CN117042778A - PI 3K-delta inhibitors for therapeutic regimens - Google Patents

Abstract

The present application provides a compound or pharmaceutically acceptable salt thereof for use in a method of treatment of a disease or condition in a patient that is pathologically involved in signaling through the PI3K delta pathway, such as cancer and inflammatory or autoimmune diseases. The compounds are provided in specific doses and have been found to have advantageous safety profiles in humans, in particular in terms of hepatotoxicity, diarrhea/colitis, respiratory tract infections and hematological toxicity.

Description

PI 3K-delta inhibitors for therapeutic regimens

The present application claims priority from GB2104416.9 submitted at 29 of 2021, 3 and GB 2117511.2 submitted at 3 of 2021, 12, the contents and elements of which are incorporated herein by reference for all purposes.

Technical Field

The present application relates to the treatment of diseases or disorders that are pathologically related to signaling through the PI3K delta pathway with PI3K delta inhibitors. Such diseases or conditions include cancer and a variety of inflammatory and autoimmune diseases.

Background

PI3 ks belong to the family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring. PI3 ks are classified into 3 classes (class I, class II and class III) according to their structure, regulation and substrate specificity. Class I PI3 ks, which include pi3kα, pi3kβ, pi3kγ, and pi3kδ, are lipid kinases that catalyze the phosphorylation of 4, 5-diphosphatidylinositol, thereby producing 3,4, 5-triphosphatidylinositol (PIP 3). PIP3 acts as a second messenger, controlling many cellular processes including growth, survival, adhesion and migration.

All 4 class I PI3K isoforms exist as heterodimers, consisting of a catalytic subunit (p 110) and closely related regulatory subunits that control expression, activation and subcellular localization. Pi3kα, pi3kβ and pi3kδ are associated with a regulatory subunit called p85 and are activated by growth factors and cytokines through a tyrosine kinase dependent mechanism (Jimenez, hernandez et al, 2002); PI3kγ is associated with 2 regulatory subunits (p 101 and p 84), 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 expressed mainly in leukocytes (Vanhaesebroeck, ali et al 2005).

The PI3K pathway is often activated in a variety of solid tumors and hematological malignancies, which makes PI3K an attractive therapeutic target in oncology. This has led to great interest in the area of developing inhibitors targeting this pathway (Buchanan 2019). Although many PI3K inhibitors have reached different stages of clinical development, few PI3K inhibitors have been approved for clinical use. While these agents are clinically effective, their use is associated with a number of serious categories as well as drug-specific adverse effects. Some of these side effects are considered 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.

Thus, a number of novel PI3K inhibitors have been synthesized with varying degrees of target selectivity in an effort to improve safety and efficacy. Some of these are currently undergoing clinical research for the treatment of various solid tumors as well as hematological malignancies. However, early clinical trial evidence suggests that these newer agents are associated not only with class-related side effects, but also with other serious and unexpected adverse effects. Therefore, many of these new agents have stopped developing.

As a class, PI3K delta inhibitors are associated with severe skin, bone marrow depression, metabolic, gastrointestinal and respiratory adverse effects (curiglano 2019). Unlike the ubiquitously expressed p110α and p110β, p110δ is mainly expressed in leukocytes such as T cells and B cells, and thus PI3K delta inhibitors have been used to target recurrent or refractory lymphomas including, but not limited to CLL, mantle cell lymphomas, and non-Hodgkin lymphomas (Buchanan 2019). As expected, these inhibitors of the PI3K delta isoform are also haemophilic, including anemia, thrombocytopenia, leukocytosis, haemolysis and neutropenia. Inhibition of pi3kδ results in activation of immune responses, which is also believed to be responsible for some of the adverse effects of these agents, such as pi3kδ selective idelalisib. The use of eidoris-induced colitis, hepatitis and pneumonia is considered an immune-mediated effect, and a higher incidence of eidoris-induced diarrhea, pneumonia and elevated liver transaminase is observed in immunocompromised patients. FDA approved eidolis tags include detailed black box warnings concerning their potential "fatal and severe toxicity: liver, severe diarrhea, colitis, pneumonia, infection and intestinal perforation). Thus, the safety of currently approved PI3K inhibitors, particularly when administered for extended periods of time, has been under scrutiny.

Adverse Events (AEs) experienced by patients treated with pi3kδ inhibitors are of clinical significance, potentially limiting their use (Phillips 2020). At present, it is not clear whether interrupting/modifying the dose due to adverse effects would negatively affect the efficacy of the pi3kδ inhibitor. Target or class-specific toxicities associated with PI3K delta inhibitors are generally considered to be hepatotoxicity, diarrhea/colitis, respiratory tract infections and hematological toxicity.

Hematological toxicity (such as neutropenia) is often seen as a common laboratory abnormality in the test results. Hepatotoxicity is most often assessed by elevated liver transaminases in the blood and is graded according to its severity (grade 1 is minimal and grade 5 is often fatal). The level of grade 3 alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) commonly observed with PI3K delta inhibitors typically results in dose interruption or modification and in a few cases treatment discontinuation. It is reported that up to one-third of patients treated with PI3K delta inhibitors develop diarrhea or colitis, and often require treatment with anti-diarrhea or anti-inflammatory drugs. Respiratory tract infections are observed up to 20% of patients receiving idarubis, and anti-infection prophylaxis is typically given to patients with PI3K delta inhibitors.

