Primary immune deficiencies

Adenosine deaminase severe combined immunodeficiency (ADA-SCID)

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).

For more information:

Please refer to the summary of product characteristics and to the patient information leaflet. Please note: these links will take you out of the Orchard website; Orchard does not accept responsibility for the content of external websites.

Strimvelis®: EMA-approved autologous ex vivo gammaretroviral gene therapy

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.

Selected Strimvelis bibliography

Manuscript bibliography:

  1. Aiuti A, Cattaneo F, Galimberti S et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58.
  2. Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017 Jun;9(6):737-740.
  3. Biasco L, Scala S, Basso Ricci L et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci Transl Med. 2015 Feb 4;7(273):273ra13. 
  4. Carriglio N, Klapwijk J, Hernandez RJ et al. Good laboratory practice preclinical safety studies for GSK2696273 (MLV vector-based ex vivo gene therapy for adenosine deaminase deficiency severe combined immunodeficiency) in NSG mice. Hum Gene Ther Clin Dev. 2017 Mar;28(1):17-27.
  5. Cicalese MP, Ferrua F, Castagnaro L et al. Gene therapy for adenosine deaminase deficiency: a comprehensive evaluation of short- and medium-term safety. Mol Ther. 2018 Mar 7;26(3):917-931. 
  6. Cicalese MP, Ferrua F, Castagnaro L et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016 Jul 7;128(1):45-54.
  7. Cockroft A, Cole B, Leacy S, Nord M. Challenges of registering an autologous cell-based gene therapy product. Regulatory Rapporteur 2017;14;9-13
  8. Ferrua F, Aiuti A. Twenty-five years of gene therapy for ADA-SCID: from bubble babies to an approved drug. Hum Gene Ther. 2017 Nov;28(11):972-981.
  9. Migliavacca M, Assanelli A, Ponzoni M et al. First occurrence of plasmablastic lymphoma in adenosine deaminase-deficient severe combined immunodeficiency disease patient and review of the literature. Front Immunol. 2018 Feb 2;9:113.
  10. Monaco L, Faccio L. Patient-driven search for rare disease therapies: the Fondazione Telethon success story and the strategy leading to Strimvelis. EMBO Mol Med. 2017 Mar;9(3):289-292. 
  11. Sauer AV, Hernandez RJ, Fumagalli F et al. Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. Sci Rep. 2017 Jan 11;7:40136.
  12. Scott O, Kim VH, Reid B et al. Long-term outcome of adenosine deaminase-deficient patients – a single-center experience. J Clin Immunol. 2017 Aug;37(6):582-591. 
  13. Stirnadel-Farrant H, Kudari M, Garman N et al. Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID. Orphanet J Rare Dis. 2018 Apr 6;13(1):49
  14. Tucci F, Calbi V, Barzaghi F, et al. Successful treatment with Harvoni® in an ADA-SCID infant with HCV infection allowed gene therapy with Strimvelis®. Hepatology. 2018 Jul 16. doi: 10.1002/hep.30160. [Epub ahead of print]

Congress bibliography:

  1. Bergemann R, Gaffuri A, Barrett J et al. ADA-SCID: qualitative assessment of caregiver perceptions of treatment options. Presentation at: 44th Annual Meeting of the European Society for Blood and Marrow Transplantation; March 18-21, 2018; Lisbon, Portugal. Abstract B056.
  2. Bergemann R, Mustchin E, Barrett J et al. ADA-SCID: the burden and impact on the patient, caregiver and family. A qualitative research in USA, Italy, France and UK. Poster presented at: International Primary Immunodeficiencies Congress: Focus on Diagnosis and Clinical Care; November 8-10, 2017; Dubai, UAE. Poster 8.
  3. Biasco L, Dionisio F, Pellin D, et al. Clonal Tracking of Engineered Hematopoiesis In Vivo in Humans By Insertional Barcoding. Mol Ther. 2015;23(Suppl 1);S189.
  4. Biasco L, Scala S, Basso Ricci L et al. Comprehensive clonal mapping of hematopoiesis in vivo in humans by retroviral vector insertional barcoding. Blood. 2014;124(21):5.
  5. Biasco L, Scala S, Cieri N et al. Clonal tracking of T-cell composition, fate and activity in vivo in humans. Mol Ther. 2014;22 (Suppl 1):S107-8. 
  6. Petrillo C, Cesana D, Piras F et al. Dissecting immunomodulatory relief of lentiviral restriction in human hematopoietic stem and progenitor cells for efficient gene transfer. Mol Ther. 2014;22 (Suppl 1):S205. 
  7. Gabaldo M, Ferrua F, Cicalese MP et al. Bringing an effective gene therapy to ADA-SCID patients: Strimvelis as a successful example of a collaborative effort involving a charity, a research hospital and a pharmaceutical company. Presented at: 3rd International Rare Diseases Research Consortium Conference; February 8-9, 2017; Paris, France. Abstract 16.
  8. Kotsopoulou N, Kirkpatrick A, Ward N, et al. Development of the manufacturing process for the ex vivo gene therapy for ADA-SCID (GSK2696273). Human Gene Therapy. 2013;24(12):A41.
  9. Kotsopoulou N, Kirkpatrick A, Ward N, et al. Development of the manufacturing process for the ex vivo gene therapy for ADA-SCID (GSK2696273): process design, validation and comparability. Human Gene Therapy. 2014;25(11):A44.
  10. Monaco L, Gabaldo M, Ferrua F et al. Strimvelis as a successful model for the development of accessible advanced therapies for ultra rare diseases. Poster presented at: 9th European Conference on Rare Disease & Orphan Products; May 10-12, 2018; Vienna, Austria. Poster 251.
  11. Scala S, Biasco L, Basso Ricci L et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Blood. 2014;124(21):547.
  12. Zonari E, Boccalatte F, Plati T et al. Genetic engineering and transplantation of highly purified hematopoietic stem cells (HSC) for improved ex vivo gene therapy. Mol Ther. 2014;22 (Suppl 1):S13. 

