Companion Diagnostic Immunoassay for Roctavian Receives FDA Approval

The FDA has approved ARUP Laboratories’ AAV5 DetectCDx, a companion diagnostic immunoassay intended to detect the presence of antibodies that bind to the adeno-associated virus serotype 5 (AAV5), for the purpose of determining the eligibility of patients with severe hemophilia A who are considering treatment with BioMarin’s gene therapy valoctocogene roxaparvovec (val-rox).¹

AAV5 DetectCDx utilizes electrochemiluminescence to detect antiAAV5 antibodies in samples of patients’ plasma. In the United States, ARUP Laboratories will provide all laboratory testing services for AAV5 DetectCDx, which is notably the first FDA-approved companion diagnostic immunoassay for a gene therapy. The results of the test are qualitative, with antibodies either “Detected” or “Not Detected”; the latter result supports a patient’s eligibility for treatment with val-rox. AAV5 DetectCDx received approval from the FDA simultaneously with val-rox itself, on June 29, 2023.

“By leveraging diagnostic testing, we can identify which patients are eligible to receive treatment,” Jay Patel, MD, MBA, the executive director of PharmaDx and Clinical Trials at ARUP Laboratories, said in a statement.¹ “We are proud of our role in the advancement of this revolutionary type of treatment.”

BioMarin and ARUP Laboratories collaborated closely on AAV5 DetectCDx’s development and the immunoassay was utilized in several of the clinical trials that evaluated val-rox. Val-rox, which is the first gene therapy for hemophilia A to be approved in the US, is indicated for adults with congenital factor VIII (FVIII) deficiency with FVIII activity of less than 1 IU/dL who do not have antibodies to AAV5 according to an FDA-approved test.^1,2 Nonpresence of antiAAV5 antibodies is part of the eligibility criteria because the presence of these antibodies could negatively impact the efficacy of the gene therapy, which delivers a functional copy of the FVIII gene via an AAV5 vector. Val-rox is additionally contraindicated for patients with acute or uncontrolled chronic infections, significant hepatic fibrosis, cirrhosis, or hypersensitivity to mannitol. Its approval was based on data from the phase 3 GENEr8-1 clinical trial (NCT03370913). A 3-year analysis of GENEr8-1 data reported by BioMarin in January 2023 included findings from 112 patients for annualized bleeding rate (ABR) and annualized Factor VIII (FVIII) utilization (AFR) and findings from 132 patients for FVIII activity.³ The mean ABR for treated bleeds was 1.9 (median, 0.0), the mean AFR was 8.4 (median, 0.0), and the mean FVIII activity was 18.8 IU/dL (median, 8.4). It was noted that 2 of the patients included in the analysis discontinued participation before reaching 3 years of follow-up and as such FVIII activity was imputed as 0 IU/dL.

Prior to its approval in the United States, val-rox was approved in the European Union (EU) with conditional marketing authorization on August 24, 2022.⁴ The conditional authorization is for adults without a history of FVIII inhibitors and without detectable antiAAV5 antibodies. AAV5 DetectCDx was approved in the EU even earlier, in August 2021.¹ It has a Conformité Européenne mark under the EU’s In Vitro Diagnostic Medical Devices Directive. ARUP Laboratories' partner facilities in the EU are authorized to carry out diagnostic testing with the AAV5 DetectCDx Kit that was approved in September 2022.^1,5

“It is extremely satisfying to see the effort and dedication of both teams come to fruition after a successful and long-standing collaboration,” Emily Coonrod, the senior director of companion diagnostics in the PharmaDx department at ARUP Laboratories, added to the statement.¹ “It has required the combined expertise, hard work, and perseverance of both teams to achieve this milestone.”

REFERENCES
1. FDA approves ARUP Laboratories’ AAV5 DetectCDx, a first-ever companion diagnostic immunoassay for a gene therapy. News release. ARUP Laboratories. June 29, 2023. Accessed July 13, 2023. https://www.aruplab.com/news/06-29-2023/fda-approves-arup-laboratories-aav5-detectcdxtm
2. U.S. Food and Drug Administration Approves BioMarin's ROCTAVIAN™ (valoctocogene roxaparvovec-rvox), the First and Only Gene Therapy for Adults with Severe Hemophilia A. News release. BioMarin Pharmaceutical Inc. June 29, 2023. Accessed July 13, 2023.https://investors.biomarin.com/2023-06-29-U-S-Food-and-Drug-Administration-Approves-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-rvox-,-the-First-and-Only-Gene-Therapy-for-Adults-with-Severe-Hemophilia-A
3. BioMarin announces stable and durable annualized bleed control for ROCTAVIAN™ in largest phase 3 gene therapy study in adults with severe hemophilia A; 134-participant study met all primary and secondary efficacy endpoints at 3-year analysis. News release. BioMarin. January 8, 2023. Accessed July 13, 2023. https://www.prnewswire.com/news-releases/biomarin-announces-stable-and-durable-annualized-bleed-control-for-roctavian-in-largest-phase-3-gene-therapy-study-in-adults-with-severe-hemophilia-a-134-participant-study-met-all-primary-and-secondary-efficacy-endpoints-at-3-ye-301716007.html
4. 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. Accessed July 13, 2023. https://investors.biomarin.com/2022-08-24-First-Gene-Therapy-for-Adults-with-Severe-Hemophilia-A,-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-,-Approved-by-European-Commission-EC
5. AAV5 DetectCDxKit is first ARUP test developed to support a new therapy. News release. ARUP Laboratories. September 26, 2022. Accessed July 13, 2023. https://www.aruplab.com/news/09-26-2022/aav5-detectcdxtm-kit-first-arup-test-developed-support-new-therapy