Identification
- Summary
Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5)-based gene therapy containing a coagulation factor VIII complementary DNA used to treat severe hemophilia A.
- Brand Names
- Roctavian
- Generic Name
- Valoctocogene roxaparvovec
- DrugBank Accession Number
- DB15561
- Background
Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5) based gene therapy vector that expresses the B-domain deleted SQ form of human coagulation factor VIII (hFVIII-SQ).5 The expression of hFVIII-SQ is driven by a liver-specific promoter, which enables hepatocytes to produce factor VIII protein and increase the levels of active factor VIII in blood.5,3 Valoctocogene roxaparvovec was approved by EMA in September 2022 and is indicated for the treatment of severe hemophilia A. It is not approved for use in the United States.6 Hemophilia A treatments such as prophylactic regimens of exogenous factor VIII or emicizumab improve the clinical outcomes of patients but do not eliminate breakthrough bleeding.1 As opposed to these therapies, valoctocogene roxaparvovec offers the advantage of continuous and measurable steady-state levels of coagulation factor VIII.3
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Gene Therapies
Other gene therapies - Synonyms
- DNA (synthetic adeno-associated virus 5 vector BMN 270 human blood-coagulation factor VIII SQ variant-specifying)
- Valoctocogene roxaparvovec
- External IDs
- BMN-270
- BMN270
Pharmacology
- Indication
Valoctocogene roxaparvovec is indicated for the treatment of severe hemophilia A (congenital factor VIII deficiency) in adult patients without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5 (AAV5).5
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Severe hemophilia a •••••••••••• ••••• •••••••••• Treatment of Severe hemophilia a •••••••••••• ••••• •••••••••• •••••••• - Contraindications & Blackbox Warnings
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The pharmacodynamic effects of valoctocogene roxaparvovec were evaluated by measuring the activity of circulating factor VIII. Adult males with severe hemophilia A were given a single intravenous infusion of 6×1013 vg/kg valoctocogene roxaparvovec, and their factor VIII activity levels were tracked at least for 6 months. Within 5 months post-infusion, 95% of patients had factor VIII activity levels equal to or higher than 5 IU/dL. Long-term data (5 years follow-up) are available from 7 patients treated with valoctocogene roxaparvovec, and they all continued to show a clinically meaningful response to treatment.5 The presence of pre-existing anti-adeno-associated virus serotype 5 (AAV5) antibodies has a significant effect on valoctocogene roxaparvovec efficiency; therefore, it should not be used in patients with detectable anti-AAV5 antibodies.4
Shortly after valoctocogene roxaparvovec infusion, patients may experience infusion-related side effects. Also, due to the increased production of active factor VIII, patients may have an increased possibility of unwanted blood clot formation. Since there is a possibility that valoctocogene roxaparvovec inserts into body cells other than liver cells, its use may contribute to a higher risk of malignancy.5
- Mechanism of action
Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5) based gene therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-specific promoter;1,5 and is used to treat hemophilia A, a condition characterized by the deficient activity of coagulation factor VIII.2 After valoctocogene roxaparvovec is infused into patients, the AAV5 vector delivers a B-domain deleted SQ form of a recombinant human factor VIII (hFVIII-SQ) to cells. This working copy of coagulation factor VIII is then expressed in the liver, producing an active form of factor VIII that is then released into the bloodstream. This leads to bleeding normalization and a lower risk of bleeding episodes. The long-term production of hFVIII-SQ is supported following valoctocogene roxaparvovec infusion.5
Target Actions Organism ACoagulation factor VIII (F8) gene replacementHumans - Absorption
The total amount of vector DNA in tissues, blood, and shedding matrices was evaluated in patients treated with valoctocogene roxaparvovec. A quantitative polymerase chain reaction (qPCR) assay was used in order to measure transgene DNA and fragments of degraded DNA. Vector DNA was detected in blood and shedding matrices, with peak concentrations between 1 and 9 days after valoctocogene roxaparvovec administration. Blood, saliva, semen, stool, and urine showed the highest vector DNA concentrations.5 The highest concentration detected in blood was 2×1011 vg/mL, and the highest concentration detected in any shedding matrix was 1×1010 vg/mL. Levels declined steadily after reaching the highest transgene DNA concentration.5
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
As a gene therapy medicinal product, valoctocogene roxaparvovec is expected to be metabolized by nucleases throughout the body.
