Last update 19 Sep 2024

Autologous CD34+ cell transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence

Last update 19 Sep 2024

Overview

R&D Status

Clinical Result

Translational Medicine

Overview

Basic Info

Drug Type

Gene therapy, Hematopoietic stem cell therapy

Synonyms

Strimvelis, autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence, autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence from human haematopoietic stem/progenitor (CD34+) cells

+ [2]

Target

ADA

Mechanism

ADA gene transference

Therapeutic Areas

Immune System DiseasesCongenital DisordersEndocrinology and Metabolic Disease+ [2]

Active Indication

Adenosine deaminase deficiencySevere Combined Immunodeficiency

Inactive Indication-

Originator Organization

Ospedale San Raffaele Srl

Active Organization

Fondazione Telethon

Inactive Organization

Orchard Therapeutics Plc

Drug Highest PhaseApproved

First Approval Date

EU (26 May 2016),

Adenosine deaminase deficiencySevere Combined Immunodeficiency

Regulation-

Clinical Trials associated with Autologous CD34+ cell transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence

NCT03311074 / WithdrawnPhase 4

Methodology Study to Investigate the Utility of Retroviral Insertion Site Analysis in Samples From Subjects Treated With Strimvelis™ Gene Therapy

Adenosine deaminase (ADA) is an enzyme involved in the development and functioning of the immune system. Deficiency of ADA results in severe combined immunodeficiency (SCID), a fatal inherited immune disorder. Strimvelis is a gene therapy that aims to insert ADA function into blood cells and halt or reverse the conditions caused by decreased ADA enzyme levels, such as impaired immune function. It is important to consider long term follow-up of patients who have received Strimvelis, including evaluation of the risk of insertion near certain genes that may lead to unexpected activation of those genes (oncogenesis). The objective of this study is to evaluate the use of a new technique to identify where Strimvelis has become inserted in the genetic sequence, and potential implications for patient care. This new technique is known as sonication linker mediated polymerase chain reaction (SLiM-PCR) for retroviral insertion site (RIS) analysis. The study will recruit at least 15 pediatric or adult patients with ADA-SCID who have been treated with Strimvelis, either in previous clinical trials or as a registered product. Recruitment for the study may remain open for up to 2 years even if 15 subjects are recruited sooner. Study participation will last for up to 5 years. A total of 5 blood samples will be collected from each subject at approximately annual intervals.

Start Date25 Jun 2020

Sponsor / Collaborator

Fondazione Telethon

NCT03232203 / CompletedNot Applicable

Evaluation of Referring HCPs' and Parents'/Carers' Understanding of Specific Risks Associated With Strimvelis™ Treatment

STRIMVELIS is a medicinal product that restores adenosine deaminase (ADA) function in hematopoietic cell lineages, thereby preventing impaired immune function. STRIMVELIS is indicated for the treatment of patients with ADA- severe combined immunodeficiency (SCID), for whom suitable human leukocyte antigen (HLA)-matched related stem cell donor is not available. The objective of this study is to evaluate the effectiveness of routine and additional risk minimization measures by assessing the understanding of referring health care providers (HCPs) and parents/carers (hereby referred as participants) with regard to the specific risks associated with STRIMVELIS. In this cross-sectional study, surveys will be provided to referring HCPs and parents/carers of children approximately six months after treatment with STRIMVELIS. The study will recruit for approximately two years or until a maximum of 10 referring HCPs and 10 parents/carers have completed their respective surveys, whichever occurs first.

Start Date12 Apr 2018

Sponsor / Collaborator

Fondazione Telethon

EUCTR2017-001731-39-IT / Not yet recruitingPhase 4

Methodology study to investigate the utility of retroviral insertion site analysis in samples from subjects treated with Strimvelis™ gene therapy - Retroviral insertion site methodology study

Start Date12 Oct 2017

Sponsor / Collaborator

Orchard Therapeutics (Europe) Ltd.

100 Clinical Results associated with Autologous CD34+ cell transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence

100 Translational Medicine associated with Autologous CD34+ cell transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence

100 Patents (Medical) associated with Autologous CD34+ cell transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence

Literatures (Medical) associated with Autologous CD34+ cell transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence

01 Aug 2023·International journal of experimental pathology

Clinical applications of gene therapy for rare diseases: A review.

