Sangamo Joins Companies Halting Sickle Cell Gene-edited Cell Therapy Programs

Sangamo Therapeutics has announced its decision to cease further material investments in the development of BIVV003, an investigational zinc finger nuclease gene-edited cell therapy intended to treat sickle cell disease (SCD), beyond those necessary to complete the ongoing phase 1/2 PRECIZN-1 clinical trial (NCT03653247).¹

The decision comes several months after positive data from a patient who received BIVV003 “manufactured using improved methods” were presented at the 64th American Society of Hematology (ASH) Annual Meeting, held December 10-12, 2022, in New Orleans, Louisiana. The results included the patient reaching fetal hemoglobin levels of 45% and a total hemoglobin level of 12.4 g/dL at 26 weeks post-treatment. While a phase 3 clinical trial plan and chemistry, manufacturing, and controls package were agreed upon with the FDA, Sangamo Therapeutics has made the decision to redirect its resources towards 2 of its other phase 1/2 programs, isaralgagene civaparvovec (formerly ST-920) and TX200, and announced its intention to seek a partner to continue development of BIVV003 beyond the PRECIZN-1 trial. Isaralgagene civaparvovec is an adeno-associated virus (AAV) vector-based gene therapy being evaluated in the STAAR clinical trial (NCT04046224) for the treatment of Fabry disease and TX200 is an autologous chimeric antigen receptor T-regulatory cell (CAR-Treg) therapy being evaluated in the STeadfast clinical trial (NCT04817774) for the prevention of immune-mediated rejection in patients receiving HLA-A2 mismatched kidney transplantation.^2,3

“2022 was a year of important clinical and non-clinical milestones across our pipeline,” Sandy Macrae, chief executive officer, Sangamo Therapeutics, said in a February 22, 2023, statement.¹ “We strengthened that momentum today by releasing compelling data from our phase 1/2 Fabry disease study, supporting a potential best-in-class product profile. In 2023, wise resource allocation is our top priority, as we focus on advancing our wholly owned Fabry program, CAR-Treg portfolio and epigenetic regulation programs in the central nervous system, alongside progression of our Zinc Finger platform and AAV delivery capabilities. We look forward to sharing additional pipeline and delivery milestones in 2023 as we continue to strive to deliver for patients in need.”

Sangamo Therapeutics is not the only company that has recently halted development of an SCD gene-edited cell therapy. On February 22, 2023, Graphite Bio announced that it is discontinuing development of its lead program, the autologous CD34+ hematopoietic stem cell gene-editing therapy nulabeglogene autogedtemcel (nula-cel; formerly known as GPH-101).^4,5 The announcement came less than 2 months after the company announced that it had paused the phase 1/2 CEDAR clinical trial (NCT04819841), which was evaluating nula-cel, in relation to an unexpected serious case of prolonged pancytopenia in 1 of the treated patients that required ongoing transfusion and growth factor support. The company has announced its intention to seek a partner to continue development of nula-cel.

Meanwhile, Intellia announced on February 23, 2023, that its partner Novartis had opted to discontinue development of OTQ923, an investigational autologous genome-edited hematopoietic stem and progenitor cell (HSPC) therapy for SCD.⁶ OTQ923, which uses an ex vivo editing approach, was being evaluated in a phase 1/2 clinical trial (NCT04443907). Intellia, noting the need for bone marrow transplantation as a drawback of the ex vivo editing approach, stated that it is currently pursuing further development of its preclinical in vivo editing approach to treating SCD, which will not require bone marrow transplantation.

On the other hand, Vertex Pharmaceuticals and CRISPR Therapeutics began a submission of a rolling biologics license applications (BLA) for exagamglogene autotemcel (exa-cel) late last year.⁷ Exa-cel is an autologous ex vivo CRISPR/Cas9 gene-edited HSPC therapy being evaluated for the treatment of both SCD and transfusion-dependent beta-thalassemia (TDT) across multiple clinical trials. Exa-cel has received regenerative medicine advanced therapy, fast track, orphan drug (OD), and rare pediatric disease designations for both SCD and TDT from the FDA.⁸ It also received OD designation from the European Commission and priority medicines designation from the European Medicines Agency for both SCD and TDT.

REFERENCES

1. Sangamo Therapeutics reports recent business highlights and fourth quarter and full year 2022 financial results. News release.Sangamo Therapeutics, Inc. February 22, 2023. Accessed March 3, 2023.https://investor.sangamo.com/news-releases/news-release-details/sangamo-therapeutics-reports-recent-business-highlights-and-5 

2. Sangamo Therapeutics. Isaralgagenecivaparvovec (formerly known as ST-920). Website. https://www.sangamo.com/programs/clinical-trials/fabry-disease/ 

3. Sangamo Therapeutics. TX200. Website. https://www.sangamo.com/programs/clinical-trials/renal-transplantation/ 

4. Graphite Bio announces process to explore strategic alternatives and corporate restructuring. News release Graphite Bio. Februrary 22, 2023. https://www.biospace.com/article/releases/graphite-bio-announces-process-to-explore-strategic-alternatives-and-corporate-restructuring/?keywords=Graphite+Bio

5. Graphite Bio announces voluntary pause of phase 1/2 CEDAR study of nulabeglogeneautogedtemcel (nula-cel) for sickle cell disease. News release. Graphite Bio, Inc. January 5, 2023. https://ir.graphitebio.com/press-releases/detail/84/graphite-bio-announces-voluntary-pause-of-phase-12-cedar 

6. Intellia Therapeutics announces fourth quarter and full-year 2022 financial results and highlights recent company progress.Intellia Therapeutics, Inc. News release. February 23, 2023. Accessed March 3, 2023. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fourth-quarter-and-full-year-5 

7. Vertex and CRISPR Therapeutics to present at the American Society of Hematology (ASH) annual meeting and exposition. News release. Vertex Pharmaceuticals Incorporated and CRISPR Therapeutics. December 10, 2022. Accessed March 3, 2023. https://news.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-present-american-society 

8. Vertex and CRISPR Therapeutics Announce Global exa-cel Regulatory Submissions for Sickle Cell Disease and Beta Thalassemia in 2022. News release. Vertex Pharmaceuticals. September 27, 2022. https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-global-exa-cel