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

This is a non-randomized, open label, multi-site, single dose, Phase 1/2 study in approximately 50 adults and adolescents with severe SCD. The study will evaluate hematopoietic stem cell and progenitor stem cell (collectively referred to as hematopoietic stem and progenitor cells or HSPCs) transplantation using lovo-cel.

Subject participation for this study will be 2 years post-transplant. Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for an additional 13 years for a total of 15 years post-drug product infusion.

Eligibility Criteria:
Inclusion Criteria:

1. Be ≥12 and ≤50 of age at time of consent.
2. Diagnosis of sickle cell disease (SCD), with either βS/βS or βS/β0 or βS/β+ genotype.
3. 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:
   1. an episode of acute pain with no medically determined cause other than a VOE
   2. 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.
   3. 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
   4. 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.
   5. 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)
4. Karnofsky performance status of ≥ 60 (≥16 years of age) or a Lansky performance status of ≥60 (\<16 years of age).
5. Have either experienced hydroxyurea (HU) failure at any point in the past or must have intolerance to HU (defined as patient being unable to continue to take HU per PI judgement).
6. Have been treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on SCD history.

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.