Valoctocogene roxaparvovec explained

Gt Target Gene:Factor VIII
Gt Vector:Adeno-associated virus
Gt Nucleic Acid Type:DNA
Gt Delivery Method:Intravenous
Tradename:Roctavian
Dailymedid:Valoctocogene roxaparvovec
Routes Of Administration:Intravenous
Class:Antihemorrhagics
Atc Prefix:B02
Atc Suffix:BD15
Legal Us:Rx-only
Legal Us Comment:[1] [2]
Legal Eu:Rx-only
Legal Eu Comment:[3]
Cas Number:1819334-78-5
Drugbank:DB15561
Unii:681K1JDI8M
Kegg:D12434
Synonyms:BMN-270, Valrox, valoctocogene roxaparvovec-rvox

Valoctocogene roxaparvovec, sold under the brand name Roctavian, is a gene therapy used for the treatment of hemophilia A. It was developed by BioMarin Pharmaceutical.[4] 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. It is an adeno-associated virus vector-based gene therapy. It is given by intravenous infusion.

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.

Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022, and in the United States in June 2023.[5] [6]

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).

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.

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.[7] [8]

History

The US Food and Drug Administration (FDA) granted valoctocogene roxaparvovec orphan drug status in 2016,[9] and breakthrough therapy designation in 2017.[10]

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.[11] The regulator was concerned that differences between results from the phase I/II trials (the 270-201 study)[12] and the phase III trial (the 270-301 study)[13] were too dissimilar with regard to durability, the latter suggesting that the protective effect of valoctocogene roxaparvovec wore off after approx. 12-18 months.[14]

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. Effectiveness was established based on results from a cohort of 112 participants followed up for at least 3 years after valoctocogene roxaparvovec treatment. Following the infusion, the mean annualized bleeding rate decreased from 5.4 bleeds per year at baseline to 2.6 bleeds per year. The majority of participants who received valoctocogene roxaparvovec received corticosteroids to suppress the immune system for the gene therapy to be effective and safe. The FDA granted the application for valoctocogene roxaparvovec orphan drug, breakthrough therapy, regenerative medicine advanced therapy, and priority review designations. The FDA granted approval of Roctavian to BioMarin Pharmaceutical Inc.

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.[15] As Roctavian is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. The applicant for this medicinal product is BioMarin International Limited.[16] Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022.[17]

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.

Notes and References

  1. Web site: Roctavian- valoctocogene roxaparvovec-rvox injection, solution . DailyMed . 20 December 2019 . 28 August 2023.
  2. Web site: Roctavian . U.S. Food and Drug Administration (FDA) . 30 June 2023 . 4 July 2023 . 5 July 2023 . https://web.archive.org/web/20230705040515/https://www.fda.gov/vaccines-blood-biologics/roctavian . live .
  3. Web site: Roctavian Product information . Union Register of medicinal products . 25 August 2022 . 6 September 2022 . 22 May 2023 . https://web.archive.org/web/20230522161630/https://ec.europa.eu/health/documents/community-register/html/h1668.htm . live .
  4. Web site: Roctavian (formerly Valrox/BMN 270). 1 July 2021. BioNews Services, LLC. 9 July 2021. https://web.archive.org/web/20210709183403/https://hemophilianewstoday.com/bmn-270/. live.
  5. 30 June 2023 . FDA Approves First Gene Therapy for Adults with Severe Hemophilia A . 4 July 2023 . U.S. Food and Drug Administration (FDA) .
  6. 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 . BioMarin Pharmaceutical . PR Newswire . 29 June 2023 . 4 July 2023.
  7. 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 . 6 . 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 . February 2018 . 29292164 . 5835117 . 10.1016/j.ymthe.2017.12.009 .
  8. Rosen S, Tiefenbacher S, Robinson M, Huang M, Srimani J, Mackenzie D, Christianson T, Pasi KJ, Rangarajan S, Symington E, Giermasz A, Pierce GF, Kim B, Zoog SJ, Vettermann C . 6 . Activity of transgene-produced B-domain-deleted factor VIII in human plasma following AAV5 gene therapy . Blood . 136 . 22 . 2524–2534 . November 2020 . 32915950 . 7714098 . 10.1182/blood.2020005683 .
  9. 1 March 2016. BioMarin Receives Orphan Drug Designation From FDA for First AAV-Factor VIII Gene Therapy, BMN 270, for Patients With Hemophilia A. live. 1 July 2021 . BioMarin Pharmaceutical Inc. . GlobeNewswire . 9 July 2021. https://web.archive.org/web/20210709184317/https://www.globenewswire.com/news-release/2016/03/01/816024/18475/en/BioMarin-Receives-Orphan-Drug-Designation-From-FDA-for-First-AAV-Factor-VIII-Gene-Therapy-BMN-270-for-Patients-With-Hemophilia-A.html.
  10. FDA Grants Breakthrough Therapy Designation for BioMarin's Valoctocogene Roxaparvovec (formerly BMN 270), an Investigational Gene Therapy for Hemophilia A. 1 July 2021. BioMarin Investors. 23 June 2021. https://web.archive.org/web/20210623230220/https://investors.biomarin.com/2017-10-26-FDA-Grants-Breakthrough-Therapy-Designation-for-BioMarins-Valoctocogene-Roxaparvovec-formerly-BMN-270-an-Investigational-Gene-Therapy-for-Hemophilia-A. live.
  11. Web site: BioMarin Receives Complete Response Letter (CRL) from FDA for Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A. 1 July 2021. BioSpace. 9 July 2021. https://web.archive.org/web/20210709184219/https://www.biospace.com/article/biomarin-receives-complete-response-letter-crl-from-fda-for-valoctocogene-roxaparvovec-gene-therapy-for-severe-hemophilia-a/. live.
  12. Web site: January 2021. Gene Therapy Study in Severe Haemophilia A Patients (270-201) . ClinicalTrials.gov. 1 July 2021. 9 July 2021. https://web.archive.org/web/20210709182333/https://clinicaltrials.gov/ct2/show/NCT02576795. live.
  13. Web site: January 2021. 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. 1 July 2021. 9 July 2021. https://web.archive.org/web/20210709181535/https://clinicaltrials.gov/ct2/show/NCT03370913. live.
  14. Web site: Adams B. FDA gets out its red pen again, rejecting BioMarin's gene therapy valrox amid durability worries. live. 1 July 2021. FierceBiotech. 19 August 2020 . 9 July 2021. https://web.archive.org/web/20210709182220/https://www.fiercebiotech.com/biotech/fda-gets-out-its-red-pen-again-rejecting-biomarin-s-gene-therapy-valrox-amid-durability.
  15. First gene therapy to treat severe haemophilia A . European Medicines Agency (EMA) . 24 June 2022 . 26 June 2022 . 26 June 2022 . https://web.archive.org/web/20220626014840/https://www.ema.europa.eu/en/news/first-gene-therapy-treat-severe-haemophilia . live .
  16. Web site: Roctavian: Pending EC decision . European Medicines Agency (EMA) . 23 June 2022 . 26 June 2022 . 26 June 2022 . https://web.archive.org/web/20220626014831/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/roctavian . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  17. Web site: Roctavian EPAR . European Medicines Agency (EMA) . 20 June 2022 . 4 March 2023 . 4 March 2023 . https://web.archive.org/web/20230304051404/https://www.ema.europa.eu/en/medicines/human/EPAR/roctavian-0 . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

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