AML case forces bluebird bio to pause gene therapy studies in sickle cell disease

Bluebird bio said Tuesday that it temporarily halted two trials, including a Phase III study, investigating its LentiGlobin gene therapy for sickle cell disease (SCD) after a suspected unexpected serious adverse reaction (SUSAR) of acute myeloid leukaemia (AML). The company, whose shares plunged as much as 34% on the news, said the suspensions affect the Phase III HGB-210 and Phase I/II HGB-206 trials.

According to bluebird bio, it received a report last week that a patient who was treated more than five years ago in HGB-206 was diagnosed with AML. The company said it is investigating the cause of the patient's AML in order to determine if there is any relationship to the use of the BB305 lentiviral vector in the manufacture of LentiGlobin for SCD. It is also looking into a second SUSAR of myelodysplastic syndrome that was reported last week in a patient from the HGB-206 trial.

Zynteglo sales paused

No cases of haematologic malignancy have been reported in any patient who has received treatment with betibeglogene autotemcel, licensed as Zynteglo in the EU and UK, for transfusion-dependent beta-thalassemia. However, bluebird bio said it is also temporarily pausing marketing of Zynteglo since the treatment is manufactured using the same BB305 lentiviral vector as in the LentiGlobin gene therapy for SCD.

Zynteglo was launched in Germany last year, and earlier this month was provisionally turned down for routine NHS use in the UK, with the National Institute for Health and Care Excellence citing "uncertainties" about cost effectiveness given that "clinical trials…are small and people have not been followed up for very long."

Positive efficacy findings

In December, bluebird bio reported updated findings from the HGB-206 trial showing complete elimination of SCD-related severe vaso-occlusive events (VOEs) through 24 months of follow-up in a cohort of LentiGlobin-treated patients with a history of suffering severe VOEs. Further, all patients in this Group C cohort were able to stop regular blood transfusions by three months post-treatment and remained off transfusions as of the data cut-off.

Meanwhile, the Phase III HGB-210 trial, which was initiated in February last year, has a target enrolment of 35 patients with SCD who will receive a single dose of LentiGlobin administered by intravenous infusion following myeloablative conditioning with busulfan. The gene therapy, also known as bb1111, uses the BB305 lentiviral vector to insert functional copies of the beta-A-T87Q globin gene into a patient's own haematopoietic stem cells.

Bluebird bio, which is in the process of splitting into two companies with separate focusses on severe genetic diseases and oncology, recently pushed back the FDA filing of LentiGlobin for SCD to late 2022, having initially targeted the second half of 2021. At the time, the company cited FDA feedback regarding product manufacturing and challenges related to the COVID-19 pandemic as reasons for the delay.

Latest gene therapy setback

The LentiGlobin pause marks the latest is a series of recent setbacks in the gene therapy space. In December, the FDA placed a clinical hold on uniQure's etranacogene dezaparvovec programme for haemophilia B after a patient who received the experimental gene therapy approximately a year before as part of the Phase III HOPE-B study was diagnosed with hepatocellular carcinoma. The US regulator has also placed a clinical hold on NBIb-1817, an experimental gene therapy being co-developed by Voyager Therapeutics and Neurocrine Biosciences for Parkinson's disease, after magnetic resonance imaging "abnormalities" were reported in some patients enrolled in the Phase II RESTORE-1 study.

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