DOCSLIB.ORG

WO 2020/0951S3 A1 14 May 2020 (14.05.2020) I 4 P Cl I P C T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

(12) INTERNATIONAL APPLICATION PI;BLISHED I. NDER THE PATENT COOPERATION TREATY (PCT) (19) World intellectual Propertv Organraation llIIlIIlllIlIlllIlIllIllIllIIIIIIIIIIIIIIIIIIIIIIllIlIlIlIllIlllIIllIlIIllllIIIIIIIIIIIIIIIIIII International Bureau (10) International Publication Number (43) International Publication Date WO 2020/0951S3 A1 14 May 2020 (14.05.2020) I 4 P Cl I P C T (51) International Patent Classification: MC. MK, MT. M., NO, PL, PT, RO, RS. SE. SI. SK. SM, A6JK3J/4166 (2006.01) A6/K&/5/t)6 (200G 01) TR). OAPI (BF, BJ, CF, CG, CI. CYI. GA, GN, GQ. GW. AGJK39/00(2006 01) C07K/6/28 (2006 01) KM,:vIL. MR, NE. SN, TD, TG) A6JP35/00(200G 01) AGJK38/68 (2019 Ol) Published: (21) International Application tiumber: »iili nrternatinrral seair 6 repurt 14rt 2113&i PCT/IB2019/059459 m Alar/ and &ilnte, the mternat»rrral app/icramn as fihrl (22) International Filing Date: crmiamerl en/«i rrr grevscale a&irl is rivrnhihiefur d«ii nlrrarl 04 November 2019 (04,11.2019) /rum P) TES"/;ST'OPE (25) Filing Langurrge: Enghsh (26) Public&stion Language: Enghsh (30) Priority Data: (&2/755.944 05 Not en&ber 2018105.11 20)8) US (i2/882.424 02 Auknrst 2019 (02 08.2019) US (71) Applicants: PFIZER INC. [US/L S], 233 East 42nd Street. Neve York. Ncw York 10017 (US). MERCK PATENT GMBH [DE/DE], Frankfurter Strasse 250, G4293 Dmm- stadi (DE) NEKTAR THERAPEUTICS [US/US]. 435 Nlission Ba) Boulmard South. Suite 100. San Francis- co, California 94158 (US). ASTELLAS PHARMA INC. f JP/JP], 2-5-1. Nihonbashi-Honcho, Chuo-Ku, Tokv o (JP) (72) Inventors: BOSHOFF, Christoffel Hendrik; c/o PFIZER INC, 235 East 42nd Street Neu York. Nevv York 10017 (US) CESARI, Rossano. c/o PI'IZER ITALIA SRL. 113 Via Valbondionc. 00188 Room (IT). MASSACESI, Crist- ian. 68 West End Avenue. Srunnut. Ncvv Jersc) 07901 (US). CHARYCH, Dcbondr, 909 Ta) lor Street. Albany. Califor- rua 94706 (US). (74) Agent: ZI ELINSKI, Br)an Cn Pfraer inc., 235 East 42nd Street, MS 235/9/S20, Yevv York, Yevv York 10017 (US) (81) Designated States ln&iles& «ther» me»idir:nted, fi&r every Dnd of natin»al protection avm/able&: AE. AG, AL, AM, AO, AT. AU. AZ, BA, B B, BG, BI I, BY,. BR, B W. BY, BZ. CA. CI I, CL, CN. CO, CR, CU. CZ. DE, DJ, DK. DVI, DO, DZ, EC. EE, EG, ES. Fl, GB. GD. GE, Gl I, GVI, GT, I IY» I IR. I IU, ID, IL. IN, IR, IS, JO, JP, KE, KG, Kl I, KY., KP, KR, KW, KZ, LA. LC, LK. LR, LS, LU. LY, MA, MD, ME. VIG. MK, MN, VIW, VIX, MY. MZ, YA, NG. Yl, YO, NZ, OVI, PA, PE, PG. Pl I, PL. PT. QA, RO, RS. RU. RW. SA. SC, SD, SE. SG, SK. SL, SNI, ST. SV SY Tll, TJ, TM, TY,, TR, TT. TZ, UA. UG. US, UZ, VC, VN, ZA. ZM, ZW (84) Designated States l»»less r&ihere ise urdicated, for ever) ln»d r f regir&nal prntecnn&i availahlei'RIPO (BW. GII. GVL KE, LR, LS, MW, NIZ, NA, RW, SD. SL. ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM. AZ, BY, KG. KZ. RU, TJ. 00 TM), European (AL, AT, BE. BG, Cl I. CY, CZ. DE, DK, EE. ES. FR, IE. LT, LL', LV. I/i FI, GB, GR, IIR, IIU, IS, IT, Ch CO (54) Title: COVIBINATION FOR TREATING CAYCER CO (57) Abstract& Provided hcrcin arc methods and combinations for treating a subject having cancer by administering to thc subject a 0 PD-I/PD-L I axis inlubitor, a CD-122-biased- c) tokiuc agonist, and an antiiandrogcn or a Phanmrccutically acccptablc salt thcrcof WO 2020/095103 PCT/IB2019/059459 COMBINATION FOR TREATING CANCER FIELD The instant application relates to cancer therapy. Certain embodiments relate to the treatment of an individual having cancer by administering to the individual a 5 combination of a PD-1 axis binding antagonist with a CD-122-biased cytokine agonist, and an anti-androgen, or a pharmaceutically acceptable salt thereof. BACKGROUND PD-L1 is overexpressed in many cancers and is often associated with poor prognosis (Okazaki T et al., Intern. Immun. 2007 19(7):813) (Thompson RH et al., 10 Cancer Res 2006, 66(7):3381) Interestingly, the majority of tumor infiltrating T lymphocytes predominantly express PD-1, in contrast to T lymphocytes in normal tissues and peripheral blood. PD-1 on tumor-reactive T cells can contribute to impaired antitumor immune responses (Ahmadzadeh et al, Blood 2009 1 14(8): 1537). This may be due to exploitation of PD-L1 signaling mediated by PD-L1 expressing tumor cells 15 interacting with PD-1 expressing T cells to result in attenuation of T cell activation and evasion of immune surveillance (Sharpe et al., Nat Rev 2002) (Keir ME et al., 2008 Annu. Rev. Immunol. 26:677). Therefore, inhibition of the PD-L1 /PD-1 interaction may enhance CD8+ T cell-mediated killing of tumors. The inhibition of PD-1 axis signaling through its direct ligands (e.g., PD-L1, PD- 20 L2) has been proposed as a means to enhance T cell immunity for the treatment of cancer (e.g., tumor immunity). Moreover, similar enhancements to T cell immunity have been observed by inhibiting the binding of PD-L1 to the binding partner B7-1. There are currently at least five PD-1 axis binding antagonists approved by the FDA in more than 10 cancer indications (A Ribas et al, Science, 359, 1350-1355, 2018). 25 Among these, nivolumab (OPDIVO ), and pembrolizumab (KEYTRUDA ) are each anti-PD-1 antibodies, while avelumab (BAVENCIO ), atezolizumab (TECENTRIQ )) and durvalumab (IMFINZI )) are each anti-PD-L1 antibodies. The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to the 30 IL-2 cytokine. The IL-2 receptor is made up of 3 subunits - IL-2Ra, IL-2RI3, and IL-2Ry, with each of IL-2Ra and IL-2RI3 having binding affinity for IL-2 while IL-2RY alone has no appreciable affinity. Theze et al. (1994) Immunol. Today 17(10).481-486. Further, WO 2020/095103 PCT/IS2019/059459 the IL-2Raj3 heterodimer has a faster association rate and a slower dissociation rate when binding IL-2 versus either chain alone. Liparoto et al. J. Mol. Recognit.12(5):316- 321. CD8+ memory T-cells, which are responsible for enhancing the immune 5 response, preferentially express the IL-2Rj3 form of the IL-2R (this form of the IL-2R is also known as CD-122). Thus, administration of compounds that are CD-122-biased cytokine agonists can be expected to enhance the immune response (by, e g., increasing the proliferation of CD8+ memory T-cells). Thus, the art recognizes the potential of administration of IL-2RP-selective 10 agonists (also known as CD-122-biased cytokine agonists) in the treatment of patients