Clare B. Billing

Varenicline versus transdermal nicotine patch for smoking cessation: Results from a randomised, open-label trial

Background: Varenicline, a new treatment for smoking cessation, has demonstrated significantly greater efficacy over placebo and sustained release bupropion (bupropion SR). A study was undertaken to compare a 12-week standard regimen of varenicline with a 10-week standard regimen of transdermal nicotine replacement therapy (NRT) for smoking cessation. Methods: In this 52-week, open-label, randomised, multicentre, phase 3 trial conducted in Belgium, France, the Netherlands, UK and USA, participants were randomly assigned (1:1) to receive varenicline uptitrated to 1 mg twice daily for 12 weeks or transdermal NRT (21 mg/day reducing to 7 mg/day) for 10 weeks. Non-treatment follow-up continued to week 52. The primary outcome was the biochemically confirmed (exhaled carbon monoxide ⩽10 ppm) self-reported continuous abstinence rate (CAR) for the last 4 weeks of the treatment period in participants who had taken at least one dose of treatment. Secondary outcomes included CAR from the last 4 weeks of treatment through weeks 24 and 52, and measures of craving, withdrawal and smoking satisfaction. Results: A total of 376 and 370 participants assigned to varenicline and NRT, respectively, were eligible for analysis. The CAR for the last 4 weeks of treatment was significantly greater for varenicline (55.9%) than NRT (43.2%; OR 1.70, 95% CI 1.26 to 2.28, p<0.001). The week 52 CAR (NRT, weeks 8–52; varenicline, weeks 9–52) was 26.1% for varenicline and 20.3% for NRT (OR 1.40, 95% CI 0.99 to 1.99, p = 0.056). Varenicline significantly reduced craving (p<0.001), withdrawal symptoms (p<0.001) and smoking satisfaction (p<0.001) compared with NRT. The most frequent adverse event was nausea (varenicline, 37.2%; NRT, 9.7%). Conclusions: The outcomes of this trial established that abstinence from smoking was greater and craving, withdrawal symptoms and smoking satisfaction were less at the end of treatment with varenicline than with transdermal NRT. Trial registration number: NCT00143325.

A double-blind study evaluating the long-term safety of varenicline for smoking cessation

ABSTRACT Objective: We assessed the safety of long-term varenicline administration for smoking cessation. Methods: In this randomized, double-blind, multicenter trial, eligible adult smokers (18–75 years) who smoked an average of ≥10 cigarettes/day were randomized to either varenicline 1 mg twice daily (BID) or placebo for 52 weeks. Subjects made weekly clinic visits until week 8, and then every 4 weeks until week 52, with a follow-up visit at week 53. The target quit date was the morning of the week 1 clinic visit. Brief counseling was provided at each visit, and vital signs, adverse events (AEs), and smoking status were documented. Other laboratory measures were collected at specified visits. Results: A total of 251 subjects were randomized to varenicline and 126 to placebo. Approximately half of the subjects in each arm completed the study (53.8% varenicline; 46.8% placebo). Treatment-emergent AEs were observed in 96.4% of varenicline- and 82.5% of placebo-treated subjects during the study. Common varenicline-associated AEs were nausea (40.2%), abnormal dreams (22.7%), and insomnia (19.1%). Most AEs were considered mild or moderate in intensity. AEs leading to discontinuation of varenicline treatment included nausea (7.6%), insomnia (3.2%), and abnormal dreams (2.4%). A single varenicline-related serious AE, bilateral subcapsular cataracts, was observed. At week 52, 7-day point prevalence abstinence rates were 36.7% (varenicline) and 7.9% (placebo). Conclusions: Varenicline 1 mg BID can be safely administered for up to 1 year. Varenicline was also a more effective smoking cessation aid than placebo throughout the study, supporting both its short- (12-week) and long-term (52-week) efficacy. Trial registration: ClinicalTrials.gov identifier: NCT00143299.

The efficacy and safety of varenicline for smoking cessation using a flexible dosing strategy in adult smokers: a randomized controlled trial.

