The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use has granted accelerated assessment for the upcoming marketing authorization application (MAA) for LentiGlobin™.

LentiGlobin is a gene therapy intended for the treatment of adolescents and adults with transfusion-dependent β-thalassemia (TDT) and a non-β0/β0 genotype.

bluebird bio intends to file an MAA for LentiGlobin with the EMA this year.

Accelerated assessment can reduce the active review time of an MAA from 210 days to 150 days once it has been validated by the EMA.

An accelerated assessment is granted to products deemed to be of major interest for public health and represent therapeutic innovation.

The accelerated assessment for LentiGlobin is supported by data from clinical studies, including the phase 1/2 Northstar (HGB-204) study, phase 1/2 HGB-205 study, phase 3 Northstar-2 (HGB-207) study, and the long-term follow-up study LTF-303.

The EMA previously granted PRIME (Priority Medicines) eligibility and orphan designation to LentiGlobin for the treatment of TDT.

LentiGlobin is also part of the EMA’s Adaptive Pathways pilot program, which is part of the EMA’s effort to improve timely access to new medicines.

Phase 1/2 trials

Results from the phase 1/2 trials of LentiGlobin—HGB-204 and HGB-205—were published in NEJM in April.

HGB-204 is a completed study that included 18 patients with TDT. Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

HGB-205 is an ongoing study, and results were reported for 4 patients with TDT. Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients. CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced red blood cell (RBC) transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 adverse events (AEs) considered possibly or probably related to LentiGlobin—abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs. Grade 3 serious AEs included 2 episodes of veno-occlusive liver disease that were attributed to busulfan, Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis. Grade 2 serious AEs included device-related thrombosis and infectious diarrhea.

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin. The 3 serious AEs were tooth infection (grade 3), major depression (grade 3), and pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) and 23.0 days (range, 20.0 to 26.0), respectively.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin administration.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

Gene therapy granted accelerated assessment