MX2011009301A - Compositions and methods for treating myelodysplastic syndrome. - Google Patents

Abstract

The invention generally relates to regimes for treating myelodysplastic syndrome.

Description

COM POSITIONS AND M ETHODS TO TREAT YES N DROM E MY ELODISPLASI CO Field of the invention This invention relates to compositions and methods for treating myelodysplastic syndrome.

State of the art Myelodysplastic syndrome (s) (MDS) refers to a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis (production of blood cells) 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 approximately 300,000 people around the world. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed each year in the United States alone. Survival rates using current therapy vary from 6 months to 6 years with patients often requiring blood transfusions to manage their disease.

Currently, there are three drugs approved to treat MDS by the U. S. Food and Drug Administration (FDA). Lenalidomide is indicated for the treatment of transfusion-dependent MDS patients with (5q) and lower risk of disease, while azacitidine and decitabine are approved for all categories. With the exception of patients of (5q), the response rate is approximately 50%, highlighting the need for clinical trials of new agents.

Ezatiostat and its salts are described in U.S. Pat. 5,763, 570. Ezatiostat has the chemical name IUPAC of (2S) -2-amlno-5 - [[(2R) -3-benzylsulfanyl-1 - [[(1 R) -2-ethoxy-2-oxo-1 ethyl phenylethyl] amino] -1-oxopropan-2-yl] amino] -5-oxopentanoate.

An example of an ezatiostat salt is the hydrochloride salt, ezatiostat hydrochloride (USAN), which has the molecular weight of 566.1, the Telintra® trademark and the CAS registry number of 286942-97-0. The US patent application no. 13/041, 1 36, filed on March 4, 201 1, describes a solvate and polymorphs of ezatiostat hydrochloride.

Ezatiostat hydrochloride has been evaluated for the treatment of MDS, in a Phase II study using a liposomal formulation (US Patent No. 7,029,695), as reported in the 2005 Annual Meeting of the American Society for Hematology (Abstract # 2250 ) and by Raza et al. , in Journal of Hematology & Oncology, 2:20 (published online May 1, 2009); and in a Phase I study using a tablet formulation, as reported in the 2007 Annual Meeting of the American Society for Hematology (Abstract # 1454) and by Raza et al. in Blood, 1 1 3: 6533-6540 (prepublished online April 27, 2009), and in a single patient case report by Quddus et al. in Journal of Hematology & Oncology, 3: 16 (published on line 23 of April 2010).

The full descriptions of each of the patents, patent applications and publications referred to in this application are incorporated in this application by reference.

BRIEF DESCRIPTION OF THE INVENTION In one embodiment, this invention is directed to a method of treating MDS in a patient, said method comprising administering to that patient a therapeutically effective amount of ezatiostat or a salt thereof equivalent to about 2 grams (g) per day of ezatiostat hydrochloride. for at least 2 weeks. In a preferred embodiment, the dosage of ezatiostat or a salt thereof is a therapeutically effective amount of up to about 1 gram of ezatiostat hydrochloride (or equivalent) administered twice daily (b. I.d.). In one embodiment, ezatiostat or a salt thereof is administered orally.

In one embodiment of this invention, the patient is treated with ezatiostat or a salt thereof equivalent to about 2 grams per day of ezatiostat hydrochloride for three weeks followed by a one week break without ezatiostat treatment. After the fourth week, the regimen can be repeated as necessary. Preferably, the ezatiostat or a salt thereof is administered twice a day, for example in equal doses.

In another aspect, this invention is directed to the use of a therapeutically effective amount of ezatiostat or a salt thereof for the preparation of an oral medicament for treating a myelodysplastic syndrome, said ezatiostat or a salt thereof is equivalent to approximately 2 grams of hydrochloride of ezatiostat per day for at least 2 weeks.

In another embodiment of this invention, the patient is continuously treated with a therapeutically effective amount of ezatiostat or a salt thereof equivalent 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 when there is a weekly break in the treatment regimen.

