WO2020231408A1 - Schéma posologique d'eltrombopag - Google Patents

Schéma posologique d'eltrombopag Download PDF

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Publication number
WO2020231408A1
WO2020231408A1 PCT/US2019/032175 US2019032175W WO2020231408A1 WO 2020231408 A1 WO2020231408 A1 WO 2020231408A1 US 2019032175 W US2019032175 W US 2019032175W WO 2020231408 A1 WO2020231408 A1 WO 2020231408A1
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WO
WIPO (PCT)
Prior art keywords
eltrombopag
tapering
dose
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/US2019/032175
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English (en)
Inventor
Miona STANKOVIC
Nichola COOPER
Waleed GHANIMA
Francesco ZAJA
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Novartis Pharmaceuticals Corporation
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Application filed by Novartis Pharmaceuticals Corporation filed Critical Novartis Pharmaceuticals Corporation
Priority to PCT/US2019/032175 priority Critical patent/WO2020231408A1/fr
Publication of WO2020231408A1 publication Critical patent/WO2020231408A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method of treating immune thrombocytopenia (ITP), especially chronic ITP, by administering eltrombopag or a pharmaceutically acceptable salt thereof to a patient.
  • ITP immune thrombocytopenia
  • the method relates to the discontinuation of administration of eltrombopag or a pharmaceutically acceptable salt thereof while remaining a treatment-free remission after eltrombopag discontinuation.
  • the method further relates to administering eltrombopag at a tapering regimen while remaining a remission.
  • Platelets are necessary for blood clotting. When platelet numbers are very low a patient is at risk of bleeding, hemorrhage, or death from hemorrhage. ITP is an autoimmune disorder characterized by transient or persistent decrease in platelet count with varied degree of bleeding. Eltrombopag is a highly effective treatment of ITP. It is used for long-term, even lifelong treatment. Long-term treatment with eltrombopag impends substantial costs and is associated with tolerability and compliance issues.
  • the invention relates to a method of treating immune thrombocytopenia (ITP) comprising administering eltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein
  • eltrombopag or a pharmaceutically acceptable salt thereof is administered at an initial dose until a complete response is achieved
  • the present invention provides a method of treating immune thrombocytopenia (ITP) comprising administering eltrombopag or a pharmaceutically acceptable salt thereof to a patient in need thereof, comprising
  • c. optionally administering a lower dose of eltrombopag or a pharmaceutically
  • the present invention provides eltrombopag or a pharmaceutically acceptable salt thereof for use in the treatment of ITP comprising administering eltrombopag or a
  • ITP refers to chronic ITP.
  • eltrombopag or a pharmaceutically acceptable salt is present in the form of its bis-monoethanolamine (bis-olamine) salt.
  • the initial dose is 100 mg, 75 mg, 50 mg, or 25 mg daily, suitably 50 mg daily.
  • a complete response is achieved when the platelet count of said patient is at least 50'000/ml_, at least 60'000/mL, at least 70'000/ml_, at least 80'000/ml_, at least 90'000/mL, or at least 100'000/mL, suitably at least 100'000/mL.
  • the consolidation phase is at least one month, one month, at least two months, or two months, suitably two months.
  • the platelet count of said patient is at least 50'000/ml_, at least 60'000/mL, at least 70'000/mL, or at least 80'000/mL, or at least 100'000/mL, suitably at least 70'000/mL.
  • patient achived complete response is in the absence of bleeding as well.
  • the tapering regimen comprises one or more tapering doses, wherein there is a decrement between two adjacent tapering doses.
  • the tapering regimen comprises one, two, three, or four tapering doses.
  • the last tapering dose of the tapering regimen is 25 mg daily, 12.5 mg daily, or 25 mg every other day.
  • the initial dose is 100 mg daily
  • the first tapering dose is 75 mg daily
  • the second tapering dose is 50 mg daily
  • the third tapering dose is 25 mg daily
  • optionally the fourth tapering dose is either 12.5 mg daily or 25 mg every other day.
  • the initial dose is 75 mg daily
  • the first tapering dose is 50 mg daily
  • the second tapering dose is 25 mg daily
  • optionally the third tapering dose is either 12.5 mg daily or 25 mg every other day.
  • the initial dose is 50 mg daily
  • the first tapering dose is 25 mg daily
  • the second i tapering dose is either 12.5 mg daily or 25 mg every other day.
