BioMarin: Phase III Gene Therapy for Adults with Severe Hemophilia A

BioMarin: Phase III Gene Therapy for Adults with Severe Hemophilia A.  BioMarin announces Phase III gene therapy for adults with severe hemophilia A.

BioMarin Pharmaceutical, a Nasdaq-listed company, today announced that its gene therapy valoctocogene roxaparvovec for the treatment of severe hemophilia A in adults has a positive one-year top-line result of the Phase III clinical trial Gene8-1.

Accordingly, BioMarin withdraws the previous European marketing application, and plans to submit the marketing application again in the second quarter of this year after discussing the efficacy and safety issues with the EU on the 1-year data. The FDA requires that all phase III clinical trials continue to be completed.

Gene8-1 is the largest global phase III clinical study of all gene therapies to date, with a total of 134 patients participating. All patients received a single dose of valoctocogene roxaparvovec and completed a one-year or longer follow-up, with an average follow-up time of 71.6 weeks.

GENEr8-1 data showed that 80% of patients had no bleeding episodes from the fifth week after treatment. In a preliminary analysis of the annualized bleeding rate (ABR), a single dose of valoctocogene roxaparvovec can significantly reduce ABR, from baseline ABR to an average of 4.8 times ( (Median 2.8 times) dropped to 0.8 times per year (median 0.0 times), a decrease of about 84%, p-value <0.0001.

Valoctocogene roxaparvovec can also significantly reduce the annual coagulation factor VIII infusion rate, from 135.9 (median 128.6) times per year to 2.0 (median 0.0) times per year, p value <0.0001.

Measured by the substrate chromogenic method (CS), at the end of the first year after valoctocogeneroxaparvovec infusion, the average expression level of endogenous coagulation factor VIII in patients with modified intention to treat (mITT) (N=132) was 42.9 (SD 45.5, median 23.9) IU/dL, consistent with clinical bleeding events and improvement of VIII infusion rate.

Compared with the results of phase 1/2 clinical studies, the expression of coagulation factor VIII decreased slowly and kept within a certain range, and the hemostatic effect was better. In mITT patients (N=17) who have been treated with valoctocogene roxaparvovec and switched to other treatments for two years, the expression of coagulation factor VIII decreased from the mean value of 42.2 (SD 50.9, median 23.9) IU/dL at the end of the first year to The average value at the end of the second year was 24.4 (SD 29.2, average 14.7) IU/dL, and the average ABR was 0.9 bleeding per year (average 0.0), showing a continuous hemostatic effect.

Safety of Valoctocogene Roxaparvovec

In the phase III clinical study, 134 patients who received a single dose of 6e13 vg/kg tolerated valoctocogene roxaparvovec well. No patients experienced factor VIII inhibitors or thromboembolic events. One patient could not be followed up continuously. By controlling the infusion rate, infusion-related reactions are effectively alleviated.

Elevated alanine aminotransferase (ALT) occurred in 115 patients, with an incidence rate of 86%, which was the most common adverse event (AE). Other common adverse reactions include headache (51 cases, 38%), nausea (50 cases, 37%), elevated aspartate aminotransferase (AST) (47 cases, 35%), arthralgia (38 cases, 28%) ) And fatigue (37 cases, 27%). 22 (16.4%) patients experienced 43 serious adverse events (SAEs), and all SAEs were resolved.

Temporary use of corticosteroids (or alternative immunosuppressive agents) to control elevated ALT may cause common corticosteroid-related side effects, the intensity is generally 1/2 level, controllable and reversible. Long-term, high-dose use of corticosteroids can observe individual grade 3 corticosteroid-related side effects (such as diabetes, hypertension, weight gain, fractures). The adverse effects of long-term use of glucocorticoids are reversible, and one case of weight gain-related glucocorticoid-related grade 3 serious adverse events occurred.

In general, the safety of valoctocogene roxaparvovec is consistent with the data previously reported in the Phase 1/2 study.

(source:internet, reference only)

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