PI3K-delta inhibitors for use in treatment regimens

Abstract

A compound or a pharma- ceutical acceptable salt thereof for use in a method for treating a disease or condition in which signaling through the PI3Kδ pathway is pathologically implicated in a patient, such as cancer and inflammatory or autoimmune diseases. The compound is provided at a particular dose and has been found to have a favorable safety profile in humans, particularly with respect to hepatotoxicity, diarrhea / colitis, respiratory infections, and hematological toxicity.

Description

Technical Field

[0001] This application claims the priority of GB2104416.9 filed on March 29, 2021 and GB2117511.2 filed on December 3, 2021. The contents and elements of these are incorporated herein by reference for all purposes.

[0002] The present invention relates to the treatment of diseases or conditions in which signal transduction via the PI3Kδ pathway is pathologically involved, with PI3Kδ inhibitors. Such diseases or conditions include cancer and a plurality of inflammatory and autoimmune diseases.

Background Art

[0003] PI3K belongs to a family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring. PI3K is classified into three classes (Class I, II, and III) according to its structure, regulation, and substrate specificity. Class I PI3K, including PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, are lipid kinases that catalyze the phosphorylation of phosphatidylinositol-4,5-bisphosphate to produce phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 functions as a second messenger that controls several cellular processes, including growth, survival, adhesion, and migration.

[0004] All four class I PI3K isoforms exist as heterodimers and consist of a catalytic subunit (p110) and closely related regulatory subunits that control expression, activation, and intracellular localization. PI3Kα, PI3Kβ, and PI3Kδ bind to a regulatory subunit known as p85 and are activated by growth factors and cytokines via a tyrosine kinase-dependent mechanism (Jimenez, Hernandez et al. 2002), while PI3Kγ binds to two regulatory subunits (p101 and p84), and its activation is driven by the activation of G protein-coupled receptors (Brock, Schaefer et al. 2003). PI3Kα and PI3Kβ are ubiquitously expressed. In contrast, PI3Kγ and PI3Kδ are mainly expressed in leukocytes (Vanhaesebroeck, Ali et al. 2005).

[0005] The PI3K pathway is frequently activated in various solid tumors and hematological malignancies, making PI3K an attractive therapeutic target in oncology. This has led to significant interest in the development of inhibitors targeting this pathway (Buchanan 2019). While many PI3K inhibitors have reached various stages of clinical development, few have been approved for clinical use. Although these drugs are clinically effective, their use is accompanied by not only drug-specific side effects but also several serious class-related side effects. Some of these are thought to be immune-mediated and include skin reactions, severe diarrhea with or without colitis, hepatotoxicity, and pneumonia. PI3K inhibitors also induce various metabolic abnormalities, such as hyperglycemia and hypertriglyceridemia.

[0006] As a result, many new PI3K inhibitors with varying degrees of target selectivity were synthesized with the expectation of improved safety and efficacy. Some of these are currently undergoing clinical trials for use in various solid tumors, not just hematological malignancies. However, evidence from early clinical trials suggests that these new drugs are associated with not only class-related side effects but also other serious and unexpected side effects. Consequently, the development of many of these new drugs has been discontinued.

[0007] As a class, PI3Kδ inhibitors are associated with serious dermatological, myelosuppressive, metabolic, gastrointestinal, and respiratory side effects (Curigliano 2019). Unlike the ubiquitously expressed p110α and p110β, p110δ is primarily expressed on leukocytes (e.g., T cells and B cells), and therefore PI3Kδ inhibitors have been used to target relapsed or refractory lymphomas, including but not limited to CLL, mantle cell lymphoma, and non-Hodgkin lymphoma (Buchanan 2019). Unsurprisingly, these PI3Kδ isoform-specific inhibitors have also attracted attention for hematological toxicity, including anemia, thrombocytopenia, leukocytosis, hemolysis, and neutropenia. Inhibition of PI3Kδ leads to activation of the immune response, which is thought to be some of the cause of side effects to these drugs, such as PI3Kδ-selective idelalisib. Idelalisib-induced colitis, hepatitis, and pneumonia are thought to be immune-mediated effects, and a high incidence of idelalisib-induced diarrhea, pneumonia, and elevated liver transaminases is observed in immunocompetent patients. The FDA-approved label for idelalisib includes a detailed black-bordered warning regarding the possibility of "fatal and serious toxicity: liver, severe diarrhea, colitis, pneumonia, infection, and bowel perforation." Therefore, the safety of currently approved PI3K inhibitors has been rigorously investigated, especially with long-term administration.

[0008] Adverse events (AEs) experienced by patients treated with PI3Kδ inhibitors are clinically significant and may limit their use (Phillips 2020). Currently, it is unclear whether discontinuation / modification of treatment due to side effects negatively impacts the efficacy of PI3Kδ inhibitors. Generally, target or class-specific toxicities associated with PI3Kδ inhibitors are considered to be hepatotoxicity, diarrhea / colitis, respiratory infections, and hematological toxicity.

[0009] Hematological toxicity, such as neutropenia, is often documented as an abnormality in general laboratory findings in the trial outcomes. Hepatotoxicity is almost always assessed by elevated serum hepatic transaminase levels and graded according to their severity (grade 1 being the least severe, and grade 5 often being lethal). Grade 3 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels commonly observed with PI3Kδ inhibitors often lead to interruption or modification of administration, and less frequently to discontinuation. Diarrhea or colitis has been reported in up to one-third of patients treated with PI3Kδ inhibitors, usually requiring treatment with antidiarrheal or anti-inflammatory drugs. Respiratory infections have been observed in up to 20% of patients treated with idelalisib, and anti-infective prophylactic drugs are usually administered to patients receiving PI3Kδ inhibitors.

