Motixafortide + Natalizumab for Sickle Cell Disease

No longer recruiting at 1 trial location

Overseen By Zachary D Crees, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: Immunosuppressants, TNF-α inhibitors

Disqualifiers: Prior HCT, Gene therapy, Infections, others

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

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to assist patients with sickle cell disease (SCD) who require more stem cells for gene therapy treatments. Researchers are testing whether two drugs, motixafortide (Aphexda) and natalizumab (Tysabri), can safely and effectively increase stem cell counts in the blood. The aim is to simplify and enhance stem cell collection for those with SCD. This trial may suit adults diagnosed with sickle cell disease who currently undergo regular red blood cell exchanges and can pause certain medications before starting the trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

Yes, you need to stop taking hydroxyurea, voxelotor, and/or crizanlizumab for at least 60 days before mobilization, and iron chelation for at least 7 days before mobilization.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that motixafortide is safe for people with sickle cell disease (SCD). It increases the number of stem cells in the blood, which is crucial for gene therapy. Research indicates that motixafortide, whether used alone or with another drug called natalizumab, is generally well-tolerated.

Natalizumab has been studied for its long-term safety in other conditions. In these studies, fewer than 14% of patients experienced serious side effects, with infections being the most common. This suggests that natalizumab is relatively safe, though it does carry some risks.

Overall, both treatments have shown promise in being safe for people with SCD. However, since this is a Phase 1 trial, researchers continue to monitor for any safety issues and side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about motixafortide and natalizumab for sickle cell disease because they offer a novel approach to treatment. Most treatments for sickle cell disease focus on managing symptoms or preventing complications, like hydroxyurea and blood transfusions. Motixafortide stands out as it mobilizes hematopoietic stem cells, potentially reducing the frequency of painful crises. Natalizumab, on the other hand, is known for its ability to reduce immune system attacks, which could play a role in managing inflammation associated with sickle cell disease. Together, these drugs could offer a new way to address the disease's root causes, not just its symptoms.

What evidence suggests that this trial's treatments could be effective for sickle cell disease?

Research has shown that motixafortide, which participants in this trial will receive, can help increase the number of blood stem cells. In one study, 92% of donors reached the needed amount of stem cells for therapy with just one injection. This finding suggests motixafortide might be effective for patients with sickle cell disease (SCD) who require stem cells for gene therapy. Although data on using motixafortide with another drug, natalizumab, for SCD is limited, this trial will explore the potential of combining them to further increase stem cell numbers. Overall, the evidence for motixafortide is promising, but more research is needed on the combination treatment. ^{2 3 4 6 7}

Who Is on the Research Team?

Zachary D Crees, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

Adults aged 18-40 with sickle cell disease (hemoglobin SS or Sβ0 genotype), able to pause certain medications, and have specific health criteria like a platelet count of at least 75,000/uL. They must not be pregnant, agree to use contraception during the study and for three months after, and cannot have had previous gene therapies or certain immunosuppressants.

Inclusion Criteria

My bone marrow and organs are functioning normally.

Left ventricular ejection fraction (LVEF) ≥ 45%

AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN at time of screening

Exclusion Criteria

Patient may not have a history of significant alloantibodies which, in the opinion of the treating physician and study investigator, significantly increase the risk of participation in this clinical trial

I am currently taking drugs that suppress my immune system.

I have never had a stem cell transplant or gene therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive a single subcutaneous injection of motixafortide, followed by leukapheresis

8 weeks

1 visit (in-person) for injection and leukapheresis, followed by monitoring

Treatment Phase 2

Participants receive a single IV infusion of natalizumab, followed by a subcutaneous injection of motixafortide, then leukapheresis

8 weeks

1 visit (in-person) for infusion and injection, followed by leukapheresis and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Leukapheresis
• Motixafortide
• Natalizumab

Trial Overview The trial is testing Motixafortide and Natalizumab's ability to mobilize hematopoietic stem cells in preparation for gene therapy in sickle cell disease patients. It aims to see if these drugs can safely increase the number of stem cells available for treatment without unacceptable risks.

How Is the Trial Designed?

Group I: Motixafortide followed by Motixafortide + Natalizumab Experimental Treatment 3 Interventions

* Consenting and eligible patients will receive a single subcutaneous injection of motixafortide, followed by leukapheresis. Patient will then be followed for 8 weeks for adverse event monitoring. * Following the 8-week monitoring period, patients will receive a single IV infusion natalizumab, then approximately 32 hours later, a single subcutaneous injection of motixafortide, followed by leukapheresis. Patients will then be followed for 8 weeks for adverse event monitoring.

