Highlights from

EHA 2019

European Hematology Association

Amsterdam 13-16 June 2019

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) into a 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 other complications. In patients who were at least six months post-treatment with lentiviral LentiGlobin for sickle cell disease (SCD), the median level of abnormal sickle haemoglobin was reduced to ≤50% of total haemoglobin. At up to 15 months post-treatment with LentiGlobin, there were no reports of serious vaso-occlusive crisis (VOEs) or acute chest syndrome in this cohort [1].

In a plenary session, Dr Olivier Hermine (Necker Hospital, France) spoke in place of his colleague Dr Maria Cavazzana, and presented the ongoing phase 1/2 HGB-206 study. Adults and children living with SCD experience unpredictable episodes of excruciating 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, HbAT87Q, such that patients with 6 or more months of follow-up after treatment with LentiGlobin for sickle cell disease 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 sickle cell disease 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 ½, 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 HbAT87Q ranged from 4.5-8.8 g/dL and total unsupported haemoglobin (Hb) levels ranged from 10.2-15.0 g/dL at the last study visit. The median concentration of HbAT87Q 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 concentration, trended toward normal levels. As of the data cut-off date, 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. One mild, non-serious event of hot flush was reported that the investigator considered to be related to LentiGlobin for SCD; it occurred and resolved on the day of drug product infusion and did not require treatment. Established tools, including high-performance liquid chromatography, are used to measure the amount of HbAT87Q in a blood sample. HbAT87Q and HbS protein expression at a cellular level from 5 patients who were at least 9 months post-treatment on average showed at least 70% of each patient’s red blood cells expressed HbAT87Q.

  1. Cavazzana M, et al. Gene therapy for hematological disorders. Plenary session, 24th Congress of the European Hematology Association, 13-16 June 2019, Amsterdam, the Netherlands.

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