suffering from cancer. Androgen receptor (AR) is a member of the nuclear hormone receptor family activated by androgens such as dihydrotestosterone (DHT). AR is a prime therapeutic target for treating prostate cancer. Several compounds have been developed as 15 chemotherapy for prostate cancer However, these compounds bind AR with affinities comparable to or less than the endogenous hormone and over time patients develop resistance to these drugs. Higher affinity and/or slower off-rate ligands (e.g. covalent ligands) are needed to provide more effective therapies. Anti-androgens are thought to suppress androgen activity by a number of 20 different mechanisms. One example of an anti-androgen approved for the treatment of metastatic castration-resistant prostate cancer and metastatic high risk castration sensitive prostate cancer is abiraterone acetate (marketed as Zytiga™), a steroidal CY17A1 inhibitor which is dosed in conjunction with prednisone. One specific class of anti-androgens are androgen receptor inhibitors, also known as androgen receptor 25 antagonists, which are thought to compete with endogenous ligands, androgens, for the androgen receptor When an antagonist binds to an androgen receptor it is thought to induce a conformational change in the receptor itself that impedes transcription of key androgen regulated genes and therefore inhibits the biological effects of the androgens themselves, such as testosterone and dihydrotestosterone. Current drugs for prostate 30 cancer include flutamide, bicalutamide, nilutamide, enzalutamide and apalutamide However, despite treatment with anti-androgens, for some subjects, their cancer will relapse or the subjects may develop therapeutic resistance. The mechanisms that underlie such resistance are, to date, not yet fully understood WO 2020/095183 PCT/IS2019/059459 -3- The combination therapy of a PD-1 axis binding antagonist with one or more anti-cancer agents has been investigated, with the first, and the only, new clinical trial started in 2009 New clinical trials directed to such combinations have increased dramatically since then with 467 new tnals registered in 2017 (C. Schmidt, Nature, Vol 5 552, 21/28 December 2017). While the combination therapy of nivolumab and ipilimumab to treat melanoma, and the combination therapy of pemborlizumab with chemotherapy to treat non-small cell lung cancer were approved by the FDA in 2015 and 2017, respectively, there is a continued need of finding optimal therapies that combine a PD-1 axis binding antagonist with one or more other anti-cancer agents, for 10 treating, stabilizing, preventing, and/or delaying development of various cancers. SUMMARY Each of the embodiments descnbed below can be combined with any other embodiment described herein not inconsistent with the embodiment with which it is combined. Furthermore, each of the embodiments described herein envisions within its 15 scope pharmaceutically acceptable salts of the compounds described herein Accordingly, the phrase "or a pharmaceutically acceptable salt thereof's implicit in the description of all compounds described herein.
Recommended publications
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances" WHO/EMP/RHT/TSN/2018.1

