hemophilia a gene therapy
Every patient will be monitored for 15 years, and any adverse events occurring from the start of administration of therapy will be recorded at 3, 6, 9, 12, 18 and 24 months, and yearly thereafter. Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. [(accessed on 28 June 2021)]; Almeida-Porada G. A New FIX for Hemophilia B Gene Therapy. Anguela X.M., High K.A. 3. In vitro, the specific activity of recombinant FX-R338L is 510 times higher than that of wild-type recombinant FIX (FIX-WT). This is due to their good safety profile and their capability for partial integration, which ensures long-term expression of the transgene. Researchers have been working to develop a gene replacement treatment (gene therapy) for Hemophilia A. Advanced therapy strategies. 1Osteoarticular Surgery Research, Hospital La Paz Institute for Health ResearchIdiPAZ (La Paz University HospitalAutonomous University of Madrid), 28046 Madrid, Spain; moc.liamtoh@nahcremrce, 2Department of Genetic, Physiology and Microbiology, Biology School, Complutense University of Madrid, 28040 Madrid, Spain; se.mcu@olbapedj. Pfizer has announced positive results from their global phase 3 BASIS clinical study of marstacimab, the company's investigational, subcutaneous therapy that targets an anticoagulant protein known as tissue factor pathway inhibitor (TFPI). Another alternative is to correct the defective genes responsible for the disease. He Q., Wang H.-H., Cheng T., Yuan W.-P., Ma Y.-P., Jiang Y.-P., Ren Z.-H. Genetic Correction and Hepatic Differentiation of Hemophilia B-Specific Human Induced Pluripotent Stem Cells. Research of gene therapy for hemophilia A is now taking place. Pediatric Hematology - Orlando Health Their drawbacks are related to their high capacity to integrate into the genome and their high insertional mutagenesis. I love that it's multidisciplinary and that the field is progressing so quickly with developments in new medications for sickle cell disease and hemophilia and new disease cures like gene therapy coming soon. Although the results of AAV-based gene therapy using FIX as a transgene have been encouraging in the context of HB, increases in hepatotoxicity resulting from the loss of expression of the transgene are not uncommon, possibly due to adaptative or innate immune responses against the vectors capsid. To be effective, these programs require the participation of academically experienced specialists [43]. Other educational programs geared at patients and healthcare providers include more specific training on matters such as the use of AAVs, whose application in patients with hemophilia is becoming increasingly common. In a study by Overbeeke et al. How Gene Therapy for Hemophilia Works Scientists put the protein they want to introduce into the body (either factor 8 or factor 9 depending on the type of hemophilia) into an. The .gov means its official. Samelson-Jones B.J., Finn J.D., George L.A., Camire R.M., Arruda V.R. Over an 18-year period, gene therapy also showed itself to be more economically efficient than on demand or prophylactic treatment in patients with severe HB. The hope is that there will be a genetic cure for hemophilia in the future. b FVIII, factor VIII. Bleeding Cut: CSL Behring Plans H1 Filings for Hemophilia B Gene Therapy Moreover, it must be remembered that patients with hemophilia tend to be well informed about their disease, the treatments and therapeutic options available and even the management of their disease, as most of them are on home self-treatment. In sum, a great deal of research is still needed into the optimization of AAV vectors, along two different paths. FOIA They performed several unidirectional and probabilistic sensitivity analyses to determine the soundness of their results. U.S. National Library of Medicine Gene Therapy Study in Severe Haemophilia a Patients (270-201). Concizumab, a humanized monoclonal antibody targeted against TFPI, is the most highly developed of these strategies. The vectors DNA integrates at a very low rate and is typically lost from replicating cells. Levels of circulating factor and any bleeding episodes will also be recorded from the start. Tang F., Wong H., Ng C.M. Another study by Samelson-Jones et al. Study demonstrates statistically significant and clinically relevant reduction in annualized bleeding rate compared to prophylaxis and on-demand intravenous regimens Marstacimab, if approved, has the potential to become the first once-weekly subcutaneous treatment for people living with hemophilia B and the first treatment administered as a flat dose for people living with hemophilia A or B A . Gene and cell therapy protocols are appropriate for monogenic and polygenic diseases and should allow expression of the deficient factor over the long term and the maintenance of steady-state plasma concentrations. This will contribute to avoiding unrealistic patient expectations and promoting a deeper understanding of the potential risks, benefits and limitations of the new therapeutic protocols. Update on clinical gene therapy for hemophilia | Blood | American