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MDD drug with new mechanism of action tested in Phase 2a trials
GENEVA, Switzerland—AddexTherapeutics, a company pioneering allosteric modulation-based drug discovery and development, announced today top-line data from a Phase 2a clinical study of ADX71149 in anxious depression, conducted by Janssen Research & Development, LLC, on behalf of its affiliate Janssen Pharmaceuticals, Inc. Overall, ADX71149 was well-tolerated and treatment emergent adverse events reported were similar to those seen in previous clinical studies. Based on a preliminary analysis of the primary efficacy end point, the 6-Item Hamilton Anxiety Subscale, (HAM-A6), ADX71149 did not meet the criterion for efficacy signal detection versus placebo. Despite a lack of signal on the primary outcome measure, treatment with ADX71149 showed efficacy signals on several anxiety measures (HDRS17 anxiety somatization factor, IDS-C30 anxiety subscale) and on all depression measures (HDRS17, HAM-D6 and IDS-C30). This study will be presented by Janssen at a future scientific meeting and submitted for publication in a peer-reviewed medical journal.
Although efficacy signals were evident, overall the data does not support the further development of ADX71149 in anxious depression. Further exploration of ADX71149 in other indications remains of potential interest, Addex said in a news release.
"This proof-of-concept study was testing a new mechanism of action in an MDD subpopulation (anxious depression) that had not been studied in clinical trials to date. We greatly appreciate the efforts and resources that our partner, Janssen has deployed to further our understanding of this mechanism and advance the program," said Tim Dyer, CEO at Addex. "In the coming months we will work with Janssen to identify the best future development path for the program."
This was a multicenter, double-blind, placebo-controlled, flexibly-dosed study of adjunctive ADX71149 in adults with major depressive disorder (MDD) with significant anxiety symptoms. The primary objective was to evaluate efficacy, as assessed by change from baseline on a 6-item subscale of the Hamilton Anxiety Scale (HAM-A6), and overall safety and tolerability of treatment with adjunctive ADX71149 compared to placebo in subjects with MDD with anxiety symptoms being treated with an SSRI or SNRI. Secondary outcome measures included those assessing depressed mood (HDRS17; IDS-C30, HAM-D6), and anxiety (HAM- A-14; HDRS17 anxiety somatization factor, IDS-C30 anxiety subscale).
The study consisted of three phases: a screening phase of up to 2 weeks, an 8-week double-blind treatment phase (included two 4-week treatment periods), and a 2-week post-treatment (follow up) phase. Following an initial fixed up-titration from 25mg to 50mg twice daily, ADX71149 was dosed flexibly in the range of 50mg to 150mg, also twice daily. Of the 121 randomized subjects, 100 subjects (82.6 percent) completed the 8-week double blind treatment phase.
ADX71149 is a novel, first-in-class potent, oral, small molecule positive allosteric modulator (PAM) of metabotropic glutamate receptor 2 (mGlu2), a Family C class of G Protein Coupled Receptor (GPCR). 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 a novel mGlu2 PAM medication 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 (approximately $151 million) in milestone payments based on potential development and regulatory achievements. In addition, Addex is eligible for low double-digit royalties on sales of any mGlu2 PAM medication developed under the agreement.
Perhaps surprisingly, according to a 2008 report by the World Health Organization (WHO) unipolar depression is the leading cause of disability worldwide (2008 WHO Global Burden of Disease Report) and anxiety symptoms are commonly reported in major depressive disorder (MDD) patients. Around 85 percent of adults with MDD exhibit significant anxiety symptoms (Gorman, 1996); and approximately 50 percent of outpatients with MDD have a comorbid anxiety disorder, 58 percent lifetime (Fava et al., 2000; Kessler et al., 1996). Co-morbid anxiety results in more severe depressive symptoms, increased suicide risk, more chronic course, poorer and slower treatment response, greater functional and occupational impairment, increased societal burden/socioeconomic costs and increased health care utilization. The first line treatments for MDD patients with co-morbid anxiety are SSRIs and SNRIs; however, this subpopulation is less responsive and continues to represent a great unmet need. Adjunctive treatments to SSRIs/SNRIs for anxious depression result in significant added side-effect burden and are often poorly tolerated in long term treatment. The STAR*D clinical study, the largest effectiveness study evaluating next-step therapies in real-world patients with major depressive disorder, showed that patients with anxious depression were less likely to achieve remission or respond to treatment than those with non-anxious depression (Fava et al. 2008).
Addex Therapeutics is a development stage company focused on advancing innovative oral small molecules against rare diseases utilizing its pioneering allosteric modulation-based drug discovery platform. The company's two lead products are being investigated in Phase 2 clinical testing: dipraglurant (an mGlu5 negative allosteric modulator or NAM) is being developed by Addex to treat Parkinson's disease levodopa-induced dyskinesia (PD-LID) and rare forms of dystonia; and ADX71149 (mGlu2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc. Addex also has several preclinical programs including: GABAB receptor positive allosteric modulator (PAM) for addiction, Charcot-Marie-Tooth (type 1a) disease, spasticity in patients with multiple sclerosis (MS), pain, overactive bladder and other disorders; and mGlu4 PAM for MS, Parkinson's disease, anxiety and other diseases. Allosteric modulators are an emerging class of small molecule drugs 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 target receptors and other proteins that are recognized as essential for the therapeutic modulation of important diseases representing unmet medical needs.