With several recent approvals in the space and more on the horizon, BioSpace looks at some of the key decisions and their larger significance both for patients and science.
Pictured: 3D rendering of human cells and DNA/iStock/iStock, anusorn nakdee
2023 was a banner year for cell and gene therapy, with seven FDA approvals, according to the Alliance for Regenerative Medicine. And the pace doesn’t appear to be slowing at all as the second quarter of this year gets underway. The advocacy group is anticipating an even bigger year for the CGT space in 2024, with a potential 17 approvals in the U.S. and EU combined, according to ARM’s annual Cell & Gene State of the Industry Briefing in January.
“It seems like the FDA is really pushing forward with accelerated approvals for cell and gene therapies, and that’s quite encouraging to see,” Jack Allen, a senior research analyst at Baird, told BioSpace. “These can be quite expensive products to develop, and if we’re able to leverage abbreviated pathways to get them to market rapidly, I think that can really reignite enthusiasm for the space.”
Allen noted that cell and gene therapy is somewhat de-risked by the fact that, in many instances, these treatments involve introducing the genetic sequence for a native functional protein. “I think there will be some bumps in the road as it relates to pressing forward rapidly with the technology,” he said, but “it seems like the FDA has buy-in and is willing to ride through some of those bumps.”
Here, we take a closer look at six of the more notable cell and gene therapies approved during the past year—two of them under the FDA’s accelerated approval pathway—and preview some of the decisions on the horizon.
Cell Therapies
BMS’s Breyanzi
Chronic lymphocytic leukemia and small lymphocytic leukemia
On March 14, the FDA approved Bristol Myers Squibb’s Breyanzi as the first CAR T cell therapy for relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia. In the pivotal TRANSCEND 004 trial, Breyanzi elicited a complete response—something that is “basically unheard of” in patients with relapsed/refractory CLL, according to Rosanna Ricafort, vice president and head of late development hematology and cell therapy at BMS—in 20% of recipients, with responses lasting more than 35 months.
The Big Picture
In November 2023, the FDA launched an investigation into the “serious risk” of secondary malignancies in patients treated with BCMA- or CD19-directed autologous CAR T cell therapies. This led to the addition of a boxed warning to all six commercial CAR-T therapies at the time, including BMS’s Breyanzi. But industry leaders and the FDA itself have been supportive of CAR-T’s risk/benefit profile. Breyanzi’s approval in two more indications, along with the recommendation of FDA advisers to move Abecma and J&J’s Carvykti into earlier lines of treatment for multiple myeloma, have cemented this tone.
Iovance’s Amtagvi
Melanoma
In one of the year’s most anticipated decisions, the FDA in February greenlit the first one-time cell therapy for a solid tumor, Iovance Biotherapeutics’ Amtagvi for unresectable or metastatic melanoma, under the accelerated approval pathway. Iovance is currently conducting a confirmatory study to verify the therapy’s benefit.
The Big Picture
Amtagvi is the first tumor-infiltrating lymphocytes (TIL) therapy, a treatment modality some experts say has advantages over CAR-T. While CAR Ts recognize only a small number of proteins on the surface of tumor cells, TILs can identify tumor targets derived from intra- or extracellular tumor proteins, Sammy Farah, CEO of Turnstone Biologics, told BioSpace. As of February 2023, there were more than 75 TIL immunotherapies in preclinical or clinical studies for various indications.
Gene Therapies
Orchard Therapeutics’ Lenmeldy
Metachromatic leukodystrophy
Last month, the FDA approved Orchard Therapeutics’ Lenmeldy as the first gene therapy for metachromatic leukodystrophy (MLD), a rare, degenerative disease characterized by loss of motor and cognitive function and early death.
MLD is caused by a deficiency in the arylsulfatase-A (ARSA) gene, leading to a buildup of fatty substances in the cells. Lenmeldy is a single-dose infusion made from a patient’s own hematopoietic stem cells, which have been genetically modified to include functional copies of the ARSA gene.
