Stem Cell Transplant for Sickle Cell Disease

(PRECIZN-1 Trial)

Recruiting at 4 trial locations

Overseen By Medical Monitor

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Bioverativ, a Sanofi company

Must not be taking: Prohibited medications

Disqualifiers: Organ dysfunction, Active malignancy, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

8 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label, multicenter, Phase 1/2 study in approximately eight adults with severe Sickle Cell Disease (SCD). The study will evaluate the safety, tolerability, and efficacy of autologous hematopoietic stem cell transplantation using BIVV003.

Will I have to stop taking my current medications?

Participants must stop taking hydroxyurea (a medication used to treat sickle cell disease) at least 30 days before starting stem cell mobilization and continue to avoid it until 100 days after the transplant. The protocol does not specify other medications, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the treatment BIVV003 for sickle cell disease?

Research shows that stem cell transplants, like the one involving BIVV003, have been effective in treating sickle cell disease, with a high disease-free survival rate of 80-85% in patients. The best outcomes are seen in young children with matched sibling donors, achieving a 93% disease-free survival rate. ^{1 2 3 4 5}

Is stem cell transplant for sickle cell disease safe?

Stem cell transplants for sickle cell disease have shown some safety concerns, such as a 28% rate of acute graft-versus-host disease (a condition where the donor cells attack the recipient's body) and a 34% incidence of posterior reversible encephalopathy syndrome (a temporary condition affecting the brain) in one study. While these treatments can be effective, they are not yet considered safe enough for widespread use without further improvements. ^{6 7 8 9 10}

How is the treatment BIVV003 for sickle cell disease different from other treatments?

BIVV003 is a novel treatment for sickle cell disease that involves stem cell transplantation, which is currently the only curative option for this condition. Unlike traditional treatments that manage symptoms, stem cell transplantation aims to replace the defective blood-forming cells with healthy ones, potentially offering a long-term cure. ^{1 4 11 12 13}

Research Team

Medical Monitor

Principal Investigator

Sangamo Therapeutics

Eligibility Criteria

Adults aged 18-40 with severe Sickle Cell Disease (SCD) who are clinically stable for stem cell mobilization and transplantation. They must have a history of significant SCD complications, adequate organ function, and agree to contraception use. Excluded are those with contraindications to the drugs used, previous transplants, certain heart conditions, or active infections.

Inclusion Criteria

I have severe sickle cell disease with major symptoms or complications.

I have completed all my cancer screenings recommended for my age.

I have been diagnosed with sickle cell disease.

Exclusion Criteria

Current enrollment in an interventional study or recent receipt of an investigational drug

Known allergy or hypersensitivity to specific medications or investigational product excipients

I have had cancer or a blood cancer in the last 5 years, or my family has a history of cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Participants receive plerixafor followed by myeloablative conditioning therapy with busulfan, and then BIVV003 is administered as a 1-time IV infusion

Up to Day 42

Post-transplantation Monitoring

Participants are monitored for safety, efficacy, and engraftment success post-transplantation

104 weeks

Long-term Follow-up

Participants are asked to participate in a separate long-term follow-up study to monitor safety and efficacy for a total of 15 years post-transplant

Treatment Details

Interventions

• BIVV003

Trial Overview The trial is testing BIVV003 in combination with Plerixafor and Busulfan for autologous hematopoietic stem cell transplantation in patients with severe SCD. It aims to assess safety, tolerability, and effectiveness of this treatment approach.

Participant Groups

Group I: BIVV003 Experimental Treatment 3 Interventions

Participants will receive plerixafor as subcutaneous (SQ) administration followed by myeloablative conditioning therapy with intravenous (IV) busulfan. BIVV003 will then be administered as a 1-time IV infusion of autologous Cluster of Differentiation 34 + Hematopoietic Stem/Progenitor Cell (CD34+HSPC) transfected ex vivo with zinc finger nuclease (ZFN) messenger ribonucleic acid (mRNAs) targeting the B-cell lymphoma/leukemia 11A (BCL11A) locus.

Who Is Running the Clinical Trial?

