Prediction of Cardiac ATTR Depletion by NI006 (ALXN2220) Using Mechanistic PK/PD Modeling

NI006 (aka ALXN2220) is a therapeutic antibody candidate in phase III clinical development for the depletion of amyloid transthyretin (ATTR) in patients with ATTR cardiomyopathy, an infiltrative cardiomyopathy leading to increased left ventricular wall thickness (LVWT). The mode-of-action consists in removal of disease-causing amyloid accumulations by activating phagocytic immune cells, a mechanism without precedent in cardiology. To select a safe and potentially efficacious dose range and treatment duration for a combined first-in-human and proof-of-concept clinical phase Ib study, we developed a mechanistic pharmacokinetic and pharmacodynamic (PK/PD) model that can predict NI006 exposure, its effects on cardiac amyloid load and on LWVT, which is a predictor of heart failure in this disease. The PK/PD model predictions supported 0.3 mg/kg monthly dosing as a safe starting dose and identified 10-60 mg/kg monthly as the potentially efficacious dose range with substantial and dose dependent cardiac amyloid burden reduction within 4 months for 60 mg/kg and 10 months for 10 mg/kg. These predictions were in good agreement with the observed primary results of the clinical phase Ib study where amyloid burden was measured by imaging. This novel translational PK/PD model provided important predictions to guide the design of the phase Ib study of NI006, indicating the value of this approach to integrate preclinical results into clinical trial design and increase translational success

ReFacto AF Is Effective and Safe in Previously Treated Patients with Severe Hemophilia A: Final Results of a Pivotal Phase III Study.

Abstract ReFacto AF (Albumin-Free Cell Culture Process) is a BDDrFVIII manufactured using an albumin-free cell culture process and purified using a chemically synthesized peptide affinity ligand instead of a murine monoclonal antibody. A virus-retaining filtration step has been included as an additional safety precaution during manufacture. The potency assignment of ReFacto AF has been aligned to the one-stage clotting assay, to permit routine clinical monitoring, as for other rFVIII products, without specialized standards. The pharmacokinetic (PK) profile of ReFacto AF vs. Advate was assessed in a randomized double blind crossover fashion, in 30 previously treated patients (PTPs) (≥ 12 years; FVIII:C ≤1%) using the standard bioequivalence approach based upon the one-stage clotting assay. Safety and efficacy of ReFacto AF was also assessed in a total of 94 PTPs (FVIII ≤2%), which included the PK subjects, during 6 months of open label routine prophylaxis supplemented with on-demand treatment as necessary. A follow-up PK assessment with ReFacto AF was performed in the PK subjects after 6 months. Pharmacokinetic equivalence of ReFacto AF and Advate was demonstrated (n = 30 subjects). The ratios of geometric least-square means for K-value, AUCt, AUC∞ were 100%, 89.8%, and 88.0%, respectively, and associated 90% confidence intervals were within the bioequivalence window of 80%–125%. Twenty five (25) subjects had a baseline and 6 month follow-up PK assessment with ReFacto AF. Mean K-value and t1/2 for ReFacto AF were 2.23 (± 0.39) IU/dL per IU/kg and 11.8 (± 5.1) hours, respectively at baseline and the 6 month follow-up PK profile was unchanged. Of the 94 patients, 89 accrued at least 50 ReFacto AF exposure days. Median routine prophylaxis dose was 30.2 IU/kg. During routine prophylaxis, the median annualized bleed rate was 1.9 (mean 3.9, range 0 to 42.1), and 43 of 94 (45.7%) patients experienced no bleeding episodes. A total of 187 bleeding episodes were treated on-demand with a median dose of 30.6 IU/kg, and 92.5% resolved with 1 or 2 infusions. The overall adverse event (AE) profile was consistent with the AE profile of ReFacto and other rFVIII products. Two of the 94 patients had transient, low-titer, clinically silent inhibitors (0.98 BU/mL and 1.21 BU/mL), each detected by routine surveillance on a single occasion and each was negative on follow-up testing. The corresponding ELISAs for FVIII antibodies were negative for both patients. No patient in the study had a positive ELISA immune response to CHO cell protein or to the peptide affinity ligand used for ReFacto AF purification. ReFacto AF is pharmacokinetically equivalent to Advate based on one-stage FVIII activity assessments, and ReFacto AF PK is stable over 6 months of use. The product is effective in the prevention and treatment of bleeding episodes. Inhibitor safety results show no evidence of neoantigenicity and the AE profile demonstrates safety in PTPs with hemophilia A.</jats:p

