KR20130020945A - Compositions and methods for treating myelodysplastic syndrome - Google Patents

Abstract

PURPOSE: A composition containing ezatiostat or salt thereof is provided to treat myelodysplastic syndrome of a patient treated with a DNA methyltransferase inhibitor. CONSTITUTION: A composition for treating myelodysplastic syndrome contains ezatiostat or salt thereof. The composition is used for treating a patient with myelodysplastic syndrome, who is treated with a DNA methyltransferase inhibitor. Ezatiostat or salt thereof is used by oral administration everyday for 2 or more weeks.

Description

Compositions and Methods for Treating Myelodysplastic Syndrome {COMPOSITIONS AND METHODS FOR TREATING MYELODYSPLASTIC SYNDROME}

The present invention relates to compositions and methods for treating myelodysplastic syndromes.

Myelodysplastic syndrome (s) (MDS) is a heterogeneous group of heterogeneous groups characterized by various risks of invalid hematopoiesis (blood cell production) and conversion to acute myeloid leukemia (AML), including one or more cell lines (erythrocytes, leukocytes or platelets). Refers to clonal hematopoietic stem cell disorders. The syndrome is more common with age. It is estimated that around 300,000 people have MDS worldwide. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed annually in the United States alone. Survival using current therapies ranges from six months to six years for patients who often require blood transfusions to manage the disease.

Currently, there are three drugs for the treatment of MDSs approved by the Food and Drug Administration (FDA). Lenalidomide is shown in the treatment of transfusion-dependent MDS patients with del (5q) and low risk diseases, while azacytidine and decitabine are approved in all categories. Except for del (5q) patients, the response rate is about 50%, highlighting the need for clinical trials of new agents.

Ezatiostat and its salts are disclosed in US Pat. No. 5,763,570. Ezathiostat is ethyl ( 2S ) -2-amino-5-[[( 2R ) -3-benzylsulfanyl-1-[[( 1R ) -2-ethoxy-2-oxo-1-phenylethyl] amino ] -1-oxopropan-2-yl] amino] -5-oxopentanoate has the IUPAC chemical name.

One example of a salt of ezathiostat is the hydrochloride salt ezathiostat hydrochloride (USAN), whose molecular weight is 566.1 and the trade name is Telintra? CAS registration number is 286942-97-0. US patent application Ser. No. 13 / 041,136, filed March 4, 2011, describes polymorphs and ansolvates of ezathiostat hydrochloride.

2005 Annual Meeting of the American Society for Hematology (Abstract # 2250) and in Raza et al. in Journal of Hematology & Oncology, 2: 20 (published online on May 13, 2009), the liposome formulations, as reported on by the (US Patent No. 7,029,695) I-IIa studies; And in the 2007 Annual Meeting of the American Society for Hematology (Abstract # 1454) and in Raza et al. in Blood , 113: 6533-6540 (published online on April 27, 2009), Phase I studies using tablet formulations, and Quddus et al. in Journal of Hematology & Oncology, 3: 16 (published online on April 23, 2010) reported a single case of a patient in to evaluate the eja Tio start hydrochloride for the treatment of MDS.

The entire disclosure of each patent, patent application, and publication mentioned in that application is incorporated herein by reference.

Summary of the Invention

The present invention relates to the discovery of a problem that patients with myelodysplastic syndrome treated with DNA methyltransferase inhibitors do not respond to treatment with ezathiostat hydrochloride. The present invention is also based on the surprising finding that the response rate to ezathiostat hydrochloride is increased in patients treated with lenalidomide prior to administration of ezathiostat hydrochloride.

Thus, in one embodiment, the present invention comprises administering lenalidomide to a patient prior to and / or in combination with administration of ezathiostat or a salt thereof, to a patient treated with a DNA methyltransferase inhibitor. A method for treating myelodysplastic syndrome.