The Big Picture
Lenmeldy joins a growing list of gene therapy firsts in pediatric diseases, including Sarepta’s Elevidys for Duchenne muscular dystrophy and bluebird bio’s Skysona for cerebral adrenoleukodystrophy. It is also the first FDA-approved treatment for MLD patients, “who previously had no treatment options beyond supportive and end-of-life care,” Orchard CEO Bobby Gaspar said in a statement.
Vertex and CRISPR Therapeutics’ Casgevy
Sickle cell disease, beta thalassemia
Possibly the most celebrated approval of 2023 went to Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy, which in December became the first-ever CRISPR-based gene editing therapy in the U.S., for sickle-cell disease (SCD). Just one month later, Casgevy was also approved for transfusion-dependent beta thalassemia, more than two months ahead of its PDUFA date.
The Big Picture
Casgevy’s SCD approval came just over a decade after the publication of the Nobel Prize-winning CRISPR-Cas9 technology—a timeline many industry experts have deemed faster than what would normally be expected of a new modality. But CRISPR is not without its risks. Researchers have cited cell toxicity and genomic instability as potential side effects, which could potentially trigger tumor development. Scientists are now working to improve on the technology with new modalities, including base editing and epigenetic editing.
Bluebird bio’s Lyfgenia
Sickle-cell disease
While the historic nature of Casgevy’s approval won the day, bluebird bio’s Lyfgenia, a lentiviral gene therapy, also got the FDA’s nod for SCD on Dec. 8, 2023. Treatment with Lyfgenia led to the complete resolution of vaso-occlusive events 6 to 18 months after infusion, making it another promising option for patients.
The Big Picture
Allen said Lyfgenia may have a couple of advantages in the SCD market. “Both [therapies] are incredibly transformative in that they effectively eliminate sickle-cell disease–induced pain crises. Lyfgenia I think is quite interesting in that there’s a longer durability of data . . . and they also have some data in stroke patients, which I think is going to be differentiating in the commercial marketplaces” given the prevalence of stroke in SCD. Lyfgenia also has the upper hand over Casgevy in terms of developing the infrastructure needed to deliver treatment to patients.
Sarepta’s Elevidys
Duchenne muscular dystrophy
In one of 2023’s more controversial decisions, the FDA approved Sarepta Therapeutics’ Elevidys as the first gene therapy for Duchenne muscular dystrophy (DMD). Elevidys missed the primary functional endpoint in a randomized trial but won accelerated approval based on data showing it increased the expression of the micro-dystrophin protein—a biomarker the agency determined is “reasonably likely to predict clinical benefit” in DMD patients 4 to 5 years of age. The FDA’s green light followed an adcomm meeting where its advisers narrowly recommended the gene therapy for approval. Then, just four months after the approval, Elevidys failed a confirmatory trial.
The Big Picture
Elevidys’ approval kicked off a wave of momentum in the DMD space. In October 2023, the FDA authorized Santhera Pharmaceuticals’ Agamree, and just last month, Italfarmaco won approval for Duvyzat, the first nonsteroidal drug approved to treat patients with all genetic variants of the disease.
On the Horizon
Rocket’s Kresladi
Leukocyte adhesion deficiency-I
Rocket Pharmaceuticals had expected a decision on its gene therapy Kresladi, in development for the rare disease leukocyte adhesion deficiency-I, in March, but the FDA pushed the date back to June 30, 2024 in order to allow for more review time.
BMS’s Breyanzi
Follicular lymphoma and mantle cell lymphoma
It’s a big year for BMS’s Breyanzi, as the company is expecting the FDA to decide on the CAR T cell therapy as a treatment for patients with relapsed or refractory follicular lymphoma on May 23 and for those with relapsed or refractory mantle cell lymphoma who have been treated with a Bruton tyrosine kinase inhibitor therapy on May 31.
Pfizer’s Beqvez
Hemophilia B
After winning approval in Canada in January, Pfizer’s adeno-associated virus-based gene therapy fidanacogene elaparvovec—marketed as Beqvez in Canada—has a PDUFA date in the second quarter of 2024.
Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.
