Advate (Antihemophilic Factor) - Description and Clinical Pharmacology

DESCRIPTION

ADVATE Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (rAHF-PFM) is a purified glycoprotein consisting of 2,332 amino acids that is synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line. In culture, the CHO cell line expresses recombinant antihemophilic factor (rAHF) into the cell culture medium. The rAHF is purified from the culture medium using a series of chromatography columns. The cornerstone of the purification process is an immunoaffinity chromatography step in which a monoclonal antibody directed against Factor VIII is employed to selectively isolate the rAHF from the medium. The cell culture and purification processes used in the manufacture of ADVATE rAHF-PFM employ no additives of human or animal origin. The production process includes a dedicated, viral inactivation solvent-detergent treatment step. The rAHF synthesized by the CHO cells has the same biological effects as Antihemophilic Factor (Human) [AHF (Human)]. Structurally the recombinant protein has a similar combination of heterogeneous heavy and light chains as found in AHF (Human).

ADVATE rAHF-PFM is formulated as a sterile, non-pyrogenic, white to off-white powder for intravenous injection. ADVATE rAHF-PFM is available in single-dose vials that contain nominally 250, 500, 1000 and 1500 International Units (IU) per vial. When reconstituted with the appropriate volume of diluent, the product contains the following stabilizers in maximal amounts: 38 mg/mL mannitol, 10 mg/mL trehalose, 108 mEq/L sodium, 12 mM histidine, 12 mM Tris, 1.9 mM calcium, 0.17 mg/mL polysorbate-80, and 0.10 mg/mL glutathione. Von Willebrand Factor (vWF) is co-expressed with FVIII, and helps to stabilize it in culture. The final product contains no more than 2 ng vWF/IU rAHF, which will not have any clinically relevant effect in patients with von Willebrand's Disease. The product contains no preservative.

Each vial of ADVATE rAHF-PFM is labeled with the AHF activity expressed in IU per vial. Biological potency is determined by an in vitro assay, which employs a Factor VIII concentrate standard that is referenced to a World Health Organization (WHO) International Standard for Factor VIII: C concentrates. The specific activity of ADVATE rAHF-PFM is 4000 to 10,000 IU per milligram of protein.

CLINICAL PHARMACOLOGY

The pharmacokinetics of ADVATE rAHF-PFM were investigated in a Phase 2/3 multicenter pivotal study of previously treated subjects. In addition, an interim analysis comparing the pharmacokinetics of ADVATE rAHF-PFM at the onset of treatment and after a period of at least 75 exposure days was performed in the context of an ongoing continuation study in subjects who completed treatment in the multicenter pivotal Phase 2/3 study. Post-infusion levels and clearance of Factor VIII during the perioperative period were examined in an interim analysis of subjects from the pivotal and continuation studies who were enrolled in an ongoing Phase 2/3 surgical study. Finally, the pharmacokinetics of ADVATE rAHF-PFM were investigated in an interim analysis of an ongoing study of pediatric previously treated subjects < 6 years of age (see Pediatric Use subsection under " PRECAUTIONS ").

PHARMACOKINETICS

A randomized, crossover pharmacokinetic comparison of ADVATE rAHF-PFM produced at a pilot-scale facility in Orth, Austria (the test article) and RECOMBINATE rAHF (the control article) was conducted in the context of the pivotal Phase 2/3 study. Study subjects were initially infused with one of the two preparations at a dose of 50 ± 5 IU/kg body weight while in a non-bleeding state. The second study preparation was infused in a non-bleeding state at 50 ± 5 IU/kg after a washout period of 72 hours to 4 weeks following the first study infusion. The order in which each study preparation was administered was assigned by randomization. Pharmacokinetic parameters (area under the Factor VIII plasma concentration versus time curve [AUC], maximal post-infusion Factor VIII level [C_max], in vivo recovery, half-life, clearance [CL], mean residence time [MRT], and volume of distribution in steady-state [V_ss]) were calculated from Factor VIII activity measurements in blood samples obtained immediately before and at standardized time intervals up to 48 hours following each infusion.

A total of 56 study subjects were enrolled and randomized. Of these, 50 (modified intent-to-treat population) received both infusions of study medication and had sufficient pharmacokinetic data for the comparison of ADVATE rAHF-PFM and RECOMBINATE rAHF. Thirty subjects (per-protocol population) received both pharmacokinetic infusions of study medication and had data for all pharmacokinetic time points. Pharmacokinetic parameters for each study preparation in the per-protocol analysis are presented in Table 1.

For the pharmacokinetic parameters AUC_0-48h and in vivo recovery, the 90% confidence intervals for the ratios of the mean values for the test and control articles were within the pre-established limits of 0.80 and 1.25 for both the per-protocol (n = 30) and intent-to-treat study (n = 50) populations. In addition, in vivo recovery at the onset of treatment and after 75 exposure days was compared for 62 subjects. Results of this analysis indicated no significant change in the in vivo recovery at the onset of treatment and after >/= 75 exposure days.

Additionally, the pharmacokinetics of ADVATE rAHF-PFM produced at the Orth facility were compared with those of ADVATE rAHF-PFM produced at a commercial-scale facility in Neuch[acirc ]tel, Switzerland. For the pharmacokinetic parameters AUC_0-48h and in vivo recovery, the 90% confidence intervals for the ratios of the mean values for the test and control articles were within the pre-established limits of 0.80 and 1.25 for both the per-protocol and intent-to-treat study populations.

