In addition to the presentation of the results of the VALOR-HCM study which compared mavacamten to septal reduction techniques, covered here in its own HCMBeat blog entry, ACC 2022 featured two other presentations about the new class of drugs known as myosin inhibitors, such as Bristol Myers Squibb’s mavacamten and Cytokinetics’ aficamten.

I.  Aficamten

The first was a poster presentation by Dr. Anjali Owens of the University of Pennsylvania, who presented data on Cohort 3 of the Redwood-HCM Study of Cytokinetics’ investigational drug aficamten.  The Redwood-HCM study looks at the effect of aficamten in patients with obstructive HCM which do not respond to drug therapies.

Who made up this cohort?

This cohort of 13 patients was made up of patients who had severe obstruction despite maximal medical therapy.  Most of the cohort were New York Heart Association (NYHA) Class 3 with baseline NT-proBNP scores (a marker of heart wall stress) over 1000 pg/mL.  The trial was open label meaning that all participants in the cohort received the active formulation of the drug.

How did the trial work?

These patients continued to taking both beta blockers or calcium channel blockers along with the drug disopyramide or Norpace which is a drug that has been excluded in past myosin inhibitor trials).

Doses were between 5mg. – 15 mg. and the drug was taken over a 10 week period. Adjustments were made based on data from echocardiogram.

What were the results?

The study showed that the left ventricular outflow tract gradient (LVOT) dropped in all patients.  Once the drug was discontinued, the LVOT gradient returned to the pre-trial baseline. The patients also saw mild drops in their left ventricular ejection fractions (LVEF), but the LVEF of all patients in the cohort stayed above 50%.

Additionally, 85% of patients had NYHA improvement and improvement in NT-proBNP and troponin from baseline (these are blood markers of heart wall stress and injury.)

Were there any safety issues?

There were no concerning safety signals, and the effects were reversible once aficamten was discontinued.  Additionally, none of the participants discontinued the drug during the trial period.

What are the implications?

This cohort sets the stage for the Phase 3 trial SEQUOIA-HCM study which will use higher doses of aficamten.  Additionally, this group showed that it is safe to use aficamten together with disopyramide.

II.  Mavacamten

On Sunday morning, Dr. Florian Rader of Cedars-Sinai Medical Center in Los Angeles presented data on the EXPLORER-HCM long term extension study which was focused on the long term efficacy and safety of the drug.

How did the trial work?

95% of the patients who participated in the EXPLORER study elected to either continue taking mavacamten (if they had been randomized to the mavacamten group in the initial study) or to begin mavacamten if they had been randomized to the placebo. These patients were then followed for up to 84 weeks. These patients were started on 5 mg. of mavacamten, and every 4 weeks they had an opportunity to change their dose based on individualized assessment based on echocardiogram.

Most patients maintained at 5mg. or 10 mg. and did not need to increase to the maximum dose of 15 mg.

What were the results?

Improvements were seen to both resting and provoked LVOT gradients. Over 80% of obstructive HCM patients were able to maintain LVOT gradients of less than 30 mmHg, meaning that after taking the drug, they met the criteria for non-obstructive HCM.

There were slight reductions seen in LVEF. A few patients did have their LVEF fall below 50%, but their LVEF recovered back to normal after discontinuation of treatment.

Additionally, the study showed sustained drops in NT-proBNP (a blood marker of heart wall stress) and patients showed a drop of at least one NYHA class.

Were there any safety issues?

Overall, the safety profile was positive. Less than 5% of the patients discontinued mavacamten due to adverse events. 20 of 26 patients were able to resume treatment after temporarily discontinuing the drug.

The FDA is likely to give additional advice and guidelines regarding safety and follow up once the drug has been approved for sale in the U.S.