FDA Puts Clinical Holds on Trials of BPX-501

The FDA has halted 4 US studies of BPX-501, a novel cellular immunotherapy for cancers and orphan inherited blood disorders, after 3 patients developed encephalopathy possibly related to treatment with BPX-501.

Bellicum Pharmaceuticals is currently conducting 4 phase I/II clinical trials of BPX-501 in the United States:

• BP-001 and BP-005: adults with hematological cancers in which BPX-501 is administered after initial allogeneic hematopoietic stem cell transplantation (HSCT);
• BP-003: children with orphan inherited blood disorders in which BPX-501 is administered after initial allogeneic HSCT;
• BP-008: adults and children with blood cancers to treat post-transplant relapse and evaluate the potential for a titrated dose of rimiducid to resolve uncontrolled graft-versus-host disease (GVHD) while preserving BPX-501 cells.

The company reported in a press release that the clinical hold does not affect its European BP-004 trial exploring BPX-501 following initial allogeneic HSCT in children with hematological cancers or orphan inherited blood disorders.

BPX-501 is an adjunct T-cell therapy administered after allogeneic HSCT, comprising genetically modified donor T cells incorporating Bellicum’s CaspaCIDe safety switch. It is designed to provide a safety net to eliminate alloreactive BPX-501 T cells in the event of uncontrollable GVHD.

Bellicum says it has treated more than 240 patients with BPX-501 in 3 allogeneic haploidentical stem cell transplantation studies.

“These 3 cases [of encephalopathy] are complex, with a number of potential confounding factors—including, in certain of the cases, prior failed transplants, prior history of immunodeficiency, concurrent infection, and administration of rimiducid in combination with other medications,” the company said. “Bellicum is working with FDA to evaluate the risk of encephalopathy in patients receiving BPX-501.”

The company added that it is awaiting formal communications from the FDA to determine the requirements for resuming studies. The FDA granted BPX-501 an orphan drug designation in February 2016.

Results for BPX-501 from the BP-004 study were presented at 2017 ASH Annual Meeting in December.

In that study, investigators evaluated immune recovery and outcomes of 112 pediatric patients who underwent a haplo-HSCT followed by treatment with BPX-501. Children in the study had acute leukemia (n = 53), primary immune deficiencies (n = 26), erythroid disorders (n = 17), Fanconi anemia (n = 7), and other diseases (n = 9).

All patients were transplanted after depletion of donor alpha/beta T cells and CD19 B cells to prevent GVHD and post-transplant lymphoproliferative disorders. BPX-501 cells were scheduled to be infused approximately 2 weeks’ post-transplant.

Twenty-four months after haplo-HSCT, investigators found that BPX-501 cells expanded progressively, peaking at 9 months after the allograft with a mean value was 144+36/μL. In the 16 patients with 2-year follow-up, the mean number of BPX-501 cells was still 62+23/μL.

Cytomegalovirus (CMV) infection was a main driver of BPX-501 cell expansion, which lead researchers to suggest that BPX-501 cells cooperate in clearing the viral infection. BPX-501 cell expansion occurred alongside improved recovery of both CD3+ and αβ T cells in patients who experienced CMV reactivation.

The overall pattern of immune recovery in the 112 children studied may be improved when compared to patients who received a similar haplo-HSCT without BPX-501, according to the investigators. Neither acute GVHD nor leukemia recurrence occurrence statistically affected the number of BPX-501 cells.

Merli P, Bertaina V, Galaverna F, et al. Donor T cells genetically modified with a novel suicide gene (inducible Caspase 9, iC9) expand and persist over time after post-allograft infusion in patients given αβ T-cell and B-cell depleted HLA-haploidentical allogeneic stem cell transplantation (αβ haplo-HSCT) contributing to accelerate immune recovery. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 211.