Valoctocogene roxaparvovec

valoctogene roxaparvovec
Gene therapy
Target geneF8
VectorAAV5
Nucleic acid typeDNA
Delivery methodIV
Clinical data
Trade namesRoctavian
Other namesBMN-270, Valrox
Identifiers
CAS Number
PubChem SID
UNII

Valoctocogene roxaparvovec (trade name Roctavian, also known as BMN-270 and Valrox) is an experimental gene therapy for hemophilia A under development by BioMarin Pharmaceutical.[1]

Development history

The Food and Drug Administration granted valoctocogene roxaparvovec orphan drug status in 2016[2] and breakthrough therapy designation in 2017.[3]

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.[4] The regulator was concerned that differences between results from the Phase 1/2 trials (the 270-201 study)[5] and the Phase 3 trial (the 270-301 study)[6] were too dissimilar with regard to durability, the latter suggesting that the protective effect of valoctocogene roxaparvovec wore off after approx. 12-18 months.[7] 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.[7]

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.[8][9] By transfecting a functional version of the F8 gene into liver cells, the patient would be able to produce sufficient amounts of biologically

Culture and society

If approved, valoctocogene roxaparvovec would be priced between US$2,000,000 and US$3,000,000.[10] Since valoctocogene roxaparvovec would be a durable therapy, the overall lifetime treatment cost may still be lower with valoctocogene roxaparvovec than with competing non-gene-therapy drug emicizumab (Hemlibra), which costs approximately US$289,000 per patient-year.[11]

References

  1. ↑ "Roctavian (formerly Valrox/BMN 270)". BioNews Services, LLC. Retrieved 2021-07-01.
  2. ↑ BioMarin Pharmaceutical Inc. (2016-03-01). "BioMarin Receives Orphan Drug Designation From FDA for First AAV-Factor VIII Gene Therapy, BMN 270, for Patients With Hemophilia A". GlobeNewswire News Room. Retrieved 2021-07-01.{{cite web}}: CS1 maint: url-status (link)
  3. ↑ "FDA Grants Breakthrough Therapy Designation for BioMarin's Valoctocogene Roxaparvovec (formerly BMN 270), an Investigational Gene Therapy for Hemophilia A". BioMarin Investors. Retrieved 2021-07-01.
  4. ↑ "BioMarin Receives Complete Response Letter (CRL) from FDA for Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A". BioSpace. Retrieved 2021-07-01.
  5. ↑ BioMarin Pharmaceutical (2021-01-20). "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". {{cite journal}}: Cite journal requires |journal= (help)
  6. ↑ BioMarin Pharmaceutical (2021-01-15). "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". {{cite journal}}: Cite journal requires |journal= (help)
  7. 1 2 Adams B. "FDA gets out its red pen again, rejecting BioMarin's gene therapy valrox amid durability worries". FierceBiotech. Retrieved 2021-07-01.{{cite web}}: CS1 maint: url-status (link)
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ Bratulic A (16 January 2020). "BioMarin eyes $2-million to $3-million price for experimental haemophilia A gene therapy Valrox". First Word Pharma. Retrieved 2021-07-01.{{cite web}}: CS1 maint: url-status (link)
  11. ↑ Patel AM, Corman SL, Chaplin S, Raimundo K, Sidonio RF (December 2019). "Economic impact model of delayed inhibitor development in patients with hemophilia a receiving emicizumab for the prevention of bleeding events". Journal of Medical Economics. 22 (12): 1328–1337. doi:10.1080/13696998.2019.1669614. PMID 31530050. S2CID 202674233.
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