On the Pulse of Gene Therapy: Continuing Progress in Cardiovascular Disease

Heart disease remains the leading cause of death for men and women of most ethnicities and racial groups in the United States, with 1 person dying every 33 seconds from cardiovascular disease (CVD).¹

While gene therapy made its first forays into rare diseases such as spinal muscular atrophy, adrenoleukodystrophy, and beta thalassemia, attentions have understandably shifted to include CVD in gene therapy investigations and development.

“This is one of those spaces where we are open to [gene therapy], for sure, in the cardiovascular space, at least for lipids and amyloidosis. There may be some other spaces, like dilated cardiomyopathies and some of the Long QT type of diseases, where, if you can get on top of that and then you're not having to put prophylactic ICDs in 20 and 30 year olds, it's just exciting to think we can really change the quality of life and really save lives in this space. Gene therapy, to me, has so much upside,” Viet Le, DMSc, PA-C, a preventive cardiology PA at Intermountain Health and the former president of the Academy of Physician Associates in Cardiology (APAC), told HCPLive.

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Some of the more advanced programs in development for CVD include, in order of development phase,

• Verve Therapeutics’ base-editing therapy for heterozygous familial hypercholesterolemia (HeFH) or premature coronary artery disease (CAD)
• Tenaya Therapeutics’ TN-201 gene therapy for hypertrophic cardiomyopathy (HCM) caused by mutations in the MYBPC3 gene
• Sardocor’s SRD-001 gene therapy for heart failure with preserved ejection fraction (HFpEF)
• Lexeo Therapeutics’ LX2006 gene therapy for Friedreich Ataxia (FA) cardiomyopathy
• Rocket Pharma’s RP-A501 for Danon disease
• Intellia Therapeutics’ NTLA-2001 CRISPR/cas9 for transthyretin amyloidosis (ATTR) with cardiomyopathy (CM)

These therapies typically target rare, monogenic diseases that can lead to CVD and heart failure, a hallmark of current gene therapy usage. However, the indications follow the mode of therapy’s shift from treating fatal childhood disease to being brought to serious diseases, but ones that often have some existing standard of care.

“Even when there is a potential treatment that is available, I think being able to do this when the when the downside is not that high, people really are looking for avenues where they could be especially in, again, monogenic cardiac diseases, where they can be treated once, if that's if that's possible, and where they can achieve a satisfactory outcome without having to continue to take different medications, continue to undergo through evaluations,” Ahmad Masri, MD, MS, director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University, told HCPLive. “If we continue to think about this as only a treatment for diseases that have no treatment, I think we're going to be significantly delayed in our efforts to develop these drugs and to help patients.”

Early Leads and Roadblocks in CVD Gene Therapy

Intellia’s NTLA-2001, which was recently given the name nexiguran ziclumeran (nex-z), is leading the pack by virtue of being the first gene therapy to enter phase 3 trials for a CVD indication. Data from the first patients dosed will be presented at later scientific meetings, as well as data from the ongoing phase 1/2 trials.² Notably, Intellia also recently demonstrated proof-of-concept of nex-z's redosability, providing a leg-up on traditional adeno-associated virus (AAV) vector gene therapies which currently cannot be redosed (although researchers are hoping to change that).³

“While this therapy NTLA-2001 does not necessarily target the myocardium, it is for a cardiac indication. So, this makes it essentially the first phase 3 trial that we’ve run across... It does signal an important milestone for us is that we are crossing over to that to that space of development [for which there have been many years of development] for different products in the hematology space and in other areas, but not really in cardiology,” Masri, who is an investigator on the nex-z program, said.

Another early frontrunner in the race for developing CVD gene therapies was Verve Therapeutics’ CRISPR/cas9 editing therapy VERVE-101, data on which made quite the splash at last year’s American Heart Association’s Scientific Sessions when the company touted an LDL-C reduction of 55% with just a single treatment at the highest dose level tested for HeFH.4 However, the program’s momentum was halted after the sixth participant dosed experienced unexpected but asymptomatic grade 3 adverse events (AEs) in April 2024.⁵

The patient experienced a Grade 3 treatment-induced transient increase in serum alanine aminotransferase (ALT) and a serious AE of Grade 3 treatment-induced thrombocytopenia. The laboratory abnormalities resolved fully within a few days and the participant did not experience any related bleeding or other symptoms. The AE prompted Verve to pause enrollment in its phase 1b heart-1 clinical trial (NCT05398029) and instead prioritize the then-preclinical program ERVE-102.

While some in the space saw the news as a step back in gene therapy’s progress for CVD, Le remains optimistic for VERVE-101 and programs like it to continue and emphasizes the need for transparency in regulating programs like these.

“I think we need to really educate folks like, what is your implicit bias here? What is your worry? And did we address a lot of that? The FDA has been kind of cagey, and I'll call them out a little bit. I don't know that there's cause to be cagey about allowing the trials to go forward here in the US... I love the safety, I like the regulation, but it's human beings that are making these decisions in the FDA, and I think that's kind of clouded by some of the [previous safety events seen with gene therapy] treatment and research in the US,” Le said.

