Reprinted with permission: Pharmascan Pharmaceutical Factory Watch
CRISPR gene-editing therapies have been approved in the UK and the US, including Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy and Bluebird’s Lyfgenia. While there is promise for the treatment of sickle anaemia, these gene-editing therapies are expensive, and while cost-benefit analyses have suggested reasonable prices, the challenge is to ensure that key populations benefit. At the same time, these therapies are exposed to off-target effects and possible cancer risks.
With the UK becoming the first country in the world to approve a CRISPR gene-editing drug on 11/16, the FDA has now approved Casgevy (exagamglogene autotemcel) co-developed by Vertex Pharmaceuticals and CRISPR Therapeutics on 12/8, as well as Lyfgenia developed by Bluebird, including Bluebird’s Lyfgenia (lovotibeglogene autotemcel) announced nearly two weeks earlier than originally anticipated that they will be used to treat patients with sickle cell disease (SCD) over 12 years of age.
While some patients can be cured of the disease through a bone marrow transplant, this requires a suitable donor, as well as a variety of anti-rejection immune drugs to ensure that the body adapts to the new cells, and the patient takes multiple risks, while gene editing takes a different approach.
Casgevy uses CRISPR/Cas9 gene editing technology to edit hematopoietic stem cells CD34+ in the bone marrow of patients to increase fetal hemoglobin (HbF) production, which in turn assists in oxygen transport and reduces sickle-shaped erythropoiesis. Lyfgenia, on the other hand, is genetically modified by using lentiviruses as vectors (Lentiviral Vectors) to produce special heme (HbAT87Q) from hematopoietic stem cells with a lower risk of sickle and vascular occlusion.
Both require a one-time infusion of hematopoietic stem cells from the patient prior to treatment and a high dose of chemotherapy to remove the cells from the bone marrow to make room for the gene-edited hematopoietic cells.
Gene editing therapies face a dual challenge: off-target effects and high drug prices
Casgevy is priced at $2.2 million, compared to Lyfgenia’s $3.1 million, which is higher than the average lifetime cost of care for patients with sickle anemia of $1.7 million.
A cost-benefit analysis by the Institute of Clinical and Economic Review (ICER) in the United States pointed out that Casgevy’s reasonable price is $1.35 million to $2.05 million, but about half of all patients with sickle anemia in the United States are low-income people, and ensuring that all patients can benefit will be a major challenge in the future.
In addition, there is a risk of off-target effects in gene editing, which may lead to incorrect gene sequences and increase the risk of cancer. Two subjects were found to have acute myeloid leukemia in Lyfgenia’s clinical trial, so the FDA added a warning about the risk of developing blood cancer to Lyfgenia’s generic list, but there are no similar cases in Casgevy subjects, and the FDA also said that patients need to be monitored for cancer throughout their lives, and gene editing therapy also involves high doses of chemotherapy, so there is a risk of causing infertility.
The next step for two gene editing companies
There is currently limited data on the long-term effects of gene editing therapies, so Vertex plans to conduct a 15-year follow-up study to evaluate potential long-term safety risks for Casgevy, which has also applied for β thalassemia indication and the FDA expects to make a decision by March 30, 2024.
On the other hand, Lyfgenia’s parent company, Bluebird, is in financial trouble, with revenue of only $21.7 million in the first nine months of 2023, compared to $7.4 billion for Vertex, despite owning two gene-editing drugs, Lyfgenia and Zynteglo (for the treatment of β thalassemia). Although Bluebird currently has cash on hand until the second quarter of 2024, Bluebird has the advantage that its gene-editing drug, Zynteglo, has established a commercial system to quickly begin receiving referrals from Lyfgenia patients, and the first batch of Lyfgenia patients’ cell collection is expected to begin in the first quarter of 2024 and contribute revenue 70 to 105 days later.
At present, various analysts are predicting that the sales of gene therapy will grow slowly in the early stage, and although the future potential is huge, it is still necessary to address the potential treatment risks and wait for the development of infrastructure such as related laboratories.
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References
- Will the High Price of Gene Therapy for Sickle Cell Disease Put This Cure out of Reach?
- US FDA approves two gene therapies for sickle cell disease
- Vertex, CRISPR score landmark FDA approval for sickle cell disease gene therapy Casgevy
- FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease
