James W. Kupiec

Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease

Objective: To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD). Methods: Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14–26 were randomized to PF-04494700 60 mg/day × 6 days, then 20 mg daily (high dose); 15 mg/day × 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimers Disease Assessment Scale–cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers. Results: A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo. Conclusions: PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses. Classification of evidence: This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months.

Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study.

ObjectivesPonezumab is a humanized antiamyloid beta (A&bgr;) monoclonal antibody designed to treat Alzheimer disease (AD). MethodsThis randomized, double-blind, single-dose-escalation study evaluated the safety, pharmacokinetics, and pharmacodynamics of 0.1, 0.3, 1, 3, and 10 mg/kg ponezumab (n = 4, 4, 4, 6, and 8, respectively) versus placebo (n = 11) after a 2-hour intravenous infusion in subjects with mild-to-moderate AD. Cerebrospinal fluid (CSF) samples were obtained from the 1- and 10-mg/kg groups at baseline and at day 29. The subjects were followed for 1 year. ResultsAll subjects completed the trial. Ponezumab was well tolerated with no drug-attributed serious adverse events. The most common adverse events were upper respiratory tract infection, headache, and back pain, all mild to moderate. One subject (10 mg/kg) experienced a mild hypersensitivity reaction. Another subject (0.1 mg/kg) demonstrated slight enlargement of a preexisting midbrain lesion. Electrocardiography and laboratory values (including CSF) were unremarkable. No evidence of new microhemorrhage, vasogenic edema, or meningoencephalitis was noted. Plasma maximum observed concentration increased approximately dose proportionally, and the area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUCinf) increased slightly more than dose proportionally. Mean terminal half-life was approximately 6 weeks. Two subjects (10 mg/kg) had measurable CSF ponezumab concentrations (~0.5% of plasma values) at day 29. Plasma A&bgr;1-x and A&bgr;1-40 increased dose dependently, and mean CSF A&bgr;1-x increased 38% from baseline with 10 mg/kg (P = 0.002 vs placebo). ConclusionsA 2-hour infusion of 0.1 to 10 mg/kg ponezumab was well tolerated in subjects with mild-to-moderate AD. Plasma pharmacokinetic profile was approximately linear. Plasma A&bgr; increased with dose, and CSF A&bgr; increased at the highest dose, suggesting that intravenous ponezumab alters central A&bgr; levels.

Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease.

ObjectivePonezumab (PF-04360365) is a humanized anti–amyloid beta (A&bgr;) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid A&bgr;. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion. MethodsSubjects with mild to moderate AD received ponezumab 1 mg/kg (n = 3), 3 mg/kg (n = 3), 5 mg/kg (n = 4), or 10 mg/kg (n = 5). They were followed up as outpatients for 6 months. ResultsAll subjects completed the trial. Ponezumab was safe and well tolerated with no deaths, withdrawals, or drug-related moderate, severe, or serious adverse events. Mild drug-related adverse events included headache (3 patients) and lethargy and hypoesthesia (both in 1 patient). No infusion reactions, clinically meaningful laboratory abnormalities, vital sign changes, electrocardiographic changes, or antidrug antibodies were detected. There was no evidence of brain microhemorrhage, vasogenic edema, encephalitis, or other imaging abnormality. Cognitive function showed no treatment-related trends. Ponezumab displayed approximately dose-proportional increases in plasma exposure. Steady-state volume of distribution was 113 to 172 mL/kg, clearance was 2.7 to 3.0 mL/d/kg, and terminal half-life was 35 to 52 days. Plasma maximum observed concentration and the area under the plasma concentration-time profile from time 0 extrapolated to infinite time of A&bgr;1-x and A&bgr;1-40 increased dose-dependently. ConclusionsAdministration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma A&bgr; species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.

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.

