Patent Application
20240277715
The present invention relates to novel combination therapies for the treatment of cancer.
Cancer is caused by uncontrolled and unregulated cellular proliferation. Precisely what causes a cell to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intense research over recent decades. This research has led to the identification of a number of molecular targets and key metabolic pathways that are known to be associated with malignancy.
Despite numerous advances in the treatment of cancer, there remains a need for new therapies that provide improved therapeutic outcomes.
One particular target that is attracting interest is METTL3. N6-methyladenosine (m6A) is an abundant internal RNA modification that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML). Yankova et al. (Nature: volume 593, pages 597-601 (2021)) describe the identification and characterisation of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3. Treatment with STM2457 resulted in a reduction in AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. The pharmacological inhibition of METTL3 in vivo led to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. METTL3 is therefore a potential therapeutic strategy against AML, and the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy more generally.
International Patent Publication No. WO2020/050898 describes further small molecule METTL3 inhibitors that are suitable for the treatment of cancer.
METTL3 inhibitors clearly show promise for the treatment of AML and other cancers. However, there is always a need to identify new therapeutic strategies that can be used to more improve therapeutic outcomes.
The present invention was devised with the foregoing in mind.
1. Combinations of METTL3 Inhibitors with Immuno-Oncology Agents (e.g. Immune Checkpoint Inhibitors)
Data presented in the example section herein shows that the administration of the METTL3 inhibitor compound STM3480 in combination with an immune checkpoint inhibitor (anti-PD1 and anti-PD-L1) resulted in a significant increase in the observed anti-tumour immune response (when compared to vehicle controls and the treatment with either the METTL3 inhibitor or the immune checkpoint inhibitor alone). Data is presented for tumour killing co-culture cell assays (see Example 1) as well as in vivo studies using the A20 B-cell lymphoma model, EMT6 breast cancer model and CT26 colorectal cancer model (see Example 2). Collectively, these data suggest that the administration of a METTL3 inhibitor together with an immune checkpoint inhibitor significantly enhances the anti-tumour immune response. METTL3 inhibition may therefore play a role in sensitising the cancer cells to immune checkpoint inhibitor therapy.
Thus, the present invention relates, in one aspect, to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use as an immune-sensitiser.
The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as an immune-sensitiser.
The present invention also relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an immune oncology agent or therapy (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BITE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy).
The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an immune oncology agent or therapy (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BiTE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy).
The present invention also relates to a method of treating cancer, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, to a patient in combination with an immune oncology agent or therapy (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BiTE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy).
Suitably, the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially or separately with the immune oncology agent or therapy (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BiTE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy.
In one aspect the present invention relates to a combination comprising a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect the present invention relates to a pharmaceutical product comprising a combination as defined herein.
In another aspect, the present invention relates to a pharmaceutical composition comprising a combination as defined herein, and one or more pharmaceutically acceptable excipients.
In another aspect, the present invention relates to a combination as defined herein, or a pharmaceutical product as defined herein, or a pharmaceutical composition as defined herein for use in therapy.
In another aspect, the present invention relates to a combination as defined herein, or a pharmaceutical product as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of cancer.
In another aspect, the present invention relates to a use of a combination as defined herein in the manufacture of a medicament for the treatment of cancer.
In another aspect, the present invention relates to a method of treating of cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a combination as defined herein.
In another aspect, the present invention relates to a method of potentiating the immune response to a tumour, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a combination as defined herein.
In another aspect, the present invention relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the immune checkpoint inhibitor is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a use of an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof are administered sequentially, separately or simultaneously with one another.
In another aspect, the present invention relates to a method of treating cancer or potentiating the effect of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of potentiating the immune response to a tumour, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof are administered sequentially, separately or simultaneously with one another.
Suitably, the cancer is a solid tumour.
2. Combinations of METTL3 Inhibitors with BCL2 Inhibitors (e.g. Venetoclax)
Data presented in the example section shows that the METTL3 inhibitor compounds STM3480, STM3006 and STM3675, when administered in combination with a BCL2 inhibitor (venetoclax), produced a synergistic increase in the observed anticancer effect. Data is presented for Kasumi1 and MOLM13 AML cell lines (see Example 3). Collectively, these data suggest that METTL3 inhibition synergistically enhances the antitumour effect of BCL2 inhibitor (e.g. venetoclax) therapy. The combination of a METTL3 inhibitor with a BCL2 inhibitor (e.g. venetoclax) therefore offers a promising therapy for diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancers such as acute myeloid leukaemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndromes (MDS)).
Thus, the present invention also relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer), wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with a BCL2 inhibitor (e.g. venetoclax).
The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer), wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with a BCL2 inhibitor (e.g. venetoclax).
The present invention also relates to a method of treating diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer), the method comprising administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, to a patient in combination with a BCL2 inhibitor (e.g. venetoclax).
Suitably, the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially or separately with the BCL2 inhibitor (e.g. venetoclax) therapy.
In one aspect the present invention relates to a combination comprising a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
In another aspect the present invention relates to a pharmaceutical product comprising a combination as defined above.
In another aspect, the present invention relates to a pharmaceutical composition comprising a combination as defined above, and one or more pharmaceutically acceptable excipients.
In another aspect, the present invention relates to a combination as defined above, or a pharmaceutical product as defined above, or a pharmaceutical composition as defined above for use in therapy.
In another aspect, the present invention relates to a combination as defined herein, or a pharmaceutical product as defined above, or a pharmaceutical composition as defined above for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer).
In another aspect, the present invention relates to the use of a combination as defined above in the manufacture of a medicament for the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer).
In another aspect, the present invention relates to a method of treating of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a combination as defined above.
In another aspect, the present invention relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a use of a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and the BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, are administered sequentially, separately or simultaneously with one another.
In another aspect, the present invention relates to a method of treating cancer, or potentiating the effect of a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount the BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of treating cancer or potentiating the effect of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
Suitably, the cancer is selected from acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndromes (MDS).
3. Combinations of METTL3 Inhibitors with Anthracycline Topoisomerase 2 Inhibitors (e.g. Daunorubicin), Cytarabine, Hypomethylating Agents (e.g. 5-Azacitidine or Decitabine) or FLT3 Inhibitors (e.g. Quizartinib)
Data presented in the example section herein shows that the METTL3 inhibitor compounds STM3480 and STM3006, when administered in combination with various standard of care drugs for the treatment of AML, such as daunorubicin, cytarabine, 5-azacitidine and quizartinib, produced an enhanced therapeutic effect in Kasumi1 or MOLM-14 AML cell lines (see Example 4). Collectively, these data suggest that the administration of a METTL3 inhibitor enhances the antitumour effects of AML standard of care agents, including anthracycline topoisomerase 2 inhibitors (e.g. daunorubicin), cytarabine, hypomethylating agents (e.g. 5-azacitidine or decitabine), and/or FLT3 inhibitors (e.g. quizartinib).
The combination of a METTL3 inhibitor with either an anthracycline topoisomerase 2 inhibitor (e.g. daunorubicin), cytarabine, a hypomethylating agent (e.g. 5-azacitidine or decitabine), and/or a FLT3 inhibitors (e.g. quizartinib) therefore offers a promising therapeutic strategies for the treatment of cancer (e.g. acute myeloid leukaemia (AML), chronic syndromes (MDS)).
Thus, the present invention also relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional agents selected from:
The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional agents selected from:
The present invention also relates to a method of treating cancer, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, to a patient in combination with one or more additional agents selected from:
Suitably, the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially or separately with:
In one aspect the present invention relates to a combination comprising a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and one or more additional agents selected from:
In another aspect the present invention relates to a pharmaceutical product comprising a combination as defined above.
