GLP-2R

Metsera, the well-funded obesity biotech from Population Health Partners and ARCH Venture Partners, has unveiled its first clinical data just a few months after emerging with $290 million and a broad pipeline of weight loss drug candidates. The New York City startup said its GLP-1 receptor agonist, a long-acting injectable known as MET-097, was able to reduce some patients’ weight from baseline by 7.5% at day 36 in a Phase 1 study. That measurement came one week after a cohort of patients received their fifth and final dose of 1.2 mg. Looking farther out, four weeks after the final dose was given, Metsera said the cumulative weight loss grew to 8.1% for that group in the 125-person placebo-controlled trial. “We have a feeling that we can be really quite competitive with this,” CEO Clive Meanwell told Endpoints News in an interview Monday night. Doses ranging from 0.16 mg to 1.6 mg were tested in the single-ascending and multiple-ascending dose trials. At 1.6 mg, there was “quite a lot of nausea, vomiting, and would not be suitable for standard of care,” Meanwell said. At the 1.2 mg dose, the CEO said side effects were “very, very similar to the class.” Almost all of the adverse events were mild, with a “few hours at most” of nausea. Less than a handful of patients had diarrhea, he said. The study was conducted in the Kansas City area by the CRO Altasciences. Novo Holdings — the controlling shareholder of one of the market leaders in obesity, Novo Nordisk — owns the contract research company and also runs some early-stage testing for the Danish drug giant, Meanwell said. Metsera’s results are early and will need to be replicated in a larger and longer Phase 2b study, which Meanwell expects to be 13 weeks in duration and could potentially test Metsera’s drug candidate head-to-head against leading obesity medications. The startup is still internally debating which dose to test in the upcoming trial, whether that be 0.8 mg or 1.2 mg, Meanwell said. Other companies have recently reported higher levels of weight loss, albeit with different types of drugs and longer time frames. Zealand Pharma’s GLP-1/GLP-2 receptor dual agonist notched up to 8.3% placebo-adjusted mean weight reduction at 13 weeks, and Roche’s once-daily pill saw up to 7.3% weight loss within one month. In long-term studies for GLP-1 receptor agonists, Meanwell said that “you’ve got to get into high-teens, low-20s.” The company also has an earlier-stage amylin-calcitonin receptor agonist being combined with its GLP-1 that would be “very competitive” if it induces 25% to 30% weight loss, Meanwell said. While Metsera’s far behind the well-entrenched first-movers of Novo Nordisk and Eli Lilly, the company thinks it can carve a lane in the obesity market with a once-monthly option that has a much longer half-life. It said MET-097, which comes from its acquisition of UK startup Zihipp, had a half-life of 380 hours. Novo cut a Phase 1 trial studying a once-monthly GLP-1/GIP agonist due to “portfolio prioritizations,” it said last month. The market leaders, Novo’s Wegovy and Lilly’s Zepbound, are indicated for once-weekly injections. Those behemoths are also testing longer-duration treatment options and have bought up a few obesity startups to get access to muscle-preserving medicines or other mechanisms of action. Novo’s bet on a second iteration of a previously shelved class, CB1, hit a speed bump last week with neuropsychiatric effects that overshadowed efficacy. Meanwell said the goal is also to get rid of the need for a titration schedule that gets patients acclimated to the higher doses. Metsera is still finalizing its Phase 2b trial, which will begin next quarter and will be conducted in the US. The trial is slated to have data by next summer, meaning the startup could quickly start a Phase 3 as soon as the second half of next year, Meanwell said.

