Factor IX gene therapy: etranacogene dezaparvovec
Etranacogene dezaparvovec is a gene therapy product, approved in the US and Europe for the treatment of adults with congenital hemophilia B who currently use factor IX prophylaxis therapy or who have current or historical life-threatening bleeding or repeated, serious spontaneous bleeding episodes. It is not approved for use in patients with a history of factor IX inhibitors or patients under 18 years of age. It is administered as a single intravenous infusion. Etranacogene dezaparvovec uses an adeno-associated virus (AAV)-5 vector that delivers a codon-optimized factor IX Padua variant transgene with a liver-specific promoter sequence.[70]National Hemophilia Foundation Medical and Scientific Advisory Council (MASAC). MASAC Document 280 - MASAC recommendations concerning products licensed for the treatment of hemophilia and selected disorders of the coagulation system. Aug 2023 [internet publication].
https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-280-masac-recommendations-concerning-products-licensed-for-the-treatment-of-hemophilia-and-selected-disorders-of-the-coagulation-system
In a phase 3 trial, a single infusion of etranacogene dezaparvovec was given to 54 men with severe or moderately severe hemophilia B following at least 6 months of factor IX prophylaxis. Follow-up for 18 months post treatment was completed by 53 participants. The study showed that etranacogene dezaparvovec is superior to factor IX prophylaxis for annualized bleeding rate. Increased factor IX activity was seen from 3 weeks after treatment and sustained over 18 months. Most participants (52 out of 54) stopped taking prophylactic factor IX; of those who continued, one received only a partial dose of etranacogene dezaparvovec and the other had the highest AAV-5 neutralizing antibody titer in the study. Adverse reactions included liver enzyme elevations, headache, mild infusion-related reactions, and flu-like symptoms.[104]ClinicalTrials.gov. HOPE-B: trial of AMT-061 in severe or moderately severe hemophilia B patients. Mar 2022 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT03569891
[105]Pipe SW, Leebeek FWG, Recht M, et al. Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. N Engl J Med. 2023 Feb 23;388(8):706-18.
https://www.nejm.org/doi/10.1056/NEJMoa2211644
http://www.ncbi.nlm.nih.gov/pubmed/36812434?tool=bestpractice.com
Etranacogene dezaparvovec may have the potential to reduce the burden of care and improve quality of life for patients with severe or moderately severe hemophilia. However, it is a high-cost treatment and there is a lack of long-term data. Research is ongoing to monitor the longer term safety and efficacy.
Factor IX gene therapy: investigational therapies
Several other factor IX gene therapy products are undergoing clinical investigation. Long-term data on adeno-associated virus (AAV)-8 factor IX gene therapy showed sustained factor IX level, at a mean of approximately 5 IU/dL for up to 10 years.[106]Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014 Nov 20;371(21):1994-2004.
https://www.nejm.org/doi/10.1056/NEJMoa1407309
http://www.ncbi.nlm.nih.gov/pubmed/25409372?tool=bestpractice.com
High-level factor IX expression (mean 33.7 IU/dL for 28-78 weeks) was reported following infusion of fidanacogene elaparvovec a single-stranded AAV vector comprising a bioengineered capsid (SPARK 100), liver-specific promoter, and factor IX Padua (factor IX-R338L, a gain of function factor IX variant) transgene (Spark).[107]George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017 Dec 7;377(23):2215-27.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029626
http://www.ncbi.nlm.nih.gov/pubmed/29211678?tool=bestpractice.com
Results at 5-year follow-up showed that fidanacogene elaparvovec was generally well tolerated. Mean factor IX activity remained in the mild hemophilia severity range and no patients resumed factor IX prophylaxis. A phase 3 study is underway.[108]Samelson-Jones BJ, Sullivan SK, et al. Follow-up of more than 5 years in a cohort of patients with hemophilia B treated with fidanacogene elaparvovec adeno-associated virus gene therapy. Blood. 2021 Nov 23;138:3975.
https://ashpublications.org/blood/article/138/Supplement%201/3975/481153/Follow-up-of-More-Than-5-Years-in-a-Cohort-of
[109]ClinicalTrials.gov. A study to evaluate the efficacy and safety of factor IX gene therapy with PF-06838435 in adult males with moderately severe to severe hemophilia B (BENEGENE-2). ClinicalTrials.gov Identifier: NCT03861273. Aug 2022 [internet publication].
https://classic.clinicaltrials.gov/ct2/show/NCT03861273
The Food and Drug Administration (FDA) is currently reviewing an application for approval of fidanacogene elaparvovec for the treatment of hemophilia B.