In another aspect, the present invention relates to a pharmaceutical composition comprising a combination as defined above, and one or more pharmaceutically acceptable excipients.
In another aspect, the present invention relates to a combination as defined above, or a pharmaceutical product as defined above, or a pharmaceutical composition as defined above for use in therapy.
In another aspect, the present invention relates to a combination as defined above, or a pharmaceutical product as defined above, or a pharmaceutical composition as defined above for use in the treatment of cancer.
In another aspect, the present invention relates to the use of a combination as defined above in the manufacture of a medicament for the treatment of cancer.
In another aspect, the present invention relates to a method of treating of cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a combination as defined above.
In another aspect, the present invention relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with one or more additional agents selected from:
In another aspect, the present invention relates to an agent selected from:
In another aspect, the present invention relates to a use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with one or more additional agents selected from:
In another aspect, the present invention relates to a use of an agent selected from:
In another aspect, the present invention relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and an agent selected from:
In another aspect, the present invention relates to a method of treating cancer, or potentiating the effect of an agent selected from:
In another aspect, the present invention relates to a method of treating cancer, or potentiating the effect of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with an agent selected from:
Suitably, the cancer is selected from acute myeloid leukaemia (AML), chronic syndromes (MDS), especially AML.
Preferred, suitable, and optional features of any one particular aspect of the present invention described herein are also preferred, suitable, and optional features of any other aspect.
Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.
It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
An “inhibitor” may be a polypeptide, nucleic acid, carbohydrate, lipid, small molecular weight compound, an oligonucleotide, an oligopeptide, siRNA, antisense, a recombinant protein, an antibody, a peptibody, or conjugates or fusion proteins thereof. For a review of siRNA see Milhavet O, Gary D S, Mattson M P. (Pharmacol Rev. 2003 December; 55(4):629-48. For a review of antisense see Opalinska J B, Gewirtz A M. Sci STKE. 2003 Oct. 28; 2003 (206): p47. A small molecular weight compound refers to a compound with a molecular weight of less than 2000 Daltons, less than 1000 Daltons, less than 700 Daltons or less than 500 Daltons.
References to “a pharmaceutically acceptable salt” of an inhibitor defined herein is refers to any salt form suitable for pharmaceutical use. Examples of pharmaceutically acceptable salts include an acid-addition salt of an inhibitor of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoracetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of an inhibitor of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
References herein to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, include, where appropriate, any isomeric, tautomeric, polymorphic, amorphous and solvate (e.g. hydrate) forms of the inhibitors. An inhibitor may also be administered in the form of a prodrug which is broken down in the human or animal body to release the active inhibitor. Examples of pro-drugs include in vivo cleavable ester derivatives of the inhibitors that may be formed at a carboxy group or a hydroxy group in an inhibitor compound and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in an inhibitor compound. Various forms of pro-drug have been described, for example in the following documents:—
References herein to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, being administered “in combination with” another agent, or a pharmaceutically acceptable salt thereof, or vice versa, unless otherwise stated otherwise, include the inhibitors being administered sequentially, separately or simultaneously with one another.
As used herein “simultaneous administration” refers to therapy in which the both agents (e.g. a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and immune checkpoint inhibitor) are administered at the same time, suitably as a mono-therapy.
As used herein “sequential administration” means that one agent is administered after the other, however, the time period between the administration of each agent is such that both agents are capable of acting therapeutically concurrently. Thus, administration “sequentially” may permit one agent to be administered within seconds, minutes, or a matter of hours after the other provided the circulatory half-life of the first administered agent is such that they are both concurrently present in therapeutically effective amounts. The time delay between the administration of the agents may vary depending on the exact nature of the agents, the interaction there between, and their respective half-lives.
As used herein, “separate administration” means that one agent is administered after the other, however, the time period between administration is such that the first administered agent is no longer present a therapeutically effective amount when the second agent is administered. Accordingly, the two agents exert their therapeutic effects separately. Nevertheless, the overall therapeutic effect observed when the two agents separately act therapeutically may be greater than either agent used alone.
As used herein the, “subject(s)” and/or “patient(s)”, suitably refer to mammals (e.g. humans and non-human mammals such as livestock (cows, sheep, goats) or companion animals (cats, dogs, horses, rabbits). Suitably, the subject(s) and/or patient(s) are human(s).
As used herein, a “pharmaceutical product” refers to a product comprising a pharmaceutical. For instance, examples of a pharmaceutical product include a medical device, a pharmaceutical composition and a kit of parts suitably comprising one or more devices, containers and/or pharmaceuticals.
METTL3 inhibitors
The present invention resides in the recognition that METTL3 inhibitors are viable agents for use in combination with
Any suitable METTL3 inhibitor may be used in the combination therapies defined herein.
Examples of suitable METTL3 inhibitors include:
The entire contents of International Patent Publication No. WO2020/050898 are incorporated herein by reference.
The compounds defined therein have the following formula (I):
X—Y—Z (I)
-L1a-L1b-Q1
-L1c-L1d-Z1
-L2a-L2b-Q2
wherein
wherein:
wherein:
Particular compounds of formula I disclosed in International Patent Publication No. WO2020/050898 include any of the following in List 1 below, or a pharmaceutically acceptable salt thereof:
A further group of METTL3 inhibitors is defined by the formula II shown below:
X—Y—Z (II)
—(CR1cR1d)p—NR1eR1f;
—(CR1gR1h)q-T1
-L2a-L2b-Q2
wherein
wherein:
Y2 is A7, wherein A7 is selected from CR18 and N; wherein R18 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 alkoxy, C1-4haloalkyl, C1-4haloalkoxy, C3-4cycloalkyl, a 3- to 4-membered heterocyclyl and C3-4cycloalkoxy;
Y3 is N or CRz1a wherein RZ1a, is selected from hydrogen, hydroxy, C1-4alkyl, cyano, halo, C1-4 haloalkyl, C1-4haloalkoxy, C1-4alkoxy, C3-6cycloalkyl and —O—C3-6cycloalkyl, wherein C3-6cycloalkyl and —O—C3-6cycloalkyl are optionally substituted by one or more of halo, methyl or methoxy;
Y5 is C—RY5 or NRY5N, wherein:
Y9 is CRZ3a or N; wherein
Z10 is N or C—RZ10, wherein RZ10 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy;
Z11 is N or C—RZ11, wherein RZ11 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy;
Z12 is N or C—RZ12, wherein RZ12 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy;
Z13 is N or C—RZ13, wherein RZ13 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy;
Z14 is N or C—RZ14, wherein RZ14 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy;
Z15 is N or C—RZ15, wherein RZ15 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy;
Z16 is N or C—RZ16, wherein RZ16 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4 haloalkoxy;
with the proviso that no more than three of Z10 to Z16 are N;
(v)
In a particular group of compounds of formula II above, the compounds are of the formula:
wherein R1a, Y, Z, n, R3a1 and R3a2 each have any one of the meanings defined above; or a pharmaceutically acceptable salt thereof.
Suitably, n is 1 and R3a1 and R3a2 are hydrogen.
Suitably, Ria is a group of the formula:
—(CR1cR1d)p—NR1eR1f;
—(CR1gR1h)q-T1
Most suitably, R1a is selected from:
wherein n is 1 and R3a1 and R3a2 are hydrogen.
