‘One giant leap for HCM’: Gene therapy may reverse hypertrophic cardiomyopathy
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Key takeaways:
- A first-in-human phase 1 trial is testing a novel gene therapy for hypertrophic cardiomyopathy.
- The one-time infusion, if successful, could be a cure for the debilitating disease.
Despite advances made for the treatment and management of hypertrophic cardiomyopathy, the condition remains a debilitating one for many patients, who are often undiagnosed until the disease has progressed.
Hypertrophic cardiomyopathy (HCM) is the most common monogenic CV disorder, causing thickening of the heart muscle, left ventricular stiffness and mitral valve changes. It affects an estimated one in 500 people and is the most common cause of sudden cardiac death among adults younger than 30 years.
There were no disease-specific treatments for HCM until 2022, when the FDA approved mavacamten (Camzyos, Bristol Myers Squibb). Mavacamten has been shown to improve symptom burden and quality of life, but it is not a cure and more options are needed, Milind Y. Desai, MD, MBA, director of Center for Hypertrophic Cardiomyopathy and vice chair for the Cleveland Clinic Heart, Vascular & Thoracic Institute and professor of medicine at Cleveland Clinic Lerner College of Medicine, told Healio.
One such new option could be gene therapy. In a new trial, researchers aim to address the leading cause of HCM, myosin binding protein C3 (MYBPC3) gene mutations. Researchers at Cleveland Clinic recently dosed the first human patient, a woman with HCM aged 27 years, as part of the MyPeak-1 phase 1b clinical trial, which will assess the safety and clinical efficacy of a one-time infusion of TN-201 (Tenaya Therapeutics).
Healio spoke with Desai about the unmet needs for HCM and what gene therapy could mean for the field. Desai is an investigator for the MyPeak-1 Phase 1b clinical trial.
Healio: Mavacamten was hailed as a game-changing therapy when it was approved for the treatment of symptomatic obstructive HCM in April 2022. But there are still unmet needs for this disease. What are those?
Desai: Mavacamten is a cardiac myosin inhibitor, developed to help with more efficient functioning of the cardiac sarcomere. It modulates the disease by reducing hypercontractility by reducing the number of actin-myosin cross-bridges, making the sarcomere function more efficiently. However, it does not address the fundamental pathology that occurs due to the genetic mutation. HCM is the most common genetically mediated mutation and the most common genetic mutation among HCM patients is myosin-binding protein C3. People who have this genetic mutation only produce about 60% of this protein. So, there is loss of function. This results in all the downstream ramifications: worsening stiffness, increased thickness and subsequent symptomatology. .
This specific type of gene therapy is designed to deliver a working MYBPC3 gene copy to the heart muscle by using an adenovirus vector with a single IV infusion. It is cardiac-specific. It goes into the heart muscle; DNA turns into RNA and RNA turns into the missing protein. For lack of a better phrase, it “tops off” the missing amount of protein. If this works, then this one-time injection can potentially cure the disease.
Healio: Can you walk us through the study design of this phase 1 trial?
Desai: This is a first-in-human trial, and a safety and dose-finding study. The concept has been tested and retested in primates and now it is time to test it in humans. Based on my assessment of the basic science data, the technology works and was it deemed safe by FDA to proceed with human studies. The virus has been used as a vehicle for gene-therapy delivery in other diseases, and there have been concerns related to liver enzyme abnormalities and thrombotic microangiopathy, the rate of which is fairly low but not zero. The FDA has data on more than 5,500 such infusions and, based on their assessment, it has been deemed safe to proceed to human trials for HCM.
The most important thing is safety. We started at the lowest dose that we think will work, and now we ascertain the safety. The next important thing is that we want to make sure the genetic material is expressed in the heart. To ascertain that, we will conduct biopsies of the heart just like we do in heart transplantation. We will also be conducting echocardiograms, doing cardiopulmonary stress testing and looking at biomarkers.
Healio: What is the timeline for this trial?
Desai: This is a small study, between six and 15 patients who have been diagnosed with MYBPC3-associated nonobstructive HCM and have implantable cardioverter defibrillators. The key time points are at week 8, when we will conduct a biopsy of the heart to see if we can see the DNA material within the heart. Then, we will conduct a biopsy at week 52 to make sure this is not a short-term expression, in addition to frequent clinical, biomarker and imaging evaluations. We should hear more in 2024, once we have the results.
Healio: If this gene therapy is successful, what could it mean for the field?
Desai: To paraphrase Neil Armstrong, this may be one small step in research, but it is one giant leap for HCM. More importantly if this concept works, then, fast forward a decade or more. A patient with HCM can receive a single IV infusion and be monitored for a few weeks and we would potentially see positive results.
But obviously, I am still waiting with bated breath. This is what science should be about: a fruitful collaboration between a well-informed patient, the academic research team and an innovative company. This took years of science and months of careful planning on how to operationalize this, detail by detail. I want to sincerely thank the brave first patient who put their trust and their life in our hands.
For more information:
Milind Y. Desai, MD, MBA, can be reached at desaim2@ccf.org.
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