Ash 2021 – Bluebird looks to revive Lentiglobin

Data in sickle cell disease look encouraging, but a filing is a way away.

Bluebird Bio has had a rough 2021, with cancer scares for two of its projects and the withdrawal of Lentiglobin in Europe. But the group will be hoping to put its annus horribilis behind it with promising Lentiglobin data in sickle cell disease, presented at Ash today. 

Still, Bluebird does not expect a US filing in sickle cell until the first quarter of 2023, it recently disclosed. By this time it is likely to have been overtaken by Crispr and Vertex, which plan to submit their gene edited sickle cell candidate CTX001 late next year.

True, Lentiglobin could hit the market soon in transfusion-dependent beta-thalassaemia, where it has a Pdufa date of May 20, 2022. Yesterday at Ash Bluebird reported positive long-term data in this setting, with investigators calling it a “potentially curative” one-time therapy.

Group C

But sickle cell disease is a much bigger opportunity. Bluebird estimates that around 1,000 beta-thalassaemia patients in the US could benefit from Lentiglobin, versus the 20,000 US sickle cell patients the group is initially targeting.

The sickle cell data, which were published simultaneously in the New England Journal of Medicine, came from group C of the HGB-206 trial. In this cohort, the treatment protocol has been altered in ways intended to increase Lentiglobin’s efficacy, and results from this group will form the basis of Bluebird’s BLA submission.

Originally the study primarily measured haemoglobin endpoints, but the primary outcome has been changed to the proportion of subjects with complete resolution of severe vaso-occlusive crises (VOCs) six to 18 months after treatment.

The trial has also been tweaked to recruit patients who had experienced at least four VOCs in the two years before enrolment.

Today’s results, from a non-prespecified interim analysis, found no severe VOCs in 25 Lentiglobin-treated patients who met this criterion and who had been followed for at least six months. Meanwhile, three of these patients experienced 12 mild VOCs after Lentiglobin infusion.

No more cancers

Safety will also be at the top of investors’ minds after this study was put on hold earlier this year on a report of acute myeloid leukaemia (Bluebird split looks premature, February 16, 2021). This occurred in group A; Lentiglobin has since been exonerated, and the clinical hold was lifted in June. This followed another case of AML, in 2018, that was also deemed unrelated to therapy.

Reassuringly, no cancers have been seen in group C, although the investigators acknowledged the short follow-up time, ranging from 3.7 to 37.6 months. The changes made to the treatment process in this cohort were designed to reduce the risk of cancers as well as to improve clinical benefit, the authors noted.

As for other adverse events, three were related or possibly related to Lentiglobin, although all of these were described as “non-serious” and resolved a week after onset. There was one death, a cardiac arrest, but this was deemed due to the patient’s underlying disease.

There are still unanswered questions for Bluebird, for example around pricing and manufacturing. On the latter point, the company is carrying out the phase 3 HGB-210 study, which will use Lentiglobin manufactured in a commercial facility; product comparability data are due in late 2022.

While the path seems to be clearing for Lentiglobin in sickle cell disease, Bluebird still has a long way to go. And even if it can get the asset over the regulatory finish line the next hurdle – making the project a commercial success – looks more daunting yet.

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