Alzheimer's Disease Clinical Trials

Total Page:16

File Type:pdf, Size:1020Kb

Alzheimer's Disease Clinical Trials Clinical Trial Perspective 5 Clinical Trial Perspective Alzheimer’s disease clinical trials: past failures and future opportunities Clin. Invest. (Lond.) Over a decade has elapsed since the US FDA has approved a medication for Alzheimer’s Roy Yaari*,1,2 & Ann Hake1,2 disease (AD) despite clinical trials of numerous agents over a wide array of mechanisms 1Eli Lilly & Company, Lilly Corporate including neurotransmitter modulation and disease modifying therapy targeting Center, Indianapolis, IN 46285, USA 2Indiana University School of Medicine, amyloid and tau. The failures of clinical trials in AD may be due to inadequate Department of Neurology, Indianapolis, understanding of mechanisms of action and/or poor target engagement; however, IN 46202, USA other factors could include inadequate study design, stage of AD along the continuum *Author for correspondence: studied, inclusion of participants without Alzheimer’s pathology into clinical trials Tel.: +1 317 651 6163 and limited power of endpoint measures. Future studies will need to carefully assess [email protected] these possible shortcomings in design of upcoming trials, especially as the field moves toward studies of disease modifying agents (as opposed to symptomatic treatment) of AD and to patients that are very early in the disease spectrum. Keywords: Alzheimer’s disease • Alzheimer’s disease biomarkers • amyloid • clinical trials • preclinical Alzheimer’s disease • tau US FDA approved medications continue to provide significant, but modest More than three decades ago, the choliner- symptomatic benefit[5–7] . gic hypothesis proposed that degeneration The compound memantine introduced a of cholinergic neurons in the basal fore- second mechanism for symptomatic treat- brain and the associated loss of cholinergic ment of AD into clinical practice. Meman- neurotransmission in the cerebral cortex, tine, an N-methyl-D-aspartate (NMDA) hippocampus and other areas contributed partial antagonist that regulates overstimu- significantly to the deterioration in cogni- lation of excess glutamate in the CNS, has tive function seen in Alzheimer’s disease also shown mild but statistically significant 3 (AD) [1] . In 1993, the first centrally act- improvement of symptoms in patients with ing cholinesterase inhibitor, tacrine, was moderate to severe AD [8]; and in 2003, it approved by the US FDA for treatment of was the last FDA-approved medication for AD based on evidence from three pivotal AD. Approval of new formulations and dos- 2015 studies [2–4] that showed statistically signifi- ing of these medications has subsequently cant, dose-related improvements on tests occurred, but no novel drugs. of cognition, clinician- and caregiver-rated Although these medications provide mod- global evaluations and quality-of-life mea- est benefit for the symptoms of AD in some sures. It was subsequently approved in sev- patients, they do not arrest or reverse the eral European countries. The adverse event underlying neurodegenerative disorder. Fur- profile of hepatotoxicity, nausea, vomiting, ther, not all patients respond to these treat- abdominal pain and diarrhea has limited ments, or their benefits are limited by intol- its use and it is no longer in production in erable side effects. Additional symptomatic the USA. Subsequent cholinesterase inhibi- treatment options are necessary, and thera- tors – donepezil, rivastigmine and galan- peutic interventions for AD that can decel- tamine – have been FDA-approved and erate or even prevent disease progression are part of 10.4155/CLI.14.127 © 2015 Future Science Ltd