Valoctocogene roxaparvovec
Gene therapy
Target geneFactor VIII
VectorAdeno-associated virus
Nucleic acid typeDNA
Delivery methodIntravenous
Clinical data
Trade namesRoctavian
Other namesBMN-270, Valrox, valoctocogene roxaparvovec-rvox
License data
Routes of
administration		Intravenous
Drug classAntihemorrhagics
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG

Valoctocogene roxaparvovec, sold under the brand name Roctavian, is a gene therapy used for the treatment of hemophilia A.[1][3] It was developed by BioMarin Pharmaceutical.[4][5][6] Valoctocogene roxaparvovec is made of a virus (AAV5) that has been modified to contain the gene for factor VIII, which is lacking in people with hemophilia A.[3] It is an adeno-associated virus vector-based gene therapy.[1] It is given by intravenous infusion.[3]

The most common side effects include increased levels of the liver enzymes alanine aminotransferase and aspartate aminotransferase (signs of possible liver problems), increased levels of the enzyme lactate dehydrogenase (sign of possible tissue damage), nausea (feeling sick), and headache.[3]

Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022,[3][4] and in the United States in June 2023.[7][8]

Medical uses

In the European Union, valoctocogene roxaparvovec is indicated for the treatment of severe hemophilia A (congenital factor VIII deficiency) in adults without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5 (AAV5).[3]

In the United States, valoctocogene roxaparvovec is indicated for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test.[1][7]

Mechanism of action

Valoctocogene roxaparvovec is a gene therapy that uses an adeno-associated virus 5 (AAV5) that codes for human Factor VIII, together with a human liver-specific promoter that encourages translation in hepatocytes, not liver endothelial and sinusoidal cells, where Factor VIII is ordinarily synthesised.[9][10]

History

The US Food and Drug Administration (FDA) granted valoctocogene roxaparvovec orphan drug status in 2016,[11] and breakthrough therapy designation in 2017.[12]

However, in August 2020, BioMarin received a Complete Response Letter from the FDA, indicating that its Biologics License Application (which would have made valoctocogene roxaparvovec the first gene therapy to be approved for a bleeding disorder) would not be approved.[13] The regulator was concerned that differences between results from the phase I/II trials (the 270-201 study)[14] and the phase III trial (the 270-301 study)[15] were too dissimilar with regard to durability, the latter suggesting that the protective effect of valoctocogene roxaparvovec wore off after approx. 12-18 months.[16]

The safety and effectiveness of valoctocogene roxaparvovec were evaluated in a multinational study in adult men 18 to 70 years of age with severe hemophilia A who were previously treated with factor VIII replacement therapy.[7] Effectiveness was established based on results from a cohort of 112 participants followed up for at least 3 years after valoctocogene roxaparvovec treatment.[7] Following the infusion, the mean annualized bleeding rate decreased from 5.4 bleeds per year at baseline to 2.6 bleeds per year.[7] The majority of participants who received valoctocogene roxaparvovec received corticosteroids to suppress the immune system for the gene therapy to be effective and safe.[7] The FDA granted the application for valoctocogene roxaparvovec orphan drug, breakthrough therapy, regenerative medicine advanced therapy, and priority review designations.[7] The FDA granted approval of Roctavian to BioMarin Pharmaceutical Inc.[7]

Society and culture

Legal status

On 23 June 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Roctavian, intended for the treatment of severe haemophilia A.[17][5] As Roctavian is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies.[5] The applicant for this medicinal product is BioMarin International Limited.[5] Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022.[3][4]

In June 2023, the US FDA approved valoctocogene roxaparvovec for the treatment of adults with severe hemophilia A without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test.[7]

References

  1. ^ a b c d "Roctavian- valoctocogene roxaparvovec-rvox injection, solution". DailyMed. 20 December 2019. Retrieved 28 August 2023.
  2. ^ "Roctavian". U.S. Food and Drug Administration (FDA). 30 June 2023. Archived from the original on 5 July 2023. Retrieved 4 July 2023.
  3. ^ a b c d e f g h "Roctavian EPAR". European Medicines Agency (EMA). 20 June 2022. Archived from the original on 4 March 2023. Retrieved 4 March 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ^ a b c d "Roctavian Product information". Union Register of medicinal products. 25 August 2022. Archived from the original on 22 May 2023. Retrieved 6 September 2022.
  5. ^ a b c d "Roctavian: Pending EC decision". European Medicines Agency (EMA). 23 June 2022. Archived from the original on 26 June 2022. Retrieved 26 June 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ^ "Roctavian (formerly Valrox/BMN 270)". BioNews Services, LLC. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  7. ^ a b c d e f g h i "FDA Approves First Gene Therapy for Adults with Severe Hemophilia A". U.S. Food and Drug Administration (FDA) (Press release). 30 June 2023. Retrieved 4 July 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ "U.S. Food and Drug Administration Approves BioMarin's Roctavian (valoctocogene roxaparvovec-rvox), the First and Only Gene Therapy for Adults with Severe Hemophilia A" (Press release). BioMarin Pharmaceutical. 29 June 2023. Retrieved 4 July 2023 – via PR Newswire.
  9. ^ Bunting S, Zhang L, Xie L, Bullens S, Mahimkar R, Fong S, et al. (February 2018). "Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice". Molecular Therapy. 26 (2): 496–509. doi:10.1016/j.ymthe.2017.12.009. PMC 5835117. PMID 29292164.
  10. ^ Rosen S, Tiefenbacher S, Robinson M, Huang M, Srimani J, Mackenzie D, et al. (November 2020). "Activity of transgene-produced B-domain-deleted factor VIII in human plasma following AAV5 gene therapy". Blood. 136 (22): 2524–2534. doi:10.1182/blood.2020005683. PMC 7714098. PMID 32915950.
  11. ^ "BioMarin Receives Orphan Drug Designation From FDA for First AAV-Factor VIII Gene Therapy, BMN 270, for Patients With Hemophilia A" (Press release). BioMarin Pharmaceutical Inc. 1 March 2016. Archived from the original on 9 July 2021. Retrieved 1 July 2021 – via GlobeNewswire.
  12. ^ "FDA Grants Breakthrough Therapy Designation for BioMarin's Valoctocogene Roxaparvovec (formerly BMN 270), an Investigational Gene Therapy for Hemophilia A". BioMarin Investors (Press release). Archived from the original on 23 June 2021. Retrieved 1 July 2021.
  13. ^ "BioMarin Receives Complete Response Letter (CRL) from FDA for Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A". BioSpace. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  14. ^ "Gene Therapy Study in Severe Haemophilia A Patients (270-201)". ClinicalTrials.gov. January 2021. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  15. ^ "A Phase 3 Open-Label, Single-Arm Study To Evaluate The Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Residual FVIII Levels ≤ 1 IU/dL Receiving Prophylactic FVIII Infusions". ClinicalTrials.gov. January 2021. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  16. ^ Adams B (19 August 2020). "FDA gets out its red pen again, rejecting BioMarin's gene therapy valrox amid durability worries". FierceBiotech. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  17. ^ "First gene therapy to treat severe haemophilia A". European Medicines Agency (EMA) (Press release). 24 June 2022. Archived from the original on 26 June 2022. Retrieved 26 June 2022.


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