In one embodiment, ezatiostat or a salt thereof can be administered as a tablet formulation. Such a tablet formulation is described in U.S. patent application no. 13/075, 1 16, filed on March 29, 201 1, entitled "TABLET FORMULATION OF EZATIOSTAT" (Formulation of ezatiostat tablets), which is incorporated by reference in its entirety.

These and other embodiments of this invention are further described in the text that follows.

Detailed description of the invention As indicated above, this invention is directed to a treatment regimen for treating MDS using ezatiostat or a salt thereof. However, before describing this invention in detail, the following terms will be defined.

It should be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the," include plural referents unless the context clearly dictates otherwise. . Thus, for example, the reference to "a pharmaceutically acceptable excipient" includes a plurality of pharmaceutically acceptable excipients.

The term "comprising" or "comprises" means that the compositions and methods include the declared elements, but do not exclude others. "Consists essentially of" when used to define compositions and methods, shall mean that it excludes other elements of any essential importance 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 characteristics of the claimed invention. "Consists of" means that it excludes more than trace elements of other ingredients and substantial method steps. The modalities defined for each of these transition terms are within the scope of this invention.

As used herein, the term "treatment" or "treating" means any treatment of MDS in a patient that produces one or more of the following: • Inhibit the disease or condition, that is, stop or suppress the development of symptoms (eg, need for blood transfusion, abnormal blood counts and the like); I • Relieve the disease or condition that is, cause the regression of symptoms.

As used herein, the term "patient" refers to mamphers and includes humans and non-human mammals.

The term "approximately" when used before a numerical designation, for example, temperature, time, amount and concentration, including range, indicates approximations which may vary by (+) or (-) 1 5%, 10%, 5 % or 1%.

The term "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 up to about 2 grams per day of ezatiostat hydrochloride administered per day. Preferably, 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 doses of 1 gram. 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 without administration of the drug. However, it is contemplated that the therapeutically effective amounts used in continuous administration may be less than the amounts used during a three-week treatment cycle followed by a week without administration.

Although twice daily administration is preferred, it is contemplated that administration once a day or administration of 3 times a day could be used in the first case, administration once a day would help the patient's condescension; While in the latter case, smaller tablets could be used for those patients who have difficulty swallowing larger tablets.

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

Methods of the invention In one embodiment, this invention is directed to a method of treating MDS in a patient in need thereof, said method comprising orally administering to that patient a therapeutically effective amount of ezatiostat or a salt thereof equivalent to about 2 grams per day of hydrochloride. of ezatiostat for at least 2 weeks. In a preferred embodiment, the dosage of ezatiostat or a salt thereof is a therapeutically effective amount of up to about 1 gram of ezatiostat hydrochloride (or equivalent) administered twice a day.

In one embodiment of this invention, ezatiostat or a salt thereof is admistated in dosages of 1 gram twice a day for three weeks followed by a 1 week break. After the interruption, the regimen can be repeated as necessary. This regimen can be referred to as the "three-week regimen".

In another embodiment of this invention, the patient is continuously treated with a therapeutically effective amount of ezatiostat or a salt thereof equivalent to about 2 grams per day of ezatiostat hydrochloride, preferably in two divided doses, for at least two weeks. In this modality, ezatiostat or a salt thereof can be administered as 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 regime can be referred to as the "continuous regime".

Treatment with ezatiostat or a salt thereof may involve one or a combination of two or more of the dosage regimens described herein. The following are example dosing schedules of ezatiostat hydrochloride: • 1 gram of ezatiostat hydrochloride (or equivalent of ezatiostat or other salt) given twice a day for 3 weeks for an aggregate total dosage of 42 grams followed by a week when ezatiostat or a salt is not given; • 1 gram of ezatiostat hydrochloride (or equivalent of ezatiostat or other salt) given twice a day continuously until the attending physician considers it appropriate to withdraw the patient from administration; • A therapeutically effective amount of up to 2 grams of ezatiostat hydrochloride (or equivalent of ezatiostat or other salt) per day administered in one, two or three divided doses for 3 weeks, followed by one week without administration of ezatiostat or a salt; • A therapeutically effective amount of up to 2 grams of ezatiostat hydrochloride (or equivalent of ezatiostat or other salt) per day administered in one, two or three divided doses continuously until the attending physician deems it appropriate to withdraw the patient from administration.