Clin. Invest. (Lond.) (2015) 5(3), 297–309 ISSN 2041-6792 297 Clinical Trial Perspective Yaari & Hake urgently needed. Numerous symptomatic as well as Glutamate-NMDA receptor modulators disease-modifying agents have been, and continue In addition to memantine, other NMDA receptor antag- to be, actively pursued. Treatments that slow or onists were tested without success including remacemide, stop disease progression remain a significant unmet EVT 101, D-cycloserine and neramexane [18–20] . medical need. Glutamate-AMPA receptor modulators Symptomatic therapy Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propio- Many investigative compounds have focused on nate (AMPA) receptors, which are another subgroup treating the cognitive symptoms of AD by modulat- of glutamate receptors, have also been tested as poten- ing neurotransmission disturbances resulting from tial therapeutic targets for AD. Compounds such as neurodegeneration. Ampalex and LY451395 have not shown success in clinical trials [20]. Acetylcholine The deficit of cholinergic function that follows the loss Serotonin of neurons in the basal forebrain has been extensively A number of serotonin receptors have been postulated studied and helped lead to development of the cur- to be potential therapeutic targets for the cognitive, rently available centrally acting cholinesterase inhibi- behavioral and affective symptoms of AD, but have tors. Other molecules designed to enhance cholinergic not yielded evidence of significant efficacy in clinical function have not been successful. trials thus far. Development of the 5HT1A antagonist Lecozotan was discontinued after Phase II due to Other cholinesterase inhibitors poor tolerability [21] . The 5-HT1A agonist xaliproden, In addition to the four cholinesterase inhibi- thought to be neuroprotective, was found to decrease tors that were approved by the FDA, several others loss of hippocampal volume in two Phase III stud- were investigated but were ultimately unsuccess- ies, but it lacked efficacy on cognitive endpoints [22]. ful due to lack of efficacy, intolerable side effects or The 5HT4 agonist PRX-3140, 5HT4 partial ago- impractical/ineffective dosing. These include velna- nists such as PF04995275 and RQ-9 and 5-HT6 crine [9], sustained-release physostigmine [10], eptas- antagonists including LU-AE58054, PRX-07034, tigmine [11], metrifonate [12] and huperzine A [13] . PF-05212365, SR57746 and SB742457 may be in Although the huperzine A study was negative on development [21,23]. its primary endpoint, a trend toward cognitive improvement was found on the higher dose. Histamine Latrepiridine, an antihistamine that was once used Nicotine receptor agonists in Russia, was thought to stabilize mitochondria and Augmentation of cholinergic function by stimulation therefore possibly have neuroprotective effects. Despite of cholinergic receptors was also attempted, with little robust findings in a Phase II study, it did not meet end- success thus far. Nicotine patches [14] and the partial points in two Phase III studies on primary or second- α7 agonists, ispronicline (AZD3480) [15], GTS-21, ary endpoints. MK-0249, an H3 receptor inverse ago- TC-5619, ABT-126 and MEM 3454 have been studied nist, showed no cognitive benefit in a 4-week, Phase II [16] . Other nicotinic agonists or modulators currently study in mild-to-moderate AD [24]. In a Phase II, under investigation are EVP-6124, MT-4666 and 16-week monotherapy trial in mild-to-moderate AD, MK-7622. GSK239512, an H3 receptor antagonist, did not meet primary cognitive endpoints [25]. Other agents target- Muscarinic agonists ing histamine, including ABT-288 and GSK189254, Development of both full and partial agonists