In view of the above, there is a need in the art for PI3K modulators that inhibit specific PI3K isoforms, particularly pi3kδ, which have high selectivity over other isoforms, and at the same time have advantageous safety profiles (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 by compounds with high selectivity and favorable safety profile, particularly with respect to elevated liver enzymes, diarrhea and neutropenia.

The inventors have recognized this need and have begun to devise the present invention.

Among the numerous disclosures relating to PI3K inhibitor compounds, WO2011058149 describes tricyclic pyrazolamine derivatives as PI3K inhibitors and their use for the treatment of autoimmune diseases, inflammatory conditions, multiple sclerosis and other diseases such as cancer.

Disclosure of Invention

In a first aspect, the present invention provides a compound of formula I

Or a pharmaceutically acceptable salt thereof,

a method for treating a disease or disorder in a patient that is pathologically involved in signaling through the PI3K delta pathway, such as but not limited to an imbalance in immune cell response or expression in tumor cells, comprising administering a dose of a compound of formula I of between 18mg and 108mg of the compound per day. In some embodiments, the dose is between 18mg and 72mg per day. Preferably, the dosage is about 36mg per day. In another embodiment, the dosage is preferably about 72mg per day.

As described and illustrated herein, the pharmaceutically acceptable salt is preferably a hemi-fumarate salt. That is, the compound is provided in the form of a salt of formula Ia.

Accordingly, the present invention provides a salt of formula Ia, a method for treating a disease or disorder in a patient that is pathologically involved in signaling through the PI3K delta pathway, such as but not limited to an imbalance in immune cell response or expression in tumor cells, comprising administering a dose of the salt of formula Ia of between 20mg and 120mg per day. In some embodiments, the dose is between 20mg and 80mg of salt per day. Preferably, the dosage is about 40mg per day. In another embodiment, the dosage is preferably about 80mg per day.

The dose may be administered on a once-daily regimen. That is, a daily dose may be administered in one or more dosage units in one administration. Thus, in some embodiments, administration is once daily. This may be referred to as QD (once daily).

Suitably, the administration is oral. This may be referred to as p.o. (peroral (peros)).

In other words, in some embodiments, the dosage of the salt of formula Ia may be 20mg to 120mg, more preferably 20mg to 80mg, more preferably 30mg to 60mg, more preferably 30mg to 50mg, most preferably about 40mg, p.o.qd. In other embodiments, the dosage of the salt of formula Ia may be 20mg to 120mg, more preferably 20mg to 80mg, more preferably 30mg to 100mg, more preferably 30mg to 80mg, more preferably 40mg to 80mg, most preferably about 80mg, p.o.qd.

Suitably, more than one solid dosage unit is used per administration. In other words, the dose is divided into a plurality of dosage units. For example, administration may comprise two solid dosage units, each containing 20mg of a salt of formula Ia. In another embodiment, administration may comprise four solid dosage units, each dosage unit containing 20mg of a salt of formula Ia.

Thus, in another aspect, the invention may provide a solid dosage unit comprising 20mg of a salt of formula Ia.

Thus, in another aspect, the invention may provide a solid dosage unit comprising 5mg of a salt of formula Ia.

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

Thus, in another aspect, the invention may provide a solid dosage unit comprising 80mg of a salt of formula Ia.

Thus, in another aspect, the invention may provide a solid dosage unit comprising 40mg of a salt of formula Ia.

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

The methods of the invention relate to the treatment of diseases or conditions that are pathologically involved in signaling through the PI3K delta pathway, such as, but not limited to, an imbalance in immune cell response 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 of treating a disease or disorder selected from the group consisting of an inflammatory disease, an autoimmune disease, and cancer.

In some embodiments, the method is a method of treating cancer.

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 Mo Busi waldenstrom (Morbus)) 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 is advanced or metastatic melanoma or ocular/uveal melanoma. Advanced or metastatic melanoma may be histologically confirmed unresectable stage III or IV melanoma. In some cases, the cancer is a B-cell lymphoma. In some cases, the cancer is a T cell lymphoma. In some cases, the cancer is melanoma. In some cases, the cancer is uveal melanoma.

In some embodiments, the inflammatory or autoimmune disease may be activated PI3K delta syndrome (APDS), allergic disease, asthma, chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel disease, crohn's disease, psoriasis, rheumatoid Arthritis (RA), multiple Sclerosis (MS), primary sjogren's syndrome (primarysyndrome), pemphigus vulgaris, autoimmune hemolytic anemia, systemic Lupus Erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis, and Idiopathic Thrombocytopenic Purpura (ITP).

In some preferred embodiments, the treatment does not result in any clinically significant elevation of alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) in the patient.

In some preferred embodiments, the treatment does not result in treatment-related grade 3 diarrhea or colitis.

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

In some preferred embodiments, the treatment results in a longer treatment time without serious adverse effects.

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

The invention includes combinations of aspects and preferred features described unless such combinations are explicitly disallowed or explicitly avoided.