- Route of elimination
Clinical studies have shown that valoctocogene roxaparvovec is eliminated through urine (all patients), saliva (99% of patients) and feces (84% of patients).5
- Half-life
Not Available
- Clearance
The maximum time to clearance of valoctocogene roxaparvovec was 8 weeks for urine, 26 weeks for saliva, and 88 weeks for stool. The maximum time to clearance of vector DNA in semen is 36 weeks. The maximum time to clearance of encapsidated and potentially infectious vector DNA in semen was 12 weeks.5
- Adverse Effects
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There are no reports of valoctocogene roxaparvovec accidental infusions or high dose volumes. If considered necessary, the treatment of a valoctocogene roxaparvovec overdose should be symptomatic and supportive. Receiving higher doses than recommended may result in higher factor VIII activity levels, associated with an increased risk of thrombotic events.5
At doses up to 2×1014 vg/kg, CD1 mice given valoctocogene roxaparvovec did not show any signs of toxicity, except for a pattern of hemorrhages, necrosis and fibrosis in the heart, lungs, epididymis and thymus. These effects were consistent with a coagulopathy likely caused by the formation of SQ form of human coagulation factor VIII (hFVIII-SQ) antibodies that cross-reacted with the murine factor VIII protein.5 Vector integration was detected in the liver samples of non-human primates (n=12), which may lead to a higher risk of malignancies. Reproductive and developmental toxicity studies have not been performed. Since the majority of the patient population are males, germline transmission was evaluated in pups sired by male mice dosed with valoctocogene roxaparvovec. No germline transmission was detected.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAcitretin The therapeutic efficacy of Valoctocogene roxaparvovec can be decreased when used in combination with Acitretin. Asparaginase Erwinia chrysanthemi The therapeutic efficacy of Valoctocogene roxaparvovec can be decreased when used in combination with Asparaginase Erwinia chrysanthemi. Bortezomib The therapeutic efficacy of Valoctocogene roxaparvovec can be decreased when used in combination with Bortezomib. Bosentan The therapeutic efficacy of Valoctocogene roxaparvovec can be decreased when used in combination with Bosentan. Dantrolene The therapeutic efficacy of Valoctocogene roxaparvovec can be decreased when used in combination with Dantrolene. - Food Interactions
- Avoid alcohol. It is recommended that patients abstain from consuming alcohol for at least one year after administration of this medicinal product and, thereafter limit alcohol use.
Products
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- Roctavian (BioMarin Pharmaceutical Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Roctavian Injection, solution 20000000000000 vg/ml Intravenous Biomarin International Limited 2022-09-13 Not applicable EU 
Roctavian Injection, solution 20000000000000 {GC}/1mL Intravenous BioMarin Pharmaceutical Inc. 2023-06-29 Not applicable US 
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 681K1JDI8M
- CAS number
- 1819334-78-5
References
- General References
- Ozelo MC, Mahlangu J, Pasi KJ, Giermasz A, Leavitt AD, Laffan M, Symington E, Quon DV, Wang JD, Peerlinck K, Pipe SW, Madan B, Key NS, Pierce GF, O'Mahony B, Kaczmarek R, Henshaw J, Lawal A, Jayaram K, Huang M, Yang X, Wong WY, Kim B: Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022 Mar 17;386(11):1013-1025. doi: 10.1056/NEJMoa2113708. [Article]
- Bunting S, Zhang L, Xie L, Bullens S, Mahimkar R, Fong S, Sandza K, Harmon D, Yates B, Handyside B, Sihn CR, Galicia N, Tsuruda L, O'Neill CA, Bagri A, Colosi P, Long S, Vehar G, Carter B: 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. doi: 10.1016/j.ymthe.2017.12.009. Epub 2017 Dec 14. [Article]
- Long BR, Veron P, Kuranda K, Hardet R, Mitchell N, Hayes GM, Wong WY, Lau K, Li M, Hock MB, Zoog SJ, Vettermann C, Mingozzi F, Schweighardt B: Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A. Mol Ther. 2021 Feb 3;29(2):597-610. doi: 10.1016/j.ymthe.2020.12.008. Epub 2020 Dec 10. [Article]
- Long BR, Sandza K, Holcomb J, Crockett L, Hayes GM, Arens J, Fonck C, Tsuruda LS, Schweighardt B, O'Neill CA, Zoog S, Vettermann C: The Impact of Pre-existing Immunity on the Non-clinical Pharmacodynamics of AAV5-Based Gene Therapy. Mol Ther Methods Clin Dev. 2019 Apr 11;13:440-452. doi: 10.1016/j.omtm.2019.03.006. eCollection 2019 Jun 14. [Article]
- EMA Summary of Product Characteristics: ROCTAVIAN (valoctocogene roxaparvovec) solution for infusion [Link]
- BioMarin: Valoctocogene roxaparvovec is an investigational AAV5 gene therapy for the treatment of severe hemophilia A. It has been approved for conditional use in the European Union and is marketed as ROCTAVIAN (valoctocogene roxaparvovec) [Link]
- FDA approved drug product: ROCTAVIAN (valoctocogene roxaparvovec-rvox) suspension for intravenous infusion [Link]
- External Links
- 2641610
- Wikipedia
- Valoctocogene_roxaparvovec
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Hemophilia A 2 3 Completed Treatment Hemophilia A 1 3 Recruiting Treatment Hemophilia A 1 1, 2 Active Not Recruiting Treatment Coagulation Disorder / Gene Therapy / Hematologic Disease and Disorders / Hemophilia A 1 1, 2 Active Not Recruiting Treatment Severe Hemophilia A 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous 20000000000000 vg/ml Injection, solution Intravenous 20000000000000 {GC}/1mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
References
- FDA approved drug product: ROCTAVIAN (valoctocogene roxaparvovec-rvox) suspension for intravenous infusion [Link]
Drug created at October 17, 2019 15:19 / Updated at July 05, 2023 20:26