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(12) United States Patent (10) Patent No.: US 9,561.236 B2 Wilhelm-Ogunbiyi Et Al

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(12) United States Patent (10) Patent No.: US 9,561.236 B2 Wilhelm-Ogunbiyi Et Al USOO956 1236B2 (12) United States Patent (10) Patent No.: US 9,561.236 B2 Wilhelm-Ogunbiyi et al. (45) Date of Patent: Feb. 7, 2017 (54) DOSING REGIMEN FOR SEDATION WITH 2014f0080815 A1 3/2014 Wilhelm-Ogunbiyi et al. 2015,0006104 A1 1/2015 Okada et al. CNS 7056 (REMIMAZOLAM) 2015,0148338 A1 5, 2015 Graham et al. 2015,02241 14 A1 8, 2015 Kondo et al. (75) Inventors: Karin Wilhelm-Ogunbiyi, Simmerath 2015,0368.199 A1 12/2015 Tilbrook et al. (DE); Keith Borkett, Houghton Camps 2016,0009680 A1 1/2016 Kawakami et al. (GB); Gary Stuart Tilbrook, 2016,0176881 A1 6, 2016 Tilbrook et al. Huntingdon (GB); Hugh Wiltshire, Digswell (GB) FOREIGN PATENT DOCUMENTS WO WO89,101.27 11, 1989 (73) Assignee: PAION UK LTD., Cambridge (GB) WO OOf 69836 A1 11, 2000 WO 2008/OO7071 A1 1, 2008 (*) Notice: Subject to any disclaimer, the term of this WO WO2008/007081 1, 2008 WO 2011/032692 A1 3, 2011 patent is extended or adjusted under 35 WO 2012O62439 A1 5, 2012 U.S.C. 154(b) by 540 days. (21) Appl. No.: 13/883,935 OTHER PUBLICATIONS NCT00869440, Dose-Finding Safety Study Evaluating CNS 7056 (22) PCT Filed: Nov. 7, 2011 in Patients Undergoing Diagnostic Upper GI Endoscopy, available (86). PCT No.: PCT/EP2011/005581 at https://www.clinicaltrials.gov/ct2/show? NCT00869440?term=CNS+7056&rank=2, update dated Sep. 8, S 371 (c)(1), 2010.* (2), (4) Date: Sep. 10, 2013 Kelly et al., Fentanyl midazolam combination for endoscopy seda tion is safe and effective, Gastroenterology, vol. 114, Apr. 15, 1998, (87) PCT Pub. No.: WO2012/062439 p. A22.* Worthington et al., S1399: A Phase IB Study of the Safety and PCT Pub. Date: May 18, 2012 Efficacy of Multiple Doses of CNS 7056 in Volunteers Undergoing (65) Prior Publication Data Colonoscopy, Including Reversal With Flumazenil, Gastrointestinal Endoscopy, vol. 71, Issue 5, Apr. 2010, pp. AB151.* US 2014f008O815 A1 Mar. 20, 2014 International Search Report issued by the European Patent Office in International Application PCT/EP2011/005581. (30) Foreign Application Priority Data “Dose-Finding Safety Study Evaluating CNS 7056 in Patients Undergoing Diagnostic Upper GI Endoscopy, in: Clinical Trials. Nov. 8, 2010 (EP) ..................................... 1OO14366 gov, Anonymous, Sep. 8, 2010. Nov. 19, 2010 (EP). ... 1 OO14784 Kelly, A. et al.: “Fentanyl Midazolam Combination for Nov. 22, 2010 (EP). ... 10014819 endoscopy . .” Gastroenterology, vol. 114, Apr. 1998, p. A22, Nov. 25, 2010 (EP) ..................................... 