Mineralys Therapeutics, headquartered in Radnor, Pa., dosed the first patient in its ADVANCE-HTN pivotal trial of lorundrostat for uncontrolled hypertension (uHTN) and resistant hypertension (rHTN). The study is evaluating the drug as an add-on therapy to two or three previous antihypertension drugs.
Jon Congleton, CEO of Mineralys, told BioBuzz that the company was formed in the summer of 2020 via a licensing agreement with Mitsubishi Tanabe. The deal was for larundrostat, a highly selective aldosterone synthase inhibitor. “They had developed it through Phase I, and like a lot of big pharma companies, they did a portfolio review and prioritization and said, ‘Hey, love the asset, but it doesn’t fit with where we’re going strategically. Let’s find it a home.’”
The company was formed around the compound with support from Japan-based venture capital firm Catalys Pacific.
“We’ve spent the last two-and-a-half years pretty much at high speed, progressing this product through its IND, through proof of concept, trying to close white space at every corner to really expedite the development of the compound. So that culminated in dosing of the first patient in the pivotal program,” Congleton said.
Less than 50% of patients with hypertension control their blood pressure with currently available drugs. About 25% of all hypertensive patients’ hypertension is driven by abnormally increased levels of aldosterone.
Congleton notes that about 35 years ago, calcium channel blockers were the major innovation in treating hypertension, followed by ACE inhibitors and selective beta-blockers. These transformed the field of cardiovascular medicine and hypertension, but, he says, “we haven’t had a lot of innovation in about 20 years.”
“We’re finally now entering a kind of second Renaissance. You’ve got about three or four different mechanisms in development in the clinic that are targeting what has become a significant global crisis, certainly in the U.S., which is uncontrolled hypertension.”
This is where Mineralys comes in, although Congleton cautions, “We’re not the silver bullet. Our goal is really to be used as an add-on after two drugs have failed to get a patient to their blood pressure goal. So a third-line position. But where we’re a little bit different than what’s been done in the past is we’re trying to bring a level of precision to the selection of lorundrostat for a patient and matching their specific needs to what we think the drug can do.”
And that specifically is controlling aldosterone, a hormone that regulates blood volume and blood pressure. When aldosterone is dysregulated, lorundrostat can reduce it back to a normal physiological level.
“The challenge,” Congleton says, “is how to identify those patients through markers or characteristics. What we have found is that there’s a pretty clear line of sight between uncontrolled hypertension, obesity, and abnormal aldosterone biology.”
And the company’s Phase II proof of concept data demonstrated an enhanced response in the obese hypertensive population.
“Being overweight or obese results in not just a mechanical burden on hypertension. It’s actually the visceral adipocytes around the gut producing countless hormones that are dysregulated and drive a lot of dysregulated biology that ultimately leads to pathology. That’s why there’s a significant need for this class of drugs, for this therapeutic approach, and for how we’re trying to develop this drug,” he said.
It’s not necessarily a wide-open field. In January, AstraZeneca acquired CinCor Pharma, picking up CinCor’s pipeline drug baxdrostat, also an aldosterone synthase inhibitor. Other companies, such as Damian Pharma, Angion Biomedica and PhaseBio also have aldosterone synthase inhibitors in their pipelines but are currently in the clinic for other indications than uncontrolled hypertension, although PhaseBio hopes to submit its IND for the compound to treat hypertension this year.
In February, Mineralys closed its Initial Public Offering (IPO) of 13.8 million shares at an initial public offering price of $16 per share, netting around $202 million. This followed a Series B raise in June 2022 that brought in $118 million, which Congleton said, enabled the company to move quickly from proof of concept into the pivotal program.
“The IPO was part of that plan process, which allowed us to do exactly what we’re doing, moving quickly to these pivotal trials, trying to move with a level of urgency to meet the needs of the patients that are struggling to get to their goal and ultimately control the outcomes that uncontrolled hypertension leads to,” he said.
Lorundrostat is the company’s primary focus. “We think there’s some significant opportunity with this compound beyond hypertension that we’re continuing to investigate how we would do the clinical program. We know aldosterone in a dysregulated state plays a role in chronic kidney disease, in heart failure, among a variety of other conditions. But our focus right now is on hypertension.”
Mineralys expects topline data from the ADVANCE-HTN trial in the first half of 2024. It will enroll up to about 300 eligible adults who will be randomized to receive either placebo, 50 mg once-a-day of lorundrostat, or lorundrostat 50 mg once-a-day and then titrated to 100 mg once-a-day, as needed, at week four. The primary endpoint is a change in systolic blood pressure versus placebo after 12 weeks.
In addition, the second pivotal trial is a Phase III study in a larger population of uHTN and rHTN patients. The company hopes to begin enrollment in the second half of this year with data expected in mid-2025. They will also run an open-label extension trial after these trials are completed. Mineralys also expects to launch a Phase II trial of the drug for treatment of uHTN and rHTN in a chronic kidney disease (CKD) population in the middle of this year, with topline data in the first half of 2024.
“We have a busy two years planned,” Congleton said.
