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

Population Pharmacokinetic Modeling of BeneFIX in Pediatric and Adult Patients with Hemophilia B Demonstrates Weight as An Important Factor Contributing to Inter-Patient PK Variability.

Abstract Clinical trials in patients with hemophilia B have demonstrated considerable inter-patient variability in the pharmacokinetics (PK) of Factor IX (FIX) replacement therapy, including the recovery, an important PK parameter from which individualized clinical dosing decisions are calculated. In clinical trials of plasma-derived and recombinant factor IX replacement therapies, the age of the patient has been demonstrated to affect recovery (younger patients have lower recovery values than older patients), however the specific contribution of age, as well as additional covariates such as body weight and race to PK variability has not been systematically evaluated. We analyzed an extensive database of BeneFIX PK data collected from 8 separate clinical trials conducted over 13 years. A systematic approach involving population PK modeling and simulation was utilized for the first time to estimate the effects of individual-specific covariate factors on PK of BeneFIX in the pooled population that included pediatric and adult patients. A total of 4025 plasma FIX activity PK data sets collected from 191 patients, aged 0 to 69 years were used for the analysis. There were 111 children (£15 years) including 53 infants &amp;lt;2 years, and 80 adults (&amp;gt;15 years) in the pooled data. The majority (84%) of patients were Caucasian. The remaining patients were African American (7%), Hispanic (4%), Asian/Japanese (3%), and other ethnicity (3%). The data were analyzed using nonlinear mixed-effects modeling with the NONMEM software system. Age, weight, and race were examined as covariates for the ability to explain inter-individual variability in the BeneFIX PK. The PK in pediatric and adult patients was described by a two-compartment model with first-order elimination and a zero-order input using the following parameters: clearance (CL), volume of central compartment (V1), volume of peripheral compartment (V2) and inter-compartmental clearance (Q). Population predicted BeneFIX PK parameters, standardized to a 70 kg patient, were 7.46 (standard error; 0.20) mL/hr/kg, 131 (4.4) mL/kg, 71.5 (2.1) mL/kg and 12.1 (1.1) mL/h/kg, for CL, V1, V2 and Q, respectively. The final model was able to simulate data in close agreement with the actual study observations. Variability (%CV) in BeneFIX PK was explained most significantly by allometrically scaled body weight (Figure 1a), while age and race had no discernible effects on BeneFIX PK in the population studied. Observed recovery values were slightly lower in children (£15 years) compared with those in adults (&amp;gt;15 years) since the initial volume of distribution (V1), normalized to body weight, was slightly higher in children than in adults, while the variability in the observed recovery values was comparable between children and adults (Figure 1b). In conclusion, the present analysis, for the first time, systematically describes and quantifies the sources of age-dependent variability of factor IX PK, using BeneFIX data, and provides a better understanding of the importance of body weight in the disposition of BeneFIX. This confirms existing weight-based dosing recommendations and further supports consideration of dosing adjustments that are individualized based on the patient’s body weight in the context of the achieving the desired clinical response, such as recovery. This also may be important in pediatric patients during growth periods associated with significant weight change. Figure 1a. Clearance versus Body weight Figure 1a. Clearance versus Body weight Figure 1b. Recovery versus Body weight Figure 1b. Recovery versus Body weight</jats:p

Assessment of current approaches of starting dose selection and dose escalation for oncology biologics in first-in-patient trials.

e14093 Background: Current approaches for starting dose selection for first-in-patient (FIP) trials of oncology biologics vary according to pharmacological properties and modality of the investigational agent. For biologics with immune agonistic properties, the FIP starting dose is typically based on the minimal anticipated biological effect level (MABEL). For non-immune activating biologics, the starting dose is typically based on allometric scaling of a threshold toxic dose determined in the most appropriate animal species. The aim of this work is to assess the performance of current approaches of FIP starting dose selection and dose escalation for oncology biologics. Methods: FIP clinical trials for oncology biologics licensed by the US FDA from 2010 to 2019 were analyzed to extract information related to starting dose and dose escalation. Source materials for the relevant FIP trials included the Drugs@FDA database, PubMed, and conference proceedings. The data were further analyzed to evaluate parameters related to appropriateness of the starting dose and dose escalation efficiency, which include the number of cohorts to reach the maximum tolerated dose [MTD] (or, when MTD was not identified, the highest human dose [HHD]) and the ratio of MTD/HHD to starting dose. Results: The 26 oncology biologics licensed by the US FDA between 2010 and 2019 included 8 ADCs/immunotoxins, 7 checkpoint inhibitors and 11 other biologics (monoclonal antibody, fusion protein or CD3 bispecific construct). The majority (69%) of these biologics were well tolerated without MTD identified in the FIP trials. All 26 FIP trials with biologics appeared to follow ICH S9 Guidance for starting dose selection, and the dose increment ranged from 1.2- to 10-fold. These FIP trials had a median of 6 cohorts (range: 3-10) to reach MTD (or HHD) from the starting dose. About 50% of these trials involved ≥ 6 cohorts to reach MTD (or HHD). The MTD/HHD to starting dose ratio was &gt; 100 for 4 of the biologics. The median label dose to starting dose ratio was 10 (range: 1-3200), suggesting that a large number of patients in these FIP trials received subtherapeutic dose levels. Conclusions: Current approaches of starting dose selection and dose escalation led to a very low starting dose and many dose escalation cohorts for the FIP trials of a large portion of recently licensed oncology biologics. There exist opportunities to improve current approaches to increase FIP trial efficiency and reduce the number of patients receiving subtherapeutic dose levels in these trials. </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