New Medicines

RoctavianSevere haemophilia A in males


New molecular entity

Development and Regulatory status

Phase III Clinical Trials
Recommended for approval (Positive opinion)
Not approved
Jun 22Recommended for conditional EU approval by CHMP “for the treatment of severe haemophilia A (congenital factor VIII deficiency) in adult patients without a history of factor VIII inhibitors and without detectable antibodies to adeno associated virus serotype 5 (AAV5)”. Roctavian will be available as a 2 x 10¹³ vg/mL solution for infusion [33].
Jun 22Anticipated June filing delayed as FDA have additional questions for company to address. Filing now expected September 2022. With and expected six-month review procedure commercial launch in US is expected Q1 23 at earliest. EMA decision anticipated by midyear 2022
Feb 22BioMarin plans to resubmit to FDA in June, followed by an expected six-month review [29].
Jan 22BioMarin plan to submit US filing Q2 22 [28].
Jun 21BioMarin resubmits MAA to EMA for valoctocogene roxaparvovec to treat severe haemophilia A. Submission includes safety and efficacy data from PIII GENEr8-1 study (n=134; minimum1 year follow-up), as well as 4 and 3 years of follow-up from 6e13 vg/kg and 4e13 vg/kg dose cohorts, respectively, in ongoing PI/II dose escalation study [26].
May 21Granted accelerated assessment by EMA [25].
May 21BioMarin has yet to decide on its plans for UK availability [24].
Apr 21BioMarin announce that, based on positive pre-submission feedback, valoctocogene is tracking as expected; they anticipate re-submitting a MAA with the EMA in June 2021 with one-year results from the Phase 3 GENEr8-1 study.[23]
Nov 20BioMarin reports that it has recently withdrawn the EU MAA and plans to resubmit the MAA with one-year top-line PIII data to the EMA in Q2 2021. The PIII study was fully enrolled in Nov 19 and will complete one-year of follow-up of all patients in Nov 20. the company plans to submit these data to the FDA in Q1 21 [20].
Sep 20EU CHMP has requested more data to review the marketing application for valoctocogene roxaparvove, the full 52-week results from the 134 patients taking part in the ongoing PIII study of the treatment. BioMarin expects the last patient to reach 52 weeks of follow-up in Nov 20, and is working with the regulator to enable a potential submission of the requested data by the end of Q1 21. The review has reverted from an accelerated assessment to a standard review [19].
Aug 20US FDA did not approve valactocogene for Hemophilia A. The application was based on interim analysis of the PIII study and also with 3-year data from the PI/II study which indicate positive outcomes. In their complete response letter (CRL), the FDA recommended BioMarin complete the PIII trial and submit 2-year follow-up safety and efficacy data to provide substantial evidence of a durable effect using Annualized Bleeding Rate (ABR) as the primary endpoint. This follows concerns over the duration of response, with some physicians suggesting that it will begin to lose clinical benefit over time. The trial will fully complete in Q4 2021 and the company. [18]
Feb 20The FDA has accepted for Priority Review the Biologics License Application (BLA) for AAV5 gene therapy valoctocogene roxaparvovec, for adults with hemophilia A. The PDUFA action date is August 21, 2020 [14].
Feb 20Analysts predict this will be one of the top 10 most-anticipated new US drug launches of 2020 based on estimated global sales in 2024 [13].
Dec 19Filed in the US, with a decision expected Feb 20. In the EU, The EMA granted valocotogene access to its Priority Medicines (PRIME) regulatory initiative in 2017 and recently granted accelerated assessment of the MAA, potentially shortening the review period, with a decision expected in Jan 20 [10].
Nov 19BioMarin has submitted a MAA to the European Medicines Agency for its investigational gene therapy, valoctocogene roxaparvovec, for adults with severe hemophilia A [9].
Aug 19BioMarin plans to submit an accelerated approval request to the FDA and to the EMA during Q4 2019 [8].
May 19BioMarin aims to meet with FDA and EMA to review the data with plans to submit marketing applications in Q3 2019.[7]
Oct 17valoctocogene roxaparvovec (previously BMN270) granted Breakthrough Therapy designation by the FDA based on data from ongoing PI/II trials. Protocols for PIII studies have been submitted to and approved by both the FDA and the MHRA. US PIII studies are expected to start after approval from institutional review boards [3].
Apr 17Biomarin plans to commence PIII study in Q3 17 [2].
Feb 17Granted PRIME status in the EU. Has orphan drugs status in the EU & US [2].


An in vivo gene therapy, given as a single dose, that uses an adeno-associated virus 5 (AAV5) vector to deliver factor VIII (FVIII) gene to liver cells, to stimulate production of FVIII.
It affects 1:4,000 to 1:5,000 live male births worldwide [1].
Severe haemophilia A in males
Intravenous infusion

