Lancet Neurology [2014] 13 (8) : 767-776 (R.A.Hauser, C.W.Olanow, K.D.Kieburtz, E.
Pourcher, A.Docu-Axelerad, M.Lew, O.Kozyolkin, A.Neale, C.Resburg, U.Meya, C.Kenney,
S.Bandak) Complete abstract : http://www.ncbi.nlm.nih.gov/pubmed/25008546
Clinical trials assessed the use 60mg, 120mg, 180mg, or 240mg tozadenant in people with
Parkinson's Disease who were being treated with L-dopa and who had motor fluctuations that involved at least 2·5 hours off-time per day. Tozadenant (SYN115) is an inhibitor of the adenosine 2a (A2a) receptor that is being developed for the treatment of Parkinson's Disease.
Compared with the use of a placebo, daily off-time was reduced by more than an hour when taking either 120mg or 180mg tozadenant. The most common adverse events were dyskinesia (16% of people taking 120mg, 20% of people
taking 180mg), nausea (11% of people taking 120mg, 12% of people taking 180mg), dizziness (5% of people taking 120mg, 13% of people taking 180mg). Tozadenant, 60 mg twice daily, was not associated with a significant reduction in off-time. Tozadenant, 240 mg twice daily, was associated with an increased rate of discontinuation because of adverse events that occurred in 20% of people taking that dosage. The researchers concluded that 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.
http://www.viartis.net/parkinsons.disease/news/140919.pdf
For more information go to Biotie Therapies :
http://www.biotie.com/en/product_portfolio/product_portfolio/syn115
Tozadenant (SYN115): A highly differentiated product for Parkinson’s disease
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 (SYN115)
SYN115 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.
SYN115 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. SYN115 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.
SYN115 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 trial status of SYN115
SYN115 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 SYN115 for up to 28 days, at doses ranging from 5mg
to 480mg per day (dosed once or twice daily). In these clinical studies, SYN115
was shown to be safe and well tolerated. In the Phase 2a study, sophisticated
imaging techniques (fMRI) were used to evaluate the effect of SYN115 on the
brain. The results showed that SYN115 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 SYN115 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 SYN115 in reducing the mean time spent in the 'off' state over a
12 week treatment period. The trial also assessed the impact of SYN115 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 relevant and
statistically highly 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.
Extensive data from the Phase 2b
study have been presented at the 65th Annual Meeting of the American Academy of
Neurology (AAN) in San Diego, March 20, 2013. as well as in the 17th
International Congress of the Movement Disorder Society in Sydney, June 2013.
Program status
Following an agreement announced in 2010,
Biotie licensed worldwide exclusive rights to UCB Pharma S.A. (UCB) in February
2013 and received a one-time payment of USD 20 million Following an agreement
announced in 2010, Biotie licensed worldwide exclusive rights to UCB Pharma
S.A. (UCB) in February 2013 and received a one-time payment of USD 20 million (Stock
exchange release; February 27, 2013); a potential additional USD 340
million in future milestone payments were payable under the agreement with
UCB.
Tozadenant is now transitioning into Phase 3 development. Since February
2013, preparations for the Phase 3 development program were undertaken in
collaboration with UCB; these included CMC and non-clinical work, and certain
Phase 3 enabling clinical pharmacology studies for which Biotie received EUR
9.7 million in additional development milestones in 2013. Patient enrolment in
the phase 3 program is currently planned to commence by the first half of
2015.
In March 2014, it was announced
that UCB were returning global rights to tozadenant to Biotie after UCB's
assessment of its early and late stage clinical development pipeline, as well
as its preclinical opportunities, and did not reflect any concerns regarding
safety or efficacy of tozadenant. UCB has confirmed that it will meet all its
contractual and scientific commitments regarding the ongoing development
program for tozadenant, including conducting together with Biotie the scheduled
End-of-Phase 2 meeting with US Food and Drug Administration in H1 2014. The
companies are working together to execute an appropriate transfer of the program
back to Biotie.
Owning full global rights to tozadenant will enable Biotie to
evaluate the most suitable development strategy for this Phase 3 ready asset to
maximize its value to Biotie’s shareholders. As part of this evaluation Biotie
will consider other partners to assist in the development and commercialization
of this novel compound.
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