Gene-Modified Stem Cell Therapy for Children With Autosomal Recessive Osteopetrosis (ARO)

This phase I/IIa clinical trial is a non-randomized, open label, single-centre, therapeutic-exploratory, prospective study, to assess safety and efficacy of FT024 in up to 8 children affected by ARO aged ≤2 years of age and will be carried out at the Pediatric Clinical Research Unit/Pediatric Immuno-haematology and Bone Marrow Transplantation Unit, IRCCS Ospedale San Raffaele, Milan, Italy.

Once written informed consent has been obtained and subsequently screening procedures have been completed, harvesting of HSPCs will occur.

In cases of strong suspicion of osteopetrosis without a confirmed genetic diagnosis, and when the patient is unable to visit the clinical center for this inclusion criteria analysis due to their clinical condition, a preliminary remote evaluation for gene mutation analysis may be considered. In this case, remote signing of genetic analysis consent will be required before any evaluation and a blood sample will be sent to the laboratory in Milan, where the analysis will be performed. Blood sample will be collected at a local health care provider (HCP) or local healthcare facility or by home nursing.

If the diagnosis of TCIRG1-associated ARO is confirmed, patients who initially underwent genetic analysis remotely may proceed to Ospedale San Raffaele to complete the screening assessments. In such case, before undergoing any further screening procedures, the patient or parent/legal guardian will be asked to sign the main informed consent for participation in the clinical study. After completing the screening assessments and confirming eligibility, harvesting of HSPCs by leukapheresis or serial blood withdrawal will occur after mobilization and then sent to GMP facility to ATMP manufacturing.

Following ATMP release, patients will be admitted to hospital for receipt of a reduced toxicity conditioning regimen based on Treosulfan and Thiotepa, and infusion of the ATMP. In-patient monitoring will occur until haematological recovery occurred. Thereafter, regular follow-up of patients will take place until 2 years (+720 days). In case of logistical issues or patient's needs, remote visits can be performed. Within the first 180 days, the patient may be re-admitted to hospital for infusion of 1 or 2 ATMP boost doses if the criteria for incomplete hematologic recovery are fulfilled.

At the end of the study (+720 days), patients will be invited to continue long-term follow-up (up to 15 years after gene therapy administration), as required by the authorities (Guideline on safety and efficacy follow-up and risk management of Advanced Therapy Medicinal Products. January 2018, EMEA/149995/2008 rev.1, Committee for Medicinal Products for Human Use [CHMP]). Additional written informed consent will be obtained to participate in this long-term follow-up study.

Recruitment of the planned 8 patients is expected to take around 3 years. The study will last approximately 5 years and 6 months, from the first visit of the first patient to the final visit of the last patient. Each patient will take part in the study for about 30 months, from screening to last follow up visit. A total of 10 visits (minimum) will be required including assessments, day hospital visits and in-patient hospitalization(s).

Inclusion criteria

• Diagnosis of autosomal recessive osteopetrosis caused by mutations in the TCIRG1 gene, defined by one of the following:

• Clinical features of osteopetrosis and documented pathogenic/likely pathogenic biallelic variants (homozygosity or compound heterozygosity, whereby at least 1 allele must contain a known pathogenic mutation) in the TCIRG1 gene causing malignant infantile osteopetrosis.
• If a patient presents with clinical features suggestive of severe osteopetrosis (i.e. generalized osteosclerosis, club-shaped long bones, skull base sclerosis, recurrent fractures and osteomyelitis, cranial nerve entrapment leading to visual and/or hearing loss, bone marrow insufficiency) and at least one pathogenic/likely pathogenic mutation of the TCIRG1 gene, the patient is eligible following discussion with an expert in this pathology.
• Patient's parents/legal guardians' capacity to understand the study goals, the study requirements (i.e., attending study visits, completing questionnaires, taking study medications), potential risks associated with joining a study, and willingness to provide verbal and written informed consent.
• Age: ≥ 28 days and ≤ 2 years old.
• Body weight: ≥ 4 kg.
• Adequate cardiac, pulmonary, renal and hepatic function as evidenced by:

• Left ventricular ejection fraction (LVEF) ≥45% by echo and normal electrocardiogram (ECG) or presence of abnormalities not significant for cardiac disease. Absence of clinically significant heart valve disease.
• Pulse oximetry ≥90% in room air and no evidence for parenchymal lung disease on chest X-ray or CT scan.
• serum creatinine <1.5x upper limit normal in the absence of any form of renal replacement therapy.
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤2.5 x and total bilirubin ≤1.5x upper limit of normal (ULN). Normal coagulation tests (INR <1.5).

Exclusion criteria

• Availability of a medically appropriate, logistically feasible, fully HLA-matched (10/10) sibling or unrelated donor. The chances of finding a suitable, fully matched unrelated donor should be estimated through a preliminary donor bank search by an experienced transplant team. If the patient is judged unlikely to be treated with a fully matched allogeneic HSCT within 6 weeks from activating search procedures, he/she can be considered eligible for this gene therapy study.

This criterion will not be applied to patients whose country of origin does not offer an allogeneic HSCT as a treatment option.

• History of uncontrolled seizures or severe psychiatric symptoms.
• Clinically relevant active viral, bacterial or fungal infection.
• Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or active infection for Treponema Pallidum or Mycoplasma.
• Known hypersensitivity to the drugs required for conditioning chemotherapy, or any excipients used in these products.
• Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if long-acting agents).
• Previous allogeneic HSCT or gene therapy with a different product.
• Patients affected by neoplasia, a familial predisposition to hematologic malignancies or any hematologic/cytogenetic alterations that may suggest a high risk of developing hematologic malignancies.
• Patients with end-organ damage or any other severe condition which, in the judgment of the investigator, would make the patient inappropriate for either HSPC collection or autologous transplant.