Gene Therapy LentiGlobin Unlikely Cause of Blood Cancer in Early Trial, Bluebird Says

LentiGlobin, Bluebird Bio’s investigational gene therapy for sickle cell disease (SCD), is unlikely to be the cause of a blood cancer that arose in one of the patients who received the therapy in an early clinical trial, according to new analyses.

In February, Bluebird paused two clinical trials testing LentiGlobin — the Phase 1/2 HGB-206 (NCT02140554) and the Phase 3 HGB-210 (NCT04293185) — after it was reported that one of the patients who received the investigational therapy in HGB-206 developed acute myeloid leukemia (AML), a type of blood cancer. The decision was made as a safety precaution, due to the concern that LentiGlobin, more specifically the BB305 lentiviral vector it uses to deliver genetic material to patient cells, might have triggered the cancer.

At the time, the company also suspended the commercialization of betibeglogene autotemcel (marketed as Zyntegelo in Europe), a gene therapy for transfusion-dependent beta-thalassemia, which uses the same viral vector as LentiGlobin.

Now, the company has reported data from new analyses that indicated it is unlikely that the development of AML was caused by the investigational gene therapy.

“The data from our assessments provide important evidence demonstrating that it is very unlikely our BB305 lentiviral vector played a role in this case and we have shared with the FDA [U.S. Food and Drug Administration] that we believe these results support lifting the clinical holds on our β-thalassemia and sickle cell disease programs,” Philip Gregory, PhD, chief scientific officer at Bluebird, said in a press release.

SCD is caused by a mutation in the HBB gene. This leads to the production of a faulty version of hemoglobin, the protein that red blood cells use to transport oxygen throughout the body, which ultimately leads to defects in red blood cell functioning.

As a gene therapy, the overall aim of LentiGlobin is to deliver a modified non-mutated version of HBB to patient cells, to restore the production of a functional non-sickling version of hemoglobin. To achieve this, a patient’s hematopoietic stem cells — blood cell precursors found in the bone marrow — are removed, then genetically modified using an engineered viral vector, and finally introduced back into the patient through a stem cell transplant.

When the non-mutated version of HBB is introduced into a patient’s cells, the gene gets inserted into the genome, which encompasses all human genes. When this type of genetic insertion occurs, it is possible that other parts of the patient’s genome could be affected, which could theoretically lead to cancer.

However, the new analyses showed that the previously-reported case of AML is unlikely to be associated with the gene therapy.

Specifically, various analyses demonstrated that, in the cells of this patient, the HBB gene introduced via LentiGlobin had integrated into a gene called VAMP4.

“VAMP4 has no known association with the development of AML nor with processes such as cellular proliferation or genome stability,” Gregory said.

Additional analyses also demonstrated that the integration of the HBB gene into VAMP4 did not disrupt the activity of other nearby genes.

These findings, along with previously announced data demonstrating the patient had multiple mutations in genes that had been associated with the development of AML, including RUNX1 and PTPN11, led Bluebird to conclude that LentiGlobin was likely not to blame for the onset of cancer in this patient.

Bluebird was also notified in February about a trial participant suspected of having myelodysplastic syndrome (MDS), another type of blood cancer. Analyses to determine whether this patient actually has MDS — and, if so, whether the MDS is related to LentiGlobin — are ongoing, according to Bluebird.