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WO2020234780A1 - Méthodes de traitement de l'asthme au moyen d'un inhibiteur de la tyrosine kinase de bruton - Google Patents

Méthodes de traitement de l'asthme au moyen d'un inhibiteur de la tyrosine kinase de bruton Download PDF

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Publication number
WO2020234780A1
WO2020234780A1 PCT/IB2020/054753 IB2020054753W WO2020234780A1 WO 2020234780 A1 WO2020234780 A1 WO 2020234780A1 IB 2020054753 W IB2020054753 W IB 2020054753W WO 2020234780 A1 WO2020234780 A1 WO 2020234780A1
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WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
acceptable salt
dose
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PCT/IB2020/054753
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English (en)
Inventor
Souvik Bhattacharya
Bruno BIETH
Caterina BRINDICCI
Bruno CENNI
Stefan De Buck
Anton DROLLMANN
Veit ERPENBECK
Martin Kaul
Andrijana RADIVOJEVIC
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Novartis Ag
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Publication of WO2020234780A1 publication Critical patent/WO2020234780A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present disclosure relates to methods for treating asthma using a Bruton’s tyrosine kinase inhibitor.
  • Asthma is characterized by chronic airway inflammation with symptoms of wheeze, shortness of breath, chest tightness and cough that vary over time and intensity. In addition, patients show variable airflow limitation. About 300 million people worldwide suffer from asthma and there are approximately 250,000 deaths caused by asthma every year (D'Amato et al 2016).
  • the aim of the invention is to provide novel method of treating asthma in a subject in need of such treatment, comprising administering to said subject, an therapeutically effective amount of N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4- cyclopropyl-2-fluorobenzamide; or a pharmaceutically acceptable salt thereof.
  • FIGURE 1 Inhibitory effects of compound of Formula (I) in the reverse passive arthus reaction
  • FIGURE 2 BTK occupancy in spleen 5 hours after dosing
  • FIGURE 3 Compound of Formula (I) inhibits PCA after low-dose IgE sensitization
  • FIGURE 4 BTK occupancy in spleen for low-dose IgE senitization
  • FIGURE 5 Eosinophils present in broncheoalveolar lavage fluid after treatment with compound of Formula (I) (HDM murine asthma model)
  • FIGURE 6 Blood concentration - time course of compound (I) after single ascending doses 0.5mg-600mg
  • FIGURE 7 Blood concentration - time course of compound (I) after multiple ascending doses of 10 mg - 400 mg, q.d. dosing
  • FIGURE 8 Blood concentration - time course of compound (I) after multiple ascending doses of 100 mg b.i.d. and 200 mg b.i.d.
  • FIGURE 9 Food effect as observed after a single oral dose of 60mg of compound of Formula
  • FIGURE 10 Arithmetic mean (SD) percent BTK occupancy in peripheral blood after a single dose of Compound of Formula (I)
  • FIGURE 11 Median percent inhibition of basophil activation versus total daily dose of
  • FIGURE 12 Reduction of whealsize in- skin prick test in multiple ascending dose
  • BTK tyrosine kinase
  • FceR 1 for IgE Fc epsilon receptor
  • BTK inhibitors like ibrutinib are approved for the treatment of B cell malignancies (Hendriks RW, Yuvaraj S, Kil
  • BTK inhibitor refered to herein as Compound of Formula (I):
  • N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide was described in the WO2015/079417 application filed June 4, 2015 (Attorney docket number PAT056021-WO-PCT).
  • This compound is a selective, potent, irreversible covalent inhibitor of Bruton’s tyrosine kinase (BTK).
  • phrases“pharmaceutically acceptable” as employed herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compound.
  • Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Isotopes that can be incorporated into the compound of the disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, and 36 Cl.
  • the present disclosure includes compound that incorporates one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, e.g., using an appropriate isotopically-labeled reagents in place of the non
  • pharmaceutical combination means a product that results from the use or mixing or combining of more than one active ingredient. It should be understood that pharmaceutical combination as used herein includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g., a compound of formula I and one or more combination partners, are administered to a patient simultaneously as a single entity or dosage form. The term in such case refers to a fixed dose combination in one unit dosage form (e.g., capsule, tablet, or sachet).
  • non-fixed combination or a“kit of parts” both mean that the active ingredients, e.g., a compound of the present disclosure and one or more combination partners and/or one or more co-agents, are administered or co-administered to a patient independently as separate entities either
  • non-fixed combination also applies to cocktail therapy, e.g., the administration of three or more active ingredients.
  • cocktail therapy e.g., the administration of three or more active ingredients.
  • non-fixed combination thus defines especially administration, use, composition or formulation in the sense that the compounds described herein can be dosed independently of each other, i.e., simultaneously or at different time points. It should be understood that the term“non-fixed combination” also encompasses the use of a single agent together with one or more fixed combination products with each independent formulation having distinct amounts of the active ingredients contained therein.
  • non-fixed combinations encompasses active ingredients (including the compounds described herein) where the combination partners are administered as entirely separate pharmaceutical dosage forms or as pharmaceutical formulations that are also sold independently of each other.
  • Instructions for the use of the non-fixed combination are or may be provided in the packaging, e.g., leaflet or the like, or in other information that is provided to physicians and/or medical staff.
  • the independent formulations or the parts of the formulation, products, or compositions can then be administered simultaneously or chronologically staggered, that is the individual parts of the kit of parts can each be administered at different time points and/or with equal or different time intervals for any part of the kit of parts.
  • the time intervals for the dosing are chosen such that the effect on the treated disease with the combined use of the parts is larger/greater than the effect obtained by use of only compound of Formula (I), or a pharmaceutically acceptable salt thereof; thus the compounds used in pharmaceutical combination described herein are jointly active.
  • the ratio of the total amounts of a compound of formula I to a second agent to be administered as a pharmaceutical combination can be varied or adjusted in order to better accommodate the needs of a particular patient sub population to be treated or the needs of the single patient, which can be due, for example, to age, sex, body weight, etc. of the patients.
  • co-administration or“combined administration” or the like as utilized herein are meant to encompass the administration of one or more compounds described herein together with a selected combination partner to a single subject in need thereof (e.g., a patient or subject), and are intended to include treatment regimens in which the compounds are not necessarily administered by the same route of administration and/or at the same time.
  • composition refers to a mixture (e.g., a solution or an emulsion) containing at least one active ingredient or therapeutic agent to be administered to a warm-blooded animal, e.g., a mammal or human, in order to prevent or treat a particular disease or condition affecting the warm-blooded animal.
  • a warm-blooded animal e.g., a mammal or human
  • a therapeutically effective amount of a compound (i.e. compound of Formula (I) or a pharmaceutically acceptable salt thereof) of the present disclosure refers to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject (patient of subject), for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the patient, the body weight, age, sex, and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the term“subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain aspects of the animals.
  • primates e.g., humans, male or female
  • cows e.g., sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a primate.
  • the subject is a human.
  • the term“subject” is used interchangeably with“patient” when it refers to human.
  • a subject is“in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the phrase“population of patients” is used to mean a group of patients.
  • composition“comprising” encompasses“including” as well as“consisting,” e.g., a composition“comprising” X may consist exclusively of X or may include something additional, e.g ⁇ , X + Y.
  • the term“about” in relation to a numerical value x means, for example, +/-10%.
  • the term“about” applies to each number in the series, e.g., the phrase“about 1-5” should be interpreted as“about 1 - about 5”, or, e.g., the phrase“about 1, 2, 3, 4” should be interpreted as“about 1, about 2, about 3, about 4, etc.”
  • treatment or“treat” is herein defined as the application or administration of a compound according to the disclosure, (compound of Formula (I), or a pharmaceutically salt thereof, or a pharmaceutical composition comprising said compound, to a subject or to an isolated tissue or cell line from a subject, where the subject has a particular disease (e.g., asthma), a symptom associated with the disease (e.g., asthma), or a predisposition towards development of the disease (e.g., asthma) (if applicable), where the purpose is to cure (if applicable), delay the onset of, reduce the severity of, alleviate, ameliorate one or more symptoms of the disease, improve the disease, reduce or improve any associated symptoms of the disease or the predisposition toward the development of the disease.
