• Clinically validated mechanism of action for PD-LID
• Second Phase IIa trial to begin this quarter with Addex allosteric modulators
• Trial funded in part by Michael J. Fox Foundation for Parkinson’s Research

 
Geneva, Switzerland, March 31 – Allosteric modulation company Addex Pharmaceuticals (SIX:ADXN) announced today the initiation of a Phase IIa clinical trial to evaluate dipraglurant in patients with Parkinson’s disease levodopa-induced dyskinesia (PD-LID), a debilitating movement disorder caused by long-term treatment with levodopa, the gold standard therapy for Parkinson’s disease. The U.S. and European study is supported in part by a grant from the Michael J. Fox Foundation for Parkinson Research. Results are expected to be announced during the first half of 2012.

Dipraglurant (ADX48621) is a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator (NAM).  The immediate-release formulation of dipraglurant (dipraglurant-IR), which has a pharmacokinetic profile similar to that of immediate release levodopa, achieved satisfactory safety, tolerability and pharmacokinetics in Phase I testing.

“This PD-LID Phase IIa study with dipraglurant is the second clinical trial involving Addex allosteric modulators to begin in 2011. We announced that our partner Ortho-McNeil-Janssen started Phase IIa testing of ADX71149, an mGluR2 PAM, for the treatment of schizophrenia earlier this week. These milestones strengthen the validation of the allosteric approach,” stated Vincent Mutel, CEO of Addex.

“We believe mGluR5 inhibition is a promising approach to alleviating the disabling side effects of levodopa, which are experienced by the majority of Parkinson’s patients as their disease progresses,” said Todd Sherer, chief program officer at The Michael J. Fox Foundation for Parkinson’s Research. “We have been driving the therapeutic development of mGluR5 since 2005 and are excited that the field has matured to the point where the inhibitor dipraglurant-IR is ready for clinical testing.”

ADX48621-201 is a randomized, double-blind, placebo-controlled, multicenter study to investigate the safety tolerability and efficacy of dipraglurant-IR in 72 Parkinson’s disease patients with levodopa-induced dyskinesia (LID). Placebo or dipraglurant (50 mg q.d. to 100 mg t.d.s.) will be administered with up to three of the patients’ daily levodopa doses over 4 weeks. The trial’s primary objective is safety and tolerability with exploratory efficiency, being the secondary objective, involving trained observer LID severity scores, Abnormal Involuntary Movement Scale (AIMS) and patient and doctor PD rating scales including the United Parkinson’s Disease Rating Scale (UPDRS).

Dipraglurant-IR is an immediate release formulation which has a similar pharmacokinetic profile to immediate release levodopa. Dipraglurant is the first drug candidate reported to reduce both of the major PD-LID symptoms, chorea (rapid uncontrolled movements) and dystonia (writhing and cramping movements) in preclinical testing.

Dipraglurant-ER, a longer-acting extended-release formulation of dipraglurant, is being developed for the treatment of non-Parkinsonian dystonia. This occurs as a variety of separate conditions of either primary (e.g. hereditary) or secondary (drug-induced or otherwise acquired) origin. The underlying biological pathways contributing to the expression of some of these types of dystonia are believed to be similar to those in PD-LID. Dipraglurant-ER will have a pharmacokinetic profile that is more appropriate for use in indications where a longer-acting once- or twice-daily form is advantageous. Phase I testing of dipraglurant-ER will commence during the second half of 2011. Phase IIa testing of dipraglurant-ER in dystonia patients is scheduled to start in 2012.

mGluR5 inhibition reduces signaling activity of the neurotransmitter glutamate. The loss of dopamine producing cells observed as a result of Parkinson’s disease leads to excess of glutamatergic stimulation in the brain’s striatopallidal pathway. The mGluR5 are found abundantly in the striatum and inhibition of mGluR5 could provide a novel and complementary treatment option for PD and PD-LID. Research shows that dipraglurant and other mGluR5 inhibitors have reduced LID and generated anti-parkinsonian effects in animal models of PD-LID and Parkinson’s disease. In addition, two small clinical studies already have shown that the mGluR5 inhibitor AFQ056 reduced LID symptoms in humans with PD-LID*.  The mGluR5 inhibition mechanism also has achieved validation for other indications including, fragile X syndrome, pain, anxiety, depression and gastroesophageal reflux disease (GERD), all of which have been validated using mGluR5 inhibitors.

*http://www.novctrd.com

Addex Pharmaceuticals (www.addexpharma.com) discovers and develops allosteric modulators for human health. The company uses its proprietary discovery platform to target cell surface receptors that are recognized as having therapeutic potential for treating diseases of the central nervous system, metabolic disorders or inflammation. Two Phase IIa clinical trials are ongoing for two lead products: dipraglurant (ADX48621) and ADX71149. Dipraglurant is an mGluR5 negative allosteric modulator (NAM), which is being tested in Parkinson's disease levodopa-induced dyskinesia (PD-LID). ADX71149, an mGluR2 positive allosteric modulator (PAM), is being tested for treatment of schizophrenia by our partner Ortho-McNeil-Janssen Pharmaceuticals Inc. In addition, Merck & Co., Inc. has licensed rights to two preclinical programs: mGluR4 PAM for Parkinson's disease and mGluR5 PAM for schizophrenia. Unpartnered products in preclinical testing include: follicle stimulating hormone receptor (FSHR) NAM, with potential for endometriosis and benign prostatic hyperplasia; mGluR2 NAM for Alzheimer's disease; and GABA-BR PAM with potential for chronic pain, Fragile X syndrome, urinary incontinence and gastroesophageal reflux disease. Preclinical diabetes and inflammation discovery programs include GLP-1R PAM, IL-1R1 NAM, and TNFR1 NAM.

Chris Maggos
Business Development & Communication
Addex Pharmaceuticals
+41 22 884 15 11
chris.maggos(at)addexpharma.com 
 

Disclaimer: The foregoing release may contain forward-looking statements that can be identified by terminology such as "not approvable", "continue", "believes", "believe", "will", "remained open to exploring", "would", "could", or similar expressions, or by express or implied discussions regarding Addex Pharmaceuticals Ltd, its business, the potential approval of its products by regulatory authorities, or regarding potential future revenues from such products. Such forward-looking statements reflect the current views of Addex Pharmaceuticals Ltd regarding future events, future economic performance or prospects, and, by their very nature, involve inherent risks and uncertainties, both general and specific, whether known or unknown, and/or any other factor that may materially differ from the plans, objectives, expectations, estimates and intentions expressed or implied in such forward-looking statements. Such may in particular cause actual results with allosteric modulators of mGluR2, mGluR4, mGluR5, mGluR7 or other therapeutic targets to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that allosteric modulators of mGluR2, mGluR4, mGluR5, mGluR7 will be approved for sale in any market or by any regulatory authority. Nor can there be any guarantee that allosteric modulators of mGluR2, mGluR4, mGluR5, mGluR7 or other therapeutic targets will achieve any particular levels of revenue (if any) in the future. In particular, management's expectations regarding  allosteric modulators of mGluR2, mGluR4, mGluR5, mGluR7 or other therapeutic targets could be affected by, among other things, unexpected actions by our partners, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; competition in general; government, industry and general public pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Addex Pharmaceuticals Ltd is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise, except as may be required by applicable laws.