Strimvelis (autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence) / GSK, Kyowa Kirin - LARVOL DELTA

Health Technology Appraisals of Gene Therapies Appraised Through NICE Highly Specialized Technology Route (ISPOR-EU 2024) - " To date (May 2024), NICE has appraised eight gene therapies through the HST route; five single-dose therapies (Strimvelis; Luxturna; Zolgensma; Libmeldy; Upstaza), and three enzyme replacement therapies with long-term dosages (Strensiq; Lamzede; Kanuma)... This overview of prior NICE HST appraisals of gene therapies provides insight to the potential issues faced by all stakeholders involved in technology appraisals of these innovative treatments. It also demonstrates the array of products that “gene therapies” captures, the differences in acquisition prices, and variation in economic model structure and approach."

Gene therapy • Gene Therapies • Rare Diseases

An Evaluation of Non-Randomized Evidence (NRE) Used in HTA Decision-Making: A Case Study Review (ISPOR-EU 2024) - "In the end, four products were selected to illustrate the use of NRE: Strimvelis for ADA-SCID, Zolgensma for Type 1 SMA, Blincyto for MRD+BCP ALL, and Libtayo for advanced CSCC... These case studies illustrate that NRE can be a critical component in HTA and regulatory decision-making, particularly when RCTs are not feasible. NRE can provide robust evidence to support the efficacy and safety of treatments, facilitating access to innovative therapies for patients with high unmet medical needs."

Case study • Clinical • Review

230: Is It Time for More Non-profits to Lead Reimbursement and Commercialization of Gene Therapies to Promote Affordable and Sustainable Access? (ISPOR-EU 2024) - "Conversely, the non-profit, Telethon Foundation, recently took over the commercialisation of Strimvelis in Europe after it was discontinued by its for-profit manufacturer...The audience will vote on whether more non-profits should commercialise gene therapies at the start and end of the session, to see if the debate changes their opinion. Time for the audience’s questions will be allocated (15 minutes)."

Gene therapy • Reimbursement • US reimbursement • Gene Therapies • Rare Diseases

Gene Therapy For Adenosine Deaminase Deficiency: Post‐marketing Experience and Long‐term Outcome (ESGCT 2023) - P2 | "Allogeneic hematopoietic stem cell transplant (HSCT) and Strimvelis, an ex-vivo retroviral hematopoietic stem cell gene therapy (GT) approved in the EU in 2016, are standard of care treatments for ADA-SCID...We also observed a significantly higher plateau of transduced CD15+ and CD3+ cells and better dAXP detoxification in STRIM vs CDP+NPP, but no differences in the lymphocyte or T cell reconstitution.Most adverse events/reactions were related to disease background, busulfan conditioning or immune-reconstitution...In the post-marketing population, the safety profile was in line with the clinical development program and we did not find evidence of clonal proliferation, nor new treatment-related events. Due to the risk of insertional oncogenesis, long-term safety monitoring remains important.Following disinvestment from the current marketing authorization holder, the license will be returned to Fondazione Telethon who has committed to establish a new model of..."

Gene therapy • P4 data • Bone Marrow Transplantation • Gene Therapies • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Oncology • Primary Immunodeficiency • Transplantation • LMO2

LONG-TERM AND REAL-WORLD SAFETY AND EFFICACY OF RETROVIRAL GENE THERAPY FOR ADENOSINE DEAMINASE DEFICIENCY (EBMT 2024) - P, P2 | " ​Nineteen patients initially referred for Strimvelis did not receive treatment due to lack of funding, other treatment choice or ineligibility due to different reasons...We also observed a significantly higher plateau of transduced CD15+ and CD3+ cells and better dAXP detoxification in STRIM vs CDP+NPP, but no differences in the lymphocyte or T cell reconstitution.Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution... In the post-marketing population, the safety profile was in line with the clinical development program and we did not find evidence of clonal proliferation, nor new treatment-related events. Due to the risk of insertional oncogenesis, long-term safety monitoring remains important.Following disinvestment from the industrial holder, the marketing authorization of the retroviral GT for ADA-SCID was transferred to Fondazione Telethon which established a nonprofit model of distributing for..."

