Addex Therapeutics announced that the company will conduct a phase IIa Proof of Concept Study of dipraglurant in focal cervical dystonia (CD). Addex expects to initiate the trial in the fourth quarter of 2016. The study was developed with support from the Dystonia Medical Research Foundation and in collaboration with investigators from the Dystonia Coalition, an international network of experts devoted to advancing research in dystonia. Buz Jinnah, Director of the Dystonia Coalition and Professor of Neurology at Emory University, will serve as the lead investigator.  

Dystonia is a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. Dystonia represents the third most common movement disorder in humans and comprises a large number of clinical syndromes. CD is the most prevalent form of dystonia; recent international prevalence estimates place the number of CD patient in the US between 50,000 and 100,000 - a range which is much higher than previously reported and considers the large portion of undiagnosed population. CD has been demonstrated to have a significant impact on quality of life. Current treatment options for focal CD include botulinum toxin (BoNT) injections, which generally reduce muscle spasms temporarily for a few months. However, the interval between BoNT injections is usually longer than the duration of action, leaving patients with sub-optimal symptom relief towards the end of the treatment for weeks. In addition, most patients rarely experience any symptom free days.

Addex’s phase IIa Proof of Concept study will include 18 focal CD patients who are currently sub-optimally treated with BoNT. The single center study will be double-blinded and placebo-controlled. A single dose of dipraglurant will be administered in a crossover design. The TWSTR scale, a well-established clinical rating scale designed to detect drug induced changes, will serve as the primary endpoint of the trial. Key secondary endpoints will include an evaluation of the Cervical Dystonia Impact Profile, a patient-reported outcome for quality of life, pharmacokinetics and safety and tolerability.

“Cervical dystonia is a rare disorder that is not easy for most doctors to treat. BoNT provides partial relief for many patients, but it has its limitations - we need to do better,” said Professor Jinnah. “An oral medication would be a great option, and dipraglurant is the first oral agent brought forward for this condition in decades. We are delighted to be able to test it for our patients."

“We are extremely pleased with our ongoing collaboration with Addex and the Company’s decision to conduct this trial,” said Jan Teller, CSO of Dystonia Medical Research Foundation. “Our foundation identified dipraglurant as the most promising drug candidate for dystonia and places Addex among a few pioneering pharmaceutical companies who are developing new oral treatments for dystonia patients. Our Foundation will continue to support these efforts in any way possible.”

“We are excited to be kicking off this phase IIa POC clinical trail with dipraglurant in focal cervical dystonia,” said Tim Dyer, CEO of Addex. “Addex intends to initiate this study in the fourth quarter of 2016, and anticipates the availability of data in the second half of 2017. We are pleased to have Professor Jinnah, a world-renowned neurologist, serving as lead investigator for our study, and are grateful for the continued support from the Dystonia Medical Research Foundation.”

Dipraglurant has demonstrated positive anti-dystonic effects in multiple animal models of dystonia (behavioral and genetic, spontaneous and induced), as well as a positive anti-dystonia effect in Parkinson’s patients. Preclinical proof of concept has been established in multiple models of dystonia and preliminary clinical evidence of efficacy in levodopa induced dystonia has previously been observed.

“Dipraglurant has demonstrated robust efficacy in a phase II study in patients suffering from levodopa-induced dyskinesia associated with Parkinson’s disease which included patients suffering from dystonia,” said Sonia Poli, CSO of Addex. “This clinical data in Parkinson’s disease patients and preclinical data in multiple models of dystonia is highly supportive of studying dipraglurant in focal cervical dystonia.”

Dystonia is a neurological disorder characterized by persistent or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. The movements are usually patterned and twisting, and may resemble a tremor. Symptoms originate from an imbalance of neurotransmitters in the brain. There are multiple forms of dystonia, and up to 100 diseases and conditions include dystonia as a prominent symptom. Dystonia may affect a single body area or be generalized throughout multiple muscle groups. Dystonia affects men, women, and children of all ages and backgrounds. Estimates suggest that no fewer than 300,000 people are affected in the United States and Canada alone. Early onset isolated dystonia is rare and frequently has a genetic basis (e.g. DYT1) and can progress to affect several parts of the body. Dystonia causes varying degrees of disability and pain, from mild to severe.

Dipraglurant is an oral, small molecule allosteric modulator that inhibits selectively the metabotropic glutamate receptor 5 (mGluR5), a Class C G¬-Protein Coupled Receptor, with potential to be used in combination with levodopa or dopamine agonists or as a standalone treatment for Parkinson's disease levodopa ¬induced dyskinesia (PD¬LID), motor and non¬motor symptoms of Parkinson's disease and other movement disorders. In a double-¬blind, placebo-¬controlled, US and European phase II study in PD¬LID, data showed that dipraglurant met the primary objective of the study by exhibiting a good safety and tolerability profile. Dipraglurant also demonstrated a statistically significant reduction in LID severity with both 50 and 100 mg doses. Dipraglurant reduced dystonia severity in addition to chorea, the two major LID components. Efficacy was measured using the modified Abnormal Involuntary Movement Scale and patient diaries documenting "off¬-time" (impaired voluntary movement), "on-¬time" (with or without dyskinesia) and sleep. Additional endpoints include the Unified Parkinson's Disease Rating Scale, the Clinical and Patient Global Impression of Changes scales, and an evaluation of the patient’s mood using the Hospital Anxiety and Depression Scale. The trial was supported by a grant from The Michael J. Fox Foundation for Parkinson's Research.