Date: 2015-07-21
Type of information: Initiation of the trial
phase: 3
Announcement: initiation of the trial
Company: Biotie Therapies (Finland)
Product: SYN115 (tozadenant)
Action
mechanism: adenosine A2a receptor antagonist. SYN115 is an orally bioavailable potent and selective adenosine A2a receptor antagonist. Adenosine A2a inhibition has been shown in preclinical studies to reverse motor deficits and enhance the effect of current PD therapies, e.g. levodopa and dopamine agonists, without inducing troublesome dyskinesia (involuntary movements). In addition, SYN115 also displays activity in preclinical models on non-motor symptoms of PD including depression, cognition and anxiety.
Disease: Parkinson's disease
Therapeutic area: Neurodegenerative diseases - CNS diseases
Country: Canada, USA
Trial
details: The Phase 3 study (TOZ-PD) is a randomized, double-blind, placebo controlled trial that will evaluate efficacy and safety of tozadenant compared to placebo in 450 PD patients experiencing end-of-dose wearing off episodes. Participants will be randomized to receive twice daily doses of 60 mg or 120 mg of tozadenant or placebo, in addition to their standard anti-PD medications, for 24 weeks. The primary endpoint will be reduction in time spent in the "off" state in patients taking tozadenant as compared to placebo between baseline and week 24. The placebo-controlled period will be followed by a 52 week open label treatment period to collect additional safety data. As previously announced, Biotie Therapies reached agreement with the U.S. Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) of this study.(NCT02453386)
Latest
news: * On July 21, 2015, Biotie Therapies announced the start of the Phase 3 clinical study of tozadenant in patients with Parkinson's disease (PD) experiencing levodopa related end-of-dose "wearing-off". A successful outcome to the study will confirm the safety and efficacy observed in the previously completed Phase 2b study of tozadenant in this indication and provide a second pivotal study to support submission of an New Drug Application (NDA) for the use of tozadenant as adjunctive treatment to levodopa in patients experiencing end-of-dose wearing off. Based on current estimates, top-line data from the double-blind portion of the study is expected to be available by the end of 2017. * On May 25, 2015, Biotie Therapies announced that the company has reached agreement with the FDA on a Special Protocol Assessment (SPA) for the Phase 3 study of tozadenant in Parkinson's disease. The Phase 3 study (TOZ-PD) will evaluate efficacy and safety of tozadenant compared to placebo in PD patients taking levodopa and experiencing end-of-dose wearing off. A positive outcome of TOZ-PD, along with the results of the completed Phase 2b study are expected to be sufficient to support a claim of efficacy for tozadenant in patients with Parkinson's disease with motor fluctuations (end-of-dose wearing off) and could form the basis of an NDA submission. Final marketing approval will be dependent, amongst other factors, on the overall results of the trial. The planned study is a randomized, double-blind, placebo controlled Phase 3 study in 450 PD patients experiencing levodopa related end-of-dose wearing off, in which participants will be randomized to receive twice daily doses of 60mg or 120mg of tozadenant or placebo, in addition to their standard anti-PD medications, for 24 weeks. The primary endpoint will be reduction in time spent in the "off" state in patients taking tozadenant as compared to placebo between baseline and week 24. The double-blind phase of the study will be followed by an open-label treatment phase of a one year duration. * On April 23, 2015, Biotie provides update on tozadenant Phase 3 program. The company announced that it has further refined its plans for the design and conduct of Phase 3 trials in Parkinson's disease patients experiencing levodopa related end-of-dose 'wearing-off' (motor fluctuations). The phase 3 program will consist of a double- blind trial with an open-label extension and, providing this demonstrates safety and efficacy, will be followed by a separate open-label trial to generate further clinical safety data. The refinement in the trial design does not impact the expected overall timeline to submission of a U.S. New Drug Application for tozadenant, but allows top-line results from the double-blind portion to be available by the end of 2017, approximately one year earlier than previously planned, while maintaining adequate statistical power in the study. In the double-blind portion, 450 participants will be randomized to receive twice daily doses of 60mg or 120mg of tozadenant or placebo in addition to their standard anti-PD medications, for 24 weeks. The primary endpoint will be time spent in the "off" state in patients taking tozadenant as compared to placebo between baseline and week 24. Secondary endpoints will include "on" time without troublesome dyskinesia, the Unified Parkinson's Disease Rating Scale, Clinical Global Impression of Change and Patient Global Impression of Change. The placebo-controlled period will be followed by a 