OTL-101: autologous ex vivo lentiviral gene therapy in clinical development for ADA-SCID

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.

For more information please contact: info@orchard-tx.com

Selected OTL-101 bibliography

Wiskott–Aldrich syndrome (WAS)

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.

OTL-103: autologous ex vivo lentiviral gene therapy in clinical development for WAS

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.

For more information please contact: info@orchard-tx.com

Selected WAS bibliography

Manuscript bibliography:

  1. Aiuti A, Biasco L, Scaramuzza S et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013 Aug 23;341(6148):1233151. 
  2. Biasco L, Pellin D, Scala S et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell. 2016 Jul 7;19(1):107-19.
  3. Brigida I, Scaramuzza S, Lazarevic D et al. A novel genomic inversion in Wiskott-Aldrich-associated autoinflammation. J Allergy Clin Immunol. 2016 Aug;138(2):619-622.
  4. Castiello MC, Scaramuzza S, Pala F et al. B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2015 Sep;136(3):692-702.
  5. Marangoni F, Bosticardo M, Charrier S, et al. Evidence for long-term efficacy and safety of gene therapy for Wiskott-Aldrich syndrome in preclinical models. Mol Ther. 2009 Jun;17(6):1073-82.
  6. Pala F, Morbach H, Castiello MC et al. Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J Clin Invest. 2015 Oct 1;125(10):3941-51.
  7. Scala S, Basso-Ricci L, Dionisio F, et al. Dynamics of genetically engineered hematopoietic stem and progenitor cells afterautologous transplantation in humans. Nat Med. 2018 Oct 1. [Epub ahead of print]

Congress bibliography:

  1. Castiello MC, Bosticardo M, Scaramuzza S, et al. B Cell Reconstitution After Lentiviral Vector-Mediated Gene Therapy in Wiskott-Aldrich Syndrome Patients. Mol Ther. 2014;22(Suppl 1);S108.
  2. Castiello MC, Pala F, Morbach H, et al. Lentiviral-Mediated Gene Therapy Restores B Cell Homeostasis and Tolerance in Wiskott-Aldrich Syndrome Patients. Mol Ther. 2016;26(Suppl 1);S112.
  3. Ferrua F, Cicalese MP, Galimberti S, et al. Safety and Clinical Benefit of Lentiviral Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome. Blood. 2015;126(23);259.
  4. Scaramuzza S, Ferrua F, Castiella MC, et al. Gene Therapy with Lentiviral Vector Transduced CD34+ Cells for the Treatment of Wiskott-Aldrich Syndrome. Mol Ther. 2011; 19(Suppl 1):S231.
  5. Scaramuzza S, Giannelli S, Ferrua F, et al. Persistent Multilineage Engraftment and WASP Restored Expression After Lentiviral Mediated CD34+ Cells Gene Therapy for the Treatment of Wiskott-Aldrich Syndrome. Mol Ther. 2014;22(Suppl 1);S88.
  6. Sereni L, Castiello MC, Ferrua F et al. Restoration of PLT structure and function in Wiskott-Aldrich syndrome patients after gene therapy treatment. Mol Ther. 2018;26(5S1);25-6.

X-linked chronic granulomatous disease (X-CGD)

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).

OTL-102: autologous ex vivo lentiviral gene therapy in clinical development for X-CGD

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).

For more information please contact: info@orchard-tx.com

Selected X-CGD bibliography