Shares of Millendo Therapeutics Inc. (NASDAQ:MLND) fell 70.1% to $1.45 on April 6 after a pivotal study of its experimental Prader-Willi syndrome (PWS) therapy, livoletide, failed to show a statistically significant improvement in hyperphagia, or insatiable hunger, and food-related behaviors vs. placebo. "We believe we recruited and ran the right study, and, unfortunately, it didn't work," Millendo President and CEO Julia Owens told BioWorld.
The disappointment, which confounded expectations at the company and hopes among patients, has convinced Millendo's team to discontinue livoletide's development in PWS and turn its attention to developing its phase II congenital adrenal hyperplasia candidate, nevanimibe, and a preclinical asset for menopausal vasomotor symptoms called MLE-301.
The outcome is, for now, the end of the road for livoletide, a drug Ann Arbor, Mich.-based Millendo acquired at the end of 2017 by merging with the privately held French biotech Alizé Pharma SAS, the first in a trio of companies founded by entrepreneur Thierry Abribat. The mostly stock-based deal, valued at $63.1 million at the time, both conserved cash for each company and evidenced a strong belief each team held in the drug's future potential, Owens said.
That faith was bolstered by the results of a phase IIa trial in which administration of livoletide to 47 patients once daily was associated with a clinically meaningful improvement in hyperphagia, as well as a reduction in appetite – key features of PWS, which is the most common genetically caused form of obesity. The outcome appeared to support the expectation that livoletide, a cyclic peptide analogue of unacylated ghrelin, would be able to address the underlying hormone dysregulation that causes PWS.
To build a pivotal picture of efficacy, Zephyr was designed to be a randomized, double-blind, placebo-controlled pivotal phase IIb/III trial. The IIb portion included a three-month, double-blind, placebo-controlled period in which 158 patients were randomized to either 60 µg/kg or 120 µg/kg of livoletide, or placebo.
But, while it did show numerical improvements from baseline in participants' Hyperphagia Questionnaire for Clinical Trials (HQ-CT) scores at 12 weeks, neither change was statistically significant. Furthermore, the -3.8 (p=0.45) improvement in score associated with the higher dose that was expected to be the greatest turned out to even less than the -4.7 (p=0.13) improvement achieved by the lower dose of the drug.
Though Millendo has only top-line data and remains early in its analysis of what it does have, "it appears that we had a much higher placebo response than what was seen in our last trial and a lot more variability" across HQ-CT measures than expected, Owens said. Furthermore, no positive trends were observed for any of the secondary endpoints of fat mass, body weight or waist circumference, she said.
Livoletide was well-tolerated during the trial, though two patients dropped out of the study. There were four serious adverse events reported during the trial, but none related to livoletide treatment.
In light of the results, Millendo is canceling both the previously planned phase III portion of the study and is discontinuing the ongoing nine-month extension of the phase IIb study. A full analysis of the data will follow, as well as an across-the-board evaluation of the best way to prioritize the small company's resources, she said.
Looking ahead, Millendo's team is focused on developing the ACAT1 inhibitor nevanimibe as a potential oral treatment of congenital adrenal hyperplasia (CAH), a rare, monogenic adrenal disease that requires lifelong treatment with exogenous cortisol, often at high doses. It will also work to move the reversible neurokinin 3 receptor antagonist MLE-301 for the potential treatment of vasomotor symptoms associated with menopause. “With the rapidly evolving COVID-19 global pandemic and the extraordinary burden it has put on hospitals and health care providers, we are monitoring the potential impact of the situation on these programs and will provide an update when we have more clarity on expected timelines,” the company said.
The company, which had a 2019 year-end cash balance of about $63.5 million, raised an additional $5.5 million from an at-the-market agreement in March.