DMC rules phase III FREEDOM-1 study of FCR 001 in kidney transplant may continue after reported death

On October 18, 2022, the Company received a report of a patient death, which triggered a pre-specified, temporary stopping requirement and review by the FREEDOM-1 Data Monitoring Committee (DMC). After their review of this case, the DMC determined that trial enrollment and dosing may continue. The Company has reported this event and the DMC’s recommendation to the FDA. The deceased patient was one of three study subjects reported in June 2022 to have been diagnosed with grade II acute graft-vs-host disease (aGvHD). As reported, this patient was also diagnosed with moderate chronic GvHD that was responding to treatment at the time of the update. The patient was recently hospitalized with grade IV GvHD that was complicated by serious infections leading to respiratory and renal failure, and ultimately death.

The deceased patient had a related, same-sex donor with an HLA mismatch of 2/6. Although plerixafor was not used to mobilize this donor, the starting FCR001 material contained a high number of CD34+ cells and total nucleated cells, both of which had been identified by the Company during its review as factors that correlated with an increased risk of GvHD. The patient had not received a second post-transplant dose of cyclophosphamide as the patient was treated prior to the June 2022 protocol amendment. At the date of this update, the other two FREEDOM-1 patients who were previously reported to have had grade II aGvHD have experienced complete resolution of their aGvHD symptoms, although one patient experienced additional flares that were also responsive to treatment. After reviewing the facts of this case, the DMC concluded that the FREEDOM-1 protocol modifications implemented in June 2022 should be sufficient to mitigate the risk of GvHD going forward, and recommended continuation of the study without further modifications.

In June 2022, the Company provided a clinical update on its FREEDOM-1 study and summarized an amendment to the trial protocol following a review of all GvHD cases to date, spanning its Phase II and Phase III studies. The Company reported that the incidence of GvHD in FCR 001 subjects was correlated with high CD34+ cell counts and high total nucleated cell counts in the FCR 001 product. It also noted a correlation between the use of plerixafor as a donor mobilizing agent and an increased risk of GvHD, as plerixafor significantly increased CD34+ and total nucleated cell counts in the FCR001 product.

The Company introduced two risk mitigation measures for GvHD in the amended trial protocol: elimination of plerixafor as a donor mobilizing agent, and addition of a second post-transplant dose of cyclophosphamide, which has been demonstrated to reduce the risk of severe GvHD in haplo-identical allogeneic hematopoietic stem cell transplants.