Methods of treating myelodysplastic syndrome

Abstract

This disclosure provides methods of treating a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject in need thereof, wherein the subject treated is classified as having an intermediate-2 or high IPSS risk MDS or AML; or has MDS or AML relapsed, refractory, or intolerant to HMA, venetoclax, or a combination thereof. The method includes administering to the subject an effective amount of a telomerase inhibitor or a pharmaceutically acceptable salt thereof, such as e.g. imetelstat or imetelstat sodium.

Description

Attorney Docket No.: GERN-203WOMETHODS OF TREATING MYELODYSPLASTIC SYNDROMEINCORPORA TION-BY-REFERENCE OF SEQUENCE LISTING XML

[0001] A Sequence Listing is provided herewith as a Sequence Listing XML, “GERN- 203WO_SEQ_LIST” created on October 31, 2025, and having a size of 1,952 bytes. The contents of the Sequence Listing XML are incorporated by reference herein in their entirety.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 855,785, filed August 1, 2025; and U.S. Provisional Application No. 63 / 716,631, filed November 5, 2024, the disclosures of which arc incorporated herein by reference in their entireties.FIELD OF THE DISCLOSURE

[0003] The present application relates to treating myelodysplastic syndrome (MDS), such as IPSS Intermediate-2 risk or high risk MDS or acute myeloid leukemia (AML). The method comprises administering a telomerase inhibitor, such as imetelstat to a subject in need thereof. In certain aspects, the subject is refractory, relapsing, or intolerant to treatment with a hypomethylating agent (HMA), venetoclax, or both.BACKGROUNDA. Myelodysplastic syndromes

[0004] Myelodysplastic syndromes (MDS) are a group of symptoms that includes cancer of the blood and bone marrow. They also include diseases such as refractory anemia, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, and chronic myelomonocytic leukemia. The MDS are a collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells. In MDS, the immature blood stem cells (blasts) do not become healthy red blood cells, white blood cells, or platelets. The blasts die in the bone marrow or soon after traveling to the blood leaving less room for healthy white cells, red cells, and / or platelets to form in the bone marrow.Attorney Docket No.: GERN-203WO

[0005] MDS primarily affect the elderly and is characterized by anemia and other cytopenias and a high risk of leukemic transformation (Cheson et al., Blood 2006;108:419- 425). In clinical practice, MDS are suspected when an otherwise unexplained anemia is associated with other cytopenias, increased mean corpuscular volume, or increased red cell distribution width. Diagnosis involves bone marrow examination and cytogenetic studies. The bone marrow is typically hyperproliferative. Diagnosis is based on demonstration of erythroid, granulocyte, or megakaryocyte dysplasia in 10% or more of informative cells (Vardiman, et al., Blood 2009; 114(5):937-951 ). MDS may progress over time. For example, patients with MDS often develop severe anemia and require frequent blood transfusions. Bleeding and risk of infections also occur due to low or dysfunctional platelets and neutrophils, respectively. In some embodiments, the disease worsens and the patient develops cytopenias (low blood counts) caused by progressive bone marrow failure. In other embodiments, the disease transforms into acute myelogenous leukemia (AML). If the overall percentage of bone marrow myeloblasts rises above a particular cutoff (20% for World Health Organization (WHO) and 30% for French-American-British (FAB) subtypes), then transformation to AML is said to have occurred.

[0006] The standard prognostic tool for assessing MDS is the International Prognostic Scoring System (IPSS), which classifies patients into low, intermediate- 1, intcrmcdiatc-2, and high-risk categories based on several prognostic variables including bone marrow blasts, cytogenetics, and presence of cytopenias. The median survival for these four groups has been estimated at 5.7, 3.5, 1.2, and 0.4 years, respectively. The median times for 25% of patients in these groups to develop AML were 9.4, 3.3, 1.1 and 0.2 years, respectively (Greenberg et al., Blood 1997; 89(6):2079-2088). Patients with low and intermediate- 1 risk MDS may be referred to as having “lower-risk” disease, whereas those with intermediate-2 and high risk MDS may be referred to as patients with “higher-risk” disease.

[0007] In patients aged >70 years in Western countries, the incidence of MDS is conservatively estimated approximately at 30 to 40 cases per 100,000 population per year. Due to an aging population, the number of cases of MDS is expected to escalate. Despite the reduced rate of leukemic transformation of lower-risk patients, most patients are affected by anemia and anemia-related symptoms with profound effects on patient-reported outcomes (Almeida et al., Leukemia Res. 2017; 52:50-57). Many anemic patients with MDS eventually develop dependence on red blood cell (“RBC”) transfusions; evidence suggests that iron overload resulting from chronic RBC transfusion may be a contributing factor in the overall morbidity of the disease (Malcovati et al., J Clin Oncol 2005;23:7594-Attorney Docket No.: GERN-203WO7603; Malcovati et al., Haematologica 2006;91 :1588-1590; Steensma DP., Mayo Clinic Proc. 2015;90(7):969-983). Analysis of retrospective data from 426 patients diagnosed with MDS according to WHO criteria in Italy between 1992 and 2004 showed that a transfusion requirement of 2 units per month reduces the life expectancy of a patient with MDS by approximately 50% (Malcovati et al., Haematologica 2006).B. Current treatments for IPSS Intermediate-2 or High Risk MDS

[0008] The treatment strategy for MDS is largely based on the IPSS score. In patients classified as IPSS intermediate-2 or high risk (higher-risk MDS), with median survival if untreated of only about 12 months, the treatment goal is modifying the disease course, avoiding progression to AML, and extending survival.

[0009] Hypomethylating agents (HMAs), alone or in combination with venetoclax (VEN), are the standard for patients with HR-MDS or AML not eligible for intensive chemo or allogeneic stem cell transplantation. However, many patients do not respond or subsequently relapse, resulting in poor outcomes with very limited further treatment options.Hypomethylating agents

[0010] Hypomethylating agents (HMA) (e.g. azacitidine and decitabine) have been approved as treatments for all French- American-British (FAB) subtypes, which includes some lower-risk MDS patients. These drugs reduce transfusion requirements in higher-risk MDS patients, but evidence for improvement of long-term outcomes for lower-risk patients who receive HMAs after ESA failure is absent.Other treatment options

[0011] Allogeneic stem cell transplantation is typically reserved for medically fit higher-risk MDS patients. However, limited treatment options are otherwise presently available to patients with high-risk MDS, especially when the first line treatment with ESAs has failed and patients become dependent on RBC transfusion. For patients with high risk MDS or AML who are relapsed or refractory to HMA therapy, there is a need for treatment options that delay or avoid transfusion dependence and the associated risks.BRIEF DESCRIPTION OF DRAWINGS

[0012] FIG. 1 describes the study design for the Phase II trial described in Example 1.Attorney Docket No.: GERN-203WOBRIEF SUMMARY OF THE DISCLOSURE

[0013] The present disclosure provides using telomerase inhibitors, such as e.g. imetelstat, in the treatment of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject in need thereof. In some embodiments, the subject in need thereof is relapsed, refractory, or intolerant to HMA, veneteclax, or a combination thereof.

[0014] In some embodiments, the subject is classified as having intermediate-2 or high risk MDS, or AML. In certain such embodiments, the subject is relapsed, refractory, or intolerant to HMA, venetoclax, or a combination thereof.

[0015] The methods disclosed herein include administering to the subject an effective amount of a telomerase inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the telomerase inhibitor is imetelstat sodium.

[0016] One embodiment disclosed herein is a method of treating a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) comprising administering to a subject in need thereof an effective amount of a telomerase inhibitor. Another embodiment disclosed herein is a method of treating a MDS or AML comprising administering to a subject in need thereof an effective amount of imetelstat. In certain other embodiments, the MDS or AML subject is relapsed, refractory, or intolerant to HMA, venetoclax, or a combination thereof. In some embodiments, the subject is classified as having intermediate-2 or high risk MDS, or AML.

[0017] The subject may be transfusion dependent. In at least one embodiment, the transfusion dependent subject has a transfusion requirement of about four units or more during the 8 weeks prior to the administration of the telomerase inhibitor.

[0018] The subject may also be a non-del5q human patient. The subject may also, or alternatively, be classified as being an intermediate- 2 or high IPSS risk MDS subject. In certain embodiments, the subject is classified as an intermediate-2 or high IPSS risk MDS subject and is non-del5q. In some embodiments disclosed herein, the MDS is relapsed or refractory MDS and the subject is classified as an intermediate-2 or high IPSS risk MDS subject.

[0019] In certain embodiments, the MDS or AML subject is relapsed, refractory, or intolerant to treatment with venetoclax, HMA, or both. In certain embodiments, the MDS or AML subject is relapsed, refractory, or intolerant to treatment with venetoclax. In other embodiments, the MDS or AML subject is relapsed, refractory, or intolerant to treatment with HMA. The HMA may be decitabine, azacitidine, or both. Accordingly, in at least oneAttorney Docket No.: GERN-203WO embodiment, the MDS or AML subject is relapsed, refractory, or intolerant to treatment with decitabine. In another embodiment, the MDS or AML subject is relapsed, refractory, or intolerant to treatment with azacitidine (also known as 5-azacytidine or azacytidine).

