Sickle Cell Disease Gene Therapy on Hold After Adverse Events

John F. Tisdale, MD

Stakeholders have put a trial testing a modified human β-globin gene that produces gene therapy-derived anti-sickling hemoglobin HbAT87Q to treat sickle cell disease (SCD) on hold.

A team, led by John F. Tisdale, MD, Cellular and Molecular Therapeutics Branch NHLBI, National Institutes of Health, updated the phase 1/2 HGB-206 study evaluating the efficacy and safety of LentiGlobin for SCD (bb1111) gene therapy, saying as of February the trial was suspended due to a pair of Suspected Unexpected Serious Adverse Reactions (SUSARs).

The update was presented as new data at the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting.

The study included patients with sickle cell disease and recurrent severe vaso-occlusive events, such as acute episodes of pain and acute chest syndrome (ACS). Each patient was infused with LentiGlobin, CD34+ cells collected by plerixafor mobilization/ apheresis and transduced with BB305 LVV, following myeloablative busulfan conditioning.

The investigators monitored laboratory evaluations, sickle cell disease-related outcomes, and adverse events.

As of 3 March 2020, 40 Group C patients (23.5 [12–38] years) began cell collection, with 25 patients treated with LentiGlobin and followed for 12.1 (2.8–24.8) months. Each patient stopped RBC transfusions by 90 days following treatment and in 16 evaluable patients with more than 6 months of follow up the median total Hb at last visit was 11.5 (9.6–16.2) g/dL, with HbAT87Q contribution of 5.2 (2.7–9.4) g/dL, HbS of 6.1 (4.9–7.8) g/dL, and median HbS ≤60% of total Hb.

For the 14 patients with at least 6 months of follow-up, as well as a history of vaso-occlusive crisis (VOC) or ACS, the annualized the annualized VOC+ACS rate was 4.0 (2.0–14.0) in the 2 years before treatment.

There were also no ACS or serious VOCs observed following treatment.

However, a nonserious Grade 2 VOC occurred about 3.5 months following treatment, resulting in a 99.5% (95% CI, 92.4–100%) mean reduction in the annualized VOC+ACS rate post-treatment.

The most common nonhematological grade ≥3 adverse events post-treatment were stomatitis (n = 15) and febrile neutropenia (n = 11).

The serious adverse events in at least 2 patients following treatment were nausea, opioid withdrawal syndrome, and vomiting (all n = 2).

In addition, 3 patients had nonserious Grade ≤2 adverse events related to LentiGlobin treatment.

There was also 1 death, which was unlikely related to treatment, that occurred more than 18 months post-treatment in a patient with significant baseline sickle cell disease burden and beyond the reported data-cut, 2 SUSARs were reported.

Also, 1 Group C patient had persistent anemia 6 months following transplantation. That care is still being investigated. In Group A, which is not being reported in the abstract, 1 patient treated more than 5 years ago had acute myeloid leukemia.

“LentiGlobin for SCD GT results in near pancellular βA-T87Q expression, reduced HbS, and increased total Hb. Complete resolution of VOC/ACS was observed in nearly all patients,” the authors wrote. “The safety profile post-LentiGlobin remains generally consistent with risk of autologous stem cell transplant, myeloablative conditioning, and underlying SCD.”

The study, “Updated Results from HGB-206 LentiGlobin for Sickle Cell Disease Gene Therapy Study: Group C Data and Group A AML Case Investigation,” was published online in Molecular Therapy.