ReFacto AF Is Effective and Safe in Previously Treated Patients with Severe Hemophilia A: Final Results of a Pivotal Phase III Study

Abstract ReFacto AF (Albumin-Free Cell Culture Process) is a BDDrFVIII manufactured using an albumin-free cell culture process and purified using a chemically synthesized peptide affinity ligand instead of a murine monoclonal antibody. A virus-retaining filtration step has been included as an additional safety precaution during manufacture. The potency assignment of ReFacto AF has been aligned to the one-stage clotting assay, to permit routine clinical monitoring, as for other rFVIII products, without specialized standards. The pharmacokinetic (PK) profile of ReFacto AF vs. Advate was assessed in a randomized double blind crossover fashion, in 30 previously treated patients (PTPs) (≥ 12 years; FVIII:C ≤1%) using the standard bioequivalence approach based upon the one-stage clotting assay. Safety and efficacy of ReFacto AF was also assessed in a total of 94 PTPs (FVIII ≤2%), which included the PK subjects, during 6 months of open label routine prophylaxis supplemented with on-demand treatment as necessary. A follow-up PK assessment with ReFacto AF was performed in the PK subjects after 6 months. Pharmacokinetic equivalence of ReFacto AF and Advate was demonstrated (n = 30 subjects). The ratios of geometric least-square means for K-value, AUCt, AUC∞ were 100%, 89.8%, and 88.0%, respectively, and associated 90% confidence intervals were within the bioequivalence window of 80%–125%. Twenty five (25) subjects had a baseline and 6 month follow-up PK assessment with ReFacto AF. Mean K-value and t1/2 for ReFacto AF were 2.23 (± 0.39) IU/dL per IU/kg and 11.8 (± 5.1) hours, respectively at baseline and the 6 month follow-up PK profile was unchanged. Of the 94 patients, 89 accrued at least 50 ReFacto AF exposure days. Median routine prophylaxis dose was 30.2 IU/kg. During routine prophylaxis, the median annualized bleed rate was 1.9 (mean 3.9, range 0 to 42.1), and 43 of 94 (45.7%) patients experienced no bleeding episodes. A total of 187 bleeding episodes were treated on-demand with a median dose of 30.6 IU/kg, and 92.5% resolved with 1 or 2 infusions. The overall adverse event (AE) profile was consistent with the AE profile of ReFacto and other rFVIII products. Two of the 94 patients had transient, low-titer, clinically silent inhibitors (0.98 BU/mL and 1.21 BU/mL), each detected by routine surveillance on a single occasion and each was negative on follow-up testing. The corresponding ELISAs for FVIII antibodies were negative for both patients. No patient in the study had a positive ELISA immune response to CHO cell protein or to the peptide affinity ligand used for ReFacto AF purification. ReFacto AF is pharmacokinetically equivalent to Advate based on one-stage FVIII activity assessments, and ReFacto AF PK is stable over 6 months of use. The product is effective in the prevention and treatment of bleeding episodes. Inhibitor safety results show no evidence of neoantigenicity and the AE profile demonstrates safety in PTPs with hemophilia A

ReFacto (R)(1) and Advate (R)(2) : a single-dose, randomized, two-period crossover pharmacokinetics study in subjects with haemophilia A

