Motixafortide and Natalizumab to Mobilize CD34+ Hematopoietic Stem Cells for Gene Therapies in Sickle Cell Disease (SCD)

NCT05618301 | Completed Phase 1 FDA Drug

• 1 other identifier: 202302190
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

Hematopoietic stem cell (HSC)-based gene therapies now offer curative potential for patients with sickle cell disease (SCD), with decreased toxicity compared to allogeneic hematopoietic cell transplantation. However, effective HSC-based gene therapy depends on collecting sufficient HSCs to generate the therapeutic product, and currently available mobilization regimens carry unacceptable risk for patients with SCD or do not reliably yield optimal numbers of HSCs for gene therapy. The investigators hypothesize that HSC mobilization with motixafortide (CXCR4i) alone and the combination of motixafortide plus natalizumab (VLA-4i) will be safe and tolerable in SCD patients. In addition, the investigators hypothesize that combined CXCR4 and VLA-4 blockade with motixafortide plus natalizumab will result in a rapid, robust, and synergistic increase in HSC mobilization to peripheral blood (PB) in patients with SCD, when compared to motixafortide alone.

Conditions

Sickle Cell Disease

Keywords

sickle cell disease; gene therapy; hematopoietic stem cell mobilization; CXCR4 inhibition; VLA4 inhibition

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs)

  * All toxicities will be graded using NCI-CTCAE Version 5.0 * A DLT is an event occurring during the DLT period of 28 days following administration of either motixafortide and/or natalizumab that is considered to be at least possibly, probably or definitely related to study treatment by the investigator, and that meets the criteria below: * Hematologic criteria * Any Grade 5 adverse event * Any Grade 4 adverse event, excluding Grade 4 hemolysis, bilirubin increase, leukocytosis, erythrocytosis, thrombocytosis, anemia, leukopenia, or febrile neutropenia * Non-hematologic criteria * Any Grade 4 or 5 adverse event. * Any Grade 3 or higher arterial or venous thromboembolic event * Any Grade 2 or 3 adverse event that does not resolve within 4 weeks; with the exception of \<grade 2 injection site reactions.

  Through 28 days following administration of either motixafortide and/or natalizumab (estimated to be 8 weeks and 4 days)

Secondary Outcomes (5)

• Number of CD34+ hematopoietic stem and progenitor cells (HSPCs) mobilized via leukapheresis per liter (L) of total volume (tV) processed following motixafortide alone and motixafortide + natalizumab

  Day 2 and Day 60

• Number of CD34+ hematopoietic stem and progenitor cells (HSPCs) mobilized via leukapheresis per liter (L) of adjusted volume (aV) processed, following motixafortide alone and motixafortide + natalizumab

  Day 2 and Day 60

• Change in kinetics of CD34+ HSC mobilization in response to motixafortide alone and motixafortide + natalizumab in SCD patients, as assessed by CD34+ cells/ul in peripheral blood

  From baseline through Day 60

• Frequency of adverse events

  From start of treatment through 8 weeks following completion of all treatment (estimated to be 16 weeks and 4 days)

• Change in peak CD34+ HSC mobilization in response to motixafortide alone and motixafortide + natalizumab in SCD patients, as assessed by CD34+ cells/ul in peripheral blood

  From baseline through Day 60

Study Arms (1)

Motixafortide followed by Motixafortide + Natalizumab

EXPERIMENTAL

* 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.

Drug: Motixafortide; Drug: Natalizumab; Procedure: Leukapheresis

Interventions

Motixafortide DRUG

Motixafortide is to be administered as a subcutaneous injection at a dose of 1.25 mg/kg

Also known as: BL-8040

Motixafortide followed by Motixafortide + Natalizumab

Natalizumab DRUG

Natalizumab will be administered as an IV infusion at a flat dose of 300 mg

Also known as: Tysabri

Motixafortide followed by Motixafortide + Natalizumab

Leukapheresis PROCEDURE

Leukapheresis consisting of a 1 Blood Volume procedure

Motixafortide followed by Motixafortide + Natalizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients at least 18 years old
• Diagnosis of sickle cell disease (hemoglobin SS or Sβ0 genotype)
• Receiving automated RBC exchanges via apheresis-capable central venous access or willing to have apheresis-capable venous access placed.
• Able to hold hydroxyurea, voxelotor, and/or crizanlizumab for at least 60 days prior to mobilization
• Able to hold iron chelation for at least 7 days prior to mobilization
• ECOG performance status ≤ 1
• Normal bone marrow and organ function at screening as defined below:
• Leukocytes ≥ 2,000/uL
• Absolute neutrophil count ≥ 1,500/uL
• Platelets ≥ 75,000/uL
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN at time of screening
• Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault
• Baseline oxygen saturation ≥ 92% on room air
• Left ventricular ejection fraction (LVEF) ≥ 45% (Of note, transthoracic echocardiogram (TTE) will not be required for study. However, if the treating physician has clinical concerns for active cardiac disease for which a TTE is clinically warranted as standard of care, then an EF of ≥ 45% will be required).
• The effects of motixafortide and natalizumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation, and 3 months after completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 3 months after completion of the study.

You may not qualify if:

• Patients may not have a history of receiving the following therapies: prior HCT or prior gene therapy
• Currently receiving concomitant immunosuppressants including 6-mercaptopurine, azathioprine, cyclosporine, methotrexate or concomitant inhibitors of TNF-α.
• 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.
• Currently receiving any other investigational agents.
• A history of progressive multifocal leukoencephalopathy
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to motixafortide or natalizumab.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (including but not limited to HIV, active/untreated Hepatitis C and/or active/untreated Hepatitis B), ongoing/active vaso-occlusive pain crisis or uncontrolled SCD-related symptoms, symptomatic congestive heart failure, cerebrovascular accident, unstable angina pectoris, or cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum/urine pregnancy test within 7 days of study entry and prior to each study agent administration/HSC mobilization.
• Determined by the investigator to be unable or unlikely to comply with the study procedures included in this protocol.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• BioLineRx, Ltd.: collaborator
• Biogen: collaborator
• Ayrmid Pharma: collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

4-fluorobenzoyl-TN-14003; Natalizumab; Leukapheresis

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cytapheresis; Biological Therapy; Therapeutics; Blood Component Removal; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques

Study Officials

• Zachary Crees, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 8, 2022
• First Posted: November 16, 2022
• Study Start: July 7, 2023
• Primary Completion: June 24, 2025
• Study Completion: June 24, 2025
• Last Updated: August 11, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)