Review

Author: Yanez-Munoz, Rafael J. ; Owen, James S. ; Papaioannou, Ioannis

A review.Rare diseases collectively exact a high toll on society due to their sheer number and overall prevalence.Their heterogeneity, diversity, and nature pose daunting clin. challenges for both management and treatment.In this review, we discuss recent advances in clin. applications of gene therapy for rare diseases, focusing on a variety of viral and non-viral strategies.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 leukemias and lymphomas.Similar retroviral and lentiviral technol. 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-thalassemia resp.Antisense oligonucleotide technologies will be highlighted through Onpattro and Tegsedi, RNA interference drugs licenced for familial transthyretin (TTR) amyloidosis, and Spinraza, a splice-switching treatment for spinal muscular atrophy (SMA).An initial comparison of the effectiveness of AAV and oligonucleotide therapies in SMA is possible with Zolgensma, an AAV serotype 9 vector, and Spinraza.Through these examples of marketed gene therapies and gene cell therapies, we will discuss the expanding applications of such novel technologies to previously intractable rare diseases.

01 Jul 2022·Applied Health Economics and Health PolicyQ4 · MEDICINE

Financing and Reimbursement Models for Personalised Medicine: A Systematic Review to Identify Current Models and Future Options

Q4 · MEDICINE

Review

Author: Zelei, Tamás ; Buchanan, James ; Huygens, Simone ; Szilberhorn, László ; Vellekoop, Heleen ; Nagy, Balázs ; Koleva-Kolarova, Rositsa ; Wordsworth, Sarah ; Mölken, Maureen Rutten-van ; Versteegh, Matthijs ; Tsiachristas, Apostolos

BACKGROUNDThe number of healthcare interventions described as 'personalised medicine' (PM) is increasing rapidly. As healthcare systems struggle to decide whether to fund PM innovations, it is unclear what models for financing and reimbursement are appropriate to apply in this context.OBJECTIVETo review financing and reimbursement models for PM, summarise their key characteristics, and describe whether they can influence the development and uptake of PM.METHODSA literature review was conducted in Medline, Embase, Web of Science, and Econlit to identify studies published in English between 2009 and 2021, and reviews published before 2009. Grey literature was identified through Google Scholar, Google and subject-specific webpages. Articles that described financing and reimbursement of PM, and financing of non-PM were included. Data were extracted and synthesised narratively to report on the models, as well as facilitators, incentives, barriers and disincentives that could influence PM development and uptake.RESULTSOne hundred and fifty-three papers were included. Research and development of PM was financed through both public and private sources and reimbursed largely through traditional models such as single fees, Diagnosis-Related Groups, and bundled payments. Financial-based reimbursement, including rebates and price-volume agreements, was mainly applied to targeted therapies. Performance-based reimbursement was identified mainly for gene and targeted therapies, and some companion diagnostics. Gene therapy manufacturers offered outcome-based rebates for treatment failure for interventions including Luxturna^®, Kymriah^®, Yescarta^®, Zynteglo^®, Zolgensma^® and Strimvelis^®, and coverage with evidence development for Kymriah^® and Yescarta^®. Targeted testing with OncotypeDX^® was granted value-based reimbursement through initial coverage with evidence development. The main barriers and disincentives to PM financing and reimbursement were the lack of strong links between stakeholders and the lack of demonstrable benefit and value of PM.CONCLUSIONSPublic-private financing agreements and performance-based reimbursement models could help facilitate the development and uptake of PM interventions with proven clinical benefit.

01 Sep 2021·Bone Marrow TransplantationQ3 · MEDICINE

EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity

Q3 · MEDICINE

Review

Author: M. Hönig ; T. Güngör ; D. Moshous ; P. Veys ; M. Slatter ; M. H. Albert ; B. Neven ; A. C. Lankester ; Marrow Transplantation ; A. Schulz ; E. C. Morris ; C. Booth ; A. R. Gennery

