Global Blood Therapeutics (GBT) recently, the European Medicines Agency (EMA) has accepted Oxbryta's (voxelotor) marketing authorization application (MAA) and has initiated a standard review process. The MAA seeks EMA to grant Oxbryta full approval for the treatment of hemolytic anemia in sickle cell disease (SCD) patients 12 years and older. Previously, EMA has granted voxelotor the Priority Drug Designation (PRIME) and Orphan Drug Designation for SCD.
In terms of US regulation, Oxbryta received accelerated FDA approval in November 2019 for the treatment of hemolytic anemia in children and adults with SCD ≥12 years old. Oxbryta was approved through the FDA's priority review channel, and it only took more than 2 months from the acceptance of the new drug application (NDA) to the final approval. Previously, the FDA has granted voxelotor the breakthrough drug designation (BTD), fast track status, orphan drug designation, and rare pediatric disease designation for the treatment of SCD. As a condition of accelerated approval by the US FDA, GBT will continue to investigate Oxbryta in the HOPE-KIDS 2 study, which is a post-approval confirmatory study that uses transcranial Doppler (TCD) blood flow velocity to assess Oxbryta reduction 2- The ability of 15-year-old children to risk stroke.
Oxbryta is a first-in-class, once-daily, oral drug, and is the first approved therapeutic drug to directly inhibit sickle hemoglobin polymerization. Hemoglobin polymerization is the fundamental cause of sickling and destruction of SCD red blood cells. The sickling process can cause hemolytic anemia (the destruction of red blood cells leads to a decrease in hemoglobin levels), blockage of capillaries and small blood vessels, which hinder the flow of blood and oxygen throughout the body. Reduced oxygen supply to tissues and organs can lead to life-threatening complications, including stroke and irreversible organ damage
Oxbryta's active drug is called voxelotor (formerly GBT440), which acts by increasing the affinity of hemoglobin for oxygen. Since oxygenated sickle hemoglobin does not polymerize, voxelotor can block polymerization and the resulting sickling and destruction of red blood cells. Voxelotor can improve hemolytic anemia and oxygen transport, and potentially change the course of SCD.
Ted W. Love, President and CEO of GBT, said: "Sickle cell disease (SCD) can have devastating effects on the lives of patients and their families, including serious life-threatening complications, which can lead to organ damage and premature death. Despite the huge demand, there is currently no approved therapy in Europe that has the potential to change the course of this disease. We look forward to working with EMA to bring the first treatment plan for the treatment of SCD hemolytic anemia to Europe as soon as possible Patients."
voxelotor molecular structure (picture source: drugapprovalsint.com)
In Europe, Oxbryta's Marketing Authorization Application (MAA) is based on data from the Phase 3 HOPE study and the Phase 2 HOPE-KIDS 1 study, both of which enrolled patients at clinical trial sites in Europe. HOPE-KIDS 1 is an open-label, single-dose and multiple-dose study that evaluated the safety, tolerability, pharmacokinetics, and exploratory efficacy of voxelotor in the treatment of pediatric patients (4-17 years old) with SCD.
HOPE is a randomized, double-blind, placebo-controlled Phase 3 study, conducted in 60 research institutions in 22 countries around the world, and evaluated two dose levels of voxelotor (1500mg and 900mg, once a day orally administered) and placebo The efficacy and safety of the treatment of SCD. A total of 274 SCD patients aged 12 years and older were enrolled in the HOPE study. Most of the patients had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sβ0-thalassemia), and about two-thirds of them were receiving hydroxyurea at baseline. treatment. In the study, patients were randomly divided into groups at a ratio of 1:1:1 and received 1500mg voxelotor, 900mg voxelotor or placebo once a day orally. The primary endpoint was the proportion of patients who achieved a hemoglobin response in the intention-to-treat analysis. The hemoglobin response was defined as an increase in hemoglobin greater than 1.0 g/L from baseline at week 24.
The results showed that the study reached the primary endpoint: at week 24 of treatment, voxelotor significantly increased hemoglobin levels and reduced hemolysis biomarkers compared to placebo. These results are consistent with the inhibition of HbS polymerization, voxelotor shows the potential to improve the disease. The specific data are: in the intention-to-treat analysis, the proportion of patients with hemoglobin response in the 1500mg voxelotor treatment group (51%, 95CI: 41-61) was significantly higher than that of the placebo group (7%, 95% CI: 1-12). From baseline to week 24, the number of patients with worsening anemia in each dose group of voxelotor was less than that in the placebo group. In addition, at week 24, the indirect bilirubin level and the percentage of reticulocytes in the 1500 mg voxelotor treatment group decreased significantly from baseline compared to the placebo group.
In the HOPE study, the most common side effects reported in the voxelotor treatment group during 24 weeks (occurring in ≥10% of patients and 3% higher than the placebo group) were headache (26% vs 22%), diarrhea (20% vs. 10%), abdominal pain (19% vs 13%), nausea (17% vs 10%), fatigue (14% vs 10%), rash (14% vs 10%), and fever (12% vs 7%).
The analysis of the complete data of the HOPE study further proves that in SCD patients 12 years and older, voxelotor once a day at a dose of 1500 mg can lastingly improve hemoglobin levels and hemolysis markers during 72 weeks of treatment. The voxelotor treatment was well tolerated, and no new safety or tolerability issues were found. The 72-week results of the HOPE study were announced at the 62nd American Society of Hematology (ASH) Annual Meeting in December 2020.
Sickle cell disease (SCD) is a serious, progressive, and debilitating genetic disease that results in abnormal production of sickle hemoglobin (HbS) due to mutations in the β-globin gene. HbS makes red blood cells sick and fragile, leading to chronic hemolytic anemia, vascular disease, elusive and painful vascular occlusion crisis (VOC). For adults and children with SCD, this means painful crises and other life-altering or life-threatening acute complications such as acute thoracic syndrome (ACS), stroke and infection. If the patient survives acute complications, vascular disease, and end-organ damage, the resulting complications can lead to pulmonary hypertension, renal failure, and early death.
As the first drug to treat the root causes of SCD, the industry is very optimistic about Oxbryta's commercial prospects. The pharmaceutical market research organization EvaluatePharma previously released a report predicting that Oxbryta will become the world's best-selling SCD drug, with sales expected to reach 1.98 billion U.S. dollars in 2024, and sales of Zynteglo/LentiGlobin, a gene therapy from Bluebird Bio, will reach 1.033 billion in the same period Dollar.
Zynteglo/LentiGlobin is a one-time gene therapy developed for the treatment of SCD and β-thalassemia. The drug uses a lentiviral vector to implant a functional copy of an improved version of the β-globin gene (βA-T87Q-globin gene) into the hematopoietic stem cells (HSC) isolated from the patient in vitro, and then the cells are imported back into In the patient's body, the patient has the βA-T87Q-globin gene, and its red blood cells can produce anti-sickle hemoglobin HbAT87Q, reduce the proportion of abnormal sickle hemoglobin (HbS), thereby reducing sickle red blood cells, hemolysis and other complications. In September 2020, EMA granted Zynteglo the Priority Drug Qualification (PRIME) for the treatment of SCD.
Regarding regulation, in June 2019, Zynteglo received conditional approval from the European Union for use in transfusion-dependent β-thalassemia (TDT) patients who are 12 years of age and older and non-β0/β0 genotype. This approval makes Zynteglo the world's first gene therapy for TDT. But industry insiders believe that a greater market opportunity for the drug exists in the field of SCD treatment.