52 week open label treatment period to collect additional clinical safety data. The study is expected to start recruiting patients in the United States, Canada and selected European countries in the middle of 2015. Based on current estimates and the number of patients being enrolled into the study, top-line data is expected to be available by the end of 2017.Providing the double-blind portion of the trial meets its primary efficacy endpoint, another open-label trial will be initiated in a separate population of 450 PD patients to establish the requisite number of unique patient exposures required for approval. The open label trial will evaluate safety over a year and is also expected to be conducted in North America and selected European countries. Patients will be dosed with 120 mg of tozadenant twice/day, although the investigator may adjust the dose to 60 mg twice/day based on individual response. * On February 20, 2015, Biotie announces further detail on its clinical development plan for tozadenant, an adenosine A2a antagonist in development for Parkinson's disease. Biotie plans to conduct one Phase 3 study in 882 PD patients experiencing levodopa related end-of-dose 'wearing-off' (motor fluctuations) in which participants will be randomized in a double-blind manner to receive twice daily doses of 60mg or 120mg of tozadenant or placebo in addition to their standard anti-PD medications, for 24 weeks. The primary endpoint will be time spent in the "off" state in patients taking tozadenant as compared to placebo between baseline and week 24. Secondary endpoints will include "on" time without troublesome dyskinesia, the Unified Parkinson's Disease Rating Scale, Clinical Global Impression of Change and Patient Global Impression of Change. The placebo-controlled period will be followed by a 52 week open label treatment period to collect additional clinical safety data. The planned Phase 3 study is expected to start recruiting patients in the United States, Canada and selected European countries in the middle of 2015. Based on current estimates, top-line data is expected to be available by the end of 2018. Biotie has previously reported positive data from a 420-patient Phase 2b study evaluating tozadenant in Parkinson's disease patients experiencing levodopa related end-of-dose 'wearing-off'. Full data from this trial was published in Lancet Neurology in 2014 (see below). The trial met its primary endpoint of a highly significant decrease in "off" time vs. placebo, as well as demonstrating efficacy across multiple secondary endpoints. The Phase 3 protocol will largely replicate that of the Phase 2b study. Biotie expects that the published Phase 2b study will be considered the first of two pivotal studies required for registration for tozadenant in PD patients with end-of-dose 'wearing-off'. Biotie is considering financing options which may involve a capital raise to fully fund the tozadenant Phase 3 program to approval. * On July 30, 2014, Biotie announced that the company has decided to advance tozadenant, its adenosine A2a receptor antagonist for Parkinson's disease, into Phase 3 development as part of the Company's proprietary portfolio. Preparations for Phase 3 development are ongoing, and it is expected that the Phase 3 clinical studies can commence recruitment in H1 2015, as originally planned. Following the decision by UCB Pharma to return global rights to tozadenant in March 2014, Biotie has been evaluating the most suitable development strategy for this Phase 3 ready asset to maximize its value to shareholders and has concluded that this can be best achieved by continuing with the Phase 3 study within its current portfolio. The Company considers tozadenant to potentially be its most valuable asset given the high unmet medical need in Parkinson's disease and stage of development and is currently evaluating various options, which may include a capital increase, to support the clinical studies and a strong regulatory filing package for tozadenant. * On July 8, 2014, Biotie announced that full data from the positive Phase 2b study evaluating tozadenant, an adenosine A2a antagonist, in Parkinson's disease patients experiencing end of dose wearing off have been published in Lancet Neurology (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; published online July 7. http://dx.doi.org/10.1016/S1474-4422(14)70148-6). The Phase 2b study was an international, randomised, double blind, placebo-controlled, parallel group, dose finding study in 420 levodopa-treated patients with end of dose wearing off (i.e at least 2.5 hours off time per day). Patients received either 60mg, 120mg, 180mg or 240mg tozadenant or matching placebo twice daily for 12 weeks. The primary outcome was a change from baseline to week 12 in hours per day spent in the off-state, assessed from patient diaries. As previously disclosed, the study demonstrated that tozadenant, when compared to placebo, decreased levodopa related motor fluctuations. Previously released topline results for this study included clinically relevant and highly statistically improvements in 'off' time, 'on' time, UPDRS part III and UPDRS parts