The State of Gene and Cell Therapy for Sickle Cell Disease

This article was orginally published in GeneTherapyLive.

Among the myriad of conditions benefitting from blood donation is sickle cell disease (SCD), in which cell and gene therapies are currently being evaluated as possible avenues of treatment. Research into cell and gene therapies for SCD is especially important right now, with blood supply shortages prompting the Red Cross to declare its first ever blood crisis this January.1 Since January is National Blood Donor Month, we’ve compiled the latest updates on cell and gene therapies in development for SCD.

ARU-1801

Aruvant Sciences is currently evaluating ARU-1801, a modified γ-globin lentiviral gene-edited cell therapy in the phase 1/2 Momentum study (NCT02186418). Data presented at the 63rd Annual American Society of Hematology (ASH) Meeting, December 11-14, 2021, by Punam Malik, MD, director, Cincinnati Comprehensive Sickle Cell Center; program leader, Hematology and Gene Therapy Program; and Marjory J. Johnson Chair, Gene and Cell Therapy, Cincinnati Children’s Medical Hospital, demonstrated the therapy’s promising safety and efficacy in SCD.2

The trial has treated 4 patients as of July 28, 2021, all of which have experienced stable HbF expression and improved SCD manifestation and greatly decreased instances of vaso-occlusion events from baseline. Patients have experienced adverse events (AEs) such as transient neutropenia and thrombocytopenia. ARU-1801 has received rare pediatric disease and orphan drug designations from the FDA.

BIVV003/SAR445136

Sangamo Therapeutics is developing BIVV003/SAR445136, a zinc finger nuclease gene-edited cell therapy candidate. The candidate was previously being developed in collaboration with Sanofi, who announced the collaboration’s termination in January 2022 to take effect in June 2022.3 The phase 1/2 PRECIZN-1 study (NCT03653247) will be completed as planned and Sangamo is currently seeking another collaborative partner to develop the cell therapy.

Sangamo previously reported positive tolerability and durability data on SAR445136 from the PRECIZN-1 study at the 2021 ASH meeting.4 All 4 treated patients no longer required blood transfusions after infusion with SAR445136 and total hemoglobin stabilized in these patients by week 26. In all 4 patients, the cell therapy had on-target BCL11A gene modification, and fetal hemoglobin and percent F cells were significantly increased at up to 91 weeks from screening levels.

Lovotibeglogene autotemcel

The turbulent development oflovotibeglogeneautotemcel(bb1111; lovo-cel; LentiGlobin) by bluebird bio has hit another bump in the road, with the FDA placing the program on partial clinical hold in December 2021 following a report of persistent anemia in an adolescent patient.5 It is the second clinical hold for the program, the first of which was lifted in June 2021 after the company demonstrated that their lentiviral vector was not associated with patients developing acute myeloid leukemia and myelodysplastic syndrome. 

Lovotibeglogene autotemcel is currently being evaluated in the phase 3 HGB-210 study (NCT04293185) and previous positive efficacy data has been presented from the phase 1/2 HGB-206 study (NCT02140554).6 The gene therapy has been granted orphan drug, fast track, regenerative medicine, and rare pediatric disease designations by the FDA.

CTX001

CTX001 is being developed by Vertex Pharmaceuticals and CRISPR Therapeutics, with Vertex taking the lead in developing and commercializing the CRISPR/Cas9-based gene editing candidate for the potential treatment of both SCD and β-thalassemia.7 It is currently being evaluated for efficacy and safety in SCD in the phase 1/2/3 CLIMB SCD-121 study (NCT03745287).

Results from the phase 1/2 study were presented at the European Hematology Association Annual Meeting, June 9-17, 2021. Seven patients with severe SCD were free of vaso-occlusion events after treatment for at least 3 months to up to a year of follow-up. Patients had clinically meaningful improvements in total hemoglobin and fetal hemoglobin levels, and no treatment-related AEs were reported.8 The gene therapy has been granted regenerative medicine, fast track, and orphan drug designations by the FDA.

GPH101

Graphite Bio’s GPH101 is being evaluated in the phase 1/2 CEDAR trial (NCT04819841). Details on the trial were presented at ASH 2021.9 The first patient in the study has been enrolled and preliminary data will be presented at the end of 2022. The trial is primarily assessing safety and secondary outcomes include pharmacodynamics and efficacy measures such as levels of adult hemoglobin (HbA), sickle hemoglobin (HbS), total hemoglobin and VOEs, and acute chest syndrome.

The autologous CD34+ hematopoietic stem cell therapy was developed using Graphite’s next-generation, targeted, Cas9 gene integration platform. GPH101 previously demonstrated a reduction in HbS production and restored HbA expression in preclinical studies. The candidate has been granted orphan drug designation by the FDA.

BEAM-101/BEAM-102

The FDA recently cleared Beam Therapeutics’ investigational new drug application (IND) for BEAM-101, a CRIPSR, ex vivo base editing autologous cell therapy product for the potential treatment of both SCD and β-thalassemia.13 The therapy will be evaluated in the phase 1/2 BEACON-101 trial.

Beam is also developing another base editing candidate for SCD called BEAM-102, which they have initiated IND-enabling studies for. BEAM-101 makes single base changes without double strand DNA breakage to mimic single nucleotide polymorphisms seen in SCD and β-thalassemia while BEAM-102 directly corrects the SCD causative mutation by recreating HbG Makassar.