Leukapheresis is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Leukapheresis for:

• Acute myeloid leukemia (AML)
• Acute lymphoblastic leukemia (ALL)
• Chronic myeloid leukemia (CML)
• Hyperviscosity syndrome

Approved in United States as Leukapheresis for:

• Acute myeloid leukemia (AML)
• Acute lymphoblastic leukemia (ALL)
• Chronic myeloid leukemia (CML)
• Hyperviscosity syndrome

Approved in Canada as Leukapheresis for:

• Acute myeloid leukemia (AML)
• Acute lymphoblastic leukemia (ALL)
• Chronic myeloid leukemia (CML)
• Hyperviscosity syndrome

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Ayrmid Pharma

Collaborator

Biogen

Industry Sponsor

Trials

655

Recruited

468,000+

Daniel Quirk

Biogen

Chief Medical Officer

MD

Christopher A. Viehbacher

Biogen

Chief Executive Officer since 2022

Graduated from Queen's University, Kingston, Ontario, Canada

BioLineRx, Ltd.

Industry Sponsor

Trials

24

Recruited

2,200+

Published Research Related to This Trial

In a study of 242 patients with acute promyelocytic leukaemia (APL), those with hyperleucocytosis (high white blood cell count) had significantly lower complete remission rates (69% vs. 88%) and higher 4-week mortality (24% vs. 9%) compared to those without hyperleucocytosis.

Treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combined with cytotoxic therapy resulted in a 100% complete remission rate and overall survival for hyperleucocytosis patients, outperforming non-ATRA/ATO treatments, which had much lower success rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis. Daver, N., Kantarjian, H., Marcucci, G., et al.[2021]

Therapeutic leukapheresis in three patients with advanced hairy cell leukemia led to significant and lasting clinical and hematologic improvements, with benefits observed for over 23 to 26 months.

In contrast, plasmapheresis did not produce any noticeable therapeutic effects in two similar patients, suggesting that leukapheresis may effectively remove inhibitory factors affecting blood cell production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic leukapheresis in hairy cell leukemia. Mielke, CH., Dobbs, CE., Winkler, CF., et al.[2007]

In a study of 27 cancer patients undergoing stem cell collection after high-dose cyclophosphamide treatment, those who received granulocyte-macrophage colony stimulating factor (rhGM-CSF) showed significantly higher yields of mononuclear cells and granulocyte-macrophage colony forming units (CFU-GM) during leukapheresis.

The use of rhGM-CSF not only accelerated hematopoietic recovery but also allowed for more efficient collection of stem cells, with procedures being well tolerated and only minor side effects reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of recombinant human granulocyte-macrophage colony stimulating factor for large scale collection of peripheral blood stem cells for autologous transplantation. Ravagnani, F., Bregni, M., Siena, S., et al.[2006]

Motixafortide, a novel CXCR4 inhibitor, shows promise in rapidly mobilizing large numbers of hematopoietic stem and progenitor cells (HSPCs) for transplantation, potentially addressing the limitations of current mobilization regimens that often require multiple days of treatment and can lead to adverse effects.

Unlike granulocyte colony-stimulating factor (G-CSF), which can cause serious complications in certain patient populations, including those with sickle-cell disease, motixafortide preferentially mobilizes more primitive HSPCs and has a longer duration of action, making it a safer and more effective option for HSPC mobilization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Innovations in hematopoietic stem-cell mobilization: a review of the novel CXCR4 inhibitor motixafortide. Crees, ZD., Rettig, MP., DiPersio, JF.[2023]

In a study of 55 newly diagnosed multiple myeloma patients, single large volume leukapheresis using either G-CSF or G-CSF plus Plerixafor successfully achieved the primary stem cell yield target of ≥2×10^6 cells per kg in all cases.

The procedure was found to be safe and cost-effective, with manageable adverse reactions, and factors such as age and pre-apheresis CD34+ count significantly influenced the stem cell yield.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective identification of potential factors influencing stem cell mobilization and the necessity for plerixafor use in newly diagnosed multiple myeloma patients undergoing autologous stem cell transplantation. Ray, GK., Jena, RK., Panda, T., et al.[2021]

In a study of 47 patients with autoimmune hemolytic anemia (AIHA) who had inadequate bone marrow response, treatment with recombinant erythropoietin (rEPO) led to a significant increase in hemoglobin levels, with 91% of patients showing a response by 12 months.

rEPO treatment also reduced the need for blood transfusions from 30% to less than 10% within 15 days, demonstrating its efficacy as an adjunct therapy alongside standard immunosuppressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant erythropoietin in autoimmune hemolytic anemia with inadequate bone marrow response: a prospective analysis. Fattizzo, B., Pedone, GL., Brambilla, C., et al.[2023]

A patient with idiopathic myelofibrosis was successfully treated with HLA-identical platelet apheresis concentrates, maintaining platelet counts between 20 and 30 x 10(9)/L using crossmatched negative products.

