Jaren W. Landen

An Innovative Design to Establish Proof of Concept of the Antidepressant Effects of the NR2B Subunit Selective N-Methyl-D-Aspartate Antagonist, CP-101,606, in Patients With Treatment-Refractory Major Depressive Disorder

This randomized, placebo-controlled, double-blind study was the first to evaluate the antidepressant efficacy, safety, and tolerability of an NR2B subunit-selective N-methyl-D-aspartate receptor antagonist, CP-101,606. Subjects had major depression, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and a history of treatment refractoriness to least 1 adequate trial of a selective serotonin reuptake inhibitor. The study had 2 treatment periods. In period 1, subjects first received a 6-week open-label trial of paroxetine and a single-blind, intravenous placebo infusion. Period 1 nonresponders (n = 30) then received a randomized double-blind single infusion of CP-101,606 or placebo plus continued treatment with paroxetine for up to an additional 4 weeks (period 2). Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale and 17-item Hamilton Depression Rating Scale. On the prespecified main outcome measure (change from baseline in the Montgomery-Åsberg Depression Rating Scale total score at day 5 of period 2), CP-101,606 produced a greater decrease than did placebo (mean difference, 8.6; 80% confidence interval, −12.3 to −4.5) (P < 0.10). Hamilton Depression Rating Scale response rate was 60% for CP-101,606 versus 20% for placebo. Seventy-eight percent of CP-101,606-treated responders maintained response status for at least 1 week after the infusion. CP-101,606 was safe, generally well tolerated, and capable of producing an antidepressant response without also producing a dissociative reaction. Antagonism of the NR2B subtype of the N-methyl-D-aspartate receptor may be a fruitful target for the development of a new antidepressant with more robust effects and a faster onset compared with those currently available and capable of working when existing antidepressants do not.

Effects of a NR2B Selective NMDA Glutamate Antagonist, CP-101,606, on Dyskinesia and Parkinsonism

Glutamate antagonists decrease dyskinesia and augment the antiparkinsonian effects of levodopa in animal models of Parkinsons disease (PD). In a randomized, double‐blind, placebo‐controlled clinical trial, we investigated the acute effects of placebo and two doses of a NR2B subunit selective NMDA glutamate antagonist, CP‐101,606, on the response to 2‐hour levodopa infusions in 12 PD subjects with motor fluctuations and dyskinesia. Both doses of CP‐101,606 reduced the maximum severity of levodopa‐induced dyskinesia ∼30% but neither dose improved Parkinsonism. CP‐101,606 was associated with a dose‐related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects.

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.

Evaluation of structural models to describe the effect of placebo upon the time course of major depressive disorder

Major depressive disorder (MDD) is the leading cause of disability in many countries. Designing and evaluating clinical trials of antidepressants is difficult due to the pronounced and variable placebo response which is poorly defined and may be affected by trial design. Approximately half of recent clinical trials of commonly used antidepressants failed to show statistical superiority for the drug over placebo, which is partly attributable to a marked placebo response. These failures suggest the need for new tools to evaluate placebo response and drug effect in depression, as well as to help design more informative clinical trials. Disease progression modeling is a tool that has been employed for such evaluations and several models have been proposed to describe MDD. Placebo data from three clinical depression trials were used to evaluate three published models: the inverse Bateman (IBM), indirect response (IDR) and transit (TM) models. Each model was used to describe Hamilton Rating Scale for major depression (HAMD) data and results were evaluated. The IBM model had several deficiencies, making it unsuitable. The IDR and TM models performed well on most evaluations and appear suitable. Comparing the IDR and TM models showed less clear distinctions, although overall the TM was found to be somewhat better than the IDR model. Model based evaluation can provide a useful tool for evaluating the time course of MDD and detecting drug effect. However, the models used should be robust, with well estimated parameters.