of the have been unsuccessful. M1 muscarinic receptor has been limited due to adverse effects. In 3–6 month Phase II and III studies, study Other neurotransmitters drugs cevimeline (AF102B), milameline, xanomeline, A number of other agents targeting various neurotrans- sabcomeline (SB 202026), talsaclidine and alvameline mitter systems have been tested but, thus far, have been (LU 25–109) generally showed the parasympatho- unsuccessful. These include the GABA-B antagonist mimetic effects of gastrointestinal symptoms, hyper- SGS-742 and the phosphodiesterase-4 inhibitors MEM salivation, sweating and frequent urination, rendering 1414 and MK-0952 [23]. Although FDA-approved and them clinically inadequate [17] . ANAVEX 2–73 targets widely used for treatment of AD in the past, ergoloid sigma-1 and muscarinic receptors and is currently mesylates, a combination of three dehydrogenated ergot being studied. alkaloids that may stimulate dopaminergic and seroto- 298 Clin. Invest. (Lond.) (2015) 5(3) future science group Alzheimer’s disease clinical trials: past failures & future opportunities Clinical Trial Perspective nergic receptors, were unsuccessful in a pivotal trial [26]. between these two pathways, they may not be mutually A meta-analysis of 47 studies showed ergoloid mesylates exclusive of each other. to be very modestly more effective than placebo [27]. The amyloid hypothesis Antidiabetic agents The amyloid hypothesis posits that excess accumula- Insulin has been tested due to alterations in cerebral tion of brain amyloid beta (Aβ), the component of glucose metabolism observed in AD. A pilot study neuritic plaques which is one of the hallmark patho- suggested a cognitive benefit of intranasal insulin logic findings, causes AD. For over two decades, the in both mild cognitive impairment (MCI) due to amyloid hypothesis has been the main target for dis- AD and patients with mild-to-moderate AD [28]. A ease-modifying therapies. This hypothesis is supported larger intranasal insulin study is currently enrolling by: the presence of Aβ in neuritic plaques; the genetics 240 participants with MCI due to AD or mild AD. of dominantly inherited familial AD involving muta- Rosiglitazone lowers blood glucose by improv- tions of amyloid precursor protein
Recommended publications
  • E30 SEM. O.C. Disclosed Is a Compound Represented by the Formula (1) (51) Int
    USOO9453000B2 (12) United States Patent (10) Patent No.: US 9.453,000 B2 Kimura et al. (45) Date of Patent: *Sep. 27, 2016 (54) POLYCYCLIC COMPOUND (56) References Cited (75) Inventors: Teiji Kimura, Tsukuba (JP); Noritaka U.S. PATENT DOCUMENTS Kitazawa, Tsukuba (JP); Toshihiko 3,470,167 A 9, 1969 Sarkar Kaneko, Tsukuba (JP); Nobuaki Sato, 3,989,816 A 1 1/1976 Rajadhyaksha Tsukuba (JP); Koki Kawano, Tsukuba 4,910,200 A 3, 1990 Curtze et al. (JP): Koichi Ito, Tsukuba (JP); 5,281,626 A 1/1994 Oinuma et al. M s Tak ishi Tsukub JP 5,563,162 A 10, 1996 Oku et al. amoru Takaishi Tsukuba (JP); 5,804,577 A 9, 1998 Hebeisen et al. Takeo Sasaki, Tsukuba (JP); Yu 5,985,856 A 11/1999 Stella et al. Yoshida, Tsukuba (JP); Toshiyuki 6,235,728 B1 5, 2001 Golik et al. Uemura, Tsukuba (JP); Takashi Doko, g R 1939. E. al. Its SE E. Shinmyo, 7,138.414 B2 11/2006 Schoenafingereatch et al. et al. sukuba (JP); Daiju Hasegawa, 7,300,936 B2 11/2007 Parker et al. Tsukuba (JP); Takehiko Miyagawa, 7,314,940 B2 1/2008 Graczyk et al. Hatfield (GB); Hiroaki Hagiwara, 7,618,960 B2 11/2009 Kimura et al. Tsukuba (JP) 7,667,041 B2 2/2010 Kimura et al. 7,687,640 B2 3/2010 Kimura et al. 7,713,993 B2 5/2010 Kimura et al. (73) Assignee: EISAI R&D MANAGEMENT CO., 7,737,141 B2 6/2010 Kimura et al. LTD., Tokyo (JP) 7,880,009 B2 2/2011 Kimura et al.