1 OO14972 Elsevier, Philadelphia, PA. Paion's Phase IIb Study With Its Anaesthetic/Sedative Remimazolam (CNS 7056) Ahead of Schedule, Aug. 2, 2010, p. 1-2, (51) Int. Cl. http://www.paion.com/images/stories/investoren? A 6LX 3/557 (2006.01) finanznachrichten/2010/en/paionp100802en.pdf. A6 IK 3/4468 (2006.01) U.S. Appl. No. 14402,590, filed Nov. 20, 2014, John Aitken A6 IK 45/06 (2006.01) Graham. (52) U.S. Cl. U.S. Appl. No. 14/772.203, filed Sep. 2, 2015, Yuji Kawakami. CPC ....... A6 IK3I/55.17 (2013.01); A61K 31/4468 U.S. Appl. No. 13/496,742, filed Aug. 30, 2015, Gary Stuart (2013.01); A61K 45/06 (2013.01) Tilbrook. (58) Field of Classification Search U.S. Appl. No. 14/424,340, filed Feb. 26, 2015, Maki Kondo. None (Continued) See application file for complete search history. (56) References Cited Primary Examiner — Svetlana M. Ivanova (74) Attorney, Agent, or Firm — Nelson Mullins Riley & U.S. PATENT DOCUMENTS Scarborough LLP; Jane E. Remillard, Esq.; Cynthia L. Kanik 7,160,880 B1 1/2007 Feldman et al. 7,435,730 B2 10/2008 Feldman et al. 7,473,689 B2 1/2009 Feldman et al. 7,485,635 B2 2/2009 Feldman et al. (57) ABSTRACT 7,528,127 B2 5, 2009 Feldman et al. 8,642.588 B2 2/2014 Tilbrook et al. The invention relates to a dosing regimen for sedation with 9,156,842 B2 10/2015 Tilbrook et al. the fast-acting benzodiazepine CNS 7056 in combination 9, 193,730 B2 11/2015 Tilbrook et al. with an opioid, in particular fentanyl, whereas CNS 7056 is 9,512,078 B2 12/2016 Tilbrook et al. 2007/0093475 A1 4/2007 Feldman et al. given in a dose of 2 to 20 mg, preferably between 4 and 9 2010.0075955 A1 3/2010 Tilbrook mg and most preferably between 5 and 8 mg. 2010.0081647 A1 4/2010 Tilbrook 2011 O294.843 A1 12/2011 SOHngen et al. 2012/0330007 A1 12/2012 Tilbrook 32 Claims, 7 Drawing Sheets US 9,561.236 B2 Page 2 (56) References Cited Stafford, J.A. et al. “Identification and structure-activity studies of novel ultrashort-acting benzodiazepine receptor agonists.” Bioorg. Med. Chem. Lett., vol. 12(21):3215-3218 (2002). OTHER PUBLICATIONS Upton, R.N., et al., “Comparison of the sedative properties of CNS .S. Appl. No. 12/373,472, filed Nov. 2, 2009, Gary Stuart Tilbrook. 7056, midazolam, and propofol in sheep,” Br. J. Anaesth., vol. 103(6):848-857 (2009). .S. Appl. No. 14/746,026, filed Jun. 22, 2015, Gary Stuart Bodor, N. et al., “Soft Drug Design: General Principles and Recent ilbrook. Applications.” Medicinal Research Reviews, vol. 20(1):58-101 .S. Appl. No. 14/948,889, filed Nov. 23, 2015, Gary Stuart (2000). ilbrook. Antonik, L. J. et al., “A Placebo- and Midazolam-Controlled Phase .S. Appl. No. 1 1/634,788, filed Dec. 5, 2006, Paul L. Feldman. I Single Ascending-Dose Study Evaluating the Safety, .S. Appl. No. 09/980,680, filed Oct. 31, 2001, Paul L. Feldman. Pharmacokinetics, and Pharmacodynamics of Remimazolam (CNS .S. Appl. No. 1 1/650,635, filed Jan. 5, 2007, Paul L. Feldman. 