Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial.

BACKGROUND: Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia. METHODS: We conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18-50 years (part A) or 18-55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5-40 mg (40 mg was administered as 20 mg twice daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873. FINDINGS: Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6. INTERPRETATION: These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile. FUNDING: Cerevel Therapeutics.

A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity.

BACKGROUND: Dopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans. METHODS: Using a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons. RESULTS: Nominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562-treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate. CONCLUSIONS: PF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period. CLINICALTRIALS.GOV IDENTIFIER: NCT02306876.

Impact of Phase 1 study design on estimation of QT interval prolongation risk using exposure-response analysis.

The International Council for Harmonisation (ICH) guidelines have been revised allowing for modeling of concentration-QT (C-QT) data from Phase I dose-escalation studies to be used as primary analysis for QT prolongation risk assessment of new drugs. This work compares three commonly used Phase I dose-escalation study designs regarding their efficiency to accurately identify drug effects on QT interval through C-QT modeling. Parallel group design and 4-period crossover designs with sequential or interleaving cohorts were evaluated. Clinical trial simulations were performed for each design and across different scenarios (e.g. different magnitudes of drug effect, QT variability), assuming a pre-specified linear mixed effect (LME) model for the relationship between drug concentration and change from baseline QT (ΔQT). Analyses suggest no systematic bias in either the predictions of placebo-adjusted ΔQT (ΔΔQT) or the LME model parameter estimates across all evaluated designs. Additionally, false negative rates remained similar and adequately controlled across all evaluated designs. However, compared to the crossover designs, the parallel design had significantly less power to correctly exclude a clinically significant QT effect, especially in the presence of substantial intercept inter-individual variability. In such cases, parallel design is associated with increased uncertainty around ΔΔQT prediction, mainly attributed to the uncertainty around the estimation of the treatment-specific intercept in the model. Throughout all the evaluated scenarios, the crossover design with interleaving cohorts had consistently the best performance characteristics. The results from this investigation will further facilitate informed decision-making during Phase I study design and the interpretation of the associated C-QT modeling output.

Estimation of Circulating Drug Metabolite Exposure in Human Using In Vitro Data and Physiologically Based Pharmacokinetic Modeling: Example of a High Metabolite/Parent Drug Ratio.

(R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol (TBPT), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product [(R)-3-(piperidin-4-ylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazole (M1)] and a cyclized oxazolidine structure [7-(((4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)octahydro-3H (M2)]. After administration of TBPT to humans the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent (M/P) ratios for M1 and M2 was attempted using in vitro metabolism, binding, and permeability data in static and dynamic physiologically based pharmacokinetic (PBPK) models. In the static model, the fraction of parent clearance yielding the metabolite (which also required taking into account secondary metabolites of M1 and M2), the clearance of the metabolites and parent, and an estimate of the availability of the metabolites from the liver were combined to yield estimated parent/metabolite ratios of 0.32 and 23 for M1 and M2, respectively. PBPK modeling that used in vitro and physicochemical data input yielded estimates of 0.26 and 20, respectively. The actual values were 0.12 for M1/TBPT and 58 for M2/TBPT. Thus, the ratio for M1 was overpredicted, albeit at values less than unity. The ratio for M2/TBPT was underpredicted, and the high ratio of 58 may exceed a limiting ceiling of the approach. Nevertheless, when considered in the context of determining whether a potential circulating metabolite may be quantitatively important prior to administration of a drug for the first time to humans, the approaches succeeded in highlighting the importance of M2 (M/P ratio >> 1) relative to M1, despite M1 being much greater than M2 in vitro.

Evaluation of D1/D5 Partial Agonist PF-06412562 in Parkinson's Disease following Oral Administration.

BACKGROUND: PF-06412562 is a moderately potent, highly selective oral D1/D5 dopamine receptor partial agonist. OBJECTIVE: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson's disease. METHODS: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using KinesiaTM technology (as the primary end point) and change from baseline in the Movement Disorder Society's Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. RESULTS: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of -10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (-inf, -7.44) at 1.5-2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. CONCLUSIONS: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D1/D5 partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D1 agonists.

Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson's Disease.

