FDA is reaffirming its willingness to clear drugs for orphan conditions on very unusual data sets with its approval of CSL Behring's Corifact for prevention of bleeding in people with congenital Factor XIII deficiency.

Corifact is the first FDA-approved treatment for the rare genetic condition, which prevents normal clotting and therefore can lead to life-threatening bleeding. The condition affects one of every 3 million to 5 million people in the U.S., and can lead to soft tissue bruising, mucosal bleeding and fatal intracranial bleeding.

The biologic product, which is made from the pooled plasma of healthy donors, received approval Feb. 17 as an orphan drug under FDA's accelerated approval regulations, which require another trial to confirm the benefit that was suggested in the earlier study.

The approval was based on a pharmacokinetic and safety trial with a total enrollment of 14.

According to the listing on ClinicalTrials.gov, CSL Behring completed the clinical trial in April 2010. The 12-week, Phase II pharmacokinetic study was conducted at five U.S. sites and one in Spain. The primary outcome measures were pharmacokinetic-based: peak and trough Factor XIII concentration at steady state, time to peak concentration, incremental recovery, terminal half-life, area under the curve at steady state, clearance, volume of distribution at steady state and mean residence time.

Per the safety assessment, the most common side effects were hypersensitivity reaction (allergy, rash, pruritus and erythema), chills, fever, arthralgia, headache, elevated thrombin-antithrombin levels and an increase in liver enzymes. Other adverse events can potentially come from abnormal bleeding if doses administered exceed the labeled dose, FDA warned.

FDA also noted that people receiving Corifact may develop antibodies against Factor XIII that may make the product ineffective.

CSL Behring, a German company, has three other, larger studies ongoing, according to ClinicalTrials.gov. One Phase III efficacy study, slated for completion in April, was set to enroll 40 patients at 22 U.S. sites and one site in Spain. The primary endpoint is the incidence of spontaneous bleeding events requiring treatment.

A Phase III safety study with the primary endpoint listed as "adverse events" was slated for completion in January 2011, with a target of 80 patients at 20 U.S. sites. The record was updated Jan. 25 and still lists the trial as enrolling.

Another efficacy study was trying to enroll 80 patients at Children's Hospital of Orange County, Calif., which is listed as the study sponsor (CSL Behring is listed as a collaborator). No trial phase was listed. The primary endpoint in the study was response to treatment, with active bleeding controlled. The trial was scheduled for completion in December 2010; ClinicalTrials.gov reports the study is recruiting, but the listing hasn't been updated since it was first submitted on March 17, 2008.

Another In A Line Of Unusual Approvals

Another orphan drug was approved last year with a similarly small data set Orphan Europe's Carbaglu (carglumic acid) treats hyperammonemia in patients with N-acetyl-glutamate synthase deficiency.

In that case, there was actually no clinical trial at all, but Office of Drug Evaluation III Director Julie Beitz said the changes in ammonia levels in 23 patients given the drug were so compelling that that outweighed concerns about the methods of data collection (Also see "FDA Approves Drug For Rare Disease Without Clinical Trial" - Pink Sheet, 19 March, 2010.).

The agency cautioned, however, that the Carbaglu approval was not to be considered a precedent-setting move (Also see "Carbaglu Does Not Set Precedent For Orphan Drugs To Skip Trials, FDA Says" - Pink Sheet, 18 January, 2010.). The disease is certainly one of a kind, in that the case studies may have included half the patients who have NAGS deficiency in the entire world. According to FDA, NAGS deficiency has an estimated worldwide prevalence of about 50 patients, fewer than 10 of whom have been identified in the U.S.

Two other drugs were approved last year based on very small data sets. Shire's VPriv (velaglucerase) for Gaucher disease, a rare lysosomal storage disorder with a prevalence of about 7,500 patients in the U.S., was approved Feb. 26, 2010 (Also see "Differentiation Will Be Key Challenge For Shire's Gaucher Disease Drug Vpriv" - Pink Sheet, 8 March, 2010.). "It was approved based on the results of a single controlled trial in 25 patients; however, supportive data and safety information were available in a total of 99 patients at the time of approval," the agency noted in an email.

On May 25, 2010, FDA approved Genzyme's Lumizyme (alglucosidase alfa), an enzyme replacement therapy for Pompe disease. Late-onset Pompe disease is a rare lysosomal storage disorder with a prevalence of about 3,300 patients in the U.S. It was approved based on the results of a single controlled trial in 90 patients (Also see "Good News For A Change At Genzyme: Consent Decree Finalized Without Surprises, Lumizyme Approved By FDA Ahead Of Schedule" - Pink Sheet, 31 May, 2010.). Four years earlier, FDA approved another formulation of alglucosidase alfa, Genzyme's Myozyme, based on the results of a single controlled trial in 18 patients and a total exposure of about 50 patients.

In 2009 there were two drug approvals based on very small data sets: Novartis' Ilaris (canakinumab) for Cryopyrin-Associated Periodic Syndromes, based on a single controlled trial in 31 patients, with additional safety and efficacy data in a total of 104 patients, and Biovail's Xenazine (tetrabenzine) for chorea of Huntingdon's disease based on a single database controlled trial in 84 patients, although in that case there was a larger safety database with healthy volunteers and open-label studies, for a total of 773 subjects.

- Martin Berman-Gorvine ( m.berman-gorvine@elsevier.com )

CSL Behring's Corifact Clears FDA On 14-Patient Trial

More from Archive

More from Pink Sheet