    [Show full text]
  • WITHOUTUS010307409B2 (12 ) United States Patent ( 10 ) Patent No
    WITHOUTUS010307409B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 307 ,409 B2 Chase et al. (45 ) Date of Patent: Jun . 4 , 2019 ( 54 ) MUSCARINIC COMBINATIONS AND THEIR (52 ) U . S . CI. USE FOR COMBATING CPC . .. .. A61K 31/ 4439 (2013 . 01 ) ; A61K 9 /0056 HYPOCHOLINERGIC DISORDERS OF THE (2013 . 01 ) ; A61K 9 / 7023 ( 2013 . 01 ) ; A61K CENTRAL NERVOUS SYSTEM 31 / 166 ( 2013 . 01 ) ; A61K 31 / 216 ( 2013 . 01 ) ; A61K 31 /4178 ( 2013 .01 ) ; A61K 31/ 439 (71 ) Applicant: Chase Pharmaceuticals Corporation , ( 2013 .01 ) ; A61K 31 /44 (2013 . 01 ) ; A61K Washington , DC (US ) 31/ 454 (2013 .01 ) ; A61K 31/ 4725 ( 2013 .01 ) ; A61K 31 /517 (2013 .01 ) ; A61K 45 / 06 ( 72 ) Inventors : Thomas N . Chase , Washington , DC (2013 . 01 ) (US ) ; Kathleen E . Clarence -Smith , ( 58 ) Field of Classification Search Washington , DC (US ) CPC .. A61K 31/ 167 ; A61K 31/ 216 ; A61K 31/ 439 ; A61K 31 /454 ; A61K 31 /4439 ; A61K (73 ) Assignee : Chase Pharmaceuticals Corporation , 31 /4175 ; A61K 31 /4725 Washington , DC (US ) See application file for complete search history. ( * ) Notice : Subject to any disclaimer, the term of this (56 ) References Cited patent is extended or adjusted under 35 U . S . C . 154 (b ) by 0 days . U . S . PATENT DOCUMENTS 5 ,534 ,520 A 7 / 1996 Fisher et al. ( 21) Appl . No. : 15 /260 , 996 2008 /0306103 Al 12 /2008 Fisher et al. 2011/ 0021503 A1* 1/ 2011 Chase . .. A61K 31/ 27 ( 22 ) Filed : Sep . 9 , 2016 514 / 215 2011/ 0071135 A1 * 3 / 2011 Chase . .. .. .. A61K 31/ 166 (65 ) Prior Publication Data 514 / 215 2011 /0245294 Al 10 / 2011 Paborji et al.
    [Show full text]
  • Wo 2007/128674 A2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 15 November 2007 (15.11.2007) PCT WO 2007/128674 A2 (51) International Patent Classification: Houtenlaan 36, NL-1381 CP Weesp (NL). KRUSE, Cor- A61K 31/00 (2006.01) A61K 31/551 (2006.01) nelis G. [NL/NL]; c/o SOLVAY PHARMACEUTICALS A61K 31/439 (2006.01) A61P 25/18 (2006.01) B.V., IPSI Department, CJ. Van Houtenlaan 36, NL-1381 A61K 31/4439 (2006.01) CP Weesp (NL). (21) International Application Number: (74) Agent: VERHAGE, Marinus; Octrooibureau Zoan B.V., PCT/EP2007/053934 NL-1380 AC Weesp (NL). (22) International Filing Date: 23 April 2007 (23.04.2007) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, (25) Filing Language: English CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, (26) Publication Language: English IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, MG, MK, MN, MW, MX, MY, (30) Priority Data: MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, 061 13476.3 4 May 2006 (04.05.2006) EP RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, 60/797,355 4 May 2006 (04.05.2006) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (71) Applicant (for all designated States except US): SOLVAY (84) Designated States (unless otherwise indicated, for every PHARMACEUTICALS B.V.
    [Show full text]
  • Muscarinic Acetylcholine Receptor
    mAChR Muscarinic acetylcholine receptor mAChRs (muscarinic acetylcholine receptors) are acetylcholine receptors that form G protein-receptor complexes in the cell membranes of certainneurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibersin the parasympathetic nervous system. mAChRs are named as such because they are more sensitive to muscarine than to nicotine. Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpineand scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists. Acetylcholine (ACh) is a neurotransmitter found extensively in the brain and the autonomic ganglia. www.MedChemExpress.com 1 mAChR Inhibitors & Modulators (+)-Cevimeline hydrochloride hemihydrate (-)-Cevimeline hydrochloride hemihydrate Cat. No.: HY-76772A Cat. No.: HY-76772B Bioactivity: Cevimeline hydrochloride hemihydrate, a novel muscarinic Bioactivity: Cevimeline hydrochloride hemihydrate, a novel muscarinic receptor agonist, is a candidate therapeutic drug for receptor agonist, is a candidate therapeutic drug for xerostomia in Sjogren's syndrome. IC50 value: Target: mAChR xerostomia in Sjogren's syndrome. IC50 value: Target: mAChR The general pharmacol. properties of this drug on the The general pharmacol. properties of this drug on the gastrointestinal, urinary, and reproductive systems and other… gastrointestinal, urinary, and reproductive systems and other… Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 1 mg, 5 mg 1 mg, 5 mg AC260584 Aclidinium Bromide Cat. No.: HY-100336 (LAS 34273; LAS-W 330) Cat.