    The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances" WHO/EMP/RHT/TSN/2018.1

    INN Working Document 19.450 04/02/2019 Addendum1 to "The use of stems in the selection of International Nonproprietary names (INN) for pharmaceutical substances" WHO/EMP/RHT/TSN/2018.1 Programme on International Nonproprietary Names (INN) Technologies Standards and Norms (TSN) Regulation of Medicines and other health technologies (RHT) World Health Organization, Geneva © World Health Organization 2019 - All rights reserved. The contents of this document may not be reviewed, abstracted, quoted, referenced, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means, without explicit prior authorization of the WHO INN Programme. This document contains the collective views of the INN Expert Group and does not necessarily represent the decisions or the stated policy of the World Health Organization. Addendum1 to "The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances" - WHO/EMP/RHT/TSN/2018.1 1 This addendum is a cumulative list of all new stems selected by the INN Expert Group since the publication of "The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances" 2018. ------------------------------------------------------------------------------------------------------------ -calcet/-calcet- calcium-sensing receptors (CaSR) agonists cinacalcet (88), etelcalcetide (112), evocalcet (113), tecalcet (87), upacicalcet (118) ------------------------------------------------------------------------------------------------------------
  • Fully Automated Dried Blood Spot Sample Preparation Enables the Detection of Lower Molecular Mass Peptide and Non-Peptide Doping Agents by Means of LC-HRMS

    Fully Automated Dried Blood Spot Sample Preparation Enables the Detection of Lower Molecular Mass Peptide and Non-Peptide Doping Agents by Means of LC-HRMS

    Analytical and Bioanalytical Chemistry (2020) 412:3765–3777 https://doi.org/10.1007/s00216-020-02634-4 RESEARCH PAPER Fully automated dried blood spot sample preparation enables the detection of lower molecular mass peptide and non-peptide doping agents by means of LC-HRMS Tobias Lange1 & Andreas Thomas1 & Katja Walpurgis1 & Mario Thevis1,2 Received: 10 December 2019 /Revised: 26 March 2020 /Accepted: 31 March 2020 # The Author(s) 2020 Abstract The added value of dried blood spot (DBS) samples complementing the information obtained from commonly routine doping control matrices is continuously increasing in sports drug testing. In this project, a robotic-assisted non-destructive hematocrit measurement from dried blood spots by near-infrared spectroscopy followed by a fully automated sample preparation including strong cation exchange solid-phase extraction and evaporation enabled the detection of 46 lower molecular mass (< 2 kDa) peptide and non-peptide drugs and drug candidates by means of LC-HRMS. The target analytes included, amongst others, agonists of the gonadotropin-releasing hormone receptor, the ghrelin receptor, the human growth hormone receptor, and the antidiuretic hormone receptor. Furthermore, several glycine derivatives of growth hormone–releasing peptides (GHRPs), argu- ably designed to undermine current anti-doping testing approaches, were implemented to the presented detection method. The initial testing assay was validated according to the World Anti-Doping Agency guidelines with estimated LODs between 0.5 and 20 ng/mL. As a proof of concept, authentic post-administration specimens containing GHRP-2 and GHRP-6 were successfully analyzed. Furthermore, DBS obtained from a sampling device operating with microneedles for blood collection from the upper arm were analyzed and the matrix was cross-validated for selected parameters.
  • Myovant Sciences Ltd. 10K 2021 V1

    Myovant Sciences Ltd. 10K 2021 V1

    UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549 FORM 10-K (Mark One) ☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended March 31, 2021 or ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from _______ to _______ Commission file number 001-37929 Myovant Sciences Ltd. (Exact name of registrant as specified in its charter) Bermuda 98-1343578 (State or other jurisdiction of incorporation or organization) (I.R.S. Employer Identification No.) Suite 1, 3rd Floor 11-12 St. James’s Square London SW1Y 4LB United Kingdom Not Applicable (Address of principal executive offices) (Zip Code) Registrant’s telephone number, including area code: +44 (207) 400 3351 Securities registered pursuant to Section 12(b) of the Act: Title of each Class Trading Symbol Name of each exchange on which registered Common Shares, $0.000017727 par value per share MYOV New York Stock Exchange Securities registered pursuant to Section 12(g) of the Act: None Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes No Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes No Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.
  • WSAVA List of Essential Medicines for Cats and Dogs