The Phase 2/3 continuation study provided a means for examining potential changes in all pharmacokinetic parameters of ADVATE rAHF-PFM at the onset of treatment and after a period of at least 75 exposure days. This comparison utilized data for ADVATE rAHF-PFM produced in the Orth facility obtained at the onset of treatment on the pivotal Phase 2/3 study with data for ADVATE rAHF-PFM produced in the Neuch[acirc ]tel facility obtained in the continuation study. A total of 13 of 34 eligible subjects were included in an interim per-protocol analysis (Table 2). Ninety-five percent (95%) confidence intervals calculated for the ratios of the mean values for AUC_0-48h and in vivo recovery before and after at least 75 exposure days indicated no evidence of a difference in the pharmacokinetics of ADVATE rAHF-PFM at the two time points.

In an interim analysis of data from 10 of 25 planned subjects in the Phase 2/3 surgery study, the target Factor VIII level was met or exceeded in all cases following a single loading dose ranging from 48.0 to 69.8 IU/kg.

HEMOSTATIC EFFICACY

In the Phase 2/3 pivotal study, a global assessment of efficacy was rendered by the subject (for home treatment) or study site investigator (for treatment under medical supervision) using an ordinal scale of excellent, good, fair, or none, based on the quality of hemostasis achieved with ADVATE rAHF-PFM produced in the Orth facility for the treatment of each new bleeding episode. A total of 510 bleeding episodes were reported, with a mean (± SD) of 6.1 ± 8.2 bleeding episodes per subject. Of the 510 new bleeding episodes treated with ADVATE rAHF-PFM, 439 (86%) were rated excellent or good in their response to treatment, 61 (12%) were rated fair, 1 (0.2%) was rated as having no response, and for 9 (2%), the response to treatment was unknown. A total of 411 (81%) new bleeding episodes were managed with a single infusion, 62 (12%) required 2 infusions, 15 (3%) required 3 infusions, and 22 (4%) required 4 or more infusions of ADVATE rAHF-PFM for satisfactory resolution. A total of 162 (32%) new bleeding episodes occurred spontaneously, 228 (45%) were the result of antecedent trauma, and for 120 (24%) bleeding episodes, the etiology was unknown.

The rate of new bleeding episodes during the protocol-mandated 75 exposure day prophylactic regimen (>/= 25 IU/kg body weight 3-4 times per week) was calculated as a function of the etiology of bleeding episodes for 107 evaluable subjects (n = 274 new bleeding episodes). These rates are presented in Table 3.

In a post-hoc analysis, the overall rate of bleeding was correlated inversely with the degree of compliance with the prescribed prophylactic regimen. Subjects who infused less than 25 IU ADVATE rAHF-PFM per kg per dose for more than 20% of prophylactic infusions or administered less than 3 infusions per week for more than 20% of study weeks (n = 37) experienced a 2.3-fold higher rate of bleeding in comparison with subjects who complied with the prescribed prophylactic regimen at least 80% of the time and for >/= 80% of doses (n = 70).

The Phase 2/3 continuation study involved subjects previously treated on the pivotal Phase 2/3 study and provided additional efficacy data on ADVATE rAHF-PFM. An interim analysis of efficacy was conducted for 27 of 82 enrolled subjects who self-administered ADVATE rAHF-PFM produced in Neuch[acirc ]tel on a routine prophylactic regimen during a minimum period of 50 exposure days to ADVATE rAHF-PFM. As in the pivotal Phase 2/3 study, new bleeding episodes were treated with ADVATE rAHF-PFM and the outcome of treatment was rated as excellent, good, fair, or none, based on the quality of hemostasis achieved. A total of 51 new bleeding episodes occurred in 13 of the 27 subjects being treated with ADVATE rAHF-PFM. By etiology, 53% of these bleeding events resulted from trauma and 27% occurred spontaneously; the other 20% had an undetermined etiology. The response to treatment with ADVATE rAHF-PFM for the majority (63%) of all new bleeding episodes was rated as excellent or good. In addition, 86% of the bleeding episodes resolved with only 1 infusion and an additional 6% were resolved by a second infusion. Thus, 92% of all bleeding episodes required 1 or 2 infusions of study product.

An interim analysis of the hemostatic efficacy of ADVATE rAHF-PFM during the perioperative management of subjects undergoing surgical procedures was conducted for 10 of 25 planned subjects. Ten subjects underwent 10 surgical procedures while receiving ADVATE rAHF-PFM. Eight subjects received the test product by intermittent bolus infusion and 2 subjects received a combination of continuous and intermittent bolus infusion. Nine of the 10 subjects completed the study. Six of the surgical procedures were classified as major, and 4 were minor. Of the 6 major surgeries, 5 were for orthopedic complications of hemophilia. A brief description of each surgical procedure, along with study duration and study medication exposure, are presented in Table 4.

For each of the 10 subjects, intra- and post-operative quality of hemostasis achieved with ADVATE rAHF-PFM was assessed by the operating surgeon and study site investigator, respectively, using an ordinal scale of excellent, good, fair, or none. The same rating scale was used to evaluate control of hemorrhage from a surgical drain placed at the incision site in one subject. The quality of hemostasis achieved with ADVATE rAHF-PFM was rated as excellent or good for all assessments.