The ezatiostat hydrochloride in the above dosages can be replaced with an equivalent amount (in terms of ezatiostat content) of ezatiostat by itself or another salt of ezatiostat.

In the above treatment regimens, ezatiostat or a salt thereof can be administered as a tablet. Examples of such tablet formulation are described in U.S. patent application no. 13/075, 1 16, filed on March 29, 201 1, entitled "TABLET FORMU LATION OF EZATIOSTAT" (Formulation of ezatiostat tablets), which is incorporated by reference in its entirety.

When the administration of ezatiostat or a salt thereof is twice a day, it is preferred that the interval between the first and second doses be from about 6 to 14 hours and preferably between about 8 and 14 hours.

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

Eighty-seven patients were randomized and treated in 23 research sites. After varying the initial dose in 14 patients, two dose levels were selected for further study. Subsequently, 37 patients were treated with 3 grams daily for two weeks followed by a one-week rest period, and 36 patients were treated at 2 grams daily for three weeks followed by a one-week rest period. Data on these 73 patients were deposited for this preliminary analysis.

The median age was 72 years, with a population distribution of low risk patients of the International Prognostic Rating System (I PSS) (23 patients, 32%) and intermediate risk-1 (50 patients, 68%). The patients had received a median of three previous MDS therapies including, 34 patients (47%) with Previous Revlimid® (lenalidomide) and 28 patients (38%) with previous DNA methyltransferase inhibitors (ITEM) [azacitidine, decitabine].

At the time of preliminary analysis, 8 patients remained in treatment to continue the clinical benefit. The global hematologic-erythroid (HL-E) improvement rate was 22%, 13 of 60 evaluable patients (95% Cl, 1 2. 1 -34.2). The median duration of response of H l-E was 46 weeks (range 2-51). The median hemoglobin level increased by 2.0 gram / dl in responders. Eleven of 38 patients dependent on red blood cell transfusion (RBC) (29%) had clinically significant reductions in RBC transfusion (reduction of 4U / 8 weeks, IWG 2006) with 4 patients (11%) achieving RBC transfusion independence and 3 patients continuing treatment. In addition, one patient continued in complete remission for more than 12 months, following discontinuation of therapy (Quddus, et al., J. Hem., And Onc. Apr. 201 0, 3: 15).

Telintra® continues to demonstrate the multilineage hematologic improvement. There was a haematological-neutrophil (Hl-N) improvement rate of 1 5% observed in 3 of 20 patients (95% Cl, 3.2-37.9) and the Hl rate of bilination (Hl-E and H lN) was 1 1% , 2 of 19 patients (95% Cl, 1 .3-33.1).

There were three complete cytogenetic responses, one in a patient with 45X, and [4], 46, XY [16] abnormal cytogenetics that became normal after four cycles of therapy. Of the four patients enrolled in this study with the 5q minus, two had a complete cytogenetic response, including one that had failed previous Revlimid® therapy.

A planned logistic regression analysis was used to evaluate all known prognostic characteristics in order to define those patients who had an increased likelihood of H l-E response to Telintra®. The treatment of previous ITIM predicts a fivefold decrease in the possibilities of an Hl-E response to Telintra® (p = 0.023). It was observed that the previous Revlimid® treatment intensifies the response of Hl-E to Telintra®.