In one embodiment, US Patent Application No. 13 / 108,752, entitled "COMPOSITIONS AND METHODS FOR TREATING MYELODYSPLASTIC SYNDROME," filed May 16, 2011, which is incorporated herein by reference. Ezathiostat or a salt thereof is administered by the dosing regimen, which is incorporated by reference in its entirety and claims priority to US Provisional Application No. 61 / 352,371, filed June 7, 2010. For example, ezathiostat or a salt thereof may be orally 3 g / day for 2 weeks on or 1 week off or 2 g / day for 2 weeks on / 1 week off It can be administered in a cycle of. The same amount of ezathiostat dosage may also be used for ezathiostat itself or for other ezathiostat salts or for other routes of administration.

In one embodiment, ezathiostat or salts thereof may be administered as a tablet formulation. Such tablet formulations are disclosed in US Patent Application No. 13 / 075,116, filed Mar. 29, 2011, entitled "TABLET FORMULATION OF EZATIOSTAT," which is incorporated by reference in its entirety.

In another aspect, the present invention provides a composition for treating myelodysplastic syndrome in a patient treated with a DNA methyltransferase inhibitor, comprising lenalidomide, ezathiostat, or a salt thereof, and optionally a pharmaceutically acceptable excipient. To provide.

In another aspect, the invention provides a myelodysplastic syndrome in a patient treated with a DNA methyltransferase inhibitor, comprising a first composition comprising lenalidomide and a second composition comprising ezathiostat or a salt thereof. Provided are kits for treatment.

In another aspect, the present invention provides the use of ezathiostat or a salt thereof for the manufacture of a medicament for the treatment of myelodysplastic syndrome in a patient treated with a DNA methyltransferase inhibitor, wherein lenalidomide is ezathiostat or The patient is administered prior to and / or in combination with the salt.

These and other embodiments of the invention are further described in the following paragraphs.

Before describing the present invention in more detail, the following terms are first defined.

It is to be understood that the invention is not limited to the specific embodiments described, as the invention may, of course, vary. Moreover, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural unless the context clearly dictates otherwise. Thus, for example, referring to a "DNA methyltransferase inhibitor" includes a plurality of DNA methyltransferase inhibitors (DMTIs).

1. Definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms have the following meanings.

The term "comprising" or "comprising" means that the compositions and methods include the elements cited but do not exclude others. "Consisting essentially of" when used in defining compositions and methods should mean excluding any essentially important other elements for the combination for the purposes stated. Thus, a composition consisting essentially of the elements as defined herein will not exclude other materials or steps that do not substantially affect the basic and novel property (s) of the claimed invention. "Consisting of" means excluding more than traces of substantial process steps and other ingredients. Embodiments defined with each of these transitions are within the scope of the present invention.

The term "about" is an approximation which may vary from (+) or (-) to 15%, 10%, 5% or 1% when used before numerical specification, eg temperature, time, amount and concentration, and range. Indicates.

"Renalimide" (also known as Revamid in the UK) is an immunomodulator with antiangiogenic and antitumor properties. It is 3- (4-amino-1-oxoisoindolin-2-yl) piperidine-2,6-dione or 1-oxo-2- (2,6-dioxopiperidin-3-yl) -4 Has the chemical name of -aminoisoindolin or 3- (7-amino-3-oxo-1H-isoindol-2-yl) piperidine-2,6-dione, and the CAS Registry Number is 191732-72-6. Lenalidomide has been shown in the treatment of blood transfusion dependent patients due to low- or medium-1 risk MDS associated with deletion 5q cytogenetic abnormalities. Lenalidomide is available in 5 mg, 10 mg, 15 mg and 25 mg capsules for oral administration.

