Interim Results from a Phase 1/2 Clinical Study of Lentiglobin Gene Therapy for Severe Sickle Cell Disease

Background

β-globin gene transfer into hematopoietic stem cells (HSCs) may reduce or eliminate the acute symptoms and long-term complications of sickle cell disease (SCD). LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the betibeglogene darolentivec (BB305) lentiviral vector, which encodes a β-globin with a single point mutation (A^T87Q) designed to confer anti-sickling properties similar to γ-globin. HGB-206 is a multi-center, phase 1/2 safety and efficacy study of LentiGlobin DP in adults with severe SCD. In 2016, the HGB-206 protocol was modified to increase DP vector copy number (VCN), require pre-harvest transfusions, increase target busulfan levels, and explore the use of plerixafor for mobilization and apheresis for cell collection. We present new data from the initial 7 patients (group A) and initial data from 2 newly treated patients (group B, with increased DP VCN and pre-harvest transfusions). Results from exploratory plerixafor-mediated HSC mobilization will be reported separately.

Methods

Patients (≥18 years of age) with severe SCD (history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were screened for eligibility. For group B, at least 2 months of regular transfusions (target Hb 10-12 g/dL and target HbS <30%) were initiated. Following bone marrow harvest (BMH), autologous CD34+ cells were transduced with the BB305 vector. Subjects underwent fully myeloablative conditioning prior to infusion of the transduced cells. After infusion, patients were monitored for adverse events (AEs), engraftment, vector copy number (VCN), HbA^T87Q expression, and laboratory and clinical parameters.

Results

As of July 21, 2017, 9 patients with severe SCD (median age 26 [range 18-42] years) have received LentiGlobin DP. All successfully underwent BMH (median 2 harvests, range 1-3). Eighteen grade 3 AEs in 6 patients were attributed to BMH: pain (12 events), anemia (3 events) and VOC (3 events). Table 1 summarizes DP characteristics and lab results. The median cell dose for group A patients was 2.1 x 10⁶ CD34+ cells/kg, median DP VCN was 0.6 copies/diploid genome, and 8%-42% CD34+ cells were transduced. In group B patients, DP VCNs were 1.4/3.3 and 2.9/5.0 (2 DP lots per patient), DP cell doses were 2.2 and 3.2 x 10⁶ CD34+ cells/kg, and 46%-95% of CD34+ cells were transduced. Median time to neutrophil engraftment (ANC ≥ 500) was 22 days (range 17-29) in group A and 28 days in group B. Median post-infusion follow-up as of June 2, 2017 was 18.3 (14.9-23.8) months in group A. Patients in group B had 1.7 and 5.6 months follow-up as of July 21, 2017. The toxicity profile observed from start of conditioning to latest follow-up was consistent with myeloablative conditioning with single-agent busulfan. To date, there have been no DP-related ≥ grade 3 AEs. Sixteen SAEs in 7 patients have been reported post DP-infusion, including 2 episodes of grade 4 bacteremia, 2 episodes of grade 3 pyrexia, and single episodes of grade 3 long QT syndrome, fever, influenza, wrist fracture, osteonecrosis, pain, iron overload, pulmonary mass, vomiting, diarrhea, and drug dependence.

In group A, median VCN in peripheral blood was 0.1 (0.1-0.2) copies/genome and median HbA^T87Q level was 0.9 g/dL (0.4-2.4 g/dL) at last measurement. Patients experiencing multiple VOCs prior to study entry (n=6; median 4, range 2-28 VOCs annually) have had numerically fewer VOCs since LentiGlobin DP infusion (median annualized frequency 1, range 0-24, 14%-100% reduction).

In group B, the marked increases in DP VCN have corresponded to higher early VCNs in peripheral blood, with VCNs in patients 1302 and 1303 of 2.6 and 0.5 at month 1 and month 3, respectively. An additional 8 patients have been enrolled in HGB-206 as of July 21, 2017 but have not yet received DP. Initial data, including mobilization results and DP characteristics, for these patients will be presented.

Conclusions

Early results from 2 patients treated under a modified protocol with LentiGlobin DP manufactured under a refined process demonstrate both higher DP VCN and higher peripheral VCN after transplant. Engraftment times in group B are comparable with group A, and no unexpected AEs have occurred to date. Additional study data should demonstrate whether improvements in LentiGlobin gene therapy will provide consistent clinical benefit to patients with severe SCD.

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