Promising news for gene therapy for sickle cell disease

An engineered lentivirus delivers functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene or LentiGlobin) into a sickle cell disease (SCD) patient’s own haematopoietic stem cells. Once patients have the βA-T87Q-globin gene, they can make functional red blood cells, with the goal of reducing sickled red blood cells, haemolysis, and ensuing complications [1]. In patients who were at least 6 months post-treatment with lentiviral LentiGlobin for SCD, the median level of abnormal sickle haemoglobin was reduced to ≤50% of total haemoglobin. At up to 15 months post-treatment with LentiGlobin, no serious vaso-occlusive crisis (VOEs) or acute chest syndrome were reported in this cohort.

In the plenary session, Dr Olivier Hermine (Necker Hospital, France) presented the ongoing, phase 1/2 HGB-206 study. Adults and children living with SCD experience unpredictable episodes of pain due to vaso-occlusion as well as other acute complications, such as acute chest syndrome (ACS), stroke, and infections, which can contribute to early mortality in these patients. LentiGlobin for SCD adds functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient’s own haematopoietic stem cells. The latest data shows robust production of gene therapy-derived anti-sickling haemoglobin, HbA^T87Q, such that patients with 6 or more months of follow-up after treatment with LentiGlobin for SCD had median sickle haemoglobin levels reduced to 50% or less of total haemoglobin, in the absence of blood transfusions. The potential for gene therapy with LentiGlobin to fundamentally alter the pathophysiology of SCD was also supported by the normalisation of haemolysis markers, increase in total haemoglobin, and substantial reduction in vaso-occlusive crises relative to baseline.

HGB-206 is an ongoing, phase 1-2, open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for SCD that includes 3 treatment cohorts: Groups A, B and C. As of March 2019, 25 patients were enrolled and a total of 13 patients had been treated with LentiGlobin in Group C, with a median post-treatment follow-up of 9 months (1.0-15.2 months). Of the 13 treated patients in Group C, 8 had at least 6 months of follow-up at the time of the data cut-off. In these patients, production of gene therapy-derived HbA^T87Q ranged from 4.5-8.8 g/dL and total unsupported Hb levels ranged from 10.2-15.0 g/dL at the last study visit. The median concentration of HbA^T87Q continued to increase, accounting for ≥50 percent of total Hb in patients with at least 12 months of follow up (n=4).
No ACS or serious vaso-occlusive crisis (VOC) was reported in patients in Group C at up to 15 months post-treatment with LentiGlobin.

In an exploratory analysis, key markers of haemolysis, including reticulocyte counts, lactate dehydrogenase (LDH), and total bilirubin levels, trended toward normal levels. As of the data cut-off date, with up to 15 months of follow-up, the safety data from all patients in HGB-206 are reflective of underlying SCD, the known side effects of haematopoietic stem cell collection and myeloablative conditioning. No serious adverse events were reported related to LentiGlobin for SCD. The amount of HbAT87Q and HbS protein in blood samples from 5 patients who were at least 9 months post-treatment showed that at least 70% of each patient’s red blood cells expressed HbA^T87Q.

1. 
   
   1. Cavazzana M, et al. Plenary session, 24th Congress of the EHA, 13-16 June 2019, Amsterdam, the Netherlands.

 



Posted on 9 August 201917 May 2024