Inborn errors of immunity (IEI) are a group of rare heterogeneous diseases. Currently, more than 400 monogenetic IEI have been identified and increasingly a genetic diagnosis can be made in patients with an immune deficiency disorder [1]. Patients may present with a variety of clinical symptoms including a broad spectrum of infections, inflammatory manifestations, auto-immune phenomena and malignant diseases. Treatment by hematopoietic stem cell transplantation (HSCT) is increasingly successful [2–10] and the joint EBMT/ESID Inborn Errors Working Party (IEWP) has played a pivotal role designing and developing common HSCT guidelines, which have contributed to this success. The wide clinical heterogeneity of patients, together with the fact that outcome data are based on observational rather than prospective studies, means that it is not yet possible to recommend strictly defined protocols for transplanting IEI patients. The current guidelines provide recommendations based on published data, center experience and expert opinions. Whenever possible, the individual transplant protocol should follow these guidelines, but modifications may be necessary according to the particular variant of the IEI and/or the patient’s clinical condition. For all these reasons the IEWP strongly recommends that all patients with primary immunodeficiency are transplanted in an experienced center that regularly transplants such patients, and also actively participates in the IEWP, as only in this way continuous improvement in outcomes can be achieved. The prognosis of survival for some patients with IEI extends for years and even decades with conservative therapy alone. In those, the decision in favor or against HSCT or other cellular therapies can be extremely challenging. This decision needs to consider multiple factors such as clinical presentation, past and current infections, immunophenotype, genotype, autoimmune manifestations, current and anticipated future organ damage, family history and family experience with the disease, psychological and social factors such as quality of life and fertility, and informed consent not only of caregivers but also patients themselves. In case of a decision for a conservative treatment strategy, this should be re-evaluated on a regular basis by a team, which is informed about and experienced in all currently available therapeutic options. Centers are strongly advised to register their transplanted patients in the EBMT, ESID, and SCETIDE registries, which will allow continuous evaluation of the outcomes in transplanted IEI patients treated in line with IEWP guidelines. Patients with IEI frequently present with or develop autoimmune or inflammatory complications eg, autoimmune cytopenias and inflammatory bowel disease as their sole clinical phenotype [11]. In recent years, monogenetic defects are increasingly identified in patients with primary immune regulation disorders (PIRD [12]). Awareness of the possibility that a monogenetic IEI may be the underlying defect in patients with aforementioned disease manifestations is pivotal in their clinical management and may provide the rationale for allogeneic HSCT as a curative approach [13]. In recent years, stem cell gene addition therapy (GT) has been explored for a limited number of IEI, including ADA-SCID, X-linked SCID, XL-CGD, and WAS. A retroviral ADA GT product (Strimvelis®) is licensed by the European Medicines Agency, and recently excellent results have been reported with lentiviral-based ADA GT [14]. There are ongoing clinical studies in a variety of other IEI [15]. GT offers the potential advantage of avoiding the negative consequences of alloreactivity (GVHD), but concerns remain about the curative potential of a mixed chimeric state in non-SCID IEI, which is inherent to current GT approaches, and the possible risk for insertional mutagenesis (although no vector related adverse events have been reported with lentiviral vectors). However, in the absence of comparative studies it is extremely difficult to make firm recommendations on the hierarchial position of GT in comparison to conventional HSCT. It has to be considered that: (a) long-term safety and efficacy data of GT are still limited, and (b) comparing outcome data from prospective single- or oligocentre studies (as is the case for GT) with retrospective multi-center studies (as most of the evidence for HSCT) does not meet the scientific standard and is therefore suboptimal. Currently, participation in a GT study may be considered for patients lacking a matched donor and able to travel to a respective study center. The IEWP guidelines are reviewed periodically and retrospective studies are regularly performed on behalf of IEWP to evaluate and compare clinical outcomes of patients with specific disease entities treated according to these guidelines [3, 9, 16]. These studies are instrumental to periodically revise and update the guidelines for specific conditions.

News (Medical) associated with Autologous CD34+ cell transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence

12 Aug 2024

·www.pharmaceutical-technology.com

Patient with rare neurodegenerative disorder improves with non-profit’s ASO therapy