Currently, available therapeutics for the treatment of Parkinson's disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant risk of adverse events (AEs). While dopaminergic agents, particularly levodopa, may initially provide strong motor control, this efficacy can vary with disease progression. Patients may suffer from motor fluctuations, including sudden and unpredictable drop-offs in efficacy. Dopamine agonists (DAs) are often prescribed during early-stage PD with the expectation they will delay the development of levodopa-associated complications, but currently available DAs are less effective than levodopa for the treatment of motor symptoms. Furthermore, both levodopa and DAs are associated with a significant risk of AEs, many of which can be linked to strong, repeated stimulation of D2/D3 dopamine receptors. Targeting D1/D5 dopamine receptors has been hypothesized to produce strong motor benefits with a reduced risk of D2/D3-related AEs, but the development of D1-selective agonists has been previously hindered by intolerable cardiovascular AEs and poor pharmacokinetic properties. There is therefore an unmet need in PD treatment for therapeutics that provide sustained and predictable efficacy, with strong relief from motor symptoms and reduced risk of AEs. Partial agonism at D1/D5 has shown promise for providing relief from motor symptoms, potentially without the AEs associated with D2/D3-selective DAs and full D1/D5-selective DAs. Tavapadon is a novel oral partial agonist that is highly selective at D1/D5 receptors and could meet these criteria. This review summarizes currently available evidence of tavapadon's therapeutic potential for the treatment of early through advanced PD.

PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [11C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator.

Stimulation of the M4 muscarinic acetylcholine receptor reduces striatal hyperdopaminergia, suggesting its potential as a therapeutic target for schizophrenia. Emraclidine (CVL-231) is a novel, highly selective, positive allosteric modulator (PAM) of M4 muscarinic acetylcholine receptors i.e. acts as a modulator that increases the response of these receptors. First, we aimed to further characterize the positron emission tomography (PET) imaging and quantification performance of a recently developed M4 PAM radiotracer, [11C]MK-6884, in non-human primates (NHPs). Second, we applied these results to determine the receptor occupancy of CVL-231 as a function of dose. Using paired baseline-blocking PET scans, we quantified total volume of distribution, binding potential, and receptor occupancy. Both blood-based and reference region-based methods quantified M4 receptor levels across brain regions. The 2-tissue 4-parameter kinetic model best fitted regional [11C]MK-6884-time activity curves. Only the caudate nucleus and putamen displayed statistically significant [11C]MK-6884 uptake and dose-dependent blocking by CVL-231. For binding potential and receptor occupancy quantification, the simplified reference tissue model using the grey cerebellum as a reference region was employed. CVL-231 demonstrated dose-dependent M4 receptor occupancy in the striatum of the NHP brain and shows promise for further development in clinical trials.

Dopamine agonists in Parkinson's disease: Impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment.

Dopamine agonists (DAs) have demonstrated efficacy for the treatment of Parkinson's disease (PD) but are limited by adverse effects (AEs). DAs can vary considerably in their receptor subtype selectivity and affinity, chemical composition, receptor occupancy, and intrinsic activity on the receptor. Most currently approved DAs for PD treatment primarily target D2/D3 (D2-like) dopamine receptors. However, selective activation of D1/D5 (D1-like) dopamine receptors may enable robust activation of motor function while avoiding AEs related to D2/D3 receptor agonism. Full D1/D5 receptor-selective agonists have been explored in small, early-phase clinical studies, and although their efficacy for motor symptoms was robust, challenges with pharmacokinetics, bioavailability, cardiovascular AEs, and dyskinesia rates similar to levodopa prevented clinical advancement. Generally, repeated dopaminergic stimulation with full DAs is associated with frontostriatal dysfunction and sensitization that may induce plastic changes in the motor system, and neuroadaptations that produce long-term motor and nonmotor complications, respectively. Recent preclinical and clinical studies suggest that a D1/D5 receptor-selective partial agonist may hold promise for providing sustained, predictable, and robust motor control, while reducing risk for motor complications (e.g., levodopa-induced dyskinesia) and nonmotor AEs (e.g., impulse control disorders and excessive daytime sleepiness). Clinical trials are ongoing to evaluate this hypothesis. The potential emerging availability of novel dopamine receptor agonists with selective dopamine receptor pharmacology suggests that the older terminology "dopamine agonist" may need revision to distinguish older-generation D2/D3-selective agonists from D1/D5-selective agonists with distinct efficacy and tolerability characteristics.

Dopamine D1 Agonists: First Potential Treatment for Late-Stage Parkinson's Disease.

Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D1/5 dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Caregiver assessment was the primary efficacy measure because caregivers were with patients throughout the study, and standard clinical metrics inadequately gauge efficacy in LsPD. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2-3). Clinicians and caregivers completed the clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings. Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and functional engagement. These data suggest for the first time that there can be useful pharmacological intervention in LsPD patients using D1/5 agonists and also that caregiver perspectives with mixed method analyses may overcome limitations using methods common in early-stage patients. The results encourage future clinical studies and understanding of the most efficacious signaling properties of a D1 agonist for this population.

Parkinson disease among patients treated for benign prostatic hyperplasia with α1 adrenergic receptor antagonists.

BACKGROUNDRecently the α1 adrenergic receptor antagonist terazosin was shown to activate PGK1, a possible target for the mitochondrial deficits in Parkinson disease related to its function as the initial enzyme in ATP synthesis during glycolysis. An epidemiological study of terazosin users showed a lower incidence of Parkinson disease when compared with users of tamsulosin, an α1 adrenergic receptor antagonist of a different class that does not activate PGK1. However, prior research on tamsulosin has suggested that it may in fact potentiate neurodegeneration, raising the question of whether it is an appropriate control group.METHODSTo address this question, we undertook an epidemiological study on Parkinson disease occurrence rate in 113,450 individuals from the United States with 5 or more years of follow-up. Patients were classified as tamsulosin users (n = 45,380), terazosin/alfuzosin/doxazosin users (n = 22,690), or controls matched for age, sex, and Charlson comorbidity index score (n = 45,380).RESULTSIncidence of Parkinson disease in tamsulosin users was 1.53%, which was significantly higher than that in both terazosin/alfuzosin/doxazosin users (1.10%, P < 0.0001) and matched controls (1.01%, P < 0.0001). Terazosin/alfuzosin/doxazosin users did not differ in Parkinson disease risk from matched controls (P = 0.29).CONCLUSIONThese results suggest that zosins may not confer a protective effect against Parkinson disease, but rather that tamsulosin may in some way potentiate Parkinson disease progression.FUNDINGThis work was supported by Cerevel Therapeutics.

PF-06649751 efficacy and safety in early Parkinson's disease: a randomized, placebo-controlled trial.

BACKGROUND: PF-06649751 is a novel, oral, non-catechol-based, D1/D5 dopamine receptor partial agonist under investigation for the treatment of motor symptoms associated with Parkinson's disease. METHODS: A 15-week, phase II, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy and safety of flexible-dose PF-06649751 in subjects with early stage Parkinson's disease (ClinicalTrials.gov identifier: NCT02847650). RESULTS: Enrollment was terminated early for reasons unrelated to the trial. Overall, 57 subjects received study medication (PF-06649751 = 29; placebo = 28) and 47 completed the study (PF-06649751 = 25; placebo = 22). Despite early termination, the study met its primary endpoint with the PF-06649751 group showing statistically significant improvement from baseline in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score at week 15 compared with placebo. Mean (SE) change in MDS-UPDRS Part III score was -9.0 (1.54) for PF-06649751 and -4.3 (1.65) for placebo. This corresponds to an improvement versus placebo of 4.8 for the PF-06649751 group (two-sided p = 0.0407; 90% CI = 1.0, 8.6). Statistically significant improvement in MDS-UPDRS-III score was also observed at all assessment time points prior to week 15. The safety profile of PF-06649751 was similar to that observed in prior studies, with the majority of adverse events (AEs) reported as mild or moderate. The most common AEs in the PF-06649751 group were nausea, headache, dry mouth, somnolence, and tremor. CONCLUSIONS: Once-daily dosing of oral PF-06649751 resulted in significant improvement of motor symptoms and was generally well tolerated in subjects with early stage Parkinson's disease.

Dopaminergic D1 Receptor Stimulation Affects Effort and Risk Preferences.

BACKGROUND: Activation of D1 receptors has been related to successful goal-directed behavior, but it remains unclear whether D1 receptor activation causally tips the balance of weighing costs and benefits in humans. Here, we tested the impact of pharmacologically stimulated D1 receptors on sensitivity to risk, delay, and effort costs in economic choice and investigated whether D1 receptor stimulation would bias preferences toward options with increased costs in a cost-specific manner. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group phase 1 study, 120 healthy young volunteers received either placebo or 1 of 3 doses (6 mg, 15 mg, or 30 mg) of a novel, selective D1 agonist (PF-06412562). After drug administration, participants performed decision tasks measuring their preferences for risky, delayed, and effortful outcomes. RESULTS: Higher doses of the D1 agonist increased the willingness to exert physical effort for reward as well as reduced the preference for risky outcomes. We observed no effects on preferences for delayed rewards. CONCLUSIONS: The current results provide evidence that D1 receptor stimulation causally affects core aspects of cost-benefit decision making in humans.

