WO2013019222A1 - Compositions et procédés de traitement du syndrome myélodysplasique - Google Patents

Compositions et procédés de traitement du syndrome myélodysplasique Download PDF

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Publication number
WO2013019222A1
WO2013019222A1 PCT/US2011/046319 US2011046319W WO2013019222A1 WO 2013019222 A1 WO2013019222 A1 WO 2013019222A1 US 2011046319 W US2011046319 W US 2011046319W WO 2013019222 A1 WO2013019222 A1 WO 2013019222A1
Authority
WO
WIPO (PCT)
Prior art keywords
ezatiostat
salt
administered
hydrochloride
per day
Prior art date
Application number
PCT/US2011/046319
Other languages
English (en)
Inventor
Gail L. Brown
Original Assignee
Telik, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Telik, Inc. filed Critical Telik, Inc.
Priority to PCT/US2011/046319 priority Critical patent/WO2013019222A1/fr
Publication of WO2013019222A1 publication Critical patent/WO2013019222A1/fr
Priority to IL230729A priority patent/IL230729A0/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to compositions and methods for treating myelodysplasia syndrome.
  • MDS Myelodysplasia syndrome(s) refers to a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis (blood cell production) involving one or more cell lineages (red blood cells, white blood cells or platelets) and a variable risk of transformation to acute myeloid leukemia (AML). This syndrome becomes more common with age. It is estimated that MDS affects
  • Ezatiostat and its salts are disclosed in US Patent No. 5,763,570.
  • Ezatiostat has the IUPAC chemical name of ethyl (2S)-2-amino-5-[[(2R)-3-benzylsulfanyl-l-[[(7R)-2- ethoxy-2-oxo-l-phenylethyl]amino]-l-oxopropan-2-yl]amino]-5-oxopentanoate.
  • ezatiostat hydrochloride (USAN)
  • U.S. Patent Application No. 13/041,136 filed March 4, 2011, describes ansolvate and polymorphs of ezatiostat hydrochloride.
  • Ezatiostat hydrochloride has been evaluated for the treatment of MDS, in a Phase I-IIa study using a liposomal formulation (US Patent No.
  • this invention is directed to a method for treating MDS in a patient which method comprises administering to that patient a therapeutically effective amount of ezatiostat or a salt thereof equivalent to up to about 2 grams (g) per day of ezatiostat hydrochloride for at least 2 weeks.
  • the dosing of ezatiostat or a salt thereof is a therapeutically effective amount of up to about 1 gram ezatiostat hydrochloride (or equivalent) administered twice a day (b.i.d.).
  • ezatiostat or a salt thereof is administered orally.
  • the patient is treated with ezatiostat or a salt thereof equivalent to up to about 2 grams per day of ezatiostat hydrochloride for three weeks followed by a week interruption without ezatiostat treatment. After the fourth week, the regimen can be repeated as necessary.
  • the ezatiostat or a salt thereof is administered twice a day, for example in equal doses.
  • this invention is directed to use of a therapeutically effective amount of ezatiostat or a salt thereof for the preparation of a oral medicament for treating a myelodysplasia syndrome, said ezatiostat or a salt thereof is equivalent to up to about 2 grams of ezatiostat hydrochloride per day for at least 2 weeks.
  • the patient is treated continuously with a therapeutically effective amount of ezatiostat or a salt thereof equivalent to up to about 2 grams per day of ezatiostat hydrochloride preferably administered in divided doses twice a day. It is contemplated that in this embodiment, the therapeutically effective amount of ezatiostat or a salt thereof may be less than that when there is a week interruption in the treatment regimen.
  • ezatiostat or a salt thereof can be administered as a tablet formulation. Such a tablet formulation is disclosed in U.S. Patent Application No.
  • this invention is directed to a treatment regimen for treating MDS using ezatiostat or a salt thereof.
  • ezatiostat or a salt thereof.
  • the singular forms "a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.
  • reference to "a pharmaceutically acceptable excipient” includes a plurality of pharmaceutically acceptable excipients.
  • compositions and methods include the recited elements, but do not exclude others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of means excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • treatment means any treatment of MDS in a patient which produces one or more of the following: • inhibiting the disease or condition, that is, arresting or suppressing the