Factor VIII gene therapy: valoctocogene roxaparvovec
Factor VIII gene therapy is challenging because of the large factor VIII complementary DNA (cDNA) size (7 kb), which limits insertion into AAV vectors. Modifications, such as factor VIII B-domain deletion and codon optimization, have resulted in a gene construct that is able to fit into an AAV vector.[110]Ward NJ, Buckley SM, Waddington SN, et al. Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood. 2011 Jan 20;117(3):798-807.
http://www.bloodjournal.org/content/117/3/798.long
http://www.ncbi.nlm.nih.gov/pubmed/21041718?tool=bestpractice.com
[111]Bunting S, Zhang L, Xie L, et al. Gene therapy with BMN 270 results in therapeutic levels of FVIII in mice and primates and normalization of bleeding in hemophilic mice. Mol Ther. 2018 Feb 7;26(2):496-509.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835117
http://www.ncbi.nlm.nih.gov/pubmed/29292164?tool=bestpractice.com
The Biomarin AAV 5-factor VIII (also known as valoctocogene roxaparvovec) phase 3 study showed factor VIII levels at a mean of 77 IU/dL at 35 weeks.[112]Rangarajan S, Walsh L, Lester W, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017 Dec 28;377(26):2519-30.
https://www.nejm.org/doi/10.1056/NEJMoa1708483
http://www.ncbi.nlm.nih.gov/pubmed/29224506?tool=bestpractice.com
An updated long-term follow-up at 3 years and 5 years showed clinically relevant benefit with substantial reduction in annualized bleeding rate.[113]Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020 Jan 2;382(1):29-40.
https://www.nejm.org/doi/10.1056/NEJMoa1908490
http://www.ncbi.nlm.nih.gov/pubmed/31893514?tool=bestpractice.com
[114]Pasi K, Rangarajan S, Robinson TM, et al. Hemostatic response is maintained for up to 5 years following treatment with valoctocogene roxaparvovec, an AAV5-hFVIII-SQ gene therapy for severe hemophilia A [abstract]. Res Pract Thromb Haemost. 2021; 5 (2 suppl):OC 67.1.
https://abstracts.isth.org/abstract/hemostatic-response-is-maintained-for-up-to-5-years-following-treatment-with-valoctocogene-roxaparvovec-an-aav5-hfviii-sq-gene-therapy-for-severe-hemophilia-a
There is, however, a concern about the long-term sustainability/durability of factor VIII gene expression. The median factor VIII activity in the high vector dose group (6 × 10¹³ vg/kg) dropped gradually from 60 IU/dL at year 1, to 20 IU/dL at year 3, and 8.2 IU/dL at year 5; while in the mid vector dose group (4 × 10¹³ vg/kg), the median factor VIII level dropped from 23 IU/dL at year 1, to 13 IU/dL at year 2, and 4.8 IU/dL at year 4.[113]Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020 Jan 2;382(1):29-40.
https://www.nejm.org/doi/10.1056/NEJMoa1908490
http://www.ncbi.nlm.nih.gov/pubmed/31893514?tool=bestpractice.com
[114]Pasi K, Rangarajan S, Robinson TM, et al. Hemostatic response is maintained for up to 5 years following treatment with valoctocogene roxaparvovec, an AAV5-hFVIII-SQ gene therapy for severe hemophilia A [abstract]. Res Pract Thromb Haemost. 2021; 5 (2 suppl):OC 67.1.
https://abstracts.isth.org/abstract/hemostatic-response-is-maintained-for-up-to-5-years-following-treatment-with-valoctocogene-roxaparvovec-an-aav5-hfviii-sq-gene-therapy-for-severe-hemophilia-a
[115]Arruda VR. Why is AAV FVIII gene therapy not approved by the US Food and Drug Administration yet? Blood Adv. 2021 Oct 26;5(20):4313.
https://ashpublications.org/bloodadvances/article/5/20/4313/477434/Why-is-AAV-FVIII-gene-therapy-not-approved-by-the
http://www.ncbi.nlm.nih.gov/pubmed/34698767?tool=bestpractice.com
The interim data from Biomarin's phase 3 trial in 132 patients receiving a high vector dose (6 × 10¹³ vg/kg) showed a mean factor VIII level of 42.9 IU/dL (median 23.9 IU/dL) at year 1, dropping to mean 24.4 IU/dL (median 14.4 IU/dL) at year 2.[116]Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022 Mar 17;386(11):1013-25.
http://www.ncbi.nlm.nih.gov/pubmed/35294811?tool=bestpractice.com
Trial participants will continue to be closely monitored for longer term safety and efficacy.[117]ClinicalTrials.gov. Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301) (BMN 270-301). ClinicalTrials.gov Identifier: NCT03370913. Dec 2022 [internet publication].
https://classic.clinicaltrials.gov/ct2/show/NCT03370913
Valoctocogene roxaparvovec is approved in the US and Europe for the treatment of adults with severe hemophilia A without antibodies to AAV5 (identified by an approved screening test for anti-AAV5 antibodies).
