Regulatory Pathway Widening for Cardiac Gene Therapy Hopefuls

CV Gene Therapy_Nicole Bean for BioSpace

Pictured: An FDA blue van drives towards cardiac-shaped mountains/ Nicole Bean for BioSpace

After five gene therapies hit the market last year, FDA officials have predicted that 2024 will be a “breakout year” for approvals of this type of treatment. With more than 17 gene therapies now available for patients, cardiovascular indications—which have recently seen increased activity—are navigating largely uncharted regulatory waters.

While recent approvals can help guide regulators in learning the new modalities of gene therapies, the cardiovascular landscape is still emerging. The arena is essentially split between companies focusing on highly prevalent diseases and those working on rare cardiovascular disorders, experts told BioSpace, and each comes with its own regulatory challenges.

Leveraging Biomarker Flexibility

A handful of biotech companies are targeting rare diseases that affect the heart. Because many of these diseases lack effective therapies, new treatments can take advantage of the FDA’s accelerated approval pathway. In general, gene therapies for orphan indications are 3.5 times more likely than average drugs to be approved once in a Phase I trial, Tim Hunt, CEO of the Alliance for Regenerative Medicine (ARM), said during the annual Cell & Gene State of the Industry Briefing in January.

Lexeo Therapeutics is developing a gene therapy, LX2006, for Friedreich’s ataxia cardiomyopathy, for which the FDA has granted Rare Pediatric Disease designation and Orphan Drug designation.  

Historically, cardiovascular (CV) treatments have relied upon large population and long-term studies with endpoints of mortality, morbidity and hospitalization, Lexeo CEO R. Nolan Townsend told BioSpace. But Townsend sees a shift occurring, which could open the door to a precision medicine approach for gene therapies in the cardiac space.

“Cardiac is beginning to look a lot more like some of the rare neurologic diseases . . . in terms of the flexibility that the FDA is giving companies to have these medicines reach patients,” he said.

A lot of this flexibility stems from a better understanding of the biomarkers associated with rare CV diseases, Townsend said, adding that using biomarkers as a surrogate endpoint allows companies to evaluate efficacy at earlier stages and often in smaller patient populations—a crucial component for targeting rare diseases.

In its Friedreich’s ataxia program, Lexeo is using both invasive and non-invasive biomarkers pretreatment and post-treatment to evaluate the one-time gene therapy’s efficacy. Townsend said he hopes the biomarker data will lead to an accelerated approval.

Rocket Pharmaceuticals is also utilizing biomarkers in the testing of its gene therapy for Danon disease, a rare genetic disorder characterized by thickening and weakening of the heart muscle that often results in heart failure. After entering the clinic in 2018, the company began pivotal trials of RP-A501 last year. Sami Corwin, a William Blair analyst who covers Rocket, credits the faster-than-usual development timeline to the smaller patient population required by the FDA, in addition to the use of biomarkers.

“The FDA has seemed to be a little more lenient in terms of pivotal trial design,” Corwin told BioSpace, adding that the required duration of follow-up is shorter for trials of gene therapies for rare diseases compared to those assessing therapies for a highly prevalent CV disease.

The shorter follow-up times, smaller patient populations and use of biomarkers to prove early efficacy are helping to de-risk gene therapy programs for investors, allowing smaller biotech companies to compete in the space, Corwin said.

Ultimately, there are a number of cardiovascular diseases that may not be large enough to attract big pharma that small-to-midsized companies can now tackle due to this increased flexibility, Townsend said. “I think we will see a broadening in the number of cardiovascular precision medicines over the coming years based on this evolving regulatory trend.” 

Large Indications Face Greater Scrutiny

In the other camp, some gene therapy players are targeting CV indications with large populations, such as levels of bad cholesterol.

“Regulators are clearly looking at rare diseases with really no other therapeutic alternative as a completely different regulatory landscape to more prevalent disorders,” Miles Minter, an analyst with William Blair covering Verve Therapeutics, told BioSpace. Indications for which treatments are already approved are treated differently, he said. 

Verve is developing a one-time gene therapy to lower cholesterol, but to be FDA approval-worthy, it will need to work in the most severe patients, Minter said. Companies like Verve need to show their therapy is effective in these patients before moving to earlier lines of treatment.

However, “Gene editing could completely transform how we treat cardiovascular disease, shifting the paradigm from daily pills or intermittent injections over decades to potentially a once-and-done [solution],” Verve CEO Sekar Kathiresan told BioSpace in an email.

Kathiresan said understanding FDA expectations is critical for Verve’s programs. VERVE-101 turns off the PCSK9 gene in the liver to lower LDL cholesterol. The program is partnered with Eli Lilly, potentially pointing to the need for big pharma collaboration to meet trial design requirements for a large population indication.

Delivery Modality Matters

Most CV-indicated gene therapies are delivered via one of two delivery modalities, Corwin said. The genetic materials for those targeting more prevalent indications like Verve’s VERVE-101 are being delivered via the liver through a lipid nanoparticle (LNP). But for indications that need to change proteins within the heart itself, adeno-associated virus (AAV) vectors are the delivery method of choice.

Corwin said the regulatory pathway is likely more complicated with AAV. The FDA is tuned in to the potential toxicity risks of AAV gene therapies, having hosted an advisory committee meeting on the subject in 2021. The manufacturing process for AAV is also complex, expensive and time-intensive. Corwin and Minter both agreed that the agency is likely more comfortable with LNP-delivered therapies, thanks to the widespread use of mRNA-based COVID-19 vaccines with LNP vectors.

“There are different nuances and points that the FDA will scrutinize” when it comes to CV-indicated gene therapies, Corwin said.

As of press time, the FDA had not responded to BioSpace’s request for comment on regulatory requirements for CV-indicated gene therapies.

For CV indications common and rare, Townsend extolled gene therapy’s potential. “At the moment, I don’t want to say it’s the only game in town, but it is probably the best game in town for delivering a nucleic acid to the heart.” 

Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at and on LinkedIn.   

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