Biomarin
Valoctocogene roxaparvovec
Biomarin’s valoctocogene roxaparvovec (now known as ValRox) is in Phase I/II and III trials in haemophilia A. The two Phase III trials are evaluating doses of 4e13vg/kg (GENEr8-2; n=40) and 6e13 vg/kg (GENEr8-1; n=134). The study protocol of GENEr8-1 was amended (by increasing the study population from 40 to 130) so that it is statistically powered to demonstrate superiority over traditional FVIII prophylaxis.
In August 2020, the Food and Drug Administration (FDA), the United States regulatory authority, declined Biomarin’s submission for marketing authorisation for valoctocogene roxaparvovec [1]. The FDA concluded that there was insufficient follow-up data from the ongoing Phase III trial (GENr8-1) and it advised Biomarin to complete the trial and obtain 2 years of follow up data. Biomarin had provided follow up data obtained from a Phase I/II trial and interim data from the Phase III trial. The company says that Phase III follow up will be complete in November 2021. The FDA decision does not imply lack of efficacy or short-term safety but rather a concern to establish the durability of effect.
The European Medicines Agency has slowed progress on Biomarin’s application pending 52-week follow up data from the Phase III trial [2]. A submission is now expected by March 2021.
Four-year follow up data in 6 patients who received 6e13 vg/kg in the Phase I/II trial of valoctocogene roxaparvovec were reported at the World Federation of Hemophilia 2020 Virtual Congress, and 3-year data in 6 treated with 4e13 vg/kg [3].
| For the higher dose | For the lower dose |
| Mean factor VIII activity in the fourth year was 24% | Mean factor VIII activity in the third year was 9.9% |
| In the fourth year, mean annualised bleeding rate was 1.3 (median zero) (compared with 16 before treatment) | In the third year, mean annualised bleeding rate was 0.5 (median zero) (compared with 12 before treatment) |
| Over four years, the cumulative mean ABR was 0.8 | Over three years, the cumulative mean ABR was 0.9 |
| Factor VIII use averaged 5.4 infusions per year over 4 years (vs 136 pre-treatment) | Factor VIII use averaged 5.7 infusions per year over 4 years (vs 143 pre-treatment) |
Graphical data reported by Biomarin show a very gradual decline in factor VIII activity over time after both doses.
References
- BioMarin Receives Complete Response Letter (CRL) from FDA for Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A. 19 August 2020.
- EMA delays review of BioMarin hemophilia A candidate. 10 September 2020.
- BioMarin Provides Additional Data from Recent 4 Year Update of Ongoing Phase 1/2 Study of Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A in Late-Breaking Oral Presentation at World Federation of Hemophilia Virtual Summit.