ALBERT

Beschreibung: It is known that the coagulation factor levels change with age. In this work, we have applied a quantitative systems pharmacology (QSP) model of the coagulation network to predict whether age related changes in coagulation factor levels will impact dose response for PF-05320907 on various pharmacodynamic endpoints. PF-05230907 (PF-907) is a variant of FXa, in which the conformational transition from zymogen to active protease is impaired. Binding to activated factor V facilitates its transition to the active conformation, rescues procoagulant activity and is hypothesized to localize PF-907 hemostatic effect to sites of hemorrhage. It is currently in development for the indication of intracerebral hemorrhage (ICH). Pharmacokinetic (PK) and pharmacodynamic (PD) data are available from the healthy subjects phase 1 study of single dose escalation of intravenous bolus infusion of PF-907. The next study for PF-907 will be conducted in ICH patients, who will have a much higher median age than the median age in the healthy subjects in the Phase 1 study. Our group has implemented a QSP model for the coagulation network to enable integrated understanding of all the data and underlying pharmacology1. The model has been optimized to describe in vitro biomarker changes including; thrombin generation assay (TGA), activated partial thromboplastin time (aPTT) and prothrombin time (PT) as well as in vivo biomarker changes including prothrombin fragment 1+2 (PF1+2), thrombin-anti-thrombin III complex (TAT) and D-dimer. In this simulation study, we used the model to first describe biomarker changes with treatment of FXa variant in hemostatic normal subjects and then used model simulations to predict the behavior of important biomarkers in an older ICH population. A single compartment PK model for PF-907 was first established to describe the PK data obtained from the phase 1 study. The PK model was then combined with the QSP model to predict biomarker changes following PF-907 treatment. Comparison with observed clinical data showed that the model adequately predicted dose-dependent change in TGA parameters, aPTT, PF1+2, TAT and D-dimer. In addition, the model also predicted that there would be no change in PT, which was consistent with observed first in human results with the PF-907 treatment. After model validation using FIH data, the model was then used to predict biomarker changes for older subjects using literature reported changes in baseline levels of coagulation factors for subjects over a period of 40 years. The simulation predicted minimal shifts in the PD responses suggesting that the dose-response to PF-907 may not change significantly between young and older populations. The model, however, did not consider other characteristics beyond coagulation factor level changes in older populations, which may impact the safety profile of PF-907 treatment. In summary, this study indicates that it is possible to predict the response of a hemostatic agent with a QSP model. Following validation, the model can also extrapolate from a standard subject to new patient populations and indicates that no dose adjustment due to age is required. Reference 1. Nayak, S., Lee, D., Patel-Hett, S., Pittman, D., Martin, S., Heatherington, A., Vicini, P. and Hua, F. (2015), Using a Systems Pharmacology Model of the Blood Coagulation Network to Predict the Effects of Various Therapies on Biomarkers. CPT: Pharmacometrics & Systems Pharmacology. doi:10.1002/psp4.50 Disclosures Nayak: Pfizer Inc: Employment. Lee:Pfizer Inc.: Employment. Arkin:Pfizer Inc: Employment. Martin:Pfizer Inc: Employment. Heatherington:Pfizer Inc.: Employment. Denney:Pfizer Inc.: Employment. Vicini:Pfizer Inc.: Employment. Hua:Pfizer Inc: Employment.

Beschreibung: Background: Intravenous immunoglobulin (IVIg), a therapeutic blood product prepared from pooled plasma of 3,000-60,000 healthy donors, is the treatment of choice for immunodeficiency syndromes. It has also been used to treat many acute and chronic autoimmune and systemic inflammatory diseases. The precise mechanism of action of IVIg is not well-understood, but occasional long-term effects presumably reflect immunomodulatory and anti-inflammatory properties. Although clinically useful, IVIg has several limitations including variable efficacy, infusion-related side effects, which may be due to prolonged infusion times and the large volumes needed, high cost, and supply shortages. IVIg alternatives could leverage the broad biological activities of IVIg and provide more consistent and potent anti-inflammatory activity with increased ease of administration. M254, a novel hyper-sialylated IgG investigational product derived from commercially available IVIg, is hypothesized to have greater potency than IVIg. M254 is designed based on scientific evidence demonstrating the relevance of glycosylation on immunoglobulin function, especially the anti-inflammatory activity of IVIg, which has been shown to be dependent on Fc-sialyation. Preclinical data suggests that M254 has up to a ~10 fold enhancement of activity in four independent in vivo model systems: collagen antibody-induced arthritis and pemphigoid skin blistering models, K/BxN- sera induced arthritis model, and an immune thrombocytopenia (ITP) mouse model. These preclinical findings along with demonstrating platelet count increases, support the clinical evaluation of M254 in healthy volunteers and in patients with ITP. Study Design and Methods: This first-in-human, phase 1/2 clinical study has 4 parts (NCT03866577). Part A enrolled 25 healthy volunteers; subsequent parts of the study will enroll patients with ITP. The study design is provided in Figure 1. Part A assessed safety, tolerability, and PK of M254 after administration of a single ascending dose in healthy volunteers (n=25). Part B will assess safety, tolerability, and PK of M254 after administration of a single ascending dose followed by 1000 mg/kg IVIg administration in patients with ITP (n=10) with an exploratory evaluation of platelet response with M254 compared to IVIg. This exploratory platelet response evaluation allows a model-based, informed dose selection for Part C, which will be a 2 arm, crossover design comparing the platelet response of M254 with IVIg in patients with ITP (n=20). Part C will have 2 cohorts: high dose of M254 in Cohort 1 and low dose of M254 in Cohort 2. In combination with Part B, Part C will allow a model-based estimate of the M254 dose which is equivalent to IVIg. Using the totality of the data and dose ranging enables high confidence in the M254 dose while requiring a minimum number of patients with ITP. Part D will be a multiple dose study of M254 for the evaluation of safety, tolerability, PK, and PD platelet response in patients with ITP. For Part B, C, and D, adult patients with ITP (with or without splenectomy) for 〉 3 months, platelet count between 15 and 50 x 109/L, receiving stable maintenance immunosuppressive therapy, and no history of other clotting disorders may be eligible. Key exclusion criteria include history of arterial or venous thrombosis and having ≥ 2 risk factors for thrombosis or clotting disorders, known history of non-responsive to IVIg, evidence of HCV, HBV, and HIV infection, and newly diagnosed ITP patients who are naïve to anti-ITP treatments. Trial Progress: Part A (healthy volunteers) has been completed. In Part A, ascending doses of M254 from 3mg/kg to 250mg/kg were administered and were determined to be well tolerated. There was a single subject at 250 mg/kg that experienced a short lasting moderate systemic infusion reaction with chills, headache, nausea, vomiting and fever. No skin reactions, no pruritus and no changes in C3, C4 or white blood cells subsets in the extra blood sample taken during the reaction. This is not an unexpected even as infusion reactions often occur with IVIg. The protocol allowed for a seamless transition from evaluating M254 in healthy volunteers to patients with ITP. We have now initiated Part B of the study. Figure 1 Disclosures Arroyo: Momenta Pharmaceuticals: Employment. Tiessen:PRA Health Sciences: Employment. Denney:Human Predictions: Employment. Jin:Momenta Pharmaceuticals: Employment. van Iersel:PRA Health Sciences: Employment. Zeitz:Momenta Pharmaceuticals: Employment. Manning:Momenta Pharmaceuticals: Employment. Schipperus:Momenta Pharmaceuticals: Consultancy. Bussel:argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 3S Bio: Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.