Researchers at the non-profit n-Lorem discovered and developed a personalised ASO therapy to treat a rare neurological disease. Credit: SurfsUp via Shutterstock. A patient with a rare progressive neurodegenerative disorder receiving a personalised experimental antisense oligonucleotide (ASO) treatment developed by the non-profit n-Lorem has reported improvements in seizure severity and quality of life. The patient, named Susannah, has a rare condition called KIF1A-associated neurological disorder (KAND). US-based non-profit n-Lorem developed a personalised, experimental ASO medicine specific to Susannah’s genetic mutation. After receiving her first dose of the personalised medicine, her seizures fell to under 30 per week and she has remained stable. KAND is caused by mutations in the KIF1A gene, leading to progressive motor impairments, developmental delays, and cognitive difficulties. Management of KAND mainly focuses on addressing symptoms and improving quality of life through supportive therapies, like speech or physical therapy. There are no other therapies for KAND in clinical development, as per GlobalData’s Pharma Intelligence Center. GlobalData is the parent company of Pharmaceutical Technology . Following the ASO treatment, the patient’s ability to walk also improved after one month; compared to having an average of 26.2 falls per day before treatment, she now experiences up to seven falls daily, with many days without any falls. See Also: Eli Lilly boosts sales forecast by $3bn as diabetes and weight loss drugs propel revenue Recursion and Exscientia merge to form drug discovery company Data from the study published in Nature Medicine also detail notable advancements in speech, attention, group interaction, and motor functions, while the patient’s cognitive abilities have remained stable. Susannah has continued on the ASO treatment for 20 months, with a favourable safety and tolerability profile. ASO therapies work by using short, synthetic strands of nucleic acids to target and modify specific genes, reducing the production of harmful proteins or correcting genetic defects. The treatment developed by n-Lorem targets and corrects the harmful version of the KIF1A gene. Founded by former Ionis Pharmaceuticals ’ CEO Stanley Crooke, n-Lorem aims to bring ASO therapies to patients who are diagnosed with a disease that is found in less than 30 people. Research physicians submit an application to the non-profit, which examines if the patient’s genetic mutation is amendable to the ASO technology. More than 130 patient applications have so far been approved by the organisation for a range of different mutations. There has been an increase in the number of nonprofits developing rare disease medications where the patient population size is too small for commercialisation. Italian research charity Telethon Foundation manufactures and distributes Strimvelis, a gene therapy for rare disease adenosine deaminase severe combined immunodeficiency (ADA-SCiD). The non-profit took over development after it was dropped by its pharmaceutical company in 2022, allowing patients to receive treatment. ASO therapies have long been investigated in rare diseases because they target the cause of disease at the molecular level. Researchers have also developed candidates that are approved to treat conditions affecting larger patient populations. Biogen ’s ASO Spinraza (nusinersen) secured approval for treating the movement disorder spinal muscular atrophy in 2016, pulling in $610.5m in sales in 2023 as per the company’s financials. In the announcement accompanying the case study, n-Lorem’s CEO Stanley Crooke said: “Prior to treatment, Susannah’s disease had progressed to her being mostly in a wheelchair, approaching nonverbal with debilitating seizures that limited her and her family’s quality of life. Susannah has now been on treatment for more than 20 months and we continue to observe improvements in her mobility, neurological function, and quality of life.” The non-profit, which launched in 2020, is also conducting a KIF1A outcome measures, assessments, longitudinal and endpoints (KOALA) study to understand how KAND symptoms develop and change over time.

Drug ApprovalClinical StudyGene TherapyOligonucleotide

18 Jul 2024

·www.pharmaceutical-technology.com

FDA launches new rare disease innovation hub

The FDA’s rare disease innovation hub aims to streamline rare disease drug development. Credit: PeopleImages.com – Yuri A via Shutterstock. A new rare disease innovation hub set up by the US Food and Drug Administration (FDA) aims to expedite the development and approval of orphan drugs. Rare disease clinical trials can be tricky to navigate, especially for conditions with very few patients. Moreover, even after clinical success, some therapies for rare diseases have been dropped by companies due to the high development costs. The FDA’s hub will act as a central point of connection and engagement with the rare disease community, aiding the navigation of FDA-related concerns. It will enhance inter-centre collaboration on scientific, clinical, and policy issues in rare disease product development, said the agency. It also aims to advance novel endpoints, biomarkers, trial designs, real-world evidence, and statistical methods. The hub will be co-led by Dr. Patrizia Cavazzoni, director at the Center for Drug Evaluation and Research (CDER), and Dr. Peter Marks, director at the Center for Biologics Evaluation and Research (CBER). In 2023, over half of all novel drugs and biologics approved by the FDA’s CDER and CBER were to treat or prevent a rare disease. While there have been important advances in treatments for rare diseases, more needs to be done, said the co-leaders in the announcement: See Also: Conflict means millions of children are missing vaccinations, UN says Moderna and Mitsubishi Tanabe link on mRNA vaccines in Japan “We see huge potential in establishing a new model, within the FDA, to leverage cross-agency expertise and greatly enhance our inter-centre connectivity to spur the development of treatments for rare diseases.” Such initiatives can be helpful to address concerns raised by key stakeholders in the field. The Italian research charity Telethon Foundation manufactures and distributes the gene therapy Strimvelis, which is used to treat the rare disease adenosine deaminase severe combined immunodeficiency (ADA-SCiD). Speaking to Pharmaceutical Technology , Francesca Pasinelli, general manager of Telethon Foundation, highlighted how one regulatory bottleneck in rare disease development affects operations. “Overall resource challenges faced by regulatory authorities extend the timelines for obtaining feedback to facilitate the development of products. We therefore understand that it might be difficult for regulatory authorities to speed up the process or even rethink some of the procedures when experts are lacking.” In order to advance treatments for patients with rare diseases, the FDA says it will hold an open public meeting later this year that will include the establishment of a public docket. This aims to provide further information about the vision for the Hub and get feedback from the community to help shape the Hub’s priorities and initiatives.