[0010] Considering the above, there is a need in the art for PI3K modulators that inhibit specific PI3K isoforms, particularly PI3Kδ, with higher selectivity than other isoforms, while simultaneously possessing a favorable safety profile (particularly with respect to elevated liver enzymes, diarrhea, and neutropenia). Furthermore, there is a need in the art for improved methods of treating (and preventing) diseases involving the PI3Kδ pathway using compounds with high selectivity and a favorable safety profile (particularly with respect to elevated liver enzymes, diarrhea, and neutropenia).

[0011] The inventors recognized this need and began working on the present invention.

[0012] Among the countless disclosures concerning PI3K inhibitors, WO2011058149 describes tricyclic pyrazoleamine derivatives that are PI3K inhibitors and their use in treating other diseases such as autoimmune diseases, inflammatory disorders, multiple sclerosis, and cancer. [Overview of the project]

[0013] In a first aspect, the present invention relates to a compound of formula I for use in a method of treating a disease or condition in which signaling via the PI3Kδ pathway is pathologically involved in the patient (e.g., an imbalance in immune cell responses or expression in tumor cells). [ka] The present invention provides a pharmaceutically acceptable salt thereof, the method comprising administering the compound of formula I in a dose of 18 mg to 108 mg of the compound per day. In some embodiments, the dose is 18 mg to 72 mg per day. Preferably, the dose is about 36 mg per day. In another embodiment, preferably, the dose is about 72 mg per day.

[0014] As described and illustrated herein, the pharmaceutically acceptable salt is preferably a hemifumarate; that is, the compound is provided as a salt of formula Ia. [ka]

[0015] Accordingly, the present invention provides a salt of formula Ia for use in a method of treating a disease or condition in which signaling via the PI3Kδ pathway is pathologically involved in the patient (e.g., an imbalance in immune cell responses or expression in tumor cells), the method comprising administering the salt of formula Ia in a dose of 20 mg to 120 mg of the salt per day. In some embodiments, the dose is 20 mg to 80 mg per day. Preferably, the dose is about 40 mg per day. In another embodiment, preferably, the dose is about 80 mg per day.

[0016] The dose may be administered in a once-daily regimen. That is, the daily dose may be taken in one or more dose units at a time. Therefore, in some embodiments, the administration is once daily. This is sometimes referred to as a quaque die (QD).

[0017] The appropriate administration is orally. This is sometimes referred to as PO (per os).

[0018] In other words, in some embodiments, the dose of the salt of formula Ia may be 20 to 120 mg, more preferably 20 to 80 mg, more preferably 30 to 60 mg, more preferably 30 to 50 mg, most preferably about 40 mg, or POQD. In other embodiments, the dose of the salt of formula Ia may be 20 to 120 mg, more preferably 20 to 80 mg, more preferably 30 to 100 mg, more preferably 30 to 80 mg, more preferably 40 to 80 mg, most preferably about 80 mg, or POQD.

[0019] Appropriately, more than one solid dose unit is used per administration. In other words, the dose is divided into multiple dose units. For example, the administration may consist of two solid dose units, each containing 20 mg of the salt of formula Ia. In another example, the administration may consist of four solid dose units, each containing 20 mg of the salt of formula Ia.

[0020] Thus, in a further aspect, the present invention may provide a solid dosage unit comprising 20 mg of a salt of formula Ia.

[0021] Thus, in a further aspect, the present invention may provide a solid dosage unit comprising 5 mg of a salt of formula Ia.

[0022] In another embodiment, one solid dosage unit is used per administration. For example, the administration may comprise one solid dosage unit comprising 40 mg of a salt of formula Ia. In another embodiment, the administration may comprise one solid dosage unit comprising 80 mg of a salt of formula Ia.

[0023] Thus, in a further aspect, the present invention may provide a solid dosage unit comprising 80 mg of a salt of formula Ia.

[0024] Thus, in a further aspect, the present invention may provide a solid dosage unit comprising 40 mg of a salt of formula Ia.

[0025] In some embodiments, the salt of formula Ia is formulated into a pharmaceutical composition comprising microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate. In some embodiments, the pharmaceutical composition is provided in a shell capsule.

[0026] The method of the present invention is directed to the treatment of diseases or conditions in which signal transduction via the PI3Kδ pathway is pathologically involved (e.g., but not limited to, imbalance of immune cell responses or expression in tumor cells). Such diseases or conditions include inflammatory diseases, autoimmune diseases and cancers. In other words, the method may be a method for treating a disease or condition selected from inflammatory diseases, autoimmune diseases and cancers.

[0027] In some embodiments, the method is a method for treating cancer.

[0028] In some embodiments, the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukemia, lymphoma, multiple myeloma (including Waldenström disease), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer, and colorectal cancer. For example, the cancer may be melanoma, lymphoma, myelofibrosis, non-small cell lung cancer, or mesothelioma. In some cases, the melanoma may be progressive or metastatic melanoma, or ocular / uveal melanoma. Progressive or metastatic melanoma may be histologically confirmed, unresectable stage III or IV melanoma. In some cases, the cancer may be B-cell lymphoma. In some cases, the cancer may be T-cell lymphoma. In some cases, the cancer may be melanoma. In some cases, the cancer may be uveal melanoma.

[0029] In some embodiments, the inflammatory or autoimmune disease may be activated PI3Kδ syndrome (APDS), allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis (RA), multiple sclerosis (MS), primary Sjögren's syndrome, pemphigus vulgaris, autoimmune hemolytic anemia, systemic lupus erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis, and idiopathic thrombocytopenic purpura (ITP).