    [Show full text]
  • Treatment of Schizophrenia Course Director: Philip Janicak, M.D
    S6735- Treatment of Schizophrenia Course Director: Philip Janicak, M.D. #APAAM2016 Saturday, May 14, 2016 Marriott Marquis - Marquis Ballroom D psychiatry.org/ annualmeetingS4637 ANNUAL MEETING May 14-18, 2016 • Atlanta Reference • Janicak PG, Marder SR, Tandon R, Goldman M (Eds.). Schizophrenia: Recent Advances in Diagnosis and Treatment. New York, NY: Springer; 2014. Schizophrenia: Recent Diagnostic Advances, Neurobiology, and the Neuropharmacology of Antipsychotic Drug Therapy Rajiv Tandon, MD Professor of Psychiatry University of Florida College of Medicine Gainesville, Florida Annual Meeting of the American Psychiatric Association New York, New York May 3–7, 2014 Disclosure Information MEMBER, WPA PHARMACOPSYCHIATRY SECTION MEMBER, DSM-5 WORKGROUP ON PSYCHOTIC DISORDERS A CLINICIAN AND CLINICAL RESEARCHER Pharmacological Treatment of Any Disease • Know the Disease that you are treating • Nature; Treatment targets; Treatment goals; • Know the Treatments at your disposal • What they do; How they compare; Costs; • Principles of Treatment • Measurement-based; Targeted; Individualized Program Outline • Nature and Definition of psychosis? • Clinical description • What is wrong in psychotic illness • Dimensions of Psychopathology • Neurobiological Abnormalities • Mechanisms underlying antipsychotic effects? • What contributes to Efficacy • Basis of Side-effect differences 5 Challenges in DSM-IV Construct of Psychotic Disorders ♦ Indistinct Boundaries ♦ With Other Disorders (eg., with OCD) ♦ Within Group of Psychotic Disorders (eg. between
    [Show full text]
  • (Tert- Butoxycarbonyl)Amino](3 361442- 3
    Alternative Name CAS 1. Product Name Use Number 320345- 2. Aclidinium bromide API 99-1 (2S)-[(tert- Butoxycarbonyl)amino](3 361442- 3. Saxagliptin int -hydroxyadamant-1- 00-4 yl)ethanoic acid 1,3- 1,3- 5001-18- 4. Dihydroxyadamantane Adamantanediol 3 1,3-Dimethyladamantane 702-79-4 memantine intermediate 5. 1-Acetylamido-3,5- 19982- 6. Memantine int dimethyladamantane 07-1 1- 7. 880-52-4 Acetylaminoadamantane 1- 4942-47- 8. 1-Adamantaneacetic acid Adamantylacetic 6 acid [2-(1- 6240-11- 9. 1-Adamantaneethanol Adamantylethano 5 l)] 1- 10. 1-Adamantanemethanol Adamantylmetha 770-71-8 nol 1- 1660-04- 1-Adamantyl methyl rimantadine intermediate; 11. Acetyladamantan 4 ketone e 1-Chloro-3,5- 707-36-8 memantine intermediate; 12. dimethyladamantane 1-Hydroxy-3,5- memantine intermediate; 13. 707-37-9 dimethyladamantane 2- 14. 2-Adamantanol Hydroxyadamant 700-57-2 ane 15. 2-Adamantanone 700-58-3 2-Aminoadamantane 10523- 16. hydrochloride 68-9 3-Amino-1-hydroxy- 3-Amino-1- 702-82-9 vildagliptin intermediate; 17. adamantane adamantanol 3- 38584- 18. (Hydroxymethyl)adamant 37-1 -1-ol 19. 3-aminomethyl- 865887- mequitazine intermediate; 20. quinuclidine 14-5 dihydrochloride zacopride intermediate; 6530-09- mezacopride intermediate; 3-Aminoquinuclidine 21. 2 pancopride intermediate; dihydrochloride azasetron intermediate; 3-Carbethoxy-dehydro- quifenadine intermediate; 50790- 22. quinuclidine sequifenadine intermediate; 85-7 hydrochloride quifenadine intermediate; 3- 6238-33- 23. sequifenadine intermediate; Carbethoxyquinuclidine 1 3-hydroxymethyl 79221- mequitazine intermediate; 24. quinuclidine 75-3 hydrochloride 3-Quinuclidine 6238-34- 25. carboxylic acid 2 hydrochloride 1619-34- penehyclidine intermediate; 26. 3-Quinuclidinol 7 clidinium intermediate; cevimeline intermediate; 3-Quinuclidinone 1193-65- 27.