Bioverativ, a Sanofi company

Lead Sponsor

Trials

18

Recruited

1,000+

Sangamo Therapeutics

Lead Sponsor

Trials

29

Recruited

950+

Findings from Research

Bone marrow transplantation has shown potential as a treatment for sickle cell anemia, as demonstrated by an 8-year-old girl who successfully transitioned from sickle cell anemia to the donor's sickle cell trait after the procedure.

Despite the promising results, the use of bone marrow transplantation for sickle cell anemia is limited by significant immunological complications, particularly graft-vs.-host disease, which poses challenges for broader application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow transplantation in the treatment of sickle cell anemia. Johnson, FL.[2019]

A novel nonmyeloablative HLA-haploidentical peripheral blood stem cell transplantation (PBSCT) approach showed promising results in 21 patients with sickle cell disease (SCD), with an overall survival rate of 87% and no transplant-related mortality.

The use of posttransplant cyclophosphamide (PT-Cy) significantly improved engraftment rates from 33% to 83% across three cohorts, while effectively preventing severe graft-versus-host disease (GVHD), indicating a safer and more effective treatment option for patients with severe organ damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT. Fitzhugh, CD., Hsieh, MM., Taylor, T., et al.[2019]

The BCH-BB694 lentiviral vector effectively reactivates fetal hemoglobin production while reducing harmful adult sickle hemoglobin in sickle cell disease, showing a 3- to 5-fold increase in fetal hemoglobin levels in transduced cells.

Preclinical studies indicate that BCH-BB694 is non-toxic and can be produced at a clinically relevant scale, supporting its potential for safe and effective use in human trials for treating sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. Brendel, C., Negre, O., Rothe, M., et al.[2020]

Targeted marrow irradiation (TMI) at a dose of 8 Gy to the bone marrow and 2 Gy to the rest of the body shows promise as a safer alternative to traditional total body irradiation (TBI) for hematopoietic stem cell transplant in sickle cell disease, resulting in reduced organ damage and better donor cell engraftment.

In a preclinical study using a sickle cell mouse model, TMI led to successful long-term engraftment and significant recovery of sickle cell disease features, including improved red blood cell counts and vascular health, indicating its potential efficacy in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and characterization of a preclinical total marrow irradiation conditioning-based bone marrow transplant model for sickle cell disease. Sargur Madabushi, S., Fouda, R., Ghimire, H., et al.[2022]

Hematopoietic stem cell transplantation is currently the only curative treatment for severe sickle cell anemia, with over 85% of 250 patients worldwide surviving free of the disease and enjoying a good quality of life.

The main challenge in this treatment is finding an HLA-identical sibling donor, and while graft-versus-host disease (GvHD) is a significant complication, the use of myeloablative conditioning and immunosuppressive medication helps manage this risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hematopoietic stem cell transplantation for severe sickle cell disease]. Klein, A., Brachet, C., Azzi, N., et al.[2006]

References

1. United States pubmed.ncbi.nlm.nih.gov

Bone marrow transplantation for sickle cell anemia. [2004]

2. United States pubmed.ncbi.nlm.nih.gov

Bone marrow transplantation in the treatment of sickle cell anemia. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation in sickle cell disease. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Busulfan-fludarabine- or treosulfan-fludarabine-based conditioning before allogeneic HSCT from matched sibling donors in paediatric patients with sickle cell disease: A study on behalf of the EBMT Paediatric Diseases and Inborn Errors Working Parties. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Development and characterization of a preclinical total marrow irradiation conditioning-based bone marrow transplant model for sickle cell disease. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Clinical outcomes following bone marrow transplantation in patients with sickle cell disease: A cohort study of US Medicaid enrollees. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Pediatric sickle cell disease: past successes and future challenges. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Stem cell transplantation for treatment of sickle cell disease: bone marrow versus cord blood transplants. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem-cell transplantation for sickle cell disease. [2022]

13. Belgium pubmed.ncbi.nlm.nih.gov

[Hematopoietic stem cell transplantation for severe sickle cell disease]. [2006]