NEW YORK – 2024 was a banner year of "firsts" in the gene therapy space, as the US Food and Drug Administration greenlit three new products and expanded indications for two others, all for rare diseases.
The regulator kicked off the year by adding a second indication to Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) in transfusion-dependent beta thalassemia, which at the end of 2023 had the distinction of being the first CRISPR gene-editing drug to reach the market after its initial approval in sickle cell disease. The agency also approved the first gene therapies for metachromatic leukodystrophy and aromatic L-amino acid decarboxylase (AADC) deficiency, Orchard Therapeutics' Lenmeldy (atidarsagene autotemcel) and PTC Therapeutics' Kebilidi (eladocagene exuparvovec), respectively. Beyond a first in AADC deficiency, Kebilidi is also the first gene therapy to enter the market that can be administered directly to the brain.
Patients with hemophilia B in 2024 got a second gene therapy option with the approval of Pfizer's Beqvez (fidanacogene elaparvovec), following the 2022 FDA approval of CSL Behring's Hemgenix (etranacogene dezaparvovec).
There are now upwards of 40 cell and gene therapies approved in the US, and that number will only grow in coming years, experts predict.
There's been a "persistent and steady drumbeat of cell and gene therapy approvals throughout 2024," said David Barrett, CEO of the American Society of Gene & Cell Therapy (ASGCT). "We've seen many cell and gene therapies that have been in the pipeline for decades, that are finally making it across the finish line."
Promoting rare disease programs
One reason more gene therapies are coming to market is the FDA. Agency officials have made good on their promises to offer flexibility to drugmakers seeking approval for gene therapies for very rare and difficult-to-treat diseases.
Under the accelerated approval pathway, the FDA can approve drugs faster than the traditional approval process by basing regulatory decisions on how treatments affect biomarkers likely to predict clinical benefits, rather than waiting for years to see if the drugs improve clinical outcomes like survival. However, the FDA's efforts to be more flexible through the accelerated approval pathway haven't been without controversy.
This summer, in converting its 2023 accelerated approval into a traditional approval, the FDA expanded the indication for Sarepta Therapeutics' Duchenne muscular dystrophy (DMD) gene therapy Elevidys (delandistrogene moxeparvovec) to include older patients, despite concerns from some agency reviewers.
The FDA initially granted Elevidys accelerated approval only in ambulatory patients who were 4 and 5 years old, after an agency advisory panel narrowly voted in favor of the gene therapy based on biomarker data. However, industry observers were surprised when the FDA opted to expand the gene therapy's approval a year later, even after it failed a Phase III confirmatory trial.
"It's been an interesting evolution in terms of seeing where FDA is going with respect to their view on greater flexibility," said Katy Spink, chief operating officer and managing partner at Dark Horse Consulting. "The amount of flexibility that they've afforded to Sarepta around that program has been more than anyone probably expected."
Sarepta in an emailed statement said the gene therapy's performance in the commercial setting so far has reinforced efficacy and safety observed in clinical trials.
"The safety remains consistent regardless of age, weight, or ambulatory status and across studied patients [and] the biomarker and functional data repeatedly demonstrate that Elevidys stabilizes or slows the progression of DMD, regardless of age, weight, or ambulatory status," a spokesperson said in an email. "FDA agreed that the data were compelling and expanded the label accordingly."
In addition to continuing to voice support for accelerated approval, the FDA this year pursued multiple other programs to spur development of rare disease treatments, many of which have implications for gene therapy.
For example, within the START pilot program, the regulator selected a cohort of rare disease treatments, including several gene therapies, that it intends to help advance through clinical development and toward market approval. The agency also issued a draft guidance detailing plans for a Platform Technology Designation Program, which it envisions could accelerate development and regulatory review of investigational medicines by defining "platform" components of approved drugs that may be reused within new products.
The program could prove particularly useful for gene-editing companies and save time and resources not only for drug manufacturers but also for the FDA.
"This is early on, but we have to be thinking now," Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, said during a fireside chat at ASGCT's annual meeting in May. "There are a lot of nucleotides out there that can go wrong in the genome. I don't think we can have 3 billion visits to the FDA a year."
It's unclear whether the FDA's focus on promoting gene therapy development will change under President-elect Donald Trump's new administration and what changes new leadership might bring to regulatory review. So far, Trump has named Robert F. Kennedy Jr. as his pick for secretary of the US Department of Health and Human Services and Marty Makary, a surgeon at Johns Hopkins Medicine, to lead the FDA.
"My sense is that everyone is going to be a little bit cautious until they find out more clearly what the new [administration] is going to do, and what the new commissioner is going to highlight as a priority," said Abla Creasey, executive strategy officer for rare disease at the California Institute for Regenerative Medicine (CIRM).
