Addex Reports Positive Top Line Phase IIa Data for Dipraglurant in Parkinson's Disease Levodopa-Induced Dyskinesia (PD-LID)
Geneva, Switzerland, 21 March 2012 - Addex Therapeutics (SIX:ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced today positive top line data from a Phase IIa clinical study of dipraglurant in Parkinson's disease (PD) patients suffering from debilitating levodopa-induced dyskinesia (LID). The data show that dipraglurant met the primary objective of the study by exhibiting a good safety and tolerability profile. Dipraglurant also demonstrated statistically significant reduction in LID severity with both 50mg and 100mg doses. Dipraglurant appears to reduce dystonia severity in addition to chorea, the two major LID components. A full analysis of the data will be presented at a scientific forum in 2012.
Dipraglurant is an oral, small molecule allosteric modulator that inhibits selectively the metabotropic glutamate receptor 5 (mGluR5), a Class C G-Protein Coupled Receptor (GPCR), with potential to be used in combination with levodopa or dopamine agonists or as a standalone treatment for PD-LID, PD-related motor symptoms, non-motor symptoms of PD and other movement disorders.
The Coordinating Investigator of the dipraglurant study, Olivier Rascol, MD, PhD, Professor of Clinical Pharmacology at the Toulouse University Hospital, and one of the world's leading experts on treating Parkinson's disease commented: "There is no drug approved for the treatment of PD-LID and dipraglurant is an exciting new approach. The study was successful in achieving the primary objective of good safety and tolerability. In addition, these proof of concept data are promising and warrant further investigation of dipraglurant in Parkinson's disease."
In this double-blind, placebo-controlled study conducted in the US and Europe, the primary objective was to demonstrate safety and tolerability in PD-LID patients. In addition, the trial was designed to evaluate exploratory efficacy as a secondary objective. Efficacy was measured using the modified Abnormal Involuntary Movement Scale (mAIMS), 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 (UPDRS), the Clinician & Patient Global Impression of Change (CGIC & PGIC), and an evaluation of the patients' mood using the Hospital Anxiety & Depression Score. The trial was supported by a grant from The Michael J. Fox Foundation for Parkinson's Research.
"Dyskinesia is a top priority for our Foundation because of its significant negative impact on patients' quality of life," said Todd Sherer, PhD, CEO of The Michael J. Fox Foundation. "A successful treatment for PD-LID will change the way Parkinson's disease is treated by enabling physicians to use levodopa earlier and more effectively. To this end, since 2006, we have been funding research on mGluR5 inhibition as one of the most promising potential treatments for LID. We are proud to have been involved in funding this trial of dipraglurant by Addex, which is at the forefront of this effort."
A total of 76 male and female patients (dipraglurant, n = 52; placebo, n = 24) with moderate or severe PD-LID were randomized into the study. Patients followed a dose-titration regimen, receiving 50mg doses from Day 1 to Day 14 and then 100mg from Day 14 until Day 28. This first-in-patients study met its primary objective of demonstrating safety and tolerability in patients with PD. There were no significant changes in any safety monitoring parameters and, in particular, no changes in liver function tests were seen in either treatment group. Both the 50mg and 100mg dose levels were well tolerated. The incidence of adverse events was similar in both active and placebo groups (88.5% for dipraglurant versus 75% for placebo). Typical mGluR5-type adverse events (vertigo, visual disturbance, feeling drunk) were seen in less than 10% of patients in the dipraglurant group but were not severe or dose limiting.
Exploratory efficacy data showed an anti-dyskinetic effect on observer evaluated mAIMS and in patient reported diary data. Both the 50mg and 100mg doses of dipraglurant showed a statistically significant reduction in LID. Peak mAIMS was significantly reduced on Day 1 (50mg; p = 0.042) and on Day 14 (100mg; p = 0.038). The targeted magnitude of effect of either a 30% reduction in mAIMS or a 20% separation from placebo was achieved on Days 1, 14 and 28. The magnitude of reduction in mAIMs was maintained for dipraglurant on Day 28 (100mg), but not statistically significant due to an increase in placebo response on that day. Similar results were seen for the area under the curve (AUC) mAIMS evaluation in the total 3 hour post levodopa dosing period, with about a 30% reduction in the dipraglurant group at Days 14 and 28, which was statistically significant at Day 14 (p = 0.042). In a subset of patients with levodopa-induced dystonia, dipraglurant appears to have reduced dystonia severity. The UPDRS Part III (motor scores) performed during mAIMS evaluation, indicated that dipraglurant did not interfere with levodopa efficacy.
Patient-reported, diary data supported the objective, observer-reported mAIMS data, with an increase in daily on-time without dyskinesia up to twice that of placebo; i.e. dipraglurant patients had as much as 70 minutes more on-time without dyskinesia than placebo patients. Furthermore, during Week 4, patients reported a reduction in daily off-time of 50 minutes, suggesting an effect on parkinsonian motor symptoms in addition to the observed reductions in LID. Patients and clinicians tended to favor dipraglurant treatment for dyskinesia with a higher percentage reporting improvement for the dipraglurant group, as measured by the PGIC and CGIC.
