Strimvelis

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Strimvelis
Clinical data
Trade names Strimvelis
License data
Routes of
administration 		Intravenous
ATC code
  • None
Legal status
Legal status
  • EU:Rx-only [1]
Identifiers
DrugBank

Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence, sold under the brand name Strimvelis, is a medication used to treat severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). [1]

Contents

ADA-SCID is a rare inherited condition in which there is a change (mutation) in the gene needed to make an enzyme called adenosine deaminase (ADA). [1] As a result, people lack the ADA enzyme. [1] Because ADA is essential for maintaining healthy lymphocytes (white blood cells that fight off infections), the immune system of people with ADA-SCID does not work properly and without effective treatment they rarely survive more than two years. [1]

Strimvelis is the first ex vivo autologous gene therapy approved by the European Medicines Agency (EMA). [2]

Medical uses

Strimvelis is indicated for the treatment of people with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID), for whom no suitable human leukocyte antigen (HLA)-matched related stem cell donor is available. [1]

Treatment

The treatment is personalized for each person; hematopoietic stem cell (HSCs) are extracted from the person and purified so that only CD34-expressing cells remain. Those cells are cultured with cytokines and growth factors and then transduced with a gammaretrovirus containing the human adenosine deaminase gene and then reinfused into the person. These cells take root in the person's bone marrow, replicating and creating cells that mature and create normally functioning adenosine deaminase protein, resolving the problem. [3] [4] [5] As of April 2016, the transduced cells had a shelf life of about six hours. [6]

Prior to extraction, the person is treated with granulocyte colony-stimulating factor in order to increase the number of stem cells and improve the harvest; after that but prior to reinfusion, the person is treated with busulfan or melphalan to kill as many of the person's existing HSCs to increase the chances of the new cells' survival. [4] [5]

Side effects

The most common side effect is pyrexia (fever). [1]

Serious side effects may include effects linked to autoimmunity (when the immune system attacks the body's own cells) such as hemolytic anemia (low red blood cell counts due to their too rapid breakdown), aplastic anemia (low blood cell counts due to damaged bone marrow), hepatitis (liver inflammation), thrombocytopenia (low blood platelet count) and Guillain-Barré syndrome (damage to nerves that can result in pain, numbness, muscle weakness and difficulty walking). [1]

Leukemia is a risk of treatment with Strimvelis. [7]

History

The treatment was developed at San Raffaele Telethon Institute for Gene Therapy and developed by GlaxoSmithKline (GSK) through a 2010 collaboration with Fondazione Telethon and Ospedale San Raffaele. GSK, working with the biotechnology company MolMed S.p.A., developed a manufacturing process that was previously only suitable for clinical trials into one demonstrated to be robust and suitable for commercial supply. [8] [9]

Strimvelis, the first ex vivo autologous gene therapy approved by the EMA, has demonstrated remarkable efficacy and safety in clinical trials for the treatment of ADA-SCID. [10]

In April 2016, a committee at the European Medicines Agency (EMA) recommended marketing approval for its use in children with adenosine deaminase deficiency, for whom no matched HSC donor is available, on the basis of a clinical trial that produced a 100% survival rate; the median follow-up time was 7 years after the treatment was administered. [3] 75% of people who received the treatment needed no further enzyme replacement therapy. [11] Efforts had begun 14 years before. The total number of children treated was reported as 22 [12] and 18. [13] Around 80% of patients have no matched donor. [14] Strimvelis was approved [15] by the European Commission on 27 May 2016.

As of 2016, the only site approved to manufacture the treatment was MolMed. [6]

In 2016, Strimvelis obtained Marketing Authorization in Europe while under GSK holding. [16]

In 2017, GSK announced it was looking to sell off Strimvelis, [17] and in March 2018, GSK sold Strimvelis to Orchard Therapeutics Ltd.; as of that time there had been only five sales of the product. [18]

As of 2023, the product has been licensed in Iceland, Norway, Liechtenstein, and the UK. [16]

Society and culture

The condition affects about 14 people per year in Europe and 12 in the U.S. [19]

Economics

The price for the treatment was set at €594,000, twice the annual cost of enzyme replacement therapy injections. [20] Enzyme replacement therapy for ADA requires weekly injections and costs about US$4.25 million for one patient over ten years. [14]

Names

Strimvelis is the brand name. [3] The common name is autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence. [3]

Related Research Articles

<span class="mw-page-title-main">Gene therapy</span> Medical field

Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

<span class="mw-page-title-main">Severe combined immunodeficiency</span> Genetic disorder leading to severe impairment of the immune system

Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in differing clinical presentations. SCID involves defective antibody response due to either direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells. Consequently, both "arms" of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is the most severe form of primary immunodeficiencies, and there are now at least nine different known genes in which mutations lead to a form of SCID. It is also known as the bubble boy disease and bubble baby disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter, have become famous for living in a sterile environment. SCID is the result of an immune system so highly compromised that it is considered almost absent.

