First hemophilia gene therapy coming to market?

January 11, 2022 / eMedClub News/--Recently, BioMarin announced the complete data of the hemophilia gene therapy valoctocogene roxaparvovec (hereinafter referred to as: valrox) in the Phase 3 clinical study GENEr8-1.
Subjects met all primary and secondary efficacy endpoints at the two-year analysis
.

Notably, the European Medicines Agency has accepted a Marketing Authorization Application (MAA) for the company's investigational gene therapy, valrox, for adults with severe hemophilia
A.

Recommended reading: BioMarin's hemophilia AAV gene therapy application is accepted by EMAYimai Meng broke the news that hemophilia is divided into two types: A and
B.

Hemophilia A is a bleeding disorder caused by deficiency of coagulation factor VIII (FVIII)
.

At present, the standard treatment for this disease is to perform preventive factor VIII replacement therapy 2-3 times a week.
Although the course of the disease can be controlled to a certain extent, there is still a risk of bleeding, and it also brings many side effects and a large economic burden to patients.

.

And valrox is a gene therapy that uses an AAV5 viral vector to deliver a transgene expressing factor VIII
.

The advantage is that patients may only need to receive a single treatment, and the liver cells can continue to express factor VIII, eliminating the need for long-term prophylactic coagulation factor injections
.

Designated primary analysis of Phase 3 clinical study GENEr8-1 on participants from previous non-interventional studies, all receiving a single 6e13vg/kg dose
.

The data showed that the annualized bleeding rate (ABR) was reduced by 85% from baseline, and the cumulative mean annualized bleeding rate (ABR) was less than 1
.

In addition to this, valrox significantly reduced the average annualized factor VIII infusion rate in the hemophiliac population, with an average annualized infusion rate of 2.
6 throughout the efficacy evaluation period (1.
5 in the first year and 3.
4 in the second year).
, a 98% reduction compared to baseline
.

▲ The use of ABR and coagulation factor VIII has consistent clinical benefits (Image source: Reference 1) BioMarin has also previously stated that it has been observed that the maintenance of factor expression is a function of expression level and time, at the current rate of decline, in a single time.
Three years after valrox injection, FVIII activity levels appear to be approaching plateau, and FVIII expression is expected to persist for a longer period of time
.

More conservative statistical models predict that bleeding control will be maintained for at least 8 years after gene transfer
.

➤ The safety profile of Valoctocogene Roxaparvovec is consistent with previously reported data, with no delayed treatment-related events
.

The subjects did not develop resistance to factor VIII, and no thrombotic events occurred
.

The most common adverse events associated with valrox use occurred early, including transient infusion reactions and mild to moderate elevations in certain protein and enzyme levels detected by liver function tests, none of which had long-term clinical sequelae
.

During the second year, no new safety signals emerged and no treatment-related serious adverse events (SAEs) were reported
.

➤ Regulatory status In August 2020, the FDA rejected BioMarin's hemophilia A gene therapy application due to fluctuations in the average annualized bleeding rate (ABR) in the Phase 1/2 study data published by BioMarin.
And factor VIII levels in patients continued to decline, which the FDA believes requires more complete follow-up data
.

▲The 3-year ABR of the two cohorts of patients in the Phase 1/2 study (Image source: BioMarin official website) FDA requires long-term effective data, making BioMarin slow down the pace of listing in the United States, but still actively seeking breakthroughs: March 8 this year Today, the FDA granted valrox Regenerative Medicine Advanced Therapy Designation (RMAT), which complements the Breakthrough Therapy designation BioMarin received in 2017 to expedite the development of new regenerative therapies
.

Cell therapies that receive RMAT designation also receive the benefits of both Fast Track designation and Breakthrough Therapy designation
.

These advantages include early FDA guidance to guide manufacturing and clinical development, such as identifying intermediate endpoints that support accelerated approval
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In addition to the RMAT designation and Breakthrough Therapy designation, valrox has been granted orphan drug designation by the FDA and EMA for the treatment of severe hemophilia
A.

Recommended reading: Gene therapy for hemophilia A, once rejected by FDA, is now designated as advanced regenerative medicine Two-year follow-up safety and efficacy data to support the benefit/risk assessment of valoctocogene roxaparvovec
.

Based on these results, BioMarin plans to resubmit a Biologics License Application (BLA) to the FDA in the second quarter of 2022, followed by a six-month review by the FDA
.

Meanwhile, the European Medicines Agency (EMA) has validated and initiated a review of BioMarin’s resubmitted Marketing Authorization Application (MAA), with comments from the Committee for Medicinal Products for Human Use (CHMP) and the Committee for Advanced Therapies (CAT) expected in the first half of 2022
.

 References: 1.
https:// -in-adults-with-severe-hemophilia-a-134-participant-study-met-all-primary-and-secondary-efficacy-endpoints-at-two-year-analysis/