, shares in BioXcel fell as much as 17% on the news, with concerns around the drugmaker's finances still representing an overhang. BioXcel reported cash reserves of $18.6 million at the end of June, a position that Mizuho Securities analysts described as placing the company "seemingly in dire financial straits."In a note earlier this month, the analysts suggested that positive data from the SERENITY At-Home study "may be sufficient to get prospective commercial partners or equity investors who see the situation as salvageable to provide a financial life-line for the company."The 12-week placebo-controlled trial included 208 patients, who collectively treated more than 2400 agitation episodes at home. BioXcel said no discontinuations occurred in the BXCL501 arm due to tolerability, and the drug's adverse-event profile was "consistent" with Igalmi's safety record in earlier SERENITY I and II trials, which supported its 2022 FDA approval for use in hospitals and clinics.In those trials, Igalmi was associated with rates of somnolence (22%), oral paresthesia/hypoesthesia (6%), dizziness (4%), dry mouth (7%), nausea (2%) and headache (5%). Across all 2437 agitation episodes in the SERENITY At-Home study, adverse event rates were 13.9% for somnolence, 0.5% for abnormal/reduced sensation in the mouth, 1.6% for dizziness, 4.8% for dry mouth, 0.5% for nausea and 0.3% for headache.Steady across repeat dosingBioXcel noted that tolerability held steady across repeat dosing, a key factor for home settings where multiple episodes can occur monthly."The unmet medical need in the at-home setting is significant with no FDA-approved treatments," remarked CEO Vimal Mehta. "We believe the total addressable market is significantly larger than previously reported."The company highlighted data suggesting US patients may experience from 57 million to 77 million agitation episodes annually in home environments. "The previous estimate of 23 million annual episodes was based on historic claims data, reflecting approximately 1.2 episode[s] per patient per month," BioXcel said, but "market research and published survey data indicate that episodes may occur 3-4 times a month on average, with the majority of these episodes being moderate or severe." The SERENITY At-Home results "are in line with these higher frequency estimates," it added.Matt Mandel, BioXcel's vice president of clinical development, described Wednesday's readout as "highly encouraging," noting that the "totality of the evidence, combined with the favourable tolerability," strengthens the company's regulatory case.The results follow BioXcel's decision last year to streamline its research priorities by scaling back commercial efforts for Igalmi while concentrating resources on late-stage trials for BXCL501.