<span class="mw-page-title-main">Adenosine deaminase deficiency</span> Medical condition

Adenosine deaminase deficiency is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–20% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) after excluding disorders related to inbreeding.

<span class="mw-page-title-main">Adenosine deaminase</span> Mammalian protein found in Homo sapiens

Adenosine deaminase is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.

Hypogammaglobulinemia is an immune system disorder in which not enough gamma globulins are produced in the blood. This results in a lower antibody count, which impairs the immune system, increasing risk of infection. Hypogammaglobulinemia may result from a variety of primary genetic immune system defects, such as common variable immunodeficiency, or it may be caused by secondary effects such as medication, blood cancer, or poor nutrition, or loss of gamma globulins in urine, as in nonselective glomerular proteinuria. Patients with hypogammaglobulinemia have reduced immune function; important considerations include avoiding use of live vaccines, and take precautionary measures when traveling to regions with endemic disease or poor sanitation such as receiving immunizations, taking antibiotics abroad, drinking only safe or boiled water, arranging appropriate medical cover in advance of travel, and ensuring continuation of any immunoglobulin infusions needed.

Enzyme replacement therapy (ERT) is a medical treatment which replaces an enzyme that is deficient or absent in the body. Usually, this is done by giving the patient an intravenous (IV) infusion of a solution containing the enzyme.

<span class="mw-page-title-main">X-linked severe combined immunodeficiency</span> Medical condition

X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.

<span class="mw-page-title-main">Purine nucleoside phosphorylase</span> Enzyme

Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. It catalyzes the chemical reaction

<span class="mw-page-title-main">Deoxyadenosine triphosphate</span> Chemical compound

Deoxyadenosine triphosphate (dATP) is a nucleotide used in cells for DNA synthesis, as a substrate of DNA polymerase.

<span class="mw-page-title-main">Purine nucleoside phosphorylase deficiency</span> Medical condition

Purine nucleoside phosphorylase deficiency is a rare autosomal recessive metabolic disorder which results in immunodeficiency.

In 1992 Doctor Claudio Bordignon working at the Vita-Salute San Raffaele University, Milan, Italy performed the first procedure of gene therapy using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases. This was a world first, but was unfortunately unsuccessful because it did not lead to sustained correction of the hematopoietic stem cells. In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (SCID). He expanded this work to stem cell gene therapy of other genetic diseases and AIDS, and for the immunotherapy of cancer.

JAK3 deficiency is a dysfunction in cytokine receptor signalling and their production of cytokines.

<span class="mw-page-title-main">Lentiviral vector in gene therapy</span>

Lentiviral vectors in gene therapy is a method by which genes can be inserted, modified, or deleted in organisms using lentiviruses.

Betibeglogene autotemcel, sold under the brand name Zynteglo, is a gene therapy for the treatment for beta thalassemia. It was developed by Bluebird Bio and was given breakthrough therapy designation by the US Food and Drug Administration in February 2015.

The 2002 French gene therapy trials were experimental gene therapy trials performed on children suffering from severe combined immunodeficiency (SCID). The trials were based in Paris and led by researchers Alain Fischer and Marina Cavazzana-Calvo. Whilst the experiment initially seemed successful, many of the children began showing symptoms of various cancer-like diseases as a result of the gene manipulation. The experiment, and others like it, were subsequently shut down.

<span class="mw-page-title-main">Adenosine deaminase 2 deficiency</span> Medical condition

Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic disease associated with systemic inflammation and vasculopathy that affects a wide variety of organs in different patients. As a result, it is hard to characterize a patient with this disorder. Manifestations of the disease include but are not limited to recurrent fever, livedoid rash, various cytopenias, stroke, immunodeficiency, and bone marrow failure. Symptoms often onset during early childhood, but some cases have been discovered as late as 65 years old.

