A Study Evaluating the Safety and Efficacy of LentiGlobin BB305 Drug Product in β-Thalassemia Major (Also Referred to as Transfusion-dependent β-Thalassemia [TDT]) and Sickle Cell Disease

A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the β-Hemoglobinopathies (Sickle Cell Anemia and β-Thalassemia Major) by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral β-A-T87Q Globin Vector (LentiGlobin BB305 Drug Product)

This is a Phase 1/2, open label, safety, and efficacy study of the administration of LentiGlobin BB305 Drug Product to participants with either transfusion dependent beta-thalassemia (TDT) or sickle cell disease (SCD).

Inclusion Criteria:

1. Be between 5 and 35 years of age, inclusive.

2. Have severe SCD or transfusion dependent beta-thalassemia major, regardless of the genotype with the diagnosis confirmed by Hb studies. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed red blood cells (pRBCs).

3. Be eligible for allogeneic hematopoietic stem cell transplant (HSCT) based on institutional medical guidelines, but without a matched related donor.

4. Be willing and able, in the Investigator's opinion, to comply with the study procedures outlined in the study protocol.

5. Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.

   Participants with severe SCD also must:

6. Have failed to achieve adequate clinical benefit following hydroxyurea treatment with sufficient dosage, for at least 4 months unless this treatment was not indicated or not well tolerated.

7. Have 1 or more of the following poor prognostic risk factors:

   • Recurrent vaso occlusive crises (at least 2 episodes in the preceding year or in the year prior to start of a regular transfusion program).
   • Presence of any significant cerebral abnormality on magnetic resonance imaging (MRI) (such as stenosis or occlusions).
   • Stroke without any severe cognitive disability.
   • Osteonecrosis of 2 or more joints.
   • Anti-erythrocyte alloimmunization (>2 antibodies).
   • Presence of sickle cell cardiomyopathy documented by Doppler echocardiography.
   • Acute chest syndrome (at least 2 episodes) defined by an acute event with pneumonia-like symptoms (e.g., cough, fever [>38.5°C], acute dyspnea, expectoration, chest pain, findings upon lung auscultation, tachypnea, or wheezing) and the presence of a new pulmonary infiltrate. Participants with a chronic oxygen saturation <90% (excluding periods of SCD crisis) or carbon monoxide diffusing capacity (DLco) less than 60% in the absence of an infection should not be included in the study.

8. Participants with severe SCD and cerebral vasculopathy (defined by overt stroke; abnormal transcranial Doppler [> 170 cm/sec]; or occlusion or stenosis in the polygon of Willis; or presence of Moyamoya disease) may be enrolled only with approval by the Comite de Surveillance after review of safety and efficacy data from >or= 2 SCD participants without cerebral vasculopathy treated with LentiGlobin BB305 Drug Product

Exclusion Criteria:

1. Availability of a willing 10 /10 matched human leukocyte antigen (HLA) identical sibling hematopoietic cell donor, unless recommendation for enrollment is provided by the Comite de Surveillance following a review of the case.

2. Clinically significant, active bacterial, viral, fungal, or parasitic infection.

3. Contraindication to anesthesia for bone marrow harvesting.

4. Any prior or current malignancy, myeloproliferative or immunodeficiency disorder.

5. A white blood cell (WBC) count <3×10^9/L and/or platelet count <120×10^9/L.

6. History of major organ damage including:

   • Liver disease, with transaminase levels >3× upper limit of normal.
   • This observation will not be exclusionary if a liver biopsy shows no evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis.
   • Histopathological evidence of extensive bridging fibrosis, cirrhosis, or acute hepatitis on liver biopsy.
   • Heart disease, with a left ventricular ejection fraction <25%.
   • Kidney disease with a calculated creatinine clearance <30% normal value.
   • Severe iron overload, which in the opinion of the physician is grounds for exclusion.
   • A cardiac T2* <10 ms by magnetic resonance imaging (MRI).
   • Evidence of clinically significant pulmonary hypertension requiring medical intervention.