Resolution of Serious Vaso-Occlusive Pain Crises and Reduction in Patient-Reported Pain Intensity: Results from the Ongoing Phase 1/2 HGB-206 Group C Study of LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Background Sickle cell disease (SCD) is caused by abnormal sickle hemoglobin (HbS) and results in chronic hemolytic anemia, painful vaso-occlusive events (VOEs), and progressive vasculopathy that lead to significant morbidity. While acute vaso-occlusive pain is a defining clinical feature, chronic daily pain also contributes significantly to poor quality of life in many adult patients. The ongoing Phase 1/2 HGB-206 Study (NCT02140554) evaluating safety and efficacy of LentiGlobin for SCD (bb1111) gene therapy (GT) uses a modified human β-globin gene that produces GT-derived anti-sickling hemoglobin (HbAT87Q). Data from Group C patients including red blood cell (RBC) physiology, clinical outcomes, and patient-reported pain intensity are presented here. Methods Patients (≥12 and ≤50 years) with SCD and stroke or severe VOEs, including acute episodes of pain and acute chest syndrome (ACS), were enrolled. CD34+ cells collected by plerixafor mobilization/apheresis were transduced with BB305 lentiviral vector. LentiGlobin was infused following myeloablative busulfan conditioning. Patients were monitored for laboratory evaluations including Hb levels and hemolysis markers, SCD-related outcomes, pain intensity using the Patient Reported Outcomes Measurement Information System (PROMIS)-57, and adverse events (AEs). Data are median (min-max) unless otherwise stated. Results As of 3 March 2020, 40 Group C patients (23.5 [12-38] years) initiated cell collection; 25/40 were treated with LentiGlobin and followed for 12.1 (2.8-24.8) months. Neutrophil and platelet engraftment were achieved at 19 (12-27) days and 28 (19-136) days, respectively. All patients stopped RBC transfusions by 90 days post-treatment. In 16 evaluable patients with ≥6 months of follow-up, total Hb at last visit was 11.5 (9.6-16.2) g/dL, with HbAT87Q contribution of 5.2 (2.7-9.4) g/dL, HbS of 6.1 (4.9-7.8) g/dL, and median HbS ≤ 60% of total Hb. Exploratory assays showed near pancellular expression of HbAT87Q ≥6 months post-treatment (N=9 patients), with ~90% of RBCs containing βA-T87Q by 18 months, and reduction in sickling propensity comparable to sickle cell trait. At last visit post-treatment, key hemolysis markers were trending towards normalization with median (quartile [Q]1-Q3) lactate dehydrogenase of 212 (201-287) U/L, reticulocyte count of 178 (146.5-236.3) ×109/L, and total bilirubin of 19 (15.4-27.4) µmol/L (all for n=25). In 14 patients with ≥6 months of follow-up and history of vaso-occ