[0020] Another embodiment disclosed herein is a telomerase inhibitor, such as e.g. imctclstat, for use in treating a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). In some embodiments, the MDS or AML subject is relapsed, refractory, or intolerant to treatment with an agent selected from a hypomethylating agent (HMA), venetoclax, and a combination thereof. Alternatively, the MDS or AML subject is relapsed, refractory, or intolerant to treatment with an agent selected from a hypomethylating agent (HMA) and venetoclax. In at least one embodiment, the MDS or AML subject is relapsed, refractory, or intolerant to treatment with venetoclax. In another embodiment, the HMA is selected from decitabine and azacitidine, and the MDS or AML subject is relapsed, refractory, or intolerant to treatment with decitabine or azacitidine. The MDS or AML subject may also be relapsed, refractory, or intolerant to treatment with both decitabine and azacitidine.

[0021] In certain embodiments, the subject is classified as an intermediate- 2 or high IPSS risk MDS subject. In certain embodiments, the subject is classified as an AML subject.

[0022] The subject may also be transfusion dependent, a non-dcl5q human patient, or both. In alternate embodiments, subject is transfusion dependent subject and has a transfusion requirement of about 4 units or more during the 8 weeks prior to the administration of the telomerase inhibitor. In other embodiments, the subject is classified as a low or intermediate- 1 IPSS risk MDS subject and is non-del5q. Alternatively, the MDS is relapsed or refractory MDS and the subject is classified as an intermediate-2 or high IPSS risk MDS subject.

[0023] Yet another embodiment disclosed herein is use of a telomerase inhibitor, such as e.g. imetelstat, to treat a myelodysplastic syndrome (MDS) in a subject. Such uses also include, use of the telomerase inhibitor in the manufacture of a medicament for treating a myelodysplastic syndrome (MDS) in a subject. Yet an alternate embodiment disclosed herein is use of a telomerase inhibitor, such as e.g. imetelstat, to treat a myelodysplastic syndrome (MDS) in a non-del5q human patient. Such uses also include, use of the telomerase inhibitor in the manufacture of a medicament for treating a myelodysplastic syndrome (MDS) in a non-del5q human patient. In certain other embodiments of the uses, the subject is relapsed, refractory, or intolerant to treatment with an agent selected from a hypomethylating agent (HMA), venetoclax, and a combination thereof. The HMA may beAttorney Docket No.: GERN-203WO selected from decitabine and azacitidine. In certain embodiments, the subject is classified as an intermediate-2 or high IPSS risk MDS or AML subject and may also be transfusion dependent, a non-del5q human patient, or both. In other embodiments, the subject is transfusion dependent subject and has a transfusion requirement of about 4 units or more during the 8 weeks prior to the administration of the telomerase inhibitor. In additional embodiments, the subject is classified as an or intermediate-2 or high IPSS risk MDS or AML subject and is non-del5q. Alternatively, the MDS is relapsed or refractory MDS and the subject is classified as an intermediate-2 or high IPSS risk MDS subject.

[0024] The telomerase inhibitor may be imetelstat or a pharmaceutically acceptable salt thereof. For example, the telomerase inhibitor may be imetelstat sodium. In other embodiments, the telomerase inhibitor is imetelstat as well as tautomers, and pharmaceutically acceptable salts thereof. In certain embodiments, imetelstat is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising: intravenous administration of about 7-10 mg / kg imetelstat once every two weeks; intravenous administration of about 7-10 mg / kg imetelstat once every four weeks; intravenous administration of about 7-10 mg / kg imetelstat once weekly for four weeks; intravenous administration of about 2.5-10 mg / kg imetelstat once every three weeks, or intravenous administration of about 0.5-9.4 mg / kg imetelstat once every four weeks. In at least one embodiment, each dosage cycle comprises intravenous administration of about 7- 10 mg / kg imetelstat, alternatively about 7.5 mg / kg, once every four weeks. In at least one embodiment, each dosage cycle comprises intravenous administration of about 7-10 mg / kg imetelstat, alternatively about 7.5 mg / kg, once every two weeks.

[0025] In at least one embodiment of the telomerase inhibitor for use in treating a MDS or AML, the telomerase inhibitor is imetelstat or a pharmaceutically acceptable salt thereof. Similarly, in at least one embodiment of the use of a telomerase inhibitor, the telomerase inhibitor is imetelstat or a pharmaceutically acceptable salt thereof. In either embodiments, the use may include administration for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles. In this embodiment, the dosage cycle may comprise: intravenous administration of about 7-10 mg / kg imetelstat once every two weeks; intravenous administration of about 7-10 mg / kg imetelstat once every four weeks; intravenous administration of about 7-10 mg / kg imetelstat once weekly for four weeks; intravenous administration of about 2.5-10 mg / kg imetelstat once every three weeks; or intravenous administration of about 0.5-9.4 mg / kg imetelstat once every four weeks. Accordingly, in at least one embodiment, each dosage cycle comprises intravenous administration of about 7-10 mg / kg imetelstat once every two or fourAttorney Docket No.: GERN-203WO weeks. In another embodiment, each dosage cycle comprises intravenous administration of about 7.5 mg / kg imetelstat once every four weeks.DETAILED DESCRIPTION OF THE DISCLOSURE

[0026] This disclosure provides methods of treating a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject by administering an effective amount of a telomerase inhibitor, such as imetelstat or a pharmaceutically acceptable salt thereof. In some embodiments, the subject treated is classified as having: intcrmcdiatc-2 IPSS risk MDS, high IPSS risk MDS, AML, or MDS or AML that is relapsed, refractory, or intolerant to treatment with an agent selected from a hypomethylating agent (HMA), venetoclax, and a combination thereof. The subject may also be non-del5q. For clarity of disclosure, and not by way of limitation, the detailed description is divided into subsections that describe or illustrate certain features, embodiments, or applications of the present disclosure.A. Definitions

[0027] As used herein, the term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of between ± 20% and ± 0.1%, such as ± 20% or ± 10%, such as ± 5%, such as ± 1%, and such as ± 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0028] The term “pharmaceutically acceptable salt” means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, and the like. Pharmaceutically acceptable salts of interest include, but are not limited to, aluminum, ammonium, arginine, barium, benzathine, calcium, cholinate, ethylenediamine, lysine, lithium, magnesium, meglumine, procaine, potassium, sodium, tromethamine, N-methylglucamine, N,N'-dibenzylethylene- diamine, chloroprocaine, diethanolamine, ethanolamine, piperazine, zinc, diisopropylamine, diisopropylethylamine, triethylamine and triethanolamine salts.Attorney Docket No.: GERN-203WO

[0029] The term “salt(s) thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. In some embodiments, the salt is a pharmaceutically acceptable salt. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt. Salts of interest include, but are not limited to, aluminum, ammonium, arginine, barium, benzathine, calcium, cesium, cholinate, ethylenediamine, lithium, magnesium, meglumine, procaine, N-methylglucamine, piperazine, potassium, sodium, tromethamine, zinc, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, ethanolamine, piperazine, diisopropylamine, diisopropylethylamine, triethylamine and triethanolamine salts. It is understood that for any of the oligonucleotide structures depicted herein that include a backbone of internucleoside linkages, such oligonucleotides may also include any convenient salt forms. In some embodiments, acidic forms of the internucleoside linkages are depicted for simplicity. In some embodiments, the salt of the subject compound is a monovalent cation salt. In certain embodiments, the salt of the subject compound is a divalent cation salt. In some embodiments, the salt of the subject compound is a trivalent cation salt. “Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.

[0030] “Stereoisomer” and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include for example cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically non-feasible. All stereoisomers are intended to be included within the scope of the present disclosure.

[0031] A person of ordinary skill in the art would recognize that other tautomeric arrangements of the groups described herein are possible. It is understood that all tautomeric forms of a subject compound are encompassed by a structure where one possible tautomeric arrangement of the groups of the compound is described, even if not specifically indicated.Attorney Docket No.: GERN-203WO

[0032] It is intended to include a solvate of a pharmaceutically acceptable salt of a tautomer of a stereoisomer of a subject compound. These are intended to be included within the scope of the present disclosure.

[0033] The present disclosure is not limited to the certain embodiments described, as such may vary. Moreover, the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to be limiting.

[0034] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the present disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the present disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the present disclosure.

[0035] 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 the present disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, representative illustrative methods, and materials are now described.

[0036] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0037] It is 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. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.Attorney Docket No.: GERN-203WO

[0038] Each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0039] As used throughout, “MDS” refers to myelodysplastic syndrome or myelodysplastic syndromes.B. Treatment

[0040] Aspects of the present disclosure include methods of treating a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with a telomerase inhibitor in a subject. In some embodiments, the subject has intermediate-2 or high IPSS risk MDS. In some embodiments, the subject has MDS or AML and is refractory, relapsing, or intolerant to treatment with a hypomethylating agent (HMA), venetoclax, or both.

[0041] A subject is a mammal in need of treatment for cancer. Generally, the subject is a human patient. In some embodiments of the present disclosure, the subject can be a nonhuman mammal such as a non-human primate, an animal model (e.g., animals such as mice and rats used in screening, characterization, and evaluation of medicaments) and other mammals. As used herein, the terms “patient,” “subject,” and “individual” are used interchangeably.

[0042] As used herein, and as well-understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For purposes of the present disclosure, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0043] In certain embodiments, the subject method provides an enhanced therapeutic response. By “enhanced therapeutic response” is meant a statistically significant improvement in a primary and / or secondary endpoint of MDS therapy and / or amelioration of one or more symptoms of MDS (e.g., as described herein), e.g., rate and / or duration of red blood cell (RBC) transfusion-independence (TI), or hematologic improvement (HI) rate relative to an appropriate control. In some embodiments, the subject methods provide aAttorney Docket No.: GERN-203WO therapeutic effect of red blood cell (RBC) transfusion-independence (TI), e.g., lasting 4 weeks or longer, such as 5 weeks or longer, 6 weeks or longer, 7 weeks or longer, 8 weeks or longer, 9 weeks or longer, 10 weeks or longer, 12 weeks or longer, 16 weeks or longer, 20 weeks or longer, 24 weeks or even longer. In some embodiments, time to TI and / or duration of TI is significantly improved. In certain embodiments, the subject method provides a duration of TI that is 24 weeks or longer, such as 30 weeks or longer, 36 weeks or longer, 42 weeks or longer, 48 weeks or longer, 60 weeks or longer, or even longer.

