Roctavian’s Benefits Sustained for Up to 5 Years in Trial Patients

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with the investigational gene therapy Roctavian (valoctocogene roxaparvovec) can reduce bleeding frequency and the use of replacement therapies, while maintaining or improving the quality of life of people with severe hemophilia A for up to five years, updated Phase 1/2 trial data show. 

“These results represent the longest duration of follow-up from any clinical gene therapy study for severe haemophilia A,” researchers wrote in a new study, which detailed the trial’s results.

The study, “Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A,” was published in the journal Haemophilia.

Hemophilia A is caused by mutations in the F8 gene, which encodes a clotting protein called factor VIII (FVIII). Developed by BioMarin Pharmaceutical, Roctavian is a one-time gene therapy that uses an engineered viral vector to deliver a healthy version of F8 to cells in the body in order to restore the production of functional FVIII.

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The therapy is currently being studied in several clinical trials. Here, researchers at BioMarin and other institutions reported new data from a Phase 1/2 trial (NCT02576795) that is evaluating the safety and efficacy of Roctavian in adult men with severe hemophilia A.

Prior findings from the study indicated that a single infusion of Roctavian was able to increase FVIII levels and lower bleeding rates for up to four years.

Now, investigators reported the latest findings from two groups of trial participants: seven who received a high dose of Roctavian (6e13 vector genomes per kilogram or vg/kg) and were followed for up to five years, and six who received a lower dose of the therapy (4e13 vg/kg) and were followed for four years.

Despite the use of prophylactic, or preventive, replacement therapies, trial participants experienced frequent bleeds before receiving Roctavian: the mean annual rate of bleeds that required treatment was 17.6 bleeds per year in the high-dose group and 12.2 bleeds per year in the low-dose group. In other words, participants in both groups were experiencing more than one bleeding episode per month, on average.

As previously reported, in the high-dose group, the mean annual bleeding rate five weeks after Roctavian treatment and onward (for up to five years) was 0.8 bleeds per year, corresponding to a 95% reduction compared with the period preceding treatment. Similarly, the mean annual bleeding rate in the low-dose group dropped by 92% at four years, with a mean of 1.7 bleeds per year.

Five of the seven participants in the high-dose group experienced no bleeds that required treatment in the fourth or fifth years following treatment with Roctavian. In the low-dose group, three of the six participants experienced no bleeds requiring treatment in the third or fourth year after receiving the gene therapy.

Consistently, the use of replacement therapies decreased substantially in both groups — by 96% at year five in the high-dose group, and by 95% at year four in the low-dose group. All patients remain off of prophylaxis.

In both groups, FVIII levels rose to a peak at one year after treatment, then slowly declined. Statistical analyses also showed that changes in FVIII activity following Roctavian treatment followed predictable mathematical patterns.

In the high-dose group, mean scores on a hemophilia-specific quality of life questionnaire (Haemo-QOL-A) were 71.9 at the study’s start. These scores increased to 82.2 at the end of year five, indicating an improvement in quality of life.

In the low-dose group, mean Haemo-QOL-A scores were relatively high at the study’s start (80.8) and remained stable during follow-up (mean score of 80.3 at the end of year four).

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The most common adverse event related to treatment was an elevation in the levels of alanine transaminase (ALT), a liver enzyme often used as a marker of liver damage. ALT elevations were generally temporary, mild to moderate in severity, and did not cause overt symptoms.

One serious treatment-related adverse event — an instance of fever accompanied by muscle pain and headache — occurred earlier in the trial and was reported previously. No other serious events related to treatment or unexpected safety concerns have been reported in the last two years of the trial.

“Gene therapy could represent a paradigm shift in the treatment of haemophilia A, enabling long-lasting treatment and improving clinical and patient-centred outcomes, including QOL [quality of life],” the researchers wrote, adding that this is currently being investigated in the larger, Phase 3 GENEr8-1 trial (NCT03370913).