Clinical • Gene therapy • Real-world • Real-world evidence • Bone Marrow Transplantation • Gene Therapies • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Oncology • Primary Immunodeficiency • Transplantation • LMO2

Methodology Study of Retroviral Insertion Site Analysis in Strimvelis Gene Therapy (clinicaltrials.gov) - P=N/A | N=15 | Active, not recruiting | Sponsor: Fondazione Telethon | Trial completion date: Dec 2023 ➔ Mar 2024 | Trial primary completion date: Sep 2021 ➔ Mar 2024

Gene therapy • Trial completion date • Trial primary completion date • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

Methodology Study of Retroviral Insertion Site Analysis in Strimvelis Gene Therapy (clinicaltrials.gov) - P=N/A | N=15 | Active, not recruiting | Sponsor: Orchard Therapeutics | Enrolling by invitation ➔ Active, not recruiting | Trial completion date: Jun 2023 ➔ Dec 2023

Enrollment closed • Gene therapy • Trial completion date • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

Cell and Gene Therapies: Cell Therapy R&D and Manufacturability (ACS-Fall 2023) - "Division/Committee: [BIOT] Division of Biochemical Technology Gene-modified cellular therapies achieved through viral transduction, such as CAR-T cells and gene-modified CD34 cells, have reached commercialization stages (e.g., Kymriah, Yescarta, Tecartus, Zynteglo, Strimvelis) with unprecedented clinical response rates and durability in oncology and complete correction of severe hematologic diseases. Production of these therapeutic cells present diverse challenges in the manufacturing process. In this session, we will cover cell therapy chemistry, manufacturing, and control (CMC) and regulatory challenges regarding product characterization with in-process, lot release specification establishment, comparability studies, process validation, and clinical safety and efficacy."

Gene therapy • Gene Therapies • Hematological Disorders • Oncology • Solid Tumor • CD34

Clinical applications of gene therapy for rare diseases: A review. (PubMed, Int J Exp Pathol) - "The use of adeno-associated virus (AAV) vectors is discussed in the context of Luxturna, licenced for the treatment of RPE65 deficiency in the retinal epithelium. Imlygic, a herpes virus vector licenced for the treatment of refractory metastatic melanoma, will be an example of oncolytic vectors developed against rare cancers. Yescarta and Kymriah will showcase the use of retrovirus and lentivirus vectors in the autologous ex vivo production of chimeric antigen receptor T cells (CAR-T), licenced for the treatment of refractory leukaemias and lymphomas. Similar retroviral and lentiviral technology can be applied to autologous haematopoietic stem cells, exemplified by Strimvelis and Zynteglo, licenced treatments for adenosine deaminase-severe combined immunodeficiency (ADA-SCID) and β-thalassaemia respectively. Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR)..."

Gene therapy • Journal • Review • Amyloidosis • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Melanoma • Movement Disorders • Muscular Atrophy • Oncology • Primary Immunodeficiency • Rare Diseases • Solid Tumor

Gene Therapy for Adenosine Deaminase Deficiency: Long-Term Outcome and Post-Marketing Experience (ASGCT 2023) - P=N/A, P2 | "Autosomal recessive adenosine-deaminase (ADA) deficiency leads to severe combined immunodeficiency, treatable by enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) or autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning. GT with bone marrow-derived CD34+ cells transduced with γ-retroviral vector (RV) (Strimvelis) was approved in 2016 in the EU...In summary the safety and efficacy data in the post-marketing population are similar to the clinical development experience and efficacy is persisting long-term. Due to the risk of insertional oncogenesis, long-term safety monitoring remains important (#NCT03478670)."

Gene therapy • P4 data • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Primary Immunodeficiency • Transplantation • CD34 • LMO2

Restrictions and Real-World Evidence Requirements in the Health Technology Assessment of Gene Therapy Medicinal Products in Europe, Canada, Australia, and the United States (ISPOR-EU 2022) - " HTA reports describing reimbursement decisions, restrictions, and RWE requirements for 5 GTMPs (atidarsagene autotemcel (AA), onasemnogene abeparvovec [OA], voretigene neparvovec [VN], Strimvelis, and talimogene laherparepvec [TL]) across 7 HTA agencies (NICE [UK], G-BA [Germany], HAS [France], SMC [Scotland], PBAC/MSAC [Australia], CADTH [Canada], and ICER [US]) were assessed... For indications that lacked effective disease modifying treatment options, GTMPs were recommended for restricted reimbursement in almost all cases. Requirements for price reductions and future reassessment after RWE collection were common, although not requested by all HTA agencies. This is likely due to the differing aims and methodologies of HTA bodies."