First-In-Human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer’s disease

BackgroundIn the First-In-Human (FIH), 39-week, randomized, adaptive design study, safety, tolerability, pharmacokinetics and biomarkers were measured in patients with mild-to-moderate Alzheimer’s disease (AD) after infusion of a humanized monoclonal antibody to amyloid β, AAB-003 (NCT01193608; registered 19 August 2010). AAB-003 was developed by modifying bapineuzumab to reduce Fc-receptor-mediated effector function as a strategy to reduce the removal of amyloid from vessel walls associated with amyloid-related imaging abnormalities with edema/effusions (ARIA-E) without diminishing overall amyloid clearance.MethodsEighty-eight patients with AD received up to three infusions of AAB-003 (or placebo) 13 weeks apart at doses of 0.5, 1, 2, 4 or 8 mg/kg in the FIH trial. Dose escalation was based on safety data reviews using a Bayesian escalation algorithm. Subjects who completed the FIH study were permitted to enter a 1-year open-label extension trial with four additional intravenous infusions of AAB-003 (NCT01369225; registered 10 May 2011).ResultsDose-dependent increases in plasma amyloid β and AAB-003 were observed. No significant changes in cerebral spinal fluid biomarkers were observed. Pharmacokinetics elimination half-life (21–28 days) clearance and volume of distribution values were consistent across dose groups indicating linearity. ARIA-E was the most notable safety finding detected by magnetic resonance imaging (MRI) at 8 mg/kg in two patients. Three cases of microhemorrhage were observed. No new safety findings or MRI abnormalities were observed for the 52 subjects who received AAB-003 in the extension trial.ConclusionBased on integrated review of laboratory, electrocardiogram, adverse events, and MRI, AAB-003 was safe and well tolerated up to 8 mg/kg for up to 91 weeks (FIH and extension trials) in patients with mild to moderate AD. Asymptomatic and resolvable ARIA-E was observed after the first or second infusion of AAB-003, similar to bapineuzumab. The AAB-003 dose at which ARIA-E was observed was higher compared to bapineuzumab, supporting the hypothesis that reducing Fc-receptor effector function may reduce the ARIA associated with monoclonal antibodies targeting cerebral amyloid.

Preliminary population pharmacokinetic modeling of PF-04360365, a humanized anti-amyloid monoclonal antibody, in patients with mild-to-moderate Alzheimer's disease

Introduction ● PF-04360365 is a humanized anti-amyloid IgG2 monoclonal antibody that recognizes amino acids 33–40 of the beta-amyloid (Aβ) 1–40 peptide, and requires a free carboxy terminus for binding. ● In transgenic mice that overexpress amyloid precursor protein, the murine analog of PF-04360365 has been observed to decrease Aβ levels in the central nervous system and to improve their performance in various models of learning and memory. ● PF-04360365 is currently undergoing clinical testing in patients with Alzheimer’s disease (AD) as a potential disease modifying agent to reduce brain Aβ burden and to improve clinical outcomes. ● A robust population pharmacokinetic (PK) model at an early stage of drug development can be critical in helping design more efficient clinical studies.

Pharmacokinetics and pharmacodynamics of ponezumab (PF-04360365) following a single-dose intravenous infusion in patients with mild to moderate Alzheimer's disease

Background: Ponezumab (PF-04360365) is a humanized anti-amyloid mAb under investigation for the treatment of Alzheimer’s disease (AD). The pharmacokinetics and pharmacodynamics of ponezumab were evaluated in two phase 1 studies in patients with mild-to-moderate AD, and the results compared. Methods: Placebo or ponezumab at 0.1 (n 1⁄4 6), 0.3 (n 1⁄4 6), 1 (n 1⁄4 6), 3 (n 1⁄4 8), or 10 mg/kg (n 1⁄4 11) were administered via 2-hour infusion to 37 patients with AD in a randomized, double-blind, placebo-controlled, dose-escalation study (A9951001). A second study (A9951008) was designed as an open-label, parallel-group, dose-escalation trial with ponezumab administered at 1 (n 1⁄4 3), 3 (n 1⁄4 3), 5 (n 1⁄4 4), or 10 (n 1⁄4 5) mg/kg via 10-minute infusion. Serum analytes for anti-drug antibodies (ADAs), plasma ponezumab and amyloid b (Ab), and CSF ponezumab, Ab, and tau/p-tau concentrations were quantified by validated bioanalytical methods. Plasma pharmacokinetics and pharmacodynamics were calculated using non-compartmental analysis. Results: Pharmacokinetics and pharmacodynamics were similar between the two studies. Plasma ponezumab reached maximum concentration (Cmax) shortly after infusion, followed by a biphasic decline. Cmax and area under the concentration-time curve increased in a dose-proportional manner. The pharmacokinetics of ponezumab were linear with a mean terminal half-life of 35-52 days. Ponezumab CSF concentrations at Day 29 post-dose (A9951001) were quantifiable in 2 of 8 patients administered a 10 mg/kg dose (?0.5% of plasma values). In both studies, plasma Ab concentrations and time to Cmax (Tmax) increased dose-dependently. The ratios of Cmax/baseline in plasma Ab concentrations were around 500 in the 10 mg/kg group compared with 1 in the placebo group. At the 10 mg/kg dose (A9951001), mean CSF Ab percentage change from baseline at Day 29 increased 38% (p < 0.05), 29% (p > 0.05), and 15% (p < 0.05) for Ab1-x, Ab1-40, and Ab1-42, respectively. There were no changes from baseline for CSF tau and p-tau concentrations. ADAs were not detected. Conclusions: The pharmacokinetics of ponezumab were similar between the two studies linear, with central penetration seen following the highest dose in some patients. Increases in plasma Ab biomarker response and Tmax were dose dependent. CSF Ab concentrations increased from baseline at Day 29 for the 10 mg/ kg dose. No ADAs were detected.