Sharpened focus
Despite new approvals and continued excitement within the biotech sector, it wasn't all good news for gene therapies in 2024, as venture funding into biopharma companies dipped below the levels seen during the COVID-19 pandemic.
Biopharma companies had used the surge in capital during the pandemic to advance many new therapeutic programs into clinical trials, Dark Horse's Spink said. Now that investment has dried up, companies must be more selective about which programs they take into clinical trials.
Citing resource constraints, many companies in 2024 made workforce cuts and even dropped promising gene therapy development programs from their pipelines.
Bluebird Bio, the maker of Lyfgenia (lovotibeglogene autotemcel), a gene therapy approved at the same time as Vertex's Casgevy for sickle cell disease in 2023, announced in the fall that it was laying off one-quarter of its workforce as part of a restructuring plan. PTC Therapeutics this year said it would discontinue multiple gene therapy programs in preclinical and early stages of development. BridgeBio said it would no longer develop a gene therapy for congenital adrenal hyperplasia, a group of rare genetic disorders.
Generally, these staff and program cuts haven't been due to a lack of promising results, according to ASGCT's Barrett, but because companies have had to make decisions based on commercial viability.
It can be particularly challenging to commercialize treatments for rare diseases. It's a massive investment to develop drugs that, ultimately, will be sold to a very small portion of the population. And, despite the transformative potential of gene therapies, there's also a lack of long-term data at present, so it's unclear in the near term whether treatments are actually a one-time cure and worth their multimillion-dollar price tags.
While biopharma companies argue that their gene therapies are priced in line with the benefit they impart to patients and factor in the investment they made, these one-time high-cost products have placed a lot of pressure on insurers.
The US Centers for Medicare & Medicaid Services is trying to address accessibility with outcomes-based reimbursement models through the Cell and Gene Therapy Access Model, in which it will negotiate agreements for sickle cell treatments with drugmakers on behalf of participating state Medicaid programs. The program, run through the CMS's Center for Medicare and Medicaid Innovation, aims to improve access to these treatments while providing states with more budget predictability.
Earlier this month, Vertex and Bluebird both said they are participating in the model.
In 2025, Creasey said she expects to see gene therapy developers explore and solidify commercialization strategies to bring gene therapies to patients. She also expects to see ongoing conversation around reimbursement. "That's going to be a key topic for 2025 and beyond," she said.
Gene editing in vivo
Casgevy was a scientific milestone as the first CRISPR gene-editing treatment to reach the market. However, to create the product, hematopoietic stem and progenitor cells must be extracted from a patient's body and edited ex vivo, which are then infused back into the patient.
During 2024, excitement mounted about the potential for editing genes inside of the body. "It would solve, or at least greatly reduce, several of the really significant challenges the space is facing right now," Spink said of in vivo gene editing. "I expect we'll be getting early clinical data from quite a few programs next year."
In vivo gene editing would cut the need for steps like stem cell collection through apheresis, a multi-month wait while these cells are engineered, and an intensive conditioning process that involves chemotherapy — which comes with its own set of risks, including infertility — before the treatment is finally infused.
The enhanced focus on bringing gene-editing treatments to patients is one of the things that's excited CIRM's Creasey most this year. That includes different types of gene editing, like base editing and prime editing, in addition to an interest in testing treatments that edit genes in vivo. "I'm optimistic that is going to flourish in the next couple years," she said.
Intellia Therapeutics, Beam Therapeutics, and CRISPR Therapeutics are among companies testing in vivo gene-editing therapies. Editas Medicine last week said it would lay off 65 percent of its workforce as it discontinued a clinical-stage ex vivo gene-editing candidate for severe sickle cell disease and transfusion-dependent beta thalassemia, so that it can focus its resources on advancing preclinical in vivo therapies in its pipeline.
Casgevy's approval "augurs the entry of CRISPR-Cas9-mediated gene editing into therapeutics for difficult-to-treat diseases," said Roger Hajjar, director of Mass General Brigham's Gene and Cell Therapy Institute. He noted that in vivo gene editing using lipid nanoparticles (LNP) has shown clinical benefits as a treatment for transthyretin amyloidosis with cardiomyopathy (ATTR-CM), for example.
Intellia this year started enrolling patients in the Phase III MAGNITUDE trial testing nexiguran ziclumeran, previously known as NTLA-2001, in patients with ATTR-CM. According to Intellia, which is developing this candidate with Regeneron Pharmaceuticals, this was the first in vivo CRISPR gene-editing therapy cleared to enter late-stage clinical development in the US.
That "would be the trial to watch over the next year," Hajjar said. He expects to see more LNP-mediated gene-editing treatments reach the market, although adeno-associated virus-based gene therapies will likely continue to constitute most of the products approved next year, he added.