The term “therapeutically effective amount” refers to the amount of lenalidomide or ezaziostat or salt thereof corresponding to an amount sufficient to exert a therapeutic effect when administered to a subject in need thereof. In one embodiment, the therapeutically effective amount of ezathiostat or salt thereof administered will be no greater than 3.5 g per day. Preferably, the ezathiostat or salt thereof is administered in an amount of 2 g per day, more preferably in an equal amount of 1 g dose twice daily. This therapeutically effective amount is particularly appropriate when the treatment regimen has not administered the drug for one week after the administration of ezathiostat or its salts for three weeks. In another embodiment, the therapeutically effective amount of ezathiostat or salt thereof administered in a single dose will be no greater than 3 g or no greater than 1.5 g in two equivalent daily doses. Such a therapeutically effective amount is particularly appropriate when the treatment regimen has not administered the drug for one week after the administration of ezathiostat or its salts for two weeks. Preferably, the dosing regimen utilizes 2 g of ezathiostat or salts thereof in a 1 g dose twice daily, with or without drug administration for 1 week after continuous administration or for 3 weeks.

In a preferred embodiment, the therapeutically effective amount will provide an efficacy result of at least about 10%, preferably at least about 15%, of the treatment population.

As used herein, the term “treatment” or “treating” means any treatment of a patient's MDS, representing one or more of the following:

Inhibiting MDS, ie, arresting or inhibiting the onset of symptoms (eg, need for blood transfusion, abnormal blood count, etc.); And / or

● Relieve MDS, ie induce regression of symptoms.

As used herein, the term “patient” refers to a mammal and includes human or non-human mammals.

2. Method

In one embodiment, the present invention is directed to a method for treating myelodysplastic syndrome (MDS) in an MDS patient treated with a DNA methyltransferase inhibitor (DMTI).

DMTI, well known as a demethylating agent, is an agent that inhibits DNA methylation by inhibiting DNA methyltransferase activity. Methylation of DNA is a major mechanism that regulates gene expression in cells. Increasing DNA methylation can cause disturbances in the activity of "inhibitory genes" that regulate cell differentiation and growth.

Examples of DMTIs include analogs of nucleoside deoxycytidine, such as azacytidine (5-azacytidine), decitabine (5-aza-2'-deoxycytidine), 1-β-d-arabino Furanosyl-5-azacytosine and dihydro-5-azacytidine; And antisense oligodeoxynucleotides such as MG98 (manufactured by MGI Pharma, Inc.) (derived for the 3'-untranslated region of DNA methyltransferase-1 enzyme mRNA and are currently in clinical research). Other DMTIs include Lyko F and Brown R., J. Natl . Cancer Inst . , 2005 97 (20); 1498-506, which is incorporated by reference in its entirety.

5-azacytidine (or azacytidine (INN), Vidaza ?, CAS Registry Number 320-67-2) is an analog of cytidine and is represented by the formula:

.

.

Decitabine (or 5-aza-2'-deoxycytidine, Dacogen ?, CAS Registry No. 2353-33-5) is a cytosine nucleoside (cytidine) analog and a deoxy derivative of azacytidine, Is indicated by:

.

.

Both azacytidine and decitabine are used to treat myelodysplastic syndrome.

Zebularine (CAS Registry No. 3690-10-6) is another DMTI and is represented by the formula:

.

.

DMTI causes a number of side effects, including but not limited to: low blood cell counts (if leukocytes, erythrocytes, and platelets temporarily decrease, may increase the risk of infection, anemia and / or bleeding in the patient, The need for blood or platelet transfusion may be increased), fatigue, fever, nausea, cough, pointed bleeding (which can cause low platelet levels), constipation, diarrhea, hyperglycemia, headache, insomnia, swelling, hypoalbuminemia , Hypomagnesemia, chills, hypokalemia, purpura, rash, hyponatremia, dizziness, general pain and pain, heart murmur, decreased appetite, sore throat, abdominal pain, hyperbilirubinemia, hyperkalemia, oral inflammation, lethargy, abnormal liver function blood Examination, confusion, anxiety, itching and heartburn.