Drawings

Embodiments and experiments illustrating the principles of the present invention will now be discussed with reference to the accompanying drawings, in which:

figures 1a and 1b show ALT levels measured in patients treated with compound 1.

Figures 2a and 2b show the levels measured in patients treated with compound 1.

Figures 3a and 3b show neutrophils measured in patients treated with compound 1.

Figures 4a and 4b show CD 63-positive basophils measured in patients treated with compound 1 after ex vivo stimulation with anti-IgE.

Detailed Description

Various aspects and embodiments of the invention will now be discussed with reference to the accompanying drawings. Additional aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

Compound 1

Compound 1 is example 339 in WO2011058149, which document is incorporated herein by reference in its entirety. The structure is according to formula I:

in IUPAC nomenclature, compound 1 described above may be referred to as 6-fluoro-3- (morpholin-4-ylcarbonyl) -1- [4- (morpholin-4-ylmethyl) phenyl ] -1, 4-dihydrochromeno [4,3-c ] pyrazole 5, 5-dioxide. Alternatively, the structural formula shown above may be described as [ 6-fluoro-1- (4-morpholin-4-yl-methylphenyl) -5, 5-dioxo-4, 5-dihydro-1H-5λ6-thiochromeno [4,3-C ] pyrazol-3-yl ] -morpholin-4-yl-methanone.

Compound 1 can be prepared and characterized as described in published patent application WO 2011028149 A1 (see compound 339 on page 69, preparation on pages 303 to 307, and characterization on pages 481 and 414 to 418), the information of which is specifically incorporated herein by reference.

Based on the method disclosed in WO 2011/058149 A1, the authors haslmayer et al describe a five-step preparation procedure for said compounds (haslmayer, 2014). The process starts with the reaction of 8-fluoro-2, 3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is cyclized with 4- (4-hydrazinobenzyl) morpholine to form a pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with m-chloroperbenzoic acid, followed by saponification of the ethyl ester to the corresponding acid, followed by coupling with morpholine, to give the compound of formula I.

Alternatively, an intermediate of 8-fluoro-2, 3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinobenzoic acid. Benzoic acid was reduced using borane-THF complex and the thioether was oxidized to the corresponding sulfone by reaction with m-chloroperbenzoic acid. Saponification of the ethyl ester to the corresponding acid and subsequent coupling with morpholine in the presence of dimethylformamide with excess thionyl chloride acid and alcohol gives compound 1.

Compound 1 may be provided in the form of a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art. Some pharmaceutically acceptable salts of compound 1 are described in WO2014121901, which is incorporated by reference in its entirety.

As used herein, compound 1 is provided in the form of an anhydrous hemi-fumarate salt (formula shown). Its synthesis and characterization is described in WO2014121901 (page 4). It is called solid form A1. Hemi-fumarate hydrate (H1) has also been identified. The anhydrous hemi-fumarate salt used was crystalline and had a powder X-ray peak list as described in WO 2014121901. It will be appreciated that the discovery of the invention is not limited to the use of such solid forms, although it is preferred.

Hassemayr et al also describe the characterization of the compounds as highly selective PI3K delta inhibitors. Johnson et al (Johnson, Z. Et al, AACR 2020, poster 666) further describe the advantageous in vitro and in vivo properties of Compound 1.

Formulations

Compound 1 is suitably provided as the hemi-fumarate salt as described above. Suitably, compound 1 is provided in the form of a pharmaceutical composition formulated for oral administration. The pharmaceutical composition may be provided in the form of a capsule or may be provided in the form of a tablet. In some cases, it is provided in the form of a tablet, for example as a coated or uncoated tablet produced by compression of a powdered or granular composition. In other cases, it is provided in the form of a capsule, for example as a powdered or granular composition within a hard shell or soft shell capsule, such as a hydroxymethyl cellulose (HPMC) capsule. In other words, oral dosage forms are preferred.

The formulation suitably comprises one or more pharmaceutically acceptable fillers, disintegrants, glidants and/or lubricants.

In some cases, the oral dosage form may comprise 5mg of compound 1 provided as a hemi-fumarate salt. In some cases, the oral dosage form may comprise 20mg of compound 1 provided as a hemi-fumarate salt. Both oral dosage forms were prepared as described in table 1. It will be appreciated that the dosage for the method, particularly when a 20mg solid dosage form is used, places a relatively low dose burden (number of capsules or tablets) on the patient. This facilitates patient compliance.

However, it will be appreciated that for some patients, smaller dosage forms may be preferred, for example if the patient has dysphagia. Even with smaller 5mg solid dosage forms, the burden on the patient (number of capsules or tablets) is not uncommon in treating the claimed condition.

TABLE 1

* Purity was corrected (based on the test report).

An oral dosage form may comprise 40mg of compound 1 provided as the hemi-fumarate salt. An oral dosage form may comprise 80mg of compound 1 provided as the hemi-fumarate salt. Both oral dosage forms can be prepared similarly to the dosage forms described in table 1. It will be appreciated that for the dosage of the method, the lowest dosage burden (number of capsules or tablets) is imposed on the patient when a single solid dosage form is used. This is most advantageous for patient compliance.