Maria Grazia Roncarolo is an Italian pediatrician who is currently George D. Smith Professor in Stem Cell and Regenerative Medicine and Professor of Medicine at Stanford University. She is also the Director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine along with Irving Weissman and Michael Longaker and the Director for Center for Definitive and Curative Medicine at Stanford.

OTL-103 (GSK-2696275) is a gene therapy for Wiskott–Aldrich syndrome, a rare primary immunodeficiency caused by mutations in the gene that codes for Wiskott–Aldrich syndrome protein (WASp). It was developed by Orchard Therapeutics in conjunction with GlaxoSmithKline. It is currently undergoing Phase I/II of clinical trials that are expected to conclude in October 2025.

References

  1. 1 2 3 4 5 6 7 8 "Strimvelis EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 11 June 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. ↑ "Pipeline". Orchard Therapeutics. 2 July 2021. Retrieved 5 July 2021.
  3. 1 2 3 4 "Strimvelis" (PDF). European Medicines Agency (EMA). Retrieved 13 April 2016.
  4. 1 2 Candotti F (April 2014). "Gene transfer into hematopoietic stem cells as treatment for primary immunodeficiency diseases". International Journal of Hematology. 99 (4): 383–92. doi: 10.1007/s12185-014-1524-z . PMID   24488786. S2CID   8356487.
  5. 1 2 Touzot F, Hacein-Bey-Abina S, Fischer A, Cavazzana M (June 2014). "Gene therapy for inherited immunodeficiency". Expert Opinion on Biological Therapy. 14 (6): 789–98. doi:10.1517/14712598.2014.895811. PMID   24823313. S2CID   207483238.
  6. 1 2 Ben Adams for FierceBiotech 4 April 2016 Strimvelis to be the start of a whole new gene therapy platform for GSK and partners
  7. ↑ "Orchard Statement on Strimvelis, a Gammaretroviral Vector-Based Gene Therapy for ADA-SCID". Orchard Therapeutics (Press release). 30 October 2020. Retrieved 5 July 2021.
  8. ↑ "GSK receives positive CHMP opinion in Europe for Strimvelis™, the first gene therapy to treat very rare disease, ADA-SCID" (Press release). London: GSK. 1 April 2016.
  9. ↑ "GSK and MolMed sign immunodeficiency deal". 9 August 2011.
  10. ↑ Papaioannou I, Owen JS, Yáñez-Muñoz RJ (August 2023). "Clinical applications of gene therapy for rare diseases: A review". Int J Exp Pathol. 104 (4): 154–176. doi:10.1111/iep.12478. PMC   10349259 . PMID   37177842.
  11. ↑ Booth C, Gaspar HB, Thrasher AJ (April 2016). "Treating Immunodeficiency through HSC Gene Therapy" (PDF). Trends in Molecular Medicine. 22 (4): 317–327. doi: 10.1016/j.molmed.2016.02.002 . PMID   26993219.
  12. ↑ Roland D (1 April 2016). "Glaxo's Potential Cure for "Bubble Boy Disease" One Step Closer". The Wall Street Journal.
  13. ↑ Ward A (1 April 2016). "GSK to allow staggered payments for EMA-approved gene therapy". The Financial Times.
  14. 1 2 Gokhale K (1 April 2016). "Glaxo's 'Bubble Boy' Gene Therapy Wins EU Drug Agency Nod". Bloomberg News.
  15. ↑ "StrimvelisTM receives European marketing authorisation to treat very rare disease, ADA-SCID - GSK". Archived from the original on 1 August 2016. Retrieved 22 July 2016.
  16. 1 2 Fratini ES, Migliavacca M, Barzaghi F, Fossati C, Giannelli S, Monti I, et al. (2023). "Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review". Front Immunol. 14: 1187959. doi: 10.3389/fimmu.2023.1187959 . PMC   10331599 . PMID   37435083.
  17. ↑ "GSK gives up on rare diseases as gene therapy gets two customers". Reuters. 26 July 2017.
  18. ↑ Paton J (6 March 2018). "Tiny U.K. Biotech Takes On Glaxo's $730,000 Gene Therapy". Bloomberg.
  19. ↑ Regalado A (6 May 2016). "Gene Therapy's First Out-and-Out Cure Is Here". MIT Technology Review. Retrieved 12 May 2016.
  20. ↑ "Does the EU price of Strimvelis create a new 'glass ceiling'? - groupH - Comment =". www.grouph.com. November 2016. Retrieved 26 February 2017.

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