Koate-DVI Mechanism of Action

Pharmacology: Hemophilia A is a hereditary bleeding disorder characterized by deficient coagulant activity of the specific plasma protein clotting factor, factor VIII. In afflicted individuals, hemorrhages may occur spontaneously or after only minor trauma. Surgery on such individuals is not feasible without first correcting the clotting abnormality. The administration of Koate-DVI provides an increase in plasma levels of factor VIII and can temporarily correct the coagulation defect in these patients.
After infusion of antihemophilic factor (human), there is usually an instantaneous rise in the coagulant level followed by an initial rapid decrease in activity, and then a subsequent much slower rate of decrease in activity. The early rapid phase may represent the time of equilibration with the extravascular compartment, and the second or slow phase of the survival curve presumably is the result of degradation and reflects the true biologic half-life of the infused antihemophilic factor (human).
The removal and inactivation of spiked relevant and model enveloped and non-enveloped viruses during the manufacturing process for Koate-DVI have been validated in laboratory studies at Bayer Corporation. Studies performed with the model enveloped viruses indicated that the greatest reduction was achieved by TNBP/polysorbate 80 treatment and 80°C heat. For this reason, VSV (vesicular stomatitis virus, model for RNA enveloped viruses) and HIV-1 (human immunodeficiency virus type 1) were studied only at these 2 steps of the manufacturing process. The efficacy of the dry heat treatment was studied using all of the viruses, including BVDV (bovine viral diarrheal virus, model for hepatitis C virus) and Reo (reovirus type 3, model for viruses resistant to physical and chemical agents eg, hepatitis A), and the effect of moisture content on the inactivation of HAV (hepatitis A virus), PPV (porcine parvovirus, model for parvovirus B19), and PRV (pseudorabies virus, model for hepatitis B virus) was investigated. (See Table 1.)

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Similar studies have shown that a terminal 80°C heat incubation for 72 hrs inactivates non-lipid enveloped viruses eg, hepatitis A and canine parvovirus in vitro, as well as lipid enveloped viruses eg, hepatitis C.
Koate-DVI is purified by a gel permeation chromatography step serving the dual purpose of reducing the amount of TNBP and polysorbate 80 as well as increasing the purity of the factor VIII.
Pharmacokinetics: A 2-stage clinical study using Koate-DVI was performed in individuals with hemophilia A who have been previously treated with other plasma-derived AHF concentrates. In Stage I of the pharmacokinetic study with 19 individuals, statistical comparisons demonstrated that Koate-DVI is bioequivalent to the unheated product, Koate-HP. The incremental in vivo recovery 10 min after infusion of Koate-DVI was 1.9% iu/kg (Koate-HP 1.82% iu/kg). Mean biologic half-life of Koate-DVI was 16.12 hrs (Koate-HP 16.13 hrs). In Stage II of the study, participants received Koate-DVI treatments for 6 months on home therapy with a median of 54 days (range 24-93). No evidence of inhibitor formation was observed either in the clinical study or in the preclinical investigations.
Clinical Studies: The objective of clinical studies with Koate-DVI was to establish bioequivalence with its predecessor product, Koate-HP, a product that has been used safely and effectively since 1989. The manufacturing processes and product parameters for Koate-HP are equivalent to those of Koate-DVI, except that Koate-HP has no terminal heating step.
Nineteen subjects with severe hemophilia A (<2% plasma FVIII) were randomly assigned to receive either Koate-DVI or Koate-HP. After a wash-out period of 4-7 days, the subjects received an infusion of the other product. FVIII levels and corresponding activated Partial Thromboplastin Time (aPTT) levels were obtained at prescribed intervals over a 48-hr period after each infusion. Dosages ranged between 44.8 and 55.1 iu/kg.
There were no significant differences between the pharmacokinetic parameters of Koate-DVI and Koate-HP (see Table 2), demonstrating that the 80°C heating step has not altered the biological activity of the product.
In an extension to the pharmacokinetic study, Koate-DVI was administered to 17 HIV-negative patients with severe hemophilia A (<2% FVIII) as prophylaxis for bleeding episodes over a 6-month period. Eleven of the 17 patients had fewer than 10 bleeding episodes. In a total of 168 bleeding episodes, 137 (86.7%) required no more than 1 or 2 treatments. Of the 69 adverse events observed in the course of 972 infusions administered, only 1 was deemed to be related (remotely) to Koate-DVI. None of the adverse events were considered severe or life-threatening. There was no evidence of inhibitor formation throughout the 26 weeks of therapy (mean exposure days 55.06±20.35) as evidenced by the absence of any detectable inhibitors on Bethesda assay, and by the stability of the in vivo recoveries over time.

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Treatment of Bleeding Episodes: Nineteen previously treated subjects with severe hemophilia A, who had participated in the pharmacokinetic study described previously were provided with Koate-DVI as their sole AHF source of home therapy for a period of 6 months. Infusions at a minimum dose level of 20-30 iu/kg had to be administered at least twice weekly. Following this schedule, each subject experienced approximately 50 exposure days during the 6-month study period. Throughout the study, subjects maintained home diaries to document AHF usage. At weeks 8, 17 and 26, subjects returned to the clinic for an interim history; physical examination; laboratory studies, including a 10-min FVIII recovery study, hematologic tests, and serum chemistry tests; and a Bethesda assay for inhibitor detection. At the end of the study, a 48-hr pharmacokinetic study with Koate-DVI was repeated, along with clinical and laboratory studies.
Over the study period, the 19 subjects experienced 152 bleeding episodes. A single treatment was effective in >90% of bleeding episodes, and 2 treatments were sufficient in another 6.6% of cases. Koate-DVI was well tolerated, with 29 adverse events (2.75%) observed in the course of 1053 infusions.
Only 10 of the adverse reactions related to 7 infusions were considered to be related to Koate-DVI, and all were mild to moderate. Koate-DVI therefore provides an effective and safe treatment for bleeding episodes.
Neoantigenicity: No evidence of inhibitor formation was observed in 19 previously treated patients after approximately 50 treatment days in the study described previously. This is supported by the absence of detectable inhibitors on repeat Bethesda assays, the stability of in vivo recovery of FVIII and the reproducibility of the pharmacokinetic parameters before and after the 26-week study. Therefore, the terminal heat treatment step in the manufacture of Koate-DVI is not shown to alter the molecule in any way that would increase the evidence of FVIII inhibitor formation.