Positive data unveiled for bluebird bio's gene therapies in sickle-cell disease, thalassaemia

Positive data unveiled for bluebird bio's gene therapies in sickle-cell disease, thalassaemia

New data from bluebird bio's ongoing Phase I/II study of its LentiGlobin gene therapy demonstrated a near elimination of serious vaso-occlusive crises (VOCs) and acute chest syndrome (ACS) in patients with sickle-cell disease [SCD], the company announced Friday. It also reported results from two Phase III trials of its betibeglogene autotemcel (beti-cel) gene therapy, showing that patients with a range of genotypes of transfusion-dependent beta-thalassaemia achieved and maintained transfusion independence, with haemoglobin (Hb) levels near normal. The findings were presented at the virtual edition of the European Hematology Association (EHA) annual congress.

Commenting on the efficacy results from the Phase I/II HGB-206 trial in SCD, bluebird bio's chief medical officer David Davidson said the near-complete reduction of VOCs indicates LentiGlobin can provide "truly meaningful" benefits. Furthermore, improvements seen in measures of haemolysis and red cell physiology, "with nearly pan-cellular distribution of the anti-sickling HbAT87Q, suggest LentiGlobin…may substantially modify the causative pathophysiology of [the disease]," he added.

Davidson said the company plans to seek accelerated approval of LentiGlobin in SCD. Earlier this year, bluebird bio indicated that the regulatory application for LentiGlobin in the US would be pushed back until mid-2021 due to the COVID-19 pandemic.

Reduction of 99.5% in annualised VOC, ACS

As of March 3, a total of 34 patients in the HGB-206 trial have been treated with LentiGlobin for SCD, with the latest analysis focused on Group C of the study, a cohort consisting of 25 subjects who have follow-up ranging from 2.8 months to 24.8 months. Group C patients also received LentiGlobin for SCD made from haematopoietic stem cells (HSCs) collected from peripheral blood, rather than via bone marrow harvest, which was used in Groups A and B. The analysis specifically looks at efficacy data for 16 patients who had at least six months of follow-up, and safety data for 18 patients.

Efficacy results showed that median levels of gene therapy-derived anti-sickling HbAT87Q were maintained, with HbAT87Q contributing at least 40% of total Hb. All patients in Group C were able to stop regular blood transfusions and remain off transfusions at three months post-treatment, bluebird bio noted. Moreover, there was a 99.5% mean reduction in the annualised rate of VOCs and ACS among the 14 patients who had at least six months of follow-up and a history of VOCs or ACS, defined as four or more such events in the two years prior to treatment. The median was eight events for this group.

Improving biological markers of SCD

In regards to key markers of haemolysis, bluebird bio said median reticulocyte counts, lactate dehydrogenase levels and total bilirubin improved compared to screening, and stabilised by the six-month mark, while among the five patients who had 24-month data, the values approached the upper limit of normal at two years. "These results suggest treatment with LentiGlobin for SCD is improving biological markers of SCD," the company said.

Meanwhile, there were no serious adverse events (AEs) related to LentiGlobin for SCD, and the non-serious, related adverse events were mild-to-moderate in intensity and self-limited. However, one patient with a history of frequent pre-treatment vaso-occlusive events (VOEs), and other health condictions, had complete resolution of VOEs following treatment, but suffered sudden death 20 months after treatment with LentiGlobin for SCD. According to bluebird bio, the autopsy concluded the cause of death was cardiovascular, with contributions from SCD and asthma.


The company also presented data from the Phase III Northstar-2 and Northstar-3 studies of beti-cel, a one-time gene therapy designed to address the underlying genetic cause of transfusion-dependent beta-thalassaemia by adding functional copies of a modified form of the beta-globin gene into a patient's own HSCs. As of March 3, all 23 patients in Northstar-2 were treated and have been followed for a median of 19.4 months, but only 19 patients were evaluable for transfusion independence.

Results showed that 89% of evaluable patients with transfusion-dependent beta-thalassaemia who do not have a β00 genotype achieved transfusion independence, with median weighted average total Hb levels of 11.9 g/dL. Prior to that, these patients had required a median of 17.5 transfusions per year, bluebird bio noted.

The company said patients also saw improved iron levels, as measured by serum ferritin and hepcidin, as well as trends toward better iron management. In addition, biomarkers of ineffective red blood cell production were evaluated in patients who achieved transfusion independence, with results showing the myeloid-to-erythroid (M:E) ratio increasing from a median of 1:3 at baseline, to 1:1.2 after one year. "The continued normalisation of red blood cell production over time among some patients who achieved transfusion independence supports the disease-modifying potential of beti-cel," the company said.


Finally, the Northstar-3 trial had 15 patients as of March 3 with various genotypes, including nine who are β00, three who are β0/ β+IVS1-110 and three who are homozygous for the IVS-1-110 mutation. Participants were treated with beti-cel and had a median follow-up of 14.4 months

Results demonstrated that six of eight evaluable patients achieved transfusion independence, with median weighted average total Hb levels of 11.5 g/dL, and they continued to maintain transfusion independence for a median duration of 13.6 months, as of the data cutoff. Moreover, 11 of 13 subjects with at least seven months of follow-up had not received a transfusion in more than seven months at time of data cutoff, whereas previously they required a median of 18.5 transfusions per year.

"Seeing patients achieve transfusion independence and maintain that positive clinical benefit over time with robust hemoglobin levels reflects our initial vision of the potential of beti-cel," Davidson said, while "improvements in bone marrow histology, iron balance and red cell biology support the potential of beti-cel to correct the underlying pathophysiology of transfusion-dependent beta-thalassaemia."

In terms of safety, bluebird noted that there were three serious events of veno-occlusive liver disease and two serious events of thrombocytopenia in the Northstar-2 trial, with one of the thrombocytopenia cases "considered possibly related to beti-cel." In Northstar-3, the company said there were two serious events of pyrexia.

The EU conditionally approved beti-cel, formerly known as LentiGlobin for β-thalassemia, last year under the name Zynteglo for patients 12 years and older with transfusion-dependent beta-thalassaemia who do not have a β00 genotype. The company said that in April, the European Medicines Agency renewed the conditional approval for Zynteglo.

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