Despite initial treatment, the patient developed refractoriness to haploidentical sibling platelets, and attempts to absorb platelet antibodies using Protein A columns were ineffective, indicating a complex immune mechanism at play.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of idiopathic myelofibrosis with alloimmunization to HLA-identical platelet transfusions not responsive to antibody absorption over protein-A columns. Menicucci, A., Di Pietro, G., Venturini, S., et al.[2019]

Motixafortide, a selective CXCR4 inhibitor, was approved in the USA on September 11, 2023, for mobilizing hematopoietic stem cells (HSCs) in combination with filgrastim for patients with multiple myeloma, marking a significant advancement in stem cell transplantation.

The drug has also received Orphan Drug Designation for treating pancreatic cancer and acute myeloid leukemia, and is being studied for mobilizing CD34+ HSCs for gene therapy in sickle cell disease, indicating its potential in various cancer treatments and therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motixafortide: First Approval. Hoy, SM.[2023]

Plerixafor is safe and well-tolerated in adult patients with sickle cell disease (SCD), effectively mobilizing hematopoietic stem cells (HSCs) for potential gene therapy, as demonstrated in a study involving 6 patients.

Using a standard dose of plerixafor (240 µg/kg) and an optimized apheresis protocol, researchers achieved high yields of CD34+ cells, which are crucial for HSC therapies, with counts reaching up to 24.5 × 10^6 cells/kg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients. Esrick, EB., Manis, JP., Daley, H., et al.[2021]

A 6-month-old boy with familial erythrophagocytic lymphohistiocytosis successfully underwent allogeneic bone marrow transplantation after achieving remission with Etoposide and prednisone, indicating the effectiveness of this pre-transplant treatment.

The conditioning regimen for the transplant was well tolerated, and the patient has remained in complete remission for over 10 months, demonstrating the potential long-term efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic Bone Marrow Transplantation for Familial Erythrophagocytic Lymphohistiocytosis, with High Dose VP16-Containing Conditioning Regimen. Todo, S., Fujiwara, F., Ikushima, S., et al.[2019]

In the GENESIS trial involving 122 adult patients with multiple myeloma, the combination of motixafortide and G-CSF significantly improved the collection of CD34+ hematopoietic stem and progenitor cells (HSPCs) for autologous stem cell transplantation, achieving a success rate of 92.5% compared to only 26.2% with placebo plus G-CSF.

Motixafortide was found to be safe and well tolerated, with mostly mild and transient side effects, indicating its potential as an effective and safe option for enhancing HSPC mobilization in patients undergoing treatment for multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial. Crees, ZD., Rettig, MP., Jayasinghe, RG., et al.[2023]

In a six-month study involving 35 subjects with sickle cell disease, elevated blood cell adhesion to P-selectin was significantly associated with vaso-occlusive crisis (VOC) events, indicating its potential as a biomarker for predicting VOC risk.

A combined multimarker risk score using both P-selectin and VCAM-1 was found to be effective in stratifying patients into low, intermediate, and high-risk categories for VOC, which could enhance personalized treatment and optimize healthcare resource allocation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flow adhesion of whole blood to P-selectin: a prognostic biomarker for vaso-occlusive crisis in sickle cell disease. Hines, PC., Callaghan, MU., Zaidi, AU., et al.[2023]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/2100.1/529157/Motixafortide-for-Hematopoietic-Stem-and

Motixafortide for Hematopoietic Stem and Progenitor Cell ... Compared to plerixafor, motixafortide results in higher and more sustained levels of mobilized PB CD34+ cells with minimal adverse effects ( ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06442761

Study Details | NCT06442761 | SCD Stem Cell ... This study is being done to see if the study drug, motixafortide, is safe in participants with sickle cell disease (SCD). Investigators also want to see if ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000649712410078X

Motixafortide for Hematopoietic Stem and Progenitor Cell ... Compared to plerixafor, motixafortide results in higher and more sustained levels of mobilized PB CD34+ cells with minimal adverse effects ( ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10500469/

Hematopoietic stem cell mobilization for allogeneic stem cell ... In this study, a single injection of motixafortide resulted in a 22 of 24 (92%) allo-donors collecting ≥2.0 × 106 CD34+ cells per kg within 2 LPs, including 11 ...

5. ir.biolinerx.com ir.biolinerx.com/news-releases/news-release-details/biolinerx-announces-presentations-cost-effectiveness

Release Details The analysis demonstrated significant net cost savings with motixafortide plus G-CSF and a greater proportion of patients achieving successful ...

6. ir.biolinerx.com ir.biolinerx.com/news-releases/news-release-details/biolinerx-announces-oral-presentation-data-phase-1-clinical

Release Details - Investors | BioLineRx "The findings in this trial suggest that patients with sickle cell disease given motixafortide alone, or in combination with natalizumab, could ...

7. stjude.org stjude.org/care-treatment/clinical-trials/scdstemm-sickle-cell-disease.html

SCDSTEMM: Improving Stem Cell Collection in Sickle Cell ... This study aims to see if motixafortide is safe and helps increase collection of stem cells in adults with sickle cell disease. Learn more about the study.