br Conflict of interest br Ethics

Conflict of interest
Ethics committee
Introduction Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is characterized by impaired function and differentiation of T, B, and natural killer (NK) cells. Non-immunological abnormalities may also occur, including failure to thrive, hepatic disorders, renal disease, skeletal alterations, and neurological/cognitive/behavioral deficits. ADA-SCID is rare: reported incidence rates range from 0.22 to 0.68 per 100,000 live births, corresponding to fewer than 50 children per year in the United States and European Union combined. From birth onward, patients with ADA-SCID are at risk of death due to life-threatening opportunistic infections; the disorder is fatal if untreated. Enzyme replacement therapy (ERT) in the form of polyethylene glycol-modified bovine adenosine deaminase (PEG-ADA) is beneficial for some patients with ADA-SCID and has been administered to over 150 patients. However, immune reconstitution is variable and usually does not persist long term; approximately 10% of treated children develop neutralizing MHC class II antigen (45-57) [Homo sapiens] to PEG-ADA and require an increase in dosage, administration of corticosteroids, or cessation of therapy. For patients who received PEG-ADA between 1986 and 2008, the overall probability of 20-year survival on PEG-ADA was estimated to be 78%. A study of PEG-ADA treatment in 42 patients with ADA-SCID reported four deaths from infections. Patients with ADA-SCID may be effectively treated with hematopoietic stem cell transplant (HSCT). The best outcomes are achieved when a human leukocyte antigen (HLA)-matched sibling donor is used. However, this type of donor is available for less than 25% of patients with ADA-SCID. In contrast, the survival rate is low (less than 68%) for patients with ADA-SCID who receive HSCTs from HLA-matched unrelated donors. In a multicenter retrospective study of patients with ADA-SCID, the majority (63%) of deaths following all types of transplantations occurred within the first 100 days after HSCT. The reported causes of death were mainly related to pneumonitis/respiratory failure and sepsis, which caused more than 50% of all deaths. Other causes of death included graft versus host disease (GvHD) (15%) and fungal infection (incidence not reported). Only 2 of the 13 deaths that occurred after 100 days were attributed to HSCT-related complications. Gene therapy (GT) provides an opportunity to treat ADA-SCID while reducing the risk of side effects, such as GvHD and circumventing donor availability limitations. Treatment with an autologous cell fraction containing CD34+ cells carrying a human ADA cDNA sequence that has been inserted using a retroviral vector (RV) has previously been shown to result in immune system reconstitution for patients with ADA-SCID. While there are publications focusing on efficacy follow-up of ADA-SCID patients treated with HSCT or ERT, there is a paucity of published safety information. Similarly, high-level safety data for GT-treated ADA-SCID patients have been previously reported. Here are provided uniquely detailed analyses of short- and medium-term safety (up to 13 years) within a GT-treated ADA-SCID patient population, which were part of the dossier presented to European regulatory authorities for marketing authorization. These analyses specifically focus on areas of special interest, including infections, neurologic and hearing impairment, autoimmunity, hepatic findings (not previously reported), and malignancy.
Results
Discussion Here, we provide comprehensive safety evaluation from a GT-treated cohort of patients with ADA-SCID that contributed to the data package for the approval of autologous GT (Strimvelis) for ADA-SCID in the EU in 2016. The listings provided here reveal unique insights into the clinical history of both pre- and post-treatment ADA-SCID. Importantly, AE grade, treatment phase, and duration are available for opportunistic infections; neurologic, CNS, and hearing events; and events related to autoimmunity. This first-of-its-kind dataset comprehensively describes the overall health of these patients, including areas of specific safety interest, in addition to their response to GT. In contrast, previous publications of alternative ADA-SCID treatments have focused on efficacy and death due to specific causes but did not provide detailed analyses of AEs and other safety-related outcomes, as they were not designed to collect events after treatment.