Dr Andrew Wang:

My name is Andrew Wang. I'm a Professor of Medicine at Duke University School of Medicine in Durham, North Carolina.

What was the rationale for conducting a responder analysis comparing aficamten with metoprolol?

We wanted to look at multiple domains that we consider markers of disease burden in obstructive hypertrophic cardiomyopathy, not just a single or secondary endpoint. We wanted to look at the response to these two monotherapies across a domain of multiple different parameters.

How were clinical responders defined in this analysis?

So we defined clinical response across five different parameters that we considered markers of disease burden, including the reduction in left ventricular outflow tract, the biomarker response, improvement of cardiac symptoms, heart failure symptoms, the reduction in left atrial volume index, as well as exercise capacity. So we felt all of this was a comprehensive assessment of really what patients with hypertrophic obstructive cardiomyopathy faces.

Could you tell us about the patient population?

We studied patients that were in the MAPLE-HCM randomised, phase 3 clinical trial that compared aficamten monotherapy to metoprolol monotherapy for 24 weeks of treatment, and we looked at the responses at 24 weeks.

What were the key findings regarding response rates and symptom improvement between the two treatments?

For symptom improvement, afacamten was superior to metoprolol therapy, and that was one of the parameters in the multi-domain assessment. Afacamten would superiror really across all of the five different parameters of clinical response to varying degrees.

Were there specific patient characteristics associated with better responses to either therapy?

When we compared the number of responses each patient had, patients who had more positive responses, meaning out of the five criteria, which ones did they meet, did have interestingly a higher prevalence of hypertension. But when we adjusted for the presence of hypertension, the results were the same.

How do these findings inform treatment selection for patients with obstructive HCM?

When we see a positive clinical trial it's usually for the primary endpoint that a single endpoint is statistically significantly better for one treatment or the other. This pre-specified analysis allowed us to look across a wider range of endpoints to see the global response. And so, if we're thinking about the patient to say what matters to the patient over time, this analysis may help to inform, oh, it's not just one endpoint we're achieving, it's multiple.

What are the next steps for research with aficamten in the HCM population?

So this was a study of patients who had symptomatic obstructive hypertrophic cardiomyopathy. There's an ongoing study now of aficamten for non-obstructive hypertrophic cardiomyopathy that should be read out next year hopefully, and that will be very important information because currently we do not have specific HCM-related medicines for non-obstructive HMC.