preladenant (SCH 420814) / Merck (MSD) - LARVOL DELTA

Efficacy of preladenant in improving motor symptoms in Parkinson's disease: A systematic review and meta-analysis. (PubMed, IBRO Neurosci Rep) - "This meta-analysis suggests that Preladenant may improve motor fluctuations in PD patients by increasing ON time and reducing OFF time. However, the high heterogeneity among studies warrants further large-scale, high-quality RCTs to confirm these findings and establish the long-term safety and efficacy of Preladenant in PD management."

Journal • Retrospective data • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

Development of Preladenant-Based Radiotracers for Imaging A2AR in Tumors. (PubMed, J Med Chem) - "B16F10 lung metastasis models were employed to expand the application scenarios, observing significantly higher uptake of [18F]F-PFP2 in metastatic lesions compared to normal lung tissue (5.55 ± 2.18% ID/g vs 1.89 ± 0.65% ID/g, tumor/lung ratio ∼3). It is given that [18F]F-PFP2 might lay the foundation for establishing an A2AR-targeted imaging evaluation system for tumors, which will provide more precise guidance for personalized treatment."

Journal • Breast Cancer • Melanoma • Oncology • Solid Tumor

Combination immunotherapy of PEG-modified Preladenant thermosensitive liposomes and PD-1 inhibitor effectively enhances the anti-tumor immune response and therapeutic effects. (PubMed, Pharm Dev Technol) - "P-pTSL has good long-term and serum stability and excellent tumor-targeting ability in mice. Moreover, the combination with PD-1 inhibitor significantly enhanced the anti-tumor effect, and the improvement of related factors in serum and lymph was more obvious under the condition of 42 °C thermotherapy in vitro."

Journal • Breast Cancer • Oncology • Solid Tumor

A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant. (PubMed, J Pharmacokinet Pharmacodyn) - "Hypothetical A antagonists with an ideal PK and pharmacology profile can achieve OFF-Time reductions ranging from 9.5 min with DuoDopa to 55 min with low dose L-DOPA formulations. Combination of the QSP model with PK modeling can predict the anticipated OFF-Time reduction of novel A2A antagonists with standard of care. With the large number of GPCR in the model, this combination can support both the design of clinical trials with new therapeutic agents and the optimization of combination therapy in clinical practice."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

A comparison of activity data generated from cardiovascular telemetry studies - With quantitative open field locomotor studies in Wistar Han rats. (PubMed, J Pharmacol Toxicol Methods) - "The goal of this work was to compare these two methodologies to assess activity in rats using reference compounds known to have central nervous system (CNS)-stimulant (preladenant) or CNS-depressant (chlorpromazine) effects. However, telemetry-derived decreases in activity were observed during the lights-off period (16-20 HPD), suggesting CNS-depressant compounds may be mischaracterized if the optimal dose administration time is not selected based on the light/dark cycle and pharmacokinetics. Overall, these results suggest that telemetry-based activity assessment is capable of detecting CNS-stimulant effects of compounds."

Journal • Preclinical • Cardiovascular

Discovery of Pyridone-Substituted Triazolopyrimidine Dual A/A AR Antagonists for the Treatment of Ischemic Stroke. (PubMed, ACS Med Chem Lett) - "Inspired by two clinical phase III drugs, ASP-5854 (dual A/A AR antagonist) and preladenant (selective A AR antagonist), and using the hybrid medicinal strategy, we characterized novel pyridone-substituted triazolopyrimidine scaffolds as dual A/A AR antagonists...Importantly, compound 1a demonstrated a dose-effect relationship in the oxygen-glucose deprivation/reperfusion (OGD/R)-treated HT22 cell model. These findings support the development of dual A/A AR antagonists as a potential treatment for ischemic stroke."

Journal • Cardiovascular • Ischemic stroke

Single Stabilizing Point Mutation Enables High-Resolution Co-Crystal Structures of the Adenosine A2A Receptor with Preladenant Conjugates. (PubMed, Angew Chem Int Ed Engl) - "They represent the first crystal structures of a GPCR in complex with PEG- and fluorophore-conjugated ligands. The applied strategy is predicted to be applicable to further class A GPCRs."

IO biomarker • Journal • CNS Disorders • Oncology • ADORA2A

Adenosine A Receptor Occupancy by Caffeine After Coffee Intake in Parkinson's Disease. (PubMed, Mov Disord) - "A sufficient A R occupancy can be obtained by drinking a cup of coffee, which is equivalent to approximately 100 mg of caffeine."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Adenosine receptor antagonists: Recent advances and therapeutic perspective. (PubMed, Eur J Med Chem) - "Istradefylline has been approved for treating Parkinson's in Japan, while preladenant, tozadenant, CVT-6883, MRS-1523, and many more are under different phases of clinical development. A special emphsesis on drug designing strategies has been also given the manuscript. The comprehensive compilation of research work carried out in the field will provide inevitable scope for designing and developing novel adenosine inhibitors with improved selectivity and efficacy."