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • TESE FINAL.Pdf
    FACULDADE DE MEDICINA DA UNIVERSIDADE DE COIMBRA TRABALHO FINAL DO 6º ANO MEDICO COM VISTA A ATRIBUIÇÃO DO GRAU DE MESTRE NO ÂMBITO DO CICLO DE ESTUDOS DO MESTRADO INTEGRADO EM MEDICINA ANA ALEXANDRA BRIGA CERQUEIRA ESTRATÉGIAS FARMACOLÓGICAS PARA AS ALTERAÇÕES PRECOCES DO COMPORTAMENTO NA DOENÇA DE ALZHEIMER TRABALHO DE REVISÃO ÁREA CIENTÍFICA DE FARMACOLOGIA TRABALHO REALIZADO SOBRE A ORIENTAÇÃO DE: PROFESSORA DOUTORA TICE DOS REIS ANASTÁCIO DE MACEDO MARÇO, 2009 ÍNDICE GERAL Agradecimentos.................................................................................................................3 Resumo..............................................................................................................................4 Abstract..............................................................................................................................6 Lista de Siglas....................................................................................................................8 Introdução........................................................................................................................11 Clínica e Diagnóstico……………...……………………………………………………11 Neuropatologia e Genética..............................................................................................15 Estratégias terapêuticas actuais...................................…………………………………23 Inibidores das colinesterases……………………………………………………23 Memantina……………………………………………………………………...27 Novas estratégias farmacológicas………………………………………………………30 Imunoterapia……………………………………………………………………34
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,005,660 B2 Tygesen Et Al
    USOO9005660B2 (12) United States Patent (10) Patent No.: US 9,005,660 B2 Tygesen et al. (45) Date of Patent: Apr. 14, 2015 (54) IMMEDIATE RELEASE COMPOSITION 4,873,080 A 10, 1989 Bricklet al. RESISTANT TO ABUSEBY INTAKE OF 4,892,742 A 1, 1990 Shah 4,898,733. A 2f1990 DePrince et al. ALCOHOL 5,019,396 A 5/1991 Ayer et al. 5,068,112 A 11/1991 Samejima et al. (75) Inventors: Peter Holm Tygesen, Smoerum (DK); 5,082,655 A 1/1992 Snipes et al. Jan Martin Oevergaard, Frederikssund 5,102,668 A 4, 1992 Eichel et al. 5,213,808 A 5/1993 Bar Shalom et al. (DK); Joakim Oestman, Lomma (SE) 5,266,331 A 11/1993 Oshlack et al. 5,281,420 A 1/1994 Kelmet al. (73) Assignee: Egalet Ltd., London (GB) 5,352.455 A 10, 1994 Robertson 5,411,745 A 5/1995 Oshlack et al. (*) Notice: Subject to any disclaimer, the term of this 5,419,917 A 5/1995 Chen et al. patent is extended or adjusted under 35 5,422,123 A 6/1995 Conte et al. U.S.C. 154(b) by 473 days. 5,460,826 A 10, 1995 Merrill et al. 5,478,577 A 12/1995 Sackler et al. 5,508,042 A 4/1996 OShlack et al. (21) Appl. No.: 12/701.248 5,520,931 A 5/1996 Persson et al. 5,529,787 A 6/1996 Merrill et al. (22) Filed: Feb. 5, 2010 5,549,912 A 8, 1996 OShlack et al.
