FDA Approval of a CRISPR/Cas9 Gene Therapy To Treat Sickle Cell Disease

In 2020, the Nobel Prize in Chemistry was awarded to Jennifer Duodna and Emmanuelle Charpentier for their work detailing the bacteria-based enzyme system that is widely used to custom edit human genes.[1] The work, first published just 12 years earlier, was a tremendous advance in the field of genetics. The gene-editing system is referred to as CRISPR/Cas9, acronyms that summarize the underlying DNA pattern and specific protein complex.

CRISPR/Cas9 is a relatively small enzyme complex that can be programmed to make precise double-stranded (full) cuts in DNA without killing the reprogrammed cells or the exposed organisms.[2] The technology is frequently used in basic and applied research, including in the development of new treatments for various diseases, especially those that can be addressed with small genetic rearrangements.

In December 2023, the Food and Drug Administration (FDA) approved two cell-based gene therapies for the treatment of sickle cell disease. One of the therapies, exagamglogene autotemcel (CASGEVY), is the first FDA-approved treatment using CRISPR/Cas9 technology[3] and is the focus of this article. The therapy, which also is known by the shorter name of exa-cel, is used to modify the patients’ hematopoietic (blood) stem cells. The therapy was approved for the treatment of sickle cell disease in patients aged 12 years or older with recurrent vaso-occlusive crises (defined in the next section). The second therapy, lovotibeglogene autotemcel (LYFGENIA), requires a viral-vector delivery system and a non-CRISPR/Cas9 gene-insertion approach.[4] Lovotibeglogene autotemcel was approved for patients aged 12 years or older with sickle cell disease and a history of vaso-occlusive events. Both therapies are expected to cost over $2 million each[5] and are time-consuming and physically demanding.

Background on sickle cell disease

Sickle cell disease is mainly caused by genetic mutations that alter the hemoglobin protein (the oxygen-carrying constituent) of red blood cells, such that their shape becomes distorted (due to aberrant protein folding) into a sharp sickle shape instead of the usual smooth disk shape.[6] A vaso-occlusive crisis occurs when sickled red blood cells sufficiently block blood flow, thereby depriving some tissues of oxygen. The health consequences can be devastating. Damage to the inner lining of the circulatory system can lead to painful and dangerous blood clots and strokes, as well as serious organ damage and death at least 20 years earlier than in the absence of the disease.[7] In the United States, sickle cell disease affects approximately 1 in 365 live births among African Americans and 1 in 16,300 among Hispanic Americans.[8]

At any given time, there are approximately 100,000 persons in the United States with sickle cell disease. For these patients, there are few therapies capable of modifying the disease and extending life. Medications such as hydroxyurea (DROXIA, SIKLOS) and crizanlizumab (ADAKVEO) can reduce the frequency of painful crises and prevent complications.[9] Hematopoietic (blood) stem cell transplants from non-sickle cell, matched donors may cure some but not all patients with the disease.

The exa-cel therapy

The exa-cel therapy involves an autologous transplant of gene-edited cells, meaning that each patient’s blood stem cells are extracted, gene edited and then transplanted back into the patient.[10] The treatment process takes months and requires four major steps: 1) “mobilizing” blood precursor cells from the patient’s bone marrow for collection and isolating the stem cells, 2) gene editing the stem cells ex vivo (outside the body) with CRISPR/Cas9 to reactivate the expression of a dormant form of hemoglobin (known as fetal hemoglobin), 3) preparing the patient for transplantation with high-dose chemotherapy and 4) transplanting the cells back into the patient as a single-dose infusion.

Preparing the patient for the transplantation is known as myeloablative conditioning.[11] The conditioning requires weeks of hospitalization, as well as chemotherapy (busulfan [MYLERAN]) to remove diseased cells from the bone marrow to make way for the infusion of reengineered cells. Blood transfusions and medications to prevent seizures are usually part of the conditioning process. Conditioning with busulfan can permanently and negatively affect the patient’s fertility.

Effectiveness and safety

The FDA approved the exa-cel therapy based on data from an ongoing single-arm, multi-center trial. Of the 44 subjects who had received the therapy at the time of the analysis, 31 had sufficient follow-up time to be evaluated.[12] The subjects were all 36 years of age or younger, including seven between the ages of 12 and 18 years. All had genetically confirmed sickle cell mutations, 97% with the same overall, common genotype. To be eligible for the study, a two-year history of at least two vaso-occlusive events per year was required. The subjects in the study had a median of 3.5 vaso-occlusive events per year and a median of two hospitalizations per year related to these events.

The 31 subjects were followed for a median of 19 months (range: one to 48 months) from the time of the stem cell transplant.[13] No cases of graft failure or rejection were observed. The primary outcome was a 12-month period free of severe vaso-occlusive events over the course of a 24-month period. Hospitalizations were a secondary outcome. Twenty-nine (94%) of the subjects had 12-month periods free of vaso-occlusion, with a median length of such crisis-free periods of 22 months. One patient experienced a five-day hospitalization after 23 months.