Particular compounds of formula II above include any of the following, or a pharmaceutically acceptable salt thereof:
One particular compound of formula I defined above that is disclosed in International Patent Publication No. WO2020/050898 is STM3006, which is 6-bromo-4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-1H-indazole, and has the structure shown below
Two particular compounds of Formulae II, VI and VII defined above are STM3480 and STM3675.
STM3480 is N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide, which has the structure shown below:
STM3675 is N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide, the structure of which is also depicted below:
The METTL3 inhibitors used in the combination therapies of the present invention may be any METTL3 inhibitor.
In a particular embodiment, the METTL3 inhibitor is a compound of formula I, II, VI or VII defined herein, or a pharmaceutically acceptable salt thereof.
In another embodiment, the METTL3 inhibitor is any one of the specific compounds listed list 1 and/or list 2 above, or a pharmaceutically acceptable salt thereof.
In another embodiment, the METTL3 inhibitor is any one of the specific compounds STM 3006, STM 3480, or STM3675 identified above, or a pharmaceutically acceptable salt thereof.
In a particular embodiment, the METTL3 inhibitor is STM3480 identified above, or a pharmaceutically acceptable salt thereof.
1. Combinations of METTL3 Inhibitors Defined Herein with Immuno-Oncology Agents (e.g. Immune Checkpoint Inhibitors)
One aspect of the present invention resides in the recognition that the METTL3 inhibitor compound, STM3480, is particularly suited to use in combination with immune checkpoint inhibitors (see Examples 1 and 2).
Immune checkpoint inhibitors are a class of anticancer agents that have shown great promise in some cancer patients. The inhibition of immune checkpoints (e.g. CTLA4, LAG3, PD1 or PD-L1 inhibitors) results in the enhancement of the immune response to a tumour. However, some cancers do not respond sufficiently well to immune checkpoint inhibitor therpay alone, so there is a need for improved treatment strategies.
The inventors have surprisingly discovered that the METTL3 inhibitor compound STM3480 can significantly potentiate the therapeutic effects of immune checkpoint inhibitors. In an embodiment, the METTL3 inhibitor compound STM3480 synergistically potentiates the therapeutic effects of immune checkpoint inhibitors (and vice versa), thereby rendering the tumours more susceptible to the combination therapy (i.e. the therapeutic effect observed is greater than the additive effect of the two agents individually).
Thus, the combination treatment of the present invention has the potential to provide better therapeutic outcomes in cancer patients, especially cancer patients that do not respond well to therapy with a METTL3 inhibitor or an immune checkpoint inhibitor alone.
In one aspect, the present invention provides a combination comprising a METTL3 inhibitor as defined herein (e.g. STM3480), or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a pharmaceutical product comprising a combination of a METTL3 inhibitor as defined herein (e.g. STM3480), or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutical product may comprise a kit of parts comprising separate formulations of a METTL3 inhibitor as defined herein (e.g. STM3480), or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof. The separate formulations of a METTL3 inhibitor as defined herein (e.g. STM3480), or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, may be administered sequentially, separately and/or simultaneously.
In another embodiment the pharmaceutical product is a kit of parts which comprises:
In one embodiment, the pharmaceutical product may comprise a one or more unit dosage forms (e.g. vials, tablets or capsules in a blister pack). In one embodiment, each unit dose comprises only one agent selected from the a METTL3 inhibitor as defined herein (e.g. STM3480) compound and the immune checkpoint inhibitor. In another embodiment, the unit dosage form comprises both the a METTL3 inhibitor as defined herein (e.g. STM3480) compound and the immune checkpoint inhibitor.
In one embodiment the pharmaceutical product or kit of parts further comprises means for facilitating compliance with a dosage regimen, for instance instructions detailing how to administer the combination.
In one embodiment, the pharmaceutical product or kit of parts further comprises instructions indicating that the combination, as defined herein, can be used in the treatment of cancer.
In one embodiment, the pharmaceutical product is a pharmaceutical composition.
Any immune checkpoint inhibitor may be used in the combination therapy defined herein.
In one embodiment, the immune checkpoint inhibitor is selected from a PD1, PD-L1 inhibitor, a LAG3 inhibitor and a CTLA-4 inhibitor. In a particular embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.
PD-1 is a cell surface receptor protein present on T cells. PD-1 plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. The PD-1 protein is an immune checkpoint that guards against autoimmunity through a dual mechanism of promoting apoptosis (programmed cell death) in antigen specific T cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory suppressive T cells).
PD-1 therefore inhibits the immune system. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
PD1 binds two ligands, PD-L1 and PD-L2. PD-L1 is of particular interest as it is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for the treatment of cancer. Many tumour cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumour activity. This is known as immune checkpoint blockade.
Examples of drugs that target PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. They are also being studied for use against many other types of cancer. Examples of drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics) and MEDI-0680 (MedImmune).
Examples of drugs that inhibit PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These drugs have also been shown to be helpful in treating different types of cancer, including bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer (Merkel cell carcinoma). They are also being studied for use against other types of cancer.
Examples of LAG3 inhibitors include BMS-986016/Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781 and LAG525.
Examples of CTLA-4 inhibitors include MDX-010/Ipilimumab, AGEN1884, and CP-675,206/Tremelimumab.
In one embodiment, the immune checkpoint inhibitor is selected from BMS-986016/Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, MDX-010/Ipilimumab, AGEN1884, and CP-675,206/Tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof.
In another embodiment, the immune checkpoint inhibitor is selected from BMS-986016/Relatlimab, MDX-010/Ipilimumab, CP-675,206/Tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutically acceptable salt thereof.
In another embodiment, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof.
In another embodiment, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof.
In another embodiment, the immune checkpoint inhibitor is selected from pembrolizumab and avelumab, or a pharmaceutically acceptable salt thereof.
Thus, the present invention relates, in one aspect, to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use as an immune-sensitiser.
The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as an immune-sensitiser.
The present invention also relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an immune oncology agent or therapy (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BITE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy).
The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with an immune oncology agent or therapy (e.g. immune checkpoint inhibitors (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BITE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy).
The present invention also relates to a method of treating cancer, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, to a patient in combination with an immune oncology agent or therapy (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BiTE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy).
Suitably, the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially or separately with the immune oncology agent or therapy (e.g. immune checkpoint inhibitors (e.g. a PD1, PD-L1 inhibitor, LAG3, CTLA-4, TIGIT, TIM3, or VISTA inhibitor), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulators, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, Bispecific T cell engagers (BiTE), oncolytic viruses, cancer vaccines, and/or CAR-T cell therapy).
Suitably, the immune oncology agent is an immune checkpoint inhibitor (e.g. a PD1, PD-L1 inhibitor, LAG3 or CTLA-4 inhibitor).
In another aspect, the present invention relates to a combination as defined herein, or a pharmaceutical product as defined herein, or a pharmaceutical composition as defined herein for use in therapy.
In another aspect, the present invention relates to a combination as defined herein, or a pharmaceutical product as defined herein, or a pharmaceutical composition as defined herein for use in the treatment of cancer.
In another aspect, the present invention relates to a use of a combination as defined herein in the manufacture of a medicament for the treatment of cancer.
In another aspect, the present invention relates to a method of treating of cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a combination as defined herein.
In another aspect, the present invention relates to a method of potentiating the immune response to a tumour, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a combination as defined herein.
In another aspect, the present invention relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the immune checkpoint inhibitor is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a use of an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof are administered sequentially, separately or simultaneously with one another.
