tozadenant (SYN115) / Acorda - LARVOL DELTA

Radiosynthesis and In Vitro Evaluation of [11C]tozadenant as Adenosine A2A Receptor Radioligand. (PubMed, Molecules) - "This approach afforded [11C]tozadenant in radiochemical yields of 18 ± 2%, with molar activities of 50-60 GBq/µmol (1300-1600 mCi/µmol) and radiochemical purities of 95 ± 3%. In addition, in vitro autoradiography in pig and rat brain slices demonstrated the expected striatal accumulation pattern and confirmed the A2AR specificity of the radioligand, making it a promising tool for in vivo PET studies on the cerebral pharmacokinetics and brain distribution of tozadenant."

Journal • Preclinical • CNS Disorders • ADORA2A

INHIBITION OF ALPHA-SYNUCLEIN SEEDING DEPENDENT AGGREGATION BY SSDNA APTAMERS SPECIFIC TO C-TERMINALLY TRUNCATED Α-SYNUCLEIN FIBRILS. (ADPD 2023) - " Full-length recombinant human α -syn (α -syn 140) and Truncated α -syn (α -syn α -syn 130, α -syn 122, α -syn 115, and α -syn107) were expressed in Escherichia coli BL21 (DE3)... The aptamers discovered in this study demonstrate potential useful tools for research as well as diagnostic or therapy towards PD and DLB."

FAS

Quantitation of the A Adenosine Receptor Density in the Striatum of Mice and Pigs with [F]FLUDA by Positron Emission Tomography. (PubMed, Pharmaceuticals (Basel)) - "For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (V) at baseline and under blocking conditions with tozadenant. The MRT of [F]FLUDA in the striatum of mice was decreased by 30% after treatment with the AAR antagonist istradefylline...This study confirms the target specificity and a high BP of [F]FLUDA in the striatum. We conclude that [F]FLUDA is a suitable tool for the non-invasive quantitation of altered AAR expression in neurodegenerative diseases such as PD and HD, by PET."

Journal • Preclinical • CNS Disorders • Huntington's Disease • 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

New drug may give hope to patients with Parkinson’s disease (Eminetra) - P=NA, N=996; "'There are advances in expanding drug use, developing new drugs, and treating symptoms that could not be treated effectively or that were not noticed to be a problem for the patient,' says Professor Robert Hauser. Says."

Clinical data • Media quote

Design, synthesis and biological evaluation of Tozadenant analogues as adenosine A receptor ligands. (PubMed, Eur J Med Chem) - "Their binding to AR was further confirmed by radiolabeling with F and in vitro autoradiography in rat brain slices, which showed almost exclusive striatal binding and complete displacement by the AR antagonist ZM 241385. We conclude that these compounds represent potential candidates for the visualization of the A receptor and open pathways to novel therapeutic treatments of neurodegenerative disorders or cancer."

Journal • CNS Disorders • Oncology

Synthesis and Biological Evaluation of a Novel F-Labeled Radiotracer for PET Imaging of the Adenosine A Receptor. (PubMed, Int J Mol Sci) - "Aiming at the development of a PET radiotracer, we herein report the design of a series of novel fluorinated analogs (TOZ1-TOZ7) based on the structure of the AR antagonist tozadenant, and the preclinical evaluation of [F]TOZ1...Investigations of the metabolic stability in mice revealed parent fractions of more than 76% and 92% of total activity in plasma and brain samples, respectively. Dynamic PET/magnetic resonance imaging (MRI) studies in mice revealed a brain uptake but no AR-specific in vivo binding."

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

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

[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

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

Biotie Therapies Corp. financial statement release 1 January (Biotie) - Biotie exercised its right to terminate the merger plan and combination agreement for safinamide; As a result Biotie was entitled to & consequently received a break-up fee of EUR 1.5M from Newron; Biotie has granted a worldwide license to UCB Pharma for the development of the SYN115 through P3 trials & subsequent commercialization; P2b ongoing (sponsored by Biotie) with results expected H1 2013

Anticipated P2 result • Parkinson's Disease

Overview of therapeutic drugs and methods for the treatment of Parkinson's disease. (PubMed, CNS Neurol Disord Drug Targets) - "Alternatively, we further discussed the potential therapeutic role of adenosine (2A) receptor antagonists such as tozadenant and istradefylline in the treatment of PD. We also discussed the important role of serotonin1A receptor agonist, adrenergic autoreceptors (α2) receptor antagonists and calcium channel blockers in the treatment of PD. Finally, neurotrophic factors such as glial cell line-derived neurotrophic growth factor and brain-derived neurotrophic are considered the primary factors for neuroprotection in PD."

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

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

Biotie presents tozadenant phase 2b data at AAN Annual Meeting (Biotie, AAN 2013) - P2, N=420; NCT01283594; Sponsor: Biotie; "Significant reductions in mean placebo-corrected change from baseline in OFF time were observed with tozadenant ...120 mg BID...and 180 mg BID... The amount of time patients spent in the ON time with troublesome dyskinesia was not significantly increased in any tozadenant group. Mean placebo-corrected scores on the ...UPDRS part III significantly improved with tozadenant 120 mg BID... and 180 mg BID...and mean placebo-corrected UPDRS I-III scores improved significantly in all tozadenant groups... plan to start phase 3 program by H1 2015"."