The safety of the treatment was assessed in all 44 subjects.[14] Nearly half (45%) of those subjects experienced serious adverse reactions to the conditioning phase of treatment. The most common serious reactions included cholelithiasis (gallstones), pneumonia, abdominal pain, constipation, pyrexia (fever), noncardiac chest pain and sepsis. One subject died from COVID-19 infection and subsequent respiratory failure.

A key concern for this CRISPR/Cas9 treatment — and any gene-editing treatment — is “off-target” changes to the patient’s genes with unintended consequences. In October 2023, the FDA hosted an advisory committee meeting on off-target gene editing as it specifically pertains to exa-cel.[15] After hearing testimony from the FDA scientists, other experts and exa-cel’s manufacturer, the advisory committee concluded that the manufacturer had provided extensive evidence that generally ruled out any widespread, acute ill effects of off-target editing.[16] Public Citizen’s Health Research Group testified that more study is needed to determine whether off-target gene editing is a near- or long-term concern for patients receiving exa-cel therapy. Our testimony emphasized that the cellular assay data reviewed by the FDA was limited to nine subjects, only three of whom had sickle cell disease.[17]

What You Can Do

If you have genetically confirmed sickle cell disease, have recurrent vaso-occlusive crises that are poorly responsive to other therapies and are 12 years of age or older, discuss your treatment options with your clinicians. Cell-based gene therapies for sickle cell disease are new, and their long-term effectiveness and safety are not known. Whether gene therapies are an unusual “breakthrough” therapy that offer a documented therapeutic benefit over older, proven therapies remains to be determined. This is the reason that Public Citizen’s Health Research Group recommends that many of the new drugs we review not be used for at least seven years after the date of FDA approval.
 

References

[1] Abrams MT. CRISPR gene editing: the immediate future of bioengineering and medicine. Health Letter. April 2023. https://www.citizen.org/article/crispr-gene-editing-the-immediate-future-of-bioengineering-and-medicine/. Accessed January 8, 2023.

[2] Sheridan C. The world’s first CRISPR therapy is approved: who will receive it? Nature Biotechnology. November 21, 2023.

[3] Feuerstein A. In historic decision, FDA approves a CRISPR-based medicine for treatment of sickle cell disease. STAT. December 8, 2023. https://www.statnews.com/2023/12/08/fda-approves-casgevy-crispr-based-medicine-for-treatment-of-sickle-cell-disease. January 8, 2024.

[4] U.S. Food and Drug Administration. Summary basis for regulatory action: Lyfgenia. December 8, 2023. https://www.fda.gov/media/175250/download?attachment. Accessed January 22, 2023.

[5] Nathan-Kazis. FDA approves first two sickle cell gene therapies, bluebird bio shares tumble. Barron’s. December 8, 2023.

[6] Sedrak A, Kondamudi NP. Sickle Cell Disease. 2023 Aug 28. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–.

[7] Vichinsky EP. Overview of the clinical manifestations of sickle cell disease. UpToDate. November 2023.

[8] Centers for Disease Control and Prevention. Data & statistics on sickle cell disease. July 6, 2023. https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed January 8, 2024.

[9] U.S. Food and Drug Administration. FDA Briefing Document. BLA#125787/0. Drug name: exagamglogene autotemcel. Cellular, Tissue and Gene Therapies Advisory Committee. October 31, 2023. https://www.fda.gov/media/173414/download. Accessed January 12, 2024.

[10] Vertex Pharmaceuticals Incorporated. Label: exagamglogene autotemcel (CASGEVY). December 2023. https://www.fda.gov/media/174615/download?attachment. Accessed January 8, 2024.

[11] Vertex Pharmaceuticals Incorporated. Label: exagamglogene autotemcel (CASGEVY). December 2023. https://www.fda.gov/media/174615/download?attachment. Accessed January 8, 2024.

[12] Ibid.

[13] Ibid.

[14] Ibid.

[15] Food and Drug Administration. Committee discussion question. The 76th meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee. October 31, 2023. https://www.fda.gov/media/173416/download. Accessed January 8, 2024.

[16] Food and Drug Administration. Meeting video recording. The 76th meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee. October 31, 2023. https://www.youtube.com/watch?v=M90IjjxOdQg. Accessed January 8, 2024.

[17] Public Citizen. Testimony before the Food and Drug Administration’s Cellular, Tissue, and Gene Therapy Advisory Committee regarding exagamglogene autotemcel gene therapy for sickle cell disease (BLA# 125787/0, Vertex Pharmaceuticals). October 31, 2023. https://www.citizen.org/article/testimony-before-the-food-and-drug-administrations-cellular-tissue-and-gene-therapy-advisory-committee-regarding-exagamglogene-autotemcel-gene-therapy-for-sickle-cell-disease-bla-125787-0/. Accessed January 8, 2024.