Stem Cell Transplant for Sickle Cell Disease

(PRECIZN-1 Trial)

No longer 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a promising new treatment called BIVV003 for individuals with severe Sickle Cell Disease (SCD). Researchers aim to determine if this stem cell therapy is safe and effective in reducing SCD symptoms. Participants will receive a special type of stem cell transplant following initial treatments to prepare their bodies. This trial may suit those diagnosed with severe SCD who experience frequent pain crises, have had strokes, or require regular blood transfusions. As a Phase 1/Phase 2 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its safety and effectiveness in symptom reduction.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that BIVV003 is well-tolerated in studies involving individuals with Sickle Cell Disease. So far, seven participants have received BIVV003, and five did not experience any serious problems. This treatment uses a person's own stem cells, reducing the risk of rejection. Some participants experienced mild side effects, but these were manageable and temporary. This suggests the treatment appears safe, though ongoing studies continue to assess its long-term effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for sickle cell disease, which often rely on managing symptoms with medications like hydroxyurea or blood transfusions, BIVV003 targets the genetic root of the disease. This treatment uses autologous stem cells that are specifically edited with zinc finger nucleases to modify the BCL11A gene, aiming to increase fetal hemoglobin production and reduce sickling of red blood cells. Researchers are excited because this approach could potentially offer a one-time treatment that addresses the underlying cause of sickle cell disease, rather than just alleviating symptoms.

What evidence suggests that this treatment might be an effective treatment for Sickle Cell Disease?

Research has shown that BIVV003, the treatment under study in this trial, may help treat severe sickle cell disease (SCD). This treatment uses gene editing to activate fetal hemoglobin, which helps prevent red blood cells from sickling. Early results from a study found that BIVV003 was safe for participants and increased their levels of fetal hemoglobin. This increase might reduce problems linked to SCD. The treatment employs a gene-editing tool called zinc finger nucleases to target specific parts of the DNA in stem cells. These promising results suggest that BIVV003 could help ease SCD symptoms. ^{1 2 3 6 7}

Who Is on the Research Team?

Medical Monitor

Principal Investigator

Sangamo Therapeutics

Are You a Good Fit for This Trial?

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

Platelet count of less than 100,000 per microliter

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. sangamo.com sangamo.com/wp-content/uploads/2022/12/22-1566-ASH-BIVV003-Phase-I-II-Interim-results_v6.pdf

Interim Safety and Efficacy Results From a Phase 1/2 Study ... There may have been insufficient suppression of endogenous erythropoiesis in this subject in the weeks prior to the BIVV003 infusion and/or the ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03653247

NCT03653247 | A Study to Assess the Safety, Tolerability, ... A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell ...

3. nature.com nature.com/articles/s41598-024-74716-7

Zinc finger nuclease-mediated gene editing in ... Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12445678/

Hematopoietic stem cell therapy with gene modification to ... Zinc finger nuclease-mediated gene editing in hematopoietic stem cells results in reactivation of fetal hemoglobin in sickle cell disease.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121048680

An Ongoing Phase 1/2 Study on Zinc Finger Nuclease ... Sickle cell disease (SCD) is caused by pathologic variants in both alleles of the β-globin gene, affecting ~100,000 patients in the US (Strouse.

6. sangamo.com sangamo.com/programs/clinical-trials/sickle-cell-disease/

Sickle Cell Disease BIVV003 is a zinc finger nuclease (ZFN) gene-edited cell therapy candidate. BIVV003 is manufactured by ex vivo gene editing of a patient's own (autologous) ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9069474/

Gene therapy for sickle cell disease: moving from the bench to ... To date, clinical trials of gene addition have focused primarily on ex vivo gene modification, primarily because of improved feasibility, safety, and efficacy ...