"These data for dipraglurant are positive and we are pleased to have demonstrated robust proof of concept," said Charlotte Keywood, MD, Chief Medical Officer of Addex. "Both dipraglurant doses had a good safety and tolerability profile and demonstrated efficacy. The increase in on-time without dyskinesia, combined with the decrease in off-time observed during week 4, is encouraging, and warrants further evaluation. It's particularly promising that the significant reduction in dyskinesia severity on the mAIMS was mirrored by a reduction in patient reported dyskinesia time and that both clinicians and patients favoured dipraglurant over placebo."
A successful treatment for PD-LID would change the way Parkinson's disease is treated, by enabling physicians to use the most effective drug for Parkinson's disease - levodopa - earlier and more aggressively, according to market research carried out by Datamonitor for Addex. In addition, based on robust preclinical data, potential label expansions for dipraglurant include: PD motor symptoms and/or non-motor symptoms, like co-morbid anxiety and depression, as well as non-parkinsonian dystonias.
"Addex is leading the effort in developing this potential breakthrough therapy, which could change the treatment paradigm for Parkinson's disease," said Dr. Bharatt Chowrira, CEO of Addex. "With these promising positive data in hand, we intend to seek a partner to progress dipraglurant to the market as rapidly as possible."
While dipraglurant has broad potential for treating Parkinson's and other diseases, the most direct path to market is treatment of PD-LID. No drug is approved for PD-LID and LID has been identified by the regulatory authorities, patient advocacy groups, such as The Michael J. Fox Foundation, and key opinion leaders as a very important unmet medical need. The potential market opportunity for dipraglurant in Parkinson's disease is well in excess of $1 billion, according to Datamonitor. Potential label expansions could more than double the peak sales potential for dipraglurant.
Dyskinesia & PD
PD is a chronic, progressive neurological disorder that affects one in 100 people over the age 60 but as young as 18. Approximately 7.5 million people worldwide are suffering from this neurodegenerative disorder. The most commonly administered drug to treat Parkinson's symptoms is levodopa (also called L-dopa), which helps restore levels of dopamine, a chemical messenger in the brain. Following prolonged use, approximately 80 percent of patients treated with levodopa will develop uncontrollable movements, i.e. dyskinesias, a major source of disability in their lives.
To learn about dyskinesia, listen to this podcast featuring Dr. Sherer and produced by The Michael J. Fox Foundation for Parkinson's Research or find additional information on PD at the Foundation's website.
There is increasingly convincing evidence that mGluR5 inhibition may be a valuable new strategy for treating Parkinson's disease. Recent clinical and preclinical research show that mGluR5 inhibition alleviates PD-LID. Clinical and preclinical evidence suggest that mGluR5 inhibition also may have an effect on parkinsonian motor symptoms. mGluR5 is found in regions of the brain considered to be key control points in the neuronal movement circuits affected by abnormal signaling by the neurotransmitter glutamate in PD. Perturbations in glutamate signaling (along with disruptions in dopaminergic signaling) are believed to be an underlying cause of movement disorders like Parkinson's disease. As such, inhibiting mGluR5 could act to re-establish normal movement via a non-dopaminergic mechanism. Separately, preclinical findings also suggest that mGluR5 inhibitors may be neuroprotective and may, therefore, hold potential as disease modifying agents that can slow or prevent progression of PD. The mGluR5 inhibition mechanism also has achieved validation for other indications including, anxiety, depression, pain and Fragile X syndrome.
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Addex Therapeutics (www.addextherapeutics.com) discovers and develops an emerging class of small molecule drugs, called allosteric modulators, which have the potential to be more specific and confer significant therapeutic advantages over conventional "orthosteric" small molecule or biological drugs. The Company uses its proprietary discovery platform to address receptors and other proteins that are recognized as attractive targets for modulation of important diseases with unmet medical needs. The Company's two lead products are being investigated in Phase II clinical testing: dipraglurant (ADX48621, an mGluR5 negative allosteric modulator or NAM) is being developed by Addex to treat Parkinson's disease levodopa-induced dyskinesia (PD-LID); and ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed by our partner Janssen Pharmaceuticals Inc. to treat schizophrenia. Addex also is advancing several preclinical programs including: GABA-BR PAM for pain, overactive bladder and other disorders; mGluR4 PAM for Parkinson's, anxiety and other diseases; GLP1R PAM for type 2 diabetes; mGluR2 NAM for treating Alzheimer's disease and depression; and FSHR/LHR NAM for sex hormone dependent tumors & reproductive system disorders. In addition, Addex has discovery programs to identify allosteric modulators of: receptor tyrosine kinase (RTK) superfamily, including TrkB PAM for treating neurodegenerative diseases (e.g. Alzheimer's, Parkinson's and Huntington's diseases); and TNF receptor superfamily, including TNFR1 NAM for inflammation (e.g. rheumatoid arthritis) and other diseases.
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