    WSAVA List of Essential Medicines for Cats and Dogs

    The World Small Animal Veterinary Association (WSAVA) List of Essential Medicines for Cats and Dogs Version 1; January 20th, 2020 Members of the WSAVA Therapeutic Guidelines Group (TGG) Steagall PV, Pelligand L, Page SW, Bourgeois M, Weese S, Manigot G, Dublin D, Ferreira JP, Guardabassi L © 2020 WSAVA All Rights Reserved Contents Background ................................................................................................................................... 2 Definition ...................................................................................................................................... 2 Using the List of Essential Medicines ............................................................................................ 2 Criteria for selection of essential medicines ................................................................................. 3 Anaesthetic, analgesic, sedative and emergency drugs ............................................................... 4 Antimicrobial drugs ....................................................................................................................... 7 Antibacterial and antiprotozoal drugs ....................................................................................... 7 Systemic administration ........................................................................................................ 7 Topical administration ........................................................................................................... 9 Antifungal drugs .....................................................................................................................
  • The Effects of Osaterone Acetate on Clinical Signs and Prostate Volume in Dogs with Benign Prostatic Hyperplasia

    The Effects of Osaterone Acetate on Clinical Signs and Prostate Volume in Dogs with Benign Prostatic Hyperplasia

    Polish Journal of Veterinary Sciences Vol. 21, No. 4 (2018), 797–802 DOI 10.24425/pjvs.2018.125601 Original article The effects of osaterone acetate on clinical signs and prostate volume in dogs with benign prostatic hyperplasia P. Socha, S. Zduńczyk, D. Tobolski, T. Janowski Department of Animal Reproduction with Clinic, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowskiego 14, 10-719 Olsztyn, Poland Abstract A clinical trial was performed to evaluate the therapeutic efficacy of osaterone acetate (OSA) in the treatment of benign prostatic hyperplasia (BPH) in dogs. Osaterone acetate (Ypozane, Virbac) was administered orally at a dose of 0.25 mg/kg body weight once a day for seven days to 23 dogs with BPH. During the 28-day trial, the dogs were monitored five times for their clinical signs and prostate volume. The OSA treatment promoted rapid reduction of clinical scores to 73.2% on day 7 and to 5.9% on day 28 (p<0.05). Osaterone acetate induced the complete clinical remission in approximately 83.0% of the dogs on day 28. The prostate volume regressed to 64.3% of the pretreatment volume after two weeks of the treatment (p<0.05) and to 54.7% at the end of the trial (p<0.05). In conclusion, OSA quickly reduced clinical signs and volume of the prostate glands in dogs with BPH. Key words: dogs, benign prostatic hyperplasia, osaterone acetate, prostate volume Introduction hyperplasia and subsequently transforms to cystic hyperplasia with the formation of multiple small cysts Benign prostatic hyperplasia (BPH) is the most within the prostatic parenchyma.
  • 207/2015 3 Lääkeluettelon Aineet, Liite 1. Ämnena I Läkemedelsförteckningen, Bilaga 1

    207/2015 3 Lääkeluettelon Aineet, Liite 1. Ämnena I Läkemedelsförteckningen, Bilaga 1

