I'm Milind Desai. I am a cardiologist and vice chair for the Heart Vascular Thoracic Institute at the Cleveland Clinic. I also direct our hypertrophic cardiomyopathy centre.
What are the current unmet needs in hypertrophic cardiomyopathy management?
Hypertrophic cardiomyopathy, for years, there's a disconnect between what we think the actual prevalence is and the number of patients that actually we know who have HCM. So that's a big unmet need and a bigger unmet need was effective proven therapies. For the longest time, the gold standard therapy is considered receptal reduction therapy, but not too many big centres offer this at a good enough success rate.
So there was always a need for access to high quality of non-invasive medical therapies, which is where mavacamten, a cardiac myosin inhibitor, was developed to help in symptom improvement initially with patients who had obstructive hypertrophic cardiomyopathy. And now it is being expanded in other realms.
So the other problem was a lot of this data was retrospective observational, not really prospective placebo controlled trials. So Mavacamten has been tested in at least three phase three randomized trials, of which VALOR was one of them. The original EXPLORER trial tested whether it improved symptoms and exercise capacity. But the concept of VALOR was designed around the simple fact that patients often when they get more symptomatic, they end up needing septal reduction therapy. So can we reduce the need for septal reduction therapy in these patients? And that was the basic premise of this phase three, randomized, controlled trial VALOR.
Could you tell us about the mechanism of action behind mavacamten?
So mavacamten, as I alluded to, is a cardiac myosin inhibitor. So it works directly on the sarcomere by reducing the number of actin myosin cross bridges. Basically, the problem with a hypertrophic cardiomyopathy heart is it is very hypercontractile and uses energy inefficiently and also results in stiffness, etc. So mavacamten by its mechanism of action is expected to reduce that significant hypercontractility, make the heart work more efficiently. And that's basically how it is thought to work.
What was the study design and patient population?
So this was a phase three randomized, controlled trial and it was divided into multiple phases. So patients got mavacamten or placebo. These were all highly symptomatic, obstructive HCM patients. So we pretty much selected vast majority of patients in NYHA Class III. Only a small proportion, 5 or 6%, were in NYHA Class II. These patients, each and every one was on maximally tolerated background HCM therapy and was referred for septal reduction therapy. So bottom line is they were at the end of the road and the only other option was to have an invasive procedure, so much sicker population compared to the prior studies.
What were the key findings?
As I alluded to, this was a randomized, controlled trial for the first 16 weeks after which everybody that got placebo got transitioned to mavacamten. So at AHA 2024, what we are presenting is end of trial week 128 results.
So, originally, we included 112 patients that were heavily symptomatic, obstructive HCM adults more than 18 years of age. In terms of age, the mean age was about 60 years. Fifty-fifty representation of women and men. As I said, 93, 94% patients were in NYHA Class III, 34% were on combination background therapy, and everybody of course had all the features consistent with obstructive HCM. So what we found here is the question was do we reduce the need or eligibility for septal reduction therapy? That was the first question. And the second is is the effect sustainable over 128 weeks, and what were the some of the secondary findings? Can we reduce the obstruction and quality of life, etc?
So what did we find? The principal finding was at 128 weeks the effect of mavacamten was sustained in terms of reducing the need for septal reduction therapy. So 95% patients transitioned to commercial mavacamten because it became available. Out of the 112 patients at the outset, 108 patients at week 16, because a few of them dropped out, 95 out of 108 chose to remain on commercial mavacamten. Only seven patients underwent septal reduction therapy. One patient was eligible, has not gone for surgery. And the remainder, about nine patients, the SRT status was unevaluable because they were missing data. So the way we did was we don't count only seven patients in the endpoint adjudication. The folks who did not have the endpoint adjudicated, they were considered mavacamten failure. So even then 95 out of 108 have stayed away from septal reduction therapy.
In addition to the primary endpoint, we also saw significant improvement in their symptom status. So NYHA class was improved by more than 80% in at least one NYHA class, more than 80%, more than 50%, at least two NYHA class and this was sustained improvement. Additionally, 14 point improvement in overall Kansas City Cardiomyopathy Questionnaire. Markers, biomarkers were improved. All gradients resting Valsalva post exercise were significantly improved to a point where patients became, in addition to symptoms, non obstructive.
We also observed significant improvement in cardiac remodeling, including wall thickness, mass index, left atrial volume index, as well as diastolic function. A couple of months ago at ESC 2024, we even showed that mavacamten in the long run shows improvement in strain, LA and LV strain.
In addition, it was also important for us to ascertain long-term safety. So there were six additional patients in this report who had EF drop of less than 50% that needed temporary interruption. No permanent withdrawal additionally were needed. The incidence of EF drop, you know, 100 patient year incidence was between five and six, so about 5.5 or so. New onset AFib was also between five and six incidents over 100 patient years. So no new additional safety signal.
Another important thing we noticed was a substantial proportion of patients we were able to down-titrate their background medical therapy like beta blocker disopyramide. In fact, no patient, only between 15 and 20% patients remained on dual therapy. Vast majority, about 77% patients, were on monotherapy in addition to mavacamten.
The other key point I think is all these favorable effects were achieved with the lowest dose. So 5 and 10 milligrams were the most common dose. 75% patients we were able to achieve optimal efficacy at these lowest three doses with only a small proportion needing the higher doses.
And of course, as we have previously described, core lab echocardiography reads were heavily utilized as part of the VALOR trial. Only after week 32 we allowed site based reading for dose titration. Before that, everything was adjudicated in a blinded core lab manner. So that's VALOR study in a nutshell, end of VALOR study in a nutshell.
What are the take-home messages for practice?
Take-home messages from the VALOR study is: A. the work, the drug is highly effective. 9 out of 10 patients who were referred for cardiac surgery or alcohol ablation no longer needed cardiac surgery or alcohol ablation. And that was not a short-term fluke. We are able to demonstrate that in the long term, 9 out of 10 patients have transitioned to commercial mavacamten that should. And in addition to that, sustained favorable effects on cardiac remodeling, in addition to the gradients and symptom improvement. And all this is able to be done using the lowest doses.
Basically the clinical trial pivoted to the commercial approval of mavacamten. And a lot of how we practice obstructive HCM now mirrors how we set up the VALOR trial. So I think it was a nice transition.
What further research is needed in this area?
Further research at this point of time, the obstructive patient. I mean, you know, obviously there are newer drugs in development for obstructive HCM, some with similar mechanism, some with slightly different modulating mechanism.
The other area is non-obstructive HCM, for which there's the ODYSSEY trial, which is ongoing, which we should hear results next year, which is testing the strategy of mavacamten versus placebo. Similar other trials are ongoing testing other molecules in non-obstructive HCM.
I think, you know, the emphasis going forward needs to be on improving and refining the diagnosis and developing therapies, effective therapies that treat the whole spectrum of HCM, not just obstructive versus non-obstructive. Gene therapies are emerging. We are using artificial intelligence to make effective diagnosis in HCM. So the field is exploding in an absolutely great way.
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