Biotie is developing a novel product, tozadenant, (SYN115) for Parkinson´s disease. The product has a unique mechanism of action and, if successful, could represent the first new treatment modality for this disease in more than 20 years. Biotie owns full global rights to tozadenant and has advanced the product into Phase 3 development as part of the Company’s proprietary development portfolio. Patient enrollment into the Phase 3 program commenced in mid-2015.
About Parkinson’s disease
Parkinson’s disease is a progressive neurodegenerative condition that is associated with four common motor symptoms: tremor of the hands, arms, legs, jaws, and or face; rigidity or stiffness of the limbs and trunk; slowness of movement and impaired balance or coordination. As the disease progresses the conditions become more pronounced and patients have difficulty walking, talking and completing simple daily tasks. Eventually patients are restricted to a bed or a chair and require constant nursing care. Parkinson’s disease is also frequently associated with co-morbid, non-motor symptoms including depression, dementia, psychosis, and sleep disorders. These may be as disabling as, or more disabling than, the motor symptoms.
The symptoms of Parkinson’s disease are related to the death of neurons that produce the chemical messenger dopamine in regions of the brain controlling movement. The non-motor symptoms experienced by Parkinson’s patients are likely secondary to the underlying loss of dopaminergic neurons and potentially other types of neurons (cholinergic, serotonergic and adrenergic).
Parkinson’s disease is one of the most common neurodegenerative disorders occurring with an incidence second only to that of Alzheimer’s disease and a prevalence in the US, five major EU countries (5MEU) and Japan of approximately 1.6 million (footnotes a, b). The average age of onset is 60 years and, as the risk of developing Parkinson’s disease increases with age, its prevalence is expected to increase as the global population ages.
There are currently no available therapies that are capable of curing Parkinson’s disease and so the goal of therapy is to reduce symptoms to allow patients to perform usual daily activities. Existing therapies include levodopa (L-Dopa), dopamine agonists and the dopamine extenders. These have limited efficacy, are associated with significant side effects (including dyskinesias, or sudden jerking movements) and their effects diminish over time, leaving patients with re-emergence of symptoms before their next dose (‘wearing off’). New therapeutic modalities that improve control of motor symptoms, delay the time to use of L-Dopa, reduce troublesome side effects, treat some of the non-motor symptoms such as dementia, depression, sleep disorders, and which slow progression of the disease are needed and will drive market growth.
Product profile for tozadenant
Tozadenant is an orally administered, potent and selective inhibitor of the adenosine 2a (A2a) receptor that is being developed initially for the treatment of Parkinson’s disease, but may also have utility in other CNS disorders.
A2a receptors are expressed in high concentration in the striatum of the brain and there is an emerging body of evidence that they play an important role in regulating motor function. Tozadenant blocks the effect of endogenous adenosine at the A2a receptors, resulting in the potentiation of the effect of dopamine at the D2 receptor and inhibition of the effect of glutamate at the mGluR5 receptor. This enables restoration of motor function in Parkinson’s disease patients without the induction of troublesome dyskinesias. Tozadenant has the potential for use as mono-therapy or adjunctive therapy in combination with L-Dopa and dopamine agonists for the treatment of the motor and non-motor symptoms associated with Parkinson’s disease.
Tozadenant may also have neuroprotective effects, which raises the possibility that it could slow the deterioration of dopamine producing cells and modify disease progression – a holy grail in Parkinson’s disease.
Clinical program completed with tozadenant to date
Tozadenant was initially studied in a single ascending dose study, two multiple ascending dose Phase 1 studies and a Phase 2a study in L-Dopa treated subjects with mild-to-moderate Parkinson’s disease. In these studies l, a total 127 normal volunteers and Parkinson’s disease patients received tozadenant for up to 28 days, at doses ranging from 5mg to 480mg per day (dosed once or twice daily). In these clinical studies, tozadenant was shown to be safe and well tolerated. In the Phase 2a study, sophisticated imaging techniques (fMRI) were used to evaluate the effect of tozadenant on the brain. The results showed that tozadenant enters the brain and causes changes in functional activity in specific regions associated with motor function and cognition. Improvements in various clinical assessments of motor function and cognition have also been demonstrated.