[0030] In some preferred embodiments, the treatment does not result in clinically significant treatment-related elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in the patient. In some preferred embodiments, the treatment does not cause treatment-related grade 3 diarrhea or colitis.

[0031] In some preferred embodiments, the treatment does not result in clinically significant treatment-related neutropenia in the patient.

[0032] In some preferred embodiments, the treatment extends the duration of treatment in the absence of serious side effects.

[0033] The present invention further provides solid dosage forms for use in these methods. Suitable solid dosage forms include tablets and hard-shell or soft-shell capsules.

[0034] The present invention includes combinations of the embodiments and preferred features described herein, except where such combinations are clearly unacceptable or clearly to be avoided.

[0035] Embodiments and experiments illustrating the principle of the present invention will be described here with reference to the attached drawings. [Brief explanation of the drawing]

[0036] [Figure 1] a and b show the ALT levels measured in patients administered compound 1. [Figure 2] a and b show the AST levels measured in patients administered compound 1. [Figure 3] Figures a and b show neutrophils measured in patients administered compound 1. [Figure 4] Figures a and b show CD63-positive basophils measured in patients who received compound 1 after exovivo stimulation with anti-IgE. [Modes for carrying out the invention]

[0037] Aspects and embodiments of the present invention are described herein. Further aspects and embodiments will be apparent to those skilled in the art. All documents referenced herein are incorporated herein by reference.

[0038] compound 1 Compound 1 is Example 339 of WO2011058149, which is incorporated herein by reference in its entirety. Its structure is as follows: [ka]

[0039] In IUPAC nomenclature, compound 1 above may be called 6-fluoro-3-(morpholine-4-ylcarbonyl)-1-[4-(morpholine-4-ylmethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide. Alternatively, the above structural formula may be written as [6-fluoro-1-(4-morpholine-4-ylmethylphenyl)-5,5-dioxo-4,5-dihydro-1H-5λ6-thiochromeno[4,3-C]pyrazole-3-yl]morpholine-4-ylmethanone.

[0040] Compound 1 can be prepared and characterized as described in Published Patent Application WO2011058149A1 (see Compound 339 on page 69, Preparation on pages 303-307, and Characterization on pages 481 and 414-418). This information is specifically incorporated herein by reference.

[0041] Based on the process disclosed in WO2011 / 058149A1, the authors Haselmayer et al. describe a five-step procedure for the preparation of the compound (Haselmayer, 2014). This procedure begins with the reaction of 8-fluoro-2,3-dihydro-4Hthiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is cyclized with 4-(4-hydrazinylbenzyl)morpholine to form a pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid, followed by saponification of the ethyl ester to the corresponding acid, and then coupling with morpholine to obtain the compound of formula I.

[0042] Alternatively, the intermediate of the reaction between 8-fluoro-2,3-dihydro-4H-thiochromen-4-one and diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinobenzoic acid. This benzoic acid is reduced using a borane-THF complex, and the resulting thioether is oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid. The ethyl ester is saponified to the corresponding acid, and both the acid and alcohol are chlorinated with excess thionyl chloride in the presence of dimethylformamide, followed by coupling with morpholine to obtain compound 1.

[0043] Compound 1 may be provided as a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art. Several pharmaceutically acceptable salts of Compound 1 are described in WO2014121901, which is incorporated as a whole by reference.

[0044] Compound 1, as used herein, is provided as hemi-fumarate anhydrous (formula shown). Its synthesis and characterization are described in WO2014121901 (page 4). This is referred to as solid form A1. Hemi-fumarate hydrate (H1) has also been identified. The hemi-fumarate anhydrous used is crystalline and has the powder X-ray peak list described in WO2014121901. The discoveries of the present invention are not limited to the use of this solid form, but it will be understood that it is preferred. [ka]

[0045] Haselmayer et al. also describe the characterization of the compound as a highly selective PI3Kδ inhibitor. Preferred in vitro and in vivo properties of compound 1 are further described by Johnson et al. (Johnson, Z. et al., AACR 2020, poster 666).

[0046] formulation Compound 1 is appropriately provided as the hemi-fumarate described above. Preferably, Compound 1 is provided in a pharmaceutical composition formulated for oral administration. The pharmaceutical composition may be provided in capsules or in tablets. In some cases, it is provided as a tablet, for example, a coated tablet or an uncoated tablet produced by compression of a powder or granular composition. In other cases, it is provided as a powder or granular composition in a capsule, for example, a hard-shell or soft-shell capsule, for example, a hydroxymethylcellulose (HPMC) capsule. In other words, an oral dosage form is preferred.

[0047] The formulation appropriately comprises one or more pharmaceutically acceptable excipients, disintegrants, flow enhancers, and / or lubricants.

[0048] In some cases, the oral dosage form may contain 5 mg of compound 1, provided as hemi-fumarate. In some cases, the oral dosage form may contain 20 mg of compound 1, provided as hemi-fumarate. Both oral dosage forms are manufactured as described in Table 1. With regard to the dosage of this method, it will be understood that the dosage burden (number of capsules or tablets) imposed on the patient is relatively low, especially when the 20 mg solid dosage form is used. This is advantageous for patient compliance.

[0049] However, it will be understood that for some patients, for example, if the patient has difficulty swallowing, a smaller dosage form may be preferred. In the treatment of the claimed condition, even the use of a smaller 5 mg antibody dosage form does not necessarily increase the burden on the patient (number of capsules or tablets). [Table 1]

[0050] The oral dosage form may contain 40 mg of compound 1, provided as hemi-fumarate. The oral dosage form may contain 80 mg of compound 1, provided as hemi-fumarate. Both oral dosage forms can be manufactured in the same manner as the dosage forms listed in Table 1. With respect to the dosage of this method, it will be understood that when a single solid dosage form is used, the dosage burden imposed on the patient (number of capsules or tablets) is lowest. This is most advantageous for patient compliance.