  • the initial dose is 25 mg daily and the tapering dose is either 12.5 mg daily or 25 mg every other day.
  • each tapering dose is administered for a period of one week, two weeks, three weeks, or four weeks, suitably two weeks. Said period can be of different lengths for each tapering dose.
  • the platelet count of said patient is at least 20'000/mL, at least 30'000/mL, at least 40,000/mL, or at least 50,000/mL, suitably at least 30'000/mL.
  • patient achived complete response is in the absence of bleeding as well.
  • treatment-free remission is achieved when the platelet count of said patient is at least 20'000/mL, at least 30'000/mL, at least 40,000/mL, or at least 50,000/mL, suitably at least 30'000/mL.
  • patient achived complete response is in the absence of bleeding as well.
  • treatment-free remission is maintained for at least 1 month, at least 3 months, at least 6 months, at least 1 year, between 1 and 12 months, between 3 and 12 months, between 6 and 12 months, between 12 and 18 months, or between 12 and 24 months.
  • treatment-free remission is achieved when a platelet count of at least 30'000/mL is maintained in the absence of bleeding, i.e. no bleeding adverse event, or in the absence of use of any rescue therapy, e.g. intravenous
  • a treatment of ITP with eltrombopag or a pharmaceutically acceptable salt thereof can be resumed at least 1 month, at least 3 months, at least 6 months, or at least 1 year after the treatment-free remission status is lost.
  • the resumption of treatment comprises the step of administering eltrombopag or a pharmaceutically acceptable salt thereof at the same dose as the initial dose.
  • the resumption of treatment comprises the step of administering eltrombopag or a pharmaceutically acceptable salt thereof at a dose that is lower than the initial dose.
  • “Lower than the initial dose” is understood here as either eltrombopag or a pharmaceutically acceptable salt thereof being administered at a lower dose per administration, or the interval between each administration being longer while the dose unchanged, or both.
  • the resumption of treatment comprises the step of administering eltrombopag or a pharmaceutically acceptable salt thereof at a dose at least 25% or at least 50% lower than the initial dose.
  • the resumption of treatment comprises the step of administering eltrombopag or a pharmaceutically acceptable salt thereof at a dose 25 mg less than the initial dose.
  • the resumption of treatment comprises the step of administering eltrombopag or a pharmaceutically acceptable salt thereof every other day.
  • the resumption of treatment comprises the step of administering eltrombopag or a pharmaceutically acceptable salt thereof at a dose of 25 mg daily.
  • the resumption of treatment comprises the step of administering eltrombopag or a pharmaceutically acceptable salt thereof at a dose of 12.5 mg daily, especially for patients who are of East Asian ancestry.
  • eltrombopag or a pharmaceutically acceptable salt thereof can be administered in combination with steroids.
  • eltrombopag can be administered in combination with dexamethasone.
  • eltrombopag or a pharmaceutically acceptable salt thereof is administered as a first line treatment.
  • eltrombopag or a pharmaceutically acceptable salt thereof is administered as a second line treatment.
  • eltrombopag or a pharmaceutically acceptable salt thereof is administered to patients who are ITP naive patient. In another embodiment of the present invention eltrombopag or a pharmaceutically acceptable salt thereof is administered to patients who are refractory or relapsed after first-line steroids.
  • eltrombopag or a pharmaceutically acceptable salt thereof is administered to an ITP patient whose platelet count is less than 30'000/mL.
  • eltrombopag or a pharmaceutically acceptable salt thereof is administered to patients who relapsed following an initial response to a first-line course of steroid therapy, i.e. steroid-relapsed or steroid-refractory, with or without intravenous immunoglobulin used as a rescue therapy.
  • a first-line course of steroid therapy i.e. steroid-relapsed or steroid-refractory
  • first line steroid therapy is defined as: prednisone/prednisolone 0.5 to 1 mg/kg/day for a minimum of 2 weeks, or minimum of 1 course of high-dose dexamethasone 20-40 mg/day for consecutive 4 days with or without intravenous immunoglobulin (used as rescue therapy), wherein maximum exposure to high dose steroids treatment (steroids tapering time excluded) is limited to 4 weeks of high dose prednisone/prednisolone or 3 courses of high-dose dexamethasone, wherein overall exposure to steroids less than 3 months, including the period of dose tapering.