    [Show full text]
  • (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest Et A1
    US007964607B2 (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest et a1. (45) Date of Patent: Jun. 21, 2011 (54) PYRAZOLO[3,4-D]PYRIMIDINE FOREIGN PATENT DOCUMENTS COMPOUNDS EP 1460077 9/2004 WO 02085904 10/2002 (75) Inventors: Patrick Robert Verhoest, Old Lyme, CT WO 2004037176 5/2004 (US); Caroline ProulX-Lafrance, Ledyard, CT (US) OTHER PUBLICATIONS Wunder et a1, M01. PharmacoL, v01. 28, N0. 6, (2005), pp. 1776 (73) Assignee: P?zer Inc., New York, NY (U S) 1781. van der Staay et a1, Neuropharmacology, v01. 55 (2008), pp. 908 ( * ) Notice: Subject to any disclaimer, the term of this 918. patent is extended or adjusted under 35 USC 154(b) by 562 days. Primary Examiner * Susanna Moore (74) Attorney, Agent, or Firm * Jennifer A. Kispert; (21) Appl.No.: 12/118,062 Michael Herman (22) Filed: May 9, 2008 (57) ABSTRACT (65) Prior Publication Data The invention provides PDE9-inhibiting compounds of For US 2009/0030003 A1 Jan. 29, 2009 mula (I), Related US. Application Data (60) Provisional application No. 60/917,333, ?led on May 11, 2007. (51) Int. Cl. C07D 48 7/04 (2006.01) A61K 31/519 (2006.01) A61P 25/28 (2006.01) (52) US. Cl. ................................... .. 514/262.1; 544/262 (58) Field of Classi?cation Search ................ .. 544/262; 5 1 4/2 62 .1 See application ?le for complete search history. and pharmaceutically acceptable salts thereof, Wherein R, R1, (56) References Cited R2 and R3 are as de?ned herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in U.S.
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • Methods and Combination Therapies for Treating Alzheimer's Disease
    (19) & (11) EP 2 420 235 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 22.02.2012 Bulletin 2012/08 A61K 31/437 (2006.01) A61K 31/445 (2006.01) A61K 45/06 (2006.01) A61P 25/28 (2006.01) (21) Application number: 11181674.0 (22) Date of filing: 26.10.2007 (84) Designated Contracting States: • Protter, Andrew Asher AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Palo Alto, CA California CA 94301 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR (74) Representative: Sexton, Jane Helen J.A. Kemp & Co. (30) Priority: 27.10.2006 US 854866 P 14 South Square Gray’s Inn (62) Document number(s) of the earlier application(s) in London WC1R 5JJ (GB) accordance with Art. 76 EPC: 07867284.7 / 2 086 538 Remarks: This application was filed on 16-09-2011 as a (71) Applicant: Medivation Neurology, Inc. divisional application to the application mentioned San Francisco, CA 94105 (US) under INID code 62. (72) Inventors: • Hung, David T. Redwood City, CA California CA 94062 (US) (54) Methods and combination therapies for treating alzheimer’s disease (57) The invention provides methods and combina- bon) in conjunction with another compound, pharmaceu- tion therapies for treating and/or preventing and/or slow- tically acceptable salt thereof or therapy for Alzheimer’s ing the onset and/or development of Alzheimer’s disease disease. using a hydrogenated pyrido (4,3-b) indole (e.g., dime- EP 2 420 235 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 420 235 A1 Description CROSS-REFERENCE TO RELATED APPLICATIONS 5 [0001] This application claims priority to U.S.
    [Show full text]