Halloween brings to mind pumpkins and trick or treat, but for the 100,000 Americans suffering from sickle cell disease, this past October 31 had a different meaning when an FDA advisory panel deemed the first potentially curative SCD therapy safe enough for clinical use, bolstering hopes of an FDA approval in December. It would also be the first-ever approval for CRISPR, the genetic modification technique that won its discoverers the Nobel Prize in 2020 for their 2012 breakthrough.

Approval of the treatment, called exa-cel and pioneered jointly by Vertex Pharmaceuticals and Swiss biotech CRISPR Therapeutics, could signal a new era for the field of cell and gene therapy, said Stephen Majors, global head of communications at the Alliance for Regenerative Medicine (ARM). “This is a crucial time for the sector,” Majors told BioSpace. “The advisory panel’s approval paves the way for the first FDA approvals of this type anywhere, in a rare disease that predominantly affects an underserved community, many of whom are patients in the Medicaid program. This all combines to make it the biggest moment for cell and gene therapy so far.”

The Oct. 31 vote by the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee is also welcome news for the many other trials underway using CRISPR technology to treat everything from rare blood diseases to eye diseases to cancers.

Exa-cel is currently targeted toward the 20,000 sickle cell sufferers who have the most severe form of the disease (as well as transfusion-dependent beta-thalassemia, another rare disease characterized by inadequate hemoglobin). Exa-cel works by disabling the gene that silences the fetal hemoglobin gene, allowing a normally quiet gene for fetal hemoglobin to switch on. Fetal hemoglobin binds more strongly to oxygen, and­­­­ natural history studies show that having fetal hemoglobin levels greater than 20% can be protective and ameliorate signs and symptoms of diseases.

And more potential gene and cell therapy approvals are coming up right behind exa-cel. A second SCD gene therapy, bluebird bio’s lovo-cel, has an FDA action date of December 20, and a novel cell therapy for metastatic melanoma—Iovance’s lifileucel—is awaiting an FDA decision by February 24, 2024. Meanwhile, Rocket Pharmaceuticals expects a March 2024 decision for its gene therapy to treat Leukocyte Adhesion Deficiency-I, a rare immune disorder that can lead to fatal infections.


FDA Braces for Regulatory Swell

As the fields of cell and gene therapy advance and the pipeline of new therapies swells, the FDA’s Center for Biologics Evaluation and Research (CBER) is updating the regulatory review process for a new era. “We still have much to learn about how cell-based gene therapy products work, how to administer them safely, and whether they will continue to work properly in the body without causing adverse side effects over long periods of time,” Peter Marks, director of CBER, told BioSpace in a previous interview. “For some of these products, we may need to accept some level of uncertainty around these questions at the time of approval.” Marks said that post-marketing safety monitoring and the possible use of additional clinical trials will be key to advancing this field.

For instance, the FDA advisory committee’s positive vote for exa-cel focused on whether the CRISPR approach could possibly cause harmful “off-target” effects by mistakenly snipping the wrong piece of DNA. Of the 44 patients reported on to date in the company’s clinical trials, only 30 have been followed for at least 16 months, with no untoward effects. In its FDA presentation, the company stated it plans to follow its patients for the next 15 years. This is just one example of how the FDA is flexing regulations and safety benchmarks to meet the shifting landscape of these new therapies.

In some cases, the FDA is accelerating potential approvals by looking at a biomarker rather than an actual clinical effect. “You get approval for increased production of a protein or enzyme,” Majors explained. He cited dystrophin, a protein that strengthens muscle fibers and can be lacking in diseases like Duchenne muscular dystrophy. “Then you do a trial to see if increasing dystrophin leads to greater muscle strength.” This approach can be particularly helpful in rare diseases where it can be challenging to assemble enough patients for a meaningful result or a traditional randomized, double-blind study.


Overcoming Obstacles

Meanwhile, Iovance’s innovation with lifileucel is on the manufacturing side: it takes a cell therapy that was first pioneered 30 years ago and scales it up so that it is more widely available and reliable. Manufacturing is an area where regulators and industry are working hard together to establish new benchmarks. “You can crank out small molecules easily in high quantities,” Majors said. “But with living materials like cells and genes, it’s much harder to manufacture these materials in a consistent, repeatable way.”

Marks agreed. “Many of these products are potentially lifesaving,” he told BioSpace. “However, currently, there is not enough manufacturing capacity available to make adequate quantities of high-quality vectors, which is in part driving up development costs. Working together, product developers, regulators and the medical communities need to find some fundamental efficiencies to help get these products to patients in need. This includes advancements in our manufacturing capabilities in terms of the ability to produce vectors at greater scale. Otherwise, the cost of these products will ultimately be prohibitive.”

Iovance is extracting and then expanding the body’s own anti-tumor cells, multiplying them from millions to billions, and then reinfusing them so that this newly enhanced, expanded army can attack melanoma cells in the body, wherever they are. “We built a manufacturing center and worked with contract manufacturers to build a proprietary 22-day process to expand the cells in a consistent GMP way,” Brian Gastman, executive vice president of Medical Affairs at Iovance, explained. “If Iovance is successful it will open the door for everybody else,” he told BioSpace. “Nobody else has gotten this far in cell therapy for a solid tumor.”

That open door for new technologies in cell and gene therapy is a global one, and for that reason, Marks said the FDA is pursuing global safety standards with “international partners, global regulators and the World Health Organization.” He said the FDA may also explore the possibility of concurrent collaborative review of applications with global regulatory partners in a manner similar to that being undertaken through Project ORBIS in the FDA’s Oncology Center of Excellence.

Meanwhile, the cell and gene therapy space will hold its collective breath leading up to exa-cel’s Dec. 8 decision date.

“I can tell you that exa-cel is life-changing,” said Haydar Frangoul, medical director of pediatric hematology/oncology at Sarah Cannon Research Institute and HCA Healthcare’s The Children’s Hospital At TriStar Centennial in Nashville and principal investigator on Vertex’s U.S. clinical trials. “There is no risk of rejection, no risk of a donor’s cells attacking the patient and causing graft versus host disease. It is transformational and the most exciting thing I have been involved in my whole career,” he told BioSpace. “I think if the FDA approves this in December, we will have truly opened the door for gene editing therapies in patients with other disorders.”

About PackGene

PackGene Biotech is a world-leading CRO and CDMO, excelling in AAV vectors, mRNA, plasmid DNA, and lentiviral vector solutions. Our comprehensive offerings span from vector design and construction to AAV, lentivirus, and mRNA services. With a sharp focus on early-stage drug discovery, preclinical development, and cell and gene therapy trials, we deliver cost-effective, dependable, and scalable production solutions. Leveraging our groundbreaking π-alpha 293 AAV high-yield platform, we amplify AAV production by up to 10-fold, yielding up to 1e+17vg per batch to meet diverse commercial and clinical project needs. Moreover, our tailored mRNA and LNP products and services cater to every stage of drug and vaccine development, from research to GMP production, providing a seamless, end-to-end solution.

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