Sickle cell disease is a group of inherited disorders that affects hemoglobin, the oxygen-carrying protein in red blood cells (RBCs), and causes these cells to distort in shape at low oxygen levels. This condition affects 1 in 500 Americans of African descent and 1 in 1,000-1,400 of Hispanic descent, as well as millions more people worldwide. The disease can vary in severity, with symptoms including severe anemia that can lead to organ damage and strokes, and serious, unpredictable, vaso-occlusive crises (VOCs), where the patient’s affected RBCs stick together and block blood vessels. Such events are extremely painful, damage tissues and organs, and increase the patient’s risk of death. No cure for sickle cell disease exists, and available symptomatic treatment options have been around for many years. In November 2019, however, the U.S. FDA approved two new treatments for patients with sickle cell disease, the first in about 20 years.
Adakveo (crizanlizumab-tmca), a monoclonal antibody developed by Novartis after its 2016 buyout of Selexys Pharmaceuticals, received approval on November 15 as the first targeted therapy to prevent VOCs. The antibody works by inhibiting P-selectin on RBCs, a protein central to enabling the sickled cells to stick together. The SUSTAIN Phase 2 study of Adakveo showed its ability to cut the median rate of VOCs by 45% compared to placebo, and to reduce median hospitalized days by 42% over a year. The FDA approved Adakveo weeks ahead of expectations for use in patients age 16 or older.
Additionally, on November 25, the FDA granted accelerated approval to Global Blood Therapeutics’ Oxbryta (voxelotor), three months ahead of expectations. Oxbryta is a daily oral drug that directly inhibits hemoglobin polymerization, helping sickled RBCs remain oxygenated and retain a normal shape, thus interfering with their clumping together. Phase 2 trial results showed that after 24 weeks on therapy, 51.1% of patients receiving Oxbryta achieved a greater than 1g/dL increase in hemoglobin versus 6.5% of placebo-treated patients, lessening anemia for many of the treated patients. However, Oxybryta did not significantly reduce the incidence of VOCs compared to placebo, which caused some experts to question the therapy’s value. As a condition of Oxybryta’s approval, the FDA is requiring Global Blood Therapeutics to conduct a follow-on trial to confirm the drug’s benefit, including imaging measurements of improved blood flow to demonstrate the likelihood of stroke reduction.
Cost is a concern for these new treatments. Both require lifetime use, and given their different mechanisms of action, patients could potentially benefit from a combination therapy. Adakveo is infused monthly based on patient weight, and cost of treatment, at $237 per vial, is expected to translate to between $7,071 and $9,428 per month before discounts. Global Blood Therapeutics has set a list price of over $10,400 per month for Oxbryta. However, managing sickle cell disease without such therapies is very expensive — $10,000 per year to treat children and $30,000 per year to treat adults, plus additional hospitalization costs as a result of VOCs, organ damage, strokes and other complications. The economic burden of sickle cell is also very high, as many of the patients are disabled and cannot work, and family members are often forced into caregiving roles.
In addition to these two landmark approvals, potentially curative treatments for sickle cell disease and other inherited blood disorders may be on the horizon. Vertex and CRISPR Therapeutics announced data from a Phase 2 trial of their CRISPR-Cas9-based treatment, CTX001, from the first two patients — one with transfusion-dependent sickle cell disease and one with beta-thalassemia. Four months after treatment, the sickle cell patient had experienced no VOCs, compared to the seven VOCs per year experienced in the two years prior to the study. Similarly, the beta-thalassemia patient, who had required 16.5 transfusions per year in the previous two years, no longer needed transfusions nine months after treatment with CTX001. Both patients also displayed near-normal hemoglobin levels.
Sickle cell disease and beta thalassemia are both caused by mutations in the beta globin gene, resulting in missing or defective hemoglobin. It is known that fetal hemoglobin — found in newborns but later replaced by adult hemoglobin — can help protect adults with blood disorders from severe anemia. CTX001 is made by editing patients’ stem cells to increase the production of fetal hemoglobin and compensate for the defective adult protein. The trial showed that 94-99% of the patients’ RBCs contained fetal hemoglobin, demonstrating that the gene editing intervention worked as designed. Vertex plans to enroll 45 patients in each Phase 2 study and follow them for two years post-infusion.
Moreover, Bluebird bio recently presented results from 17 patients with sickle cell disease who were treated with Zynteglo, a gene therapy already approved in the European Union for beta-thalassemia (Lentiglobin BB305). Over 21 months, none of the patients either required transfusions or experienced VOCs, and more than 40% of the hemoglobin in the treated RBCs was in a healthier, more normal form than before treatment. Bluebird bio is currently recruiting patients for a Phase 3 trial of LentiGlobin BB305 in beta-thalassemia patients and is planning a Phase 2/3 study in sickle cell disease in 2020.
Finally, Novartis is developing its own CRISPR-Cas9 treatment, with Intellia Therapeutics, to edit human hematopoietic stem cells to express fetal hemoglobin, and hopes to enter clinical studies soon.