Nonetheless, some serotypes may be hepatotoxic and more immunogenic [35]. This replacement therapy can be given to treat a bleeding episode in progress. In vivo gene therapy where the (typically organ-specific) adeno-associated viral (AAVs) or lentiviral (LVs) vectors carried by the therapeutic gene are administered systemically to the patient. Crudele J.M., Finn J.D., Siner J.I., Martin N.B., Niemeyer G.P., Zhou S., Mingozzi F., Lothrop C.D., Arruda V.R. Evolution of Haemophilia Integrated Care in the Era of Gene Therapy: Treatment Centres Readiness in United States and EU. [41], the majority of patients with hemophilia showed a positive attitude toward gene therapy and claimed to be keen to receive this treatment (40%; n = 8) o (35%; n = 7). Given emicizumabs unique structure, its effect is not likely to be neutralized by inhibitors against FVIII. It is caused by a deficiency in clotting factor IX. Advanced therapies comprise a set of novel and innovative strategies such as cell therapy, gene therapy and regenerative medicine or tissue engineering. Production of longer half-life recombinant coagulation factors capable of reducing dosing frequency has also greatly contributed to reducing costs, with comparable clinical outcomes [50]. Introduction to Stem Cells and Regenerative Medicine. One alternative to therapeutic gene-based gene therapy is correction of the defective genes causing the condition through a wide range of gene-editing tools (TALENs, ZFNs and CRISPR/Cas9). Equality: Whats the Difference? The main problem in the case of FVIII is related to the packaging in the vector as the gene of this protein is much larger (7 kb) and exceeds the packaging capacity of AAVs, which is around 5 kb. To do that, several gene-editing tools are available such as CRISPR/Cas9 or ZFNs (zinc finger nucleases). BioMarin Pharmaceutical pioneered the first clinical trial devoted to HA, using hepatic gene transfer with an AAV serotype 5 (AAV5) vector expressing B-domain deleted FVIII (BDD-FVIII-DQ, BMN 270) [58]. To evaluate the cost-effectiveness of gene therapy treatment of severe hemophilia A compared with prophylaxis with fac Mannucci P.M., Franchini M. Is Haemophilia B Less Severe than Haemophilia A? HHS Vulnerability Disclosure, Help Entering 2021, gene therapy for hemophilia is in a peculiar position. These therapies are intended to modify the translation of messenger RNA, inhibiting or modifying production of the protein without affecting the encoding gene [29]. The first gene therapy clinical studies in coagulopathies, which used retroviral, adenoviral and non-viral (ex vivo) vectors were associated with transient expressions and low levels of the coagulation factor [31,32]. It must, however, be remembered that they may lead to an intense immunogenic response and, in some cases, to hepatotoxicity. The study is intended to evaluate the efficacy and safety of PF-06838435 (rAAV-SPARK100-HFIX-PADUA) in male adult subjects with moderate or severe HB, with circulating FIX concentrations <2%. Educational programs should be introduced to provide all stakeholders with the information they require about gene therapy as a therapeutic option, including the management of adverse events and the strategies conducive to ensuring the cost-effectiveness of the treatment. The severity of HA and HB is contingent on the functional levels of the corresponding circulating factors, with levels of FVIII or FIX below 1% considered diagnostic of severe hemophilia, levels between 1 and 5% diagnostic of moderate hemophilia and those between 5% and 40% of mild hemophilia. This kind of vector derives from a native non-pathogenic and barely immunogenic AAV of the parvovirus family which, given its inability to replicate, requires an auxiliary virus to do so [33]. Among persons with hemophilia, those with severe . Zhuang W.-Z., Lin Y.-H., Su L.-J., Wu M.-S., Jeng H.-Y., Chang H.-C., Huang Y.-H., Ling T.-Y. Available non-clinical data support the use of a serpin (serpinPC), a monoclonal antibody against APC, and protein S-targeted siRNA. E.C.R.-M. and A.L. [53] compared the potential economic efficiency of AAV-mediated Factor IX-Padua gene therapy in patients with severe HB in the United States with on-demand FIX replacement and primary prophylaxis with standard FIX or extended half-life FIX products. Gene therapy for hemophilias: The end of phenotypic testing or the start of a new era? The investment and dedication required by these procedures is fully justified as many of the conditions they are meant to treat are chronic and/or severe and either lack a curative treatment or are associated with tedious or inconvenient treatments or therapies, leading to significant side effects which hinder patient adherence. National Library of Medicine Etranacogene Dezaparvovec (AMT-061 Phase 2b): Normal/near Normal FIX Activity and Bleed Cessation in Hemophilia B. U.S. National Library of Medicine HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients. Valoctocogene roxaparvovec, the first gene therapy for treatment of hemophilia A, has been granted conditional marketing