Riastap Advisory Committee Review Will Evaluate Surrogate Endpoint

CSL Behring seeks accelerated approval for the first human fibrinogen concentrate since the products were withdrawn in 1977, but FDA first wants validation of the surrogate endpoint used to show efficacy.

CSL Behring is hoping to receive accelerated approval for its fibrinogen concentrate product Riastap , but first FDA is asking its Blood Products Advisory Committee to discuss whether the surrogate endpoint for the proposed Phase IV confirmatory trial can be validated.

There are no human fibrinogen concentrate products currently approved in the U.S. Fibrinogen for intravenous use was marketed in the U.S. by several companies in the 20 century, FDA explains in briefing documents, but the agency revoked all licenses for fibrinogen concentrates in 1977 because of the risk of hepatitis transmission and insufficient evidence of effectiveness.

In addition to the strict regulatory environment for blood products, another barrier for Riastap is the indication itself: because of the rarity of congenital fibrinogen deficiency, a bleeding disorder with an estimated prevalence of around 300 patients in the U.S., prospective controlled clinical trials are not feasible.

But use of the accelerated approval pathway allows FDA instead to approve a product based on a surrogate endpoint, filling an unmet medical need faster but tying approval to a Phase IV post-marketing study to verify the product's clinical benefit.

One of the two questions for the Jan. 9 advisory committee review of Riastap is whether the Phase IV study is adequately designed to correlate the surrogate efficacy endpoint - maximum clot firmness, which measures the structural integrity of a clot - with a meaningful clinical outcome; in this case, hemostasis.

Safety and efficacy profile are acceptable, FDA says

The pivotal trial supporting the BLA met the surrogate endpoint designed by CSL Behring, showing maximum clot firmness levels significantly increased one hour post-infusion in 15 patients from baseline (pre-infusion; p<0.0001). No difference was detected in clot firmness values by gender or age.

Values were consistent with literature and other studies, FDA's briefing documents state, and correlated well with expected fibrinogen levels. The clinical significance (correlation of maximum clot firmness values with hemostatic efficacy) will be evaluated in the ongoing Phase IV study.

The safety profile also was acceptable, the agency noted. Adverse events were mild and not considered to be related to Riastap. A boost to Riastap's safety profile comes from ex-U.S. post-marketing surveillance - only 49 adverse events have been reported over 22 years, reflecting 1 million grams of HFC.

Approval contingent on success of Phase IV

CSL's briefing documents detail the ongoing post-market study. The primary objective is to demonstrate hemostatic efficacy in 23 patients treated with human fibrinogen concentrate to a 39-patient historical control group, as well as correlate efficacy with the surrogate endpoint, maximum clot firmness.

The Blood Products Advisory Committee will review the risk/benefit profile of Riastap as well as the Phase IV design. The panel also will consider GTC Biotherapeutics' NDA for recombinant antithrombin candidate ATryn for hereditary antithrombin deficiency at the same meeting.

- Becky Jungbauer ([email protected])