The invention therefore further relates to pharmaceutical compositions formulated for oral administration, comprising compound 1, preferably provided in the form of a hemi-fumarate salt.

Exemplary formulations include compound 1 hemi-fumarate salt, microcrystalline cellulose, mannitol, croscarmellose sodium, and magnesium stearate. The formulation may be provided in a solid dosage form, for example as a tablet or powder or granular composition enclosed in a shell capsule. It will be appreciated that a single tablet may contain a higher dose of compound 1 hemi-fumarate than a single capsule. Thus, for higher dosage units, tablets are preferred. The tablets may be coated to improve taste or swallowing.

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

Thus, in some embodiments, the invention provides a solid dosage unit comprising a pharmaceutical composition comprising 5mg of compound 1 hemi-fumarate salt. Thus, in some embodiments, the invention provides a solid dosage unit comprising a pharmaceutical composition comprising 20mg of compound 1 hemi-fumarate salt. Thus, in some embodiments, the invention provides a solid dosage unit comprising a pharmaceutical composition comprising 40mg of compound 1 hemi-fumarate salt. Thus, in some embodiments, the invention provides a solid dosage unit comprising a pharmaceutical composition comprising 80mg of compound 1 hemi-fumarate salt.

Thus, in some embodiments, the present invention provides a solid tablet comprising a pharmaceutical composition comprising 40mg of compound 1 hemi-fumarate salt. Thus, in some embodiments, the present invention provides a solid tablet comprising a pharmaceutical composition comprising 80mg of compound 1 hemi-fumarate salt. It will be appreciated that the pharmaceutical composition of the tablet may be similar to that of the capsule or may be optimised for tabletting.

The method of the invention

As described in more detail below, the inventors surprisingly found that compound 1 has advantageous safety profiles in humans, in particular in terms of hepatotoxicity, diarrhea/colitis, respiratory tract infections and hematological toxicity. Furthermore, treatment of patients with compound 1 did not result in elevated liver enzymes, diarrhea and neutropenia. Thus, PI3K inhibitors may be provided that are specific for isoform delta and have advantageous safety profiles in patients.

Other advantageous properties of the treatment methods using compound 1 may include one or more of higher efficacy, longer treatment duration, fewer dose reductions or interruptions or stops.

In other words, the inventors surprisingly found that patients (in this case patients with melanoma, uveal melanoma and mesothelioma; thus, this is expected to apply to all human subjects) could be treated with compound 1 with fewer adverse reactions than would be expected with a treatment regimen using a PI3K inhibitor. This may allow the treatment to be tailored to long-term prescriptions without reducing or interrupting the dose.

In the clinical trials and examples described herein, compound 1 was administered as the hemifumarate salt. Thus, in some cases, compound 1 is administered as the hemifumarate salt. However, it is to be understood that the invention is not so limited and that other solid forms (e.g., other pharmaceutically acceptable salts) are contemplated.

The weight equivalent of compound 1 in the free base form in the 40mg dose is calculated to be about 36mg (i.e., about 90% of the weight of compound 1 hemi-fumarate salt corresponds to free base and about 10% of the remaining weight corresponds to hydrochloric acid).

The weight equivalent of compound 1 in the form of the free base in the 80mg dose is calculated to be about 72mg (i.e., about 90% of the weight of compound 1 hemi-fumarate salt corresponds to the free base and about 10% of the remaining weight corresponds to hydrochloric acid).

The present invention therefore relates to a method of treating a disease or disorder in a patient that is pathologically involved in signaling through the PI3K delta pathway, comprising administering compound 1 in an amount of between 18mg and 108mg per day. In some cases, the amount is between 18mg and 72mg per day. In some cases, the amount is between 27mg and 54mg per day. In some cases, the amount is between 27mg and 45mg per day, for example about 36mg per day. In some cases, the amount is between 27mg and 108mg per day. In some cases, the amount is between 27mg and 72mg per day. In some cases, the amount is between 36mg and 90mg per day, for example about 72mg per day. In some cases, the amount is between 36mg and 72mg per day.

In the case of compound 1 administered as the hemi-fumarate salt (formula Ia), the present invention relates to a method of treating a disease or disorder in a patient that is pathologically involved in signaling through the PI3K delta pathway, comprising administering compound 1 in the form of the hemi-fumarate salt in an amount of between 20mg and 120mg per day. In some cases, the amount is between 20mg and 80mg per day. In some cases, the amount is between 30mg and 60mg per day. In some cases, the amount is between 30mg and 50mg per day, for example about 40mg per day. In some cases, the amount is between 30mg and 120mg per day. In some cases, the amount is between 30mg and 80mg per day. In some cases, the amount is between 40mg and 100mg per day, for example about 80mg per day. In some cases, the amount is between 40mg and 80mg per day.

Lower doses are also studied and envisaged. Thus, it is to be understood that in any of the methods described herein, the method may comprise administering compound 1 in an amount of between 9mg and 108mg per day. In some cases, the amount of compound 1 is between 9mg and 72mg per day. In the case of compound 1 being administered as the hemi-fumarate salt, in any of the methods described herein, the method may comprise administering compound 1 in the hemi-fumarate salt form in an amount between 10mg and 120mg per day. In some cases, the amount of compound 1 in the form of the hemi-fumarate salt is between 10mg and 80mg per day.