ReFacto is a recombinant B-domain-deleted, monoclonal antibody-purified, solvent-detergent-treated factor VIII (BDDrFVIII) with no albumin added to the final formulation. Although ReFacto has been shown to be bioequivalent to a plasma-derived FVIII product (Hemophil-M) in a randomized, crossover pharmacokinetic (PK) study, the comparability of ReFacto with the full-length (complete sequence) recombinant FVIII (FLrFVIII, Advate) product has not been previously examined in this manner. The primary objective of this study was to compare the PKs of ReFacto with those of Advate in patients with severe haemophilia A. This was a third-party unblinded, randomized, multicentre, two-period crossover PKs study of ReFacto and Advate in subjects with severe haemophilia A (FVIII:C 641%). Blood samples were collected over a 48-h period after i.v. administration of each of the FVIII products. FVIII:C was determined using the chromogenic substrate assay (CSA) in a central laboratory. The plasma FVIII:C PK parameters of ReFacto and Advate were determined using non-compartmental analysis. Bioequivalence was assessed on maximum plasma concentration (Cmax) and the area under the plasma concentration vs. time curves (AUCs) using an anova. The two products were judged to be equivalent if the 90%; confidence limits of the ratio of the geometric mean values of Cmax and AUC s fell within the interval of 80-125%. Results from this PKs comparison of two different rFVIII products, using chromogenic substrate assay to measure FVIII:C, showed that ReFacto and Advate are bioequivalent to each other

A New Formulation of Recombinant Human Factor IX Is Bioequivalent to BeneFIX: A Double-Blind, Randomized, Crossover Pharmacokinetic and Open-Label Safety and Efficacy Study.

Abstract A new formulation (rFIX-R) of BeneFIX has been developed to reduce the possibility of RBC agglutination, a phenomenon associated with the low ionic strength of the reconstituted drug product. The new formulation contains NaCl to increase the ionic strength and the recombinant factor IX concentration is increased for the 1000 IU strength and a new 2000 IU strength by reconstituting all strengths in 5 mL, facilitating the administration of larger doses in decreased volumes. Thirty-four (34) previously treated (≥150 exposure days [EDs]) males (≥12 years) with moderately severe/severe hemophilia B (FIX:C ≤2%) were enrolled and treated in this 2 part study. In the randomized, double-blind, crossover pharmacokinetic (PK) period of the study, the PK characteristics of rFIX-R were compared with those of the currently available formulation of BeneFIX. Subjects received either rFIX-R or BeneFIX as a 75 IU/kg bolus infusion over 10 minutes after a suitable washout. Blood samples were collected at defined times over 72 hours to measure pre-/post-infusion plasma factor IX activity. Subjects then received the alternate treatment following the same procedure. The mean plasma factor IX activity-versus-time profile after the infusion of rFIX-R was essentially identical to that seen with BeneFIX. From the 26 evaluable subjects, the mean PK parameter estimates of factor IX activity establish bioequivalence of the products since the 90% confidence intervals for rFIX-R to BeneFIX ratios of the geometric means of Cmax and AUCs fell within the bioequivalence interval of 80% to 125%. Figure Figure In the open-label treatment period, subjects used rFIX-R for on-demand control of bleeding, routine prophylaxis, and/or surgical prophylaxis for 6- to 12-months to achieve at least 30 EDs. The plasma factor IX activity-versus-time profile was recharacterized after 6 months of rFIX-R treatment and was unchanged compared with the baseline rFIX-R PK profile. Over 1000 infusions (&amp;gt;3,500,000 IU of rFIX-R) have been administered with no serious adverse events related to rFIX-R. No clinically significant adverse events related to rFIX-R have been reported, including FIX inhibitor development, allergic-type manifestations, or thrombotic complications. One subject, with a prior history of frequent RBC agglutination, reported two instances without any associated adverse events. The overall results of this study demonstrate the safety of rFIX-R and the bioequivalence of the new formulation and BeneFIX. Since bioequivalence is the most important surrogate endpoint for efficacy, these data predict a favorable rFIX-R efficacy profile, consistent with that of BeneFIX, but with increased convenience in that larger doses can be administered using decreased volumes relative to BeneFIX.</jats:p