• There was an HL-E rate of 40% (6 of 15 patients, 95% CI, 16.3% - 67.7%) in patients who had had previous Revlimid® treatment, but without previous TIMM treatment. Within this group of patients, five of 1 1 patients (45%) achieved a reduction in transfusion of significant RBC with three of those patients (27%) achieving independence of transfusion.

• There was an HL-E rate of 26% (6 of 23 patients, 95% CI, 10.2% - 48.4%) in patients who did not have prior Revlimid® treatment and without previous TIMM treatment. Within this group, five of 11 patients (45%) achieved a significant reduction in RBC transfusion.

• There was a Hl-E rate of 0% (0 of 17 patients, 95% Cl, 0% - 19.5%) in patients who did not have previous Revlimid® treatment but who had received previous TIMM treatment.

More than 403 Telintra® therapy cycles have been administered. The safety data are based on all treated patients. The most common non-haematological adverse events (AEs) were gastrointestinal (Gl) grade 1 and 2 respectively, nausea (45%, 16%), diarrhea (25%, 7%) and vomiting (30%, 1 2%). Grade 3 events were not common: nausea (1%), diarrhea (3%) and vomiting (2%). Previous DMT treatment was associated with an increased incidence of Gl AEs.

The treatment of Telintra® may result in clinically significant hematologic improvement in patients with DSM and may offer an alternative to TB transfusions. These results are consistent with levels of efficacy observed in previous studies with Telintra®, the first inhibitor of GST P1 -1 enzyme tested in MDS patients.

The following table summarizes the results of the clinical study.

The data show both administration of 2 grams of ezatiostat hydrochloride per day over a period of 3 weeks and administration of 3 grams of ezatiostat hydrochloride per day over a period of 2 weeks provided efficacy to treat M DS. Additionally and unexpectedly, the data show that administration of 2 grams of medication per day over a 3-week period gave a response duration of 46.1 weeks versus 18.4 weeks when 3 grams of ezatiostat hydrochloride per day were administered over a period of 2 weeks.

Table 1 Haematological-erythroid improvement (HI-E): Response time and response duration starting with Telintra® dose of 3,000 mg / day (1.5 g b.i.d.) or 2,000 mg / day (1 g b.i.d.) (Efficacy of evaluable population) [1] Days from the date of the first dose of study medication to the date of the first response documentation plus one divided by 7. [2] Total number of days where the answer is seen divided by 7.

Claims (10)

REIVI N DICACIONES

1 . The use of ezatiostat or a salt thereof for the preparation of an oral medicament for treating a myelodysplastic syndrom, said ezatiostat or a salt thereof is equivalent to approximately 2 grams of ezatiostat hydrochloride per day for at least 2 weeks.

2. The use of claim 1, wherein the ezatiostat or a salt thereof is ezatiostat hydrochloride.

3. The use of claim 1, wherein said therapeutically effective amount of ezatiostat hydrochloride is 2 grams per day.

4. The use of claim 3, wherein the ezatiostat hydrochloride is admistated in two doses of 1 gram separated per day.

5. The use of claim 4, wherein the second dose is administered at a range from 6 to 14 hours after the first dose.

6. The use of any of claims 1-5, wherein the ezatiostat or a salt thereof is administered in a tablet form.

7. The use of ezatiostat or a salt thereof for the preparation of a drug to treat myelidosplastic syndrome, said ezatiostat or salt thereof is equivalent to dosages of 1 gram of ezatiostat hydrochloride twice a day for three weeks followed by a week where nothing of ezatiostat or a salt thereof is administered.

8. The use of claim 7, wherein after the fourth week, the administration of ezatiostat or a salt thereof is repeated.

9. The use of claim 7 or claim 8, wherein the ezatiostat or a salt thereof is administered in a tablet form.

10. A method for treating a myelodysplastic syndrome in a patient, said method comprises orally administering to said patient a therapeutically effective amount of ezatiostat or a salt thereof equivalent to about 2 grams per day of ezatiostat hydrochloride for at least 2 weeks.