Inhibition of the pi3kδ pathway in patients can be demonstrated by measuring the pharmacodynamic activity (PD) of compound 1 in a blood sample. A specific PD marker of pi3kδ inhibition in blood is CD63 expression on basophils. Treatment of patients with compound 1 in the form of hemi-fumarate salt resulted in a dose-dependent decrease in the percentage of CD 63-positive basophils in the patient's blood sample, comparable to that reported for other pi3kδ inhibitors (e.g., eidoles). Particularly at a dose of 40mg, the percentage of CD63 positive basophils in all measured samples was low, which confirms effective inhibition of the PI3K delta pathway during treatment. The percentage of CD63 positive basophils was also low in all the samples measured, especially at the 80mg dose, confirming an effective inhibition of the PI3K delta pathway during the treatment.

Thus, certain preferred embodiments relate to a dose of 40mg of a salt of formula Ia, or a dose of 36mg of a compound of formula I.

However, it should be understood that higher doses are contemplated and contemplated. For example, the dose may be a dose of 60mg of a salt of formula Ia, or 54mg of a compound of formula I. For example, the dose may be a dose of 80mg of a salt of formula Ia, or 72mg of a compound of formula I, which may be preferred in some embodiments.

In some cases, lower doses may be envisaged. For example, the dose may be a dose of 10mg of a salt of formula Ia, or 9mg of a compound of formula I.

The inventors have found that once daily doses are effective and well tolerated. Compared to some known and used PI3K inhibitors, once daily dosing is advantageous (e.g., the prescription of erirrass is 150mg dose twice daily unless a dose reduction is required due to adverse effects). A once daily dose improves patient experience and may improve patient compliance. Patients with especially advanced cancers often experience considerable pill burden and may have dysphagia.

Thus, in the method of the invention, the dosage may be taken once daily. In other words, the doses are not separated and spaced during the day. It may be administered in a single dosage unit (e.g., a single tablet or capsule) or in multiple dosage forms (e.g., as two or more tablets or capsules).

Thus, in some cases, the method comprises administering one or more solid dosage units. For example, in some cases, the daily dose is 40mg, and the method comprises administering two 20mg solid dosage units (i.e., a solid dosage unit comprising 20mg of compound 1 in the form of a hemi-fumarate salt), or more preferably, administering one 40mg solid dosage unit.

In another embodiment, the daily dose may be 60mg and administration may comprise three solid dosage units, each containing 20mg of the salt of formula Ia. In another embodiment, the daily dose may be 80mg and administration may comprise four solid dosage units, each containing 20mg of the salt of formula Ia. In another embodiment, administration may comprise two dosage units comprising 40mg of a salt of formula Ia, or more preferably, one dosage unit comprising 80mg of a salt of formula Ia.

As described herein, the inventors have identified that compound 1 has surprisingly good safety profiles in humans, it was observed that treatment may result in fewer treatment-related increases in grade 3 alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) than would be expected for such inhibitors.

Thus, in some cases, treatment of a patient with compound 1 does not result in more than 5% of patients experiencing a treatment-related elevation of grade 3 alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST). More preferably, treatment of a patient with compound 1 does not result in more than 1% of patients exhibiting a treatment-related elevation of alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST). Most preferably, treatment of a patient with compound 1 does not result in any clinically significant elevation of alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) in the patient.

The inventors have further identified from the initial trial that treatment with compound 1 resulted in fewer adverse effects than expected for such inhibitors. In particular, severe diarrhea and/or colitis are expected to occur less frequently. This is most surprising, especially for the 80mg dose, since at this dose level almost complete inhibition of PI3K delta activity can be expected.

Thus, in some cases, treatment of patients with compound 1 does not result in more than 5% of patients presenting with treatment-related grade 3 diarrhea or colitis. More preferably, treatment of patients with compound 1 does not result in more than 1% of patients presenting with treatment-related grade 3 diarrhea or colitis. Most preferably, treating a patient with compound 1 does not result in any clinically significant treatment-related diarrhea or colitis in the patient.

As described in the examples, the inventors observed that treatment with compound 1 did not appear to result in clinically significant treatment-related neutrophil depletion below the normal range.

Thus, in some cases, treatment of patients with compound 1 does not result in more than 5% of patients exhibiting treatment-related grade 3 neutropenia. More preferably, treatment of patients with compound 1 does not result in more than 1% of patients exhibiting treatment-related grade 3 neutropenia. Most preferably, treatment of a patient with compound 1 does not result in any clinically significant treatment-related neutropenia in the patient.

It will be appreciated that adverse reactions may interrupt or even interfere with ongoing treatment, depending on its severity. In the event that serious adverse effects are noted, treatment may be suspended, the amount of the drug down-regulated (potentially detrimental to efficacy) may even result in a decision to terminate treatment. Any of these disruptions can have significant negative effects on patient health, prognosis, and/or morale in cancer treatment.

The inventors identified from initial experiments that treatment with compound 1 resulted in longer treatment times than expected for such inhibitors. In particular, longer treatment times without serious adverse effects are expected to benefit patients. In solid tumors, this has led to a partial anti-tumor response in one patient at a dose of 20mg and to a long-term stable disease in several other patients at dose levels of 40mg and 80 mg.