Because of these side effects, it is desirable for some patients being treated with DMTI to switch to other therapies, and some of these patients cannot continue DMTI therapy and must be replaced with other agents for the treatment of MDS. In addition, patients who do not respond to or insufficiently respond to DMTIs may want to switch to another MDS therapy. Other MDS patients who have been receiving DMTI to treat tumors require MDS therapy except DMTI. However, it was surprising to know in clinical trials that the potential MDS formulation, ezathiostat hydrochloride, has no effect on patients pre-exposed to DMTI treatment. As shown in Table 2, none of the evaluable patients who had been exposed to DMTI more than one time prior to administration of ezathiostat hydrochloride in this study did not respond to ezathiostat hydrochloride and had been previously exposed to DMTI. The response rate for ezathiostat hydrochloride in patients who were not present was about 22%. These results limit the patient's choice in determining alternative therapies that may replace DMTI.

 This unexpected problem is likely to maintain the therapeutic effect of ezathiostat hydrochloride in MDS treatment by administering lenalidomide prior to and / or in combination with the administration of ezathiostat hydrochloride to MDS patients who have been previously exposed to DMTI. It can be solved by the surprising discovery that it can. As shown in Table 2, the response rate of ezathiostat hydrochloride returned to about 20% in patients treated with both lenalidomide and DMTI prior to administration of ezathiostat hydrochloride.

 Thus, in one embodiment, the present invention comprises administering to the patient an amount of lenalidomide prior to and / or in combination with the administration of a therapeutically effective amount of ezatiostat or a pharmaceutically acceptable salt thereof. The present invention relates to a method for treating myelodysplastic syndrome in a patient treated with a DNA methyltransferase inhibitor.

In some embodiments, the patient is treated with one or more doses of DMTI. In some embodiments, the patient is treated with DMTI for at least 2 days, 3 days, 4 days, 5 days or 6 days. In some embodiments, the patient is treated with DMTI for at least 1 week, 2 weeks or 3 weeks. In some embodiments, the patient completes one, two, three, four, five, or six or more treatment cycles. In some embodiments, the DMTI treatment is performed immediately prior to administering ezathiostat or salts thereof. As used herein, “immediately” means that the final DMTI dose is administered about one day or less prior to the first administration of ezatiostat or salts thereof. In some embodiments, the DMTI treatment is performed less than one week prior to administering the ezathiostat or salt thereof. In some embodiments, the DMTI treatment is performed less than 1 month prior to administering the ezathiostat or salt thereof. In some embodiments, the DMTI treatment is performed less than 2 months, 6 months, or 12 months prior to administering the ezathiostat or salt thereof.

In some embodiments, the patient requires parallel treatment with DMTI and ezathiostat or salts thereof.

In some embodiments, lenalidomide is administered prior to administering ezathiostat or salts thereof. A typical lenalidomide treatment schedule involves a 28-day-cycle, during which time lenalidomide is administered once daily for 21 days (3 weeks), followed by 7 days (1 week) (Does not receive lenalidomide). The 28-day-cycle can be repeated for a period of up to 6 months. Lenalidomide capsules have four different intensities: 5 mg, 10 mg, 15 mg, and 25 mg.

In some embodiments, the patient is treated with one or more doses of lenalidomide prior to administering ezathiostat or salts thereof. In some embodiments, the patient is treated with lenalidomide for at least two days, three days, four days, five days, or six days before administering ezthiostat or salts thereof. In some embodiments, the patient is treated with lenalidomide for at least one week, two weeks, or three weeks prior to administering ezathiostat or salts thereof. In some embodiments, the patient is treated in one, two, three, four, five, or six treatment cycles prior to administering ezathiostat or salts thereof. In some embodiments, the patient is treated according to a full 6 month lenalidomide treatment plan prior to administering ezathiostat or salts thereof.