  • treatment or “treat” includes treating a patient suspected to have the disease as well as patients who are ill or who have been diagnosed as suffering from the disease or medical condition, and includes suppression of clinical relapse.
  • “selecting” and“selected” in reference to a patient is used to mean that a particular patient is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criteria.
  • “selectively treating” refers to providing treatment to a patient having a particular disease, where that patient is specifically chosen from a larger group of patients on the basis of the particular patient having a
  • “selectively administering” refers to administering a drug to a patient that is specifically chosen from a larger group of patients on the basis of (due to) the particular patient having a predetermined criterion.
  • “selectively treating and selectively administering” it is meant that a patient is delivered a personalized therapy based on the patient’s personal history (e.g., prior therapeutic interventions, e.g., prior treatment with biologies), biology (e.g., particular genetic markers), and/or manifestation (e.g., not fulfilling particular diagnostic criteria), rather than being delivered a standard treatment regimen based solely on the patient’s membership in a larger group.
  • Selecting in reference to a method of treatment as used herein, does not refer to fortuitous treatment of a patient having a particular criterion, but rather refers to the deliberate choice to administer treatment to a patient based on the patient having a particular criterion.
  • selective treatment/administration differs from standard treatment/administration, which delivers a particular drug to all patients having a particular disease, regardless of their personal history, manifestations of disease, and/or biology.
  • the patient was selected for treatment based on having asthma.
  • Embodiments of the invention Asthma and effectiveness of treatment according to the invention
  • the disclosed BTK inhibitor i.e., compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be used in vitro, ex vivo, or incorporated into pharmaceutical compositions and administered in vivo to treat asthma patients (e.g., human patients).
  • the effectiveness of a asthma treatment may be assessed using various known methods and tools that measure asthma and/or asthma’s clinical response.
  • Some examples include, e.g. Spirometry (Forced Expiratory Volume in 1 second) (FEV1), peak expiratory flow rate (PEF), Daytime and nighttime asthma symptom score (captured in eDairy), ACQ-5 score, number of puffs of short-acting beta2-agonist (SABA) taken per day (captured in eDairy).
  • Spirometry reversibility testing is performed at screening to assess eligibility for the study. If reversibility is not demonstrated at the screening visit, then two additional attempts are permitted up to and including at the time of the run-in visit. Reversibility testing is performed according to the American Thoracic Society guidelines.
  • FEV1 is the maximal amount of air a patient can forcefully exhale in one second. It is expressed in mL. It is then converted to a percentage of normal. For example, your FEV1 may be 80% of predicted based on your height, weight, and race. FEV1 is a marker for the degree of obstruction with a patient/ s asthma: FEV1 greater 80% of predicted normal
  • COAs Clinical Outcome Assessments
  • the validated questionnaire (Asthma Control Questionnaire or ACQ 1999, Eur. Respir J; 902-7) is used and is administered at various timepoints during the study as depicted in the Assessment Schedule.
  • the questions are equally weighted and the ACQ score is the mean of the 5 questions and therefore between 0 (totally controlled) and 6 (severely uncontrolled).
  • the ACQ has been fully validated for use in both clinical practice and clinical trials.
  • a patient with an inadequately controlled asthma has an ACQ score 31.0, preferably an ACQ score 31.5.
  • a change from baseline of the ACQ score which is considered to be clinically relevant is a change or decrease in the ACQ score of at least 0.5, preferably at least 1, more preferably at least 1.5.
  • the daytime asthma symptom scale uses a range of response categories for each question from 0 to 6, indicating the least to the most asthma symptomatology.
  • the nocturnal diary scale uses response categories ranging from 0 (indicating no awakening with asthma symptoms) to 3 (indicating awake all night).
  • Nocturnal diary scale question 1 Did you wake up with asthma symptoms. (This can be awakening in the middle of the night or on awakening in the morning)? 0( No), 1 (Once), 2 (More than once) and 3 (Awake "all night”Daily).
  • Daytime scale scores were computed as the average of the four questions on the daytime symptom scale.
  • An overall diary score for the week is computed as the average of the daily daytime scale scores.
  • Weekly average scores for the nocturnal diary scale are computed in a similar manner.
