SCDAA 46th Annual National Convention

Abstract 

Authors:
Dr. Gershwin T. Blyden- Foundation for Sickle Cell Disease Research,
Dr. Kenneth R. Bridges- Global Blood Therapeutics, Dr. Lanetta Bronté- Foundation for Sickle Cell Disease Research
 
Objective: Voxelotor (GBT440) is a first-in-class, oral, once-daily therapy designed to modulate the affinity of hemoglobin (Hb) for oxygen and delay sickle Hb polymerization, thereby reducing consequent red blood cell damage and life-threatening complications from sickle cell disease (SCD). Seven patients with severe SCD ineligible for ongoing clinical trials because of high mortality risk from comorbidities, including renal dysfunction, frequent hospitalizations for vaso-occlusive crisis (VOC), extreme anemia, and multiorgan failure were provided compassionate-use access to voxelotor by US Food and Drug Administration single-patient international new drug application.
Methods: Once-daily voxelotor began at 900 mg with possible increase to 1500 mg. Baseline echocardiograms were performed. Initial assessments at 2 and 4 weeks were followed by routine evaluations at least monthly. Key data captured included Hb levels, reticulocyte count, indirect bilirubin, resting oxygen saturation, pain level on 0-10 scale, transfusions, and hospitalizations for VOC. Patient Health Questionnaire 9-item (PHQ-9) assessed depression.
Results: Four female and 3 male patients aged 22-67 years had severe comorbidities at baseline including iron overload in all patients, frequent transfusions in 5/7, severe fatigue in 4/7, chronic oxygen supplementation in 2/7, and progressive severe renal dysfunction or multiorgan failure in 1 each. In 5/7 patients, baseline Hb was ≤6.4 g/dL, with three <6 g/dL. Hb level increased in all 7 patients by 24 weeks of voxelotor, with 5 reaching ≥1.0 g/dL. Hb increase due to voxelotor was clearest in 3 patients who experienced 1.0 to 5.4 g/dL Hb rises without transfusion. The number of transfusions fell by 60% in the 7 patients. VOC hospitalizations fell by 67%. Baseline oxygen saturation improved to 98%-99% from <95% in 4 patients following voxelotor treatment, permitting 2 patients to discontinue long-term supplemental oxygen. Overall well-being improved, typically 2-3 weeks after treatment initiation, for all patients, and the PHQ-9 score registered reduced depression. Voxelotor was well-tolerated with no discontinuations during treatment periods of up to 2 years. There was 1 dose reduction because of grade 2 diarrhea. Two patients with advanced end-stage organ injury died of SCD complications unrelated to treatment.
Conclusions: Seven patients given compassionate-use voxelotor after exhausting all treatment options achieved substantial improvements in clinical and mental health parameters for as long as 2 years. Controlled clinical trials will be needed to confirm the benefit of voxelotor in patients with severe SCD and multiple comorbidities.