Tozadenant

Tozadenant (SYN115) is an orally active, selective adenosine A2A receptor antagonist.

In animal models of Parkinson’s disease, tozadenant improves motor neuron function.

Tozadenant (60 mg twice daily) was not associated with a signi?cant reduction in o?-time, and tozadenant (240 mg twice daily) was associated with an increased rate of discontinuation because of adverse events (17 of 84 patients [20%]). Tozadenant at dose of 120 or 180 mg twice daily was e?ective at reducing o?-time and was generally well tolerated. Further investigation of tozadenant treatment in phase 3 trials is guaranteed . Perfusion MRI showed that tozadenant induced highly signi?cant suppressed in regional cerebral blood ?ow, with the most important decreases occurring in bilateral thalami.

Reference:
Hauser RA, Olanow CW, Kieburtz KD et al.  Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol. 2014 Aug;13(8):767-76.

Pharmacokinetics and metabolism of [(14)C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand, in healthy volunteers.[Pubmed:27489076]

Xenobiotica. 2017 Aug;47(8):705-718.

1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of (14)C-Tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease. 2. Six healthy male subjects received a single oral dose of Tozadenant (240 mg containing 81.47 KBq of [(14)C]-Tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection. 3. At 4 h, the Cmax of Tozadenant was 1.74 mug/mL and AUC(0-t) 35.0 h mug/mL, t1/2 15 h, Vz/F 1.82 L/kg and CL/F 1.40 mL/min/kg. For total [(14)C] radioactivity, the Cmax was 2.29 mug eq/mL at 5 h post-dose and AUC(0-t) 43.9 h mug eq/mL. Unchanged Tozadenant amounted to 93% of the radiocarbon AUC(0-48h). At 312 h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged Tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites. 4. The only identified species circulating in plasma was unchanged Tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.

Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial.[Pubmed:25008546]

Lancet Neurol. 2014 Aug;13(8):767-76.

BACKGROUND: Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of Tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa. METHODS: We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of Tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2.5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive Tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594. FINDINGS: Of 420 randomised patients (mean age 63.3 [SD 8.3] years; mean duration of Parkinson's disease 8.7 [4.7] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined Tozadenant 120 mg twice-daily and 180 mg twice-daily group (-1.1 h, 95% CI -1.8 to -0.5; p=0.0006), the Tozadenant 120 mg twice-daily group (-1.1 h, -1.8 to -0.4; p=0.0039), and the Tozadenant 180 mg twice-daily group (-1.2 h, -1.9 to -0.4; p=0.0039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and Tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients). INTERPRETATION: Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of Tozadenant treatment in phase 3 trials is warranted. FUNDING: Biotie Therapies.

Adenosine 2A receptor occupancy by tozadenant and preladenant in rhesus monkeys.[Pubmed:25082853]

J Nucl Med. 2014 Oct;55(10):1712-8.

UNLABELLED: Motor symptoms in Parkinson disease (PD) are caused by a loss of dopamine input from the substantia nigra to the striatum. Blockade of adenosine 2A (A(2A)) receptors facilitates dopamine D(2) receptor function. In phase 2 clinical trials, A(2A) antagonists (istradefylline, preladenant, and Tozadenant) improved motor function in PD. We developed a new A(2A) PET radiotracer, (18)F-MNI-444, and used it to investigate the relationship between plasma levels and A(2A) occupancy by preladenant and Tozadenant in nonhuman primates (NHP). METHODS: A series of 20 PET experiments was conducted in 5 adult rhesus macaques. PET data were analyzed with both plasma-input (Logan graphical analysis) and reference-region-based (simplified reference tissue model and noninvasive Logan graphical analysis) methods. Whole-body PET images were acquired for radiation dosimetry estimates. Human pharmacokinetic parameters for Tozadenant and preladenant were used to predict A(2A) occupancy in humans, based on median effective concentration (EC(50)) values estimated from the NHP PET measurements. RESULTS: (18)F-MNI-444 regional uptake was consistent with A(2A) receptor distribution in the brain. Selectivity was demonstrated by dose-dependent blocking by Tozadenant and preladenant. The specific-to-nonspecific ratio was superior to that of other A(2A) PET radiotracers. Pharmacokinetic modeling predicted that Tozadenant and preladenant may have different profiles of A(2A) receptor occupancy in humans. CONCLUSION: (18)F-MNI-444 appears to be a better PET radiotracer for A(2A) imaging than currently available radiotracers. Assuming that EC(50) in humans is similar to that in NHP, it appears that Tozadenant will provide a more sustained A(2A) receptor occupancy than preladenant in humans at clinically tested doses.

Two new adenosine receptor antagonists for the treatment of Parkinson's disease: istradefylline versus tozadenant.[Pubmed:24673462]

Expert Opin Pharmacother. 2014 Jun;15(8):1097-107.

INTRODUCTION: Adenosine A2A receptors are localized in the brain, mainly within the caudate and putamen nuclei of the basal ganglia. Their activation leads to stimulation of the 'indirect' pathway. Conversely, administration of A2A receptor antagonists leads to inhibition of this pathway, which was translated into reduced hypomotility in several animal models of parkinsonism. AREAS COVERED: In this review, the effects of two A2A receptor antagonists, istradefylline and Tozadenant, on parkinsonian symptoms in animal and humans will be discussed. EXPERT OPINION: Animal studies have shown potent antiparkinsonian effects for several A2A receptor antagonists, including istradefylline. In clinical trials, istradefylline reduced OFF time when administered with levodopa, but results are inconclusive. Results with Tozadenant are scarce. Modification of thalamic blood flow compatible with reduced inhibition was noted in one small trial, followed by a significant reduction in OFF time in a larger one. Therefore, both drugs show promising efficacy for the reduction of OFF time in levodopa-treated Parkinson's disease patients, but further research is needed in order to obtain definitive conclusions.