Pipeline

CVXL – 0069

A first-in-class dual antagonist of adenosine receptors for motor and non-motor symptoms treatment in Parkinson’s disease.

CVXL-0069 is a dual A2A/A1 receptor antagonist. It has demonstrated efficacy in increasing the efficacy of levodopa activity in a well recognized preclinical model of Parkinson’s Disease. Its dual A2A and A1 antagonism, addressing both motor and non-motor symptoms of Parkinson’s Disease, makes CVXL-0069 a major advance in patients’ lives.

Adenosine is a neuromodulator involved in a large array of cerebral activities. It engages four receptors of the adenosine receptors family. A specific inhibition of A2A and A1 receptors is expected to improve multiple symptoms of Parkinson’s Disease :
A2A and A1 receptor antagonism synergizes with dopamine signaling in the striatum, and therefore improve motor symptoms
A1 receptors antagonists enhance cognitive function
A2A and A1 antagonists, such as the non-selective antagonist caffeine, decrease risk of treatment- or disease-related somnolence by eliciting active waking
A2A and A1 antagonists have potential to increase dopamine release by the substantia nigra, therefore reducing exogenous dopamine needs in early-stage Parkinson’s Disease

Graphique Pipeline CVXL-0069 Eng

CVXL-0069 is now in preclinical development.

1. Mori, A. Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int. Rev. Neurobiol. 119, 87–116 (2014).
2. Salmi, P., Chergui, K. & Fredholm, B. B. Adenosine-dopamine interactions revealed in knockout mice. J. Mol. Neurosci. 26, 239–44 (2005).
3. Mango, D. et al. Adenosine A1 receptor stimulation reduces D1 receptor-mediated GABAergic transmission from striato-nigral terminals and attenuates l-DOPA-induced dyskinesia in dopamine-denervated mice. Exp. Neurol. 261, 733–43 (2014).
4. Maemoto, T. et al. Pharmacological characterization of FR194921, a new potent, selective, and orally active antagonist for central adenosine A1 receptors. J. Pharmacol. Sci. 96, 42–52 (2004).
5. Huang, Z.-L., Zhang, Z. & Qu, W.-M. Roles of adenosine and its receptors in sleep-wake regulation. Int. Rev. Neurobiol. 119, 349–71 (2014).
6. Borycz, J. et al. Differential glutamate-dependent and glutamate-independent adenosine A1 receptor-mediated modulation of dopamine release in different striatal compartments. J. Neurochem. 101, 355–63 (2007).
7. Jankovic, J. & Poewe, W. Therapies in Parkinson’s disease. Curr. Opin. Neurol. 25, 433–47 (2012).
8. http://www.pdf.org/en/parkinson_statistics

PARKINSON’S DISEASE

 

Parkinson’s disease (PD) is a major chronic and progressive neurodegenerative disorder, affecting 1-2% of individuals aged Under 65 years and 3% aged over 65 years worldwide.

PD results from the neurodegeneration of dopaminergic neurons in the substantia nigra leading to a decrease in the dopaminergic tone essential to movement.

First clinical signs are motor symptoms such as bradykinesia, rigidity, and resting tremor. As the disease progresses, motor coordination is dramatically reduced and non-motor symptoms appear (autonomic dysfunction, cognitive impairment, dementia).

Current medications involve symptomatic dopaminergic drugs, notably L-Dopa and dopamine agonists (DA). However, the extended use of dopaminergic therapies lead to motor fluctuations leaving patients with re-emergence of symptoms before their next dose (‘wearing off’). Moreover, DA have serious side effects including hallucinations and control disorders.

Non-dopaminergic compounds represent promising alternatives to avoid dopamine agonists side-effects and limit the wearing-off phenomenon.

Finally, although 80% of patients after 20 years of disease progression will experience non-motor complications; there is no treatment specifically addressing this need.