VaccineClinical Study

20 Mar 2024

·www.biopharmadive.com

Orchard sets out to sell world’s priciest gene therapy

Dive Brief:Orchard Therapeutics said Wednesday it will offer a new gene therapy to children with a rare, devastating disease at a record-setting wholesale price of $4.25 million.The therapy, Lenmeldy, won Food and Drug Administration approvalon Monday to treat patients with early-onset metachromatic leukodystrophy, or MLD. The disease, which most often attacks infants between six months and two years of age, robs patients of the ability to walk, talk and function in the world, killing most of its earliest victims within five years of onset.Lenmeldys price tag will leapfrog those of the two most expensive gene therapies available in the U.S. Sarepta Therapeutics sells its Elevidys treatment for Duchenne muscular dystrophy for $3.2 million, while CSL and UniQures hemophilia treatment Hemgenix costs $3.5 million.Dive Insight:Gene therapy makers like Orchard are counting on insurers to recognize the value proposition of their products. Unlike traditional pharmaceuticals that might be taken regularly for the rest of a persons life, gene therapies carry the promise of a long-lasting treatment that can alter the course of a disease and offer significant savings for the care needed to treat patients.The argument doesnt always work. Difficulty winning reimbursement forced gene therapy maker Bluebird bio to pull out of Europe in 2021. More recently, BioMarin has struggled with the launch of its hemophilia gene therapy, scaling back projections significantly. Orchard itself gave up on a gene therapy called Strimvelisin 2022.But Orchard sees a different trajectory for Lenmeldy, in part because of its long-term data. Researchers have 12 years of follow-up on the earliest patients treated with Lenmeldy, the longest duration of any gene therapy launched in the U.S. Orchard also plans to develop outcomes- and value-based agreements designed to share risks with payers.In studies, Orchard found that all patients with pre-symptomatic late infantile MLD treated with Lenmeldy were still alive at age six, compared with just 58% of such children historically. In addition, 71% of treated children could walk at age five without assistance and 85% had normal language and performance IQ scores. That has not been seen with untreated children.MLD places an enormous emotional and economic burden on families and caregivers who face substantial wage loss and added expenses each year as the disease progresses all while dealing with the unquantifiable anguish of losing their child, Bennett Smith, Orchards senior vice president and general manager of North America, said in the companys statement. Gene therapy can be transformative, he said.In Wednesdays release, Orchard highlighted the findings of the Institute for Clinical and Economic Review, which found that Lenmeldy had the highest value-based price of any treatment it has evaluated. Still, Orchard priced its therapy above the $2.3 million to $3.9 million cost-effectiveness threshold determined by that group.Orchard, which was acquired by Kyowa Kirin this year, is setting up five treatment centers across the U.S. to administer Lenmeldy. The first, in Minnesota, is in the final stages of qualification and has already treated several children on a compassionate use basis. Four others, in Atlanta, Philadelphia, San Francisco and Texas, are in the process of qualification. '

Gene TherapyAcquisition

100 Deals associated with Autologous CD34+ cell transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence

External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Adenosine deaminase deficiency	NO	Fondazione Telethon	26 May 2016
Adenosine deaminase deficiency	LI	Fondazione Telethon	26 May 2016
Adenosine deaminase deficiency	IS	Fondazione Telethon	26 May 2016
Adenosine deaminase deficiency	EU	Fondazione Telethon	26 May 2016
Severe Combined Immunodeficiency	NO	Fondazione Telethon	26 May 2016
Severe Combined Immunodeficiency	LI	Fondazione Telethon	26 May 2016
Severe Combined Immunodeficiency	EU	Fondazione Telethon	26 May 2016
Severe Combined Immunodeficiency	IS	Fondazione Telethon	26 May 2016

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Adenosine deaminase deficiency	Discovery	US	Orchard Therapeutics Plc	08 Jul 2014

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03478670 \| NCT00598481 (Pubmed) Manual	Phase 2	Adenosine deaminase deficiency	43	Autologous CD34+ cell gene therapy	(giejzeqnrv) = Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. ewawbuavuv (fvjucupnfj )	Positive	01 Feb 2024

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