Journal • Review • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease

Test-retest reproducibility of cerebral adenosine A receptor quantification using [C]preladenant. (PubMed, Ann Nucl Med) - "In this study, moderate test-retest reproducibility and large inter-subject differences were observed with [C]PLN PET, possibly attributable to competition by baseline amount of caffeine. Analysis of plasma caffeine concentration is recommended during [C]PLN PET studies."

Journal

Neuroinflammation and L-dopa-induced abnormal involuntary movements in 6-hydroxydopamine-lesioned rat model of Parkinson's disease are counteracted by combined administration of a 5-HT receptor agonist and A receptor antagonist. (PubMed, Neuropharmacology) - "Finally, tyrosine hydroxylase and dopamine transporter examined to evaluate neurodegeneration, showed a significant equal decrease in all experimental groups. The present findings suggest that combination of l-dopa with eltoprazine and preladenant may be promising therapeutic strategy for delaying the onset of dyskinesia, preserving l-dopa efficacy and reducing neuroinflammation markers in nigrostriatal system of 6-OHDA-lesioned rats."

Journal • Preclinical • CNS Disorders • Immunology • Inflammation • Movement Disorders • Oncology • Parkinson's Disease • GFAP • IL10 • IL1B • TNFA

[VIRTUAL] TT-702, a selective and potent A2B receptor antagonist for the treatment of cancer (AACR 2021) - "By contrast, preladenant, an A2AR antagonist, had no effect on cancer cell growth and DC differentiation. TT-702, a novel, selective and potent A2B receptor antagonist, has the potential to treat a diverse range of hard-to-treat and aggressive tumors (including cold ones) as a monotherapy, and in combination with anti-PD-1, enzalutamide and other anticancer therapies. TT-702 exhibits excellent safety and PK profiles in animals and is slated to enter clinical development in 2021."

Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Melanoma • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8

The challenge of developing adenosine A antagonists for Parkinson disease: Istradefylline, preladenant, and tozadenant. (PubMed, Parkinsonism Relat Disord) - "Reports of hematological toxicity necessitated ceasing an ongoing Phase 3 investigation of tozadenant. Following a challenging approval process, based on the results of randomized clinical trials carried out in the U.S. and Japan, istradefylline received approval in these countries for treatment of OFF episodes."

Clinical • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Subtype-selective Fluorescent Ligands as Pharmacological Research Tools for the Human Adenosine A2A Receptor. (PubMed, J Med Chem) - "In the present study, two families of fluorescent probes were designed around the known hAAR selective antagonist preladenant (SCH 420814)...Within the second family of hA2AAR fluorescent ligands, the AlexaFluor647-labelled conjugate allowed measurement of ligand binding affinities of unlabeled hA2AAR antagonists through the recently described bioluminescence resonance energy transfer (NanoBRET) approach. The novel hA2AAR fluorescent ligands developed here can be broadly applied to a range of fluorescence-based techniques to study the signaling and dynamics of A2AAR receptors in their native cellular environment providing a robust and specific platform for further pharmacological investigations."

Journal

[VIRTUAL] A2A RECEPTOR ANTAGONISTS FOR THE TREATMENT OF PARKINSON’S DISEASE: IS IT A PROMISING STRATEGY? (AAT-ADPD 2020) - "Whilst the development of preladenant and tozadenant were interrupted prematurely, istradefylline (ISD) has been available in Japan since 2013 and was approved by the FDA in 2019 for use as adjunctive therapy to levodopa in patients with PD experiencing off episodes. However, there was a lack of other prominent dopaminergic side effects such as excessive daytime sleepiness, impulse control disorders and orthostatic hypotension. Conclusions ISD may offer a favourable alternative to dopaminergic adjunctive therapies in order to enhance levodopa whilst minimising the risk of motor complications."

CNS Disorders • Depression • Excessive Daytime Sleepiness • Mood Disorders • Parkinson's Disease

Post-hoc analyses of phase-3 data with preladenant, an adenosine 2a antagonist, in patients with Parkinson's disease (AAN 2014) - Presentation time: Thursday, May 1, 2014 3:00 PM; Abstract #P7.088; P3, N=769; Sponsor: Merck; NCT01155466; "Treatment responses varied by region with placebo-responses highest in Turkey, India, and Latin America....treatment responses in the other regions, Eastern and Western Europe and North America, were directionally as expected in that preladenant and rasagiline showed greater decreases in “off” time than placebo. Improvements were generally modest(<1h) and there was no evidence of a dose-response."

P3 data • Parkinson's Disease

Phase-3 clinical trials of adjunctive therapy with preladenant, an adenosine 2a antagonist, in patients with Parkinson's disease (AAN 2014) - Presentation time: Thursday, May 1, 2014 3:00 PM; Abstract #P7.087; P3, N=1,242; Sponsor: Merck; NCT01155466; NCT01227265; "In Trial-1, neither preladenant nor rasagiline was superior to placebo after 12-weeks. The differences versus placebo [95% CI] in average “off” time were: preladenant 2mg = -0.1h [-0.69, 0.46], preladenant 5mg = -0.2h [-0.75,0.41], preladenant 10mg = -0.0h [-0.62,0.53], rasagiline 1mg= -0.3h [-0.90,0.26]. In Trial-2, preladenant was not superior to placebo after 12-weeks."

