Gene Transfer for Patients With Sickle Cell Disease

Gene Transfer For Patients With Sickle Cell Disease Using A Gamma Globin Lentivirus Vector: An Open-Label Phase 1 / 2 Pilot Study

The purpose of this Phase 1/2 study is to determine the feasibility and safety of stem cell collection and gamma-globin gene transfer, and success of gene correction in subjects with sickle cell disease

This study will assess the feasibility, safety and efficacy of gene transfer using ARU-1801 (CD34+ cells transduced with the gamma-globin lentiviral vector). Gene transfer will occur ex-vivo into CD34+ enriched human bone marrow or plerixafor-mobilized peripheral blood hematopoietic stem cells (HSC) collected from subjects with severe sickle cell disease (SCD). Subjects will undergo reduced intensity chemotherapy conditioning with single-dose melphalan to facilitate engraftment of ex-vivo ARU-1801 via IV infusion. Subjects will return to the study site at regular intervals for follow-up for 2 years after the ARU-1801 infusion. It is anticipated that a separate long-term follow-up (LTFU) clinical study will be initiated, in which all subjects completing the 2 year study visit will be asked to consent and enroll, and will followed for a further 13 years.

Inclusion Criteria

• Signed informed consent form.

• Has confirmed diagnosis of sickle cell disease (SCD)

• Has severe sickle cell disease, defined as one or more of the following:

  1. Minimum of two episodes of clinically diagnosed acute chest syndrome (ACS) requiring hospital admission, or one life threatening episode of ACS requiring intensive care unit (ICU) admission for exchange transfusion and/or intubation, or frequent ACS episodes which necessitate treatment with chronic transfusion therapy.
  2. Frequent painful vaso-occlusive episodes (VOEs) which significantly interfere with normal life activities, defined as a history of 2 or more severe acute sickle pain events per year requiring additional treatment at a medical facility outside of home pain management over the preceding 2-year period prior to study enrollment, or that necessitate chronic transfusion therapy.
  3. Subjects on chronic transfusion therapy for severe disease symptoms other than those listed above, and which interfere with normal life activities.

• Has failed hydroxyurea therapy, was unable to tolerate hydroxyurea therapy, or has actively made the choice to not take the recommended daily hydroxyurea advised for severe disease (Note: must be off hydroxyurea therapy for 2 months prior to stem cell collection). If refusing hydroxyurea, the subject must document that they have been educated about the benefits and continue to refuse the treatment. Patients placed on chronic transfusion therapy instead of hydroxyurea for severe disease are eligible. Subjects unable to take hydroxyurea due to financial or safety monitoring constraints are eligible.

• Has adequate functional status and organ function as determined at Screening.

Exclusion Criteria

• Female subjects who are pregnant or lactating/breastfeeding.
• Female subjects who are not surgically sterile, postmenopausal or who refuse to practice effective method of birth control as determined by the Investigator for one year after receiving the study drug. Women must also agree not to breastfeed for 1 year after receiving the study drug.
• Any participant of reproductive potential who refuses to agree to use an appropriate contraceptive method determined by the Investigator, for 1 year after receiving the study drug.
• Patients with an active malignant disease or receiving treatment for any type of cancer (except squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ of the skin).
• Current diagnosis or history of hepatitis B, hepatitis C, or HIV.
• Has received another study drug within 30 days, or 5 half-lives of the last dose (whichever is longer), prior to screening.
• Has severe obstruction, restriction or diffusion defect on pulmonary function tests.
• Has uncontrolled bacterial, viral or fungal infections within 1 month prior to starting the conditioning part of the study. Subjects with fever should wait for symptoms to resolve before starting the conditioning part of the study.
• Has a history of stroke or is at moderate to high risk of primary stroke (eg receiving chronic transfusions or hydroxyurea for primary prevention of stroke; has severe cerebral vasculopathy defined as moderate stenosis in >2 arterial segments; and/or has sever stenosis/occlusion in ≤2 segments in the polygon of Willis or presence of Moyamoya-like disease).
• Patients with alpha thalassemia sickle cell disease.
• Has previous liver biopsy showing cirrhosis, bridging hepatic fibrosis, or active hepatitis; or has received chronic transfusions and has previous evidence of iron overload and evidence of liver fibrosis by noninvasive liver imaging.
• Has a matched sibling donor, unless the subject has declined this option or this option is not feasible. Documentation must be included as part of the informed consent process for subjects who decline this option.
• Has a known hypersensitivity to any study treatments (e.g. melphalan, plerixafor).

Other protocol-defined inclusion-exclusion criteria may apply.