  • a decrease in the weekly score for the daytime and nocturnal scales indicate an improvement in asthma symptoms.
  • the change from baseline in the asthma scale scores is computed as the difference between the score prior to dosing with compound of Formula (I), or a pharmaceutically acceptable salt thereof and at week 12 of the active treatment phase with compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • eDiary or eDiary/ePEF patient electronic diary
  • SABA salbutamol/albuterol
  • the data captured in the patient eDiary is used in conjunction with the patient's asthma characteristics to monitor the patient's asthma. Subjects are instructed to call the study site if they experience symptoms of worsening asthma. Additionally, the eDiary is programmed to generate some alerts of signs of possible worsening asthma based on data collected. These alerts are sent to the subject and/or to investigator.
  • the asthma diary contains daytime and nocturnal asthma symptom questions (Santanello et al 1997).
  • the format of the electronically administered diary may vary.
  • the total number of inhalations of SABA (number of puffs taken in the previous 12 hours) is recorded in the morning and evening by the subject in the eDiary/ePEF.
  • PEF is a person's maximum speed of expiration, as measured with a peak flow meter. PEF is measured at consistent times for a subject in the morning and evening each day. It measures the airflow through the bronchi and thus the degree of obstruction in the airways. Peak expiratory fl ow is typically measured in units of liters per minute (L/min). To determine the significance of peak expiratory flow measurements, a comparison is made to reference (normal, predicted) values based on measurements taken from the general population. Various reference values have been published in the literature and vary by population, ethnic group, age, sex, height and weight of the patient. It is also expressed as a percentage of the usual or normal peak flow readings. A desired PEF for a patient is at least 80%, preferably at least 90% of the usual or normal peak flow rate for this particular patient.
  • the measurements are performed using an eDiary/ePEF provided to the subjects.
  • Subjects must be encouraged to perform morning and evening PEF measurements BEFORE the use of any rescue medication (i.e., SABA), and subjects are asked to record if they have taken their SABA 6 hours prior to the peak flow assessment.
  • SABA rescue medication
  • the BTK inhibitor i.e., compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may contain, in addition to the compound of Formula (I), carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art.
  • the characteristics of the carrier depends on the route of administration.
  • the pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for treatment of the particular targeted disorder. For example, a
  • the pharmaceutical composition may also include anti-inflammatory or anti-itch agents. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or to minimize side effects caused by the compound of Formula (I).
  • the pharmaceutical composition for use in the disclosed methods comprise compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a dose of 10mg, 20mg, 25 mg, about 50mg or about 100mg.
  • compositions for use in the disclosed methods may be manufactured in conventional manner.
  • the pharmaceutical composition is provided for oral administration.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures
  • absorbents colorants, flavors and sweeteners.
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid;
  • binding agents for example, starch, gelatin or acacia
  • lubricating agents for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered to a patient, e.g., a mammal (e.g., a human). While it is understood that the disclosed methods provide for treatment of asthma patients using compound of Formula (I), or a pharmaceutically acceptable salt thereof, the therapy is not necessarily a monotherapy. Indeed, if a patient is selected for treatment with a compound of Formula (I), then the compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be administered in accordance with the methods of the disclosure either alone or in combination with other agents and therapies for treating asthma patients, e.g., in combination with at least one additional asthma agent.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof may be administered either simultaneously with the other agent, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering the compound of Formula (I), or a
  • Such therapies may be beneficially combined with the disclosed compound of Formula (I) or a pharmaceutically acceptable salt thereof, during the treatment of asthma.
  • Such therapies include short acting b2-adrenergic agonists (SABA) such as for example salbuterol, levosalbuterol; long acting b2-adrenergic agonists such as for example formoterol; inhaled corticosteroid (ICS) such as budesonide; leukotriene receptor antagonist (LTRA) such as for example Montekulast, Zafirlukast and Pranlukast; or long lasting muscarinic antagonist (LAMA) such as for example Tiotropium .
  • SABA short acting b2-adrenergic agonists
  • ICS inhaled corticosteroid
  • LTRA leukotriene receptor antagonist
  • Montekulast Zafirlukast and Pranlukast
  • LAMA long lasting muscarinic antagonist
  • kits for treating asthma comprise a BTK inhibitor, e.g., N-(3-(6-Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutical composition thereof.