Safety of the anti-amyloid monoclonal antibody ponezumab (PF-04360365) following a single-dose intravenous infusion in Japanese patients with mild-to-moderate Alzheimer's disease: Preliminary results

P1-454 SAFETY OF THE ANTI-AMYLOID MONOCLONAL ANTIBODY PONEZUMAB (PF-04360365) FOLLOWING A SINGLE-DOSE INTRAVENOUS INFUSION IN JAPANESE PATIENTS WITH MILDTO-MODERATE ALZHEIMER’S DISEASE: PRELIMINARY RESULTS Yoko Fujimoto, Izuru Miyoshi, Taro Ishibashi, Kanae Togo, Sadahiro Abe, James W. Kupiec, Martin M. Bednar, Pfizer Japan Inc., Tokyo, Japan; Pfizer Inc., New York, NY, USA. Contact e-mail: Yoko. Fujimoto@pfizer.com

A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer’s disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil

BackgroundSymptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg.MethodsThis was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data.ResultsAt the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment).ConclusionsSAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists.Trial registrationClinicaltrials.gov, NCT01712074. Registered 19 October 2012.

Safety and Pharmacokinetics Following a Single Infusion of the Anti-amyloid Monoclonal Antibody Ponezumab (pf-04360365) in Patients With Mild-to-moderate Alzheimer's Disease: Final Results

and radiological findings of MRI/CT and SPECT. We analyzed CSF phosphorylated tau (ptau-181) for every 3-4 years respectively. Results: After gene analyis, we have found four different PS1 mutations in all five FAD cases (H131R, H163R, L219R, M233L). Two siblings in FAD1 family (M233L) had common initial phenotype characterized by neurological symptoms (dementia, apraxia, apathy), with severe motor deficits since onset of the disease. A proband of FAD2 family (H163R) presented dementia and parkinsonism. MRI of two siblings in FAD1 family showed that the temporo-parietal lobes and hippocampus were atrophied at the initial stage, then atrophies of the frontal lobe were followed. Phosphorylated ptau-199 and ptau-181 in CSF slightly increased in three patints except one FAD3 case. MRI of the proband of FAD2 family showed severe temporal and fronto-temporal atrophy, corresponding to low CBF in SPECT. While two cases of FAD3 (L219R) resemble clinical and radiological findings of FAD1, FAD4 (H131R) case is reminiscent of FAD1. In time process of 5 AD cases, ptau-181 have slight decreased since initial CSF examination. Conclusions: We have demonstrated four PS1 mutations including two novel mutations (L219R, H131R) in four FAD. FAD patients showed common initial phenotype characterized by dementia, apraxia, apathy with severe motor deficits since onset of the disease. In time process of 5 AD cases, CSF ptau-181 and ptau-199 have slight decreased since initial CSF examination. We consider that AD clinical progress and CSF ptau181 may close relationship in time process, and that further deterioration of dmentia and pathological/clinical stable AD condition might decrease ptau-181.