Anindita Banerjee

Evaluation of the agonist PET radioligand [11C]GR103545 to image kappa opioid receptor in humans: Kinetic model selection, test–retest reproducibility and receptor occupancy by the antagonist PF-04455242

INTRODUCTION Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [(11)C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (V(ND)) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated. METHODS For determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [(11)C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n=1 and 30 mg, n=5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (V(T)). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and V(ND). The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [(11)C]GR103545 in vivo K(D) was also estimated. RESULTS Regional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that V(T) was reduced in all regions; thus no suitable reference region is available for the radiotracer. V(ND) was estimated reliably from the occupancy plot of naltrexone blocking (V(ND)=3.4±0.9 mL/cm(3)). The IC50 of PF-04455242 was calculated as 55 ng/mL. [(11)C]GR103545 in vivo K(D) value was estimated as 0.069 nmol/L. CONCLUSIONS [(11)C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy.

Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study.

Objective This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn’s disease (CD). Design Eligible adults were aged 18–75 years, with active moderate-to-severe CD (Crohn’s Disease Activity Index (CDAI) 220–450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12. Results In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen. Conclusions Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells. Trial registration number NCT01276509; Results.

First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430

This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand 18F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test–retest variability. Methods: In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test–retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials. Results: The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time–activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify VT and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test–retest variability in the whole brain (excluding the cerebellum) of VT, BPND, and BPP were 8%, 16%, and 17%, respectively. Conclusion: 18F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.

Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II)

Objective Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn’s disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported. Design Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up. Results 247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis. Conclusions PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development. Trial registration number NCT01287897 and NCT01345318.

Clinical dose–response for a broad set of biological products: A model-based meta-analysis:

Characterizing clinical dose–response is a critical step in drug development. Uncertainty in the dose–response model when planning a dose-ranging study can often undermine efficiency in both the design and analysis of the trial. Results of a previous meta-analysis on a portfolio of small molecule compounds from a large pharmaceutical company demonstrated a consistent dose–response relationship that was well described by the maximal effect model. Biologics are different from small molecules due to their large molecular sizes and their potential to induce immunogenicity. A model-based meta-analysis was conducted on the clinical efficacy of 71 distinct biologics evaluated in 91 placebo-controlled dose–response studies published between 1995 and 2014. The maximal effect model, arising from receptor occupancy theory, described the clinical dose–response data for the majority of the biologics (81.7%, n = 58). Five biologics (7%) with data showing non-monotonic trend assuming the maximal effect model were identified and discussed. A Bayesian model-based hierarchical approach using different joint specifications of prior densities for the maximal effect model parameters was used to meta-analyze the whole set of biologics excluding these five biologics (n = 66). Posterior predictive distributions of the maximal effect model parameters were reported and they could be used to aid the design of future dose-ranging studies. Compared to the meta-analysis of small molecules, the combination of fewer doses, narrower dosing ranges, and small sample sizes further limited the information available to estimate clinical dose–response among biologics.

The Safety and Efficacy of PF-04958242 in Age-Related Sensorineural Hearing Loss: A Randomized Clinical Trial

IMPORTANCE To our knowledge, this is the first study to assess the potential to pharmacologically improve auditory function in adults with age-related sensorineural hearing loss. OBJECTIVE To explore the potential for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid potentiator mechanism to affect auditory function in individuals with mild to moderate age-related sensorineural hearing loss. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled, single-dose, 3-way crossover study was conducted in 3 academic ear, nose, and throat clinics and 2 private clinical research centers between December 22, 2011, and February 26, 2013. Participants were 50- to 75-year-old men and women of nonchildbearing potential with mild to moderate sensorineural hearing loss. INTERVENTIONS Three single doses of PF-04958242, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate-positive allosteric modulator, and placebo. MAIN OUTCOMES AND MEASURES Pure-tone average, speech discrimination score, and speech in noise testing change from baseline at 1 and 5 hours after a single dose of PF-04958242. RESULTS The treatment was safe and well tolerated. The estimates for the primary end point change from baseline in pure-tone average compared with placebo at 1 hour were -0.77 (95% CI, -2.14 to 0.59) and 0.37 (95% CI, -0.97 to 1.72) for 0.27 and 0.35 mg, respectively. At 5 hours the estimates were -0.57 (95% CI, -2.43 to 1.29) and -0.56 (95% CI, -2.45 to 1.33) for 0.27 and 0.35 mg, respectively. No significant change from baseline was demonstrated compared with placebo in the primary or secondary study end points at 1 or 5 hours after receiving treatment. CONCLUSIONS AND RELEVANCE To our knowledge, this clinical trial is the first study of a pharmacologic treatment for age-related sensorineural hearing loss and provides information with regard to study design, end points, variability, data characteristics, and operational feasibility to guide the design of future hearing loss trials. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01518920.

Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn’s Disease

Abstract Objective To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn’s disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. Methods In this Phase 2, randomised, double-blind, controlled study [OPERA], blood samples were analysed from patients with moderate to severe active CD who received placebo or 22.5 mg, 75 mg, or 225 mg of PF-00547659 subcutaneously at baseline and at Weeks 4 and 8, with follow-up at Week 12. Soluble MAdCAM [sMAdCAM] was measured by mass spectrometry, β7-expressing T cells by flow cytometry, and gene transcriptome by RNA sequencing. Results A slight increase in sMAdCAM was measured in the placebo group from baseline to Week 12 [6%], compared with significant decreases in all PF-00547659 groups [–87% to –98%]. A slight increase from baseline to Week 12 was observed in frequency and molecules of equivalent soluble fluorochrome for β7+ central memory T cells in the placebo group [4%], versus statistically significant increases in the active treatment groups [48% to 81%]. Similar trends were seen for β7+ effector memory T cells [placebo, 8%; PF-00547659, 84–138%] and β7+ naïve T cells [8%; 13–50%]. CCR9 gene expression had statistically significant up-regulation [p = 1.09e-06; false discovery rate < 0.1] with PF-00547659 treatment, and was associated with an increase in β7+ T cells. Conclusions Results of the OPERA study demonstrate positive pharmacology and dose-dependent changes in pharmacodynamic biomarker measurements in blood, including changes in cellular composition of lymphocytes and corresponding CCR9 gene expression changes.

A Profile Analysis Approach Using MMRM in Acute Schizophrenia: A Comparison to Some Traditional Approaches

The analysis of schizophrenia studies is plagued by inefficiency and bias due to much missing data. Mixed-effect models for repeated measures designs help address these problems, but to gain even more efficiency it is desirable to judiciously use additional longitudinal data in such designs by comparing treatment groups over multiple time points. Simulations were conducted to compare a profile analysis approach to other commonly used analysis methods in the presence of data missing at random. One gains efficiency by using a composite contrast over multiple time points when the treatment effect over the time points is not substantially different.