Clinical • HEOR • Real-world evidence • Gene Therapies • Rare Diseases

Methodology Study of Retroviral Insertion Site Analysis in Strimvelis Gene Therapy (clinicaltrials.gov) - P=N/A | N=15 | Enrolling by invitation | Sponsor: Orchard Therapeutics | Trial completion date: Jun 2022 ➔ Jun 2023

Trial completion date • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

"'Strimvelis is a type of advanced therapy medicine called a ‘gene therapy product...works by delivering genes into the body.' Sounds familiar 🤔" (@opassingham)

Gene Therapies

Financing and Reimbursement Models for Personalised Medicine: A Systematic Review to Identify Current Models and Future Options. (PubMed, Appl Health Econ Health Policy) - "Public-private financing agreements and performance-based reimbursement models could help facilitate the development and uptake of PM interventions with proven clinical benefit."

Journal • Reimbursement • Review • Gene Therapies

Evaluating the Effectiveness of STRIMVELIS Risk Minimization Measures (RMMs) (clinicaltrials.gov) - P=N/A | N=16 | Completed | Sponsor: Orchard Therapeutics | Enrolling by invitation ➔ Completed | N=10 ➔ 16 | Trial completion date: Mar 2022 ➔ Jun 2021 | Trial primary completion date: Mar 2022 ➔ Jun 2021

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Genetic Disorders • Immunology • Primary Immunodeficiency

Methodology Study of Retroviral Insertion Site Analysis in Strimvelis Gene Therapy (clinicaltrials.gov) - P=N/A | N=15 | Enrolling by invitation | Sponsor: Orchard Therapeutics | Trial completion date: Dec 2021 ➔ Jun 2022

Trial completion date • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

An overview of health technology assessments of gene therapies with the focus on cost-effectiveness models. (PubMed, J Mark Access Health Policy) - "We identified economic models of gene therapies from six countries (NICE, IQWiG, SMC, HAS, CADTH, ICER) and focused on nine agents (Glybera, Imlygic, Strimvelis, Yescarta, Kymriah, Luxturna, Zynteglo, Zolgensma, Tecartus)...Although challenges were resolved by adjustments to the currently used value assessment framework, new methodological approaches would be useful. In addition, to improve the methods and quality of an evaluation, further research would be valuable."

HEOR • Journal • Review • Gene Therapies • Genetic Disorders

Evaluation of Advanced Therapy Medicinal Products by the National Institute for Health and Care Excellence (NICE): An Updated Review. (PubMed, Pharmacoecon Open) - "There were ten gene therapy products (talimogene laherparepvec [TA410], strimvelis [HST7], tisagenlecleucel [TA554 and TA567], axicabtagene ciloleucel [TA559], voretigene neparvovec [HST11], autologous anti-CD19-transduced CD3+ cells [TA677], betibeglogene autotemcel [ID968], onasemnogene abeparvovec [HST15] and OTL-200 [ID1666]), one tissue engineered product (holoclar [TA467]) and three somatic cell therapy products (darvadstrocel [TA556] and autologous chondrocyte implantation [ACI] [TA477 and TA508])...In conclusion, the challenges raised by the economic appraisal of ATMPs, albeit not unique, may be exacerbated by the uncertainty related to the often scant evidence base. Adaptations of the conventional decision-making process rather than completely new methods may improve appraisals of ATMPs."

Journal • NICE • Reimbursement • Review • Gene Therapies • Oncology

Methodology Study of Retroviral Insertion Site Analysis in Strimvelis Gene Therapy (clinicaltrials.gov) - P; N=15; Enrolling by invitation; Sponsor: Orchard Therapeutics

Clinical • New trial • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency

Evaluating the Effectiveness of STRIMVELIS Risk Minimization Measures (RMMs) (clinicaltrials.gov) - P=N/A; N=10; Enrolling by invitation; Sponsor: Orchard Therapeutics; Recruiting ➔ Enrolling by invitation; Trial completion date: Dec 2021 ➔ Mar 2022; Trial primary completion date: Dec 2021 ➔ Mar 2022

Enrollment status • Trial completion date • Trial primary completion date • Genetic Disorders • Immunology • Primary Immunodeficiency

[VIRTUAL] RETROVIRAL GENE THERAPY FOR THE TREATMENT OF ADA-SCID: LONG-TERM FOLLOW UP AND FIRST CASE OF T-CELL ACUTE LEUKAEMIA DUE TO INSERTIONAL MUTAGENESIS (EHA 2021) - "Methods Since 2000, 40 patients have been infused with autologous CD34+ cells engineered with a γ-RV encoding ADA following low dose busulfan...The patient showed poor prednisone response, while morphological complete remission was obtained at the end of induction therapy of the AIEOP-BFM ALL 2017 protocol...Due to the identified risk of leukaemogenesis, patients will continue long-term FU to closely monitor the safety of the product. EMA CHMP confirmed that the risk/benefit balance remains favorable for Strimvelis in its approved indication."