In some embodiments, the patient is administered in combination with lenalidomide and ezathiostat or salts thereof. In such cases, the patient may or may not be treated with lenalidomide prior to administering the ezathiostat or salt thereof. If the patient is prior to treatment with lenalidomide, the lenalidomide treatment may be administered in combination with ezathiostat or its salt at the same dose and / or frequency, or at a reduced dose and / or frequency Or can completely stop lenalidomide treatment.

When administered in combination, lenalidomide and ezathiostat or salts thereof can be administered in any manner in which the pharmacological effects of both are simultaneously present in the patient. Thus, co-administration of lenalidomide and ezathiostat or a pharmaceutically acceptable salt thereof does not require that a single pharmaceutical composition, the same dosage form, the same route of administration be used for the two agents. It is not required to administer two agents simultaneously or for a similar period of time. When administered substantially simultaneously in the same dosage form and in the same route of administration, it may proceed by simultaneous delivery of both active ingredients in a novel single pharmaceutical composition according to the invention. In addition to the above, it is understood that the present invention is contemplated that concurrent administration may be administration of first and second pharmaceutical compositions comprising lenalidomide and ezathiostat or salts thereof, respectively. The term “combination” includes both simultaneous delivery as well as sequential delivery, where each drug is administered separately in a manner that simultaneously provides both drugs at the serum level to the patient.

In some embodiments of the invention, when administered in combination with ezathiostat or salts thereof, lenalidomide is administered according to a typical 28-day-cycle as described above and provided according to any dosage intensity. . In some embodiments, lenalidomide may be administered at a reduced dosage and / or frequency, for example, lenalidomide is once every other day, every three, four, five or six days May be administered. Alternatively, it may be administered or discontinued once a week while continuing treatment with ezathiostat or salts thereof.

In some embodiments, the patient is pre-exposed to DMTI prior to administering lenalidomide to the patient. In some embodiments, the patient is pre-exposed to DMTI after administering lenalidomide to the patient. In some embodiments, the patient is pre-exposed to DMTI while concurrently administering lenalidomide to the patient.

In some embodiments, US patent application Ser. No. 13 / 108,752, entitled "COMPOSITIONS AND METHODS FOR TREATING MYELODYSPLASTIC SYNDROME," filed May 16, 2011, which is incorporated herein in its entirety. Is administered with ezathiostat or a salt thereof, for example ezathiostat hydrochloride.

Generally, ezathiostat or salts thereof are administered in a therapeutically effective amount. In some embodiments, up to about 3.5 g of ezathiostat hydrochloride per day, or an equivalent amount of ezathiostat itself or ezathiostat, based on the ezathiostat or salt thereof, Administration with other salts. In a preferred embodiment, the dose of ezathiostat or salt thereof is a therapeutically effective amount of up to about 1.5 g when administered twice daily (b.i.d.).

In some embodiments, the ezathiostat or salt thereof is administered daily for at least two weeks. In some embodiments, the ezathiostat or salt thereof is administered daily for at least 3 weeks.

In an embodiment of the invention, the ezathiostat or salt thereof is administered in a 1 g dose twice daily for three weeks, followed by one week of discontinuation (without administering the ezathiostat or salt thereof). After the interruption, the plan can be repeated as needed. The plan may be referred to as a “three week plan”.

In another embodiment of the invention, the ezathiostat or salt thereof is administered at a 1.5 g dose twice daily for two weeks, followed by one week of discontinuation (no administration of the ezathiostat or salt thereof). . After the interruption, the plan can be repeated as needed. The plan may be referred to as a "two week plan".

In another embodiment of the invention, the patient is continuously treated with a therapeutically effective amount of ezathiostat or its salt at 3 g or less per day, preferably at a dose of 1.5 g or less twice daily. . In this embodiment, the ezathiostat or salt thereof may be administered as long as the patient requires and can withstand such treatment. In such embodiments, it is contemplated that a therapeutically effective amount of ezathiostat or salts thereof may be lower or higher than if the treatment plan was interrupted. Such a plan may be referred to as a "continuous plan".