While speaking about setbacks in gene therapy development, both Le and Victoria Parikh, MD, associate professor of medicine and director of the Stanford Center for Inherited Cardiovascular Disease (SCICD), called back to a death that occurred in Cure Rare Disease’s (CRD) Duchenne muscular dystrophy (DMD) gene therapy program, wherein a 27-year-old man (the trial’s only participant and the brother of CRD’s founder) with DMD died after receiving the CRISPR/cas9 gene therapy.⁶

Le noted that, in addition to being an extremely rare outcome, no events close to that outcome have been seen in CVD gene therapy trials. Parikh was encouraged by CRD publishing the clinical course and postmortem findings of the participant and emphasized that such transparency is important for learning more about best practices with gene therapy across all fields. Parikh pointed out that the data from CRD’s death have underlined the importance of considering patient frailty when administering gene therapy and being prepared with set protocols for managing known AEs.

“Trying to find ways to minimize the dose that you have to give in order to see a benefit is really important. The way that we select our patients is also really critical and being prepared with protocols to address any unlikely adverse reactions for patients is really critical,” Parikh told HCPLive.

Progressing Gene Therapy for CVD

Despite setbacks, Le, Masri, and Parikh, as well as Jonathan W. Weinsaft, MD, chief of cardiology and professor of medicine at Weill Cornell Medical College, remain optimistic about gene therapy’s trajectory in the field CVD and believe they are not in the minority. As always, more research needs to be conducted to better understand the interactions of different types of gene therapies in the body and to better understand the diseases being targeted for treatment themselves.

“We're trying to minimize risk to the heart, a very vital organ. We have learned so much from ophthalmology and from dermatology and pushing these technologies forward, and now we need to ensure we just need to tweak them so that they're safe to be given systemically into the heart,” Parikh said.

Masri advocated for the platform development system for gene therapies, which can accelerate and streamline development by developing one platform that can be tailored to target individual genes on a case-by-case basis, as a potential future strategy. He also emphasized the importance of engaging patients and principal investigators to design effective and meaningful trials, and of continuing to move the needle forward in the field. Watch more of what Masri had to say below.

“It cannot follow the traditional development pathway for other drugs like take, for example, small oral molecules. I don't think you can think of gene editing and gene therapy in a way following the same exact pathway. It's just not going to be feasible.”

Weinsaft highlighted similar needs in the field, including diving deeper into genetic research to unlock the full, and safe, potential of gene therapy and engaging patient, investigators, and basic scientists to communicate and work together more effectively.

“There needs to be much more crosstalk between basic scientists, clinical investigators, and clinicians in the field so that advances, in terms of our understanding of the molecular basis of disease, is translated into actual practice. Number 2, we need to be much, much better in terms of patient outreach and engagement, so as to identify and promptly treat at-risk, underserved, and under resourced communities. And number three, we continually need to fund sought and support science. Without advances in terms of scientific understanding, and molecular pathogenesis of these conditions, gene therapy is going to remain stagnant,” Weinsaft told HCPLive.

While the road has not been the smoothest in gene therapy development for cardiovascular disease, cardiologists believe its trajectory will grow, continue to advocate for its potential to improve outcomes for their patients, and look forward to the field progressing to address more conditions.

Parikh's disclosures include Lexeo, Biomarin, Neuvovor, and Borealis. Weinsaft's disclosures include Bitterroot Bio and General Electric HealthCare. Le's disclosures include Amarin, Novartis, Idorsia, Janssen, Lexicon, and Pfizer. Disclosures for Masri include Cytokinetics, Bristol Myers Squibb, Eidos, Pfizer, Ionis, Lexicon, AstraZeneca, Tenaya, and others.

REFERENCES

1. Heart Disease Facts. Website. Center for Disease Control. October 24, 2024. Accessed November 8, 2024.https://www.cdc.gov/heart-disease/data-research/facts-stats/index.html#:~:text=Heart%20disease%20is%20the%20leading,every%205%20deaths.12

2. MedStar Health launches participation in phase 3 MAGNITUDE gene-editing study with first US Heart patient treated at MedStar Washington Hospital Center. News release. MedStar Health. May 2, 2024. Accessed May 6, 2024. https://www.prnewswire.com/news-releases/medstar-health-launches-participation-in-phase-3-magnitude-gene-editing-study-with-first-us-heart-patient-treated-at-medstar-washington-hospital-center-302134470.html

3. Taubel J, Gane E, Fontana M, et al. Activity Of Follow-on Dosing ForAn Investigational In Vivo CRISPR-Based LNP Therapy In Transthyretin Amyloidosis. Presented at: 2024 PNS Annual Meeting, June 22-25; Montreal, Canada. Poster #O435

4. Vafai SB, Gladding PA, Scott R, et al. Safety and pharmacodynamic effects of VERVE-101 an investigational DNA Base editing medicine designed to durably inactivate the PCSK9 gene and lower LDL cholesterol – interim results of the phase 1b heart-1 trial. Presented at: AHA Scientific Sessions 2023; November 10-13; Philadelphia, Pennsylvania.

5. Verve Therapeutics announces updates on its PCSK9 program. Verve Therapeutics. April 2, 2024. Accessed April 2, 2024. https://ir.vervetx.com/news-releases/news-release-details/verve-therapeutics-announces-updates-its-pcsk9-program.

6. Lek A, Wong B, Keeler AL, et al. Death after high-dose rAAV9 gene therapy in a patient with Duchenne’s muscular dystrophy. N Engl J Med. 2023 (389): 1203-1210 doi: 10.1056/NEJMoa2307798