In another aspect, the present invention relates to a method of treating cancer or potentiating the effect of an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount the immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of treating cancer or potentiating the effect of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of potentiating the immune response to a tumour, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor, or a pharmaceutically acceptable salt thereof are administered sequentially, separately or simultaneously with one another.
The term “cancer” is used herein to refer to an unwanted, uncontrolled and abnormal malignant cellular proliferation, whether in vitro or in vivo. The term includes benign, pre-malignant and malignant cellular proliferation. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, bladder, kidney, bone, nerves and skin.
The anti-proliferative effects of the combination therapy of the present invention has particular application in the treatment of human cancers. In particular, the combination therapy of the present invention will be useful for treating any human cancer in which METTL3 and/or immune checkpoint activity is implicated. This includes any cancer that has been unresponsive to therapy comprising either a METTL3 inhibitor or immune checkpoint inhibitor alone.
In an embodiment of the invention, the anti-tumour effects of the combination therapy of the present invention has particular application in the treatment and/or prevention of a wide range of cancers including, but not limited to, non-solid tumours such as leukaemia, for example acute myeloid leukaemia, multiple myeloma, haematologic malignancies or lymphoma, and also solid tumours and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, oesophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumours and haematological malignancies.
Suitably, the cancer is a solid tumour.
In one embodiment the cancer is selected from lung, colon, rectal, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer.
In one embodiment the cancer is a human cancer. Suitably, the human cancer is selected from lung, colon, breast, ovarian, bladder, kidney, prostate, liver, pancreas, brain, bone, blood and skin cancer. In one embodiment, the human cancer is selected from glioblastoma, lung cancer, breast cancer, renal cell carcinoma and Hodgkin lymphoma.
The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the promotion of an antitumour immune response, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures or within an organ), or the promotion of apoptosis (programmed cell death).
As indicated above, the immune checkpoint inhibitor may be any immune checkpoint inhibitor as defined in any of the embodiments herein and the METTL3 inhibitor may be any known METTL3 inhibitor.
In one embodiment, the immune checkpoint inhibitor is selected from BMS-986016/Relatlimab, TSR-033, REGN3767, MGD013 (bispecific DART binding PD-1 and LAG-3), GSK2831781, LAG525, and MDX-010/Ipilimumab, AGEN1884, CP-675,206/Tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is as defined herein.
In another embodiment, the immune checkpoint inhibitor is selected from BMS-986016/Relatlimab, MDX-010/Ipilimumab, CP-675,206/Tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is selected from STM3006, STM3480 or STM3675, or a pharmaceutically-acceptable salt thereof, as defined herein.
In another embodiment, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is selected from STM3006, STM3480 or STM3675, or a pharmaceutically-acceptable salt thereof, as defined herein.
Suitably, the METTL3 inhibitor is STM3480.
2. Combinations of METTL3 Inhibitors with BCL2 Inhibitors (e.g. Venetoclax)
One aspect of the present invention resides in the recognition that the METTL3 inhibitor compounds, STM3480, STM3006 and STM3675, when administered in combination with a BCL2 inhibitor (venetoclax), produced a synergistic increase in potency (see Example 3).
Thus, the administration of a METTL3 inhibitor synergistically enhances the antitumour effect of BCL2 inhibitor (e.g. venetoclax) therapy and vice versa. The combination of a METTL3 inhibitor with a BCL2 inhibitor (e.g. venetoclax) therefore offers a promising therapy for diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancers including acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndromes (MDS)).
The combination treatment of the present invention has the potential to provide better therapeutic outcomes in cancer patients, especially cancer patients that do not respond well to therapy with a METTL3 inhibitor or a BCL2 inhibitor (e.g. venetoclax) alone.
In one aspect, the present invention provides a combination comprising a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675), or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a pharmaceutical product comprising a combination of a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675), or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutical product may comprise a kit of parts comprising separate formulations of a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675), or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof. The separate formulations of a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675), or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, may be administered sequentially, separately and/or simultaneously.
In another embodiment the pharmaceutical product is a kit of parts which comprises:
In one embodiment, the pharmaceutical product may comprise a one or more unit dosage forms (e.g. vials, tablets or capsules in a blister pack). In one embodiment, each unit dose comprises only one agent selected from the a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675) compound and the BCL2 inhibitor (e.g. venetoclax). In another embodiment, the unit dosage form comprises both the a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675) compound and the BCL2 inhibitor (e.g. venetoclax).
In one embodiment the pharmaceutical product or kit of parts further comprises means for facilitating compliance with a dosage regimen, for instance instructions detailing how to administer the combination.
In one embodiment, the pharmaceutical product or kit of parts further comprises instructions indicating that the combination, as defined herein, can be used in the treatment of cancer.
In one embodiment, the pharmaceutical product is a pharmaceutical composition.
Any suitable BCL2 inhibitor approved for therapeutic use may be used in this combination therapy of the present invention
Suitably, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof. The chemical name for ventoclax is 4-{4-[(4′-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1′-biphenyl]]-2-yl)methyl]piperazin-1-yl}-N-(3-nitro-4-{[(oxan-4-yl)methyl]amino}benzene-1-sulfonyl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide, and its chemical structure is shown below:
The present invention also relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer), wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with a BCL2 inhibitor (e.g. venetoclax).
The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer), wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with a BCL2 inhibitor (e.g. venetoclax).
The present invention also relates to a method of treating diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer), the method comprising administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, to a patient in combination with a BCL2 inhibitor (e.g. venetoclax).
Suitably, the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially or separately with the BCL2 inhibitor (e.g. venetoclax) therapy.
In one aspect the present invention relates to a combination comprising a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
In another aspect the present invention relates to a pharmaceutical product comprising a combination as defined above.
In another aspect, the present invention relates to a pharmaceutical composition comprising a combination as defined above, and one or more pharmaceutically acceptable excipients.
In another aspect, the present invention relates to a combination as defined above, or a pharmaceutical product as defined above, or a pharmaceutical composition as defined above for use in therapy.
In another aspect, the present invention relates to a combination as defined herein, or a pharmaceutical product as defined above, or a pharmaceutical composition as defined above for use in the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer).
In another aspect, the present invention relates to the use of a combination as defined above in the manufacture of a medicament for the treatment of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer).
In another aspect, the present invention relates to a method of treating of diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer) in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a combination as defined above.
In another aspect, the present invention relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a use of a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and the BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, are administered sequentially, separately or simultaneously with one another.
In another aspect, the present invention relates to a method of treating cancer, or potentiating the effect of a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount the BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to a method of treating cancer or potentiating the effect of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with a BCL2 inhibitor (e.g. venetoclax), or a pharmaceutically acceptable salt thereof.
The anti-proliferative effects of the combination therapy of the present invention has particular application in the treatment of human cancers. In particular, the combination therapy of the present invention will be useful for treating any human cancer in which METTL3 and/or BCL2 activity is implicated. This includes any cancer that has been unresponsive to therapy comprising either a METTL3 inhibitor or BCL2 inhibitor alone.
Suitably, the cancer is selected from acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndromes (MDS).
In an embodiment, this combination therapy of the invention is suitable for the treatment of acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL).
The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the promotion of an antitumour immune response, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures or within an organ), or the promotion of apoptosis (programmed cell death).
As indicated above, the BCL2 inhibitor may be any BCL2 inhibitor and the METTL3 inhibitor may be any known METTL3 inhibitor.
In one embodiment, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is as defined herein.
In one embodiment, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is selected any compound of the formulae I, II, VI or VII defined above, or a pharmaceutically acceptable salt thereof.
In one embodiment, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is selected from STM3006, STM3480 or STM3675, or a pharmaceutically-acceptable salt thereof.