Factor VIII gene therapy: investigational therapies
A phase 1-2 trial of the AAV vector (SPK-8011) factor VIII gene therapy showed sustained factor VIII expression in 12 participants followed up for more than 2 years, permitting discontinuation of prophylaxis and a reduction in bleeding episodes with no major safety concerns.[118]George LA, Monahan PE, Eyster ME, et al. Multiyear factor VIII expression after AAV gene transfer for hemophilia A. N Engl J Med. 2021 Nov 18;385(21):1961-73.
https://www.nejm.org/doi/10.1056/NEJMoa2104205
http://www.ncbi.nlm.nih.gov/pubmed/34788507?tool=bestpractice.com
A phase 3 trial is planned. Another phase 3 trial (NCT4370054) on recombinant AAV 2/6-factor VIII gene therapy is recruiting.[119]ClinicalTrials.gov. Study to evaluate the efficacy and safety of PF-07055480/giroctocogene fitelparvovec gene therapy in moderately severe to severe hemophilia A adults (AFFINE). Apr 2020 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04370054
Half-life extension technologies
Several technologies to extend factor half-life are the subject of ongoing research: fusion of the factor VIIa molecule to the C terminus peptide of human chorionic gonadotropin (factor VIIa-CTP); linking albumin to the factor VIIa molecule (factor VIIa-FP); a novel fusion protein, factor VIIIFc-VWF-XTEN, consisting of the factor VIII binding D'D3 domains of von Willebrand factor fused to a single-chain recombinant factor VIIIFc.[120]Négrier C. Entering new areas in known fields: recombinant fusion protein linking recombinant factor VIIa with recombinant albumin (rVIIa-FP): advancing the journey. Thromb Res. 2016 May;141 Suppl 3:S9-12.
https://www.thrombosisresearch.com/article/S0049-3848(16)30416-9/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/27288065?tool=bestpractice.com
[121]Bar-Ilan A, Livnat T, Hoffmann M, et al. In vitro characterization of MOD-5014, a novel long-acting carboxy-terminal peptide (CTP)-modified activated FVII. Haemophilia. 2018 May;24(3):477-86.
https://onlinelibrary.wiley.com/doi/full/10.1111/hae.13428
http://www.ncbi.nlm.nih.gov/pubmed/29537116?tool=bestpractice.com
[122]Konkle BA, Shapiro AD, Quon DV, et al. BIVV001 fusion protein as factor VIII replacement therapy for hemophilia A. N Engl J Med. 2020 Sep 10;383(11):1018-27.
https://www.nejm.org/doi/10.1056/NEJMoa2002699
http://www.ncbi.nlm.nih.gov/pubmed/32905674?tool=bestpractice.com
Clinical trials of extended half-life products in children and previously untransfused patients are in progress or have been published.[123]Nolan B, Mahlangu J, Pabinger I, et al. Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: final results from the ASPIRE extension study. Haemophilia. 2020 May;26(3):494-502.
https://onlinelibrary.wiley.com/doi/10.1111/hae.13953
http://www.ncbi.nlm.nih.gov/pubmed/32227570?tool=bestpractice.com
[124]Nolan B, Klukowska A, Shapiro A, et al. Final results of the PUPs B-LONG study: evaluating safety and efficacy of rFIXFc in previously untreated patients with hemophilia B. Blood Adv. 2021 Jul 13;5(13):2732-9.
https://ashpublications.org/bloodadvances/article/5/13/2732/476278/Final-results-of-the-PUPs-B-LONG-study-evaluating
http://www.ncbi.nlm.nih.gov/pubmed/34242387?tool=bestpractice.com
[125]Young G, Mahlangu J, Kulkarni R, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost. 2015 Jun;13(6):967-77.
https://onlinelibrary.wiley.com/doi/full/10.1111/jth.12911
http://www.ncbi.nlm.nih.gov/pubmed/25912075?tool=bestpractice.com
[126]Collins PW, Young G, Knobe K, et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014 Dec 18;124(26):3880-6.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271178
http://www.ncbi.nlm.nih.gov/pubmed/25261199?tool=bestpractice.com
Fitusiran
Fitusiran (also known as ALN-AT3), an investigational silencing RNA (siRNA), targets antithrombin (III) mRNA in the liver, with the goal of reducing circulating levels of antithrombin to a degree that enhances thrombin generation in an acceptably safe manner.[127]Sehgal A, Barros S, Ivanciu L, et al. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med. 2015 May;21(5):492-7.
