Until recently, CRISPR, the gene-editing technology that earned Jennifer Doudna and Emmanuelle Charpentier the 2020 Nobel Prize in Chemistry, sounded more like science fiction than medicine; with it, diseased patients’ cells are treated by using lab-made molecular scissors to snip out problematic DNA sections. The first gene-editing therapy, however, may soon be approved by authorities in an effort to address rare inherited blood illnesses that affect millions of people worldwide.
In a $900 million collaboration, rare disease specialist Vertex and CRISPR Therapeutics developed the therapy, dubbed exa-cel (short for exagamglogene autotemcel). It has already amassed promising evidence that it can help patients with beta thalassemia and sickle cell disease (SCD), both of which are genetic blood diseases that are relatively rare in the U.S. but somewhat more common inherited conditions globally.
Beta thalassemia is characterized by damaged or missing genes that cause the body to produce less hemoglobin (an essential protein that transports oxygen), potentially leading to enlargement of the liver, spleen, or heart, and malformed or brittle bones. It is estimated to afflict 1 in 100,000 people in the world, and regular blood transfusions are necessary to stave off its most serious effects.
While the exact statistics are unknown, SCD is estimated to affect 100,000 people in the U.S. and millions around the world; it is attributed to a defective gene that causes malformed hemoglobin that are stiff, sticky, and sickle-shaped (hence the name) and can thus block healthy blood cells from transporting oxygen around the body.
Exa-cel reportedly slashed the need for blood transfusions or incidence of serious, life-threatening medical events for months to years after patients received the treatment. New and impressive clinical trial results were announced at a major international medical conference in June and bolstered the companies’ prospect of producing the first gene-editing therapy of its kind to reach the broader market and patients.
The drug makers say they intend to submit exa-cel for regulatory approval in the U.S., U.K., and Europe by the end of this year, meaning the drug could receive marketing authorization sometime in 2023 as more and more biopharma companies pursue novel gene therapies.
Vertex and CRISPR Therapeutics’ therapy uses what’s called an “ex-vivo” application of CRISPR gene editing (one done outside the actual body): The patient’s stem cells are extracted, the cellular DNA is modified by exa-cel to spur the production of a type of hemoglobin that the body usually makes only in infancy, and the modified cells are put back into the patient in order to boost healthy hemoglobin and red blood cell production.
The latest exa-cel clinical data, unveiled during the 2022 European Hematology Association Congress in Switzerland, found that all 75 patients with either beta thalassemia or SCD given the gene-editing therapy showed zero or a greatly reduced need for blood transfusions (in the case of beta thalassemia) or incidences of life-threatening blockages (in the case of SCD). All but 2 of the 44 patients with thalassemia hadn’t needed a single blood transfusion in the 1 to 37 months of follow-up after the treatment’s administration, and the remaining 2 had 75% and 89% reduction in how much blood they needed transfused.
Similarly impressive, all 31 patients with a severe and life-threatening form of SCD experienced no vaso-occlusive crises (the life-threatening incidents in which healthy blood is blocked from moving freely) in anywhere from 2 to 32 months of posttreatment follow-up. Those same patients usually experienced, on average, nearly four of these crises per year for the two years before they received exa-cel.
CRISPR isn’t the only type of gene therapy that’s made waves in just the past few weeks. Earlier in June, a group of advisers to the Food and Drug Administration (FDA) gave unanimous recommendations for a pair of non-CRISPR-based gene therapies from Bluebird Bio. The treatments target genes associated with beta thalassemia and a rare disorder afflicting children called cerebral adrenoleukodystrophy (CALD). The latter is a disease that eats away at white brain matter in children as young as 4, has few treatments, and usually leads to death within 5 to 10 years.
Bluebird’s eli-cel therapy has faced clinical setbacks because of its association with higher risk of a type of cancer, but the independent advisers decided its benefits still outweighed the risks for some patients with few other options. The FDA doesn’t have to follow the recommendations of its advisory panels, but typically does.
There are about 20 cell and gene therapies (though none based on CRISPR gene editing) that have received FDA approval to date. According to MIT’s NEWDIGS drug development program, more than 60 gene and cell therapies could be on the U.S. market by 2030. That could lead to a transformation in how we think about incurable conditions, with gene and cell therapies potentially being used to treat everything from rare diseases to HIV to heart disease.
Drug discovery is a long and unpredictable process. But the impact that gene editing can make in drug development and how we think of disease is already clear. As Jon Moore, chief scientific officer at biotechnology company Horizon Discovery, said in 2016, “The targets we’re finding with CRISPR . . . are going to guide the drugs coming out in the 2020s.”
The early potential of exa-cel just six years later would suggest that’s a reasonable bet.
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