  • eltrombopag is administered to newly diagnosed primary ITP patients, wherein the time from diagnosis is within 3 months, with a platelet count less than 30'000/mL and a need for treatment, wherein optionally patients were treated with intravenous immunoglobulin 14 days before eltrombopag administration or with any ITP-directed therapy 3 days before eltrombopag administration.
  • dexamethasone induces a treatment-free response.
  • eltrombopag induces a complete response at least once by week 4.
  • eltrombopag increases the platelet count from baseline for 1 , 2, 4, 12, 26 and 52 weeks.
  • Numerical values stated herein are to be understood as approximate values. This generally includes an acceptable degree of error for the value measured, due to the nature or precision of the measurements, and/or any underlying biological/chemical/physical fluctuations. Exemplary degrees of error are within 20%, typically, within 10%, and more typically, within 5% of a given value.
  • the actual value can vary by up to 20% from the stated amount. This recognizes that first, the precise amount of a measured platelet count may differ from the actual platelet number in the blood stream due to technical limitations of the method of measuring, and second, it recognizes that the platelet count can vary, fluctuate, or oscillate in a patient for various reasons and individual outlying
  • Platelet count may vary, fluctuate, or oscillate between measurements or can be imprecise due to limitations of the measuring methods. Therefore, a 20% variation, a 10% variation, or a 5% variation from any platelet count value stated herein should be tolerated.
  • the frequency of the measurements can be adjusted by the treating physician.
  • the platelet count is measured once per day, every other day, once per week, once every other week, once per month, once every other month, or once every 6 months.
  • the platelet count is first measured weekly, and once a stable platelet count is reached, the platelet count is measured monthly. The platelet count can be measured prior to initiation of the treatment with
  • a platelet count might have to be measured more frequently than then following establishment of a stable initial dose of eltrombopag.
  • "Complete response" or "complete remission” is achieved when a platelet count reaches a defined level.
  • the defined level is typically understood when the platelet count is at least 70'000/mL, at least 80'000/mL, at least 90'000/mL, at least 100'000/mL, at least 1 10'000/mL, or at least double or at least triple the baseline platelet count of the same patient. In a particular embodiment the defined level is at least 100'000/mL.
  • consolidation phase refers to the time period during which the platelet count is maintained above a defined value, which can be lower than that defined level for a complete response.
  • said level is least 50'000/mL, at least 60'000/mL, at least 70'000/mL, or at least 80'000/mL. In a particular embodiment said level is at least 70'000/mL.
  • the consolidation phase is at least one month, one month, at least two months, or two months. In a particular embodiment the consolidation phase is two months.
  • tapering regimen refers to a dosing regimen consisting of one, two, three or four tapering d doses, wherein the tapering dose is reduced stepwise, i.e. each dose is lower than its preceding dose. There can be one, two, thee, or four steps of dose reductions. In some embodiments each tapering dose is given during a period of one week, two weeks, three weeks, or four weeks. In another embodiment, each tapering dose is given for a different duration, e.g. the first tapering dose is given for 2 weeks and the second one for 4 weeks. In a particular embodiment a tapering dose is given during a period of two weeks. The dose decrement can be a certain percentage, e.g.
  • the platelet count is maintained at least 20'000/mL, at least 30'000/mL, at least 40'000/mL, or at least 50'000/mL during the tapering regimen. In a particular embodiment the platelet count is at least 30'000/mL during the tapering regimen.
  • dose refers to a certain amount of eltrombopag given at a certain frequency, e.g.
  • doses are daily doses.
  • the term "initial dose” refers to the dose the patient is given to achieve a complete response.
  • a particular initial dose is 50 mg daily.
  • a reduced dose of 25 mg daily is particular for patients who are of East Asian ancestry, e.g. Chinese, Japanese, Taiwanese, or Korean.
  • the initial dose can be changed according to the response of the patient.
  • the dose can be increased, e.g. to 75 mg or 100 mg, if the response is too weak, e.g. platelet count decreases, does not increase, or increases too slowly.
  • the dose can be reduced, e.g. to 25 mg, if the response is too strong, e.g. platelets increase too quickly.
  • the initial dose can be adjusted one or multiple times to reach the optimal initial dose for a patient.
  • the initial dose is the dose that is administered before initiating a tapering regimen.