    207/2015 3 LÄÄKELUETTELON AINEET, LIITE 1. ÄMNENA I LÄKEMEDELSFÖRTECKNINGEN, BILAGA 1. Latinankielinen nimi, Suomenkielinen nimi, Ruotsinkielinen nimi, Englanninkielinen nimi, Latinskt namn Finskt namn Svenskt namn Engelskt namn (N)-Hydroxy- (N)-Hydroksietyyli- (N)-Hydroxietyl- (N)-Hydroxyethyl- aethylprometazinum prometatsiini prometazin promethazine 2,4-Dichlorbenzyl- 2,4-Diklooribentsyyli- 2,4-Diklorbensylalkohol 2,4-Dichlorobenzyl alcoholum alkoholi alcohol 2-Isopropoxyphenyl-N- 2-Isopropoksifenyyli-N- 2-Isopropoxifenyl-N- 2-Isopropoxyphenyl-N- methylcarbamas metyylikarbamaatti metylkarbamat methylcarbamate 4-Dimethyl- ami- 4-Dimetyyliaminofenoli 4-Dimetylaminofenol 4-Dimethylaminophenol nophenolum Abacavirum Abakaviiri Abakavir Abacavir Abarelixum Abareliksi Abarelix Abarelix Abataceptum Abatasepti Abatacept Abatacept Abciximabum Absiksimabi Absiximab Abciximab Abirateronum Abirateroni Abirateron Abiraterone Acamprosatum Akamprosaatti Acamprosat Acamprosate Acarbosum Akarboosi Akarbos Acarbose Acebutololum Asebutololi Acebutolol Acebutolol Aceclofenacum Aseklofenaakki Aceklofenak Aceclofenac Acediasulfonum natricum Asediasulfoni natrium Acediasulfon natrium Acediasulfone sodium Acenocoumarolum Asenokumaroli Acenokumarol Acenocumarol Acepromazinum Asepromatsiini Acepromazin Acepromazine Acetarsolum Asetarsoli Acetarsol Acetarsol Acetazolamidum Asetatsoliamidi Acetazolamid Acetazolamide Acetohexamidum Asetoheksamidi Acetohexamid Acetohexamide Acetophenazinum Asetofenatsiini Acetofenazin Acetophenazine Acetphenolisatinum Asetofenoli-isatiini
  • The Use of an Intravaginal Triptorelin Gel to Induce Ovulation in the Mare

    The Use of an Intravaginal Triptorelin Gel to Induce Ovulation in the Mare

    THE USE OF AN INTRAVAGINAL TRIPTORELIN GEL TO INDUCE OVULATION IN THE MARE by CHELSEA D. SINCLAIR B.S., Clemson University, 2013 A THESIS submitted in partial fulfillment of the requirements for the degree MASTER OF SCIENCE Department of Animal Sciences and Industry College of Agriculture KANSAS STATE UNIVERSITY Manhattan, Kansas 2016 Approved by: Major Professor Dr. Joann M. Kouba Copyright CHELSEA D. SINCLAIR 2016 Abstract The objective of these studies was to investigate the efficacy of an intravaginal triptorelin acetate (TA) gel as an ovulation-inducing agent in mares. In Exp 1, 24 mares were stratified by parity and age and randomly assigned to 3 treatment groups receiving either: 5 mL TA gel (500 μg TA; TA5), 10 mL TA gel (1,000 μg TA; TA10), or 5 mL vehicle gel only (CON). Following the appearance of a follicle ≥ 25 mm, blood samples were obtained every 24 h until treatment administration for measurement of luteinizing hormone (LH) concentrations. Once a follicle ≥ 35 mm in diameter was detected, treatment was administered intravaginally. Following treatment, blood samples were collected and ovaries were scanned via transrectal ultrasonography every 12 h until 48 h post-ovulation. Both TA5 and TA10 tended (P = 0.08) to experience a brief surge in LH by 12 h post-treatment. Regarding LH concentrations, there was a significant (P < 0.005) treatment by time interaction. The interval from treatment to ovulation was not different (P > 0.05) between groups, nor was there a difference (P > 0.05) in the percentage of mares ovulating within 48 h of treatment administration.
  • (12) United States Patent (10) Patent No.: US 6,235,712 B1 Stevenson Et Al

