Severe combined immunodeficiencies (SCIDs) are rare, life-threatening inherited diseases of the immune system. ADA-SCID is a specific form of SCID caused by mutations in the ADA (adenosine deaminase) gene, which leave patients vulnerable to severe and recurrent infections. The first symptoms of ADA-SCID typically manifest during infancy and the condition is fatal usually within the first years of life without treatment. The incidence of ADA-SCID is currently estimated to range from 1 in 200,000 to 1 in 1 million live births, with significant variability between regions.
Treatment options currently available for ADA-SCID include allogenic haematopoietic stem cell transplantation, chronic enzyme replacement therapy or autologous ex vivo gammaretroviral gene therapy (Strimvelis®). Allogeneic transplants can be associated with a significant risk of mortality (for example, survival rate of 43 to 67% at one year for transplants from haploidentical and human leukocyte antigen (HLA)-matched unrelated donors, respectively; source: Hassan 2012). Enzyme replacement with pegylated-ADA can be highly effective at restoring the immune function in the short term, but chronic use involves lifelong weekly injections and long-term survival is limited (78% survival at 20 years; source: Gaspar 2009).
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Strimvelis® is the first approved ex vivo gene therapy product in Europe, having received a marketing authorization from the European Medicines Agency (EMA) in 2016. Strimvelis® is indicated for the treatment of patients with ADA-SCID for whom no suitable HLA-matched related stem cell donor is available. The treatment is available at the Ospedale San Raffaele in Milan, Italy.
Strimvelis® has not been approved by the FDA.
Orchard is developing OTL-101, autologous ex vivo lentiviral gene therapy for ADA-SCID. Based on the most recent data cut from the ongoing clinical program, more than 50 patients have been treated with OTL-101 with 100% survival after a follow-up of over 5 years in some patients. In ongoing clinical studies OTL-101 was associated with 100% survival (53 patients out of 53) and 96% event-free survival (51 patients out of 53, where an event was defined as the need for a rescue transplant or for enzyme replacement therapy), and a favourable safety and tolerability profile. OTL-101 is formulated as a cryopreserved product and is intended to be made available as a licensed treatment at multiple treatment centres. OTL-101 is currently undergoing registrational clinical studies, and Orchard Therapeutics is planning to submit a marketing authorization application with regulatory authorities.
Wiskott–Aldrich syndrome (WAS) is a rare, life-threatening inherited disease of the immune system. WAS is referred to as an “X-linked-recessive” disease as it associated with a genetic defect on the X chromosome. Therefore, it affects mainly boys. Patients with Wiskott–Aldrich syndrome are born with a defect in the gene that produces the WAS protein. As a result, they have low platelet counts (thrombocytopenia) and dysfunctional immune cells which put them at risk of severe bleeds, severe infections, eczema, autoimmunity and malignancies. The incidence of WAS is currently estimated at approximately 1 in 200,000 live births.
Treatment options for WAS include prophylactic anti-infective medicines, although they do not always prevent severe infections. In addition, platelet transfusions are given to prevent bleeds. Haematopoietic stem cell transplantation is used at some treatment centres and offers a potentially curative option; however, this approach can be associated with significant risks, especially when well-matched donors are not available.
Orchard is developing OTL-103, autologous ex vivo lentiviral gene therapy for WAS. Data from the ongoing registrational study were presented at the American Society of Hematology (ASH) Annual Meeting in December 2015. All seven patients treated with OTL-103 were alive after a follow-up of 0.7–5.0 years following gene therapy. Treatment with OTL-103 was associated with a marked reduction in the rate of severe infections, bleeding events and hospitalizations compared with the period prior to gene therapy (source: Ferrua 2015); no adverse reaction to the gene therapy product OTL-103 was observed. OTL-103 was acquired from GSK in April 2018. While the programme is transferred to Orchard during 2018, discussions with regulatory authorities will continue to clarify the requirements for a submission for marketing authorization.
X-linked chronic granulomatous disease (X-CGD) is a rare, life-threatening inherited disease of the immune system. X-CGD is referred to as an “X-linked-recessive” disease as it is associated with a genetic defect on the X chromosome. Therefore, it affects mainly boys. Because of the underlying genetic defect in the CYBB gene, white blood cells are unable to kill bacteria and fungi, leading to repeated chronic infections, especially in the lung, and abscesses in organs such as the liver. Patients with CGD typically start to develop infections in the first decade of life. Mortality in X-CGD has been estimated at ~40% by the age of 35 years (source: Van den Berg 2009). The incidence of X-CGD is currently estimated to range from 1 in 100,000 to 1 in 200,000 live births. Despite the limited data available, the prevalence is estimated at several thousand patients, globally.
Management options for X-CGD include prophylactic antibiotics, antifungal medications and interferon-gamma; although this does not always prevent severe infections. Haematopoietic stem cell transplantation is used in some centres and offers a potentially curative option; however, this approach can be associated with significant morbidity, especially when well-matched family donors are not available (source: Güngor 2014).
Orchard is developing OTL-102, autologous ex vivo lentiviral gene therapy for X-CGD. The programme is currently undergoing clinical studies at Great Ormond Street Hospital (London, UK), Boston Children’s Hospital, the National Institute of Health in Bethesda and at The University of California, Los Angeles or UCLA (USA).