Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID

Efficacy and Safety of Cryopreserved Formulation of Autologous CD34+ Hematopoietic Stem Cells Transduced Ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for Human ADA Gene in Subjects With Severe Combined Immunodeficiency Due to ADA Deficiency

This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101 (autologous CD34+ hematopoietic stem/progenitor cells transduced ex vivo with EFS (Elongation Factor 1α Short form) Lentiviral Vector (LV) encoding for the human ADA gene) administered to ADA-SCID subjects between the ages of 30 days and 17 years of age, who are not eligible for an Human Leukocyte Antigen (HLA) matched sibling/family donor and meeting the inclusion/exclusion criteria. The OTL-101 product is infused after a minimal interval of at least 24 hours following the completion of reduced intensity conditioning. For subjects who successfully receive the OTL-101 product, pegademase bovine (PEG-ADA) Enzyme Replacement Therapy (ERT) is discontinued at Day+30 (-3/+15) after the transplant. After their discharge from hospital, the subjects will be seen at regular intervals to review their history, perform examinations and draw blood samples to assess immunity and safety.

Inclusion Criteria:

1. Provision of written informed consent prior to any study related procedures. In this study consent must be provided by the parents/legal guardians and, where applicable according to local laws, a signed assent from the child,

2. Subjects ≥30 days and <18 years of age,

3. With a diagnosis of ADA-SCID based on:

   Evidence of ADA deficiency, defined as:

   i. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-SCID as determined by the reference laboratory, or ii. Identified mutations in ADA alleles consistent with a severe reduction in ADA activity,

   Evidence of ADA-SCID based on either:

   i. Family history of a first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, or ii. Evidence of severe immunologic deficiency in subjects prior to the institution of immune restorative therapy, based on

   • Lymphopenia (absolute lymphocyte count (ALC) <400 cells/µL) OR absence or low number of T cells (absolute CD3+ count < 300 cells/µL), or
   • Severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, or <10% of the response of the normal control of the day, or stimulation index <10), or
   • Identification of SCID by neonatal screening revealing low T cell Receptor Excision Circle (TREC) levels.

4. Ineligible for matched family allogeneic Bone Marrow (BM) transplantation, defined as the absence of a medically eligible HLA-identical sibling or family donor, with normal immune function, who could serve as an allogeneic bone marrow donor.

5. Females of child-bearing age will be required to provide a negative pregnancy test 30 days prior to Visit 2.

6. Subjects and their parents/legal guardians must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow up evaluation as specified in the protocol.

Exclusion Criteria:

1. Ineligible for autologous Hematopoietic Stem Cell Transplantation (HSCT) as per clinical site criteria.

2. Other conditions which in the opinion of the Principal Investigator and/or Co Investigators, contraindicate the harvest of bone marrow, the administration of Busulfan and the infusion of transduced cells, or which indicate an inability of the subject or subject's parent/legal guardian to comply with the protocol.

3. Hematologic abnormality, defined as:

   • Anemia (Hb <8.0 g/dl).
   • Neutropenia (ANC <500/mm3). Note: ANC <500 with absence of myelodysplastic syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics are acceptable for eligibility.
   • Thrombocytopenia (platelet count <50,000/mm3, at any age).
   • Prothrombin time or international normalized ratio (INR) and partial thromboplastin time (PTT) >2 x upper limit of normal (ULN) (subjects with a correctable deficiency controlled on medication will not be excluded).
   • Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
   • Prior allogeneic HSCT with cytoreductive conditioning.

4. Pulmonary abnormality, defined as:

   • Resting O2 saturation by pulse oximetry <90% on room air.
   • Chest X-ray indicating active or progressive pulmonary disease. Note: Chest X ray indicating residual signs of treated pneumonitis is acceptable for eligibility.

5. Cardiac abnormality, defined as:

   • Abnormal ECG indicating cardiac pathology.
   • Uncorrected congenital cardiac malformation with clinical symptoms.
   • Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
   • Poor cardiac function as evidenced by left ventricular ejection fraction <40% on echocardiogram.

6. Neurologic abnormality, defined as:

   • Significant neurologic abnormality revealed by examination.
   • Uncontrolled seizure disorder.

7. Renal abnormality, defined as:

   • Renal insufficiency: serum creatinine ≥1.2 mg/dl (106 µmol/L), or ≥3+ proteinuria.
   • Abnormal serum sodium, potassium, calcium, magnesium or phosphate levels at >2 x ULN.

8. Hepatic/gastrointestinal abnormality, defined as:

   • Serum transaminases >5 x ULN.
   • Serum bilirubin >2 x ULN.
   • Serum glucose >1.5 x ULN.

9. Oncologic disease, defined as:

   • Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP).
   • Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells (if anti-neoplastic therapy has been completed, a subject with a history of DFSP can be included).
   • Evidence of DFSP expected to be life limiting within the 5 years following the infusion of genetically corrected cells.

10. Known sensitivity to Busulfan.

11. Confirmation of an infectious disease by deoxyribonucleic acid (DNA) Polymerase chain reaction (PCR) positive at time of screening assessment for the following:

    • HIV-1,
    • Hepatitis B,
    • Parvovirus B19.

12. The subject is pregnant or has a major congenital anomaly.

13. Is likely to require treatment during the study with drugs that are not permitted by the study protocol.

14. The subject has previously received another form of gene therapy.