[0044] A hypomethylating agent (HMA) is an agent that inhibits DNA methylation, e.g., by blocking the activity of DNA methyltransferase (DNA methyltransferase inhibitors / DNMT inhibitors). HMAs of interest include, but are not limited to, decitabine (CAS Registry Number: 2353-33-5; 5-aza-2'-deoxycytidine) and azacitidine (CAS Registry Number: 320-67-2, 5 -azacytidine).

[0045] Venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor. It blocks BCL-2 action that causes killing of cancer cells. The chemical name of venetoclax is: 4-(4-((2-(4- chlorophenyl)-4,4-dimethylcyclohex- 1-en- 1 -yl)methyl)piperazin- 1 -yl)-N-((3-nitro-4- ((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(lH-pyrrolo(2,3-b)pyridin-5- yloxyjbenzamide

[0046] Deletion 5q (dcl5q) refers to a chromosomal abnormality found in particular forms of MDS subjects (Adema et al., Haematologica. 2013 Dec; 98(12): 1819-1821; Sole et al., Haematologica. 2005; 90(9): 1168-78). In some embodiments of the subject methods, the subject is a human patient who has del5q. In some embodiments, the subject is a human patient who is non-del5q. A non-del5q subject is a subject that does not have the del5q chromosomal abnormality. In certain embodiments, the non-del5q subject is human. C. Myelodysplastic syndrome (MDS)

[0047] Myelodysplastic syndrome (“MDS”) is a group of diseases that includes cancers of the blood and bone marrow, which in some cases can be characterized by cytopenias resulting from ineffective hemopoiesis. A variety of MDS can be treated using the subject methods, including but not limited to, diseases such as refractory anemia, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, chronic myelomonocytic leukemia, MDS with isolated del (5q) and MDS unclassifiable.

[0048] MDS is characterized by clonal myeloproliferation arising from malignant progenitor cell clones that have shorter telomeres and multiple clonal genetic abnormalities.Attorney Docket No.: GERN-203WOTelomerase activity (TA) and expression of human telomerase reverse transcriptase (hTERT) is significantly increased in MDS and may play a role in dysregulated cell growth, leading to continued and uncontrolled proliferation of malignant progenitor cell clones. Higher TA and hTERT as well as shorter telomere length are poor prognostic features for patients with low-risk MDS, leading to shorter overall survival.

[0049] In some embodiments, the subject methods find use in alleviating at least one symptom associated with myelodysplastic syndrome, such as, e.g., refractory anemia, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with unilineage dysplasia, and chronic myelomonocytic leukemia. In some embodiments, the symptoms include shortness of breath, fatigue, weakness, fainting, nosebleeds, bruising, bleeding from mouth or gums, bloody stool, petechiae, or stroke.

[0050] In some embodiments, the subject has a relapsed or refractory MDS.“Refractory MDS” refers to patients who still have MDS cells in their bone marrow after treatment with any convenient MDS-related therapy. “Relapsed MDS” refers to patients who have a return of MDS cells in their bone marrow and a decrease in normal blood cells after remission.

[0051] In certain embodiments of the subject method, the subject is classified as an intcrmcdiatc-2 or high IPSS risk MDS subject. Myelodysplastic syndromes (MDS) patients can divided into lower-risk groups (low and intermediate- 1 [INT-1] IPSS), in which apoptotic events in the marrow are prevalent and there is a defective response to cytokines (including erythropoietin), and higher-risk groups (intermediate-2 [INT-2] and high IPSS), in which a block in the maturation of marrow progenitors is the principal alteration. In some embodiments, transfusion dependence is a negative prognostic variable. As such, in certain embodiments of the method, the subject is Red Blood Cell (RBC) transfusion dependent. In some embodiments, the transfusion-dependent subject has a RBC transfusion requirement of about 4 units or more over 8 weeks; or from 4-14 units over an 8-week period, or about 6 units or more per 8 weeks prior to administration according to the subject method. A unit of packed red blood cells (PRBCs) can be about 300 niL / unit. A unit of Whole blood can be about 450-500 mL / unit.

[0052] The International Prognostic Scoring System (IPSS) is a system developed for staging MDS. The IPSS rates 3 factors: the percentage of leukemic blast cells in the bone marrow cells (scored on a scale from zero to 2); chromosome abnormalities, if any, in the marrow cells (scored from zero to 1); and the presence of one or more low blood cell counts (scored as zero or 0.5). Each factor is given a score, with the lowest scores having the bestAttorney Docket No.: GERN-203WO outlook. Then the scores for the factors are added together to make the IPSS score. The IPSS puts people with MDS into 4 groups: low risk; intermediate - 1 risk; intermediate - 2 risk; and high risk.D. Telomerase Inhibitors

[0053] Any convenient telomerase inhibitors can find use in the subject methods. In some embodiments, the telomerase inhibitor is an oligonucleotide with telomerase inhibiting activity, such as an oligonucleotide as defined in WO 2005 / 023994 and / or WO 2014 / 088785, the disclosures of which are herein incorporated by reference in their entirety. In some embodiments, one or more than one telomerase inhibitor (e.g., two or three telomerase inhibitors) can be administered to a mammal to treat a hematological malignancy.Imetelstat

[0054] In certain embodiments, the telomerase inhibitor is imetelstat (RYTETO®), including tautomers thereof and salts thereof, e.g., pharmaceutically acceptable salts. Imetelstat is a novel, first-in-class telomerase inhibitor with clinical activity in hematologic malignancies (Baerlocher et al., NEJM 2015; 373:920-928; Tefferi et al., NE.IM 2015; 373:908-919) (shown below):where “nps” represents a thiophosphoramidate linkage — NH — P(=O)(SH) — O — , connecting the 3 '-carbon of one nucleoside to the 5 '-carbon of the adjacent nucleoside.

[0055] In certain embodiments, the telomerase inhibitor is imetelstat sodium including tautomers thereof. Imetelstat sodium is the sodium salt of imetelstat. Imetelstat is a telomerase inhibitor that is a synthetic lipid-conjugated, 13-mer oligonucleotide N3'— P5'- thio-phosphoramidate complimentary to the human telomerase RNA (hTR) template region The chemical name for imetelstat sodium (shown below) is: DNA, d(3’-amino-3’-deoxy-P-Attorney Docket No.: GERN-203WO thio) (T-A-G-G-G-T-T-A-G-A-C-A-A), 5’-[O-[2-hydroxy-3-(hexadecanoylamino)propyl] phosphorothioate], sodium salt (1: 13) (SEQ ID NO: 1). Imetelstat does not function through an anti-sense mechanism and therefore lacks the side effects commonly observed with such therapies.Imetelstat sodium

[0056] Unless otherwise indicated or clear from the context, references herein to imetelstat also include tautomers thereof and salts thereof, e.g., pharmaceutically acceptable salts. As mentioned, imetelstat sodium is the sodium salt of imetelstat. Unless otherwise indicated or clear from the context, references herein to imetelstat sodium also include all tautomers thereof.

[0057] Imetelstat and imetelstat sodium can be produced, formulated, or obtained as described elsewhere see e.g. Asai et al., Cancer Res., 63:3931- 3939 (2003), Herbert et al., Oncogene, 24:5262-5268 (2005), and Gryaznov, Chem. Biodivers., 7:477-493 (2010)). Unless otherwise indicated or clear from the context, references herein to imetelstat also include salts thereof.Attorney Docket No.: GERN-203WO

[0058] Imetelstat targets the RNA template of telomerase and inhibits telomerase activity and cell proliferation in various cancer cell lines and tumor xenografts in mice. Phase 1 studies involving patients with breast cancer, non-small-cell lung cancer and other solid tumors, multiple myeloma, or chronic lymphocytic leukemia have provided information on drug pharmacokinetics and pharmacodynamics. A subsequent phase 2 study involving patients with essential thrombocythemia showed platelet-lowering activity accompanied by a significant reduction in JAK2 V617F and CALR mutant allele burdens. Imetelstat sodium is routinely administered intravenously; it is contemplated that in the practice of the subject methods other administration routes also can be used, such as intrathecal administration, intratumoral injection, oral administration and others. Imetelstat sodium can be administered at doses comparable to those routinely utilized clinically. In certain embodiments, imetelstat sodium is administered as described elsewhere herein.