Drepaglobe

The Assistance Publique - Hôpitaux de Paris isconducting the phase 1/2 Drepaglobe trial (NCT03964792) of the titular cell therapy, which consists of autologous CD34+ cells transduced ex vivo with the GLOBE1 lentiviral vector expressing the βAS3 globin gene.

Results from the Drepaglobe trial were presented at ASH 2021 by Elisa Magrin, PharmD, Assistance Publique-Hôpitaux de Paris.10 Three treated patients with follow-up of at least 6 months showed no serious treatment-related AEs. Investigators found that 2 patients clinically benefitted from treatment, but the third did not due to engraftment issues. The observed variable efficacy of the treatment puts its future into question and further research and analysis to define critical parameters for success is needed.

βAS3-FB Vector Transduced Peripheral Blood CD34+ Cells

The UCLA Broad Stem Cell Research Center, in collaboration with the California Institute for Regenerative Medicine, is conducting a phase 1/2 clinical trial (NCT02247843) of a cell therapy candidate consisting of autologous, βAS3-FB vector-transduced peripheral blood CD34+ cells.11 The trial is currently recruiting up to 6 participants with SCD.

The study’s primary objectivesare to assess safety and feasibility, and its secondary objectives are to assess efficacy by measuring engraftment, βAS3-globin gene expression, red blood cell function, and clinical hematologic and disease parameters. Participants will be followed up every 3 months for 2 years and then as part of a long-term follow-up study for 15 years.

CD34+ BCH-BB694 Lentiviral Vector Cells with BCL11A-Targeted shRNA in MicroRNA

Boston Children’s Hospital is conducting a phase 1 study (NCT03282656) of a cell therapy consisting of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA. The study is currently recruiting up to 15 participants with SCD.

Results were published in January 2021 that demonstrated positive engraftment results and a tolerable safety profile.12 All evaluable patients had robust and stable HbF induction and reduced clinical manifestations of SCD.

REFERENCES

1. Red Cross declares first-ever blood crisis amid Omicron surge. News release. American Red Cross. January 11, 2022. https://www.redcross.org/about-us/news-and-events/press-release/2022/blood-donors-needed-now-as-omicron-intensifies.html
2. Grimley M, Asnani M, Shrestha A, et al. Safety and efficacy of Aru-1801 in patients with sickle cell disease: Early results from the phase 1/2 Momentum study of a modified gamma globin gene therapy and reduced intensity conditioning. Presented at: 63rd Annual ASH Meeting; December 11-14, 2021, Atlanta, GA. Abstract 3970.
3. Sangamo announces transition of SAR445136 sickle cell disease program from Sanofi to Sangamo. News release. Sangamo Therapeutics. January 6, 2022. https://investor.sangamo.com/news-releases/news-release-details/sangamo-announces-transition-sar445136-sickle-cell-disease
4. Sangamo Therapeutics announces updated preliminary SAR445136 phase 1/2 proof-of-concept data showing tolerability and sustained effects in sickle cell disease. News release. Sangamo Therapeutics. December 12, 2021. https://investor.sangamo.com/news-releases/news-release-details/sangamo-therapeutics-announces-updated-preliminary-sar445136
5. bluebird bio Announces Partial Clinical Hold for Patients Under 18 in Sickle Cell Gene Therapy Clinical Program. News release. bluebird bio. December 20, 2021. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-partial-clinical-hold-patients-under-18
6. Walters MC, Thompson AA, Kwiatkowski JL, et al. Resolution of Serious Vaso-Occlusive Pain Crises: Results from the ongoing phase 1/2 HGB-206 group C study of lentiglobin for sickle cell disease (SCD; bb1111) gene therapy. Presented at: 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, February 8-12, 2021. Abstract 13.
7. Vertex Pharmaceuticals and CRISPR Therapeutics amend collaboration for development, manufacturing and commercialization of CTX001™ in sickle cell disease and beta thalassemia. News release. Vertex Pharmaceuticals. April 20, 2021. https://investors.vrtx.com/news-releases/news-release-details/vertex-pharmaceuticals-and-crispr-therapeutics-amend
8. Vertex and CRISPR Therapeutics present new data in 22 patients with greater than 3 months follow-up post-treatment with investigational CRISPR/Cas9 gene-editing therapy, CTX001™ at European Hematology Association Annual Meeting. News release. Vertex Pharmaceuticals. June 11, 2021. https://www.businesswire.com/news/home/20210611005069/en/
9. Graphite Bio presents overview of phase 1/2 CEDAR trial evaluating investigational gene editing therapy GPH101 in sickle cell disease at 63rd ASH Annual Meeting and Exposition. News release. Graphite Bio. December 11, 2021. https://www.businesswire.com/news/home/20211211005014/en/Graphite-Bio-Presents-Overview-of-Phase-12-CEDAR-Trial-Evaluating-Investigational-Gene-Editing-Therapy-GPH101-in-Sickle-Cell-Disease-at-63rd-ASH-Annual-Meeting-and-Exposition
10. Magrin E, Magnani A, Semeraro M, et al. Clinical results of the Drepaglobe trial for sickle cell disease patients. Presented at 63rd Annual ASH Meeting; December 11-14, 2021, Atlanta, GA. Abstract 1854.
11. Stem cell gene therapy for sickle cell disease. NIHUS National Library of Medicine. August 31, 2021. https://clinicaltrials.gov/ct2/show/NCT02247843
12. EsrickEB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med 2021; 384:205-215. doi: 10.1056/NEJMoa2029392
13. Beam Therapeutics provides business and pipeline updates and reports third quarter 2021 financial results. News release. November 8, 2021. https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-provides-business-and-pipeline-updates-and-0