Case series of patients with severe sickle cell disease treated with voxelotor (GBT440) by compassionate access
Authors: Gershwin Blyden, Kenneth R. Bridges, Lanetta Bronte
Journal: American Journal of Hematology (2018)

To the Editor: Sickle cell disease (SCD) is caused by a single nucleotide substitution (A to T) at the sixth amino acid position in the β chain of the hemoglobin (Hb) gene, replacing glutamic acid with valine and resulting in production of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, producing deformed, fragile, and inflexible sickled red blood cells (RBCs). These inflexible RBCs occlude the microvasculature and hemolyze, with downstream effects that include tissue ischemia, painful vaso-occlusion, inflammation, significant end-stage organ damage, and early death.1 Voxelotor (previously GBT440) is a first-in-class, oral, once-daily drug in development (Global Blood Therapeutics [GBT], South San Francisco, CA) that binds to the α-chain of HbS, stabilizing the molecule in the R-state conformation, which is known to interrupt HbS polymerization.2, 3 The target for HbS modification with voxelotor is 20%-30%.3 In phase 1/2 trials, voxelotor inhibited HbS polymerization, RBC sickling, and hemolysis, with a consequent increase in Hb concentration,4 while also demonstrating an acceptable safety profile and was well tolerated.5 Patients with severe SCD have few treatment options due to the paucity of US Food and Drug Administration (FDA)–approved therapies and systematic exclusion from ongoing clinical trials of investigational agents. Herein we report the experiences of seven patients with severe SCD to whom GBT granted compassionate-use voxelotor access in 2016. Eligibility criteria were severe SCD with Hb level <6.0 g/dL or extreme or life-threatening complications. These patients were required to have exhausted available treatment options in the judgment of the treating physician and were not eligible to participate in existing trials of voxelotor. Investigators obtained investigational new drug applications from the FDA for each patient, and treatment was consistent with guidelines for compassionate use. Voxelotor treatment was initiated between May 2016 and June 2017. Patients received once-daily voxelotor 900 mg, with a possible increase to 1500 mg, according to a treatment plan formulated by the patient's physician. Initial assessments at 2 and 4 weeks were followed by routine evaluations at least monthly. Complications such as avascular necrosis of the hip limited the utility of 6-minute walk testing (6MWT) for some patients, but periodic testing was performed in several others. Data on hospitalizations and transfusions were obtained from medical records review. A complete evaluation of opioid use was not available, as patients may have had access from other providers. Depression was assessed at each clinical visit using the Patient Health Questionnaire-9 (PHQ-9); diagnosis of depression was made by a board-certified psychiatrist. Patients were questioned about their pain at each visit by use of a simple pain score index on a 0 to 10 scale, with 0 being no pain and 10 extreme pain. Patient characteristics for the four women and three men are summarized in Table 1. Ages ranged from 22 to 67 years, and treatment durations ranged from 6 to 17 months. Overall, voxelotor was well tolerated for up to 17 months. Patient F had transient grade 1 diarrhea at the 900-mg dose that resolved with no treatment change. The sole adverse event at the 1500-mg dose was grade 2 diarrhea in patient A, which resolved with a return to the 900-mg dose. No voxelotor-related serious adverse events occurred. Patients B and C, each with extensive preexisting end-stage organ injury, died while receiving voxelotor for compassionate use. Both deaths were considered to be related to progression of severe underlying SCD and unrelated to voxelotor therapy, per the treating physician's assessment. Progressive long-standing renal dysfunction resulted in hemodialysis for Patient B several months into voxelotor support. The patient ultimately chose to discontinue hemodialysis. Progressive hepatic failure due to massive iron overload became critical at month 15, and the patient died at month 16. Patient C survived two episodes of multiorgan failure requiring intensive care support in the 18 months prior to voxelotor treatment. Seven months into voxelotor therapy, he experienced a sickle cell pain crisis that deteriorated into a third episode of multiorgan failure over 2 days and died of cardiopulmonary arrest. Table 1 summarizes the changes in clinical parameters after 24 weeks of voxelotor treatment. Hb levels increased rapidly in all patients, occurring as early as 2 weeks after initiation in most patients, with increases from baseline to 24 weeks that ranged from 5.4 to 0.5 g/dL. In 5 of 7 patients, the increase equaled or exceeded 1 g/dL (Supporting Information Figure 1A). The increase in Hb of 5.4 g/dL for patient E followed a voxelotor dose increase from 900 mg to 1500 mg. Patient A, who was refractory to transfusion because of RBC alloimmunization, maintained Hb levels at values 1-1.5 g/dL greater than baseline over 70 weeks of treatment. The number of transfusions decreased by 60% in the 24 weeks after voxelotor initiation, compared with the 24 weeks before treatment initiation (13 vs. 33; Supporting Information Figure 1B). Except Patient A, who was alloimmunized to RBCs, six patients received transfusions before receiving voxelotor, whereas 2 of 6 patients received no transfusions afterward. Baseline oxygen saturation for patients A, C, D, and E was <95%, which improved to 98%-99% with voxelotor treatment, allowing Patients A and E to discontinue long-term supplemental oxygen. Patient A, who had a 6MWT at baseline and after 14 and 24 weeks of voxelotor treatment, experienced steady improvements in distance walked (330 m, 375 m, and 387 m, respectively), post-walk pulse rate (102 beats per minute [bpm], 96 bpm, and 93 bpm, respectively), and post-walk room air oxygen partial pressure (86%, 93%, and 96%, respectively) over the course of treatment. Most patients experienced improved well-being typically 2–3 weeks after starting voxelotor treatment. Although this is partially reflected in pain assessments at clinic visits, a more informative measure involved hospitalizations for vaso-occlusive crisis (VOC) pain. The number of hospitalizations for VOC pain decreased by 67% in the 24 weeks after voxelotor initiation compared with the 24 weeks before treatment initiation (9 vs. 28; Supporting Information Figure 2). The number of hospitalizations per patient ranged from 2 to 5 during the 24 weeks before voxelotor, and that number decreased in all patients during the 24 weeks of treatment. Two patients had no hospitalizations after treatment initiation, and the number of hospitalizations decreased by half for four other patients. At baseline, Patient D had moderate depression and Patient A had moderately severe depression, whereas five patients had no/minimal depression, as assessed by the PHQ-9 (Table 1). After 24 weeks of treatment with voxelotor, affect improved in Patients A and D, with Patient A showing no/minimal depression and Patient D showing mild depression. Through this compassionate use activity, the seven patients described here, who had exhausted all treatment options, demonstrated several meaningful improvements, including increased Hb levels, improved oxygen saturation, and fewer transfusions and hospitalizations for VOC. Although the patients were followed closely with structured data collection, this is an uncontrolled case series and cannot be equated with data from a controlled clinical trial. Nonetheless, the consistency, robustness, and durability of response to voxelotor in these patients with severe SCD is encouraging and support the ongoing clinical trials to assess the safety and efficacy of voxelotor in patients with SCD, including the phase 3 HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) study for patients with SCD aged 12 years and older (clinicaltrials.gov identifier, NCT03036813).6 Medical writing assistance was provided by Adam Bastidas (ApotheCom; San Diego, CA) and was funded by Global Blood Therapeutics, Inc. This study was sponsored by Global Blood Therapeutics, Inc. Kenneth R. Bridges is an employee of and has equity ownership in Global Blood Therapeutics, and Gershwin Blyden and Lanetta Bronte have no conflicts of interest to disclose. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting information 1 Supporting information 2 Supporting information 3 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.