While twice daily administration is preferred, it is considered that once daily administration or three times daily administration may be utilized. In the former case, once daily administration aids patient compliance; In the latter case, smaller tablets may be used in patients who have difficulty swallowing larger tablets. The dose of drug will be adjusted such that the total drug administered per day is a therapeutically effective amount.

Treatment with ezathiostat or salts thereof may comprise one or a combination of two or more of the dosage regimes described above. The following illustrates the dosing schedule for ezathiostat hydrochloride:

For a total dose of 42 g, dosing 1.5 g ezathiostat hydrochloride twice per day for 2 weeks, followed by no ezathiostat or salt for 1 week;

For a total dose of 42 g, dosing 1 g ezathiostat hydrochloride twice per day for 3 weeks, followed by no ezathiostat or salt for 1 week;

Continually administering 1 g of ezathiostat hydrochloride twice per day until the primary clinician deems it appropriate for the patient to withdraw from the administration;

Administering a therapeutically effective amount of up to 3 g of ezathiostat hydrochloride per day divided by 1, 2 or 3 doses for 2 weeks, followed by no ezathiostat or salt for 1 week;

Administering a therapeutically effective amount of up to 2 g of ezathiostat hydrochloride per day in three divided doses of 1, 2 or 3 times, followed by no ezathiostat or salt for 1 week; And / or

• Continuously administer a therapeutically effective amount of up to 2 g of ezathiostat hydrochloride per day in divided doses of 1, 2 or 3 until the physician considers it appropriate to withdraw from the administration.

Equivalent amounts of ezathiostat or salts thereof (based on ezathiostat content) may replace the above doses of ezathiostat hydrochloride.

If the administration of ezathiostat or salts thereof is twice daily, the interval between the first and second administrations is preferably about 6 to 14 hours, preferably about 8 to 14 hours.

In one embodiment, ezathiostat or a salt thereof, such as ezathiostat hydrochloride, may be administered intravenously as a lipid formulation, such as those described in US Pat. No. 7,029,695, which is incorporated by reference in its entirety. have.

In one embodiment, ezathiostat or salts thereof may be administered orally. In another embodiment, ezathiostat or salts thereof may be administered as a tablet formulation. Such tablet formulations are disclosed in US patent application Ser. No. 13 / 075,116, filed March 29, 2011 under the heading "TABLET FORMULATION OF EZATIOSTAT", which is incorporated by reference in its entirety.

3. Composition

In another aspect, the present invention provides a composition for treating myelodysplastic syndrome in a patient treated with a DNA methyltransferase inhibitor, the composition comprising lenalidomide, ezathiostat or a salt thereof, and optionally a pharmaceutical. Acceptable excipients. In some embodiments, ezathiostat or a salt thereof and lenalidomide are present together in a therapeutically effective amount.

In some embodiments, the composition comprises about 5 mg, 10 mg, 15 mg or 25 mg of lenalidomide and about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg Or 1000 mg ezathiostat or salts thereof.

In one embodiment, lenalidomide may be added to the tablet formulation of ezatostat or salts thereof. Such tablet formulations are disclosed in US patent application Ser. No. 13 / 075,116, filed Mar. 29, 2011, entitled "TABLET FORMULATION OF EZATIOSTAT", which is incorporated by reference in its entirety. Included.

4. Kit

In another embodiment, the present invention provides a myelodysplastic syndrome in a patient treated with a DNA methyltransferase inhibitor comprising a first composition comprising lenalidomide and a second composition comprising ezathiostat or a salt thereof. It provides a kit for treating. In some embodiments, ezathiostat or a salt thereof and lenalidomide are present together in a therapeutically effective amount.

