BioMarin to Investigate B-ALL Case in Val-Rox Gene Therapy Clinical Trial


The gene therapy received a conditional marketing approval in the European Union in August 2022.

BioMarin revealed in an SEC filing that it is investigating a case of b-cell acute lymphoblastic leukemia (B-ALL) in a patient who received its investigational gene therapy for hemophilia, valoctocogene roxaparvovec (val-rox; BMN-270).1

Genetic testing of the patient's leukemic cells showed that 85% carried a Philadelphia-like chromosomal translocation, a known driver in leukemic cells. In addition, leukemic cells enriched to 90% purity from peripheral blood carried negligible levels of the gene therapy BMN-270 vector DNA.

"These negligible, near background levels of BMN 270 indicate that BMN 270 is not clonally expanding in these leukemic cells," the company said in the filing.1 "Additional genomic analyses are underway, which BioMarin expects to confirm the absence of BMN 270 vector integration events contributing to leukemic growth, as well as to provide further insights into the underlying genetic etiology of this case."

At this time, neither the FDA nor the EU has imposed a hold on the study, and the independent Data Safety Monitoring Board has not recommended any changes to study protocols.

The patient participated in one of the company's ongoing phase 3 clinical trials, GENEr8-1 study (NCT03370913) and GENEr8-3 (NCT04323098). Both studies are evaluating a single administration of the val-rox gene therapy at a dose of 6x1013 vg/kg, though the GENEr8-3 couples the gene therapy with prophylactic corticosteroids. The primary end point of both studies is change from baseline in median FVIII activity at 52 weeks post-infusion.

Results from GENEr8-1 were published earlier this year in the New England Journal of Medicine,2 demonstrating a statistically significant increase in mean factor VIII activity level at weeks 49 through 52 (41.9 IU per deciliter; 95% CI, 34.1-49.7; P <.001) as well as a 98.6% and 83.8% decrease in rates of factor VIII concentrate use and treated bleeding after week 4, respectively (P <.001). All participants experienced at least 1 adverse event (AE), with 16.4% experiencing a serious AE. Elevations in alanine aminotransferase levels occurred in 85.8% of participants, with other common AEs including headache, nausea, and elevations in aspartate aminotransferase levels.

These findings supported the val-rox marketing authorization in the EU,3 which was granted on August 25, 2022 under conditions, including an indication for adult patients with severe hemophilia A without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus (AAV) serotype 5. Roctavian will retain its orphan drug designation and was also granted 10-year market exclusivity.

Meanwhile in the US, the FDA's call for additional data has delayed BioMarin's biologics license application submission for val-rox twice,4 with the company intending on resubmitting by the end of September.


1. Securities and Exchange Commission, Form 8-K. BioMarin Pharmaceuticals. September 12, 2022. Accessed September 14, 2022.
2. Ozelo MC, Mahlangu J, Pasi KJ, et al; GENEr8-1 Trial Group. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022;386(11):1013-1025. doi:10.1056/NEJMoa2113708
3. First gene therapy for adults with severe hemophilia A, BioMarin's ROCTAVIAN™ (valoctocogene roxaparvovec), approved by European Commission (EC). News release. BioMarin. August 24, 2022.,-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-,-Approved-by-European-Commission-EC
4. BioMarin delays hemophilia a therapy valoctocogeneroxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022.

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