ACC 2022 – Bristol's rare hit could justify Myokardia

Mavacamten prevails again, but the big question for Bristol is the commercial opportunity.

Bristol Myers Squibb paid $13bn for mavacamten’s developer, Myokardia, so it needs the project to be a hit. Today the company got a boost with impressive results from Valor-HCM study, in a sicker population of hypertrophic cardiomyopathy patients than the one in which the asset had previously been tested.

Bristol looks like it will have its work cut out to hit the $4bn-plus peak sales target it has set for mavacamten but, as with many rare diseases, the group hopes that having a therapy available will spur more patients to be diagnosed.

Amyloidosis on steroids

Valor’s lead investigator, Dr Milind Desai of the Cleveland Clinic, told Evaluate Vantage on the sidelines of the ACC meeting that in terms of market size hypertrophic cardiomyopathy (HCM) was "amyloidosis on steroids". 

Amyloidosis, of course, is a disorder that has proven a nice little earner for the likes of Pfizer and Alnylam.

HCM involves excessive contraction and progressive thickening of the heart muscle tissue, and can lead to heart failure and sudden cardiac death. There are no specific therapies approved.

Bristol is initially targeting the disorder's obstructive form, which involves blockage of the left ventricular outflow tract, where blood leaves the heart, and affects around two thirds of patients.

Here, mavacamten has a Pdufa date of April 28, based on data from the Explorer-HCM study (ESC 2020 – Myokardia odds-on for first approval in heart muscle disease, August 29, 2020).

Valor focused on a sicker group of patients than Explorer: those with severely symptomatic obstructive HCM who were candidates for septal reduction therapy, a procedure to reduce the thickness of the heart tissue that comes with its own risk of death.

Patients were randomised to either mavacamten or placebo, and continued on background therapy including disopyramide and beta blockers. At any time during the trial patients could opt for septal reduction.

The primary endpoint of Valor was the proportion of patients who had either decided to have the procedure, or were still eligible, at week 16. Only 18% of mavacamten-treated patients fell into these groups, versus 77% of those receiving placebo.

The study also hit all of its secondary endpoints.

Valor results at ACC 2022
Endpoint Mavacamten Placebo P value
Proportion of pts who had or were eligible for SRT* 18% 77% <0.0001
Change in post-exercise LVOT gradient -39.1mmHg -1.8mmHg ?
No. of pts with ≥1 class NYHA improvement 63% 21% <0.0001
Change in KCCQ-23 clinical summary score +10.4 points +1.9 points <0.0001
*Primary endpoint; KCCQ=Kansas City cardiomyopathy questionnaire; LVOT=left ventricular outflow tract; NYHA=New York Heart Association. Source: ACC 2022.

As for safety, Valor did not throw up any new issues. As mavacamten, a cardiac myosin inhibitor, is designed to reduce the hypercontractility seen in HCM, there are concerns that the project could cause dangerously low ejection fractions.

Dr Desai explained that the “hard stop” in Valor was an LVEF of 30% or below, and highlighted that no patient met this criterion. However, two patients had LVEF that dropped below 50% – these subjects briefly stopped taking mavacamten, their ejection fractions recovered, and they subsequently resumed treatment on a lower dose.

Bristol plans to address these concerns with a risk-evaluation mitigation strategy (REMS), and it was updates to this that caused an FDA decision on mavacamten to be pushed back from the original target of November.

“The REMS was always something we’d planned for given the mechanism of action of the drug,” Marie-Laure Papi, the development lead for mavacamten at Bristol, told Vantage.

In Valor, echocardiogram measures were used to help titrate the dose of mavacamten to individual patients. It should soon become clear whether this strategy will be enough for the FDA.

HFpEF plans

Assuming it is, and mavacamten becomes the first approved therapy for HCM, Bristol is not stopping there. The group plans to start a phase 3 study in non-obstructive HCM this year, and the project is in phase 2 in heart failure with preserved ejection fraction, another cardiac disorder that until recently has had few options.

The competition is some way behind: Cytokinetics recently started the phase 3 Sequoia-HCM trial of its rival cardiac myosin inhibitor aficamten (CK-274), while a couple of projects are in phase 2 for non-obstructive disease.

Dr Desai reckons that the 100,000 patients who are currently diagnosed with HCM in the US is the “tip of the iceberg”. If he is right there should be room for more than one player in this market.

Projects in development for hypertrophic cardiomyopathy
Project Company Description Trial
Mavacamten Bristol Myers Squibb Cardiac myosin inhibitor Pdufa April 2022 based on Explorer-HCM
Phase 3
Aficamten Cytokinetics Cardiac myosin inhibitor Sequoia-HCM in obstructive HCM completes Sep 2023
Phase 2
IMB-101 Imbria Pharmaceuticals Partial fatty acid oxidation inhibitor Improve-HCM in non-obstructive HCM completes Nov 2022
Entresto Novartis Angiotensin receptor-neprilysin inhibitor NCT04164732 in non-obstructive HCM completes May 2023
Cufence (trientine dihydrochloride) Univar Solutions Copper chelating agent Tempest completes Dec 2023*
Phase 1
CT-G20 Celltrion Cardiac myosin inhibitor NCT04418297 in obstructive HCM completes Apr 2022
MYK-224 Bristol Myers Squibb Cardiac myosin inhibitor NCT05304533 completes Sep 2022
*Investigator-sponsored trial. Source: Evaluate Pharma &

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