  • the term "patient” refers to mammals and includes humans and non-human mammals.
  • a numerical designation e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by ( + ) or ( - ) 15 %, 10 %, 5 % or 1 %.
  • therapeutically effective amount refers to the amount of ezatiostat or a salt thereof that is an amount sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment. In one embodiment, the
  • therapeutically effective amount will be ezatiostat or a salt thereof equivalent to up to about 2 grams per day of ezatiostat hydrochloride administered per day.
  • ezatiostat or a salt thereof is administered in an amount of 2 grams per day and, more preferably, is administered twice a day in equal 1 gram doses.
  • Such a therapeutically effective amount is particularly relevant when the treatment regimen is for 3 weeks of administration of ezatiostat or a salt thereof followed by a week of no administration of the drug.
  • therapeutically effective amounts used in continuous administration may be lower than the amounts used during a three week treatment cycle followed by a week of no administration.
  • this invention is directed to a method for treating MDS in a patient in need thereof which method comprises orally administering to that patient a therapeutically effective amount of ezatiostat or a salt thereof equivalent to up to about 2 grams per day of ezatiostat hydrochloride for at least 2 weeks.
  • the dosing of ezatiostat or a salt thereof is a therapeutically effective amount of up to about 1 gram ezatiostat hydrochloride (or equivalent) administered twice a day.
  • ezatiostat or a salt thereof is administered in 1 gram dosages twice a day for three weeks followed by an interruption of 1 week. After the interruption, the regimen can be repeated as necessary. This regimen may be referred to as the "three-week regimen.”
  • the patient is treated continuously with a therapeutically effective amount of ezatiostat or a salt thereof equivalent to up to about 2 grams per day of ezatiostat hydrochloride, preferably in two divided doses, for at least two weeks.
  • ezatiostat or a salt thereof can be administered so long as the patient is in need of and can tolerate such treatment. It is contemplated that in this embodiment, the therapeutically effective amount of ezatiostat or a salt thereof may be less than that when there is an interruption in the treatment regimen. This regimen may be referred to as the "continuous regimen.”
  • the treatment with ezatiostat or a salt thereof may involve one or a combination of two or more of the dosing regimens described herein.
  • the following are exemplifying dosing schedules of ezatiostat hydrochloride:
  • ezatiostat hydrochloride or equivalent of ezatiostat or another salt
  • Ezatiostat hydrochloride in the above dosings can be replaced with an equivalent amount (in terms of ezatiostat content) of ezatiostat itself or another salt of ezatiostat.
  • ezatiostat or a salt thereof can be delivered as a tablet.
  • Examples of such a tablet formulation are disclosed in U.S. Patent Application No. 13/075,116, filed March 29, 2011, titled "TABLET FORMULATION OF
  • the interval between the first and second doses be from about 6 to 14 hours and more preferably between abut 8 and 14 hours.
  • the median age was 72 years, with a patient population distribution of
  • IDS International Prognostic Scoring System
  • DMTI DNA methyltransferase inhibitors
  • HI-N Hematologic Improvement - Neutrophil
  • GI gastrointestinal
  • nausea 45%, 16%), diarrhea (25%), 7%>) and vomiting (30%>, 12%).
  • Grade 3 events were uncommon: nausea (1%), diarrhea (3%) and vomiting (2%).
  • Prior DMTI treatment was associated with an increased incidence of GI AEs.
  • Telintra® treatment may result in clinically significant hematologic improvement in patients with MDS and may offer an alternative to RBC transfusions. These results are consistent with levels of efficacy observed in prior studies with Telintra®, the first GST Pl-1 enzyme inhibitor tested in MDS patients.
  • the data show both administration of 2 grams of ezatiostat hydrochloride per day over a 3 week period and administration of 3 grams of ezatiostat hydrochloride per day over a 2 week period provided efficacy in treating MDS. Furthermore and unexpectedly, the data show that administration of 2 grams of drug per day over a 3 week period gave a duration of response of 46.1 weeks versus the 18.4 weeks when 3 grams of ezatiostat hydrochloride per day were administered over a 2 week period.