authorization in Europe. Persons with mild or moderate factor deficiencies may experience spontaneous bleeding, with excessive bleeds occurring only after trauma or an invasive medical procedure. Received 2021 Jun 30; Accepted 2021 Jul 15. The clinical and preclinical experience with FIX-R338L gene therapy in the realm of HB has not provided evidence of a higher thrombogenic or immunogenic risk [68,75,76]. A total of over 40 active gene therapy clinical trials were found on the subject of hemophilia, with an approximate 50/50 split between HA and HB. This treatment concept makes it difficult for both doctors and patients to switch to a different alternative such as gene therapy, particularly given the uncertainties around its medium- and long-term adverse events. Castaman G., Matino D. Hemophilia A and B: Molecular and Clinical Similarities and Differences. However, individuals with the same coagulation factor levels may exhibit varying bleeding phenotypes. Gene therapy for hemophilia - PubMed The choice between a viral or non-viral vector, and between the different kinds of viral vectors available, must be based on a compromise between the phenotypic features of the disease and the therapeutic targets pursued. Mannucci P.M., Cortesi P.A., Di Minno M.N.D., San M., Mantovani L.G., Di Minno G. Comparative Analysis of the Pivotal Studies of Extended Half-life Recombinant FVIII Products for Treatment of Haemophilia A. Hyperactivity of Factor IX Padua (R338L) Depends on Factor VIIIa Cofactor Activity. The results are encouraging. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A Paulk et al. Factor concentrates account for 90% of all direct costs of treating hemophilia. The Arrival of Gene Therapy for Patients with Hemophilia A Mesenchymal Stem/Stromal Cell-Based Therapy: Mechanism, Systemic Safety and Biodistribution for Precision Clinical Applications. Treatment of hemophilia based on plasma-derived products can be very costly, especially if such products are of a recombinant nature [49]. Gene therapy for hemophilia: a review on clinical benefit, limitations Lastly, lentiviral vectors (LVs), based on single-stranded RNA lentiviruses, are integrative and not very likely to result in insertional mutagenesis, nor do they induce a significant immune response or produce a hepatotoxic effect. Adachi H., Hengesbach M., Yu Y.-T., Morais P. From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies. Hemophilia A gene therapy: current and next-generation approaches Gene replacement therapies provide safe, durable, and stable transgene expression while avoiding the challenges of clotting factor replacement therapies in patients with hemophilia. It is a multiple-cohort research study to be conducted among diverse groups within the hemophilia community whose lives may have been impacted by gene therapy. Top-line results are expected in 2023, and the trial is anticipated to end in July 2026. However, it must be said that retrovirus (RNA virus)-based vectors are practically absent from clinical practice despite their high transduction efficacy and their ability to maintain transgene expression over time. The cells used in cell therapy are generally stem cells equipped with a series of special characteristics, such as being undifferentiated, having the ability to self-renew and to differentiate to different cell lines or to different embryonic layers [12,13,14,15]. A third alternative is to modify the transgene to boost the efficacy of the clotting factor once it has been expressed. Nair et al. An official website of the United States government. [(accessed on 28 June 2021)]; U.S. National Library of Medicine An Exploration of the Impact of Gene Therapy on the Lives of People with Haemophilia and Their Families. The clinical potential of hemophilia gene therapy has now been pursued for the past 30 years, and there is a realistic expectation that this goal will be achieved within the next couple of years with the licensing of a gene therapy product. Although gene therapy protocols are in general more efficient than cell therapy ones, they may be associated with a higher incidence of adverse events, derived mainly from the viral transfection vector used. In the case of gene therapy, this is more necessary, and the multidisciplinary team should include practitioners from departments such as molecular biology, clinical pharmacology and virology. Indeed, a slight increase in plasma levels (to more than 1% of the reference value) is enough to reduce the morbidity and mortality risk. According to international medicine agencies, the products used in the context of advanced therapies are drugs for human use that are based on genes, tissues or cells and that offer innovative solutions for the treatment of some diseases [11] (Figure 1). Encouraging News on Gene Therapy for Hemophilia A However, these therapies are associated with immunogenicity and hepatotoxicity. This is not an issue in HB as the FIX gene is smaller than the FVIII gene. T Cell-Mediated Immune Responses to AAV and AAV Vectors. Australian drugmaker CSL Ltd's gene therapy Hemgenix offers