[0059] A particular embodiment is according to any one of the other embodiments, wherein imetelstat is limited to imetelstat sodium.E. Pharmaceutical compositions

[0060] For ease of administration, the telomerase inhibitor (e.g., as described herein) may be formulated into various pharmaceutical forms for administration purposes. In some embodiments, the telomerase inhibitor is administered as a pharmaceutical composition. The carrier or diluent of the pharmaceutical composition must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. The pharmaceutical composition may be in unitary dosage form suitable, for example, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation. In some embodiments, administration can be via intravenous injection. For example, in preparing the composition in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.Because of their ease in administration, tablets and capsules represent advantageous oral dosage unit forms in which case solid pharmaceutical carriers are usually employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution,Attorney Docket No.: GERN-203WO glucose solution or a mixture of saline and glucose solution. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing the telomerase inhibitor described herein may be formulated in oil for prolonged action. Appropriate oils for this purpose arc, for example, peanut oil, sesame oil, cottonseed oil, com oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired composition. The composition may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

[0061] It can be advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

[0062] In order to enhance the solubility and / or the stability of the drug described herein in pharmaceutical compositions, it can be advantageous to employ a-, 0- or y-cyclodextrins or their derivatives, such as hydroxyalkyl substituted cyclodextrins, e.g. 2 hydroxypropyl-P- cyclodextrin or sulfobutyl-P-cyclodextrin. Also, co-solvents such as alcohols may improve the solubility and / or the stability of the telomerase inhibitor in phamraceutical compositions.

[0063] Depending on the mode of administration, the pharmaceutical composition may comprise from 0.05 to 99 % by weight, such as from 0.1 to 70 % by weight, such as from 0.1 to 50 % by weight of the telomerase inhibitor described herein, and from 1 to 99.95 % by weight, such as from 30 to 99.9 % by weight, such as from 50 to 99.9 % by weight of aAttorney Docket No.: GERN-203WO pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.F. Administration and Administration Regimens

[0064] The frequency of administration can be any frequency that reduces the severity of a symptom of a MDS or AML (e.g., as described herein) without producing significant toxicity to the subject. For example, the frequency of administration can be from about once every two months to about once a week, alternatively from about once a month to about twice a month, alternatively about once every six weeks, about once every 5 weeks, alternatively about once every 4 weeks, alternatively about once every 3 weeks, alternatively about once every 2 weeks or alternatively about once a week. The frequency of administration can remain constant or can be variable during the duration of treatment. A course of treatment with a composition containing one or more telomerase inhibitors can include rest periods. For example, a composition containing a telomerase inhibitor can be administered weekly over a three-week period followed by a two-week rest period, and such a regimen can be repeated multiple times. As with the effective amount, various factors can influence the actual frequency of administration used for a particular application. For example, the effective amount, duration of treatment, use of multiple treatment agents, route of administration, and severity of the MDS or AML and related symptoms may require an increase or decrease in administration frequency.

[0065] An effective duration for administering a composition containing a telomerase inhibitor (e.g., imetelstat or imetelstat sodium) can be any duration that reduces the severity of a symptom of a MDS or AML (e.g., as described herein) without producing significant toxicity to the subject. Thus, the effective duration can vary from one month to several months or years (e.g., one month to two years, one month to one year, three months to two years, three months to ten months, or three months to 18 months). In general, the effective duration for the treatment of a MDS or AML can range in duration from two months to twenty months. In some embodiments, an effective duration can be for as long as an individual subject is alive. Multiple factors can influence the actual effective duration used for a particular treatment. For example, an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, route of administration, and severity of the MDS or AML and related symptoms.

[0066] In certain embodiments, a course of treatment and the severity of one or more symptoms related to a MDS or AML can be monitored. Any method can be used toAttorney Docket No.: GERN-203WO determine whether or not the severity of a symptom of a MDS or AML is reduced. For example, the severity of a symptom of a MDS or AML (e.g., as described herein) can be assessed using biopsy techniques.

[0067] Telomerase inhibitors as used in the subject methods can be administered at any dose that is therapeutically effective, such as doses comparable to those routinely utilized clinically. Specific dose regimens for known and approved anti-cancer agents (e.g., the recommended effective dose) are known to physicians and are given, for example, in the product descriptions found in the PHYSICIANS’ DESK REFERENCE, 2003, 57th Ed., Medical Economics Company, Inc., Oradell, N.J.; Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS" 2001, 10th Edition, McGraw-Hill, New York; and / or are available from the Federal Drug Administration and / or are discussed in the medical literature.

[0068] In some aspects, the dose of a telomerase inhibitor, imetelstat sodium, administered to the subject is about 1.0 mg / kg to about 13.0 mg / kg. In other aspects, the dose of a telomerase inhibitor is about 4.5 mg / kg to about 11.7 mg / kg or about 6.0 mg / kg to about 11.7 mg / kg or about 6.5 mg / kg to about 11.7 mg / kg. In some embodiments, the dose of a telomerase inhibitor includes at least about any of 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.5 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, 10 mg / kg, 10.1 mg / kg, 10.2 mg / kg, 10.3 mg / kg, 10.4 mg / kg, 10.5 mg / kg, 10.6 mg / kg, 10.7 mg / kg, 10.8 mg / kg, 10.9 mg / kg, 11 mg / kg, 11.1 mg / kg, 11.2 mg / kg, 11.3 mg / kg, 11.4 mg / kg, 11.5 mg / kg, 11.6 mg / kg, 11.7 mg / kg, 11.8 mg / kg, 11.9 mg / kg, 12 mg / kg, 12.1 mg / kg, 12.2 mg / kg, 12.3 mg / kg, 12.4 mg / kg, 12.5 mg / kg, 12.6 mg / kg, 12.7 mg / kg, 12.8 mg / kg, 12.9 mg / kg, or 13 mg / kg.

[0069] In some embodiments, the effective amount of a telomerase inhibitor administered to the individual includes at least about any of 1 mg / kg, 2.5 mg / kg, 3.5 mg / kg, 4.7 mg / kg, 5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 9.4 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. In some embodiments, the effective amount of a telomerase inhibitor administered to the individual is about any of 1 mg / kg, 2.5 mg / kg, 3.5 mg / kg, 5 mg / kg, 6.5 mg / kg, 7.5 mg / kg, 9.4 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. In various embodiments, the effective amount of a telomerase inhibitor administered to the individual includes lessAttorney Docket No.: GERN-203WO than about any of 350 mg / kg, 300 mg / kg, 250 mg / kg, 200 mg / kg, 150 mg / kg, 100 mg / kg, 50 mg / kg, 30 mg / kg, 25 mg / kg, 20 mg / kg, 10 mg / kg, 7.5 mg / kg, 6.5 mg / kg, 5 mg / kg, 3.5 mg / kg, 2.5 mg / kg, 1 mg / kg, or 0.5 mg / kg of a telomerase inhibitor.

[0070] Exemplary dosing frequencies for the pharmaceutical composition including a telomerase inhibitor include, but arc not limited to, daily; every other day; twice per week; three times per week; weekly without break; weekly, three out of four weeks; once every three weeks; once every two weeks; weekly, two out of three weeks. In some embodiments, the pharmaceutical composition is administered about once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks or once every 8 weeks. In some embodiments, the composition is administered at least about any of lx, 2x, 3x, 4x, 5x, 6x, or 7x (z.e., daily) a week, or three times daily, two times daily. In some embodiments, the intervals between each administration are less than about any of 6 months, 3 months, 1 month, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the intervals between each administration are more than about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no break in the dosing schedule. In some embodiments, the interval between each administration is no more than about a week.

[0071] Telomerase inhibitors such as imetelstat {e.g., imetelstat sodium) can be administered using any appropriate method. For example, telomerase inhibitors such as imetelstat {e.g., imetelstat sodium) can be administered intravenously once every 4 weeks over a period of time e.g., one, two, three, four, or five hours). In some embodiments, imetelstat is administered intravenously once weekly over a period of about 2 hours at 7-10 mg / kg. In certain embodiments, imetelstat is administered intravenously once every 3 weeks over a period of about 2 hours at 2.5-7 mg / kg. In an embodiment, imetelstat is administered intravenously for a period of about 2 hours once every 4 weeks at 0.5-5 mg / kg. In an embodiment, imetelstat is administered intravenously once every 3 weeks over a period of about 2 hours at about 2.5-10 mg / kg. Alternatively, imetelstat is administered intravenously for a period of about 2 hours once every 4 weeks at about 0.5-9.4 mg / kg.

[0072] In certain embodiments of the method, imetelstat is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising: intravenous administration of about 7-10 mg / kg imetelstat once every four weeks, intravenous administration of about 7- 10 mg / kg imetelstat once weekly for four weeks, intravenous administration of about 2.5-10 mg / kg imetelstat once every three weeks, or intravenous administration of about 0.5-9.4Attorney Docket No.: GERN-203WO mg / kg imetelstat once every four weeks. In certain instance, each dosage cycle comprises intravenous administration of about 7-10 mg / kg imetelstat once every four weeks. In some embodiments, each dosage cycle comprises intravenous administration of about 7.5 mg / kg imetelstat about once every four weeks.

[0073] In at least one embodiment disclosed herein, imetelstat is administered intravenously at a dosage of about 7-10 mg / kg imetelstat once every four weeks following premedication with an antihistamine, corticosteroid, or both. In other embodiments, imetelstat is administered intravenously at a dosage of about 7.5 mg / kg, alternatively from about 7.0 mg / kg to about 7.7 mg / kg, imetelstat once every four weeks following premedication with an antihistamine, corticosteroid, or both.

[0074] In certain embodiments, imetelstat is administrated at a dosage about 7.5 mg / kg, alternatively from about 7.0 mg / kg to about 7.7 mg / kg, once every four weeks for at least three cycles and then the dosage is increased. In certain embodiments, the dosage of imetelstat may be increased to about 9.4 mg / kg, alternatively from about 8.8 mg / kg to about 9.6 kg / mg, provided ANC and platelet nadir have not dropped between about 1.5 x 109 / L and about 75 x 109 / L, respectively, and there is no grade > 3 non-hematological toxicity.