Abstract

La présente invention concerne des schémas de traitement spécifiques du syndrome myélodysplasique.
PCT/US2011/046319 2011-08-02 2011-08-02 Compositions et procédés de traitement du syndrome myélodysplasique WO2013019222A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US2011/046319 WO2013019222A1 (fr) 2011-08-02 2011-08-02 Compositions et procédés de traitement du syndrome myélodysplasique
IL230729A IL230729A0 (en) 2011-08-02 2014-01-30 Preparations and methods for the treatment of myelodysplastic syndrome

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2011/046319 WO2013019222A1 (fr) 2011-08-02 2011-08-02 Compositions et procédés de traitement du syndrome myélodysplasique

Publications (1)

Publication Number Publication Date
WO2013019222A1 true WO2013019222A1 (fr) 2013-02-07

Family

ID=44630570

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/046319 WO2013019222A1 (fr) 2011-08-02 2011-08-02 Compositions et procédés de traitement du syndrome myélodysplasique

Country Status (2)

Country Link
IL (1) IL230729A0 (fr)
WO (1) WO2013019222A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4113611A (en) 1976-11-16 1978-09-12 Westinghouse Electric Corp. Magnetic pipe cleaner
US5763570A (en) 1987-10-13 1998-06-09 Terrapin Technologies, Inc. Glutathione analogs and paralog panels comprising glutathione mimics
US7029695B2 (en) 2001-07-10 2006-04-18 Telik, Inc. Therapeutic compositions containing glutathione analogs
US7511611B2 (en) 2006-05-18 2009-03-31 Casella Waste Systems, Inc. Systems for and methods of asset management in a waste management service environment

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4113611A (en) 1976-11-16 1978-09-12 Westinghouse Electric Corp. Magnetic pipe cleaner
US5763570A (en) 1987-10-13 1998-06-09 Terrapin Technologies, Inc. Glutathione analogs and paralog panels comprising glutathione mimics
US7029695B2 (en) 2001-07-10 2006-04-18 Telik, Inc. Therapeutic compositions containing glutathione analogs
US7511611B2 (en) 2006-05-18 2009-03-31 Casella Waste Systems, Inc. Systems for and methods of asset management in a waste management service environment

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ANNUAL MEETING OF THE AMERICAN SOCIETY FOR HEMATOLOGY, 2005
ANNUAL MEETING OF THE AMERICAN SOCIETY FOR HEMATOLOGY, 2007
ANONYMOUS: "Phase 2 Study Comparing Two Dose Schedules of Telintra in Myelodysplastic Syndrome", INTERNET CITATION, pages 1 - 3, XP002651485, Retrieved from the Internet <URL:http://clinicaltrials.gov/ct2/show/NCT00700206?term=ezatiostat&rank=3> [retrieved on 20110719] *
ANONYMOUS: "Telik report phase II data on ezatiostat in MDS", INTERNET CITATION, 9 June 2010 (2010-06-09), pages 1, XP002651700, Retrieved from the Internet <URL:https://integrity.thomson-pharma.com/integrity/xmlxsl/pk_ref_list.xml _show_ficha_ref?p_ref_id=1513842> [retrieved on 20110720] *
QUDDUS ET AL., JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 3, 23 April 2010 (2010-04-23), pages 16
RAZA AZRA ET AL: "Phase 2 Randomized Multicenter Study of Extended Dosing Schedules of Oral Ezatiostat HCl (Telintra), a Glutathione Analog Prodrug GSTP1-1 Inhibitor, In Low to Intermediate-1 Risk Myelodysplastic Syndrome (MDS)", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 116, no. 21, 1 November 2010 (2010-11-01), pages 1198, XP009150424, ISSN: 0006-4971 *
RAZA ET AL., BLOOD, vol. 113, 27 April 2009 (2009-04-27), pages 6533 - 6540
RAZA ET AL., JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 2, 13 May 2009 (2009-05-13), pages 20

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