SUMMARY: The FDA on December 8, 2023, approved CASGEVY® and LYFGENIA®, representing the first cell-based gene therapies for the treatment of Sickle Cell Disease in patients 12 years and older. Both products are made from the patients’ own hematopoietic stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a Hematopoietic Stem Cell Transplant. Prior to treatment, a patients’ own stem cells are collected, and then the patient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells.
Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder caused by mutations in the hemoglobin beta-globin gene, and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the US is approximately 40-60 years.
HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea. None of the presently available therapies addresses the underlying cause of this disease nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure this genetic disorder, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for Sickle Cell Disease.
CASGEVY®: (Exagamglogene Autotemcel)
Fetal hemoglobin which consists of two alpha and two gamma chains is produced in utero, but the level of gamma-globulin decreases postnatally as the production of beta-globin and adult hemoglobin, which consists of two alpha and two beta chains, increases. It has been noted that elevated levels of fetal hemoglobin facilitates oxygen delivery, prevents the sickling of red blood cells, and is associated with decreased morbidity and mortality in patients with Sickle Cell Disease. BCL11A gene is a repressor of gamma-globin expression and fetal hemoglobin production in adult red blood cells. Downregulating BCL11A can therefore reactivate gamma-globin expression and increase fetal hemoglobin in RBC.
The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease gene editing technique can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. The modified hematopoietic stem cells are transplanted back into the patient where they engraft within the bone marrow and increase the production of fetal hemoglobin. The researchers in this study used this gene-editing technique in Hematopoietic Stem and Progenitor Cells at the erythroid-specific enhancer region of BCL11A to down-regulate BCL11A expression in erythroid-lineage cells, restore gamma-globin synthesis, and reactivate production of fetal hemoglobin. CASGEVY® is the first FDA-approved treatment to utilize CRISPR/Cas9, a type of genome editing technology, to modify patients hematopoietic stem cells.
The FDA approval of CASGEVY® is based on the ongoing single-arm, multi-center trial, involving adult and adolescent patients with Sickle Cell Disease. The trial focused on individuals with a history of at least two protocol-defined severe Vaso-Occlusive Crises (VOCs) during each of the two years prior to screening. The Primary efficacy outcome was freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period. Out of the 44 patients treated with CASGEVY®, 31 had sufficient follow-up time to be evaluable. Remarkably, 29 of these patients, representing 93.5%, achieved the Primary efficacy outcome, which is freedom from severe VOC episodes for at least 12 consecutive months. Notably, all treated patients achieved successful engraftment, a crucial aspect confirming the efficacy of the CRISPR/Cas9 genome editing technology in modifying hematopoietic stem cells. Importantly, no instances of graft failure or rejection were reported, affirming the safety and viability of CASGEVY® as a therapeutic option. This high success rate underscores the therapeutic potential of CASGEVY® in mitigating the recurrent and debilitating crises associated with Sickle Cell Disease. The most common side effects were stomatitis, cytopenias, febrile neutropenia, nausea, vomiting, headache and itching.
LYFGENIA® (Lovotibeglogene Autotemcel)
LYFGENIA® is a cell-based gene therapy that uses a lentiviral vector as the gene delivery vehicle to add a functional gene to the hematopoietic stem cells, thereby enabling production of HbAT87Q, which is a gene therapy-derived hemoglobin, that functions similarly to hemoglobin A (normal adult hemoglobin produced in persons not affected by Sickle Cell Disease). Red blood cells containing HbAT87Q have a lower risk of sickling , resulting in VOCs. These modified stem cells are then delivered to the patient.
The safety and effectiveness of LYFGENIA® was based on the analysis of data from a single-arm, 24-month, multicenter study in patients with Sickle Cell Disease and history of Vaso Occlusive Events (VOEs). The assessment of efficacy was based on the complete resolution of VOEs between 6 and 18 months after LYFGENIA® infusion. Of the 32 patients included in the study, 88% (28 patients) achieved complete resolution of VOEs within the stipulated timeframe. The most common side effects included stomatitis, cytopenias and febrile neutropenia. Hematologic malignancy has occurred in patients treated with LYFGENIA®, and patients receiving this product should have lifelong monitoring for these malignancies.
In conclusion, the two revolutionary cell-based gene therapies with CASGEVY® and LYFGENIA® heralds a transformative era in the management of Sickle Cell Disease (SCD), for individuals aged 12 and above.
https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