  • tapering dose refers to a dose that is administered after the patient had been treated with an initial dose. A tapering dose is lower than an initial dose.
  • discontinue and discontinuation refer to the end of the treatment.
  • the drug is not given to the patient anymore during a period of time. This period can either be a drug holiday, after which the drug administration is resumed, or it can be a final discontinuation. If drug administration is resumed the dose can be the same as the previous initial dose or less.
  • treatment-free remission refers to a remission that remains after discontinuation of the administration of eltrombopag or a pharmaceutically acceptable salt thereof.
  • the platelet count of a patient during treatment-free remission is at least 20'000/mL, at least 30'000/ml_, at least 40,000/mL, or at least 50,000/mL, suitably at least 30'000/mL.
  • Loss of remission response is achieved when the platelet count drops below 30'000/mL and/or a bleeding event occurs for a period of at least 2 weeks or at least one month.
  • Example 1 A phase I I, open-label, prospective, single-arm, study to assess ability of eltrombopag to induce sustained remission in subjects with ITP who are refractory or relapsed after first-line steroids (TAPER)
  • TAPER first-line steroids
  • the purpose of this trial is to assess the ability of eltrombopag to induce sustained treatment- free remission in ITP subjects who failed to respond or have relapsed after an initial treatment with steroids.
  • the primary objective is to assess the ability of eltrombopag to induce sustained remission by month 12 in ITP subjects who relapsed or failed to respond to first-line steroid treatment.
  • the primary endpoint is the proportion of subjects with sustained remission by month 12, where sustained remission is defined as:
  • the main secondary objectives are:
  • Endpoint Number (%) of subjects with at least one platelet count > 30'000/mL after eltrombopag is re-introduced, in case of loss of response ( ⁇ 30'000/mL and/or bleeding event) without bleeding and no rescue therapy.
  • Endpoint Number (%) of subjects who maintain a platelet count > 30'000/mL from the first time of reaching that level to month 3, 6, 9, 12 and end-of-study without bleeding and no rescue therapy.
  • the study is designed to include adult subjects with primary ITP who have failed to respond or who relapsed following an initial response to a first-line course of steroid therapy (steroid- relapsed or steroid-refractory) with or without ⁇ intravenous immunoglobulin (IVIG) used as a rescue
  • Second line of steroid therapy will be defined as: prednisone/prednisolone 0.5 to 1 mg/kg/day for a minimum of 2 weeks, or minimum of 1 course of high-dose dexamethasone 20- 40 mg/day for consecutive 4 days ⁇ IVIG (used as rescue therapy).
  • Maximum exposure to high dose steroids treatment should be limited to: 4 weeks of high dose prednisone/prednisolone or 3 courses of high-dose dexamethasone. Overall exposure to steroids must not be longer than 3 months, including period of dose tapering. Main exclusion criteria are:
  • ITP subjects previously treated with any ITP second-line therapies, thrombopoietin receptor agonists for ITP, except steroids / IVIG.
  • Subjects will be treated with eltrombopag 50 mg daily (QD) for 2 weeks to reach a target platelet count of > 10O'OOO/mL. For those subjects who do not achieve the target platelet count within 2 weeks, the dose of eltrombopag will be increased to 75 mg QD. Those subjects who have not reached the target platelet count > 100'000/mL after being treated with eltrombopag 75 mg/day will continue on eltrombopag until month 12. Treatment with eltrombopag will be continued at the minimal dosage necessary to achieve and maintain a platelet count around 100'000/mL for 2 months.
  • QD eltrombopag 50 mg daily
  • CR complete response
  • the duration of tapering will be individualized and depend upon starting dose and response of the subject: decreases in dose will be performed by 25 mg reductions every 2 weeks. If platelet counts are stable, the next reduction should be carried out within 2 weeks, with dosing at 25 mg on alternate days for 2 weeks until treatment is totally discontinued.
  • a reduced initial dosage of 25 mg QD is recommended for subjects of Asian ancestry.
  • the dose of eltrombopag in subjects with Asian ancestry will be reduced to account for the lower eltrombopag clearance (CL/F) observed in these subjects compared to the non-Asian population. Therefore, drug tapering for subjects with Asian ancestry will be done in 12.5 mg decrements every second week.
  • Platelet count will be performed at screening visit 1 to assess the eligibility of the subject.
