HIGH IMPACT – BioMarin released 3-year data from its ongoing global phase 3 GENEr8-1 study for Roctavian in adults with severe hemophilia A.

  • Mean/median FVIII activity (chromogenic) at year 3 was 18.8/8.4% (n=132). The 3 year mean FVIII activity was slightly better than 3 year mean activity of 15.2% listed in the Roctavian SmPC (n=19). Mean/median ABR for all bleeds in year 3 was 1.6/0.0 (see below for treated bleeds). At the end of year 3, 92% of patients remained off prophylaxis, a reduction from the 95% at year 2
  • BioMarin reported 4 year data (n=17) for the first time from this trial. Mean/median FVIII was 15.2/7.4%. Mean/median ABR for all bleeds in year 4 were 1.6/1.0 (see below for treated bleeds)
  • BioMarin has executed an outcomes-based agreement with one of the three largest health insurance groups in Germany and is targeting signing additional agreements in Germany in the coming weeks. BioMarin stated there are 40 patients queued for pre-treatment screening in Germany


Phase 3 (6e13 vg/kg dose)
In Year 3*In Year 4**
FVIII Activity (chromogenic)Mean18.815.2
ABR for treated bleedsMean1.00.8
ABR for all bleeds (regardless of being treated with exogenous FVIII replacement)Mean1.41.6
Annualized FVIII Utilization (infusions per year)Mean8.411.1

*N=132 (FVIII Activity); N=112 (ABR and AFR). Two of these patients discontinued from the study prior to reaching Year 3. FVIII imputed to be 0 IU/dL; no imputation was carried out for ABR and AFR.
**N=17. One of these patients discontinued from the study prior to reaching Year 4. FVIII activity imputed to be 0 IU/dL; no imputation was carried out for ABR and AFR.

  • At the end of year 3, 92% of patients remained off prophylaxis. Those who returned to FVIII or emicizumab prophylaxis did so safely
  • Two patients discontinued from the study during year 3 and one additional patient discontinued from the study during year 4. The press release did not provide additional information on these discontinuations


  • Safety profile was consistent with that which was previously reported
  • No delayed-onset treatment related AEs or treatment-related SAEs or Grade 3 events attributed to Roctavian or corticosteroid use
  • No participants have developed inhibitors to FVIII, thromboembolic events or malignancy associated with Roctavian

Regulatory Status:

  • The company continued to state that the March 31 PDUFA date may be extended
  • FDA has completed pre-license inspection of manufacturing facility in early December – BioMarin stated that all comments are addressable

EU Launch Update:

  • The three largest health insurance groups BioMarin is targeting represent 80% of German citizens
  • The OBAs in Germany are multiyear agreements which provide companion diagnostic testing and reimbursement of Roctavian and cover payer risk of patients potentially returning to prophylaxis through direct BioMarin financial commitment in return for substantial and full upfront payment
  • BioMarin has had meetings with authorities in France and has submitted a reimbursement dossier in Italy

Additional details to year-3 data will be presented at a future scientific conference (In 2022, BioMarin presented 2 year results at EAHAD, but a presentation is currently not on the EAHAD 2023 schedule).

inThought Analysis

While the FVIII activity is still declining over time, the rate of decline continues to decrease:  51% decline from year 1 to 2; 39% decline from year 2 to 3; 12% decline from year 3 to 4 (only 17 patients).  This is in general similar to the phase 1/2 declines, which have continued out to 6 years now but have also shown a reduction in the rate of decline.

While median ABR for treated bleeds remained 0.0 at year 3 and the limited number of patients in year 4, the median ABR for all bleeds increased to 1.0 at year 4 – this increase may spark questions about efficacy, especially if it eventually translates into treated bleeds.

Additionally, the increase in the number of patients returning to prophylaxis may lead to some patients waiting to see how fast this percentage increases over time.

FDA had previously requested 3-year data for Roctavian to evaluate longer-term efficacy and safety. BioMarin has continuously advertised to investors that the FDA review may take 3 months longer than the March 31st PDUFA date, which would imply an approval in June 2023 instead. The 3-year mean FVIII activity for all the patients of 18.8 (CSA) is only slightly greater than the EU SmPC with 19 patients at 15.2 (CSA), providing BioMarin only marginal benefit with the full dataset going into the FDA review process.


Source: BioMarin Press Release