Further information


Trial or other data

Apr 22BioMarin is conducting an additional study - PI/II (NCT04684940), to evaluate the safety and efficacy of valoctocogene roxaparvovec in patients with severe haemophilia A and inhibitors to FVIII. Part A of the study will involve subjects who have active inhibitors to FVIII, and Part B involving subjects with a prior history of inhibitors. 20 adults will be enrolled in the Children ´s Hospital Los Angeles and at the Royal Free Hospital in London [31].
Mar 22Company announces publishing of PIII trial (NCT03370913) results in the New England Journal of Medicine. After a single infusion of valoctocogene roxaparvovec, pts experienced substantially reduced annualised bleeding rates, reduced Factor VIII utilisation and increased Factor VIII activity. 90% of pts dosed had either no treated bleeds or fewer treated bleeds after infusion vs Factor VIII prophylactic treatment. At weeks 49 and 52, 88% of pts had a median Factor VIII activity of 5 IU/dL or higher [30]
Feb 22PI/II trial (NCT03520712) to determine the safety of valoctocogene roxaparvovec (an Adenovirus-Associated Virus (AAV) based gene therapy vector) in severe Hemophilia A patients with pre-existing antibodies against AAV5 is recruiting. It started in Apr 18, and is recruiting adults in South Africa and the UK (at the Royal Free Hospitaland University Hospital Southampton NHS Foundation Trust). All participants will receive a single dose of BMN270 at a dose of 6E13 vg/kg. Primary outcome is safety, including development of FVIII neutralising antibody; collection of these data is due to complete Nov 27 [31].
Jan 22BioMarin announce results from GENEr8-1 study (n=134); treatment with valoctocogene roxaparvovec reduced annualised bleeding rate (ABR) by 4.1 treated bleeds per year, from a baseline mean of 4.8 (85% RR, p<0.0001) [28].
Jul 21Updated trial data shows pts treated with valoctocogene roxaparvovec had a median of 8.2% the amount of factor VIII levels that would be found in a healthy individual. The level of factor VIII was 60.3% after a one-year follow-up. Pts were mostly free of symptoms despite consistent reductions in protein levels over time. It reduced the annualized bleeding rate in six pts by 95%. At 5 years, six out of the seven pts in the study had no bleeding events. [27]
May 21A further PIII study, GENEr8-3 (NCT04323098, n=20) is underway has a primary completion date of December 2021. [22]
Aug 20Analysts in the USA estimate valoctocogene would be priced somewhere in the range of $1 million to $3 million - the price has been debated and BioMarin have noted that the current price of blood clotting treatments over the lifetime of a patient is ~$25 million per patient.[18]
Jun 20Updated PI/II data presented virtually at the annual meeting of the World Federation of Hemophilia. Seven patients who received the highest dose of valoctocogene roxaparvovec saw their bleeding episodes fall 95% over four years. Before gene therapy, those patients needed more than 130 infusions of factor VIII to manage their disease each year; after treatment, that number dropped to an average of five infusions per year. Six of the seven patients (86%) were bleed-free in the fourth year and all seven remain off prophylactic doses of factor VIII. However, treatment effects on factor VIII activity levels waned over time, with four-year figures for patients who got the highest dose showing a noticeable decrease from those recorded at the three-year follow-up. And the three-year data had already shown a drop in factor VIII levels, raising the possibility that patients might need to be re-dosed to keep up protection against bleeds [17].
Apr 20Valoctocogene has been prioritised for potential TA guidance production. Topic has been passed to scoping team to prepare for a consultation exercise [16]
Jan 20PIII BMN 270-302 study (NCT03392974) is ongoing to confirm the safety and effectiveness of the 4E13 vg/kg dose of valoctocogene roxaparvovec. 40 adults will be recruited [15].
Jan 20PIII BMN 270-301 study (NCT03370913) is ongoing to confirm the safety and effectiveness of the 6E13 vg/kg dose of valoctocogene roxaparvovec. 134 adults have been recruited [15].
Jan 20NCT02576795 - UK trial sites (Hampshire, Birmingham, Bristol, Cambridge, Glasgow, Barts, Guy´s, Imperial, Southampton) [12]
Jan 20Follow up data published showed sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×1013 vg per kilogram or 6×1013 vg per kilogram of the gene therapy. [11]
May 19Positive PIII clinical trial results announced for valoctocogene roxaparvovec in adults with hemophilia A. Eight out of 20 pts in the GENEr8-1 study showed Factor VIII levels of 40 IU/dL or more at 23-26 wks (which was the pre-specified criteria for Factor VIII activity levels). Of the 16 pts who made it to week 26 by the April 30 cutoff, the estimated median Annual Bleed Rate (ABR) was zero and the estimated ABR was 1.5. This comes to a decrease of 85% from baseline levels where all pts were receiving standard of care prophylaxis. There was also an 84% decrease in annualized Factor VIII usage and a 94% decrease in mean FVIII usage annualized between week 5 and 26. In May 2018, BioMarin reported a 98% drop in mean Factor VIII usage the change from 98% to 94% suggests there may be a diminishing treatment effect.[7]
Dec 18Two phase III studies (GENEr8-1 and GENEr8-2) ongoing, both with estimated primary completion date of Dec 2022. [6]
Dec 17Press reports claim this could be a cure for haemophilia, following results published in NEJM. A single infusion of the gene therapy drug showed improved levels of the essential blood clotting protein Factor VIII, with 85% of patients achieving normal or near-normal Factor VIII levels even many months after treatment. The transformational results have particular significance as the first successful gene therapy trial for haemophilia A [5].
Dec 17Results of PI/II study (NCT02576795) published in NEJM. A single intravenous dose of AAV5-hFVIII-SQ was infused in 9 men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected [4].
Oct 16MHRA, based on a review of data from nine enrolled subjects, approves continuation of enrolment in a PI/II study, designed to assess the safety and efficacy of BMN 270 in patients with severe haemophilia A; recruitment is expected to resume before end of 2016 (NCT02576795). The MHRA also approved increasing the additional enrolment to up to six patients, of whom three will be enrolled at the 4 x 1013 vg/kg dose and an additional three at the same dose or a previously tested 6 x 1013 vg/kg dose, as well as approved the removal of the requirement for prophylactic corticosteroid therapy for the additional subjects; threshold to initiate therapeutic corticosteroids has also been increased. Data from these subjects will support the design of the planned PIIb study. BioMarin, in June 2016, had suspended enrolment in the trial due to reports of elevated alanine aminotransferase (ALT) levels in some patients. Based on the results, prophylactic corticosteroid therapy was started and no abnormal levels of ALT were observed after that [2].

Evidence based evaluations