Clinical • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Gene Therapies • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • CD2 • CD34 • CD7 • LMO2 • NCAM1

"A fact earlier demonstrated by Glybera (remember Glybera?) and Strimvelis." (@JacobPlieth)

Current Clinical Applications of in vivo Gene Therapy with AAVs. (PubMed, Mol Ther) - "There are now five treatments approved for commercialization and currently available, i.e., Luxtura, Zolgensma, the two CAR-T therapies (Yescarta and Kymriah) and Strimvelis (the gammaretrovirus approved for ADA-SCID in Europe). The review article presents a broad overview of the field of therapy by in vivo gene transfer. We review gene therapy for neuromuscular disorders (spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), X-linked myotubular myopathy (XMTM), diseases of the central nervous system (including Alzheimer's Disease, Parkinson's Disease, Canavan Disease, Aromatic Amino Acid Decarboxylase Deficiency, Giant Axonal Neuropathy) and ocular disorders (Leber congenital amaurosis, age related macular degeneration (AMD), Choroideremia, Achromatopsia, Retinitis Pigmentosa and X-linked retinoschisis), the bleeding disorder hemophilia, and lysosomal storage disorders."

IO biomarker • Journal • Review • Achromatopsia • Age-related Macular Degeneration • Alzheimer's Disease • CNS Disorders • Complement-mediated Rare Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Inherited Retinal Dystrophy • Lysosomal Storage Diseases • Macular Degeneration • Metabolic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Myositis • Ocular Infections • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain • Parkinson's Disease • Rare Diseases • Retinal Disorders • Retinitis Pigmentosa

[VIRTUAL] Market Access Landscape for Advanced Therapy Medicinal Products in the EU-5 (ISPOR-EU 2020) - "The reimbursement and pricing vary between countries as outlined below: France: 7/11 ATMPs were assessed (vs 6/10 in 2019) and 6 (vs 5 in 2019) obtained a positive reimbursement decision: three (vs 0 last year) have a public price (Yescarta, Kymriah, Alofisel)...Italy: 5/11 drugs (vs 2/10 in 2019) are reimbursed to date (Strimvelis, Holoclar, Zalmoxis, Kymriah, Yescarta)...UK: 7/11 drugs (vs 6/10 in 2019) are approved by NICE: Spherox via STA with the two CAR-Ts included in the CDF. Three technologies (Holoclar, Imlygic and Luxturna) were recommended with a simple discount Patient Access Scheme. Two ATMPs, Zynteglo and Zolgensma are currently being evaluated by NICE. CONCLUSIONS Most ATMPs are granted patient access in EU5 even though HTA bodies have imposed monitoring requirements to ensure the value reflects the price."

[VIRTUAL] Cost-Effectiveness and Reimbursement of CELL and GENE Therapies- A Review (ISPOR-EU 2020) - "This research aims to review the cost-effectiveness evidence for ex vivo gene therapy Strimvelis, and CAR T-cell therapies Kymriah (Tisagenlecleucel), Yescarta (Axicabtagene Ciloleucel) and explore the emerging reimbursement models. Pubmed, MEDLINE and Cochrane Library database were searched to December 2019 for (i) ex vivo gene therapy for adenosine deaminase deficiency severe combined immunodeficiency (Strimvelis) and CAR T-cell therapies (ii) tisagenlecleucel (Kymriah) and (iii) axicabtagene ciloleucel (Yescarta) and (iv) reimbursement models for cell and gene therapies. A total of 13 articles were identified as relevant for full-text screening: 8 (66%) analysed cost-effectiveness of Strimvelis, Kymriah and Yescarta in a NHS healthcare setting. New reimbursement models are set to accommodate future high-cost of cell and gene therapy with data uncertainty. Proposed managed access agreements (MMA) encourage collaboration between NHS England and the manufacturer to..."

HEOR • Reimbursement • Gene Therapies • Genetic Disorders • Immunology • Primary Immunodeficiency