a long-term solution for hemophilia B patients, but is among the world's most expensive treatments. The narratives will represent a true sharing of experiences and offer an insight into how these patients and families have coped with hemophilia following the application of the new therapies. Some people receive continuous replacement therapy. Hemophilia A gene therapy: current and next-generation approaches official website and that any information you provide is encrypted ClinicalTrials.gov Identifier: NCT03392974. However, as the mechanism underlying R338Ls clotting hyperactivity remains unknown, the potential adverse events associated with a random coagulation pattern and the possibility of developing thrombotic complications cannot be ascertained. Trinchero A., Sholzberg M., Matino D. The Evolution of Hemophilia Care: Clinical and Laboratory Advances, Opportunities, and Challenges. Toon K., Bentley E.M., Mattiuzzo G. More than Just Gene Therapy Vectors: Lentiviral Vector Pseudotypes for Serological Investigation. Optimizing Language for Effective Communication of Gene Therapy Concepts with Hemophilia Patients: A Qualitative Study. [(accessed on 28 June 2021)]; Pasi K.J., Rangarajan S., Mitchell N., Lester W., Symington E., Madan B., Laffan M., Russell C.B., Li M., Pierce G.F., et al. Rational Clinical Dose Selection of Adeno-Associated Virus-Mediated Gene Therapy Based on Allometric Principles. For these reasons, further research must be conducted with a view to optimizing AAV vectors, and should come up with less immunogenic and hepatotoxic serotypes. Lippi G., Favaloro E.J. [(accessed on 28 June 2021)]; {"type":"clinical-trial","attrs":{"text":"NCT02695160","term_id":"NCT02695160"}}. Bolous N.S., Chen Y., Wang H., Davidoff A.M., Devidas M., Jacobs T.W., Meagher M.M., Nathwani A.C., Neufeld E.J., Piras B.A., et al. [(accessed on 28 June 2021)]; Lombardi S., Aaen K.H., Nilsen J., Ferrarese M., Gjlberg T.T., Bernardi F., Pinotti M., Andersen J.T., Branchini A. Fusion of Engineered Albumin with Factor IX Padua Extends Half-life and Improves Coagulant Activity. Appropriate multidisciplinary planning will also be necessary at the different stages of the procedure, including evaluation, informed consent, dosing and short- and long-term treatment and follow-up. These results led to a change in strategy and to the use of non integrative recombinant viruses such as AAVs. Stem Cells: Their Source, Potency and Use in Regenerative Therapies with Focus on Adipose-Derived Stem CellsA Review. [(accessed on 28 June 2021)]; Machin N., Ragni M.V., Smith K.J. [(accessed on 28 June 2021)]; U.S. National Library of Medicine A Factor IX Gene Therapy Study (FIX-GT) (FIX-GT). Advanced (gene and cell) therapies could provide a cure for many hereditary conditions such as hemophilia. BAX 335 Hemophilia B Gene Therapy Clinical Trial Results: Potential Impact of CpG Sequences on Gene Expression. In a nutshell, careful multidisciplinary planning will be required [48] before any gene therapy procedures can be applied. At the same time, the gastroenterology and hepatology departments will have to monitor the hepatic function of recipients of gene therapy, especially during the first few months of treatment. [71] analyzed safety, pharmacokinetic profile, FIX activity and immune response in patients undergoing a gene therapy protocol based on the AAV virus serotype 8 (AskBio009) [72]. Protocols are currently highly variable on account of the wide range of target cell types and gene transfection vectors available and the possibility of modifying the transgene to boost its expression efficacy. The study has been designed to allow patients and their families to tell their own life stories through narrative accounts. Pasi et al. There is also considerable uncertainty as to whether payers will be willing to defray the high upfront costs of the one-and-done cure promised by gene therapy, especially considering that reimbursements are normally made based on real world results. The analysis made in this article is based on some of the clinical trials in progress on HA or HB reported in the ClinicalTrials.gov repository [55] and the European Union Clinical Trials Register [56]. Patients with severe hemophilia tend to experience bleeds into their joints, muscles or soft tissues following trauma or even without any apparent cause. Investments in investigating these new therapies are clearly justified as there are multiple chronic and severe conditions for which no treatment is currently available and others for which the existing treatment either results in severe side effects or is tedious and/or inconvenient, making adherence difficult. Krystal Biotech just got the first approved gene therapy for skin Gene therapy for hemophilia: a review on clinical benefit, limitations The DNA sequences transported by AAV vectors are stabilized in an episomal form, so that long-term expression is only possible through delivery into long-living postmitotic cells. