A Study Evaluating the Safety and Efficacy of Lovo-cel in Severe Sickle Cell Disease

Exclusion Criteria

• •1. Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV).
• •2. Clinically significant and active bacterial, viral, fungal, or parasitic infection.
• •3. Inadequate bone marrow function, as defined by an absolute neutrophil count of \< 1000/µL (\< 500/µL for subjects on HU treatment) or a platelet count \< 100,000/µL.
• •4. Any history of severe cerebral vasculopathy: defined by overt or hemorrhagic stroke; abnormal transcranial Doppler \[≥200 cm/sec\] needing chronic transfusion; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease. Subjects with radiologic evidence of silent infarction in the absence of any of the above criteria would still be eligible
• •5. Baseline oxygen saturation \< 90% without supplemental oxygen (excluding periods of SCD crisis, severe anemia or infection).
• •6. Baseline carbon monoxide diffusing capacity (DLCO) \< 50% (corrected for Hb) in the absence of infection. If DLco cannot be assessed due to age or cognition-related restrictions, there must be a normal respiratory exam, chest radiograph without pulmonary infiltrates, and oxygen saturation by pulse oximetry ≥ 90% on room air.
• •7. Baseline left ventricular ejection fraction (LVEF) \< 45% measured by cardiac echography.
• •8. Clinically significant pulmonary hypertension at baseline, as defined by the requirement for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental home oxygen.
• •9. Baseline estimated glomerular filtration rate (eGFR) \< 70 mL/min/1.73 m2, as determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (see http://www.kidney.org/professionals/kdoqi/gfr\_calculator.cfm).
• •10. Advanced liver disease, defined as:
• •1. Persistent aspartate transaminase, alanine transaminase, or direct bilirubin value \>3× the upper limit of normal (ULN), or
• •2. Baseline prothrombin time or partial thromboplastin time \>1.5× ULN, suspected of arising from liver disease, or
• •3. Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of cirrhosis, or
• •4. MRI findings suggestive of active hepatitis, significant fibrosis, inconclusive evidence of cirrhosis, or liver iron concentration ≥15 mg/g require follow-up liver biopsy in subjects ≥18 years of age. In subjects \<18 years of age, these MRI findings are exclusionary, unless in the opinion of the Investigator, a liver biopsy could provide additional data to confirm eligibility and would be safe to perform. If a liver biopsy is performed based on MRI findings, any evidence of cirrhosis, bridging fibrosis, or significant active hepatitis will be exclusionary.
• •11. For subjects who have history of iron overload or serum ferritin levels \> 1000 ng/mL, a cardiac MRI is required. Cardiac T2\* \< 10 ms results in exclusion.
• •12. Contraindication to anesthesia.
• •13. Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients.
• •14. Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.
• •15. Prior receipt of an allogeneic transplant.
• •16. Immediate family member with a known or suspected Familial Cancer Syndrome.
• •17. Diagnosis of significant psychiatric disorder of the subject that, in the Investigator's judgment, could seriously impede the ability to participate in the study.
• •18. Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects.
• •19. Participation in another clinical study with an investigational drug within 30 days of Screening.
• •20. Prior receipt of gene therapy.
• •21. An assessment by the Investigator that the subject or parents/caregivers (as required) will not be able to comply with the study procedures outlined in the study protocol.
• •22. Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment (patients on prophylactic doses of anticoagulants not excluded per this criteria).
• •23. Unable to receive Red Blood Cell (RBC) transfusion.
• •24. Any other condition that would render the subject ineligible for hematopoietic stem cell transplant (HSCT), as determined by the attending transplant physician.
• •25. Applicable to subjects \< 18 years of age only: Availability of a willing, matched HLA-identical sibling hematopoietic cell donor.