The potential of gene therapies as cures for some hard-to-treat genetic diseases can be very attractive. But one such product is now suspected of causing a serious safety problem.
Friday, Orchard Therapeutics said its Strimvelis treatment, approved by European authorities in 2016 to treat the rare inherited condition ADA-SCID, has been linked to a patient’s leukemia.
“Preliminary findings suggest this diagnosis may be attributable to an insertional event related to treatment with Strimvelis,” the company said. It’s now investigating whether there’s indeed a causal relationship.
Since its 2016 EU approval—when it was owned by original developer GlaxoSmithKline—only 16 patients have been treated with Stimvelis. The patient who developed leukemia had apparently been treated under a GSK compassionate use program in 2016.
No more patients will get the therapy before the investigation is complete, Orchard said. The drug was never approved in the U.S.
ADA-SCID is a condition marked by a mutation in the gene making the adenosine deaminase (ADA) enzyme, which is essential for maintaining normal white blood cells. ADA-SCID patients, with a dysfunctional immune system, have less than two years to live without effective intervention.
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Strimvelis, originally developed by GSK and bought by Orchard in 2018, offers an option for patients who can’t find a matched stem cell donor. It works by editing the patients’ own hematopoietic stem cells with the functional ADA gene. The cells are then transferred back into the patient's bone marrow to mature and produce the normal ADA protein.
The therapy uses a gammaretrovirus as the vector to carry the gene. Problem is, retrovirus can incorporate their own genetic information into the human genome, causing unintended changes that can give rise to cancer. It is a known risk factor of gammaretroviral vector-based gene therapy and has been described as one of the “important potential risks” for Strimvelis in its EU approval.
Besides Strimvelis, Orchard is also developing OTL-101, which uses a lentivirus to insert a functional copy of the ADA gene into a patient’s cells. The drug is currently undergoing a registrational trial and has won breakthrough and orphan drug designations from the FDA.
All the gene therapy candidates in Orchard’s pipeline use lentiviral vectors that have been “specifically designed to avoid insertional oncogenesis after administration,” Orchard said, adding that no dangerous gene insertion has been reported around lentiviral vector-based stem cell gene therapy in any indication.