The gene-editing era arrives: the UK and US approve treatments for blood disorders, yet a dual challenge remains
AI-translated from the Chinese original · editorially reviewed
Licensed reprint: Pharmascan
The UK and US have successively approved CRISPR gene-editing therapies, including Casgevy from Vertex Pharmaceuticals and CRISPR Therapeutics, and Lyfgenia from Bluebird. While these promise to treat sickle cell disease, such gene-editing therapies are extremely expensive. Even though cost-effectiveness analyses have suggested a reasonable price, the challenge is how to ensure that key populations benefit. At the same time, these therapies also face off-target effects and a possible cancer risk.
After the UK became, on 11/16, the first country in the world to approve a CRISPR gene-editing drug, the FDA on 12/8 also approved Casgevy (exagamglogene autotemcel), jointly developed by Vertex Pharmaceuticals and CRISPR Therapeutics, and Lyfgenia (lovotibeglogene autotemcel), developed by Bluebird. Bluebird's Lyfgenia was announced nearly two weeks earlier than originally expected. Both can be used to treat sickle cell disease (SCD) patients aged 12 and over.
SCD causes red blood cells to fold into a sickle shape, and the mutated cells therefore accumulate more easily in blood vessels, depriving muscles of oxygen. Although some patients can be cured of the disease through a bone marrow transplant, this requires a suitable donor as well as various anti-rejection immunosuppressive drugs to help the body adapt to the new cells, and patients must bear multiple risks. Gene editing takes a different approach.
Casgevy uses CRISPR/Cas9 gene-editing technology to edit the CD34+ hematopoietic stem cells in the patient's bone marrow to increase the production of fetal hemoglobin (HbF), thereby aiding oxygen transport and reducing the formation of sickle-shaped red blood cells. Lyfgenia, on the other hand, uses lentiviral vectors for genetic modification, enabling hematopoietic stem cells to produce a special hemoglobin (HbAT87Q) that carries a lower risk of sickling and vascular occlusion.
Before treatment, both require the patient's hematopoietic stem cells to be extracted, and the patient must undergo high-dose chemotherapy to clear the cells in the bone marrow, making room for the subsequently gene-edited hematopoietic cells. After the genes are modified in the laboratory, only a single infusion back into the patient is needed, but afterward all patients must undergo long-term safety and efficacy follow-up.
Gene-editing therapy faces a dual challenge: off-target effects and a high drug price
Casgevy is priced at USD 2.2 million and Lyfgenia at USD 3.1 million, both higher than the average lifetime medical cost of USD 1.7 million for a sickle cell disease patient. Such a high one-time drug price will pose a challenge to insurers and reimbursement systems and limit the drug's accessibility.
A cost-effectiveness analysis by the US Institute for Clinical and Economic Review (ICER) noted that a reasonable price for Casgevy would be USD 1.35 million to USD 2.05 million; but about half of US sickle cell disease patients are currently low-income, so ensuring that all patients can benefit will be a major challenge going forward.
In addition, gene editing currently carries the risk of off-target effects, which could cause gene-sequence errors and increase the risk of cancer. In Lyfgenia's clinical trials, two subjects were found to have developed acute myeloid leukemia, so the FDA added a warning about the risk of blood cancer to Lyfgenia's label. However, no similar cases have appeared among Casgevy subjects so far. The FDA has also stated that patients must undergo related cancer monitoring for life; moreover, gene-editing treatment also involves high-dose chemotherapy and therefore carries a risk of infertility.
The next steps for the two gene-editing companies
Long-term efficacy data on gene-editing therapies is currently limited, so Vertex plans to conduct a 15-year follow-up study to evaluate the potential long-term safety risks of Casgevy, and Casgevy has also applied for a beta-thalassemia indication, on which the FDA is expected to decide by 3/30, 2024.
On the other hand, Bluebird, Lyfgenia's parent company, is in financial difficulty. Although it holds two gene-editing drugs, Lyfgenia and Zynteglo (for treating beta-thalassemia), Bluebird's revenue for the first nine months of 2023 was only USD 21.7 million, compared with Vertex's revenue of USD 7.4 billion. Although Bluebird's cash on hand can only sustain operations until the second quarter of 2024, it has one advantage: its gene-editing drug Zynteglo has already established a commercialization system, allowing it to quickly move on to accepting referrals of Lyfgenia patients. Cell collection for the first batch of Lyfgenia patients is expected to begin in the first quarter of 2024 and to contribute revenue 70 to 105 days later.
Analysts currently predict that early gene-therapy sales will grow slowly. Although the future potential is enormous, various potential treatment risks still need to be resolved, and the completion of supporting infrastructure such as the relevant laboratories must be awaited.
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