[0075] It will be appreciated that treatment for cancer sometimes involves multiple “rounds” or “cycles” of administration of a drug, where each cycle comprises administration of the drug one or more times according to a specified schedule (e.g., every three weeks for three consecutive days: once per week; etc.). For example, anti-cancer drugs can be administered for from 1 to 8 cycles, or for a longer period. When more than one drug e.g., two- drugs) is administered to a subject, each can be administered according to its own schedule e.g., weekly; once every three weeks; etc.). Administration of drugs, even those administered with different periodicity, can be coordinated so that both drugs are administered on the same day at least some of the time or, alternatively, so the drugs are administered on consecutive days at least some of the time.

[0076] As is understood in the art, treatment with cancer therapeutic drugs can be suspended temporarily if toxicity is observed, or for the convenience of the patient, without departing from the scope of the methods and uses disclosed herein, and then resumed.

[0077] In certain embodiments, the present disclosure relates to a telomerase inhibitor for use in a method of treating myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), the method comprising administering to a subject in need thereof an effective amount of a telomerase inhibitor. In other embodiments, the present disclosure relates to a telomerase inhibitor for use in a method of treating myelodysplastic syndrome (MDS), theAttorney Docket No.: GERN-203WO method comprising administering to a subject in need thereof an effective amount of a telomerase inhibitor. In yet other embodiments, the present disclosure relates to a telomerase inhibitor for use in a method of treating acute myeloid leukemia (AML), the method comprising administering to a subject in need thereof an effective amount of a telomerase inhibitor.

[0078] In certain embodiments, the present disclosure relates to a telomerase inhibitor for use in a method as defined in any of the other embodiments.G. Exemplary embodiments

[0079] Exemplary embodiments of the methods of treating MDS or AML disclosed herein, which involve administering to a subject in need thereof an effective amount of a telomerase inhibitor, are shown in Table A below.

[0080] Exemplary embodiments include using any of the telomerase inhibitors in Table A to treat any one of the types of MDS or AML shown in Table A in any one of the subjects shown in Table A. In certain embodiments, one of the administration regimens described in Table A is used. In other embodiments, the methods may be used to treat any one of the types of MDS or AML shown in Table A in any one of subjects shown in Table A using imetelstat (or imetelstat sodium). When imetelstat (or imetelstat sodium) is used, any of the administration regimens shown in Table A may be used.Table A. Exemplary embodiments of the present disclosureAttorney Docket No.: GERN-203WO

[0081] The following examples are offered by way of illustration and not by way of limitation.Attorney Docket No.: GERN-203WOEXAMPLESExample 1: A phase II study evaluating the efficacy and safety of IMetelstat in Patients with HR myElodvsylastic SvndromeS or AML failins HMA-based therapy (IMpress™)Introduction

[0082] IMpress™: A phase II study evaluating the efficacy and safety of imetelstat in patients with HR myelodysplastic syndromes or AML failing HMA-based therapy.

[0083] Data from a previous phase II study as well as cytogenetic and mutational data for lower risk MDS provided an encouraging basis for further investigation of imetelstat in higher risk MDS and AML patients ineligible for allo-HSCT, constituting entities with an even greater need for new therapeutic options.

[0084] There are currently very few licensed drugs to treat MDS or AML patients having failed or being refractory to treatment with HMAs. Further, allo-HSCT can be offered only to a minority of those patients. Therefore, new treatment options are desired for this patient cohort. Imetelstat, a first-in-class telomerase inhibitor, with its novel mechanism of action, may provide clinical benefit to HR MDS and AML patients. Earlier clinical trial results suggest an activity in lower risk MDS and good tolerability.Methods

[0085] Various details of the IMpress™ study, such as eligibility criteria (inclusion and exclusion criteria), number of participants, study objectives, study, endpoints, and study treatments are described below.

[0086] Briefly, the multicenter phase II IMpress trial led by the European Myelodysplastic Neoplasms Cooperative Group (EMSCO) evaluated the safety and efficacy of imetelstat in patients with HR-MDS or AML, refractory, relapsing or intolerant after at least six or four cycles of either azacitidine (AZA) or decitabine (DAC), respectively, or 3 cycles of venetoclax (VEN) plus AZA.

[0087] In this first part of the trial, patients received imetelstat at a dose of 7.5 mg / kg i.v. once every 4 weeks for 4 cycles of 28 days until disease progression, unacceptable toxicity, withdrawal of consent or lack of response. Responding patients (defined as at least PR - partial remission or HI - hematologic improvement) were eligible to continue treatment until loss of response / disease progression.Attorney Docket No.: GERN-203WO

[0088] The primary endpoint (PE) was overall response rate assessed after 4 months of treatment (CR - complete remission, Cri - CR with incomplete hematological recovery, PR, HI). All patients achieving CR, CRi, PR or HI after 4 months of imetelstat were considered as responders and allowed to continue treatment until loss of response / disease progression. Non-responding patients had to stop treatment after 4 months.Planned Interventions

[0089] All patients received 2-hour intravenous (i.v.) infusion with imetelstat twice in a 28-day cycle (once every 14 days) for at least 4 cycles. After 4 treatment cycles (8 administrations of imetelstat), response assessment was performed on all patients.Imetelstat treatment was discontinued in non-responding patients. These patients undewent end of treatment (EOT) and entered the follow-up phase of the trial. Patients who were categorized as responders according to the primary endpoint (PE) definition and had bone marrow (BM) blasts > 5% at the response assessment continued imetelstat treatment every 14 days until loss of response / disease progression. Patients who were categorized as responders according to the PE definition and had BM blasts < 5% continued imetelstat treatment every 28 days until loss of response / disease progression.Study Endpoints

[0090] Primary endpoints

[0091] Overall response rate assessed after 4 months of treatment using combined response assessment criteria for MDS and AML based on IWG 2018 criteria (MDS) and the criteria of the European LeukemiaNet (AML), as defined in Table B below.

[0092] Table B. Combined response assessment criteria for MDS and AML.Attorney Docket No.: GERN-203WOAttorney Docket No.: GERN-203WOf : Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation syndrome, that is, a transient increase in the percentage of bone marrow blasts and an absolute increase in blood blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily indicate PD.

[0093] Secondary endpoints

[0094] Secondary endpoints included safety measurements and efficacy measurements.

[0095] The safety measurements included toxicity as measured by NCI CTCAE v5.0.

[0096] The efficacy measurements included overall survival, progression-free survival, duration of best overall response, response based on IWG 2023 criteria (MDS population only) and scores of EORTC QLQ-C30 (version 3).

[0097] “Overall survival” is defined as the time from the beginning of imetelstat treatment until death or censored at the date of the last follow-up visit.

[0098] “Progression-free-survival” is defined as the duration of time from time of imetelstat treatment to time of progression or death, whichever occurs first. A subject who has neither progressed nor died will be censored on the date of last follow-up visit.Attorney Docket No.: GERN-203WO

[0099] “Duration of the best overall response” is measured from the time measurement criteria are met for CR, CRi, PR or SD (whichever is recorded first) until the first date at which recurrent or progressive disease is objectively documented.

[0100] “Best overall response” is defined as the best response recorded from the start of the imctclstat treatment until disease progression (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

[0101] Response based on IWG 2023 criteria (MDS population only) was assessed in week 17 of treatment with imetelstat.

[0102] Quality of life assessment (EORTC QLQ-C30) was based on global health status / QoL, functional scales, and / or symptom scales / items.

[0103] The medical condition to be treated included AML and MDS patients failing or being refractory to hypomethylating agent (HMA)-based treatment.

[0104] Eligibility criteria

[0105] Eligibility criteria included the following inclusion and exclusion criteria:Attorney Docket No.: GERN-203WOAttorney Docket No.: GERN-203WOAttorney Docket No.: GERN-203WOAttorney Docket No.: GERN-203WOAttorney Docket No.: GERN-203WO

[0106] Study Treatments

[0107] Test drug: Imetelstat sodium.

[0108] Starting dose: 7.5 mg / kg.

[0109] Dosing regimen: Every 2 weeks for 4 cycles of 28 days until disease progression, unacceptable toxicity, withdrawal of consent, or lack of response. Responding patients at cycle 5 (defined as CR, Cri, or PR and / or showing a hematologic improvement for one or several lines) were eligible to continue treatment. Responding patients who have BM blasts > 5% at the response assessment were continued imetelstat treatment every 14 days until loss of response / disease progression. Responding patients who have BM blasts < 5% were continued imetelstat treatment every 28 days until loss of response / disease progression. Non-responding patients were discontinued imetelstat treatment, undergo EOT and enter the follow-up phase of the trial.

[0110] Administration route: Intravenous (IV).

[0111] Time plan for the individual patients:• Minimum of 4 months of treatment every 2 weeks (until primary endpoint assessment).• For responders with BM blasts > 5% at the response assessment: treatment every 2 weeks until loss of response / progression, followed by 3 months of follow-up.• For responders with BM blasts < 5% at the response assessment; treatment every 4 weeks until loss of response / progression, followed by 3 months of follow-up.• For Non-responders: treatment stopped after 4 months / cycles followed by 3 months of follow-up.