Anticipated new P3 trial • P2 data • Parkinson's Disease

Biotie presents tozadenant phase 2b data at AAN Annual Meeting (Biotie, AAN 2013) - P2, N=420; NCT01283594; Sponsor: Biotie; "Significant reductions in mean placebo-corrected change from baseline in OFF time were observed with tozadenant ...120 mg BID...and 180 mg BID... The amount of time patients spent in the ON time with troublesome dyskinesia was not significantly increased in any tozadenant group. Mean placebo-corrected scores on the ...UPDRS part III significantly improved with tozadenant 120 mg BID... and 180 mg BID...and mean placebo-corrected UPDRS I-III scores improved significantly in all tozadenant groups... plan to start phase 3 program by H1 2015"."

Anticipated new P3 trial • P2 data • Parkinson's Disease

Acorda acquires Biotie to expand in Parkinson's disease (PMLive) - "The acquisition gives Acorda rights to Biotie's tozadenant (SYN115), an adenosine A2a receptor antagonist which is in a phase III trial - with results expected before the end of 2017 - that could form the basis of marketing applications....The deal will also give Acorda four phase III programmes that - if successful - could add sales of $1bn or more to its sales in the coming years. Tozadenant itself has been tipped to become a $400m product."

Anticipated P3 data • Anticipated sales • Parkinson's Disease

Acorda stock up despite Phase III trial on tozadenant stops (Nasdaq) - "Acorda Therapeutics, Inc. ACOR announced that it has decided to immediately discontinue the phase III study on one of its lead Parkinson's disease ("PD") candidates, tozadenant....Shares of Acorda climbed almost 10% following this news release as investors probably consider the company's decision to be a prudent as it will reduce the company's R&D spending and allow it to focus on its other late-stage PD candidate, Inbrija."

Stock price • CNS Disorders • Parkinson's Disease

Acorda to acquire Biotie Therapies (Businesswire) - "...Acorda will also obtain global rights to SYN120...for Parkinson’s-related dementia, in Phase 2 development with support from the Michael J. Fox Foundation....Dr. Cohen added, 'Tozadenant is a compelling opportunity with potential market exclusivity to 2030. The Phase 2 data were highly statistically significant and clinically meaningful. We are targeting an NDA filing by the end of 2018.' Subject to customary closing conditions, the tender offer is expected to be completed in the first or second quarter of 2016, and the acquisition is expected to be completed in the third quarter of 2016."

Anticipated launch • Anticipated NDA • M&A • Alzheimer's Disease • Parkinson's Disease

A Phase 3 Study of Tozadenant (TOZ-PD) as a Maintenance Therapy for Patients With Parkinson's Disease Experiencing Motor Fluctuations: Characterization of Study Population (AAN 2018) - "The characteristics of the TOZ-PD study population are comparable with the tozadenant phase 2b study population and with other previously completed motor fluctuation studies. The study presents an opportunity to evaluate the potential impact of an investigational therapy for PD patients."

Clinical • P3 data • CNS Disorders • Parkinson's Disease

Acorda provides financial and pipeline update for second quarter 2017 (Acorda Press Release) - " 'We submitted our NDA for INBRIJA on schedule....We expect the FDA to notify us by the end of September if the submission is accepted for full review. Commercial preparations for the launch of INBRIJA are well underway and we expect to submit a Marketing Authorization Application to the European Medicines Agency by the end of 2017. We are also on track to announce top-line data from our Phase 3 study of tozadenant in the first quarter of 2018.' "

European regulatory • FDA event • CNS Disorders • Parkinson's Disease

Acorda provides update on tozadenant development program (Acorda Press Release) - "Acorda Therapeutics...today announced that it has increased the frequency of blood cell count monitoring for participants to weekly in its Phase 3 program of tozadenant for Parkinson’s disease. The Company took this action in response to cases of agranulocytosis...The Company also has paused new enrollment in the long-term safety studies, pending further discussion with the independent Data Safety Monitoring Board (DSMB) and the United States Food and Drug Administration (FDA)....'Contingent on further input from the DSMB and FDA, we continue to expect to report efficacy and safety results of the double-blind Phase 3 study in the first quarter of 2018.' "

P3 data • Pipeline update • Trial suspension • CNS Disorders • Parkinson's Disease

Quantitative Analysis of Tozadenant Using Liquid Chromatography-Mass Spectrometric Method in Rat Plasma and Its Human Pharmacokinetics Prediction Using Physiologically Based Pharmacokinetic Modeling. (PubMed, Molecules) - "The predicted human PK parameters and profiles were similar to the observed clinical data. As a result, optimized PBPK model could reasonably predict the PK in human."

Journal • PK/PD data • Preclinical