    (12) United States Patent (10) Patent No.: US 6,235,712 B1 Stevenson Et Al

    US006235.712B1 (12) United States Patent (10) Patent No.: US 6,235,712 B1 Stevenson et al. (45) Date of Patent: May 22, 2001 (54) NON-AQUEOUS POLARAPROTIC PEPTIDE Helm, et al., “Stability of Gonadorelin and Triptorelin in FORMULATIONS Aqueous Solution”, Pharm. Res., 7/12, pp. 1253-1256 (1990). (75) Inventors: Cynthia L. Stevenson; Steven J. Johnson, et al., “Degradation of the LH-RHAnalog Nafare Prestrelski, both of Mountain View, CA lin Acetate in Aqueous Solution”, Intl. J. Pharm., 31, pp. (US) 125-129 (1986). 73) Assignee:9. ALZA Corporation,p Mountain View, Lupron (leuprolide acetate for Subcutaneous injection), Phy CA (US) sician's Desk Ref, 50th Ed., pp. 2555-2556 (1996). Lupron Depot (leuprolide acetate for depot Suspension), * ) Notice: Subject to anyy disclaimer, the term of this Physician's Desk Ref, 50th Ed., pp. 2556-2562 (1996). patent is extended or adjusted under 35 Lutrepulse (gonadorelin acetate for IV injection), Physi U.S.C. 154(b) by 0 days. cian's Desk Ref, 50th Ed., pp.980–982 (1996). Okada, et al., “New Degradation Product of (21) Appl. No.: 09/514,951 Des-Gly'-NH-LH-RH-Ethylamide (Fertirelin) in Aque (22) Filed: Feb. 28, 2000 ous Solution”, J. Pharm. Sci., 80/2, pp. 167–170 (1991). Okada, et al., “Preparation of Three-Month Depot Injectable Related U.S. Application Data MicroSpheres of Leuprorelin Acetate Using Biodegradable Polymers”, Pharm. Res., 11/8, pp. 1143–1147 (1994). (62) Division of application No. 09/293,839, filed on Apr. 19, 1999, now Pat. No. 6,124,261, which is a continuation of Oyler, et al., “Characterization of the Solution Degradation application No.
  • Obseva SA Reports Consistent Long-Term Findings from Phase 2B EDELWEISS Trial of Linzagolix for Endometriosis-Associated Pain

    Obseva SA Reports Consistent Long-Term Findings from Phase 2B EDELWEISS Trial of Linzagolix for Endometriosis-Associated Pain

    ObsEva SA Reports Consistent Long-Term Findings from Phase 2b EDELWEISS trial of Linzagolix for Endometriosis-Associated Pain Geneva, Switzerland and Boston, MA – May 3, 2019 – ObsEva SA (NASDAQ: OBSV / SIX: OBSN), a clinical- stage biopharmaceutical company focused on the development and commercialization of novel therapeutics for serious conditions that compromise a woman’s reproductive health and pregnancy, today reported follow-up results from the Phase 2b EDELWEISS clinical trial of its oral gonadotropin releasing hormone (GnRH) receptor antagonist, linzagolix, for the treatment of endometriosis-associated pelvic pain. These new data include 28-week extension study treatment (52 weeks of continuous treatment), as well as the 24-week post treatment follow-up (PTFU) results for patients who did not enter the extension study after completing the initial 24-week treatment period. "We are pleased to report long-term data from the EDELWEISS trial of linzagolix, which show that in patients treated with linzagolix for 52 weeks, pelvic pain response rates are maintained with the 75mg or the 200mg dose. Bone mineral density remains within safe limits. Patients that were followed for 6 months after treatment completion continue to experience pain control, and showed BMD increase,” said Ernest Loumaye, Co-Founder and Chief Executive Officer of ObsEva. “These data further support the long term therapeutic potential of linzagolix and support the currently starting Phase 3 program for the endometriosis indication, as we anticipate initial Phase 3 clinical results later this year from the trial in uterine fibroids.” Overall Pelvic Pain reduction sustained long-term After 52 weeks of treatment, responder rates for Overall Pelvic Pain (OPP)— defined as the proportion of patients experiencing an OPP score reduction >30% from baseline using a verbal rating scale— were 69% for the 75mg once daily dose and 82% for the 200mg/100mg once daily dose.
  • Androgen Receptor Targeted Agents for Castration Resistant Prostate Cancer: a Review of Clinical Effectiveness and Cost- Effectiveness

    Androgen Receptor Targeted Agents for Castration Resistant Prostate Cancer: a Review of Clinical Effectiveness and Cost- Effectiveness

    CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL APPRAISAL Androgen Receptor Targeted Agents for Castration Resistant Prostate Cancer: A Review of Clinical Effectiveness and Cost- Effectiveness Service Line: Rapid Response Service Version: 1.0 Publication Date: June 6, 2019 Report Length: 30 Pages Authors: Khai Tran, Suzanne McCormack Cite As: Androgen Receptor Targeted Agents for Castration Resistant Prostate Cancer: A Review of Clinical Effectiveness and Cost-Effectiveness. Ottawa: CADTH; 2019 Jun. (CADTH rapid response report: summary with critical appraisal). ISSN: 1922-8147 (online) Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect.
  • Reproductionresearch

    Reproductionresearch

    REPRODUCTIONRESEARCH Relationships between FSH patterns and follicular dynamics and the temporal associations among hormones in natural and GnRH-induced gonadotropin surges in heifers J M Haughian, O J Ginther1,KKot1 and M C Wiltbank Department of Dairy Science, 1675 Observatory Drive and 1Department of Animal Health and Biomedical Sciences, University of Wisconsin, Madison, Wisconsin 53706, USA Correspondence should be addressed to M C Wiltbank; Email: [email protected] Abstract Preovulatory LH and FSH surges and the subsequent periovulatory FSH surge were studied in heifers treated with a single injection of GnRH (100 mg, n 5 6) or saline (n 5 7). Blood samples were collected every hour from 6 h before treatment until 12 h after the largest follicle reached $8.5 mm (expected beginning of follicular deviation). The GnRH-induced preovulatory LH and FSH surges were higher at the peak and shorter in duration than in controls, but the area under the curve was not different between groups. The profiles of the preovulatory LH and FSH surges were similar within each treatment group, suggesting that the two surges involved a common GnRH-dependent mechanism. Concentrations of FSH in controls at the nadir before the preovulatory surge and at the beginning and end of the periovulatory surge were not significantly different among the three nadirs. A relationship between variability in the periovulatory FSH surge and number of 5.0 mm follicles was shown by lower FSH concentrations during 12–48 h after the beginning of the surge in heifers with more follicles (11.0 6 1.0 follicles (mean6S.E.M.) n 5 7) than in heifers with fewer follicles (5.7 6 0.4, n 5 6).
  • Investigation of the Presence of Gnrh and Gnrh-R System in Bovine

    Investigation of the Presence of Gnrh and Gnrh-R System in Bovine

    Investigation of the Presence of GnRH and GnRH-R System in Bovine Oocytes, Sperm and Early Embryos and their Functional Role in Reproduction by USWATTELIYANARALALAGE FELICIA RUWANIE PERERA B.V.Sc., University of Peradeniya, Peradeniya, Sri Lanka, 2001 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Animal Science) THE UNIVERSITY OF BRITISH COLUMBIA (VANCOUVER) April 2010 ©Uswatteliyanaralalage Felicia Ruwanie Perera, 2010 ABSTRACT The objectives of this study were to investigate: 1) the effect of GnRH agonist on oocyte maturation, sperm function and fertilization, 2) the presence of GnRH-R in bovine oocytes, sperm and early embryos. To examine the effect of GnRH agonist on sperm function, sperm were incubated in modified Tyrode’s medium with 0, 0.2, 0.4, 0.8 and 1.2 µgmL -1 of buserelin and with1 -1 µgmL P4 for 3 h. Acrosome status in each group was assessed at 0 h and 3 h. For zona- binding assay, in vitro matured oocytes were co-incubated with sperm in different concentrations of buserelin and P 4 for 4 h and the zona-bound sperm in each treatment group was determined. Acrosome reacted percentage were higher in sperm treated with 0.4, 0.8 µgmL -1 buserelin than the control group (p<0.001). The number of zona-bound sperm were higher in 0.8 µgmL -1 buserelin compared to negative control (p<0.01). Effect of buserelin was blocked by antide. To investigate the effect of GnRHa on maturation of bovine oocytes 0.8 µgmL -1 buserelin was added to the in vitro maturation media and maturation rate was obtained after 24 h against control groups with FSH and without FSH.