Challenges in Alzheimer's Disease Drug Discovery and Development: The Role of Modeling, Simulation, and Open Data.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. With 35 million people over 60 years of age with dementia, there is an urgent need to develop new treatments for AD. To streamline this process, it is imperative to apply insights and learnings from past failures to future drug development programs. In the present work, we focus on how modeling and simulation tools can leverage open data to address drug development challenges in AD.

The D1/D5 Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson's Disease: A Feasibility Study.

BACKGROUND: Current drug treatments have little efficacy in advanced-to-end-stage Parkinson's disease (advPD), yet there are no reports of interventional trials in advPD. D1 dopamine agonists have the potential to provide benefit. OBJECTIVE: To determine the feasibility and safety of the selective D1/D5 dopamine partial agonist PF 06412562 in advPD. METHODS: A two-week, randomized, double blind, crossover phase Ib study in advPD patients compared standard-of-care (SoC) carbidopa/levodopa with PF 06412562. Each week, there was a Day 1 baseline evaluation with overnight levodopa washout, then treatment on Days 2 and 3 with either SoC or PF-06412562 (split dose 25 + 20 mg), followed by discharge on Day 4. Primary endpoints were safety and tolerability. Secondary endpoints were global clinical impression of change (GCI-C) rated by clinicians and caregivers. RESULTS: Eight advPD patients and their caregivers consented to participate and six were randomized (average disease duration: 22 y). None withdrew voluntarily. One participant with baseline Day 1 dehydration, pre-renal kidney injury, and autonomic dysfunction experienced symptomatic and serious hypotension after receiving PF-06412562 in Week 1 and was discontinued from the study. All other adverse events were rated mild (PF-06412562: n = 1, SoC: n = 0), moderate (PF-06412562: n = 1, SoC: n = 1), or severe but non-serious (PF-06412562: n = 3, SoC: n = 2). No clinically meaningful laboratory changes were observed. Among the five participants who completed the study, GCI-C favored PF-06412562 in two per clinicians' and four participants per caregivers' rating. CONCLUSION: PF-06412562 was tolerated in advPD patients. This study provides the feasibility for future safety and efficacy studies in this population with unmet needs.

A novel approach to evaluate the pharmacodynamics of a selective dopamine D1/D5 receptor partial agonist (PF-06412562) in patients with stable schizophrenia.

BACKGROUND: PF-06412562 is an orally bioavailable, selective dopamine D1/D5 receptor partial agonist with a non-catechol structure under evaluation for treatment of cognitive impairment in schizophrenia. AIMS: This randomized, double-blind, placebo-controlled, parallel-group, Phase 1b study examined the pharmacokinetics and pharmacodynamics of three doses of PF-06412562 (3 mg, 9 mg, and 45 mg twice daily) over 15 days in patients with schizophrenia receiving antipsychotics. METHODS: Primary endpoints included adjunctive safety/tolerability and effects on MATRICS Consensus Cognitive Battery Working Memory domain and reward processing (Monetary Incentive Delay) tasks. Exploratory endpoints included other behavioral/neurophysiological tasks, including the N-back task. RESULTS: Among 95 subjects (78% male; mean age 34.8 years), baseline characteristics were similar across groups. The MATRICS Consensus Cognitive Battery Working Memory composite change from baseline on Day 13 improved in all groups, the smallest improvement was observed in the 45 mg group and was significantly smaller than that in the placebo group (two-sided p=0.038). For the Monetary Incentive Delay task (change from baseline in blood-oxygen-level-dependent functional magnetic resonance imaging activation in anterior ventral striatum for the contrast of cue gain>cue no gain on Day 15), no PF-06412562 dose was significantly different from placebo. No doses of PF-06412562 showed a significant difference on two-back task accuracy versus placebo. CONCLUSIONS: Adjunctive treatment with PF-06412562 was safe and well tolerated in patients with schizophrenia. PF-06412562 failed to show clinical benefit relative to placebo on assessments of cognition or reward processing in symptomatically stable patients over a 15-day treatment period. Numerous limitations due to the safety study design warrant further efficacy evaluation for this drug mechanism.

A Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Dopamine D1 Receptor Partial Agonist, PF-06669571, in Subjects with Idiopathic Parkinson's Disease.

