DRUG DISCOVERY AND DEVELOPMENT 25
which received matching placebo for one night. Te objective of the study was to further explore safety and tolerability in the sleep apnea population, as well as to assess putative efficacy of CX1739 on a range of sleep apnea parameters assessed by overnight polysomnography.
“Te results from this pilot study are encouraging, and warrant undertaking a larger clinical study to better understand the sleep apnea patient population most responsive to the treatment of CX1739.”
Oxygen saturation Te study demonstrated that selected oxygen saturation parameters were statistically improved by one dose of CX1739, but the interpretation of these results was complicated by a reduced sleep time during the night following drug treatment. CX1739 did not reduce the mean apnea/hypopnea index (AHI; frequency of apnea or hypopnea events per hour of sleep). However, in the AHI responder analysis, defined as a greater than 40 per cent reduction in the AHI, three subjects (20 per cent) in the CX1739 treatment group were responders, and there were no responders in the placebo group. Furthermore, CX1739 significantly (p<0.05)
reduced the apnea/hypopnea time (AHT; cumulative time of all apneas and hypopneas over the night) between the baseline and the treatment night by an average of 21 min, compared to an increase of 12 min in the placebo group. In the AHT responder analysis, defined as a greater than 40 per cent reduction in the AHT, five subjects (30 per cent) in the drug treatment group were responders, with no AHT responders in the placebo group. Tere were also statistically significant improvements in a number of blood oxygenation measurements: mean blood oxygen saturation was increased (p<0.01); minimum blood oxygen saturation was increased (p < 0.001); there was a reduction in the total time that blood oxygen saturation was reduced below 90 per cent (p<0.01); and a reduction of the number of times per hour of sleep time that the blood oxygen saturation went below 90 per cent (p<0.05).
Sleep efficiency, the per cent of time asleep in bed for the eight hour session, was (p<0.001) reduced by about 20 per cent after CX1739, although the level of daytime sleepiness, determined by the Clinical Global Impressions Daytime Vigilance test, given the morning following treatment, was unaffected by CX1739.
CX1739 was safe but the dose appeared to be near the limits of tolerability when administered just before bedtime to this moderately overweight (mean BMI >31), middle-aged (~50yrs) group of sleep apnea subjects. Tere were no serious adverse events and no clinically relevant changes in vital signs, cardiovascular or other safety assessments. Adverse events were generally mild to moderate and no new unexpected adverse events were seen.
Te single centre study was a double-blind, placebo-controlled design. Subjects who met inclusion/ exclusion and other eligibility criteria were screened for sleep apnea severity by polysomnography during an overnight stay in the clinic sleep laboratory. Acceptable subjects returned for a second overnight polysomnography session and those subjects who met certain consistency criteria on key sleep apnea parameters between screening and baseline polysomnogram nights were enrolled and returned to the sleep clinic for a third overnight polysomnography session when they randomly received a single dose of either CX1739 (900mg) or matching placebo capsules in a four to one ratio just prior to the beginning of the sleep session.
Predicting binding affinities in drug discovery
A German scientist consortium just completed a milestone achievement on the way to a very elegant solution to the so-called ‘scoring problem’ – the prediction of binding affinity in drug discovery. The new method, HYDE, is said to
perform significantly better than those currently available; experts expect a productivity boost for the early phases of the costly drug discovery. Exclusive sales of HYDE are to be conducted by premium software maker BioSolveIT Ever since the 80s when the first
computer methods emerged, computer predictions of the strength of binding of small molecules in a protein cavity
have so far largely failed, even when employing enormously long compute times. Professor Matthias Rarey from the
Center for Bioinformatics (ZBH) at the University of Hamburg, consortium member and world renowned expert in the field says: “When we first started this research project almost seven years ago, scientists all over the world were already engaged in the quest for improved scoring functions for more than a decade. It was clear to me that that we had to devise completely new ways to approach this problem. At that time, the key idea for HYDE was introduced to me by Dr Gudrun Lange and colleagues at
Bayer CropScience. Dr Lange suggested a hitherto unknown, unified description of the most important driving forces to complex formation. This was the basis on which the consortium started to develop HYDE.” BioSolveIT’s premium docking
suite FlexX, an industry standard for structure-based design, served as the basis of the HYDE implementation. After mastering dozens of seemingly insurmountable hurdles along the way, the development partners ZBH, Bayer CropScience (ISIN DE0005752000 / WKN 575200), and BioSolveIT finally mastered the consistent description of hydrogen bonding, the hydrophobic
effect, and desolvation using a single, concise formula. Early drug discovery applications
of HYDE have been reported as being extremely successful. Dr Lange presented at the ICCS conference in 2008 hit rates of up to 70 per cent in real-life projects. At this year’s National ACS Meeting in Anaheim, CA, the successful application of HYDE on several benchmark data sets was reported. FlexX/Hyde ranks among the top-tier computer programs and outperforms the competition on many targets.
For more information, visit
www.biosolveit.de
www.scientistlive.com
Te Principal Investigator of the study, Adrian J Williams, FRCP, Dip AASM, Professor of Sleep Medicine at King’s College, London commented: “Te results from this pilot study are encouraging, and warrant undertaking a larger clinical study to better understand the sleep apnea patient population most responsive to the treatment of CX1739.”
Mark Varney, PhD, President and Chief Executive Officer of Cortex stated: “A single dose of CX1739 improved a number of sleep apnea parameters across most of the 16 subjects who were given the drug, and there were some CX1739- treated subjects who demonstrated a robust reduction in sleep apnea symptoms.
“We may find that repeated daily treatment with CX1739 for several weeks may provide additional benefit over a single dose and improve sleep apnea symptoms in those subjects who did not respond after a single dose. Additionally, testing this drug in a population which suffers from predominantly central apneas also appears to hold some potential for Cortex.”
Cortex Pharmaceuticals Inc is based in Irvine, CA, USA.
www.cortexpharm.com
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44