Its excellent safety profile means that the treatment regimen provided by compound 1 may be suitable for long-term uninterrupted use. Thus, it is contemplated that patients may be prescribed a treatment regimen that lasts for months. In some cases, the treatment prescription is at least 1 month. In some cases, the treatment prescription is at least 2 months. In some cases, the treatment prescription is at least 3 months. In some cases, the treatment prescription is at least 4 months. In some cases, the treatment prescription is at least 5 months. In some cases, the treatment prescription is at least 6 months. In some cases, the treatment prescription is at least 1 year.

In some cases, the treatment duration is at least 1 month without interruption. In some cases, the treatment duration is at least 2 months without interruption. In some cases, the treatment duration is at least 3 months without interruption. In some cases, the treatment duration is at least 4 months without interruption. In some cases, the treatment duration is at least 5 months without interruption. In some cases, the treatment duration is at least 6 months without interruption. In some cases, the treatment duration is at least 1 year without interruption.

In some cases, the treatment is administered at a 28 day period. The duration of treatment may be a number of 28-day cycles, uninterrupted. In some cases, the duration of treatment is at least 1 year, with 28 days being a period, without interruption.

It will be appreciated that the methods of the invention may be particularly useful in the treatment of certain patient groups, for example elderly and/or frail patients who are currently unsuitable for receiving pi3kδ inhibitors due to their poor tolerability.

Thus, in some cases, the patient is 50 years old or older, such as 55 years old or older, such as 60 years old or older, such as 65 years old or older, such as 70 years old or older, such as 75 years old or older, such as 80 years old or older.

In some cases, the physician considers or would consider the patient unsuitable for treatment with idarubicin and/or other PI3K delta inhibitors.

In some cases, the patient is a patient who has been previously diagnosed with a gastrointestinal condition (e.g., colitis or chronic diarrhea).

Treatment of diseases or disorders pathologically involving signaling through the PI3K delta pathway using compound 1

Compound 1 is a PI3K delta inhibitor. The art recognizes that the PI3K pathway is often activated in a variety of diseases. Thus, the methods of the invention relate to the treatment of diseases involving activation of the PI3K pathway, preferably causally related to the activation of the PI3K pathway (as compared to the status of healthy individuals), such as inflammatory diseases, autoimmune diseases or cancer.

Thus, the methods of the invention may relate to the treatment of diseases or conditions characterized by up-regulation of the PI3K pathway. Thus, the methods of the invention may relate to the treatment of diseases or conditions characterized by modulation of the PI3K pathway.

In some embodiments, the inflammatory or autoimmune disease may be activated PI3K delta syndrome (APDS), allergic disease, asthma, chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel disease, crohn's disease, psoriasis, rheumatoid Arthritis (RA), multiple Sclerosis (MS), primary sjogren's syndrome, pemphigus vulgaris, autoimmune hemolytic anemia, systemic Lupus Erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis, and Idiopathic Thrombocytopenic Purpura (ITP).

The PI3K pathway is often activated in solid tumors and hematological malignancies. In some embodiments, the methods of the invention relate to the treatment of cancer. The cancer may be a solid tumor or 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 Mo Busi-waldenstrom), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer, and colorectal cancer.

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

In some embodiments, the melanoma is selected from advanced or metastatic melanoma or ocular/uveal melanoma. Advanced or metastatic melanoma may be histologically confirmed unresectable stage III or IV melanoma. In some embodiments, the melanoma is uveal melanoma.

In some embodiments, the lymphoma is selected from B-cell lymphoma or T-cell lymphoma.

* * *

The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

While the 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 in light of this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are to be considered as illustrative and not limiting. Various changes may be made to the described embodiments without departing from the spirit and scope of the invention.

For the avoidance of any doubt, any theoretical explanation provided herein is intended to enhance the reader's understanding. The inventors do not wish to be bound by any one of these theoretical explanations.

Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Throughout the specification including the claims, unless the context requires otherwise, the words "comprise" and "comprising" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. The term "about" in relation to a numerical value is optional and means, for example, +/-10%.

Examples

Example 1

Initial dose study of IOA-244 in humans in patients with advanced or metastatic cancer

To determine the safety and tolerability profile of compound 1 in patients, clinical studies were performed in patients with advanced or metastatic cancer. Clinical study number NCT04328844 is described on clinicaltrias.gov and compound 1 is provided as the hemifumarate salt. The estimated primary completion date was 2022, 9, and the estimated study completion date was 2023, 4.

Example 2

Measurement of ALT levels in blood samples of patients treated with Compound 1

Hepatotoxicity of compound 1 in patients was determined by measuring ALT levels in blood samples of patients treated with compound 1 hemi-fumarate. The initial dose groups were 10mg, 20mg and 40mg, taken once daily as oral formulations as described herein, and the data for these dose groups are depicted in fig. 1 a. Yet another dose group was 80mg once daily taken as an oral formulation as described herein, and the data for all dose groups including 80mg once daily is depicted in fig. 1 b. This also shows further treatment cycles for the once daily dose groups of 10mg, 20mg and 40 mg. The x-axis shows the time points of sample collection, where "Cx" means the x-th period of 28 days, and "Dy" means the y-th day within the 28-day period. Thus, C1D1 corresponds to day 1 of treatment, C1D8 corresponds to day 8 of treatment, etc., and C2D1 corresponds to day 29 of treatment, C3D1 corresponds to day 57 of treatment, etc., each being a continuous treatment period.