BACKGROUND AND OBJECTIVES: There is an unmet medical need for additional treatment options for Parkinson's disease. This was a Phase I, double-blind clinical trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of the novel dopamine D1 receptor partial agonist, PF-06669571, in subjects with idiopathic Parkinson's disease on a stable dose of L-DOPA. METHODS: Subjects received PF-06669571 (or matching placebo) titrated from 1 mg to 3 mg over 7 days. The primary pharmacodynamic endpoint was the change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III total motor score at the pharmacodynamic time of maximum change from baseline on day 7. RESULTS: Twenty subjects were randomized and 19 completed the study. Maximum plasma concentrations (Cmax) of PF-06669571 were reached 3.35 and 3.19 h post-dose on day 1 and day 7. Geometric mean Cmax and area under the plasma concentration-time profile from time 0 to 24 h post-dose on day 7 were 92.51 ng/mL and 1626 ng·h/mL, respectively. The primary pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement; however, the criteria were met in a sensitivity analysis excluding data from a L-DOPA outlier (L-DOPA dose of 2550 mg/d). The most common adverse events (AEs) were nausea (experienced by 2 subjects each in the PF-06669571 and placebo groups). There were no permanent discontinuations or dose reductions due to AEs. DISCUSSION: Multiple daily doses of PF-06669571 were safe and well tolerated with no notable safety concerns. The pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement. CLINICALTRIALS. GOV IDENTIFIER: NCT02565628.

Phase 1 Parkinson's Disease Studies Show the Dopamine D1/D5 Agonist PF-06649751 is Safe and Well Tolerated.

INTRODUCTION: There is a need for new therapies in Parkinson's disease that may help to address known limitations of current options. PF-06649751 is a novel, highly selective dopamine D1/D5 agonist targeted for Parkinson's disease treatment. METHODS: The safety, pharmacokinetics, and pharmacodynamics of PF-06649751 were assessed in single ascending dose and multiple ascending dose clinical trials in patients with Parkinson's disease. The single ascending dose study (N = 18) was a double-blind, placebo-controlled study with a three-way crossover design consisting of three treatment periods separated by 7-day study drug washout periods. PF-06649751 doses were 0.75 mg, 1.5 mg, 3 mg, 6 mg, and 9 mg. In the open-label multiple ascending dose study, eligible subjects received once-daily doses of PF-06649751 (N = 45) over 21 days, with up-titration to 5 mg, 15 mg, and 25 mg once daily. Pharmacodynamics were assessed by measuring change from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at different time points post dose. RESULTS: PF-06649751 was safe and well tolerated across studies and in all cohorts. Peak plasma concentrations were attained 1-4 h post dose across both studies, and exposure increased with increasing dose. PF-06649751 demonstrated sustained pharmacodynamic effects compared with placebo, with mean reductions from baseline in the MDS-UPDRS Part III up to 12 h post dose at 9 mg single dose. MDS-UPDRS Part III changes in the open-label multiple dose study on day 22 also demonstrated sustained pharmacodynamic activity. CONCLUSIONS: PF-06649751 represents a novel therapeutic candidate for Parkinson's disease with an initial safety, tolerability, and pharmacokinetic profile and potential for efficacy that merits further study in larger clinical trials. TRIAL REGISTRATION: These studies are registered at www.clinicaltrials.gov as NCT02373072, NCT02224664. FUNDING: Pfizer.

Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats.

Saquinavir (SQV) was the first human immuno-virus-1 (HIV-1) protease inhibitor approved by FDA. However, P-glycoprotein (P-gp), an efflux pump limits its oral and brain bioavailabilities. The objective of this study is to investigate whether prodrug modification of SQV to dipeptide prodrugs Valine-Valine-Saquinavir (Val-Val-SQV) and Glycine-Valine-Saquinavir (Gly-Val-SQV) targeting intestinal peptide transporter can enhance intestinal permeability of SQV by circumventing P-gp mediated efflux. Single pass intestinal perfusion experiments in rat jejunum were performed to calculate the absorption rate constant and intestinal permeability of SQV, Val-Val-SQV and Gly-Val-SQV. Equimolar concentration (25 microM) of SQV, Val-Val-SQV and Gly-Val-SQV were employed in the perfusion studies. Perfusion experiments were also carried out in the presence of cyclosporine (10 microM) and glycyl-sarcosine (20 mM). Absorption rate constants in rat jejunum (ka) for SQV, Val-Val-SQV and Gly-Val-SQV were found to be 14.1+/-3.4x10(-3), 65.8+/-4.3x10(-3), and 25.6+/-5.7x10(-3) min(-1), respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. Significant permeability enhancement of SQV across rat jejunum was observed in the presence of cyclosporine 10 microM (P-gp inhibitor). However, permeability of Val-Val-SQV was unchanged in the presence of cyclosporine suggesting lack of any interaction of the prodrug with efflux pump. Intestinal absorption of Val-Val-SQV was significantly inhibited in the presence of gly-sar indicating the involvement of peptide transporter in intestinal absorption. In conclusion, peptide transporter targeted prodrug modification of P-gp substrates could lead to shielding of these drug molecules from efflux pumps.