  • the kit comprises two or more two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I).
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and inhaled, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the other asthma agent may be manufactured and/or formulated by the same or different manufacturers.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the other asthma agent may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the other asthma agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the other asthma agent.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is conveniently administered to a patient (preferably orally) in a dose of about 10mg to about 200mg daily.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 10mg to about 100mg.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 100mg.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 50mg.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 35mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 25mg.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 20mg.
  • compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once daily in a dose of about 10mg, about 35mg, about 50mg or about 100mg.
  • compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily in a dose of about 10mg, about 25mg, about 50mg or about 100mg.
  • dosages of the compound of Formula (I) may be less than about 10 mg, about 20 mg, about 25 mg, about 50mg, or about 100mg orally
  • the timing of dosing is generally measured from the day of the first dose of compound of Formula (I) (which is also known as“baseline”).
  • the timing of dosing is generally measured from the day of the first dose of compound of Formula (I) (which is also known as“baseline”).
  • day 1 the first day of dosing is referred to as day 1.
  • day 0 the first day of dosing is referred to as day 1.
  • day 1 the first day of dosing is referred to as day 1.
  • this naming convention is simply used for consistency and should not be construed as limiting, i.e., daily dosing is the provision of a daily dose of the compound of Formula (I) and the physician may refer to a particular day as“day 0” or“day 1”.
  • Also disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating asthma, wherein the daily dose of the compound is about 10 mg - about 200 mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 1 Omg to about 100mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 10 mg, about 20mg, about 25mg, about 35mg, about 50mg, about 100mg or about 200mg.
  • Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a daily dose of about 100mg.
  • Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a daily dose of about 50mg.
  • Formula (I), or a pharmaceutically acceptable salt thereof, is administered in a daily dose of about 35mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 25mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 20mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered once daily in a dose of about 10 mg, about 35mg, about 50mg, or about 100mg.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in a dose of about 10 mg, about 25mg, about 50mg, or about 100mg twice a day.
  • the patient has a physician-diagnosed history of asthma according to the Global Initiative for Asthma (GINA) guidelines 2018 [https ://ginasthma.org/wp- content/uploads/2019/01/2018 GINA.pdf] . (i.e. the patient has symptoms such as wheezing, shortness of breath, chest tightness and cough associated with reduced expiratory airflow due to bronchoconstruction, airway wall thickening and increased mucus)
  • GINA Global Initiative for Asthma
  • the patient has moderate to severe asthma.
  • a patient with moderate to severe asthma has a reduced FEV1 ( FEV1 340% but no more than 85% of personal predicted and have symptoms as evidenced by an ACQ of more than 1.5 at baseline despite treatment with inhaled corticosteroids and long -acting beta-2 agonists.
  • the patient has inadequately controlled asthma with standard background therapy of inhaled corticosteroid plus long acting beta-2 agonist (ICS/LABA).
  • ICS/LABA inhaled corticosteroid plus long acting beta-2 agonist
  • the patient with inadequately controlled asthma is characterized by an ACQ-5 31, preferably 31.5.
  • the patient has inadequately controlled asthma with standard background therapy of budesonide
  • the patient with inadequately controlled asthma is characterized by an ACQ-5 31, preferably 31.5.
  • the patient with inadequately controlled asthma is selected according to at least one of the following criteria:
  • the patient prior to treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the patient has a spirometry with pre-bronchodilator FEV1340% and ⁇ 85%;
  • the patient with inadequately controlled asthma is selected according to all 3 of the following criterias:
  • the patient prior to treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the patient has a spirometry with pre-bronchodilator FEV1340% and ⁇ 85%;
  • the patient has previously been treated with a treatment regimen selected from ICS; ICS plus LAB A; ICS plus LTRA and ICS plus LABA plus LAMA.
  • a treatment regimen selected from ICS; ICS plus LAB A; ICS plus LTRA and ICS plus LABA plus LAMA.