[0051] Accordingly, the present invention further relates to a pharmaceutical composition comprising compound 1, which is formulated for oral administration and is preferably provided as a hemi-fumarate.

[0052] An exemplary formulation comprises hemi-fumarate of compound 1, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. The formulation may be provided in solid dosage forms, such as tablets or powder or granular compositions encapsulated in shell capsules. It will be understood that a single tablet can contain a higher dose of hemi-fumarate of compound 1 than a single capsule. Therefore, tablets are preferred for higher dose units. Tablets may be coated to improve taste or swallowability.

[0053] The amount of hemi-fumarate of compound 1 may be 5 mg to 20 mg, for example, 5 mg or 20 mg. In another embodiment, the amount of compound 1 may be 5 mg to 80 mg, for example, 5 mg, 20 mg, 40 mg or 80 mg.

[0054] Therefore, in some embodiments, the present invention provides a solid dose unit comprising a pharmaceutical composition comprising 5 mg of hemi-fumarate of compound 1. Therefore, in some embodiments, the present invention provides a solid dose unit comprising a pharmaceutical composition comprising 20 mg of hemi-fumarate of compound 1. Therefore, in some embodiments, the present invention provides a solid dose unit comprising a pharmaceutical composition comprising 40 mg of hemi-fumarate of compound 1. Therefore, in some embodiments, the present invention provides a solid dose unit comprising a pharmaceutical composition comprising 80 mg of hemi-fumarate of compound 1.

[0055] Accordingly, in some embodiments, the present invention provides tablets comprising a pharmaceutical composition comprising 40 mg of hemi-fumarate of compound 1. Accordingly, in some embodiments, the present invention provides tablets comprising a pharmaceutical composition comprising 80 mg of hemi-fumarate of compound 1. It will be understood that the pharmaceutical composition of the tablets may be the same as the pharmaceutical composition of the capsules, or may be optimized for tableting.

[0056] Method of the present invention As described in further detail below, the inventors have surprisingly found that compound 1 has a favorable safety profile in humans, particularly with respect to hepatotoxicity, diarrhea / colitis, respiratory infections, and hematological toxicity. Furthermore, treatment of patients with compound 1 does not result in elevated liver enzymes, diarrhea, or neutropenia. Thus, a PI3K inhibitor with specificity for isoform δ and patient-friendly safety properties can be provided.

[0057] Further advantageous characteristics of treatment methods using compound 1 may include one or more of the following: higher efficacy, longer duration of administration, and less dose reduction, interruption, or discontinuation.

[0058] In other words, the inventors have surprisingly found that patients (in this case, patients with melanoma, uveal melanoma, and mesothelioma, and therefore expected to apply to all human subjects) can be treated with compound 1 with fewer side effects than expected with treatment regimens using PI3K inhibitors. This makes the treatment suitable for long-term prescription without dose reduction or interruption.

[0059] In the clinical trials and examples described herein, Compound 1 is administered as hemi-fumarate. Therefore, in some cases, Compound 1 is administered as hemi-fumarate. However, it will be understood that the present invention is not limited thereto, and other solid forms (e.g., other pharmaceutically acceptable salts) are also conceivable.

[0060] The weight equivalent of compound 1 as a free base in a 40 mg dose is calculated to be approximately 36 mg (i.e., about 90% of the weight of compound 1 hemifumarate corresponds to the free base, and the remaining approximately 10% corresponds to the acid that forms the salt).

[0061] The weight equivalent of compound 1 as a free base in an 80 mg dose is calculated to be approximately 72 mg (i.e., about 90% of the weight of compound 1 hemifumarate corresponds to the free base, and the remaining approximately 10% corresponds to the acid that forms the salt).

[0062] The present invention relates to a method for treating a disease or condition in which signaling via the PI3Kδ pathway is pathologically involved in a patient, the method comprising administering compound 1 in an amount of 18 mg to 108 mg per day. In some cases, the amount is 18 mg to 72 mg per day. In some cases, the amount is 27 to 54 mg per day. In some cases, the amount is 27 to 45 mg per day, for example, about 36 mg per day. In some cases, the amount is 27 to 108 mg per day. In some cases, the amount is 27 to 72 mg per day. In some cases, the amount is 36 to 90 mg per day, for example, about 72 mg per day. In some cases, the amount is 36 to 72 mg per day.

[0063] When compound 1 is administered as hemi-fumarate (formula Ia), the present invention relates to a method for treating a disease or condition in which signaling via the PI3Kδ pathway is pathologically involved in the patient, the method comprising administering compound 1 as hemi-fumarate in an amount of 20 mg to 120 mg per day. In some cases, the amount is 20 mg to 80 mg per day. In some cases, the amount is 30 to 60 mg per day. In some cases, the amount is 30 to 50 mg per day, for example, about 40 mg per day. In some cases, the amount is 30 to 120 mg per day. In some cases, the amount is 30 to 80 mg per day. In some cases, the amount is 40 to 100 mg per day, for example, about 80 mg per day. In some cases, the amount is 40 to 80 mg per day.