Surprisingly, it was observed that treatment of patients with compound 1 did not result in any clinically significant elevation of ALT associated with treatment above the normal range. Even more surprisingly, treatment with compound 1 resulted in a decrease in ALT levels in one patient whose ALT levels were elevated prior to treatment with compound 1. Figure 1b shows that compound 1 resulted in a decrease in ALT levels in three patients who had increased ALT levels on day 1 of cycle 1 prior to treatment with compound 1. In another patient, ALT levels increased during treatment with Compound 1, however this increase was associated with neoplastic lesions growing in the liver.

This is surprising because treatment of patients with idarray reportedly resulted in elevated ALT levels in 42.9% of patients and was considered pi3kδ target and class-specific toxicity (see table 57 in CHMP Zydelig evaluation report).

Example 3

Measurement of AST levels in blood samples of patients treated with compound 1

Hepatotoxicity of compound 1 in patients was determined by measuring AST levels in blood samples of patients treated with compound 1. The initial dose groups were 10mg, 20mg and 40mg, taken once daily as oral formulations as described herein, and the data for these dose groups are depicted in fig. 2 a. Yet another dose group was 80mg once daily taken as an oral formulation as described herein, and the data for all dose groups including 80mg once daily is depicted in fig. 2 b. This also shows further treatment cycles for the once daily dose groups of 10mg, 20mg and 40 mg.

Surprisingly, it was observed that treatment of patients with compound 1 did not result in any clinically significant elevation of therapeutically relevant AST above the normal range. Even more surprisingly, treatment with compound 1 resulted in a decrease in AST levels in a patient whose AST levels were elevated prior to treatment with compound 1. Even more surprisingly, treatment with compound 1 resulted in a decrease in AST levels in three patients who had elevated AST levels at day 1 of cycle 1 prior to treatment with compound 1. In another patient AST levels increased during treatment with compound 1, however this increase was associated with neoplastic lesions growing in the liver.

The finding that treatment with compound 1 did not increase AST levels was surprising, as treatment of patients with idarubicin was reported to result in elevated AST levels in 41.8% of patients and was considered pi3kδ target and class-specific toxicity (see table 57 in CHMP Zydelig assessment report).

Example 4

Reported treatment-related Adverse Events (AE) for patients treated with compound 1

AE reported by the treating physician in connection with the treatment of patients treated with compound 1 were mild and all rated 1, with only one uveitis rated 2. Surprisingly, it was observed that treatment of patients with compound 1 did not lead to the typical toxicities observed for other pi3kδ inhibitors, such as diarrhea/colitis and (respiratory) infections. Only 1 suspected diarrhea case, but the case is light (grade 1) and short in duration (2 days), and thus may also be associated with the occurrence of food poisoning. No cases of colitis or (respiratory tract) infection. This is very surprising since it was reported that treatment of patients with idarray resulted in diarrhea/colitis in 38.2% of patients and infection in 59.3% of patients (see table 49 in CHMP evaluation report on Zydelig). Table 2 records the adverse events assessed by the investigator in relation to compound 1 treatment. No adverse reactions were noted in patients dosed with 80mg QD.

TABLE 2

Example 5

Measurement of neutrophils in blood samples of patients treated with Compound 1

The hematological toxicity of compound 1 in a patient was determined by measuring the neutrophil count in a blood sample of the patient treated with compound 1. The initial dose groups were 10mg, 20mg and 40mg, taken once daily as oral formulations as described herein, and the data for these dose groups are depicted in fig. 3 a. Yet another dose group was 80mg once daily taken as an oral formulation as described herein, and the data for all dose groups including 80mg once daily is depicted in fig. 3 b. This also shows further treatment cycles for the once daily dose groups of 10mg, 20mg and 40 mg.

Surprisingly, it was observed that treatment of patients with compound 1 did not result in clinically significant treatment-related neutrophil depletion below the normal range.

This is surprising because treatment of patients with idarray reportedly resulted in a decrease in neutrophil counts in 45.5% of patients and was considered pi3kδ target and class-specific toxicity (see table 55 in CHMP evaluation report on Zydelig).

Example 6

CD63 marker information

The Pharmacodynamic (PD) activity of compound 1 in patients was determined by measuring the percentage of CD 63-positive basophils in blood samples of patients treated with compound 1 after ex vivo stimulation with anti-IgE using Basophil Activation Test (BAT). See fig. 4a and 4b.

Basophil degranulation after fcer 1 receptor cross-linking has been shown to be PI3kδ dependent (Ali 2008), and PI3kδ inhibitor activity on basophil degranulation can be measured by inhibiting ex vivo IgE-mediated CD63 expression (Lannutti 2011). Compound 1 showed a dose-dependent decrease in CD 63-positive basophils in patient blood samples comparable to that reported for idary (Horak 2016).