In some embodiments, the kit administers a first dose of lenalidomide one, two, three, four, five, six days prior to the first administration of ezathiostat or a salt thereof. Include a label with instructions for In some embodiments, the kit comprises a rabbet with instructions for administering lenalidomide one week, two weeks, three weeks, four weeks, five weeks, or six weeks prior to administering ezathiostat or salts thereof. Includes additional. In some embodiments, the kit further comprises a label with instructions for administering lenalidomide in combination with ezathiostat or a salt thereof. In some embodiments, the kit further comprises a label with instructions for administering lenalidomide and ezathiostat or salts thereof according to any dosing schedule described herein.

Example

The invention is further defined with reference to the following examples. It will be apparent to those skilled in the art that numerous modifications to both materials and methods can be made without departing from the scope of the present invention.

International prognosis scoring system International Prognostic System Score  ( IPSS )) Low to medium -1 risk Myelodysplasia  Syndrome Eza Tiostat Hydrochloride  refine

87 patients were randomized to treatment at 23 irradiation sites. After the initial administration in 14 patients, two dose levels were selected for further study. 37 patients were then treated with 3 g per day for 2 weeks, followed by a 1 week rest period, and 36 patients were treated with 2 g per day for 3 weeks, followed by a 1 week rest period. Data for the 73 patients were pooled for the preliminary analysis.

The median age was 72 years and the patient population distribution was IPSS low risk (23 patients, 32%) and medium-1 risk (50 patients, 68%). Patients received intermediate among 3 pre-MDS treatments (34 patients (47%) were pretreated with Revlimid® (lenalidomide) and 28 patients (38%) were DNA methyltransferase inhibitors) (DMTI) [pretreated with azacytidine, decitabine].

In preliminary analysis, eight patients were on treatment to sustain clinical benefit. Total blood improvement-erythrocyte (HI-E) rate was 22% (13 of 60 evaluable patients) (95% CI, 12.1-34.2). The median duration of HI-E response was 46 weeks (range 2-51). Median hemoglobin levels increased 2.0 g / dL in respondents. Eleven of 38 red blood cell (RBC) transfusion-dependent patients had a clinically significant decrease in RBC transfusion (4U / 8 week reduction, IWG 2006), with four patients (11%) independent of RBC transfusion independence. Was achieved, and 3 patients continued the treatment. In addition, one patient sustained complete relief after more than 12 months of treatment (Quddus et. Al., J. Hem. And Onc. Apr. 2010, 3:15).

Telintra? Consistently showed multi-system blood improvement. A 15% blood improvement-neutrophil (HI-N) rate was observed in 3 of 20 patients (95% CI, 3.2-37.9) and bilateral HI rate (HI-E and HI-N) was 11% (19 Of 2 patients) (95% CI, 1.3-33.1).

There are three cytogenetic complete responses, and one of the patients with 45X, -Y [4], 46, XY [16] abnormal cytogenes returned to normal after 4 cycles of treatment. Of the 4 patients enrolled in the study with a del 5q minus, 2 had a complete cytogenetic response, which was determined by prior Revlimid? Includes one who did not receive treatment.

Telintra? By evaluating all known prognostic characteristics using planned logistic regression analysis. Patients with an increased likelihood of responding to HI-E were defined. Advance DMTI Treatment Is Telintra? Predict a 5-fold decrease in the probability for the HI-E response to (p = 0.023). Dictionary Revlimid? Does Telintra? It has been observed to improve the HI-E response to.

● Dictionary Revlimid? The HI-E rate of patients treated but not pre-DMTI was 40% (6 of 15 patients, 95% CI, 16.3% -67.7%). Within this patient group, 5 of 11 patients (45%) achieved significant RBC transfusion reductions and 3 of these patients (27%) achieved transfusion independence.

● Dictionary Revlimid? The HI-E rate of untreated and pre-DMTI untreated patients was 26% (6 of 23 patients, 95% CI, 10.2% -48.4%). Within this group, 5 of 11 patients (45%) achieved a significant decrease in RBC transfusions.

● Dictionary Revlimid? The HI-E rate of untreated but pre-DMTI treated patients was 0% (0 of 17 patients, 95% CI, 0% -19.5%).