7056): Part I. Safety, Efficacy, and Basic Pharmacokinetics.” Anes .S. Appl. No. 12/373,457, filed Nov. 13, 2009, Gary Stuart thesia & Analgesia, vol. 115 (2): 274-283 (2012). Upton, R. N. et al., “Pharmacokinetics and pharmacodynamics of ilbrook. the short-acting sedative CNS 7056 in sheep.” British Journal of .S. Appl. No. 14/841,899, filed Sep. 1, 2015, Gary Stuart Tilbrook. Anaesthesia, vol. 105(6):798-809 (2010). .S. Appl. No. 13/124,476, filed Aug. 30, 2012, Gary Stuart Upton, R.N., et al., “A dose escalation study in sheep of the effects ilbrook. of the benzodiazepine CNS 7056 on sedation, the EEG and the .S. Appl. No. 15/336,143, filed Oct. 27, 2016, Gary Stuart respiratory and cardiovascular systems.” British Journal of Phar ilbrook. macology, vol. 155 (1): 52-61 (2008). .S. Appl. No. 13/124,476, filed Aug. 15, 2011, Mariola Söhngen. Wiltshire, H. R. et al., “A placebo- and midazolam-Controlled Phase Bodor, N. et al., “Retrometabolic drug design: Principles and recent I Single Ascending-Dose Study Evaluating the Safety, developments.” Pure Appl. Chem., vol. 80 (8): 1669-1682 (2008). Pharmacokinetics, and Pharmacodynamics of Remimazolam (CNS Greenblatt, D. et al., “Effect of Age, Gender, and Obesity in 7056): Part II. Population Pharmacokinetic and Pharmacodynamic Midazolam Kinetics.” Anesthesiology, vol. 61:27-35 (1984). Modeling and Simulation.” Anesthesia & Analgesia, vol. 115 (2): Kilpatrick, G.J. et al., “Drug development in anaesthesia: industrial 284-296 (2012). perspective.” Curr. Opin. Anaesth., vol. 19 (4):385-389 (2006). Upton, R.N., et al..." A dose escalation study in sheep of the effects Kilpatrick, G.J. et al., “CNS 7056: a novel ultra-short-acting of the benzodiazepine CNS 7056 on sedation, the EEG and the Benzodiazepine.” Anesthesiology, vol. 107(1):60-66 (2007). respiratory and cardiovascular systems.” British Journal of Phar Pacofsky, G.J. et al., “Relating the structure, activity, and physical macology, vol. 155 (1): 52-61 (2008). properties of ultrashort-acting benzodiazepine receptor agonists.” Bioorg. Med. Chem. Lett., vol. 12(21):3219-3222 (2002). * cited by examiner U.S. Patent Feb. 7, 2017 Sheet 1 of 7 US 9,561.236 B2 Figure 1 Study CNS 7056-002 Cohort Success rate nin (%) Reasons for failure Intitial dose Cohort 10/15 (66.7%) Insufficient sedation (n=5) 0.04 mg/kg Cohort 2 15715 (100%) No failures 0.075 mg/kg Cohort 3 9/14 (64.3%) Insufficient sedation (n=4) 0.10 mg/kg Adverse event' (n=1) Study CNS 7056-003 Drug Success rate nin (%) Dose CNS 7056 8/25 (32.7%) 0.10 mg/kg CNS 7056 14/25 (56.0%) 0.15 mg/kg CNS 7056 16125 (64.0) 0.20 mg/kg Midazolam 11125 (44.0%) 0.075 mg/kg U.S. Patent Feb. 7, 2017 Sheet 2 of 7 US 9,561.236 B2 Figure 2 Peripheral S. U.S. Patent Feb. 7, 2017 Sheet 3 of 7 US 9,561.236 B2 Figure 3 pa 70 W. 0. K 0 0 0Y 0 () 50 4) () () { 0. (d 40 K) { 30 y = 0.1017x +41.732 20 R=0.0155 50 60 70 80 90 100 Body-weight (kg) U.S. Patent Feb. 7, 2017 Sheet 4 of 7 US 9,561.236 B2 Figure 4 2.5 3.5 4.0 4.5 5.0 kop-up Doses(mg) 4 2 O 8 6 4 - 7 9. O 2. O 3.0 3.5 40 4.5 5.0 bp-up Doses(mg) 3.0 3.5 40 4.5 5.0 Top-up Doses(mg) U.S. Patent Feb. 7, 2017 Sheet 5 of 7 US 9,561.236 B2 Figure 5 Time after Dose of Fentanyl (Minutes U.S. Patent Feb. 7, 2017 Sheet 6 of 7 US 9,561.236 B2 Figure 6 Scopable after Loading Dose (%o) Dose of 1000 -------------- Fentany - 100 g 75ug 50 ug 5 6 7 8 9 LoadingDose of CNS7056 (mg) Zero Scores (%) U.S.
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