Controlled delivery of ganciclovir to the retina with drug-loaded Poly(d,L-lactide-co-glycolide) (PLGA) microspheres dispersed in PLGA-PEG-PLGA Gel: a novel intravitreal delivery system for the treatment of cytomegalovirus retinitis.

PURPOSE: The aim of this study was to develop a formulation for intravitreal delivery by dispersing ganciclovir (GCV)-loaded Poly(d,L-lactide-co-glycolide (PLGA) microspheres in thermogelling PLGA-PEG-PLGA gel and to study the mechanism of drug-release characteristics both in vitro and in vivo. METHODS: PLGA microspheres of GCV were prepared by the solvent evaporation method from Resomer RG 502H (D,L-lactide:glycolide::50:50; Mw, 8000 Da) and a 1:3 polymer blend of Resomer RG 502H and PLGA 6535 (D,L-lactide:glycolide::65:35; Mw, 45,000-75,000 Da). The prepared microspheres were dispersed uniformly and as a mixture (1:1) in 23% w/w of PLGA-PEG-PLGA aqueous gel solutions. GCV release in the aqueous medium was studied in vitro. A conscious rabbit microdialysis model with permanently implanted probes was selected as the method for investigating the vitreous GCV levels following an intravitreal administration of the formulation. RESULTS: The formulation prepared, by a physical mixture of microspheres, was prepared from Resomer RG 502H, and the polymer blend exhibited fairly constant in vitro GCV release profiles. The amounts of GCV entrapped in the microspheres were sufficient to administer therapeutically relevant doses in 60 microL of the formulation. The vitreal elimination half-life of GCV in the conscious rabbit microdialysis model was 6.45 +/- 0.83 h, with an apparent volume of distribution (V(z)) of 1.18 +/- 0.61 mL. A direct vitreous injection of GCV resulted in the maintenance of concentrations in the vitreous for only 54 h, whereas the gel formulation produced steady-state GCV levels in the vitreous for at least 14 days. CONCLUSIONS: PLGA microspheres containing GCV were prepared by two kinds of PLGA polymers and their blend (1:3). A formulation suitable for in vivo administration was prepared by dispersing GCV-loaded microspheres in a thermogelling PLGA-PEG-PLGA solution. An ideal in vitro release of encapsulated GCV was obtained by physically mixing microspheres prepared from different polymer blends prior to its dispersion in the thermogelling polymer. The formulation maintained mean vitreal concentrations of GCV at approximately 0.8 microg/mL for 14 days, whereas direct injections could maintain drug levels above 0.8 microg/mL for 54 h only.

Studying the Progression of Amyloid Pathology and Its Therapy Using Translational Longitudinal Model of Accumulation and Distribution of Amyloid Beta.

Long-term effects of amyloid targeted therapy can be studied using a mechanistic translational model of amyloid beta (Aß) distribution and aggregation calibrated on published data in mouse and human species. Alzheimer disease (AD) pathology is modeled utilizing age-dependent pathological evolution for rate constants and several variants of explicit functions for Aß toxicity influencing cognitive outcomes (Adas-cog). Preventive Aß targeted therapies were simulated to minimize the Aß difference from healthy physiological levels. Therapeutic targeted simulations provided similar predictions for mouse and human studies. Our model predicts that: (1) at least 1 year (2 years for preclinical AD) of treatment is needed to observe cognitive effects; (2) under the hypothesis with functional importance of Aß, a 15% decrease in Aß (using an imaging biomarker) is related to 15-20% cognition improvement by immunotherapy. Despite negative outcomes in clinical trials, Aß continues to remain a prospective target demanding careful assessment of mechanistic effect and duration of trial design.