Carol Cronenberger

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

OBJECTIVE PF-04360365 is a humanized IgG(2)Δa anti-amyloid β (Aβ) antibody designed to improve outcome in Alzheimers disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD. This Phase 1, multicenter, randomized, double-blind, dose-escalation study was the first to evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of PF-04360365 in Japanese subjects. MATERIALS AND METHODS 30 subjects with mild-to-moderate AD were enrolled. In each cohort, 3 subjects received PF-04360365 (0.1, 0.5, 1, 5, or 10 mg/kg) and 1 subject received placebo as a single 2-hour intravenous infusion. Subjects were monitored as inpatients for 24 hours and then as outpatients for 1 year. RESULTS All subjects completed the study. There were no serious or National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥ 3 adverse events, hypersensitivity reactions, or antidrug antibodies. No clinical or MRI evidence of brain microhemorrhage, cerebral edema, or encephalitis was observed. PF-04360365 plasma concentrations increased with dose, and pharmacokinetics were consistent with a small steady-state volume of distribution, slow clearance, and long elimination half-life. Cerebrospinal fluid (CSF):plasma ratios were < 0.5%. Plasma Aβ species showed dose-dependent increases in C(max) and AUC(∞), but CSF biomarkers did not differ clearly between treatment arms. CONCLUSIONS PF-04360365 was safe and well tolerated in Japanese subjects. Pharmacokinetics and plasma pharmacodynamic responses in Japanese subjects were comparable to those in Western subjects. *No longer affiliated with Pfizer.

Safety, efficacy, pharmacokinetics and pharmacodynamics of multiple doses of Ponezumab in subjects with mild-to-moderate Alzheimer's disease

ploring a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6 month randomized, placebo-controlled, double-blind, single-site trial, with change in episodic recall as the primary outcome and biomarker change and safety/tolerability as secondary measures. Results: The results of this proof-of-concept trial underlie a “Go-No-Go” decision. If we observe a significant improvement in clinical outcomes, we will propose a definitive trial of carvedilol in AD. If we observe a change only in biomarker outcomes, this will inform further studies of similar treatment mechanisms (whether carvedilol or alternative agents). Conclusions: Should carvedilol prove to be effective in AD, it has several advantages over novel agents in human trials since it has a well-characterized, generally well-tolerated safety profile and is available as a generic drug.

An Extension Study of PF-05280586, a Potential Rituximab Biosimilar, versus Rituximab in Subjects with Active Rheumatoid Arthritis

This extension study provided continued treatment to subjects with active rheumatoid arthritis who had participated for ≥16 weeks in a pharmacokinetic similarity study of PF‐05280586 (potential rituximab biosimilar). Objectives were to evaluate overall pharmacokinetics, pharmacodynamics, immunogenicity, safety, and tolerability of PF‐05280586 after transition from rituximab reference products to PF‐05280586, and follow‐up of biomarker and efficacy assessments.

FRI0137 Efficacy, safety and immunogenicity from week 30 to week 54 in a randomised, double-blind phase iii study comparing a proposed infliximab biosimilar (PF-06438179/GP1111) with reference infliximab

