Dive Brief:

• Bluebird bio can say with more conviction that tweaks made to its LentiGlobin gene therapy are bearing fruit, unveiling Monday updated trial results with longer follow-up from treated patients with beta-thalassemia and sickle cell disease.
• Across three small studies testing the gene therapy in the two blood diseases, patients given LentiGlobin saw their levels of the crucial oxygen-carrying protein hemoglobin rise to approach normal, eliminating the need for blood transfusions in most over the studied period.
• But a case of myelodysplasia syndrome (MDS) reported in one patient treated with LentiGlobin three years ago could renew safety worries that have lingered in the gene therapy field. Bluebird said analysis of the patient’s cells showed no evidence of the vector used in its gene therapy triggered the cancer-like bone marrow disease. An independent data monitoring committee agreed the case was unlikely tied to LentiGlobin.

Dive Insight:

ASH is perennially an important conference for Bluebird, which specializes in gene therapy for blood diseases as well as cell therapies for hematological cancers.

Already, the biotech has given an initial look at its successor CAR-T treatment for multiple myeloma. LentiGlobin, though, is a more near-term focus for investors and the first experimental candidate for which Bluebird hopes to win regulatory approval.

Updated data at ASH underscore the therapy’s potential as a treatment for both transfusion-dependent beta-thalassemia and sickle cell disease. The new results were from three studies: Northstar-2 for beta-thalassemia patients with less severe forms of the disease; Northstar-3 in the more severe ß0/ß0 type; and HGB-206 for patients with sickle cell disease.

In 11 patients treated in Northstar-2 with Bluebird’s new version of LentiGlobin and followed for at least three months, 10 stopped receiving blood transfusions altogether and achieved total hemoglobin levels ranging from 11.1 to 13.3 g/dL of blood — close to what’s considered normal.

Notably, Bluebird also indicated that three patients treated in Northstar-3 experienced total hemoglobin levels above 10g/dL, including one with essentially normal hemoglobin levels a year out from treatment.

In sickle cell, where Bluebird has faced more setbacks, four patients with greater than six months of follow-up saw gene therapy-derived hemoglobin levels match or exceed sickled hemoglobin levels — an important threshold for patient symptoms. No vaso-occulsive events, which are the severe pain crises common in sickle cell, were reported in those four patients at up to nine months post-treatment.

“The theoretical threshold of success for making anti-sickling globins is 30% based on natural history data of individuals with hereditary persistence of fetal hemoglobin,” said Bluebird’s chief medical officer David Davidson in an interview with BioPharma Dive.

“Not only are we achieving that, but are consistently exceeding that,” he continued, noting that patients with anti-sickling globin exceeding sickled globin more closely resemble individuals with the sickle cell trait rather than the disease.

The one case of MDS, though, could spur some concerns in a field that’s remained cautious of signs the viral vectors used to deliver gene therapy could spur mutations in cell DNA. The patient in question was treated with the older version of LentiGlobin and Bluebird disclosed the case in a Saturday update of earlier LentiGlobin studies.

“MDS is still a concern as it could be related to the conditioning regimen,” wrote John Strouse, an associate professor of medicine at Duke University School of Medicine, in an email to BioPharma Dive, referring to drugs given before gene therapy infusion.

Leerink analyst Mani Foroohar suggested the same in a Monday note to investors. “Secondary malignancy is a known clinical risk of preconditioning with alkylating agents, marking this case as a tragedy for the patient involved and their family, but not a surprise from a scientific standpoint,” wrote the analyst.

Bluebird plans to expand the cohort that’s treated with the modified version of LentiGlobin in its HGB-206 study and aims to begin a Phase 3 U.S. study in sickle cell next year.

In beta-thalassemia, the biotech has already filed an application for approval in Europe and hopes to gain approval there in 2019.