Telintra over 403 cycles? Treatment was administered. Safety data is based on all patients treated. The most common non-blood adverse events (AEs) were nausea (45%, 16%), diarrhea (25%, 7%) and vomiting (30%, 12%), which are grade 1 and 2 gastrointestinal (GI), respectively. . Grade 3 cases were rare: nausea (1%), diarrhea (3%) and vomiting (2%). Prior DMTI treatment is associated with an increased incidence of GI AEs.

Telintra? Treatment may lead to clinically significant blood improvement in patients with MDS and may provide an alternative to RBC transfusion. These results are Telintra? Consistent with the level of efficacy observed in prior studies with (the first GST P1-1 enzyme inhibitor tested in MDS patients).

Tables 1 and 2 summarize the results of these clinical studies.

Table 1

Blood improvement-red blood cells (HI-E): time to response and duration of response

Initiated Telintra? Dose 3,000 mg / day (1.5 g b.i.d.) or 2,000 mg / day (1 g b.i.d.)

(Efficacy evaluation group)

[1] 1 divided by 7 plus the number of days from the first administration of the test agent to the day on which the response was first recorded.

[2] The total number of days for which the response was shown divided by seven.

Table 2

Blood Improvement-Red Blood Cells (HI-E): Revlimid? And use of DNA methyltransferase inhibitor disorder states

(Efficacy evaluation group)

[1] RBC transfusion reduction from baseline => 4 units per 8 weeks; Or achieve hemoglobin increase of hemoglobin <11 g / dL, maintained for a period of 8 weeks> = 1.5 g / dL in patients with transfusion-independent symptomatic anemia.

[2] Contains azacytidine or decitabine.

Table 2 shows the following: (1) Revlimid? Or Telintra to patients without prior DMTI treatment. If you provide Telintra? The response rate is about 22%, and (2) Telintra? If patients were given Telintra? Without responding, and (3) Telintra? Revlimid before treatment? And Telintra from patients treated with both DMTI? Response rate for is about 20%.

Claims (12)

Ezathiostat or salts thereof for the treatment of myelodysplastic syndromes in patients treated with DNA methyltransferase inhibitors, wherein lenalidomide is administered before and / or in combination with ezathiostat or salts thereof to the patient Pharmaceutical comprising a. The agent according to claim 1, wherein lenalidomide is administered before administration of ezaziostat or a salt thereof. The agent according to claim 1, wherein lenalidomide is administered in combination with administration of ezathiostat or a salt thereof. The agent according to any one of claims 1 to 3, wherein the ezathiostat or salt thereof is administered daily for at least two weeks. The agent according to any one of claims 1 to 3, wherein the ezaziostat or a salt thereof is orally administered. The agent according to any one of claims 1 to 3, wherein the ezathiostat or a salt thereof is ezathiostat hydrochloride. 7. The medicament of claim 6, wherein the ezathiostat hydrochloride is administered according to a treatment schedule comprising a one-week suspension without administration of ezathiostat or its salt after administration of 2 g of the daily dose for three weeks. 7. The agent according to claim 6, wherein the ezathiostat hydrochloride is administered according to a treatment schedule comprising a one-week discontinuance of administration of 3 g of the daily dose for 3 weeks followed by no ezathiostat or salt thereof. A composition for treating myelodysplastic syndromes in a patient treated with a DNA methyltransferase inhibitor comprising lenalidomide, ezathiostat or a salt thereof, and optionally a pharmaceutically acceptable excipient. The composition of claim 9, wherein the ezathiostat or salt thereof and lenalidomide are present in a therapeutically effective amount together. A kit for treating myelodysplastic syndrome in a patient treated with a DNA methyltransferase inhibitor, comprising a first composition comprising lenalidomide and a second composition comprising ezathiostat or a salt thereof. 12. The kit of claim 11, wherein the ezathiostat or salt thereof and lenalidomide are present together in a therapeutically effective amount.