Orphan drug Coagadex for hereditary Factor X deficiency gets FDA approval.

coagdex October 20, 2015.
FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder.

The U.S. Food and Drug Administration approved orphan drug Coagadex, Coagulation Factor X (Human), for hereditary Factor X (10) deficiency. Until today’s orphan drug approval, no specific coagulation factor replacement therapy was available for patients with hereditary Factor X deficiency.

In healthy individuals, the Factor X protein activates enzymes to help with normal blood clotting in the body. Factor X, Stuart-Prower factor,deficiency is an inherited disorder, affecting men and women equally, where the blood does not clot as it should.

Patients with the disorder are usually treated with fresh-frozen plasma or plasma-derived prothrombin complex concentrates (plasma products containing a combination of vitamin K-dependent proteins) to stop or prevent bleeding.

The availability of a purified Factor X concentrate increases treatment options for patients with this rare bleeding disorder.

Genetics

Factor X deficiency is inherited in an autosomal recessive manner. Heterozygotes have factor X levels that are approximately 50 percent of normal and are generally asymptomatic. The genetic defects causing a deficiency of factor X are classified according to functional and immunologic analysis as CRM+, CRM–, and CRMred.

The currently described 95 mutations that cause factor X deficiency include large deletions, small frameshift deletions, nonsense mutation, and missense mutations. The deletions result in impaired protein synthesis or in synthesis of unstable or dysfunctional proteins. CRM+ or CRMred variants may affect factor X function in several ways.

Activation through the tissue factor pathway may be affected when the mutations are located for example in the Gla domain, as in Glu7Gly, or Glu19Ala. Activation through factor IXa is affected by, for example, Thr318Met.

Activation of factor X through Russell viper venom is almost intact in the Pro343Ser (Friuli) mutation, whereas its activation through the intrinsic and tissue factor pathways is only 5 to 9 percent of normal.

Missense mutations also may affect synthesis or secretion, thus producing CRM– phenotypes, as with the mutation identified in Mr. Stuart, one of the first two patients described with factor X deficiency.

 An interesting cluster of unrelated families with a Phe31Ser mutation was described in Algeria and haplotype analysis was consistent with a founder effect.

Biochemistry and Molecular Features of Factor X

The protein encoded by the factor X gene is 488 amino acids long. A 23-amino-acid signal peptide is located at the N-terminus. The Gla domain forms the N-terminus of the mature protein and contains 11 Gla residues that are responsible for calcium and phospholipid binding.

 Adjacent to the Gla domain is a short aromatic amino acid stack of predominantly hydrophobic amino acids, followed by the epidermal growth factor domain, which contains two epidermal growth factor motifs that are believed to mediate protein–protein interactions.

 The heavily glycosylated 52-amino-acid activation peptide of factor X separates the epidermal growth factor domain from the C-terminal catalytic domain. Factor X zymogen is synthesized in the liver, its plasma concentration is 8 to 10 mcg/mL and its half-life is 30 to 40 hours.

Factor X undergoes proteolytic processing in the endoplasmic reticulum so that circulating factor X is a two-chain, disulfide-linked protein consisting of a 17-kDa light chain composed of the Gla and epidermal growth factor domains and a 40-kDa heavy chain composed of the activation and catalytic domains.

Factor X can be activated by a complex of negatively charged phospholipids, factor IXa, and factor VIIIa, or by membrane-bound factor VIIa–tissue factor complex.

Factor X also can be activated by a component of Russell viper venom121 and by trypsin. In each case, activation of factor X is accomplished by proteolytic cleavage and subsequent removal of the activation peptide.

Factor Xa, in turn, activates prothrombin to thrombin in a reaction that requires negatively charged phospholipids, calcium ions, and factor Va.

Indications

Coagadex, which is derived from human plasma, is indicated for individuals aged 12 and older with hereditary Factor X deficiency for on-demand treatment and control of bleeding episodes, and for perioperative management of bleeding in patients with mild hereditary Factor X deficiency.

Safety and Efficacy

The safety and efficacy of Coagadex was evaluated in a multi-center, non-randomized study involving 16 participants (208 bleeding episodes) for treatment of spontaneous, traumatic and heavy menstrual (menorrhagic) bleeding episodes. Coagadex was demonstrated to be effective in controlling bleeding episodes in participants with moderate to severe hereditary Factor X deficiency. Coagadex was also evaluated in five participants with mild to severe Factor X deficiency who were undergoing surgery. The five individuals received Coagadex for perioperative management of seven surgical procedures. Coagadex was demonstrated to be effective in controlling blood loss during and after surgery in participants with mild deficiency. No individuals with moderate or severe Factor X deficiency received Coagadex for perioperative management of major surgery, and no safety concerns were identified in either study.

The FDA granted Coagadex orphan product designation for these uses. Orphan product designation is given to drugs intended to treat rare diseases in order to promote their development. Coagadex was also granted fast track designation and priority review.

Coagadex is manufactured by Bio Products Laboratory Limited in Elstree, Hertfordshire, United Kingdom.

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