Plain language summary of the GENEr8-1 clinical trial of valoctocogene roxaparvovec gene therapy for hemophilia A

Plain Language Summary

In healthy people, a protein called factor VIII (FVIII) helps blood to clot and prevents excessive bleeding. People with hemophilia A lack FVIII because a faulty F8 gene is giving the wrong instructions to the liver cells that make it. Valoctocogene roxaparvovec (ROCTAVIAN™) is a gene therapy designed to transfer working copies of the F8 gene into liver cells. This summary describes the GENEr8-1 study, which looked at how well valoctocogene roxaparvovec works for treating people with severe hemophilia A compared with their usual FVIII replacement therapy, and its safety. 134 men received valoctocogene roxaparvovec; results from the first 2 years are reported.

What were the results?

Valoctocogene roxaparvovec significantly improved bleed control in men with severe hemophilia A. A single infusion reduced average treated bleeding episodes per year from almost 5 while on FVIII prophylaxis to less than one after gene therapy. Eight out of every 10 participants had no bleeds needing treatment and 9 out of every 10 had no joint bleeds needing treatment; FVIII levels improved to normal or mild hemophilia ranges. All except 6 participants remained off regular FVIII prophylaxis for at least 2 years. All participants had at least one side effect and 22 (16%) reported serious adverse events. Nine out of every 10 participants (89%) showed increased blood levels of liver enzymes, indicating an expected immune response to the product’s viral shell; this was manageable with steroids. Other common side effects included headache (41%), joint pain (40%), feeling sick (38%), and side effects to steroids (60%).

What do the results mean?

After a one-time dose of valoctocogene roxaparvovec, people with severe hemophilia A start producing their own FVIII and require fewer or no FVIII injections to protect them from bleeds. Results showing bleed control for at least 2 years have led to approvals of valoctocogene roxaparvovec in Europe and the USA for use in adults with severe hemophilia A who do not have antibodies against FVIII or AAV type 5. How well valoctocogene roxaparvovec works and the side effects over a longer period are still being studied.

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Tweetable abstract

This summary reports on the largest clinical study of gene therapy in hemophilia A. The study, known as GENEr8-1, looked at how well valoctocogene roxaparvovec works for treating people with severe hemophilia A compared with their usual factor VIII replacement therapy.

Keywords::

• clinical trial
• factor VIII
• FVIII
• gene therapy
• hemophilia A
• lay summary
• plain language summary
• ROCTAVIAN
• valoctocogene roxaparvovec

Acknowledgments

The authors and sponsor would like to thank the participants of the GENEr8-1 study, their family members and caregivers, and the study investigators and staff.

Ethical conduct of research

The GENEr8-1 study was conducted in accordance with Good Clinical Practice guidelines and local regulations. Independent ethics committees or institutional review boards at each study site approved the protocol and materials for informed consent. Participants provided written informed consent before enrollment. The study investigator at each site explained the nature of the study to the participant, that the drugs are being used for investigational purposes and expectations regarding participation in the study, and provided written information prior to obtaining consent to participate. An independent data and safety monitoring committee oversaw the safety of the participants and the ethics of the study conduct.

Financial disclosure

Gillian Lowe reports the following: Clinical fellowship at BioMarin Pharmaceutical Inc.; speaker fees from Novartis, Leo, Alexion, Sobi, Takeda and NovoNordisk. Simon Fletcher reports the following: Consulting fees from Roche and CSL Behring; research grants from uniQure and Roche; participation as a clinical trial investigator for Haemnet Ltd.; speaker fees from Novo Nordisk, Bayer and Roche; travel support from Bayer and Novo Nordisk. Patrick James Lynch reports the following: Speaker fees from NHF, Sanofi and Spark Therapeutics; travel support from NHF, WFH, Takeda, Sanofi, Spark Therapeutics and CSL Behring; other (marketing contracts) from BioMarin Pharmaceutical Inc., Bayer, Sanofi, Takeda, CSL Behring, Genentech and Spark Therapeutics. Johnny Mahlangu reports the following: Consulting fees from BioMarin Pharmaceutical Inc., Novo Nordisk, Roche, Takeda, Sanofi and Spark; participation as a clinical trial investigator with BioMarin Pharmaceutical Inc., Novo Nordisk, Pfizer, Roche, Sanofi, Spark and UniQure; speaker fees from ISTH, Novo Nordisk, Pfizer, Roche, Sanofi, Takeda and WFH. Margareth C Ozelo reports the following: Consulting fees from BioMarin Pharmaceutical Inc., Bayer, Novo Nordisk and Takeda; research grants from BioMarin Pharmaceutical Inc., Pfizer, Roche and Takeda; participation as a clinical trial investigator with BioMarin Pharmaceutical Inc., Novo Nordisk, Pfizer, Sanofi, Roche and Takeda; speaker fees from BioMarin Pharmaceutical Inc., Novo Nordisk, Pfizer, Roche and Takeda; travel support from Roche and Takeda; grant review fees from Grifols. Luke Pembroke reports the following: Director of Community Engagement at Haemnet; Haemnet shareholder; speaker fees from The France Foundation, Takeda, Sobi, CSL Behring; and BioMarin Pharmaceutical Inc.; consulting and content creation fees from Roche and Novo Nordisk; clinical trial participant in B-AMAZE Study by Freeline. Steven W Pipe reports the following: Consulting fees from Apcintex, ASC Therapeutics, Bayer, BioMarin Pharmaceutical Inc., CSL Behring, GenVentiv, HEMA Biologics, Freeline, LFB, Novo Nordisk, Pfizer, Regeneron/Intellia, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics and uniQure; participation as a clinical trial investigator with BioMarin Pharmaceutical Inc., Bayer, uniQure, Freeline, Spark Therapeutics, ASC Therapeutics and Regeneron/Intellia. Gabriela G Yamaguti-Hayakawa reports the following: Consulting fees and research grants from BioMarin Pharmaceutical Inc.; participation as a clinical trial investigator with BioMarin Pharmaceutical Inc., Pfizer and Sanofi; speaker fees from BioMarin Pharmaceutical Inc., Roche, Pfizer, Takeda and Novo Nordisk; travel support from BioMarin Pharmaceutical Inc. and Roche. Tara M Robinson is an employee of BioMarin Pharmaceutical Inc. Hua Yu is an employee of BioMarin Pharmaceutical Inc.

The opinions expressed in this manuscript are not necessarily reflective of those of the National Hemophilia Foundation (NHF) or the NHF Board of Directors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

Medical writing and editorial assistance for this summary and the graphic concepts were provided by Joanne Fitz-Gerald, BPharm, and Jonathan A C Lee, PhD, of FourWave^™ Medical Communications, funded by BioMarin Pharmaceutical Inc.