Background PF-06438179/GP1111 (GP1111) is an infliximab (IFX) biosimilar in development for the treatment of immune-mediated inflammatory diseases, including rheumatoid arthritis (RA). The efficacy, safety and immunogenicity of GP1111 and European reference IFX (IFX-EU) have been reported to be similar over 30 weeks (Wks). Objectives To evaluate the efficacy, safety and immunogenicity of GP1111 and IFX-EU with longer-term treatment, and after treatment transition from IFX-EU to GP1111. Methods A randomised, double-blind, parallel-group study compared GP1111 with IFX-EU in biologic-naïve, adult patients with moderate-to-severe active RA on a stable dose of methotrexate (MTX). Patients were randomised (1:1) to GP1111 or IFX-EU (3 mg/kg IV at Wks 0, 2, 6, and then every 8 wks, with one dose escalation to 5 mg/kg allowed at or after Wk 14 for inadequate responders) for 30 weeks (treatment period 1). The primary endpoint was a≥20% improvement in ACR response (ACR20) at Wk 14. At Wk 30 (treatment period 2 [TP2]), patients receiving IFX-EU were blindly re-randomised (1:1) to remain on IFX-EU or transition to GP1111 for 24 wks. Here we report longer-term efficacy, safety and immunogenicity data from Wks 30–54. Results 650 patients were randomised initially (GP1111, n=324; IFX-EU, n=326). At Wk 30, 566 patients entered TP2 (continued GP1111, n=280; continued IFX-EU, n=143; switched from IFX-EU to GP1111, n=143). ACR20 rates and DAS28-CRP scores were comparable between groups at all TP2 visits after re-randomisation in the TP2 population (figure 1). Incidences of TP2 treatment-emergent adverse events (AEs) (36.8%, 33.6%, and 37.8%), serious AEs (4.6%, 7.7% and 2.8%) and infusion-related reactions (3.2%, 8.4% and 4.2%) were comparable between the GP1111/GP1111, IFX-EU/IFX-EU, and IFX-EU/GP1111 groups, respectively. Pre-dose ADA rates at Wk 30 (TP2) were 47.1%, 53.8% and 45.5% for the GP1111/GP1111, IFX-EU/IFX-EU, and IFX-EU/GP1111 groups, respectively. Overall, post-dose ADA rates in TP2 were comparable between groups (52.1%, 60.1%, and 58.0% respectively).Abstract FRI0137 – Figure 1 ACR20 response rate and change in DAS28-CRP score at Wk 30 and 54 for the overall population during TP2 Conclusions Results from TP2 (Wks 30–54) continued to show the absence of clinically meaningful differences in efficacy, safety and immunogenicity between patients with RA remaining on GP1111 or IFX-EU, or when blindly switched from IFX-EU to GP1111. Disclosure of Interest R. Alten Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., Speakers bureau: Pfizer Inc., V. Tseluyko Speakers bureau: Pfizer Inc., AstraZeneca, Bayer, Boehringer Ingelheim, Servier, Sanofi, Takeda, KRKA, T. Hala: None declared, S. Mehmedagic: None declared, M. Pileckyte: None declared, E. Dokoupilová: None declared, D. Jovic: None declared, M. Rehman Shareholder of: Proctor and Gamble, Employee of: Pfizer Inc., M. Zhang Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., L. Sewell Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Hackley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Salts Shareholder of: Pfizer Inc., Mirati Therapeutics, Employee of: Pfizer Inc., C. Cronenberger Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., K. Schumacher Shareholder of: Novartis, Employee of: Sandoz Biopharmaceuticals, O. von Richter Employee of: Sandoz Biopharmaceuticals, B. Batko Consultant for: Pfizer Inc., Sandoz, MSD

Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II PET-PIB study

The safety, pharmacokinetics, and effect on peripheral and central amyloid β (Aβ) of multiple doses of ponezumab, an anti‐Aβ monoclonal antibody, were characterized in subjects with mild‐to‐moderate Alzheimers disease treated for 1 year.

A comparative clinical study of PF-06410293, a candidate adalimumab biosimilar, and adalimumab reference product (Humira®) in the treatment of active rheumatoid arthritis

BackgroundThis double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10–25 mg/week). We report results for the first 26 weeks of treatment.MethodsPatients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (−12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28–4(CRP)], European League Against Rheumatism (EULAR) response, DAS28–4(CRP) of less than 2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26.ResultsPatients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28–4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was −2.98% and corresponding CIs—95% CI (−10.38%, 4.44%) and 90% CI (−9.25%, 3.28%)—were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU).ConclusionsThe study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX.Trial registrationClinicalTrials.gov Identifier: NCT02480153. First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29. Start date: October 27, 2014.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy

Multiple intravenous doses of ponezumab, an anti‐amyloid antibody, were evaluated in subjects with mild‐to‐moderate Alzheimers disease (AD).