P3 data • Parkinson's Disease

Phase-3 clinical trial of the adenosine 2a antagonist preladenant, given as monotherapy, in patients with Parkinson's disease (AAN 2014) - Presentation time: Tuesday, April 29, 2014 1:45 PM; Abstract #S7.004; P3, N=1,007; Sponsor: Merck; NCT01155479; "Neither preladenant nor rasagiline was superior to placebo after 26-weeks. The differences versus placebo [95% CI] in UPDRS2+3 scores were: preladenant 2mg = 2.60 [0.86,4.30], preladenant 5mg = 1.30 [-0.41,2.94], preladenant 10mg = 0.40 [-1.29, 2.11], rasagiline 1mg = 0.30 [-1.35,2.03]....Preladenant was generally well-tolerated with few patients discontinuing due to adverse events (preladenant = 7%, rasagiline = 3%, placebo = 4%)."

P3 data • Parkinson's Disease

Levodopa add-on disappoints in late-stage Parkinson's (MedPageToday) - "The adenosine 2A (A2A) receptor antagonist preladenant didn't reduce 'off' time in Parkinson's in two trials, but that may have been due to poor trial design and management at individual sites, researchers reported. In one of the trials, the active control rasagiline also failed, Robert Hauser....'Because the active control (rasagiline) also failed to demonstrate a significant reduction in off time, it is not possible to determine from these results whether they represent a finding of inefficacy for preladenant, or are related to issues of study design or conduct,' the researchers wrote. Three adenosine 2A receptor antagonists -- istradefylline, preladenant, and tozadenant -- are in development for Parkinson's disease, and this is the second phase III trial with disappointing results with this class of agents"

P3 data • Parkinson's Disease

Reversing effort-related motivational impairments with the adenosine A2A receptor antagonist preladenant (Neuroscience 2017) - "Tetrabenazine (TBZ) is a VMAT-2 inhibitor that blocks DA storage, depletes accumbens DA, and reduces D1 and D2 signaling. Preladenant reversed the effort-related effects of TBZ in rats tested on the FR5/chow feeding choice task and increased high-effort progressive ratio lever pressing when administered alone. The ability of preladenant to enhance effort-related motivational functions underscores the potential utility of selective A2A receptor antagonists for the treatment of motivational dysfunctions associated with psychiatric or neurological disorders such as depression, Parkinsonism and schizophrenia."

Depression • Parkinson's Disease • Schizophrenia

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors. (PubMed) - "MRS-1523 acts as a selective A3AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biological studies."

Preclinical • Biosimilar

Antiparkinsonian effect of caffeine in unilateral 6-OHDA-lesioned rat model: Comparison with selective A2A antagonist drugs (Neuroscience 2017) - "...One selective A2A antagonist, Tozadenant, is currently in phase III clinical trials, while another, Istradefylline, is approved in Japan as add-on treatment to L-Dopa [1]...The objective of this study was to evaluate the antiparkinsonian effects of caffeine in the 6-OHDA lesioned rat model and to compare them to those of two selective A2A antagonists, Tozadenant and Preladenant...What was more remarkable was that chronic (10 d.) caffeine treatment either with or without L-Dopa did not induce tolerance, while chronic treatment with A2A antagonists led to pharmacological tolerance. In conclusion, this study demonstrates that caffeine has strong antiparkinsonian properties when given to 6-OHDA lesioned rats and that, unlike selective A2A antagonists which displayed marked pharmacological tolerance, the behavioural effects of caffeine were sustained even in chronic treatment paradigms."

Parkinson's Disease

Modular Antigen-Specific T Cell Suppression Assay for In Vitro Drug Screening (IMMUNOLOGY 2020) - "We have shown that in some donor PBMCs, ICI drugs such as pembrolizumab are able to boost antigen-specific T cell recall. Importantly, T cell suppression was partially reversed with addition of adenosine receptor targeting drug Preladenant (~doubling of antigen-specific T cell proliferation). This assay is modular in that TME metabolites can be used alone or in combination, with the potential to screen for donors who are in vitro “responders” and “non-responders” to various drug classes."

IO Biomarker • Immune Modulation • Immunology • Inflammation • Oncology

Study of Preladenant (MK-3814) Alone and With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3814A-062) (clinicaltrials.gov) - P1; N=120; Not yet recruiting; Sponsor: Merck Sharp & Dohme Corp.

New P1 trial • Biosimilar • Oncology

A study to assess pharmacokinetics of preladenant in participants with chronic hepatic impairment (P06513) (clinicaltrials.gov) - P1, N=42; Not yet recruiting; New P1 trial

New trial • Parkinson's Disease