Development of ADX10059 Ended for Long-term Use
Geneva, Switzerland, 15 December 2009 – Addex Pharmaceuticals (SIX:ADXN) announced today that based on preliminary review of the unblinded data from study 206, it has terminated development of ADX10059 for chronic indications, including long term treatment of gastroesophageal reflux disease and migraine prophylaxis.
In study 206 the incidence of alanine transaminase (ALT) levels greater than five times the upper limit of normal (>5xULN) levels was 6% (16 of 257 patients); however, bilirubin remained normal in all but one patient. The elevation of ALT occurred in all dose groups and appears to be related to the duration of dosing. The incidence was 3.9% (10 patients) in the 100 mg group; 0.8% (2 patients) in the 50 mg group; 1.6% (4 patients) in the 25 mg group. No abnormalities of liver function were observed in the placebo group.
A rise in transaminases to >5x ULN is considered to be predictive of a potential for drug induced liver injury. As these significant elevations in ALT have been observed in all the dose groups, Addex considers that future development of ADX10059 for long term use appears unlikely. The company will evaluate potential development options based on the complete analysis of the data from study 205, a 4-week study in GERD patients, which will report top-line data in early January.
Study 205 is still blinded however, a review of blinded safety data show an incidence of ALT >5x ULN of 0.6% (2 of 295 patients). This is in-line with expectations for this type of study.
“The occurrence of liver function abnormalities in patients receiving the lowest dose, makes future development of this compound difficult, especially for long term use,” said Charlotte Keywood, chief medical officer.
“We have cash for operations until the end of 2011 and plan to focus our efforts on development of ADX48621, which has completed Phase I testing and is scheduled to start Phase II testing for the treatment of Parkinson’s disease levodopa induced dyskinesia in the fourth quarter of 2010,” said Vincent Mutel, chief executive officer. “We also will accelerate development of selected programs in discovery and preclinical development and continue to leverage our unique discovery and development platform for allosteric modulator drugs.”
No liver function abnormalities have been seen in any of the previously reported clinical trials, several of which explored higher doses, including the recently reported study ADX10059-204, a 2-week study of monotherapy in 103 GERD patients. Study 205 a 4-week study of ADX10059 as an add-on therapy to PPIs in GERD patients, is due to un-blind around the end of the year and data will be reported in January.
A webcast and conference call will be held at 2pm CET (8am ET) today, December 15. Please see www.addexpharma.com or use the following dial-in numbers:
+41 91 610 56 00 (Europe)
+44 207 107 06 11 (UK)
+1 866 291 41 66 (USA)
Study ADX10059-206 is a double-blind, placebo-controlled, dose range finding, multi-center European Phase IIb trial in 240 patients who suffer from three or more migraine attacks per month. Following a one-month baseline period, patients take study medication for 3 months. The primary endpoint compares migraine frequency and severity in the last month of treatment with the baseline. The data are being un-blinded and will be analyzed and any indications of efficacy will be reported in early January.
Study ADX10059-205 is a double-blind, placebo-controlled, multi-center U.S. and European Phase IIb trial in 280 GERD patients who are partial responders to proton pump inhibitors (PPIs). In Study 205 ADX10059 is being used as an add-on therapy to the patients’ existing PPI treatment. There was a baseline symptom evaluation period followed by four weeks of administration of twice-daily ADX10059 (50mg, 100mg or 150mg). The primary endpoint is patient reported symptom control compared to baseline. Data are expected to be communicated in early January.
Study ADX10059-204 was a double-blind, placebo-controlled, multi-center European Phase IIb trial in 103 GERD patients known to respond well to PPIs. There was a two-week baseline symptom evaluation period followed by two weeks of administration of ADX10059 120 mg twice daily. ADX10059 achieved the co-primary endpoints of patient reported symptom control compared to baseline and the effects of ADX10059 on lower esophageal sphincter (LES) function as well as multiple secondary endpoints. There were no serious adverse events in the study and safety monitoring parameters were within normal limits. Mild or moderate adverse events included dizziness, vertigo and sleep disturbance.
Migraine is a condition distinguished by recurrent episodes of a characteristic headache, which can be accompanied by a variety of other symptoms such as nausea, and sensitivity to light and sound. The average migraine patient suffers 12 attacks a year. The International Headache Society estimates that about 25% of migraine patients have three or more attacks per month and could benefit from migraine prevention treatment. A migraine attack, which typically lasts about 24 hours but can range from 4-72 hours, has three distinct phases: the prodrome phase, when an array of individual warning signs - like blurred vision or tingling of the skin - may begin to appear; the headache phase; and the postdrome phase, when many patients report fatigue or other “hangover-like” symptoms. As migraine attacks are prolonged, many patients and especially those with frequent attacks, lose a significant amount of work and family time to suffering caused by the disease. Indeed, migraine is currently estimated to cost employers $13 billion annually in lost productivity in the United States. Prevalence of migraine is estimated at 12% in the United States, where about 30 million people suffer from migraine.
GERD (gastroesophageal reflux disease) is a chronic condition caused by stomach contents flowing back into the esophagus on a regular basis. The underlying cause of this is an abnormally functioning lower esophageal sphincter (LES) muscle that allows stomach contents to pass back into the esophagus too easily. GERD leads to painful symptoms like heartburn and can also damage the lining of the esophagus. It is a common disorder with prevalence at about 15% in the United States and between 10% and 25% in EU. Marketed GERD products work by reducing the acidity of the stomach contents but do nothing to reduce reflux events, so that in many patients symptoms of GERD persist.
ADX10059 is a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator (NAM). Glutamate overstimulation is thought to contribute via different mechanisms to pathology in both migraine and GERD. ADX10059 has been shown in clinical studies to reduce symptoms of acute migraine and, separately, to reduce reflux and GERD symptoms.
Addex Pharmaceuticals (www.addexpharma.com) discovers and develops allosteric modulators for human health. Allosteric modulators are a different kind of orally available small molecule therapeutic agent, which we believe will offer a competitive advantage over classical drugs. Our lead allosteric modulator product, ADX10059, an mGluR5 negative allosteric modulator (NAM), has achieved clinical proof of concept and is in Phase IIb testing for the treatment of GERD and, separately, migraine prevention. ADX48621, our next-stage mGluR5 NAM, has completed Phase I testing and will enter Phase II for Parkinson’s disease levodopa-induced dyskinesia (PD-LID) in 2010.
Our products and technology already have proven their value through our relationships with four of the top 10 pharmaceutical companies in the world. Specifically, under an agreement with Ortho-McNeil-Janssen Inc., a Johnson & Johnson company, ADX71149, an mGluR2 positive allosteric modulator (PAM), is undergoing Phase I clinical testing and has potential for treatment of schizophrenia and anxiety. Under two separate agreements with Merck & Co., Inc., we are developing PAMs of mGluR4 and mGluR5 as drugs to treat Parkinson's disease and schizophrenia, respectively. In addition, SR-One, the corporate venture arm of GlaxoSmithKline, and Roche Venture Fund have made equity investments in Addex.
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Disclaimer: The foregoing release contains 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, and involve known and unknown risks, uncertainties and other factors that may cause actual results with allosteric modulators of mGluR4, mGluR2, mGluR5 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 mGluR4, mGluR2 or mGluR5 will be approved for sale in any market or by any regulatory authority. Nor can there be any guarantee that allosteric modulators of mGluR4, mGluR2, mGluR5 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 mGluR4, mGluR2, mGluR5 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 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.