[0112] Sample size: The study was designed as a single-arm Phase II trial. The design of the trial focused on demonstrating that the efficacy is greater than an undcsircd level of efficacy (pO) which would indicate that the treatment is ineffective. A Simon’s two-stage design was used to allow for initial assessment of efficacy in a first interim analysis. The sample size calculation was based on the following assumptions.• Given Null hypothesis HO: p < pOAttorney Docket No.: GERN-203WO• Alternative hypothesis Hl : p > pO• Level of inefficacy pO = 0.05• Expected true response rate pl = 0.2• Type-l-error a = 0.05, one-sided• Type-2-error [3 = 0.1

[0113] The null hypothesis that the true response rate is 0.05 was planned to be tested against a one-sided alternative. In the first stage, 21 patients were accrued. If there were 1 or fewer responses in these 21 patients, the study would be stopped. Otherwise, it was planned to accrue 20 additional patients for a total of 41. The null hypothesis would be rejected in favor of the alternative hypothesis if 5 or more responses are observed in these 41 patients. This design yielded a one-sided type I error rate of no more than 0.05 and power of at least 0.9 when the true response rate is 0.2. To account for a loss of follow up of -10%, enrollment of up to 46 patients was expected. Similarly, a total of 23 patients were planned to be enrolled prior to this first interim analysis to ensure 21 evaluable patients for the first interim analysis.

[0114] After the first interim analysis was conducted, no responder according to the primary endpoint definition was identified. Due to the transient improvement seen in WBC and peripheral blasts in patients early in treatment, the study was continued in an exploratory approach with a change in dose frequency.

[0115] A decision was made to increase the initial frequency of dosing from once in 4 weeks to once in 2 weeks for at least the first 4 cycles due to a lack of response according to the primary endpoint definition seen in the first interim analysis.

[0116] Based on data collected from the initial patients enrolled in the study, no new safety signals were observed. The most frequently recorded AEs were under the following Medical Dictionary for Regulatory Activities (MedDRA) system organ classes: infections and infestations, gastrointestinal disorders, general disorders and administration site conditions, and respiratory, thoracic and mediastinal disorders. A total of 30 severe adverse events were recorded in 18 patients, of which three were assessed as being at least possibly related to imetelstat. Of these three, two were assessed as unexpected and were reported as SUSARs.

[0117] According to the safety data collected, no major change to the risk assessment was seen and there was no cause to conclude that imetelstat should not be used in patients with MDS / AML. Early data did not suggest a response according to the primary efficacyAttorney Docket No.: GERN-203WO endpoint. However, in a few patients, a transient improvement in certain hematological values was noted. In some patients, some antiproliferative effects of imetelstat, such as a decline in leukocytes, were seen. Additionally, four patients who were treated with imetelstat experienced a decrease in peripheral blast counts shortly after treatment. In many of the patients, treatment was discontinued early as a result of disease progression or death caused by infection secondary to uncontrolled MDS / AML. Given the short half-life of imetelstat, an increased frequency of dosing may be beneficial to patients by prolonging or strengthening the initial transient improvement seen in certain hematological values.

[0118] Given that no new safety signals to argue stopping imetelstat therapy were seen, the limited existence of treatment options and poor prognosis in this patient population, a decision was made to treat patients at a higher frequency of imetelstat administration for at least the first 4 cycles. There is a potential that neutropenia could be aggravated by the increased frequency of imetelstat. Therefore, the prophylactic use of antibiotics and antifungals was recommended for use in patients according to local standards, especially when they were on the 2-weekly dosing. This prophylactic use of antimicrobials might have also prevented infections as a reason for disease progression.

[0119] Study Design Overview:

[0120] The present study was designed as a multiccntcr, open-label, single arm, prospective phase II study. Patients with AML or higher-risk MDS patients failing or being refractory to hypomethylating agent (HMA)-based treatment were eligible for the study. All study participants received the same investigational medicinal product (IMP) comprising imetelstat.

[0121] Imetelstat sodium was administered at a starting dose of 7.5 mg / kg given intravenously every 2 weeks for 4 cycles of 28 days or until disease progression, unacceptable toxicity, withdrawal of consent, or lack of response. Participants were assessed for response in cycle 5 according to the combined response assessment criteria for MDS and AML. Non-responding patients were discontinued imetelstat treatment, underwent EOT and entered the follow-up phase of the trial. Patients who were categorized as responders based on at least PR and who have BM blasts > 5% at the response assessment in cycle 5 continued to receive imetelstat every 2 weeks. Patients who were categorized as responders as per the primary endpoint definition and who had BM blasts < 5% at the response assessment in cycle 5 continued to receive imetelstat every 4 weeks.Treatment was continued until the subject experienced unacceptable toxicities or shows lossAttorney Docket No.: GERN-203WO of response / disease progression per the combined disease assessment criteria used in this trial, withdrew consent, or met any other discontinuation criteria.

[0122] The study was split into two phases. At first, it was planned to enroll 21 patients in the trial. According to the initial study design, if 1 or fewer responses were seen in these patients, the study would be stopped. Although no responders were observed in these initial patients, a decision was made to amend the frequency of imetelstat administration, at least for the first 4 cycles. An additional 23 patients were planned to be enrolled due to the potential early transient effect of increasing the initial dose frequency on some hematological parameters.

[0123] Responding patients (defined as at least PR [partial remission]) were eligible to continue treatment until loss of response / disease progression.

[0124] The study consisted of a screening period, a primary treatment period (all patients), an extension treatment period (responders after 4 cycles of treatment only) and a posttreatment follow-up period. Patients who stopped the study treatment for any cause underwent an EOT visit at the latest 14 days after the decision of treatment discontinuation. The EOT visit was be followed by a first follow-up visit (FU1) 28 ± 5 days after EOT and a second FU visit = EOS visit approximately 2 months after EOT. When appropriate, FU2 / EOS was carried out on the phone and represented the last study visit for the patient.

[0125] The End of Study was considered at the time the last patient completed their evaluation 6 months after the end of the primary treatment period (in case of a continued responder) or following their follow-up period (in case of a non-responder). The subjects benefiting from treatment with imetelstat were able to continue treatment after the End of the Study.

[0126] The study design is described schematically in FIG. 1.

[0127] Imetelstat treatment in the primary phase:

[0128] Imetelstat sodium was administered at a dose of 7.5 mg / kg, i.v., once every two weeks. Subjects received imetelstat on day 1 and day 15 of each 28-day treatment cycle.

[0129] Imetelstat was administered as a 2-hour IV infusion (± 10 minutes) at a constant rate using an infusion pump. The baseline weight (i.e., body weight determined at Screening) was used to calculate the dose of imetelstat sodium to the nearest 0.1 mg. The dose was recalculated if there is a > 10% weight change from baseline. Note that the total dose may be recalculated more frequently (e.g., at each study visit) depending on local practice. The first dose of imetelstat was typically administered within 72 hours of enrollment.Attorney Docket No.: GERN-203WO

[0130] Dose modifications for hematologic toxicities:

[0131] For any occurrence of Grade > 3 thrombocytopenia or neutropenia, additional weekly blood counts were performed until there is a return to baseline values. For treatment of hematologic toxicities, granulocyte-colony stimulating factors (G-CSF) were permitted for neutropenia as well as blood transfusions for anemia or thrombocytopenia.

[0132] In the case of Grade > 3 hematologic toxicities please proceed as follows:• Patients with < 5% blasts in the bone marrow (current assessment): hold imetelstat administration until recovery to at least baseline values.• Patients with > 5% blasts in the bone marrow (current assessment): continue treatment with imetelstat at the discretion of the treating physician.

[0133] Best supportive care (BSC) was used in combination with imetelstat when clinically indicated per investigator. BSC includes, but is not limited to, treatment with transfusions, antibiotic, antiviral, and / or antifungal therapy as well as nutritional support as needed.

[0134] Subjects received imetelstat for at least the first 4 cycles after the date of first dose, unless the subject experiences unacceptable toxicities, withdraws consent, or meets any other treatment discontinuation criteria.

[0135] Disease assessments in the primary phase of treatment period (cycle 3 and cycle 5):

[0136] After cycles 2 and 4 (i.e., at the beginning of cycles 3 and 5) response assessments was carried out based on bone marrow and peripheral blood samples. For that, blood counts to assess potential cytopenias were carried out and bone marrow and peripheral blood smears were prepared to perform cytomorphology assessments.

[0137] Of these response assessments, the assessment at the end of cycle 4 (performed at the beginning of cycle 5) was the primary endpoint (pEP) assessment.

[0138] Based on the outcome of the disease assessment in cycle 3, if signs of disease progression were seen in the bone marrow, treatment with imetelstat was stopped and the patient underwent EOT and entered the follow-up phase.

[0139] MDS / AML disease assessment at week 17: the primary MDS / AML disease assessment according to the combined MDS / AML response criteria (primary endpoint assessment) was performed on samples taken at visit 9 in week 17 (cycle 5).

[0140] The disease assessment for the primary endpoint was completed after four completed cycles with imetelstat (allowing for dose delays). For the disease assessment atAttorney Docket No.: GERN-203WO least the results of the cytomorphology assessment, automated CBC values and cytogenetic results of visit 9 as well as any information on Hb and transfusions between enrollment and week 17 were required.

[0141] In order for subjects to remain on treatment beyond the first four cycles, the following criteria were confirmed upon the completion of the disease assessment based on the combined response criteria based on IWG 2018 criteria (MDS)l and the criteria of the European LeukemiaNet (AML):• At least partial remission (PR): o This includes CR, CRi, and PR and HI (any line) as per the combined response criteria used.

[0142] MLES were recorded but was not a criterion for treatment continuation.

[0143] Based on the outcome of the disease assessment, subjects were either were discontinued from treatment with IMP and entered the post-treatment follow-up period or continued treatment with IMP in the extension phase of the treatment period.