I-III. In addition to providing more details on these endpoints, further data published in Lancet Neurology include highly significant improvements in the clinician global impression of severity and clinician global impression of improvement in all tozadenant groups compared with placebo and patient global impression of improvement in the 120 mg BID group. Results of sensitivity analyses of the primary efficacy outcome using multiple methods were consistent with the improvements of the primary analysis.The company plans to start the phase 3 program in the first half of 2015. * On March 21, 2013, Biotie has announced that full data from a Phase 2b study evaluating tozadenant (SYN115) in Parkinson's disease patients experiencing levodopa related end of dose wearing off were presented at the 65th Annual Meeting of the American Academy of Neurology in San Diego. These data were selected by the AAN for the Emerging Science Program (formerly Late-breaking Science Program) and were presented by Dr. C. Warren Olanow, Professor of Neurology and Neuroscience at the Mount Sinai School of Medicine. The study was an international, 12-week, double-blind, phase 2 trial in which patients on stable dosages of levodopa with at least 2.5 hours (hr) of OFF time per day were randomized to tozadenant 60, 120, 180 or 240 mg BID, or matching placebo. The primary outcome measure was the change from baseline to Week 12 in hours per day spent in the OFF state. A mixed-model repeated-measures ANCOVA was used for analyses with a pre-specified hierarchical step-down approach to test multiple dose groups. Of 420 patients randomized, 337 completed treatment. Their mean age was 63.3 years, mean duration of Parkinson's disease 8.7 years, and their mean OFF time at baseline was about 6 hr/day. Significant reductions in mean placebo-corrected change from baseline in OFF time were observed with tozadenant (modified Intention to Treat population) 120 mg BID (-1.1 hr, p=0.0039) and 180 mg BID (-1.2 hr, p=0.0039). 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 Unified Parkinson's Disease Rating Scale (UPDRS) part III significantly improved with tozadenant 120 mg BID (-2.2, p=0.0325) and 180 mg BID (-2.5, p=0.0325), and mean placebo-corrected UPDRS I-III scores improved significantly in all tozadenant groups (all groups, p< 0.03) The changes were also perceptible to both physicians and patients, as reflected in statistically significant improvements on global ratings. Mean placebo-corrected scores on the clinician-administered global impressions of severity (CGI-S) and improvement (CGI-I) improved significantly in all tozadenant groups, and placebo-corrected scores on patient ratings (Patient Global Impression; PGI) significantly improved in the 120 mg BID group. The most common adverse events in the combined tozadenant groups were dyskinesia, nausea, dizziness, constipation, PD worsening, insomnia and falls. Biotie has indicated that the company is working closely with its partner UCB Pharma for further development of tozadenant. The companies plan to start the phase 3 program by H1 2015. * On December 11, 2012, Biotie Therapies has reported top-line data from a Phase 2b study evaluating its adenosine A2a antagonist tozadenant (SYN115) in Parkinson's disease patients experiencing levodopa related end of dose wearing off. The study met its primary endpoint of a statistically highly significant decrease in \'off\' time vs. placebo, as well as demonstrating efficacy across multiple secondary endpoints. Full data from the study will be disclosed at upcoming medical conferences and in scientific publications. In the 420 patient study, tozadenant displayed clinically relevant and statistically highly significant effects on PD across multiple pre-specified evaluation metrics including: a decrease vs. placebo in \'off\' time, an increase in \'on\' time, an improved score on UPDRS part III and UPDRS parts I-III combined, as well as improvements on clinician- and patient-assessed global impression scores. Additionally, the study identified the minimally efficacious and maximum feasible dose levels, as well as clinically useful target doses for Phase 3. Tozadenant was generally well tolerated in the study. Biotie Therapies is now looking forward to analyzing the results in detail with its license partner UCB. The company expects a decision from UCB in the first quarter of 2013 regarding the next steps. * On July 5, 2012, Biotie Therapies Corp has announced that enrollment is complete in its Phase 2b trial evaluating the safety and efficacy of tozadenant in Parkinson's disease. Biotie now expects the top-line data from this study to be available at around the end of 2012, previous guidance was H1 2013. Biotie has granted UCB Pharma S.A. a license for exclusive, worldwide rights to tozadenant. Pending evaluation of the results of the ongoing study UCB Pharma will be responsible for conducting the Phase 3 program and commercializing tozadenant. * On April 7, 2011, Biotie Therapies has announced the start of a Phase 2b trial evaluating SYN115 in Parkison's Disease. Results from the study are expected in the first half of 2013.