In one embodiment, the BCL2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is STM3480, or a pharmaceutically-acceptable salt thereof.
3. Combinations of METTL3 Inhibitors with Anthracycline Topoisomerase 2 Inhibitors (e.g. Daunorubicin), Cytarabine, Hypomethylating Agents (e.g. 5-Azacitidine), FLT3 Inhibitors (e.g. Quizartinib) and Decitabine
One aspect of the present invention resides in the recognition that the METTL3 inhibitor compounds, STM3480 and STM3006, when administered in combination with daunorubicin, cytarabine, 5-azacitidine and quizartinib, produced an enhanced therapeutic effect in Kasumi1 or MOLM-14 AML cell lines (see Example 4).
Collectively, these data suggest that the administration of a METTL3 inhibitor enhances the antitumour effects of these AML standard of care agents. Thus, the combination of a METTL3 inhibitor with either an anthracycline topoisomerase 2 inhibitors (e.g. daunorubicin), cytarabine, hypomethylating agents (e.g. 5-azacitidine or decitabine) and/or FLT3 inhibitors (e.g. quizartinib) offers a promising therapy for the treatment of cancer (and especially acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) and/or Myelodysplastic syndromes (MDS)).
This combination treatment of the present invention therefore has the potential to provide better therapeutic outcomes in cancer patients, especially cancer patients that do not respond well to therapy with a METTL3 inhibitor or an anthracycline topoisomerase 2 inhibitor (e.g. daunorubicin), cytarabine, a hypomethylating agent (e.g. 5-azacitidine or decitabine) and/or a FLT3 inhibitor (e.g. quizartinib).
In one aspect, the present invention provides a combination comprising a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675), or a pharmaceutically acceptable salt thereof, and an anthracycline topoisomerase 2 inhibitor (e.g. daunorubicin), cytarabine, a hypomethylating agent (e.g. 5-azacitidine or decitabine) and/or a FLT3 inhibitor (e.g. quizartinib), or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a pharmaceutical product comprising a combination of a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675), or a pharmaceutically acceptable salt thereof, and an anthracycline topoisomerase 2 inhibitor (e.g. daunorubicin), cytarabine, a hypomethylating agent (e.g. 5-azacitidine or decitabine) and/or a FLT3 inhibitor (e.g. quizartinib), or a pharmaceutically acceptable salt thereof.
In one embodiment, the pharmaceutical product may comprise a kit of parts comprising separate formulations of a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675), or a pharmaceutically acceptable salt thereof, and an anthracycline topoisomerase 2 inhibitor (e.g. daunorubicin), cytarabine, a hypomethylating agent (e.g. 5-azacitidine or decitabine) and/or a FLT3 inhibitor (e.g. quizartinib), or a pharmaceutically acceptable salt thereof. The separate formulations of a METTL3 inhibitor as defined herein and an anthracycline topoisomerase 2 inhibitor (e.g. daunorubicin), cytarabine, a hypomethylating agent (e.g. 5-azacitidine or decitabine) and/or a FLT3 inhibitor (e.g. quizartinib), or a pharmaceutically acceptable salt thereof, may be administered sequentially, separately and/or simultaneously.
In another embodiment the pharmaceutical product is a kit of parts which comprises:
In one embodiment, the pharmaceutical product may comprise a one or more unit dosage forms (e.g. vials, tablets or capsules in a blister pack). In one embodiment, each unit dose comprises only one agent selected from the a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675) and the anthracycline topoisomerase 2 inhibitor (e.g. daunorubicin), cytarabine, hypomethylating agent (e.g. 5-azacitidine or decitabine) and/or FLT3 inhibitor (e.g. quizartinib). In another embodiment, the unit dosage form comprises both the a METTL3 inhibitor as defined herein (e.g. STM3480, STM3006 and STM3675) and the anthracycline topoisomerase 2 inhibitor (e.g. daunorubicin), cytarabine hypomethylating agent (e.g. 5-azacitidine or decitabine) and/or FLT3 inhibitor (e.g. quizartinib).
In one embodiment the pharmaceutical product or kit of parts further comprises means for facilitating compliance with a dosage regimen, for instance instructions detailing how to administer the combination.
In one embodiment, the pharmaceutical product or kit of parts further comprises instructions indicating that the combination, as defined herein, can be used in the treatment of cancer.
In one embodiment, the pharmaceutical product is a pharmaceutical composition.
Any suitable anthracycline topoisomerase 2 inhibitors, hypomethylating agents and FLT3 inhibitors may be used in this combination therapy of the present invention.
Suitably, the anthracycline topoisomerase 2 inhibitor is selected from daunorubicin, doxorubicin, epirubicin or idarubicin. Most suitably, the anthracycline topoisomerase 2 inhibitor is selected from daunorubicin and doxorubicin. In an embodiment, the anthracycline topoisomerase 2 inhibitor is daunorubicin.
Suitably, the hypomethylating agent is selected from 5-azacitidine or decitabine. In an embodiment, the hypomethylating agent is 5-azacitidine. In another embodiment, the hypomethylating agent is decitabine.
Suitably, the FLT3 inhibitor is selected from sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, or gilteritinib. More suitably, the FLT3 inhibitor is selected from midostaurin, quizartinib or gilteritinib. In an embodiment, the FLT3 inhibitor is midostaurin. In another embodiment, the FLT3 inhibitor is quizartinib. In another embodiment, the FLT3 inhibitor is gilteritinib.
The present invention also relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional agents selected from:
The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional agents selected from
The present invention also relates to a method of treating cancer, the method comprising administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, to a patient in combination with one or more additional agents selected from:
Suitably, the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is administered simultaneously, sequentially or separately with the:
In another aspect the present invention relates to a pharmaceutical product comprising a combination as defined above.
In another aspect, the present invention relates to a pharmaceutical composition comprising a combination as defined above, and one or more pharmaceutically acceptable excipients.
In another aspect, the present invention relates to a combination as defined above, or a pharmaceutical product as defined above, or a pharmaceutical composition as defined above for use in therapy.
In another aspect, the present invention relates to a combination as defined above, or a pharmaceutical product as defined above, or a pharmaceutical composition as defined above for use in the treatment of cancer.
In another aspect, the present invention relates to the use of a combination as defined above in the manufacture of a medicament for the treatment of cancer.
In another aspect, the present invention relates to a method of treating of cancer in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a combination as defined above.
In another aspect, the present invention relates to a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, is for simultaneous, separate or sequential administration with one or more additional agents selected from:
In another aspect, the present invention relates to an agent selected from:
In another aspect, the present invention relates to a use of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with one or more additional agents selected from:
In another aspect, the present invention relates to a use of an agent selected from:
In another aspect, the present invention relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and an agent selected from:
In another aspect, the present invention relates to a method of treating cancer, or potentiating the effect of an agent selected from:
In another aspect, the present invention relates to a method of treating cancer, or potentiating the effect of a METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of the METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously with an agent selected from:
The anti-proliferative effects of the combination therapy of the present invention has particular application in the treatment of human cancers.
Suitably, the cancer is selected from acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndromes (MDS).
In an embodiment, this combination therapy of the invention is suitable for the treatment of acute myeloid leukaemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL).
The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the promotion of an antitumour immune response, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures or within an organ), or the promotion of apoptosis (programmed cell death).
As indicated above, any suitable anthracycline topoisomerase 2 inhibitor, hypomethylating agent and FLT3 inhibitor may be used in the combination therapy of the present invention.