http://www.ncbi.nlm.nih.gov/pubmed/25849132?tool=bestpractice.com
A phase 3 clinical trial of fitusiran showed significant reduction in bleeding rates (overall, joint, spontaneous; all by approximately 90%, compared with on-demand replacement factor therapy), with meaningful improvement in health-related quality of life.[128]Srivastava A, Rangarajan S, Kavakli K, et al. Fitusiran, an investigational siRNA therapeutic targeting antithrombin for the treatment of hemophilia: first results from a phase 3 study to evaluate efficacy and safety in people with hemophilia a or B without inhibitors (ATLAS-A/B). Blood. 2021 Dec 4; 138 (suppl 2): LBA-3.
https://www.sciencedirect.com/science/article/pii/S0006497121069913
Concizumab
Concizumab is a humanized monoclonal antibody against the K2 domain of tissue factor pathway inhibitor (TFPI), the primary inhibitor of the initiation of coagulation. Administration has been shown to improve thrombin generation in healthy volunteers and hemophilia A and hemophilia B patients with or without inhibitors.[129]Chowdary P, Lethagen S, Friedrich U, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost. 2015 May;13(5):743-54.
https://onlinelibrary.wiley.com/doi/full/10.1111/jth.12864
http://www.ncbi.nlm.nih.gov/pubmed/25641556?tool=bestpractice.com
Phase 3 clinical trials are ongoing.[130]ClinicalTrials.gov. A trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia A and B patients with inhibitors (explorer™4). Oct 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03196284
[131]ClinicalTrials.gov. A trial evaluating efficacy and safety of prophylactic administration of concizumab in patients with severe haemophilia A without inhibitors (explorer™5). Nov 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03196297
[132]ClinicalTrials.gov. Research study to look at how well the drug concizumab works in your body if you have haemophilia without inhibitors (explorer8). Jun 2022 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT04082429?term=04082429&draw=2&rank=1
[133]ClinicalTrials.gov. Research study to look at how well the drug concizumab works in your body if you have haemophilia with inhibitors (explorer7). Mar 2022 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT04083781?term=04083781&draw=2&rank=1
[134]Shapiro AD, Angchaisuksiri P, Astermark J, et al. Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Blood. 2019 Nov 28;134(22):1973-82.
https://ashpublications.org/blood/article/134/22/1973/374968/Subcutaneous-concizumab-prophylaxis-in-hemophilia
http://www.ncbi.nlm.nih.gov/pubmed/31444162?tool=bestpractice.com
[135]Shapiro AD. Concizumab: a novel anti-TFPI therapeutic for hemophilia. Blood Adv. 2021 Jan 12;5(1):279.
https://ashpublications.org/bloodadvances/article/5/1/279/474883/Concizumab-a-novel-anti-TFPI-therapeutic-for
http://www.ncbi.nlm.nih.gov/pubmed/33570646?tool=bestpractice.com
Marstacimab
Marstacimab is a human monoclonal antibody against the K2 domain of TFPI.[136]Cardinal M, Kantaridis C, Zhu T, et al. A first-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-06741086, an anti-tissue factor pathway inhibitor mAb, in healthy volunteers. J Thromb Haemost. 2018 Sep;16(9):1722-31.
https://onlinelibrary.wiley.com/doi/10.1111/jth.14207
http://www.ncbi.nlm.nih.gov/pubmed/29908043?tool=bestpractice.com
A phase 3 crossover study of marstacimab for hemophilia A or B with or without inhibitors is ongoing.[137]ClinicalTrials.gov. Study of the efficacy and safety PF-06741086 in adult and teenage participants with severe hemophilia A or moderately severe to severe hemophilia B. Jun 2022 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT03938792?term=03938792&draw=2&rank=1
[138]ClinicalTrials.gov. Open-label extension study of marstacimab in hemophilia participants with or without inhibitors. Jun 2022 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT05145127?term=05145127&draw=2&rank=1
von Willebrand factor-containing products
There is some evidence to suggest that von Willebrand factor (VWF)/factor VIII complex may reduce inhibitor levels in patients with high-risk factors for poor immune tolerance induction (ITI) outcome or who have previously failed ITI.[47]Astermark J, Donfield SM, Gomperts ED, et al. The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) combined cohort. Blood. 2013 Feb 21;121(8):1446-54.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578958
http://www.ncbi.nlm.nih.gov/pubmed/23223434?tool=bestpractice.com
[139]Wu JK, Woo C, Crilly E. Immune tolerance induction in severe hemophilia a patients using Wilate®, a von Willebrand factor/factor VIII concentrate. Blood 2014;124(21):5057.
http://www.bloodjournal.org/content/124/21/5057
[140]Gringeri A, Musso R, Mazzucconi MG, et al. Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response. Haemophilia. 2007 Jul;13(4):373-9.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2516.2007.01484.x
http://www.ncbi.nlm.nih.gov/pubmed/17610550?tool=bestpractice.com