Efficacy and Safety of Pregabalin in Patients with Fibromyalgia and Comorbid Depression Taking Concurrent Antidepressant Medication: A Randomized, Placebo-controlled Study

Objective. To assess pregabalin efficacy and safety in patients with fibromyalgia (FM) with comorbid depression taking concurrent antidepressant medication. Methods. This randomized, placebo-controlled, double-blind, 2-period, 2-way crossover study was composed of two 6-week treatment periods separated by a 2-week taper/washout phase. Patients with FM (aged ≥ 18 yrs) taking a stable dose of a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) for depression were randomized 1:1 to receive pregabalin/placebo or placebo/pregabalin (optimized to 300 or 450 mg/day). Antidepressant medication was continued throughout the study. The primary efficacy outcome was the mean pain score on an 11-point numerical rating scale. Secondary efficacy outcomes included measures of anxiety, depression, patient function, and sleep. Results. Of 197 patients randomized to treatment, 181 and 177 received ≥ 1 dose of pregabalin and placebo, respectively. At baseline, 52.3% of patients were taking an SSRI and 47.7% an SNRI, and mean pain score was 6.7. Mean pain scores at endpoint were statistically significantly reduced with pregabalin (least squares mean difference from placebo −0.61, 95% CI −0.91 – −0.31, p = 0.0001). Pregabalin significantly improved Hospital Anxiety and Depression Scale-Anxiety (difference −0.95, p < 0.0001) and -Depression (difference −0.88, p = 0.0005) scores, Fibromyalgia Impact Questionnaire total score (difference −6.60, p < 0.0001), and sleep quality (difference 0.57, p < 0.0001), but not EuroQol 5-Dimensions score (difference 0.02, p = 0.3854). Pregabalin safety was consistent with previous studies and current product labeling. Conclusion. Compared with placebo, pregabalin statistically significantly improved FM pain and other symptoms in patients taking antidepressant medication for comorbid depression. ClinicalTrials.gov identifier: NCT01432236.

A randomized, double-blind, placebo-controlled trial and open-label extension study to evaluate the efficacy and safety of pregabalin in the treatment of neuropathic pain associated with human immunodeficiency virus neuropathy.

&NA; This randomized, placebo‐controlled trial and open‐label extension study of pregabalin for the treatment of human immunodeficiency virus–associated distal sensory polyneuropathy did not demonstrate significant effects of pregabalin. &NA; The objective of these studies was to assess the efficacy and safety of pregabalin in the treatment of human immunodeficiency virus (HIV)–associated neuropathic pain. Patients with HIV‐associated distal sensory polyneuropathy (DSP) were randomized to treatment with flexible‐dose pregabalin (150–600 mg/day) or placebo for 17 weeks in a single‐blind, placebo lead‐in, randomized, double‐blind, parallel‐group, placebo‐controlled multinational trial. The primary efficacy outcome was the change in mean pain score on an 11‐point numeric rating scale (NRS) from baseline to study endpoint. Participants who completed this trial were invited to participate in a 6‐month open‐label extension study with pregabalin. Of the 377 patients enrolled in the randomized controlled trial (pregabalin, n = 183; placebo, n = 194), 68.4% completed treatment. In the open‐label extension, 217 patients were treated and 59.4% completed treatment. Both studies were terminated by the sponsor after a preplanned interim analysis indicated trial futility. At endpoint, the change from baseline in least‐squares mean NRS pain scores in the intent‐to‐treat population was −2.04 for pregabalin versus −2.11 for placebo (P = .709). There were no significant differences between the pregabalin and placebo groups in the secondary efficacy measures. Incidence of adverse events was lower than seen in previous pregabalin studies. Overall, this trial did not show pregabalin to be more efficacious than placebo in treating HIV‐associated DSP. Studies such as these, which fail to support their primary hypotheses, may be important in informing the methodology of future trials, especially when novel approaches to limit variability in the control group are included. ClinicalTrials.gov identifiers: NCT01049217 and NCT01145417.

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.