In an embodiment, the METTL3 inhibitor is as defined herein and the second agent is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacitidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib or cytarabine.
In an embodiment, the METTL3 inhibitor is selected any compound of the formulae I, II, VI or VII defined above, or a pharmaceutically acceptable salt thereof and the second agent is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacitidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib or cytarabine.
In an embodiment, the METTL3 inhibitor is selected any compound of the formulae I, II, VI or VII defined above, or a pharmaceutically acceptable salt thereof and the second agent is selected from daunorubicin, doxorubicin, 5-azacitidine, decitabine, midostaurin, quizartinib, gilteritinib or cytarabine.
In an embodiment, the METTL3 inhibitor is selected any compound of the formulae I, II, VI or VII defined above, or a pharmaceutically acceptable salt thereof and the second agent is selected from daunorubicin, 5-azacitidine, decitabine, quizartinib, or cytarabine.
In an embodiment, the METTL3 inhibitor is selected from STM3006, STM3480 or STM3675, or a pharmaceutically-acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacitidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib or cytarabine.
In an embodiment, the METTL3 inhibitor is selected from STM3006, STM3480 or STM3675, or a pharmaceutically-acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, 5-azacitidine, decitabine, midostaurin, quizartinib, gilteritinib or cytarabine.
In an embodiment, the METTL3 inhibitor is selected from STM3006, STM3480 or STM3675, or a pharmaceutically-acceptable salt thereof, and the second agent is selected from daunorubicin, 5-azacitidine, decitabine, quizartinib, or cytarabine.
In an embodiment, the METTL3 inhibitor is STM3480, or a pharmaceutically-acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacitidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib or cytarabine.
In an embodiment, the METTL3 inhibitor is STM3480, or a pharmaceutically-acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, 5-azacitidine, decitabine, midostaurin, quizartinib, gilteritinib or cytarabine.
In an embodiment, the METTL3 inhibitor is STM3480, or a pharmaceutically-acceptable salt thereof, and the second agent is selected from daunorubicin, 5-azacitidine, decitabine, quizartinib, or cytarabine.
In one aspect the present invention relates to a pharmaceutical composition comprising a combination of METTL3 inhibitor as defined herein, or a pharmaceutically acceptable salt thereof, and the other agent present in the combination as defined above, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
The pharmaceutical compositions of the invention will typically be for parenteral administration, especially when the inhibitors are antibodies.
The pharmaceutical compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
An effective amount of each component of the combination therapy will be present. Such an amount is an amount sufficient to treat or prevent a cancer condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a combination of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
In using a combination of the invention for therapeutic or prophylactic purposes it will generally be administered within a therapeutically effective dose of the particular agent concerned. These dosages are known in the art and will vary from one agent to another. The dosage may, for example, be in the range of 0.1 mg/kg to 30 mg/kg body weight. The dosing schedule will also vary from one immune checkpoint inhibitor to another. Suitable dosing schedules are known in the art.
The combination of the invention or pharmaceutical compositions comprising said combination may be administered to a subject by any appropriate or convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
Depending on the nature of the agent, routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
Combinations with Additional Therapeutic Agents
The combination treatments defined herein may be applied as a sole therapy for the treatment of the specified condition or it may involve, in addition to the combination therapy of the present invention, one or more additional therapies (including treatment with another therapeutic agent, surgery or other therapeutic interventions such as radiotherapy in the oncology setting).
Typically, the other therapeutic agent used in combination with the combination therapy of the present invention will be one or more therapeutic agents used as the standard of care for the treatment of the disease or condition concerned. The other therapeutic agent may include, for example, another drug used for the treatment of the condition concerned, or an agent that modulates the biological response to the combination therapy of the invention, such as, for example, an immunomodulatory agent.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
For example, the combination therapies defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may further include one or more of the following categories of anti-tumour agents:—
In a particular embodiment, the combination therapies defined hereinbefore may involve, in addition to the combination therapy of the invention, conventional surgery or radiotherapy or chemotherapy.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the combination therapy of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
According to this aspect of the invention there is provided a combination as defined hereinbefore for use in the treatment of a cancer as defined herein, comprising a combination therapy of the invention as defined hereinbefore, and another anti-tumour agent.
According to this aspect of the invention there is provided a combination for use in the treatment of cancer as defined herein, comprising a combination therapy of the invention as defined hereinbefore, and any one of the anti-tumour agents listed herein above.
In a further aspect of the invention there is provided a combination product of the invention for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.
In a particular aspect, the present invention provides a combination of a METTL3 inhibitor and a BCL2 inhibitor as defined above for use in the treatment of acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) or myelodysplastic syndromes (MDS), wherein the METTL3 inhibitor and BCL2 inhibitor are administered in combination with an additional anti-tumour agent.
In a further aspect, the present invention provides a combination of STM3480 and venetoclax for use in the treatment of acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) or myelodysplastic syndromes (MDS), wherein STM3480 and venetoclax are administered in combination with another anti-tumour agent.
Suitably, the additional anti-tumour agent is selected from an agent that is the standard of care for the treatment of AML, CLL, SLL or MDS. In particular, the additional anti-tumour agent may be selected from:
More particularly, the additional anti-tumour agent may be selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacitidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib or cytarabine. Suitably, the combination is for the treatment of AML, CLL or SLL, especially AML.
In one particular aspect, the present invention provides a combination of STM3480 and venetoclax for use in the treatment of acute myeloid leukaemia (AML), wherein STM3480 and venetoclax are administered in combination with another anti-tumour agent. Suitably, the additional anti-tumour agent is selected from an agent that is the standard of care for the treatment of AML. In particular, the additional anti-tumour agent may be selected from:
Embodiments of the invention will be described, by way of example only, with reference to the accompanying drawings, in which:
The following abbreviations have been used:
Methyl 4-oxopyrido[1,2-a]pyrimidine-2-carboxylate [Tetrahedron (2014), 70(17), 2761-2765] (3.94 g, 19.3 mmol) was dissolved in hydrogen chloride solution (8M, 7.5 mL) at room temperature (An exotherm was noted on addition) and the mixture was heated at reflux at for 2 h. The mixture was cooled to room temperature and the precipitate was collected by filtration and dried under vacuum to give the title compound (3.00 g, 81%) as a white solid.
Method A: LC-MS (electrospray): m/z=191.1 (M+H)+, RT=0.32 min
To a solution of 3-amino-4-iodobenzonitrile (8.00 g, 32.8 mmol) in THF-Anhydrous (40 mL) and triethylamine (80 mL, 0.574 mol) was added Pd2(PPh3)2Cl2 (230 mg, 0.328 mmol) and triphenylphosphine (172 mg, 0.656 mmol) at ambient temperature. The solution was degassed by bubbling nitrogen into the solution for 20 minutes. Then copper (I) iodide (125 mg, 0.66 mmol) and 3,3-diethoxyprop-1-yne (5.04 g, 39.3 mmol) were added sequentially and the reaction was stirred under nitrogen atmosphere for 18 hours. The precipitate (triethylamine hydrochloride) was collected by filtration and washed with EtOAc (˜20 mL). The filtrate was concentrated at reduced pressure and the residue was purified by chromatography on SiO2 [Biotage KP-Sil 100 g, eluting with 0-50% EtOAc in heptane]. The product containing fractions were combined and concentrated in vacuo to afford the title compound (8.19 g, Quant) as an orange oil.
Method B: LC-MS (electrospray): m/z=262.3 (M+H)+, RT=1.65 min.