  • the patient had inadequately controled asthma under said treatment regimen as characterized by all the following criteria:
  • the patient has a spirometry with pre-bronchodilator FEV1340% and ⁇ 85%;
  • the patient achieves by week 12 of treatment a change from baseline in pre-dose FEV1.
  • FEV1 was calculated as the difference between the average FEV1 measurements performed 45 in and 15 min prior to dosing on Day 1 and the FEV1 at week 12 of the active treatment phase with compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the FEV1 has improved (i.e. change from baseline) by at least, 80 mL or by at least 130mL for said patient by week 12 of treatment with compound of Formula (I) or a
  • the patient achieves by week 12 of treatement a FEV1 385%.
  • the patient achieves by week 12 of treatment a change from baseline in morning and evening PEF.
  • the change from baseline in the PEF was calculated as the difference between the PEF measurements performed prior to dosing with compound of Formula (I) or a pharmaceutically acceptable salt thereof, on Day 1 and the PEF at week 12 of the active treatment phase with compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the morning and evening peak expiratory flow rate have improved by at least 18 L/min.
  • the patient achieves by week 12 of treatement a morning and evening PEF 380%.
  • the patient achieves by week 12 of treatment a change from baseline in ACQ-5 score.
  • the change from baseline in the ACQ-5 score was calculated as the difference between the ACQ-5 score prior to dosing with compound of Formula (I) or a pharmaceutically acceptable salt thereof, on day 1 and the ACQ-5 score at week 12 of the active treatment phase with compound of Formula (I) or a
  • the patient achieves by week 12, a reduction of the ACQ-5 of 0.5 point, preferably of 1 point.
  • the patient achieves by week 12 of treatment a change from baseline in daytime and nighttime asthma symptom score.
  • the change from baseline in the daytime and asthma symptom score was calculated as the difference between the daytime and nighttime symptoms score prior to dosing with compound of Formula (I) or a pharmaceutically acceptable salt thereof, on day 1 and the daytime and nightime symptoms score at week 12 of the active treatment phase with compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the patient achieves by week 12, a decrease in the weekly score for the daytime and nocturnal scales of at least 1 point, at least 2 points, or at least 3 points.
  • the patient is free of symptoms by week 12. (i.e. daytime and nighttime asthma symptom score of zero).
  • the patient achieves by week 12 of treatment a change from baseline in the number of puffs of SABA taken per day over the 12 weeks period.
  • the change from baseline in the number of puffs of SABA was calculated as the difference between the number of puffs of SABA prior to dosing with compound of Formula (I) or a pharmaceutically acceptable salt thereof, on day 1 and the number of puffs of SABA at week 12 of the active treatment phase with compound of Formula (I) or a
  • the patient achieves by week 12 a reduction of the number of puffs of SABA needed. In another embodiment, the patient does not need any rescue medication by week 12.
  • the patient is an adult. In some embodiments of the disclosed methods, uses and kits, the patient is an adolescent.
  • a method of treating asthma comprising administering to a subject in need thereof a daily dose of about 10 mg to about 200 mg of N-(3-(6-Amino-5-(2-( N- methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2- fluorobenzamide, or a pharmaceutically acceptable salt thereof.
  • the subject prior to treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the subject has a spirometry with pre-bronchodilator FEV1340% and ⁇ 85%;
  • N-(3-(6-Amino- 5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2- fluorobenzamide, or pharmaceutically acceptable salt thereof is disposed in a pharmaceutical formulation, wherein said pharmaceutical formulation further comprises pharmaceutically acceptable carriers.
  • TEC tec protein tyrosine kinase (TEC is a gene family of protein tyrosine kinases) Tmax Time of maximum concentration observed in concentration/time profile Vz/F the apparent volume of distribution during the terminal elimination phase following administration (volume)
  • Example 1a BTK occupancy and preclinical PK/PD relationship
  • the in vivo PD effects of an irreversible BTK inhibitor like compound (I) are determined by the extent and duration of covalent BTK occupancy by the inhibitor.
  • BTK occupancy after treatment with Compound of Formula (I) also referenced to as Compound (I) or Cpd(I)
  • the fraction of unoccupied BTK protein was assayed after in vitro incubation with a covalent biotinylated BTK probe, since compound (I) and the probe bind to BTK in a mutually exclusive manner.
