Sixteen years ago, Mason Freeman was “very disappointed.” A first-in-human study of an aldosterone synthase inhibitor, or ASI, had done what it was supposed to do: block aldosterone production. But it also blocked cortisol.
So, his managers at Novartis scrapped the program that the decades-long Harvard/Mass General physician and a French professor had drummed up just a year earlier.
“It’s been pretty clear for a long time that aldosterone is a hormone that, while incredibly important for most of us in maintaining our salt and fluid level, it wreaks havoc on the cardiovascular system when it’s there in excess,” Freeman told Endpoints News on the sidelines of the European Society of Cardiology Congress ahead of a presentation on an ASI drug out of his latest company, CinCor Pharma.
Novartis’ drug ended up getting approved for Cushing’s disease in 2020 — after being sold to Recordati — but culling the work in hypertension was a letdown for Freeman.
“Novartis at the time [in 2006] had the best-selling hypertensive drug in the world at that point, which was valsartan, and they wanted to develop an ASI primarily as a first-line anti-hypertensive therapy,” Freeman said, “and it clearly wasn’t going to be safe enough to do that.”
Other large pharmas got out of the field because of similar selectivity issues between the enzyme that makes cortisol and the one that makes aldosterone — with a 93% sequence similarity — so a “tour de force of medicinal chemistry” would be needed to make a drug that blocks one without hampering the other, Freeman said.
Roche chemists developed a better inhibitor, but the Swiss pharma giant, like other Big Pharmas of the early-to-mid 2010s, looked away from hypertension drugs — generic medicines likely dissuaded the drug developers from moving forward, Freeman said — and ended up putting the drug on the shelf.
In came CinCor, which picked up the drug and has been developing it for the past few years as CIN-107, now dubbed baxdrostat.
At the European Society of Cardiology Congress on Sunday, the company said the drug was well-tolerated in a Phase I study, which included 56 healthy volunteers who received either baxdrostat or placebo once daily while being kept in a clinical trial facility for 10 days. Two patients discontinued the trial, but neither were for drug-related reasons, Freeman said.
The patients on study drug were split into five dosing groups: 2.5 mg and 5 mg on a low salt diet; and 0.5 mg, 1.5 mg and 2.5 mg on a normal salt diet. All treatment-emergent adverse events were mild in severity. Levels of plasma aldosterone were reduced by about 51% to 73% on day 10, the company reported in its presentation.
There was “nearly 100% absorption” of CinCor’s drug in the trial, Freeman told Endpoints in a preview of the data in Barcelona. The small molecule’s half-life was 24 to 30 hours, he noted, saying it takes “about five days to get to steady state.”
“Drugs that are rapidly absorbed, absorbed at a high level, dose-dependent in their exposure, when they have all of those features, we just call them well-behaved,” Freeman said. “It’s like children: It’s well-behaved, it’s doing exactly what you want it to do when you want it to do it, and the baxdrostat is a really beautifully-behaved drug and that was a major thing to learn.”
The Massachusetts biotech presented topline data earlier this month showing the drug cleared the primary endpoint in a mid-stage study of patients with treatment-resistant hypertension. That initial data drop, with more results to come at a medical conference, led the company to immediately ask the market for nearly $260 million, following a data-to-financing trend in recent months.
Some patients in that Phase II trial had been on seven antihypertensive agents — and they still weren’t at control, Freeman noted.
Another company, Idorsia, will file its hypertension drug by year’s end. The biotech said earlier this year that its J&J-partnered drug, aprocitentan, significantly reduced blood pressure on top of standardized combination background therapy in patients with resistant high blood pressure.
“The world and physicians, certainly experts in the field, understand there’s a need for more effective blood pressure medicines, hopefully that can be combined with some of the earlier generics in simpler regimens that can actually bring blood pressure under control because it’s still the biggest cardiovascular risk there is for all kinds of cardiovascular complications — kidney disease, strokes and heart attacks,” Freeman said. “We’re doing a pretty poor job, actually, of controlling patients’ hypertension.”
CinCor hopes to also get its drug across the finish line in uncontrolled hypertension, chronic kidney disease and primary aldosteronism. Topline data from the uncontrolled hypertension Phase II are slated before the end of 2022. Data from mid-stage studies in CKD and PA are expected for the second half of next year.
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.