[0064] Lower doses have also been considered and are anticipated. Therefore, it will be understood that in any method described herein, the method may include administering compound 1 in amounts of 9 mg to 108 mg per day. In some cases, the amount of compound 1 is 9 mg to 72 mg per day. When compound 1 is administered as hemi-fumarate, in any method described herein, the method may include administering compound 1 as hemi-fumarate in amounts of 10 mg to 120 mg per day. In some cases, the amount of compound 1 as hemi-fumarate is 10 mg to 80 mg per day.

[0065] Inhibition of the PI3Kδ pathway in patients can be demonstrated by measuring the pharmacodynamic activity (PD) of compound 1 in blood samples. A PD marker specific to PI3Kδ inhibition in blood is CD63 expression on basophils. Treatment of patients with compound 1 as hemi-fumarate reduces the percentage of CD63-positive basophils in patient blood samples in a dose-dependent manner, to a degree comparable to that reported for other PI3Kδ inhibitors (e.g., idelalisib). Particularly at a dose of 40 mg, the percentage of CD63-positive basophils was low in all samples measured, confirming effective inhibition of the PI3Kδ pathway during the course of treatment. Particularly at a dose of 80 mg, the percentage of CD63-positive basophils was similarly low in all samples measured, confirming effective inhibition of the PI3Kδ pathway during the course of treatment.

[0066] Therefore, certain preferred embodiments relate to a salt of formula Ia in a dose of 40 mg, or a compound of formula I in a dose of 36 mg.

[0067] However, it will be understood that higher doses are included and assumed. For example, the dose may be 60 mg of the salt of formula Ia or 54 mg of the compound of formula I. For example, the dose may be 80 mg of the salt of formula Ia or 72 mg of the compound of formula I, and in some embodiments this may be preferred.

[0068] In some cases, lower doses may be considered. For example, such doses may be 10 mg of the salt of formula Ia or 9 mg of the compound of formula I.

[0069] The inventors have found that once-daily administration is effective and well-tolerated. Once-daily administration offers advantages compared to some known and used PI3K inhibitors (for example, idelalisib is prescribed at a dose of 150 mg twice daily unless dose reduction is necessary due to side effects). Once-daily administration can improve patient experience value and improve patient compliance. Cancer patients, especially those with advanced cancer, often experience a burden of a considerable number of tablets, which can be difficult to swallow. Therefore, in the method of the present invention, the dose can be taken once daily. In other words, the dose is not divided and dispersed throughout the day. It can be taken as a single dose unit (e.g., a single tablet or capsule) or as multiple dosage forms (e.g., two or more tablets or capsules).

[0070] Therefore, in some cases, the method includes administering one or more solid dose units. For example, in some cases, the daily dose may be 40 mg, and the method includes administering two 20 mg solid dose units (i.e., solid dose units containing 20 mg of compound 1 as hemi-fumarate), or more preferably, one 40 mg solid dose unit.

[0071] In another example, the daily dose may be 60 mg, and the administration may consist of three solid dose units, each containing 20 mg of the salt of formula Ia. In yet another example, the daily dose may be 80 mg, and the administration may consist of four solid dose units, each containing 20 mg of the salt of formula Ia. In yet another embodiment, the administration may consist of two dose units containing 40 mg of the salt of formula Ia, or more preferably, one dose unit containing 80 mg of the salt of formula Ia.

[0072] As described herein, the inventors have confirmed that Compound 1 has a surprisingly favorable safety profile in humans, and have observed that treatment with it can reduce the expected treatment-related Grade 3 elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) for inhibitors of this class.

[0073] Therefore, in some cases, treatment of patients with compound 1 does not result in treatment-related grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations in more than 5% of patients. More preferably, treatment of patients with compound 1 does not result in treatment-related grade 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations in more than 1% of patients. Most preferably, treatment of patients with compound 1 does not result in clinically significant treatment-related alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations in patients.

[0074] The inventors further confirmed from initial trials that treatment with compound 1 resulted in fewer side effects than expected with inhibitors in this class. In particular, a lower incidence of severe diarrhea and / or colitis was anticipated. This was especially surprising at a dose of 80 mg, at which nearly complete inhibition of PI3Kδ activity could be expected.

[0075] Therefore, in some cases, treatment of patients with compound 1 does not result in treatment-related grade 3 diarrhea or colitis in more than 5% of patients. More preferably, treatment of patients with compound 1 does not result in treatment-related grade 3 diarrhea or colitis in more than 1% of patients. Most preferably, treatment of patients with compound 1 does not result in clinically significant treatment-related diarrhea or colitis in patients.

[0076] As described in the examples, the inventors observed that treatment with compound 1 does not appear to result in clinically significant treatment-related neutrophil reduction below the normal range.

[0077] Therefore, in some cases, treatment of patients with compound 1 does not result in treatment-related grade 3 neutropenia in more than 5% of patients. More preferably, treatment of patients with compound 1 does not result in treatment-related grade 3 neutropenia in more than 1% of patients. Most preferably, treatment of patients with compound 1 does not result in clinically significant treatment-related neutropenia in patients.

[0078] It should be understood that, depending on their severity, side effects may interrupt or even make ongoing treatment impossible. If serious side effects occur, treatment may be temporarily suspended, the dose may be reduced (which could negatively impact efficacy), or it may even lead to a decision to discontinue treatment. In cancer treatment, any of these interruptions can have a significant adverse effect on the patient's health, prognosis, and / or morale.

[0079] The inventors confirmed from initial trials that treatment with compound 1 resulted in a longer duration of treatment than expected with inhibitors in this class. In particular, a longer duration of treatment in the absence of serious side effects is expected to be beneficial for patients. In solid tumors, a partial antitumor response has already been observed in one patient at a dose of 20 mg, and long-term disease stabilization has been achieved in several other patients at dose levels of 40 mg and 80 mg.