In April 2011, Biotie commenced a randomized, double-blind, placebo-controlled Phase 2b study that evaluated four doses of tozadenant versus placebo as adjunctive therapy in 420 levodopa-treated PD patients with end of dose wearing off. In these patients, treatment with levodopa is insufficient to control Parkinson’s disease symptoms until their next dose, resulting in an 'off' period when symptoms reappear. The aim of the Phase 2b study was to determine the efficacy and safety of tozadenant in reducing the mean time spent in the 'off' state over a 12 week treatment period. The trial also assessed the impact of tozadenant on various measures of motor symptom severity, dyskinesia and non-motor symptoms. Enrolment in the study was completed in July 2012 and top-line data reported in December 2012. In this study, tozadenant displayed clinically important and statistically significant effects on Parkinson’s disease 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.
In addition to presentations at multiple scientific meetings, full data from the Phase 2b study were published in Lancet Neurology in July 2014 (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. 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'.
In July 2015, Biotie announced the start of the tozadenant Phase 3 study in Parkinson's disease (study TOZ-PD). The Company has agreed on a Special Protocol Assessment for TOZ-PD with the FDA. Based on discussions with the FDA at the End of Phase 2 meeting, Biotie believes that the planned Phase 3 clinical program, together with existing data, could form the basis for approval of tozadenant as an adjunctive treatment to levodopa in Parkinson's patients experiencing end-of-dose wearing off episodes.
The TOZ-PD study will use the primary and secondary endpoints and enrollment criteria used in the Phase 2b clinical trial. The study is expected to enroll 450 patients experiencing levodopa related end-of-dose wearing off, who will be randomized to receive twice daily doses of 60mg or 120mg of tozadenant or placebo in addition to their standard anti-Parkinson's disease medications for 24 weeks. The primary endpoint will be the reduction in the number of hours spent in the "off" state in patients taking tozadenant as compared to placebo between baseline and week 24, as assessed by patient-completed diaries and averaged over three consecutive days. The double-blind placebo controlled period is expected to be followed by a 52 week open label treatment period to collect additional clinical safety data. The study is currently planned to be conducted in the United States, Canada and selected European countries. Based on current estimates top-line data from the double-blind portion is expected to be available by the end of 2017.
Providing the double-blind portion of TOZ-PD meets its primary efficacy endpoint, another open label trial is expected to be initiated in a separate population of 450 patients to establish the requisite number of unique exposures required for approval.
Biotie has exclusive worldwide rights to develop and commercialize tozadenant for all uses to treat or prevent human diseases and disorders under a license agreement with F. Hoffmann-La Roche Ltd (Roche).
Scientific literature related to the project
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, 2014. Available here
Olanow, C.W., Hauser, R.A., Kieburtz, K., Neale, A., Resburg, C., Meya, U., Bandak, S. (2013) A Phase 2, placebo-controlled randomized, double-blind trial of tozadenant (SYN115) in patients with Parkinson's disease with wearing-off fluctuations on levodopa. Poster presented at the 65th Annual Meeting of the American Academy of Neurology, San Diego, March 20, 2013. Available here
Fuxe, K., Marcellino, D., Genedani, S., & Agnati, L. (2007). Adenosine A2A receptors, dopamine D2 receptors and their interactions in Parkinson’s disease. Movement Disorders, 22(14), 1990-2017.
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Black, K. J., Jonathan, M., Campbell, M. C., Gusnard, D, A., & Bandak, S, l. (2010). Quantification of indirect pathway inhibition by the adenosing A2a antagonistic SYN115 in Parkinson disease. The Journal of Neuroscience, 30(48), 16284-16292.
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