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

Inclusion Criteria

• Be ≥12 and ≤50 of age at time of consent.
• Diagnosis of sickle cell disease (SCD), with either βS/βS or βS/β0 or βS/β+ genotype.
• Have severe SCD. i.e., in the setting of appropriate supportive care measures for SCD (e.g., pain management plan), have experienced at least 4 severe VOEs in the 24 months prior to informed consent.

For the purposes of this study, a severe VOE is defined as an event with no medically determined cause other than a vaso-occlusion, requiring a ≥ 24-hour hospital or Emergency Room (ER) observation unit visit or at least 2 visits to a day unit or ER over 72 hours with both visits requiring intravenous treatment. Exception: priapism does not require hospital admission but does require a medical facility visit; 4 priapism episodes that require a visit to a medical facility (without inpatient admission) are sufficient to meet criterion.

Severe VOEs include:

• an episode of acute pain with no medically determined cause other than a VOE
• Acute chest syndrome (ACS), defined by an acute event with pneumonia-like symptoms (e.g., chest pain, fever [> 38.5°C], tachypnea, wheezing or cough, or findings upon lung auscultation) and the presence of a new pulmonary infiltrate consistent with ACS and requiring oxygen treatment and/or blood transfusion.
• Acute hepatic sequestration, defined by a sudden increase in liver size associated with pain in the right upper quadrant, abnormal results of liver-function test not due to biliary tract disease, and reduction in Hb concentration by at least 2 g/dL below the baseline value
• Acute splenic sequestration, defined as sudden enlargement of the spleen and reduction in Hb concentration by at least 2 g/dL below the baseline value.
• Acute priapism: defined as a sustained, unwanted painful erection lasting more than 2 hours and requiring care at a medical facility (with or without hospitalization)
• Karnofsky performance status of ≥ 60 (≥16 years of age) or a Lansky performance status of ≥60 ( 3× the upper limit of normal (ULN), or
• Baseline prothrombin time or partial thromboplastin time >1.5× ULN, suspected of arising from liver disease, or
• Magnetic Resonance Imaging (MRI) of the liver demonstrating clear evidence of cirrhosis, or
• 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 1000 ng/mL, a cardiac MRI is required. Cardiac T2* < 10 ms results in exclusion.
• Contraindication to anesthesia.
• 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.
• Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.
• Prior receipt of an allogeneic transplant.
• Immediate family member with a known or suspected Familial Cancer Syndrome.
• Diagnosis of significant psychiatric disorder of the subject that, in the Investigator's judgment, could seriously impede the ability to participate in the study.
• Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects.
• Participation in another clinical study with an investigational drug within 30 days of Screening.
• Prior receipt of gene therapy.
• 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.
• Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment (patients on prophylactic doses of anticoagulants not excluded per this cr