[0080] Its excellent safety profile means that compound 1 provides a treatment regimen that may be suitable for uninterrupted long-term use. Therefore, it is expected that patients may be prescribed a treatment regimen lasting several months. In some cases, the treatment may be prescribed for at least one month. In some cases, the treatment may be prescribed for at least two months. In some cases, the treatment may be prescribed for at least three months. In some cases, the treatment may be prescribed for at least four months. In some cases, the treatment may be prescribed for at least five months. In some cases, the treatment may be prescribed for at least six months. In some cases, the treatment may be prescribed for at least one year.

[0081] In some cases, the treatment period is at least one month without interruption. In some cases, the treatment period is at least two months without interruption. In some cases, the treatment period is at least three months without interruption. In some cases, the treatment period is at least four months without interruption. In some cases, the treatment period is at least five months without interruption. In some cases, the treatment period is at least six months without interruption. In some cases, the treatment period is at least one year without interruption.

[0082] In some cases, the treatment is administered in 28-day cycles. The treatment period may consist of multiple 28-day cycles without interruption. In some cases, the treatment period may be at least one year, consisting of 28-day cycles without interruption.

[0083] It will be understood that the method of the present invention may be particularly useful in treating certain patient groups, such as elderly and / or frail patients who are currently not eligible to receive PI3Kδ inhibitors due to poor tolerability.

[0084] Therefore, in some cases, the patient is 50 years of age or older, for example, 55 years of age or older, for example, 60 years of age or older, for example, 65 years of age or older, for example, 70 years of age or older, for example, 75 years of age or older, for example, 80 years of age or older.

[0085] In some cases, the patient may be unsuitable for treatment with idelalisib and / or other PI3Kδ inhibitors, or may be deemed unsuitable by the physician.

[0086] In some cases, the patient may have previously been diagnosed with a gastrointestinal disorder, such as colitis or chronic diarrhea.

[0087] Therapy using compound 1 for diseases or conditions in which signaling via the PI3Kδ pathway is pathologically involved. Compound 1 is a PI3Kδ inhibitor. It is recognized in the art that the PI3K pathway is frequently activated in various diseases. Therefore, the method of the present invention is intended for the treatment of diseases that involve, preferably causally, activation of the PI3K pathway (compared to a healthy state), such as inflammatory diseases, autoimmune diseases, or cancer.

[0088] Therefore, the method of the present invention may be relevant to the treatment of diseases or disorders characterized by upregulation of the PI3K pathway. Therefore, the method of the present invention may be relevant to the treatment of diseases or disorders by modulating the patient's PI3K pathway.

[0089] In some embodiments, the inflammatory or autoimmune disease may be activated PI3Kδ syndrome (APDS), allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis (RA), multiple sclerosis (MS), primary Sjögren's syndrome, pemphigus vulgaris, autoimmune hemolytic anemia, systemic lupus erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis, and idiopathic thrombocytopenic purpura (ITP).

[0090] The PI3K pathway is frequently activated in solid tumors and hematological malignancies. In some embodiments, the methods of the present invention are targeted at the treatment of cancer, which may be a solid tumor or a hematological malignancy. In some embodiments, the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukemia, lymphoma, multiple myeloma (including Waldenström disease), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer, and colorectal cancer.

[0091] In some embodiments, the cancer is melanoma, lymphoma, myelofibrosis, non-small cell lung cancer, or mesothelioma.

[0092] In some embodiments, the melanoma is selected from progressive or metastatic melanoma, or ocular / uveal melanoma. The progressive or metastatic melanoma may be a histologically confirmed, unresectable stage III or IV melanoma. In some embodiments, the melanoma is uveal melanoma.

[0093] In some embodiments, the lymphoma is selected from B-cell lymphoma or T-cell lymphoma. ***

[0094] Features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, and represented in a particular form or in terms of means for performing the disclosed function, or methods or processes for obtaining the disclosed results, may be used separately or in any combination as necessary to realize the present invention in a variety of forms.

[0095] While the present invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art if this disclosure is given. Therefore, the exemplary embodiments of the present invention described above are illustrative and not limiting. Various modifications to the embodiments described herein may be made without departing from the spirit and scope of the invention.

[0096] To avoid misunderstanding, the theoretical explanations provided herein are intended to enhance the reader's understanding. The inventors do not intend to be bound by any of these theoretical explanations.

[0097] Any section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described.

[0098] Throughout this Specified Specification, including the following claims, unless the context specifically requires otherwise, the words “comprise” and “include,” and their variations, such as “comprises,” “comprising,” and “including,” are understood to imply that they encompass an explicitly stated component or step, or group of components or steps, but do not exclude other components or steps, or groups of components or steps.

[0099] It should be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” encompass multiple references unless explicitly indicated otherwise in the context. Ranges may be expressed herein as “about” a particular value and / or “about” another particular value. When such ranges are expressed, another embodiment includes one particular value and / or another particular value. Similarly, when values ​​are expressed as approximations, the use of the antecedent “about” will be understood to mean that a particular value forms another embodiment. The term “about” in relation to numerical values ​​is arbitrary and means, for example, + / - 10%. [Examples]

[0100] Example 1 First-in-human trial of IOA-244 in patients with advanced or metastatic cancer A clinical study was conducted in patients with advanced or metastatic cancer to identify the safety and tolerability profile of compound 1 in patients. This clinical study is listed on clinicaltrials.gov under the number NCT04328844, and compound 1 is provided as hemifumarate. The estimated base completion date is September 2022, and the estimated study completion date is April 2023.