ABSTRACT Objective: To determine whether self-regulated flexible dosing with varenicline tartrate is safe and effective for smoking cessation. Research design and methods: 320 healthy, motivated-to-quit smokers (≥10 cigarettes/day) aged 18–65 years, entered a multicenter, randomized, double-blind, placebo-controlled study – conducted between December 26, 2001 and June 24, 2003 – with a 12-week treatment phase and 40-week, double-blind, non-treatment follow-up. Treatment consisted of varenicline or placebo in fixed doses (Week 1: titrated from 0.5 to 1.0 mg/day) followed by a self-regulated flexible schedule (Weeks 2–12: 0.5–2.0 mg/day). Main outcome measures: Primary outcomes included carbon monoxide-confirmed continuous abstinence rate (CAR) from smoking for Weeks 4 through 7, 9 through 12, and 9 through 52. Secondary outcomes included CAR from Weeks 9 through 24, 7-day point prevalence of abstinence, safety assessments, and measures of craving, withdrawal, and smoking reward. Results: Superior CARs were observed in varenicline-treated (n = 157) versus placebo participants (n = 155) for Weeks 4 through 7 (38.2 vs. 11.6%), 9 through 12 (40.1 vs. 11.6%), 9 through 24 (28.0 vs. 9.0%), and 9 through 52 (22.3 vs. 7.7%) (all p < 0.001). Seven-day point prevalence was higher in varenicline-treated than placebo participants at Weeks 12 (46.5 vs. 14.2%; p < 0.001), 24 (32.5 vs. 13.5%; p < 0.001), and 52 (28.0 vs. 13.5%; p = 0.001). Overall, medication compliance was high, although varenicline-treated, but not placebo, participants tended to taper down their dosage over time. Total treatment-emergent AEs were 77.1% (varenicline: 121/157) and 65.8% (placebo: 102/155). Few AEs led to treatment discontinuation (varenicline: 11/157, 7.0% and placebo: 7/155, 4.5%). Participants were primarily healthy Caucasians, so more research is necessary to determine how applicable these findings are to other populations. Conclusions: A self-regulated, flexible dosing regimen of varenicline is well tolerated, with superior effectiveness versus placebo for smoking cessation. Trial registration: ClinicalTrials.gov identifier: NCT00150228.

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.

Development of a straightforward and sensitive scale for MCI and early AD clinical trials

Although the Clinical Dementia Rating Scale‐Sum of Boxes score (CDR‐SB) is a widely accepted and commonly used global scale, validated clinical endpoints of cognitive changes are unavailable in the predementia stages of Alzheimers disease (AD), and a new clinical assessment with reliability and sensitivity is needed in the mild cognitive impairment (MCI) population.

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.

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.

Comment and Reply: A double-blind study evaluating the long-term safety of varenicline for smoking cessation

OBJECTIVE We assessed the safety of long-term varenicline administration for smoking cessation. METHODS In this randomized, double-blind, multicenter trial, eligible adult smokers (18-75 years) who smoked an average of > or =10 cigarettes/day were randomized to either varenicline 1 mg twice daily (BID) or placebo for 52 weeks. Subjects made weekly clinic visits until week 8, and then every 4 weeks until week 52, with a follow-up visit at week 53. The target quit date was the morning of the week 1 clinic visit. Brief counseling was provided at each visit, and vital signs, adverse events (AEs), and smoking status were documented. Other laboratory measures were collected at specified visits. RESULTS A total of 251 subjects were randomized to varenicline and 126 to placebo. Approximately half of the subjects in each arm completed the study (53.8% varenicline; 46.8% placebo). Treatment-emergent AEs were observed in 96.4% of varenicline- and 82.5% of placebo-treated subjects during the study. Common varenicline-associated AEs were nausea (40.2%), abnormal dreams (22.7%), and insomnia (19.1%). Most AEs were considered mild or moderate in intensity. AEs leading to discontinuation of varenicline treatment included nausea (7.6%), insomnia (3.2%), and abnormal dreams (2.4%). A single varenicline-related serious AE, bilateral subcapsular cataracts, was observed. At week 52, 7-day point prevalence abstinence rates were 36.7% (varenicline) and 7.9% (placebo). CONCLUSIONS Varenicline 1 mg BID can be safely administered for up to 1 year. Varenicline was also a more effective smoking cessation aid than placebo throughout the study, supporting both its short- (12-week) and long-term (52-week) efficacy.

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.