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here . Endpoints will be covering #ESMO24 throughout the weekend, so make sure to follow along online. Deputy editor Reynald Castañeda and reporters Kyle LaHucik, Lei Lei Wu and Ayisha Sharma will be reporting from Barcelona. — Max Gelman On Monday, the US House of Representatives passed the Biosecure Act with broad bipartisan support. The bill would force biopharma companies to cut ties or restrict their work with contract manufacturers WuXi AppTec , WuXi Biologics and three genetic sequencing companies by 2032. However, it still faces an uncertain future in the Senate. Opponents have argued that the bill was written to quickly and too broadly. Zachary Brennan has the latest. Biotech’s Covid-19 superstar has faced a rough go of it since the pandemic ended, saying since late last year that it would adopt a more “restrained” approach. But after leading off 2024 with $4 billion in expected cuts, Moderna said this week that it’s planning even more . Executives mapped out an additional $1.1 billion in cuts by 2027 and pushed back the company’s breakeven point by two years, from 2026 to 2028. Moderna’s stock is down more than 80% over the last three years. Our Andrew Dunn also framed how to think about this news in our Post-Hoc newsletter. Our reporters shared updates from #ESMO24, including lackluster data on Amgen’s PRMT5 inhibitor, a Phase 2 look at Jazz’s HER2 antibody, Bicycle’s early case for its Padcev competitor, mid-stage data for GSK and iTeos’ PD-1 and TIGIT doublet , and more. Stay tuned for more conference coverage throughout the weekend. In May, Summit surprised the industry by claiming its PD-1/VEGF bispecific antibody called ivonescimab beat Merck’s Keytruda in a head-to-head Phase 3 study. This Sunday, Summit backed up its case. Ivonescimab reduced the risk of lung cancer progression or death by 49% in the study, with patients going an average of 11.1 months before their disease worsened. Keytruda recorded an average of 5.8 months. Summit’s stock is up more than 800% since the May reveal, and more than 900% for the whole year. Friday afternoon, Jared Whitlock reported that the SEC’s probe of the Illumina-Grail deal is focused on sales forecasts made by Grail’s management in the run-up to the 2021 transaction. In June, Illumina spun off Grail and it began trading as a public company. We covered a string of early-stage GLP-1 readouts this week, including from Roche’s dual GLP-1/GIP candidate which showed promising weight loss, but also high rates of vomiting in a Phase 1b study . Terns also offered an early look at its oral GLP-1 agonist, which it says could be more tolerable at higher doses than currently marketed GLP-1s that are administered the same way. And Zealand’s GLP-1/GLP-2 receptor dual agonist showed promising weight loss after a previous effort with lower doses ended with “underwhelming” efficacy. SPOTLIGHT R&D PHARMA FINANCING FDA DEALS MANUFACTURING HEALTH TECH DON’T MISS

Dapiglutide was tied to a mean reduction of up to 8.3% in body weight. On the heels of disappointing low-dose data results, Zealand Pharma is back with separate findings for its GLP-1/GLP-2 receptor dual agonist that have emboldened the biotech to push the candidate into phase 2b development.  The Danish biotech’s investigational weight loss candidate, dubbed dapiglutide, was tied to a mean placebo-adjusted reduction of up to 8.3% in body weight in a phase 1b multiple ascending dose trial, according to a Sept. 9 release.The trial, known as MAD, assessed dapiglutide among 54 people overweight or obese against placebo. Patients were split up across three dose cohorts receiving 13 once-weekly doses of up to 13 mg of dapiglutide or placebo, with rapid up-titration every second week. Lifestyle modifications, such as diet or exercise, were not included in the study.The trial’s primary endpoint, as listed on ClinicalTrials.gov, is the incidence of treatment-emergent adverse events (TEAEs). The new findings show dapiglutide to be safe and well tolerated, according to Zealand Pharma, with gastrointestinal (GI) symptoms reported as the most common TEAEs. Two participants discontinued treatment due to GI system adverse events. Overall, the number of GI events observed was consistent with studies with a similar escalation design for other incretin-based therapies, according to Zealand Pharma. Higher dosing regimens up to 26 mg over 28 weeks are currently being tested in part 2 of the trial, with topline results slated for the first half of next year. “Preliminary data further support that dapiglutide possesses a differentiated profile based on its unique dual agonist effects which we expect to translate to a positive effect on inflammation,” Zealand’s Chief Medical Officer David Kendall, M.D., said in the release. “Importantly, today’s exciting data give us the confidence needed to rapidly progress dapiglutide into a comprehensive phase 2b trial in people living with overweight and obesity planned for initiation in the first half of 2025.”The biotech also intends to examine dapiglutide’s potential in certain obesity-related comorbidities, according to the company.Back in May, dapiglutide failed to impress in a phase 2 trial, mustering up to an average 4.3% reduction in weight loss when given in low doses. The 54-person study involved administering either 4 mg weekly subcutaneous doses of dapiglutide, a 6 mg dose or placebo over 12 weeks. Participants who received 4 mg saw an average weight loss of 2.9%, barely above the 2.2% seen in the placebo arm. The 6 mg group saw a slightly larger weight loss of 4.3%.  The results suggest that the 4 mg and 6 mg doses are at the “lower end of the therapeutic range,” according to Zealand.At the time, the biotech pointed to the MAD study, noting the higher doses being investigated.The biotech’s main focus centers around petrelintide, a long-acting amylin analog. After reporting phase 1b data that suggest petrelintide may provide GLP-1-like efficacy without the side effects, Zealand Pharma said it believes the candidate could be “the backbone of therapy for weight management.”