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Shukla V., Seoane-Vazquez E., Fawaz S., Brown L., Rodriguez-Monguio R. The Landscape of Cellular and Gene Therapy Products: Authorization, Discontinuations, and Cost. Liver-directed gene therapy may transform congenital hemophilia from an incurable disease characterized by a severe phenotype into a moderate or even mild type of hemophilia. ClinicalTrials.gov. Inclusion in an NLM database does not imply endorsement of, or agreement with, Iriart J.A.B. Pfizer's hemophilia therapy reduces bleeding in late-stage study ClinicalTrials.gov Identifier: NCT04883710. SerpinPC is currently in the early stages of clinical investigation. [(accessed on 28 June 2021)]; Miesbach W., Meijer K., Coppens M., Kampmann P., Klamroth R., Schutgens R., Tangelder M., Castaman G., Schwble J., Bonig H., et al. The incidence of hemophilia A is ~1 in 5000 and that of hemophilia B is 1 in 25 000 live male births. The novel gene efficiency factor (GEF) concept was developed to describe the efficiency of the in vivo AAV-mediated gene transfer system. Hemophilia A (HA) and hemophilia B (HB) are X-linked hereditary hemorrhagic disorders arising from mutations in the genes encoding coagulation factors VIII (FVIII) in HA and IX (FIX) in HB [1]. About Hemophilia - National Human Genome Research Institute George L.A., Sullivan S.K., Giermasz A., Rasko J.E.J., Samelson-Jones B.J., Ducore J., Cuker A., Sullivan L.M., Majumdar S., Teitel J., et al. SB-FIX is a ZFN-mediated genome-editing therapy administered by means of AAV vectors. Prevalence of Adeno-Associated Virus 3 Capsid Binding and Neutralizing Antibodies in Healthy and Hemophilia B Individuals from India. The Cost-Effectiveness of Gene Therapy for Severe Hemophilia B: Microsimulation Study from the United States Perspective. Skinner M.W., Nugent D., Wilton P., OMahony B., Dolan G., OHara J., Berntorp E. Achieving the unimaginable: Health equity in haemophilia. [(accessed on 28 June 2021)]; U.S. National Library of Medicine Single-Arm Study to Evaluate the Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia a Patients at a Dose of 4E13 vg/kg (BMN270-302). In this regard, Lombardi et al. Although treatments based on advanced therapies are costly, several economic forecasting studies have demonstrated that they could become less costly than the currently used regimens. However, the highest vector dose used in the UniQure Biopharma BV study was higher than the AAV8 vector dose used by Nathwani et al. Two phase 2/3 clinical trials are currently underway in patients with HA and HB with or without inhibitors. Miesbach W., OMahony B., Key N.S., Makris M. How to Discuss Gene Therapy for Haemophilia? As a result, switching the therapeutic strategy from the current optimized and safe standard-of-care treatment based on recombinant products to a gene therapy strategy is not easy, especially considering the uncertainties around the medium- and long-term effects of gene therapy protocols, the lack of experience with these new procedures and the potentially unfavorable cost-effectiveness ratio associated with them. Simioni P., Tormene D., Tognin G., Gavasso S., Bulato C., Iacobelli N.P., Finn J.D., Spiezia L., Radu C., Arruda V.R. The advances made in the last few years by gene therapy for the treatment of congenital coagulopathies have caused an unprecedented upheaval, specifically in the treatment of patients with HA and HB. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. Certain strategies have been implemented to reduce the economic impact of hemophilia, such as disease management programs and programs to control the price of drugs. Another approach (etranacogene dezaparvovec, AMT-061) for hemophilia B is also under review by regulators. a AAV, adeno-associated viral vector. At the same time, every effort should be made to address the current inequalities in access to treatment by promoting social access and ensuring that patients receive the treatments they need regardless of geographical or economic factors. APC is regulated by serine protease inhibitors (serpins), the protein C inhibitor (PCI), protein S and 1-antitrypsin. [36] reported two AAV serotypes (NP40 and NP59) capable of improving in vivo transduction of human hepatocytes in murine models. Since May 2021, the World Federation of Hemophilia (WFH) has been working on a Gene Therapy Registry [44,45] intended to put together a worldwide database of patients with hemophilia receiving gene therapy. Specifically, TFPI inhibits activated FX (FXa) while activated protein C (APCa) degrades activated factor V (FVa) and activated FVIII (FVIIIa). ICER Publishes Final Report and Policy Recommendations for Hemophilia A For example, very effective treatments such as extended half-life recombinant products, or the new non-replacement-based therapies, are palliative treatments which, when administered prophylactically, are capable of boosting patients quality of life. [77] showed that the high specific activity of FIX-R338L requires FVIIIa as a cofactor. Generally, the results of the trials carried out so far on the use of AAVs in patients with HA and HB have yielded promising results.
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