[0101] Example 2 Measurement of ALT levels in blood samples from patients administered compound 1. The hepatotoxicity of compound 1 in patients was identified by measuring ALT levels in blood samples from patients administered compound 1 hemi-fumarate. The initial dose groups received 10, 20, and 40 mg of the oral formulation described herein once daily. Data for these dose groups are shown in Figure 1a. Further dose groups received 80 mg of the oral formulation described herein once daily. Data for all dose groups, including the 80 mg once daily dose, are shown in Figure 1b. This also shows further administration cycles for the 10, 20, and 40 mg once daily dose groups. The x-axis represents the time of sample collection, "Cx" represents the x-cycle of 28 days, and "Dy" represents day y within the 28-day cycle. Therefore, for each continuous administration period, C1D1 corresponds to day 1 of administration, C1D8 corresponds to day 8 of administration, etc., C2D1 corresponds to day 29 of administration, C3D1 corresponds to day 57 of administration, etc.

[0102] Surprisingly, administration of compound 1 to patients was observed not to result in clinically significant treatment-related increases in ALT levels above the normal range. Even more surprisingly, administration of compound 1 decreased the ALT level in one patient whose ALT levels were elevated before compound 1 administration. Figure 1b shows that compound 1 decreased ALT levels in three patients whose ALT levels were elevated on day 1 of cycle 1 before compound 1 administration. In another patient, ALT levels increased during compound 1 administration, but this increase was associated with the growth of tumor lesions in the liver.

[0103] This is surprising, given that administration of idelalisib to patients has been reported to result in elevated ALT levels in 42.9% of patients, which is thought to be a target and class-specific toxicity of PI3Kδ (see Table 57 in Zydelig's CHMP evaluation report).

[0104] Example 3 Measurement of AST levels in blood samples from patients administered compound 1. The hepatotoxicity of compound 1 in patients was identified by measuring AST levels in blood samples from patients administered compound 1. The initial dose group received 10, 20, and 40 mg of the oral formulation described herein once daily. Data for these dose groups are shown in Figure 2a. The further dose group received 80 mg of the oral formulation described herein once daily. Data for all dose groups, including the 80 mg once daily dose, are shown in Figure 2b. This also shows further administration cycles for the 10, 20, and 40 mg once daily dose groups.

[0105] Surprisingly, administration of compound 1 to patients was observed not to result in clinically significant treatment-related increases in AST levels above the normal range. Even more surprisingly, administration of compound 1 decreased ALT levels in one patient whose AST levels were elevated before compound 1 administration. Even more surprisingly, administration of compound 1 decreased AST levels in three patients whose AST levels were elevated on day 1 of cycle 1 before compound 1 administration. In one other patient, AST levels increased during compound 1 administration, but this increase was associated with the growth of tumor lesions in the liver.

[0106] The finding that administration of compound 1 does not increase AST levels is surprising, given that administration of idelalisib to patients has been reported to cause elevated AST levels in 41.8% of patients, which is thought to be a target and class-specific toxicity of PI3Kδ (see Table 57 in Zydelig's CHMP evaluation report).

[0107] Example 4 Treatment-related adverse events (AEs) reported in patients administered compound 1. Treatment-related adverse events reported in patients administered compound 1 by the treating physician were mild, with the exception of one case of grade 2 uveitis, all of which were grade 1. Surprisingly, administration of compound 1 to patients did not result in typical toxicities associated with other PI3Kδ inhibitors, such as diarrhea / colitis and (respiratory) infections. There was only one suspected case of diarrhea, but this case was mild (grade 1) and short-lived (2 days), and may have been related to food poisoning. There were no cases of colitis or (respiratory) infections. This is quite surprising, given that administration of idelalisib to patients has been reported to result in diarrhea / colitis in 38.2% of patients and infections in 59.3% of patients (see Table 49 in Zydelig's CHMP evaluation report). Table 2 documents adverse events assessed by the principal investigator in connection with the administration of compound 1. No adverse events were recorded in patients administered 80 mg QD. [Table 2]

[0108] Example 5 Measurement of neutrophils in blood samples from patients administered compound 1. The hematological toxicity of compound 1 in patients was identified by measuring the neutrophil count in blood samples from patients administered compound 1. The initial dose group received 10, 20, and 40 mg of the oral formulation as described herein once daily. Data for these dose groups are shown in Figure 3a. The further dose group received 80 mg of the oral formulation as described herein once daily. Data for all dose groups, including the 80 mg once daily dose, are shown in Figure 3b. This also shows further administration cycles for the 10, 20, and 40 mg once daily dose groups.

[0109] Surprisingly, administration of compound 1 to patients was observed not to result in clinically significant treatment-related neutrophil reduction below the normal range.

[0110] This is surprising, given that administration of idelalisib to patients has been reported to cause a decrease in neutrophil count in 45.5% of patients, which is thought to be a target and class-specific toxicity of PI3Kδ (Table 55 of Zydelig's CHMP evaluation report).

[0111] Example 6 CD63 marker information The pharmacodynamic (PD) activity of compound 1 in patients was determined by measuring the percentage of CD63-positive basophils using a basophil activation test (BAT) in blood samples from patients who received compound 1 after exovivo stimulation with anti-IgE. See Figures 4a and 4b.

[0112] Basophil degranulation after crosslinking of the FcεR1 receptor is known to be PI3Kδ-dependent (Ali 2008), and the activity of PI3Kδ inhibitors on basophil degranulation can be measured by inhibiting IgE-mediated CD63 expression ex vivo (Lannutti 2011). Compound 1 shows a dose-dependent decrease in CD63-positive basophils in patient blood samples to a degree similar to that reported for idelalisib (Horak 2016).

