Trial of Cell Therapy to Raise HbF Levels Showing Potential, But Sanofi Leaving

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by Patricia Inacio PhD |

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Sangamo Therapeutics is assuming all rights to SAR445136, an investigational gene-edited cell therapy co-developed with Sanofi and now in a Phase 1/2 trial in adults with severe sickle cell disease (SCD).

Early trial data support the therapy’s safety and tolerability, and its effectiveness at raising levels of fetal hemoglobin in patients, the companies have announced.

Sanofi had been leading the Phase 1/2 PRECIZN-1 trial (NCT03653247) — with the therapy under that company’s assigned name of BIVV003 — as part of a cooperation agreement between the two pharmas. It decided in December to transition the rights and obligations for genomic therapies to Sangamo in a process that is expected to be completed by late June.

“We remain committed to progressing this program and believe SAR445136 has the potential to relieve people living with sickle cell disease of some of their most challenging symptoms. We appreciate Sanofi’s collaboration in advancing the SAR445136 program and presenting promising preliminary proof-of-concept clinical data,” Sandy Macrae, CEO of Sangamo, said in a press release.

PRECIZN-1, an open-label (no placebo group) study in adults, ages 18 to 40, with clinically stable but severe disease, is underway at six U.S. sites and will continue as planned, Sangamo stated.

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The trial is recruiting adults, ages 18 to 40, withz severe disease as defined by six or more pain crises requiring IV pain killer treatment in the two years prior to enrolling, or a “significant neurological event” like a stroke, among other complications. Site and contact information can be found here.

Sanofi is expected to cover the trial’s costs through June 28, when the collaboration agreement between the companies is set to end.

“We expect the Phase 1/2 study to be completed as planned, for final patients in the study to be dosed in the third quarter of 2022, and for discussions regarding potential future clinical trials to continue with health authorities,” Macrae added. “We will vigorously investigate alternative options to bring this genomic medicine forward to patients.”

Among the options Sangamo is considering is a new collaboration partner in advancing SAR445136.

SCD is caused by mutations in the HBB gene, which provides instructions for making part of hemoglobin, the protein that carries oxygen throughout the body.

These mutations lead to the production of a faulty version of hemoglobin — known as hemoglobin S — that causes normally oval-shaped red blood cells to assume a sickle-like shape. Sickled red blood cells fail to move readily through blood vessels and can block them, causing a painful vaso-occlusive crisis (VOC).

SAR445136 is designed to work via the modification of a short sequence of the BCL11A gene in red blood precursor cells, acquired from a patient’s own (autologous) hematopoietic stem cells (stem cells that give rise to other blood cells).

The therapy uses Sangamo’s proprietary ZFN gene editing technology to target the BCL11A gene, which normally switches off the production of fetal hemoglobin (HbF) in adults. HbF is a form of hemoglobin produced during fetal development that is more effective at transporting oxygen than its adult counterpart.

Restoring HbF production has shown promise in treating SCD by preventing red blood cells from taking on a damaging sickle-like shape.

Preliminary trial findings were shared in the poster — “Preliminary Safety and Efficacy Results from Precizn-1: An Ongoing Phase 1/2 Study on Zinc Finger Nuclease-Modified Autologous CD34+ HSPCs for Sickle Cell Disease (SCD)”— at the 2021 annual meeting of the American Society of Hematology (ASH).

As of the data cutoff date of Sept. 22, 2021, nine patients were enrolled and the target number of hematopoietic stem cells had been successfully collected from five of them. Two patients were unable to provide that target cell number, and one other patient left the trial.

Four patients — two male and two female African-Americans, ages 18–35 — received a one-time infusion of their hematopoietic stem cells after genetic modification. In the two years before enrolling in the study, three of the four had between six and 22 pain crises.

Following infusion, all four showed higher levels of total hemoglobin, HbF, and the percentage of red blood cells containing HbF (called F-cells), the researchers reported. None required a blood transfusion.

Their percentage of HbF at the trial’s start ranged from 1–11%, and increased to 15–29% at 13 weeks post-infusion. In the three patients followed for at least 26 weeks, HbF levels increased by 14–39%.

During this period, F-cell counts rose by 48–94%. One patient showed a persistent increase of 38% of HbF levels and a 99% increase in F-cells at 81 weeks post-infusion.

A serious VOC was reported in one patient about nine months after the infusion, but no other disease-related events were found in this group.

Most side effects reported after SAR445136 infusion were related to busulfan, the researchers reported. This chemotherapy agent is given pre-infusion to destroy blood stem cells in the bone marrow in preparation for the genetically modified blood stem cells.

Preliminary results in this small patient group also showed a trend of improvement across most domains of the Patient-Reported Outcome Measurement System (PROMIS)-57, a patient-reported health-related quality of life.

“Although the preliminary Phase 1/2 clinical data for the autologous sickle cell treatment are encouraging, Sanofi has made the decision to terminate the collaboration on the SAR445136 program, which is consistent with our strategy to focus on universal genomic medicine approaches,” said John Reed, MD, PhD, global head of research and development at Sanofi.

“Sangamo has been a good partner and this decision is not a reflection on the potential of the SAR445136 program. We continue to view them as a pioneer in the area of genomic medicines and will explore other possible collaboration opportunities as we work together to transition the autologous sickle cell program back to Sangamo,” Reed added.

SAR445136 was given fast track designation by the U.S. Food and Drug Administration and orphan medicinal product status by the European Medicines Agency.

PRECIZN-1 is due to conclude in May 2024.