[0144] For subjects that met the criteria to continue treatment in the extension phase, the duration between the last dose of IMP administered in the primary phase and the first extension phase dose was not be delayed solely due to awaiting cytomorphology / cytogenetics results in the absence of signs of disease progression based on review of peripheral blood parameters.

[0145] A BM biopsy was collected only when adequate aspirate was not attainable or if the BM aspirate showed fewer than 5% bone marrow blasts. Whenever a BM sample was collected, both BM and PB smears were prepared.

[0146] Extension Phase of the Treatment Period:

[0147] After Week 17:

[0148] Subjects who meet the criteria to remain on treatment after completion of the week 17 disease assessment and had BM blasts > 5% continued dosing on Day 1 and Day 15 of each 28-day treatment cycle in the extension phase of the treatment period. Subjects who meet the criteria to remain on treatment after completion of the week 17 disease assessment and had BM blasts < 5% continued dosing on Day 1 (only) of each 28-day treatment cycle in the extension phase of the treatment period.

[0149] Treatment continued until the subject experienced unacceptable toxicides, disease progression per the combined response criteria, withdraws consent, or met any other discontinuation criteria.Attorney Docket No.: GERN-203WO

[0150] For subjects who continued treatment in the extension phase of the treatment period, each disease assessment confirmed continued clinical benefit and absence of disease progression per the combined disease assessment criteria. For patients exhibiting a response to treatment, each disease assessment also determined the frequency of imetelstat treatment (once in 2 weeks or once in 4 weeks) based on BM blast levels. Serial measurements of safety and efficacy were continued on scheduled study visits in the extension phase of the treatment period. BSC was continued in combination with imetelstat when clinically indicated. All subjects who receive at least one dose of imetelstat underwent end of treatment (EOT) evaluations when imetelstat was discontinued. The reason for discontinuation was recorded.

[0151] BM and PB samples were collected (e.g., for cytomorphology, cytogenetic analysis) and the disease assessment was repeated at cycle 7, day 1 (week 25) and at cycle 9, day 15 in the extension phase. Patients showing a benefit from the therapy in cycle 9 continued treatment with the IMP. Beyond cycle 9, disease assessments (including cytomorphology and therefore collection of BM and PB samples) was carried out every 3 months and at every timepoint of suspected progression starting 12 weeks after the last disease assessment in cycle 9.

[0152] Each BM assessment (cycle 7, cycle 9 and every 3 months thereafter) was also be used to determine the frequency of treatment with imetelstat until the next disease assessment: every 2 weeks (if BM blasts are > 5%) or every 4 weeks (if BM blasts are < 5%).

[0153] A BM biopsy was collected only when adequate aspirate was not attainable or if the BM aspirate showed fewer than 5% bone marrow blasts. Whenever a BM sample was collected, both BM and PB smears were prepared for the cytomorphology assessment.

[0154] In addition, information related to all transfusions received during the treatment period (including those received outside the trial site) was made available prior to completion of each disease assessment.

[0155] For subjects to continue treatment in the extension phase of the treatment period, each disease assessment confirmed continued clinical benefit and absence of disease progression per the combined criteria.

[0156] Additional procedures / assessments were also continued in the extension phase. The frequency of procedures / assessments in the extension phase may differ from the primary phase.Attorney Docket No.: GERN-203WO

[0157] Thus, based on the outcome of the pEP (cycle 5 / week 17) visit disease assessment, subjects were either discontinued from treatment with imetelstat and entered the posttreatment follow-up phase (non-responders) or continued treatment with imetelstat until loss of response / disease progression in the extension phase of the treatment period (responders). Responders who had BM blasts > 5% at the response assessment in cycle 5 continued to receive imetelstat every 2 weeks. Responders who had BM blasts < 5% at the response assessment in cycle 5 continued to receive imetelstat every 4 weeks.

[0158] Evidence of clinical benefit was defined as: At least partial remission (PR), which included CR, CRi, PR and HI (any line) as per the combined response criteria.

[0159] All other assessment outcomes resulted in treatment discontinuation. Morphologic Leukemia-Free State (MLFS) was recorded but was not a criterion for treatment continuation. The corresponding patients (= non-responders) then underwent the EOT visit and the follow-up period.

[0160] Patients with at least PR at this pEP assessment continued in the extension phase.

[0161] A risk / benefit assessment was performed when 10 patients started treatment, of which at least 8 patients completed 2 full cycles of imetelstat (after 4 doses).

[0162] Post-treatment follow-up period

[0163] All AEs were recorded from the time the subject signed the IGF until 28 ± 5 days after the last dose of IMP. Additionally, all serious AEs (S AEs) made known to the investigator at any time thereafter and are suspected of being related to imetelstat were also documented. Therefore, at 28 ± 5 days the first follow-up visit took place.

[0164] End of Treatment (EOT) visit:

[0165] An EOT evaluation was performed for subjects who were withdrawn from treatment for any reason as soon as possible after the decision to permanently discontinue treatment was made.

[0166] If a subject was discontinued during a regular scheduled visit, all EOT procedures were completed at that visit. If a procedure was performed within 14 days of the EOT visit, it was not needed to be repeated unless clinically indicated.

[0167] BM sample collection was only be performed at EOT visit if > 90 days from prior BM procedure.

[0168] The reason for discontinuation was recorded in the source document for all subjects, regardless of whether they are dosed.

[0169] End of the clinical study:Attorney Docket No.: GERN-203WO

[0170] For this study, the primary outcome were analyzed after the last patient completed the study (individual EOS). The end of the study as a whole was the date when the clean database was available and ready for export for the statistical analyses. However, the primary completion event of the study was the date of last patient end of study.Results

[0171] 23 patients (MDS=6, AML=17) received at least one dose of imetelstat with an average of 2.8 doses administered per patient. In this first part of the trial, none of the 23 treated subjects reached the primary endpoint visit (V9), which was scheduled after 4 cycles of treatment. Sixteen of the 23 patients reached the first (preliminary) disease assessment visit (V5) after two cycles of imetelstat. At this assessment, only 1 patient showed a response in form of both HI-E and HI-P. Seven patients had stable disease (SD) and 8 had progressive disease (PD).

[0172] In addition, short-term transient improvement in hematological values was observed in individual cases. Notably, with the current LR-MDS schedule (i.e. once every 4 weeks), imetelstat showed some antiproliferative effects, including a decline in blasts and leukocytes.

[0173] A total of 30 serious adverse events (SAEs) occurred in 18 patients of which 21 SAEs required hospitalizations. The majority of SAEs (17 / 30) was of infectious nature with infections of the lung, febrile neutropenia and sepsis being the most common complications (n=8, n=3 and n=2, respectively). Overall, 10 of the 30 SAEs resulted in death (n=5 due to disease progression / transformation to AML, n=4 due to infectious complications and n=l due to ileus) and one was assessed as being possibly related to imetelstat (pneumonia). 11 of the SAEs resolved without sequalae. Overall, no new safety signals occurred beyond those already known for imetelstat.Example 2 - Interim Results of more frequent dosing schedule used in the IMpress™ study

[0174] As noted in Example 1, due to a lack of response based on the primary endpoint (response) and no new safety signals observed in the first interim analysis, the protocol of the IMpress study was amended to have a more frequent dosing schedule for a second cohort of patients being enrolled and treated with this modified schedule.

[0175] Under the modified schedule, the second cohort of patients were administered imetelstat every 2 weeks for at least the first 4 cycles (instead of every 4 weeks).Attorney Docket No.: GERN-203WO

[0176] Patients continued to receive the same dose of imetelstat, but the administration frequency was increased to every 2 weeks.

[0177] The primary endpoint (PE) for this second cohort and second interim analysis was overall response rate assessed after 4 months of treatment (CR, CRi, PR, HI). All patients achieving CR, CRi, PR or HI after 4 months of imetelstat were considered responders and allowed to continue treatment until loss of response / disease progression. Non-responding patients stopped treatment after 4 months.

[0178] Patients from 8 centers in various countries were screened for the second cohort. Of these, 23 (MDS = 6, AML = 17) received at least 1 dose of imetelstat. The median number of doses was 5 per patient, compared to 3 in the first cohort, suggesting an increase in drug exposure. Median age of patients was 77 years in both the first (range: 68-87) and second cohort (range: 66-88). More men than women were enrolled, with 15 men and 8 women in the first cohort, and 14 men and 9 women in the second. The median ECOG performance status was 1 (range: 0-2) in both cohorts. Complex karyotype was reported in 6 / 23 patients across both cohorts. Median percentage of bone marrow blasts at screening was 30% (range: 8-91; IQR: 41) in the first cohort and 27% (range: 5.5-86; IQR: 26) in the second. Prior treatment with VEN was reported in 47.8% (11 / 23) of the first cohort and 39.1% (9 / 23) of the second.

[0179] In the second cohort, 6 / 23 patients reached the primary endpoint visit, scheduled after 4 cycles of treatment, compared to none in the first cohort: 3 patients had stable disease (SD) and 3 showed progressive disease (PD). One patient with SD achieved neutrophil response (HLN) and received 3 additional doses in the extension phase. Thirteen of the 23 patients reached the first (preliminary) disease assessment after 2 cycles of imetelstat. At this point, only 1 patient showed a response (SD with HLN), 9 patients had SD and 2 had PD.

[0180] About 10 months after initiation of the second cohort of the study, the median overall survival of the first and second cohort was 119 (95% CI: 83-144) and 102 days (95% CI: 67-not available), respectively. The median progression free survival (PFS) of the first and second cohort was 69 (95% CI: 57-113) and 92 days (95% CI: 57-not available), respectively.

