Orforglipron

Kallyope, a New York City biotech that has raised about $480 million over the past decade, quietly released results of its Phase 2 study in obesity in an update to the US federal trials database on Wednesday. The study evaluated an experimental pill, dubbed K-757, both alone and in combination with another oral Kallyope asset, K-833. After 13 weeks of treatment, patients given K-757 monotherapy lost 1.6% of their body weight, the database update reveals, and those in the combo arm lost 2.9%. The monotherapy did not reach statistical significance versus placebo, but the combo arm did, with a p-value of 0.0008. Placebo recipients shed 0.2% of their body weight. Even so, a 2.7-point delta over placebo is nothing to write home about. Lilly’s pill orforglipron managed roughly 6.5% placebo-adjusted weight loss at 12 weeks, and oral therapies from both Structure Therapeutics and Regor Therapeutics have achieved higher weight loss at the three-month mark than what Kallyope’s products managed. In the K-757 group, 17.6% of patients lost at least 5% of their weight, versus 21.2% of those in the combo cohort. Neither hit significance versus the 11.5% figure with placebo. Doses of both Kallyope’s oral drugs were increased gradually, with K-757 reaching the maintenance dose of 120 mg twice daily on day 22 and K-833 titrated to its maintenance dose of 100 mg twice daily on day 8. Backed by large VC firms like Lux Capital and The Column Group as well as Bill Gates, Kallyope is attempting to develop oral obesity and type 2 diabetes drugs that stimulate secretion of GLP-1 and other satiety hormones and mimic the effects seen after bariatric surgery , according to an announcement from the company when the trial started in the fall of 2023. K-757 and K-833 are so-called nutrient receptor agonists that go after GLP-1, PYY and CCK, among other satiety hormones, Kallyope has said. Other small drug developers have attracted interest in these areas: In the CCK space, Aardvark Therapeutics went public this month, and CinRx Pharma nabbed $73 million last year as its portfolio company CinFina undergoes early-stage testing with a PYY analog derived from Johnson & Johnson. The Phase 2 is a pivotal moment for Kallyope, founded in 2015. The biotech is trying to crack into the hottest, potentially most lucrative area of drug R&D as pharmaceutical giants, mid-cap biotechs and new startups try developing the next wave of obesity medicines behind market leaders Novo Nordisk and Eli Lilly. Investors were likely keenly awaiting the Phase 2 data, which could dictate Kallyope’s next funding steps. The company could be nearing the end of its runway. At the time of its last raise, a $236 million Series D in February 2022, CEO Jay Galeota told Endpoints News that funding would keep the startup’s R&D engine humming for about three years. Then, last January, Bloomberg News reported that Kallyope was exploring an IPO and was reportedly working with JP Morgan on a potential listing in 2024. It didn’t follow through with a Wall Street debut last year. Other biotechs in the clinic with obesity medicines, or with intentions to explore the booming area, have gone public since then. That includes BioAge Labs, Metsera, Aardvark, Fractyl Health and MBX Biosciences. Beyond obesity and type 2 diabetes, Kallyope is also looking at migraine, celiac disease and allergies, among other areas. Kallyope also disclosed plans for a Phase 2b trial in migraine, according to a separate update to the US federal trials database on Wednesday. Elismetrep, the asset in that trial, appears to have come from Mitsubishi Tanabe Pharma, which lists the investigational medicine in its pipeline. Bain Capital is buying the centuries-old Japanese pharma for $3.3 billion . Kallyope is also working on a gastrointestinal partnership with Nxera (formerly Sosei Heptares). In 2018, it also disclosed an obesity and diabetes collaboration with Novo to discover new peptide therapies. Under their collaboration, Novo exercised an option last fall. Well-known investors have swarmed to Kallyope since its founding by Columbia University researchers Richard Axel, Tom Maniatis and Charles Zuker. Its financial backers include Bill Gates, Mubadala Investment Company, The Column Group, Lux Capital, Alexandria Venture Investments and other blue-chip names. Leading the biotech is Galeota, a 28-year Merck veteran. Former Roche CEO and chair Franz Humer is Kallyope’s board chair.

Kallyope has removed one of its weight loss candidates from its online pipeline and shuffled metabolic diseases lower on its priority list, below its efforts on neurological disorders.The changes on the company's website were spotted this week after the results of a Phase II obesity study were quietly posted to ClinicalTrials.gov — the same day a Phase IIb trial testing Kallyope's elismetrep (K-304) in patients with migraine was listed on the site.The obesity study's outcome could, in part, explain the lack of fanfare. While the combination of Kallyope's two oral "nutrient receptor agonists" K-757 and K-833 may have demonstrated a more tolerable gastrointestinal (GI) profile than other oral contenders, the rate of weight loss seen in the study falls well short of the levels achieved by the pack leaders (see – Vital Signs: A safety snapshot of oral GLP-1s).Kallyope had raised a $236-million series D in 2022 on the strength of its metabolic and GI programmes.Less than 3% weight lossKallyope was evaluating K-757 alone, and in combination with K-833, against placebo in 155 participants with obesity and without diabetes. The company has previously described the two compounds as agonists that "stimulate the secretion of multiple appetite-suppressing satiety hormones, including GLP-1, and several other well validated satiety hormones, such as PYY and CCK" (see – Vital Signs: Mapping the next generation of obesity targets after GLP).After 13 weeks, K-757 led to a 1.57% reduction in weight from baseline, while patients who received the duo saw a 2.94% decline; those in the placebo arm had a 0.15% reduction.Of the 52 patients who received K-757 plus K-833, 14 discontinued treatment due to an adverse event (AE). The overall AE rate in the cohort was 80.8%, with the most common side effects being nausea (51.9%), constipation (36.5%), vomiting (23.1%), dyspepsia (19.2%) and diarrhoea (11.5%).K-833 is no longer listed on Kallyope's pipeline, leaving K-757 as the sole disclosed metabolic candidate. The company lists three undisclosed assets in the discovery stage for the disease area, while three neurology programmes are named on its website. Outshined by competitors Keeping in mind the caveats with cross-trial comparisons, the rate of weight loss seen with Kallyope's combo appears to be less than a quarter than that of Novo Nordisk's oral obesity hopeful in a similar timeframe. At the European Association for the Study of Diabetes (EASD) meeting last year, the Danish drugmaker reported that patients given oral amycretin achieved mean weight loss of 13.1% after 12 weeks.Two other oral candidates have achieved a greater degree of weight loss in less time — albeit in far fewer participants. Roche's CT-996 showed placebo-adjusted mean weight loss of 6.1% in six patients at week four in a Phase I study; and earlier this month, China-based Ascletis reported up to a 6.2% weight reduction at week four in eight patients given its homegrown oral GLP-1 agonist ASC30. Phase III data for Eli Lilly's oral GLP-1, orforglipron, are due next quarter — and it's one of the most highly anticipated readouts of the year. At the American Diabetes Association (ADA) scientific sessions in 2023, the pharma reported weight loss of up to 12.6% after 26 weeks (see – Spotlight On: Viking, Structure prep for Eli Lilly's oral GLP-1 reckoning).