  • Hematology including platelet counts will be assessed at week 1/day 1 and weekly during the first 8 weeks of treatment. Based on subject response, hematology will be performed biweekly thereafter until the end of treatment. Additional assessments of platelet count may be performed more frequently than the biweekly schedule if needed in accordance with the clinical judgment of the investigator. Bleeding events will be assessed at each visit.
  • the purpose of this trial is to assess the ability of eltrombopag to induce sustained treatment- free
  • the primary objective is to assess the ability of eltrombopag to induce sustained response off treatment at month 6 in ITP subjects who were treated with second line eltrombopag and previously achieved CR.
  • the primary endpoint is the proportion of subjects with sustained response off treatment at month 6 wherein sustained response off treatment is defined as:
  • the study is designed to include adult subjects with ITP who failed to respond or who relapsed after first-line steroid treatment and are on treatment with eltrombopag. Platelet count is > 100'000/ml_ and stable (above 70'000/ml_) for 2 months.
  • Subjects will begin stepwise reduction of the eltrombopag dose on day 1. In case of relapse they will be re-treated with eltrombopag. Relapse is defined as platelet count ⁇ 30'000/mL. Treatment will be with 50 mg - 75 mg eltrombopag until end-of-study. Subjects in sustained response off treatment at month 6 will enter a 1 year follow-up period. Sustained response off treatment is defined as: • Reach platelet count of 100'000/ml_ (complete response) and then maintain platelet counts about 100'000/mL for 2 months (no counts below 70'000/ml_) and
  • the study includes a second arm which are patients on second line steroids.
  • the steroids will be stopped on day 1 and there will be re-treatment with steroids or eltrombopag after relapse.
  • the timing and endpoints of the second arm are the same and subjects in sustained response off treatment at month 6 will also enter a 1 year follow-up period.

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Abstract

La présente invention concerne une méthode de traitement de la thrombocytopénie immunitaire (ITP) par administration d'eltrombopag ou d'un sel pharmaceutiquement acceptable de celui-ci à un patient.
PCT/US2019/032175 2019-05-14 2019-05-14 Schéma posologique d'eltrombopag WO2020231408A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150148385A1 (en) * 2012-06-29 2015-05-28 Shionogi & Co., Ltd. Pharmaceutical composition containing a compound having a thrombopoietin receptor agonistic activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150148385A1 (en) * 2012-06-29 2015-05-28 Shionogi & Co., Ltd. Pharmaceutical composition containing a compound having a thrombopoietin receptor agonistic activity

Non-Patent Citations (10)

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Title
ANONYMOUS: "History of Changes for Study: NCT03524612", 2 May 2018 (2018-05-02), XP055656370, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/history/NCT03524612?A=1&B=23&C=merged#StudyPageTop> [retrieved on 20200109] *
BAHAREH GHADAKI ET AL: "Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists : Sustained ITP Remissions after TPO Receptor Agonists", TRANSFUSION., vol. 53, no. 11, 1 November 2013 (2013-11-01), US, pages 2807 - 2812, XP055656200, ISSN: 0041-1132, DOI: 10.1111/trf.12139 *
BUSSEL ET AL: "Paper: Tapering Eltrombopag in Patients with Chronic ITP: How Successful Is This and in Whom Does It Work?", BLOOD, 5 December 2015 (2015-12-05), XP055656399 *
BUSSEL, BLOOD, 2015
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CERVINEK, INT. J. HAEMATOL., 2015
GHADAKI, TRANSFUSION, 2013
JOSE RAMON GONZALEZ-PORRAS ET AL: "Eltrombopag in immune thrombocytopenia: efficacy review and update on drug safety", THERAPEUTIC ADVANCES IN DRUG SAFETY, vol. 9, no. 6, 11 June 2018 (2018-06-11), pages 263 - 285, XP055656212, ISSN: 2042-0986, DOI: 10.1177/2042098618769587 *
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TOMÁS JOSÉ GONZÁLEZ-LÓPEZ ET AL: "Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia : Discontinuation of Eltrombopag in Primary ITP", AMERICAN JOURNAL OF HEMATOLOGY, vol. 90, no. 3, 1 March 2015 (2015-03-01), US, pages E40 - E43, XP055656124, ISSN: 0361-8609, DOI: 10.1002/ajh.23900 *

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