[0113] References Numerous publications are cited above in order to more fully describe and disclose the present invention and the cutting edge to which it belongs. A complete citation of these references is provided below. The entirety of each of these references is incorporated herein. WO2011058149 WO201412190 CHMP assessment report on Zydelig(2014) Ali, K. et al. (2008). Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110δ but Not p110γ Promotes Optimal Allergic Responses In Vivo. J Immunol 180, 2538-2544. Brock, C. et al. (2003). Roles of Gβγ in membrane recruitment and activation of p110γ / p101 phosphoinositide 3-kinase γ. J Cell Biology 160, 89-99. Buchanan, C. M. Et al. (2019). For Better or Worse: The Potential for Dose Limiting the On-Target Toxicity of PI 3-Kinase Inhibitors. Biomol 9, 402. Curigliano and Shah(2019). Safety and Tolerability of Phosphatidylinositol-3-Kinase(PI3K) Inhibitors in Oncology. Drug Saf. 42(2), 247-262. Esposito, A. Et al. (2019). Safety, Tolerability, and Management of Toxic Effects of Phosphatidylinositol 3-Kinase Inhibitor Treatment in Patients With Cancer. Jama Oncol 5, 1347-1354. Haselmayer, P. et al., Frontiers in Immunology(2014), Vol.5, Art.233, p.1-15; p.2, col.2, section “Chemical Synthesis”, par.1 refer to Horak,F.et al.(2016).Randomized phase 1 study of the phosphatidylinositol 3-kinase δ inhibitor idelalisib in patients with allergic rhinitis.J Allergy Clin Immun 137,1733-1741. Jimenez,C.et al.(2002).The p85 regulatory subunit controls sequential activation of phosphoinositide 3-kinase by Tyr kinases and Ras.J Biol Chem 277,41556-62. Johnson,Z.et al.,AACR 2020,poster 666 Lannutti,B.J.et al.(2011).CAL-101,a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies,inhibits PI3K signaling and cellular viability.Blood 117,591-594 Phillips,T.J.et al.(2020).Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma? Clin Lymphoma Myeloma Leukemia 21,8-20.e3. Vanhaesebroeck,B.et al.(2005).Signalling by PI3K isoforms:insights from gene-targeted mice.Trends Biochem Sci 30,194-204.

[0114] For standard molecular biology techniques, please refer to Sambrook, J., and Russel, DWMolecular Cloning, A Laboratory Manual, 3rd ed. 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

Claims

1. A pharmaceutical composition for use in a method of treating cancer, inflammatory diseases, or autoimmune diseases, comprising a compound of formula I. 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, The pharmaceutical composition comprising the method of administering the compound of formula I once daily at a dose of 36 mg to 72 mg of the compound per day.

2. A pharmaceutical composition for use in the method according to claim 1, wherein the dose is approximately 36 mg per day.

3. A pharmaceutical composition for use in the method according to claim 1, wherein the dose is approximately 72 mg per day.

4. A pharmaceutical composition for use in a method of treating cancer, inflammatory diseases, or autoimmune diseases, comprising a salt of formula Ia. 【Chemistry 2】 The pharmaceutical composition comprising, wherein the method comprises administering the salt of formula Ia once daily at a dose of 40 mg to 80 mg of the salt per day.

5. A pharmaceutical composition for use in the method according to claim 4, wherein the dose is approximately 40 mg per day.

6. A pharmaceutical composition for use in the method according to claim 4, wherein the dose is approximately 80 mg per day.

7. A pharmaceutical composition for use in the method according to any one of claims 4 to 6, wherein the administration comprises one solid dose unit comprising 40 mg or 80 mg of the salt of formula Ia.

8. A pharmaceutical composition for use in the method according to any one of claims 4 to 7, wherein the administration comprises two solid dose units, each dose unit comprising 20 mg or 40 mg of the salt of formula Ia.

9. A pharmaceutical composition for use in the method according to either claim 4 or 6, wherein the administration comprises four solid dose units, each dose unit comprising 20 mg of the salt of formula Ia.

10. A pharmaceutical composition for use in any one of claims 1 to 9, wherein the disease is cancer.

11. A pharmaceutical composition for use in the method of claim 10, wherein the cancer is selected from skin cancer, eye cancer, endometrial cancer, ovarian cancer, bladder cancer, gastric cancer, lung cancer, breast cancer, pancreatic cancer, myelofibrosis, leukemia, lymphoma, multiple myeloma (including Waldenström disease), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer, and colorectal cancer.

12. The pharmaceutical composition according to claim 10, wherein the cancer is selected from melanoma, lymphoma, myelofibrosis, non-small cell lung cancer, and mesothelioma.

13. A pharmaceutical composition for use in the method according to any one of claims 1 to 9, wherein the disease or condition is an inflammatory disease or an autoimmune disease.

14. A pharmaceutical composition for use in the method according to claim 13, wherein the disease or condition is selected from allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, Crohn's disease, psoriasis, rheumatoid arthritis (RA), multiple sclerosis (MS), primary Sjögren's syndrome, pemphigus vulgaris, autoimmune hemolytic anemia, systemic lupus erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis, and idiopathic thrombocytopenic purpura (ITP).

15. A pharmaceutical composition comprising a solid dosage unit containing 20 mg, 40 mg, or 80 mg of a salt of formula Ia, 【Transformation 3】 A pharmaceutical composition in which the aforementioned pharmaceutical composition is administered once a day.

16. The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition further comprises microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate.

17. The pharmaceutical composition according to claim 16, wherein the pharmaceutical composition is provided in the form of a shell capsule or a tablet.

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