To a stirred solution of 3-amino-4-(3,3-diethoxyprop-1-ynyl)benzonitrile (8.00 g, 31.1 mmol) in NMP (99 mL) was added potassium tert-butoxide (6.98 g, 62.2 mmol) at 0° C. (the colour of the solution turned from orange to dark red). After warming to RT, the solution was stirred at ambient temperature for 16 hours. Saturated aqueous ammonium chloride solution (25 mL) was added and the resulting mixture was partitioned between EtOAc (250 mL) and water (250 mL). The layers were separated and the organic layer washed twice more with water (2×200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a brown oil. The first aqueous layer was re-extracted with EtOAc (200 mL) and the layers separated. The organic layer was washed twice with water (2×200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude material was purified by chromatography on SiO2 [BIOTAGE KP-Sil 100 g, eluting with 0-50% EtOAc in heptane]. The product containing fractions were combined and concentrated in vacuo. The residue (yellow solid) was recrystallised from EtOAc/heptane to afford the title compound (5.86 g, 24.0 mmol, 77%) as colourless crystalline solid. Method B: LC-MS (electrospray): m/z=262.3 (M+H)+, RT=1.69 min.
To a degassed solution of 2-(diethoxymethyl)-1H-indole-6-carbonitrile (5.8 g, 24 mmol) in ethanol (70 mL) was added ammonia in MeOH (7M, 20 mL, 0.14 mmol) and the reaction was degassed and backfilled with nitrogen 3 times. Raney nickel (assumed 50%, about 5.4 g, 0.1 mmoL) was added and the reaction evacuated and backfilled with nitrogen 3 times. The flask was evacuated one final time and put under a hydrogen atmosphere and stirred at ambient temperature for 3 hours. More Raney nickel (about 2.7 g) was added and the reaction evacuated and placed under a hydrogen atmosphere and stirred at ambient temperature for 16 hours. The catalyst was removed by filtration (through Kieselguhr) and washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to afford the title compound (5.96 g, 100%) as a colourless oil which crystallised upon standing.
Method C: LC-MS (electrospray): m/z=247.3 (M−H)−, RT=2.74 min.
To a stirred solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (455 mg, 2.39 mmol) (Intermediate 1) and DIPEA (1.0 mL, 5.98 mmol) in DMF (10 mL) was added HATU (910 mg, 2.39 mmol). A colour change was observed from colourless to green and a suspension formed. After a further 30 minutes of stirring at ambient temperature, a solution of [2-(diethoxymethyl)-1H-indol-6-yl]methanamine (500 mg, 1.99 mmol) in DMF (5 mL) was added dropwise to the reaction. A colour change of green to red was observed and the reaction became homogeneous and was stirred at ambient temperature overnight.
The mixture was partitioned between EtOAc (100 mL) and sat. NaHCO3 solution (50 mL). The organic layer was separated, washed with water (80 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated at reduced pressure to give a viscous red oil.
The crude product was dissolved in THF (10 mL), water (1 mL) and acetic acid (0.5 mL) were added and the mixture was stirred at ambient temperature for 2 hours.
The THF was removed in vacuo and water (10 mL) was added to the resulting mixture causing further solid to precipitate out. The brown solid was collected by washed with water (2×5 mL) then ether (3×5 mL) and dried under vacuum to give the title compound (520 mg, 75%) as a brown solid.
Method C: LC-MS (electrospray): m/z=347.2 (M+H)+, RT=2.37 min.
A pressure vial was charged with N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (185 mg, 0.53 mmol), DCE (5 mL) and 1-cyclobutylmethanamine (0.13 mL, 1.0 mmol) at ambient temperature. The vial was sealed and the mixture was stirred at 65° C. for 2 hours. After cooling to RT, sodium triacetoxyborohydride (340 mg, 1.85 mmol) was added and the mixture was heated to 65° C. for 2 hours.
The mixture was partitioned between EtOAc (40 mL) and sat. sodium bicarbonate solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue (pale yellow oil) was purified by reverse phase chromatography (basic method, SNAP ULTRA 30 g Cartridge, eluting with MeCN+0.1% NH3/H2O+0.1% NH3, 10 to 90%). The fractions containing desired product were freeze dried overnight to give the title compound (85 mg, 38%) as an off-white solid.
Method C: LC-MS (electrospray): m/z=416.4 (M+H)+, RT=3.14 min.
This compound was prepared in the same manner as STM3480 described above using commercial amines or described intermediates.
Method C: LC-MS (electrospray): m/z=446.4 (M+H)+, RT=3.01 min.
The preparation of STM3006 is described in Example 227 on page 285 of International Patent Publication No. WO2020/050898.
This experiment evaluates the effects of human donor Peripheral Blood Mononuclear Cells (PBMCs) to attack and kill fluorescently-labelled tumour cells in a co-culture assay. Briefly, test agents are incubated at different concentrations with SKOV3 human ovarian cancer cells in the presence or absence of human donor PBMCs and tumour growth is monitored continuously by real time imaging of the NucLight Red-labelled SKOV3 cells for several days.
NucLight Red (Incucyte, Essen Biosciences)-transduced SK-OV-3 (SK-OV-3-NLR) cells were transferred into Ultra-low attachment 96 well plates with spontaneous spheroid formation occurring over 48 hours. Peripheral blood mononuclear cells (PBMC) were isolated from healthy single donor buffy coats by density separation. Prior to co-culture of SK-OV-3-NLR spheroids with PBMC, SK-OV-3-NLR spheroids were treated with 10 ng/ml of interferon gamma (IFNγ). All treatments, including STM3480 and Pembrolizumab, were added at the point of co-culture in a final total volume of 200 μl/per well. Assay plates were transferred into an IncuCyte S3 and images were collected every 2 hours for 7 days. Following experimental completion, an analysis definition was applied to quantify the Total NLR Integrated Intensity present on a per well basis. Changes in spheroid size were quantified by plotting Total NLR Integrated Intensity against time.
Similarly, the treatment of SKOV3/PBMC co-cultures with STM3480 and/or avelumab (anti-PD-L1 antibody; open circles) leads to the greatest anti-tumour activity, greater than that seen with either single agent alone (grey circles, open triangles), demonstrating the surprising and beneficial effect of this combination treatment (see
The in vivo effect of METTL3 inhibition in combination with anti-PD1 immune checkpoint inhibitor was investigated using syngeneic mouse tumour models in immune-competent hosts. Mouse tumour models can be grown in appropriate host strains and are widely used to investigate the effects of therapeutic agents on the immune system and cancer growth. There are a limited range of mouse syngeneic tumour models available, far fewer than human cell lines, and they are widely used in the art to support potential clinical utility of immune stimulatory approaches across multiple indications. We exemplify the potential role of STM3480 and combinations with immune checkpoint inhibitors such as anti-PD-1 antibodies in multiple tumour models including A20 (murine B cell lymphoma), EMT-6 (murine breast cancer) and CT-26 (murine colorectal cancer).
The objective of this study is to assess the anti-tumour efficacy of STM3480 in combination with anti-PD1 in subcutaneous A20 mouse B cell lymphoma cancer model in female BALB/c mice.
A20 (#ATCC TIB-208) mouse B cell lymphoma cells were cultured in (RPMI-1640+10% non H.I. FBS+0.05 mM 2-mercaptoethanol) media. 5×105 viable cells in 0.1 ml PBS were injected subcutaneously into the left flank of 7-9 week old female BALB/cN (BALB/cAnNCrl) Crl mice utilising 27 gauge needles following skin disinfection with 70% ethanol.
