LentiGlobin Gene Therapy for Sickle Cell Demonstrates Therapeutic Potential

Mark Walters, MD

The ongoing Phase 1/2 HGB-206 Study has reported that LentiGlobin for sickle cell disease (SCD) gene therapy resulted in near pancellular β^A-T87Q expression and reduced HbS among affected patients.

The investigators also observed reduced hemolysis, increased total hemoglobin, and a complete resolution of vaso-occlusive crises and acute chest syndrome (ACS) in nearly all patients.

These findings were presented at the 2021 Transplantation & Cellular Therapy (TCT) Meetings Digital Experience.

Led by Mark Walters, MD, UCSF Benioff Children's Hospital, Oakland, the study evaluated the efficacy and safety of LentiGlobin for SCD gene therapy, which uses a modified human β-globin gene that produces GT-derived anti-sickling hemoglobin (HbA^T87Q).

The team enrolled patients aged ≥12 and ≤50 years of age with SCD and severe vaso-occlusive events. Included in the study were those with acute episodes of pain and ACS.

Walters and team collected CD34+ cells using plerixafor mobilization/apheresis. The cells were then tranduced with BB305 LVV. 

Following infusion of LentiGlobin after myeloablative busulfan conditioning, patients were assessed for laboratory evaluations, SCD-related outcomes, and adverse events.

According to the team’s Group C data, 40 patients (median, 23.5 years) initiated cell collection and underwent a median of 2 mobilization cycles. Furthermore, 25 of the 40 patients were treated with LentiGlobin.

Red blood cell transfusions were stopped among all patients up to 90 days following treatment.

“In 16 evaluable patients with ≥6 months of follow-up, total Hb at last visit was 11.5 g/dL, with HbA^T87Q contribution of 5.2 g/dL, HbS of 6.1 (g/dL, and median HbS ≤60% of total Hb,” wrote the investigators.

“Exploratory assays showed near pancellular expression of HbA^T87Q ≥6 months post-treatment with ~90% of RBCs containing β^A-T87Q by 18 months (n=9),” they continued.

Their data also reported that, at last visit, hemolysis markers were trending toward normalization in 25 patients.

Furthermore, the team evaluated 14 patients with ≥6 months of follow-up and history of vaso-occlusive crisis or ACS. The annualized combined vaso-occlusive crisis and ACS rate in this population was a median of 4 in the 2 years preceding treatment.

However, there were no noted ACS or serious vaso-occlusive crises post-treatment — save for 1 non-serious Grade 2 vaso-occlusive crisis, which occurred about 3.5 months after treatment.

Stomatitis occurred in 15 patients and febrile neutropenia in 11 patients—both of which were considered the most common non-hematologic ≥ Grade 3 adverse events following treatment.

The serious adverse events that occurred in ≥2 patients post-treatment were nausea, opioid withdrawal syndrome, and vomiting (n = 2 in all). No treatment-related serious adverse events have been reported so far.

Additionally, no events of graft failure, vector-mediated replication-competent lentivirus, or clonal dominance have been observed.

“The safety profile post-LentiGlobin remains generally consistent with myeloablative single-agent busulfan conditioning and underlying SCD,” Walters and team concluded.