Addex Reports Top-line Data from a Successful Phase 2a Clinical Study with ADX71149 in Schizophrenia Patients
• Key objectives achieved
• Safety and tolerability demonstrated
• Sub population identified for potential treatment with ADX71149
• ADX71149 dose with optimal benefit / risk identified
Geneva, Switzerland, 5 November 2012 - (SIX:ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced today top-line data from a successful Part B of the first-in-patient Phase 2a clinical study of ADX71149 in schizophrenia, that was conducted by Janssen Research & Development, LLC, on behalf of its affiliate Janssen Pharmaceuticals Inc. The data show that ADX71149 met the primary objectives of safety and tolerability. ADX71149 also demonstrated an effect in patients with residual negative symptoms. The 50mg b.i.d. dose was identified as having the optimal benefit/risk ratio in this study.
ADX71149 is an oral, selective, small molecule, positive allosteric modulator (PAM) of the metabotropic glutamate receptor 2 (mGluR2), a Class C G-Protein Coupled Receptor (GPCR), with potential to be used in the treatment of schizophrenia and the treatment of anxiety in patients suffering from major depressive disorder.
This first-in-patient study is being conducted in the EU, to determine the safety and tolerability of ADX71149 and to explore the potential clinical effect of this mGluR2 PAM in patients with schizophrenia. The study has two concurrent parts (A and B) and is designed to identify the patient populations most likely to benefit from treatment with ADX71149.
Part A: Safety, tolerability and efficacy of ADX71149 as monotherapy in the treatment of patients with sub-acute psychosis. This is a 12 week open-label treatment in 15 patients not on antipsychotic medication. Dose range from 50 mg b.i.d titrated up to 150 mg b.i.d. Part A is ongoing.
Part B: ADX71149 as adjunctive therapy to antipsychotics. This part of the study for which top-line data are being reported today, was a randomised double-blind, placebo-controlled trial designed to evaluate the safety, tolerability and exploratory efficacy of ADX71149, in 92 patients who were on stable doses of antipsychotic medication. The study population comprised 3 groups: patients with residual negative symptoms (n = 47); patients with residual positive symptoms (n = 25); and patients with insufficient response to clozapine treatment (n = 20). For the first 4 weeks of treatment all patients were randomised to receive either ADX71149 50 mg b.i.d, ADX71149 150 mg b.i.d or placebo, taken concomitantly with their currently prescribed antipsychotic medication (randomized 2:2:1).
"I am delighted that the study achieved its objectives of demonstrating good safety and tolerability and identifying the population of schizophrenia patients most likely to benefit from adjunctive treatment with ADX71149," noted Dr. Charlotte Keywood, CMO at Addex.
Negative symptoms (typically comprising apathy, social withdrawal, loss of emotional expression and sleep disorders) are common, and occur in up to 90% of patients with schizophrenia. Currently available drugs do not always provide effective control and many patients remain with substantial disability as a result. Therefore, effective treatment of negative symptoms is a major unmet medical need in the management of schizophrenia.
"We are extremely proud of our partnership with Janssen and greatly appreciate their continued commitment towards advancing ADX71149 and our mGluR2 PAM program in these psychiatric indications with significant unmet medical need," said Dr. Bharatt Chowrira, CEO at Addex. "These top-line results are a significant achievement for Addex and serve as further validation for our innovative oral small molecule allosteric modulation drug discovery technology platform."
The development of ADX71149 is part of a worldwide research collaboration and license agreement between Addex and Janssen Pharmaceuticals Inc. to discover, develop and commercialize novel mGluR2 PAM for the treatment of anxiety, schizophrenia and other undisclosed indications. Under the terms of the agreement, Addex is eligible for up to a total of €112 million in milestone payments upon potential development and regulatory achievements. In addition, Addex is eligible for low double-digit royalties on sales of mGluR2 PAM developed under the agreement.
Glutamate is a powerful transmitter in the brain and integral to the normal functioning of memory, learning and perception. Too much glutamate can lead to seizures and the death of brain cells. Too little glutamate can cause psychosis, coma and death. Glutamate exerts these effects by interacting with many receptors in the brain, especially NMDA and AMPA receptors. In addition to these primary receptors, glutamate triggers other receptors, termed metabotropic because they adjust the amount of glutamate that cells release rather than simply turning glutamate transmission on or off. In addition, there are eight types of metabotropic glutamate receptors (mGluR), each with different functions. Thus, these mGluRs, because of their ability to fine-tune glutamate signaling, appear to be attractive targets for drug treatment. Indeed, industry has been investing in mGluR research for about three decades and research shows that mGluR drugs have potential for the treatment of schizophrenia, anxiety, Parkinson's disease, fragile X syndrome, Alzheimer's disease, depression and post-traumatic stress disorder. The effects of positive allosteric modulators of mGluR2 are independent of dopamine receptors, indicating the potential for mGluR2 modulators to offer efficacy while avoiding the side effects associated with market leading antipsychotic drugs which appear to work predominantly via their effects on dopamine receptors. Furthermore, mGluR2 activation has shown efficacy in patients suffering from schizophrenia and, separately, anxiety.
Schizophrenia is a chronic progressive highly disabling and distressing disease which affects the way patients perceive the world around them, and profoundly decreases their ability to function normally. Symptoms are divided into three categories, positive, negative and cognitive. Positive symptoms reflect an excess or distortion of normal functions (delusions, hallucinations, thought disorder and disorganized behavior. Negative symptoms refer to a diminishment or absence of characteristics of normal function, and may appear with or without positive symptoms. Negative symptoms include loss of interest in everyday activities, appearing to lack emotion, reduced ability to plan or carry out activities, neglect of personal hygiene, social withdrawal and loss of motivation. Cognitive symptoms involve problems with thought processes and may be the most disabling in schizophrenia because they interfere with the ability to perform routine daily tasks. As a result, schizophrenia patients often withdraw from society and are unable to support themselves. The prevalence of schizophrenia is estimated at about 1% of the population worldwide. The prevalence of negative symptoms in first-episode psychosis is high, 50-90%, and 20-40% of schizophrenia patients have persisting negative symptoms. Estimates of the costs to society from schizophrenia run at approximately $65 billion per year in the United States, despite the use of antipsychotic drugs. Notwithstanding their over $15 billion in annual sales, not all of the currently marketed antipsychotic drugs fully address the negative symptoms of schizophrenia, such as anxiety, depression and cognitive dysfunction. In addition, marketed antipsychotic drugs may cause side effects, including sedation, extrapyramidal symptoms (impairment of control of movements), hormonal imbalances leading to hyperprolactinemia and weight gain.
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 2 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 in collaboration with Janssen Pharmaceuticals Inc. to treat schizophrenia and anxiety seen in patients suffering from major depressive disorder. Addex also is advancing several preclinical programs including: GABA-BR PAM for spasticity in MS, OAB and other disorders; mGluR4 PAM for Parkinson's, MS, anxiety and other diseases. In addition, Addex is applying its proprietary discovery platform to identify highly selective and potent allosteric modulators of a number of both GPCR and non-GPCR targets that are implicated in diseases of significant unmet medical need.
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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 Therapeutics, formerly known as, Addex Pharmaceuticals, 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 Therapeutics 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, GABA-BR 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, GABA-BR or other therapeutics targets 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, GABA-BR 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, GABA-BR 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 Therapeutics 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.
Posted: November 2012