Valoctocogene roxaparvovec

Valoctocogene roxaparvovec, sold under the brand name Roctavian, is a gene therapy for the treatment of hemophilia A.[2] It was developed by BioMarin Pharmaceutical.[1][2][3]

Valoctocogene roxaparvovec
Gene therapy
Target geneF8
VectorAAV5
Nucleic acid typeDNA
Delivery methodIV
Clinical data
Trade namesRoctavian
Other namesBMN-270, Valrox
Routes of
administration		Intravenous
ATC code
  • None
Legal status
Legal status
  • EU: Rx-only [1]
Identifiers
CAS Number
UNII
KEGG

Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022.[1]

Mechanism of action

Hemophilia A is a bleeding disorder that results from mutations in the F8 gene, which codes for the Factor VIII protein essential to the clotting process. Patients with hemophilia A produce too little Factor VIII or an ineffective version of the protein. Conventional treatment for severe cases is typically through regular intravenous infusions of recombinant or plasma concentrated Factor VIII.

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 liver endothelial and sinusoidal cells, where Factor VIII is ordinarily synthesised.[4][5] By transfecting a functional version of the F8 gene into liver cells, the patient would be able to produce sufficient amounts of biologically

History

The Food and Drug Administration granted valoctocogene roxaparvovec orphan drug status in 2016[6] and breakthrough therapy designation in 2017.[7]

However, in late 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.[8] The regulator was concerned that differences between results from the phase I/II trials (the 270-201 study)[9] and the phase III trial (the 270-301 study)[10] were too dissimilar with regard to durability, the latter suggesting that the protective effect of valoctocogene roxaparvovec wore off after approx. 12-18 months.[11] The FDA advised BioMarin to resubmit two-year follow-up evidence of safety and effectiveness on all study participants, which puts the earliest date of resubmission to late 2021.[11]

Society and culture

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.[12][2] As Roctavian is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies.[2] The applicant for this medicinal product is BioMarin International Limited.[2] Valoctocogene roxaparvovec was approved for medical use in the European Union in August 2022.[1]

References
  1. "Roctavian". Union Register of medicinal products. 25 August 2022. Retrieved 6 September 2022.
  2. "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.
  3. "Roctavian (formerly Valrox/BMN 270)". BioNews Services, LLC. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  4. 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.
  5. 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.
  6. BioMarin Pharmaceutical Inc. (1 March 2016). "BioMarin Receives Orphan Drug Designation From FDA for First AAV-Factor VIII Gene Therapy, BMN 270, for Patients With Hemophilia A". GlobeNewswire News Room. Archived from the original on 9 July 2021. Retrieved 1 July 2021.
  7. "FDA Grants Breakthrough Therapy Designation for BioMarin's Valoctocogene Roxaparvovec (formerly BMN 270), an Investigational Gene Therapy for Hemophilia A". BioMarin Investors. Archived from the original on 23 June 2021. Retrieved 1 July 2021.
  8. "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.
  9. BioMarin Pharmaceutical (20 January 2021). "A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of Valoctocogene Roxaparvovec, an Adenovirus-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Patients With Severe Haemophilia A". Archived from the original on 9 July 2021. Retrieved 1 July 2021. {{cite journal}}: Cite journal requires |journal= (help)
  10. BioMarin Pharmaceutical (15 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". Archived from the original on 9 July 2021. Retrieved 1 July 2021. {{cite journal}}: Cite journal requires |journal= (help)
  11. 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.
  12. "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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