Can a next-gen take on a deadly weight loss pill conquer cardiometabolic diseases? A Medicxi-backed startup thinks so
Most drug developers might remember DNP, the yellowish compound that’s been used over the years as a herbicide and chemical intermediate, as a deadly diet pill. But Shaharyar Khan and Allen Cunningham wondered about the effect that it has shown, first in a 1930s study, in burning excess calories.
The duo, who have worked together for close to 20 years at a biotech focused on mitochondria-based therapies, found the biology familiar. In cells — whether you’re a yeast or a human being — a mitochondria takes substrates, fats and sugars and generates energy. Slow that down, the theory goes, and the body burns more calories to get its energy then returns to a state of energy balance.
At Rivus Pharmaceuticals, the new company Khan and Cunningham have launched, the goal is to direct that mechanism, known as mitochondrial uncoupling, at a broad range of cardiometabolic diseases from heart failure and NASH to Type 2 diabetes and hypertension.
More importantly, they would do it safely, the partners said.
“So what we’ve done is we’ve taken that really potent pharmacology, and we’re trying to make it a modern-day, cutting edge drug,” CSO Khan told Endpoints News. “And we think that it’s about time someone does that, because there’s this profound epidemic of dysmetabolism, of energetic excess, that we know this particular mechanism can essentially fix.”
Longitude Capital and Medicxi are leading the $35 million Series A, which also features RxCapital and comes after Phase I data that “exceeded our expectations,” according to Medicxi chief scientific advisor David Grainger. Not only was Rivus’ lead candidate, HU6, well-tolerated, it also hit the marks on key metabolic parameters.
The trick for creating these controlled metabolic accelerators — or CMAs, as Rivus has named them — lies in avoiding the pitfalls Khan reckons caused DNP’s toxicities. First, you “flatten the PK curve,” leading to sustained low activity of uncoupling rather than too much at the same time. Secondly, you preclude the dangers of overdose by selecting compounds whose absorption is capped at a certain level.
Despite its small size (the headcount stands at seven at the moment, including the two co-founders), Rivus is unabashed about its disproportionate ambitions.
At a time when the concept of precision medicine is seeping beyond cancer, startups taking on cardiometabolic indications are much more likely to zero in on genetically defined subgroups of patients. And it works: MyoKardia served as the poster child with Bristol Myers Squibb’s $13 billion takeover of its drug for a subset of obstructive hypertrophic cardiomyopathy.
Cunningham, the CEO, noted that within the basket of diseases Rivus will be going after, there are still differences in market sizes. After using the Series A cash to complete an ongoing Phase IIa metabolic study, all “strategic alternatives” will be on the table to set up ideally concurrent Phase IIb studies in type 2 diabetes, NASH and severe hypertriglyceridemia. A second Phase IIa for HFpEF (heart failure with preserved ejection fraction) is slated to begin early next year.
Hurdles and questions abound. Any one of those indications, on their own, bring enormous challenges that have tripped up players big and small — although Khan believes that’s the wrong way of looking at it.
“When you conduct a trial in NASH, half of your patients have diabetes; so you’re conducting a trial in diabetes as well. If you conduct a trial in heart failure, 80% of your patients have obesity and hypertension; you’re conducting a trial in obesity and hypertension,” he said. “And so if you attend yourself to the fact that these diseases are not siloed, but that you’re trying to treat the patient, I think that gives you an opportunity that other approaches just don’t provide you.”