[0181] In the second cohort, in the first 10 months of the study, 24 serious adverse events (SAEs) occurred in 19 patients, of which none were deemed related to imetelstat. The most common SAEs were febrile neutropenia (n = 6), disease progression / transformation to AML (n = 4), sepsis (n = 2) and fever (n = 2). Overall, 11 / 24Attorney Docket No.: GERN-203WOSAEs resulted in death (n = 4 due to disease progression or AML, n = 2 due to cardiac / cardiorespiratory arrest, n = 1 due to febrile neutropenia, n = 1 due to sepsis, general health alteration and death of unknown reason). 8 of the SAEs resolved without sequalae and 2 remained unresolved. In the first cohort, 30 SAEs occurred in 18 patients, with 3 possibly related to imctclstat (pneumonia [n = 2], febrile neutropenia [n = 1]). The most common SAEs were disease progression / transformation to AML (n = 9), pneumonia (n = 3), febrile neutropenia (n = 3), and sepsis (n = 2). 10 / 30 SAEs resulted in death. Despite higher drug exposure in the second cohort, no increase in toxicity was observed.

[0182] Thus, increased exposure to imetelstat in a population of refractory AML and MDS patients did not appear to be associated with additional toxicity. From 0 / 23 patients reaching the PE visit, the number increased to 6 / 23 (26%) in the second cohort, despite only one achieving HI, and no marrow responses were observed. About 10 months after the initiation of the second cohort, one patient remained on treatment and two were in followup. Thus, imetelstat has at least some single agent activity in this adverse prognosis group.

[0183] In the future, an even more frequent dosing schedule (imetelstat every 1 week for at least the first 4 cycles) will be administered to a third cohort of patients.

[0184] In addition, a more frequent dosing schedule (imetelstat every 1 week for at least the first 4 cycles) in combination with higher dose of imctclstat higher than 7.5 mg / kg i.v., such as 8 mg / kg, 9 mg / kg, or 10 mg / kg, will be administered.

[0185] The higher doses and / or increased frequencies of imetelstat administration will be expected to provide improved outcomes in imetelstat treated patients as compared to control patients.Numbered Embodiments of the Present Disclosure

[0186] Exemplary numbered embodiments of the present disclosure are shown below:1. A method of treating a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) comprising administering to a subject in need thereof an effective amount of a telomerase inhibitor, wherein the subject is classified as an intermediate-2 or high IPSS risk MDS or AML subject.2. The method of Embodiment 1, wherein the MDS subject is relapsed, refractory, or intolerant to hypomethylating agent (HMA), venetoclax, or a combination thereof.Attorney Docket No.: GERN-203WO3. The method of Embodiment 1, wherein the AML subject is relapsed, refractory, or intolerant to hypomethylating agent (HMA), venetoclax, or a combination thereof.4. The method of any one of Embodiments 1-2, wherein the subject is classified as the intermediate-2 IPSS risk MDS subject.5. The method of any one of Embodiments 1-2, wherein the subject is classified as the high IPSS risk MDS subject.6. The method of any one of Embodiments 1 and 3, wherein the subject is classified as the AML subject.7. The method of any one of Embodiments 1-6, wherein the subject is transfusion dependent.8. The method of Embodiment 7, wherein the transfusion dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to the administration of the telomerase inhibitor.9. The method of any one of Embodiments 1-8, wherein the subject is a non-del5q human patient.10. The method of any one of Embodiments 1-2, 4-5, and 7-9, wherein the subject is classified as an intermediate-2 or high IPSS risk MDS subject and is non-del5q.11. The method of Embodiment 2, wherein the MDS subject is relapsed, refractory, or intolerant to treatment with venetoclax.12. The method of Embodiment 2, wherein the MDS subject is relapsed, refractory, or intolerant to treatment with HMA.13. The method of Embodiment 2, wherein the MDS subject is relapsed, refractory, or intolerant to treatment with the combination of venetoclax and I IMA.14. The method of either of Embodiment 12 or 13, wherein the HMA is decitabine.15. The method of either of Embodiment 12 or 13, wherein the HMA is azacitidine.Attorney Docket No.: GERN-203WO16. The method of Embodiment 3, wherein the AML subject is relapsed, refractory, or intolerant to venetoclax.17. The method of Embodiment 3, wherein the AML subject is relapsed, refractory, or intolerant to I IMA.18. The method of Embodiment 3, wherein the AML subject is relapsed, refractory, or intolerant to the combination of venetoclax and HMA.19. The method of Embodiment 17 or 18, wherein the HMA is decitabine.20. The method of Embodiment 17 or 18, wherein the HMA is azacitidine.21. The method of any one of Embodiments 1-20, wherein the telomerase inhibitor is imetelstat or a pharmaceutically acceptable salt thereof.22. The method of any one of Embodiments 1-21, wherein the imetelstat is imetelstat sodium.23. The method of any one of Embodiments 1-22, wherein the telomerase inhibitor is imetelstat or a pharmaceutically acceptable salt thereof and is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:(a) intravenous administration of about 7-10 mg / kg imetelstat once every two weeks;(b) intravenous administration of about 7-10 mg / kg imetelstat once every four weeks;(c) intravenous administration of about 7-10 mg / kg imetelstat once weekly for four weeks;(d) intravenous administration of about 2.5-10 mg / kg imetelstat once every three weeks; or(e) intravenous administration of about 0.5-9.4 mg / kg imetelstat once every four weeks.24. The method of Embodiment 23, wherein each dosage cycle comprises intravenous administration of about 7-10 mg / kg imetelstat once every two or four weeks.25. 1'he method of Embodiment 23, wherein each dosage cycle comprises intravenous administration of about 7.5 mg / kg imetelstat once every two or four weeks.Attorney Docket No.: GERN-203WO26. The method of any one of Embodiments 21-25, wherein the subject is transfusion dependent.27. The method of any one of Embodiments 21-26, wherein the subject is a non-del5q human patient.

Claims

Attorney Docket No.: GERN-203WOClaimsWe claim:

1. A method of treating a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) comprising administering to a subject in need thereof an effective amount of a telomerase inhibitor, wherein the subject is classified as an intermediate- 2 or high IPSS risk MDS or AML subject.

2. The method of claim 1, wherein the MDS subject is relapsed, refractory, or intolerant to hypomethylating agent (HMA), venetoclax, or a combination thereof.

3. The method of claim 1, wherein the AML subject is relapsed, refractory, or intolerant to hypomethylating agent (HMA), venetoclax, or a combination thereof.

4. The method of any one of claims 1-2, wherein the subject is classified as the intermediate-2 IPSS risk MDS subject.

5. The method of any one of claims 1 -2, wherein the subject is classified as the high IPSS risk MDS subject.

6. The method of any one of claims 1 and 3, wherein the subject is classified as the AML subject.

7. The method of any one of claims 1-6, wherein the subject is transfusion dependent.

8. The method of claim 7, wherein the transfusion dependent subject has a transfusion requirement of about 4 units or more during the 8 weeks prior to the administration of the telomerase inhibitor.

9. The method of any one of claims 1 -8, wherein the subject is a non-del5q human patient.

10. The method of any one of claims 1-2, 4, 5, and 7-9, wherein the subject is classified as an intermediate-2 or high IPSS risk MDS subject and is non-deL5q.

11. The method of claim 2, wherein the MDS subject is relapsed, refractory, or intolerant to treatment with venetoclax.Attorney Docket No.: GERN-203WO12. The method of claim 2, wherein the MDS subject is relapsed, refractory, or intolerant to treatment with HMA.

13. The method of claim 2, wherein the MDS subject is relapsed, refractory, or intolerant to treatment with the combination of venetoclax and I IMA.

14. The method of either of claim 12 or 13, wherein the HMA is decitabine.

15. The method of either of claim 12 or 13, wherein the HMA is azacitidine.

16. The method of claim 3, wherein the AML subject is relapsed, refractory, or intolerant to venetoclax.

17. The method of claim 3, wherein the AML subject is relapsed, refractory, or intolerant to HMA.

18. The method of claim 3, wherein the AML subject is relapsed, refractory, or intolerant to the combination of venetoclax and HMA.

19. The method of claim 17 or 18, wherein the HMA is decitabine.

20. The method of claim 17 or 18, wherein the HMA is azacitidine.

21. The method of any one of claims 1-20, wherein the telomerase inhibitor is imetelstat or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 1 -21, wherein the imetelstat is imetelstat sodium.

23. The method of any one of claims 1-22, wherein the telomerase inhibitor is imetelstat or a pharmaceutically acceptable salt thereof and is administered for 1, 2, 3, 4, 5, 6, 7, 8 or more than 8 dosage cycles, each cycle comprising:(a) intravenous administration of about 7-10 mg / kg imetelstat once every two weeks;(b) intravenous administration of about 7-10 mg / kg imetelstat once every four weeks;(c) intravenous administration of about 7-10 mg / kg imetelstat once weekly for four weeks;(d) intravenous administration of about 2.5-10 mg / kg imetelstat once every three weeks; orAttorney Docket No.: GERN-203WO(e) intravenous administration of about 0.5-9.4 mg / kg imetelstat once every four weeks.

24. The method of claim 23, wherein each dosage cycle comprises intravenous administration of about 7-10 mg / kg imetelstat once every two or four weeks.

25. The method of claim 23, wherein each dosage cycle comprises intravenous administration of about 7.5 mg / kg imetelstat once every two or four weeks.

26. The method of any one of claims 21-25, wherein the subject is transfusion dependent.

27. The method of any one of claims 21-26, wherein the subject is a non-del5q human patient.

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