Tumours were measured three times a week and tumour volumes estimated using the formula 0.5 (L×W2) by measuring the tumour in two dimensions using electronic callipers for the duration of the study.
Mice were randomly allocated to four treatment groups and treatment commenced when tumours reached a mean volume of ˜50-100 mm3. Mice were allocated to their treatment groups with uniform mean tumour volume between groups. Treatment was continued for up to 3 weeks, or until individual mice were sacrificed for humane reasons according to Home Office license regulations (e.g. body weight loss >20%; tumour volume >1500 mm3; tumour ulceration; loss of clinical condition). The final dose was given on day 32 after implantation.
Vehicle for STM3480—Hydroxypropyl-β-Cyclodextrin (HPBCD)/Sodium Acetate buffer pH:4.6 50 mM (10%/90%; w/v): Weigh 1.025 g of sodium acetate anhydrous. Add 700 μl of glacial acetic acid then make up to 500.0 ml with ultrapurified water. pH:4.6 50 mM.
For 1 ml volume 5 mg/ml STM3480 dosing solution: Weigh 5.0 mg of STM00003480 compound (Batch: EV-WZM001-421-002). Add 1.0 mL of HPBCD/Acetate buffer pH:4.6 50 mM (10%/90%; w/v). Magnetic stirring at high speed at ambient temperature; Overnight stirring may be required if there are any signs of precipitation. The formulation is a slight yellow solution with very few particles in suspension. Homogenize with a vortex before administration.
For PD-1 treatments, a mouse-specific anti-PD1 antibody (clone ID RMP1-14) was used, dissolved in PBS as described in the table below.
Vehicle treatment (solid black lines, upper left panel) shows progressive tumour growth in 9/10 animals. STM3480 treatment (dashed grey lines, upper right panel) shows progressive tumour growth in 8/10 animals. Anti-PD1 treatment (black dotted lines, lower left panel) shows progressive tumour growth in 8/10 animals. Combination of STM3480 and anti-PD1 (black dotted and dashed lines, lower right panel) shows progressive tumour growth in 2/10 animals, tumour regressions in 8/10 and complete tumour regressions in 6/10 animals.
Animals treated with the combination of STM3480 and anti-PD1 antibodies showed complete tumour regressions (i.e. no measurable tumour remaining) in the majority of treated animals. 6/10 animals remained tumour-free for 29 days after treatment ceased, indicating that these animals had all been cured.
See Table 5 below and
The objective of this study is to assess the anti-tumour efficacy of STM3480 in combination with anti-PD1 in subcutaneous EMT6 mouse breast cancer model in female BALB/c mice.
EMT6 (#ATCC CRL-2755) mouse breast cancer cells were cultured in (Waymouth's MB 752/1 Medium with 2 mM L-glutamine, 85%; foetal bovine serum (non-heat inactivated), 15%) media. 5×104 viable cells in 0.1 ml PBS were injected subcutaneously into the left flank of 8-9 week old female BALB/cN (BALB/cAnNCrl) Crl mice utilising 27 gauge needles following skin disinfection with 70% ethanol.
Tumours were measured three times a week and tumour volumes estimated using the formula 0.5 (L×W2) by measuring the tumour in two dimensions using electronic callipers for the duration of the study.
Mice were randomly allocated to four treatment groups and treatment commenced when tumours reached a mean volume of ˜50-100 mm3. Mice were allocated to their treatment groups with uniform mean tumour volume between groups. Treatment was continued for up to 3 weeks, or until individual mice were sacrificed for humane reasons according to Home Office license regulations (e.g. body weight loss >20%; tumour volume >1500 mm3; tumour ulceration; loss of clinical condition). The final dose was given on day 32 after implantation.
See Table 5 below.
The objective of this study is to assess the anti-tumour efficacy of STM3480 in combination with anti-PD1 in subcutaneous CT26 mouse colorectal cancer model in female BALB/c mice. CT26.WT (CRL-2638) mouse breast cancer cells were cultured in (RPMI—1640+10% FBS+2 mM L-Glutamine) media. 1×105 viable cells in 0.1 ml PBS were injected subcutaneously into the left flank of 8-9 week old female BALB/cN (BALB/cAnNCrl) Crl mice utilising 27 gauge needles following skin disinfection with 70% ethanol.
Tumours were measured three times a week and tumour volumes estimated using the formula 0.5 (L×W2) by measuring the tumour in two dimensions using electronic callipers for the duration of the study.
Mice were randomly allocated to four treatment groups and treatment commenced when tumours reached a mean volume of ˜50-100 mm3. Mice were allocated to their treatment groups with uniform mean tumour volume between groups. Treatment was continued for up to 3 weeks, or until individual mice were sacrificed for humane reasons according to Home Office license regulations (e.g. body weight loss >20%; tumour volume >1500 mm3; tumour ulceration; loss of clinical condition). The final dose was given on day 32 after implantation.
See Table 5 below.
The combination of STM3480 and anti-PD-1 antibody was highly efficacious in multiple in vivo syngeneic cancer models derived from a range of cancer indications (Table). In each case, the combination treatment caused the greatest number of tumour regressions compared to single agents, and in two models (A20 and EMT6), these regressions were complete and no tumour was detected after treatment, indicating a profound anti-tumour response.
The sensitivity of AML cell lines to combinations of METTL3 inhibitor and standards of care was determined as described. Dose response curves of venetoclax were determined either alone or in the presence of different concentrations of METTL3 inhibitor that are known to be active in cells.
Synergistic interactions occur when the IC50 value decreases in the presence of METTL3 inhibitor. Additive interactions occur when the IC50 value does not change in the presence of METTL3 inhibitor. Antagonistic interactions occur when the IC50 value increases in the presence of METTL3 inhibitor.
See
In
The same synergistic interaction and decrease in IC50 values were observed in the Kasumi1 cell line with additional METTL3 inhibitors, and in other AML cell lines (see
24 h before cell treatment, homogenize, stain with Trypan blue and count viable cells using CellOMeter Auto T4. Dilute cells in media at 400 000 cells/ml to ensure an exponential growth the day after.
On treatment day, homogenize, stain with Trypan blue and count viable cells using CellOMeter Auto T4. Dilute to the proper cell seeding density according to Table 6 in cell media.
Raw data were converted to % viability by normalization to DMSO controls. IC50 determination was performed using GraphPad Prism and fitting curves to the standard nonlinear regression four parameter equation (Y=Bottom+(Top-Bottom)/(1+(IC50/X){circumflex over ( )}HillSlope)) least squares method, and synergy was assessed by comparison of IC50 values of the standard of care in the presence or absence of different concentrations of METTL3 inhibitor (see
Daunorubicin is a major component of the standard of care for AML treatment.
Additive interactions occur when the combination leads to an enhanced decrease in tumour cell viability with the addition of METTL3 inhibitor, yet the IC50 value does not change.
In
The same additive interaction was observed in the Kasumi1 cell line with additional METTL3 inhibitor STM3006 (see
Cytarabine is a major component of the standard of care for AML treatment.
MOLM-14 cells have a FLT3 mutation and are known to be highly dependent on FLT3 activity for survival and are highly sensitive to FLT3 inhibitors such as quizartinib.
All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).
All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.
The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise paragraphed. No language in the specification should be construed as indicating any non-paragraphed element as essential to the practice of the invention.
The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.
This invention includes all modifications and equivalents of the subject matter recited in the paragraphs appended hereto as permitted by applicable law.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2107907.4 | Jun 2021 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2022/051400 | 6/1/2022 | WO |
