While AstraZeneca didn't unveil any splashy data at this year's ObesityWeek conference, it projected confidence in its trio of weight-loss hopefuls during its presentation on Monday, though that boldness may soon be tested, as obesity programmes — which have driven some of the year's biggest valuation climbs — have, of late, fallen under increased investor scrutiny.The UK pharma disclosed that it will advance oral GLP-1 agonist AZD5004 — licensed almost exactly a year ago from Eccogene in a deal worth about $2 billion in biobucks — into a pair of Phase IIb trials, justified by "encouraging data" from its Phase I study."This is AstraZeneca, and we played a win. If we didn't think we had a highly competitive molecule we would not be further investing in that molecule and moving it forward rapidly through clinical development," commented Sharon Barr, executive vice president of biopharmaceuticals R&D at AstraZeneca.The drugmaker traded flat for the day in London. While whispers of weight-loss success were once able to drive double-digit pharma moves earlier in the year (looking at you, Amgen), that no longer appears to be the case as analysts raise the bar on what will be obesity's 'next big thing,' as well as the current market leaders.Both incretin front-runners Eli Lilly and Novo Nordisk have seen their shares buckle under high expectations. The former fell 6% last week after posting disappointing third-quarter sales for Mounjaro/Zepbound (tirzepatide), and it's possible the latter will see similar downward movement this week when it shares its own earnings report, given Ozempic/Wegovy (semaglutide) had missed estimates for the second quarter (see – Vital Signs: Eli Lilly attempts to drum up demand for GLP-1s and Vital Signs: Novo’s US pricing struggles).Clinical programmes are also feeling the pressure. Novo Nordisk took a hit of more than $25 billion to its market cap in September when it reported somewhat mediocre data for a mid-stage candidate. That same month, investors shaved a few billion dollars off of Roche's valuation on the news that its oral incretin agonist left something to be desired in terms of gastrointestinal tolerability (see – Vital Signs: Novo Nordisk rout raises expectations for Amgen). Meanwhile on Monday, Viking Therapeutics suffered a $1-billion dent to its market cap after seemingly positive data for its oral GLP-1/GIP agonist failed to overcome production capacity concerns. Advancing assets AstraZeneca's ObesityWeek presentation was scant on details, but featured positive forward momentum for each of its weight-loss assets. In addition to AZD5004, the pharma is developing AZD6234, a long-acting amylin analogue with once-weekly subcutaneous dosing, and AZD9550, an injectable GLP-1/glucagon agonist.The drugmaker reported that AZD5004, a once-daily oral small molecule, had an "encouraging safety profile at a range of doses" as well as "promising potency" in Phase I testing, with average weight loss of 5.8% over four weeks. There was a "dose dependent increase in nausea and vomiting consistent with molecules in this class," noted Sharon Barr, executive vice-president of biopharmaceuticals R&D, although no patients discontinued treatment due to these side effects, with higher doses of the drug set to be tested,The results prompted AstraZeneca to launch the Phase IIb VISTA trial in patients with overweight and obesity, and the Phase IIb SOLSTICE study for type 2 diabetes. The former is expected to enrol 304 participants and wrap up by the end of next year, and the later is projected to recruit 384 patients and finish in early 2026. The company also revealed it has already kicked off the Phase IIb APRICUS study of AZD6234 in individuals with obesity or overweight that's expected to conclude in 2026. In Phase I testing, the candidate had a favourable tolerability profile with no safety concerns, as well as "encouraging weight loss after a single dose."AstraZeneca is in the planning stages for yet another Phase IIb trial, but this one will combine AZD6234 with AZD9550 to achieve a "triple mechanism" effect that it hopes will lead to higher quality, fat mass-specific weight loss with end-organ protection. The company didn't provide a timeline for the upcoming study, but shared that "encouraging Phase I data provided confidence for the combination strategy."Other combinations also appear to be in the works. The pharma told FirstWord that "due to the complexity of interconnected obesity and cardiometabolic disease, we are uniquely positioned to deliver this through mono and combination therapies, given the breadth of our portfolio."