Reference to the literature

Numerous publications are cited above to more fully describe and disclose the present invention and the state of the art to which the present invention pertains. The complete citations for these references are provided below. Each of these references is incorporated herein in its entirety.

WO2011058149

WO201412190

CHMP assessment report on Zydelig(2014)

Ali，K.et al.(2008)Isoform-Specific Functions of Phosphoinositide 3-Kinases：p110δbut Not p110γPromotes Optimal Allergic Responses In Vivo.J Immunol 180，2538—2544.

Brock，C.et al(2003)Roles of Gβγ in membrane recruitme nt and activation of p110γ/p101phosphoinositide 3-kinase Y.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 Tolerabilify of Phosphatidylinositol-3-Kinase(PI3K)lnhibitors 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 Treafment in Patients With Cancer.Jama Oncol 5，1347-1354.

Haselmayer，P.et al，Frontiers in lmmunology(2014)，Vol.5，Art.233，p.1-15；see p.2，col.2，section″Chemical Synthesis″，par.1

Horak，F.et al.(2016).Ranndomized phase 1study of the phosphatidylinositol 3-kinase δinhibitor 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 phosphoinosifide 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 p110δselective phosphatidylinositol-3-kinase inhibitor for the treatment of B—cellmalignancies，inhibits PI3K signaling and cellular viability.Blood 117，591-594

Phillips，T.J.et al.(2020).Can Next-Generation PI3K Inhibitors Unlock the FullPotential of the Class in Patients With B-CellLymphomaClin 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

For standard molecular biology techniques，see Sambroek，J.，Russel，D.W.Molecular Clonining，A Laboratory Manual.3ed.2001，Cold Spring Harbor，New York：Cold Spring Harbor Laboratory Press.

Claims (19)

1. A compound of the formula I,

or a pharmaceutically acceptable salt thereof,

a method for treating a disease or disorder in a patient that is pathologically involved in signaling through the PI3K delta pathway, the method comprising administering a dose of the compound of formula I of between 18mg and 108mg of the compound per day.

2. The compound or salt for use in the method of claim 1, wherein the dose is about 36mg per day.

3. The compound or salt for use in the method of claim 1, wherein the dose is about 72mg per day.

4. A salt of the formula (Ia),

a method for treating a disease or disorder in a patient that is pathologically involved in signaling through the PI3K delta pathway, the method comprising administering a dose of the salt of formula Ia of between 20mg and 120mg per day.

5. The salt for use in the method of claim 4, wherein the dose is about 40mg per day.

6. The salt for use in the method of claim 4, wherein the dose is about 80mg per day.

7. The compound or salt for use in the method of any preceding claim, wherein the administration is once daily.

8. The compound or salt for use in a method of any preceding claim, wherein the administration comprises a solid dosage unit comprising 40mg or 80mg of the salt of formula Ia.

9. The compound or salt for use in a method of any preceding claim, wherein the administration comprises two solid dosage units, each dosage unit comprising 20mg or 40mg of the salt of formula Ia.

10. The compound or salt for use in the method of any one of claims 1, 3, 4, 6 or 7, wherein the administration comprises four solid dosage units, each dosage unit comprising 20mg of the salt of formula Ia.

11. A compound or salt for use in a method according to any preceding claim, wherein the disease is cancer.

12. The compound or salt for use in the method of claim 11, 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 Mo Busi-waldenstrom), brain cancer, mesothelioma, head and neck cancer, prostate cancer, liver cancer, kidney cancer, and colorectal cancer.

13. The compound or salt for use in the method of claim 11 or claim 12, wherein the cancer is selected from melanoma, lymphoma, myelofibrosis, non-small cell lung cancer and mesothelioma.

14. A compound or salt for use in a method according to any one of claims 1 to 10, wherein the disease or condition is an inflammatory or autoimmune disease.

15. A compound or salt for use in a method according to claim 14, wherein the disease or condition is selected from allergic disease, asthma, chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel disease, crohn's disease, psoriasis, rheumatoid Arthritis (RA), multiple Sclerosis (MS), primary sjogren's syndrome, pemphigus vulgaris, autoimmune hemolytic anemia, systemic Lupus Erythematosus (SLE), lupus nephritis, membranous nephropathy, glomerulonephritis, diabetic nephropathy, vasculitis and Idiopathic Thrombocytopenic Purpura (ITP).

16. The compound or salt for use in the method of any preceding claim, wherein the treatment does not result in any clinically significant elevation of treatment-related alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) in the patient.

17. A compound or salt for use in a method according to any one of the preceding claims, wherein the treatment does not result in treatment-related grade 3 diarrhea or colitis.

18. The compound or salt for use in the method of any preceding claim, wherein the treatment does not result in any clinically significant treatment-related neutropenia in the patient.

19. A solid dosage unit comprising 20mg, 40mg or 80mg of a salt of formula Ia,

optionally, wherein the salt of formula Ia is formulated in a pharmaceutical composition comprising microcrystalline cellulose, mannitol, croscarmellose sodium and magnesium stearate;

optionally, wherein the pharmaceutical composition is provided in the form of a shell capsule or tablet.