  • Unoccupied BTK, as well as total BTK relative protein levels were determined in lysates of selected tissues and levels of unoccupied BTK were normalized to total BTK protein levels in the same samples.
  • BTK occupancy was determined in rats and mice after single oral dose of compound (I) for spleen, blood, lymph nodes and lung.
  • BTK occupancy showed a long half-life in blood of approximately 87 hours.
  • the estimated BTK occupancy half-life in rat spleen is significantly shorter than in blood with only approximately 5 hours.
  • the different turnover rates may reflect the fact that BTK expressing B cells and monocytes in peripheral blood are resting and metabolically relatively inactive compared to the spleen.
  • the longer persistence of BTK occupancy in blood has been reported before (Advani et al 2013, J Clin One; 31(1): 88-94). All other tissues analyzed (lung and lymph node) showed a similar BTK turnover and occupancy half-life as spleen.
  • the duration of the PD effect in skin after single dose was assessed in the reverse passive Arthus (RPA) model of mast cell FcgRIII - mediated inflammation.
  • RPA reverse passive Arthus
  • the inhibition of skin swelling was maximal when compound (I) was dosed 2 hours prior to eliciting the Arthus reaction.
  • the effect diminished gradually and reached baseline when the Arthus reaction was triggered 45 hours or later after compound (I) dosing. This suggests that BTK occupancy in the skin shows a similar time course like spleen, lung and lymph nodes.
  • BTK occupancy is a suitable PD biomarker for use in clinical studies and therefore was used in Phase 1 clinical studies.
  • Example IB In vivo efficacy in acute mouse models of cutaneous hypersensitivity
  • RPA reverse passive Arthus
  • a polyclonal IgG antibody is injected locally into the dermis, while the soluble antigen is given systemically by i.v. injection.
  • mast cell FcgRIII has a dominant role with only minor contributions by the complement system (Hazenbos et al. 1998, journal of immunology, 161(6), pp.3026; Hazenbos et al, Immunity, 1996, 5(2), pp.
  • mice are protected in the passive Arthus skin reaction (Fiedler et al. 2011, blood, 117(4), pp.1329). Oral treatment with compound (I) at a single dose of 3, 10, 30 and 100 mg/kg, given 2 hours prior to induction of the RPA response, reduced skin swelling in a dose-related manner.
  • BTK occupancy in the skin shows a similar time course like spleen, lung and lymph nodes.
  • Example lc efficacy of compound of Formula (I) in mouse asthma model
  • Compound of Formula (I) was tested in a (house dust mite) HDM murine asthma model where allergic inflammation was induced by sensitizing and challenging the animals with HDM. Briefly, animals were sensitized with intraperitoneal administration of HDM (10 mg)/alum on days 0 and 7 before subsequent intranasal challenged with HDM (5 mg) or saline on days 21, 22 and 23. Oral treatment with Compound of Formula (I) began 1 hour prior to the first challenge on day 21 and continued twice daily. Approximately 24 hours after the final HDM or saline challenge the animals were euthanized, a broncheoalveolar lavage was performed before the eosinophils enumerated. Treatment with Formula (1) significantly reduced house dust mite allergy-induced eosinophilia in this model ( Figure 5).
  • BTK occupancy and the respective pharmacologic readouts showed a strong correlation.
  • BTK occupancy and mast cell- mediated skin hypersensitivity reactions are suitable PD biomarker for use in clinical studies and therefore were used in Phase 1 clinical studies.
  • PK pharmacokinetics
  • PD pharmacodynamics
  • the SAD part (Part 1) had ten dose levels and the MAD parts (Parts 2 & 4) consisted of eight dose levels (6 cohorts using single daily dosing in Part 2 and 2 cohorts using twice daily dosing in Part 4). Eight subjects were randomized into each cohort to receive either compound (I) or matching placebo in a 6:2 (active: placebo) ratio in the SAD and MAD parts. Within the SAD part, doses up to approximately 4 times the estimated pharmacologically active dose (PAD) were to be evaluated before the MAD part of the study was started, providing there was no safety signal emerging from the SAD part until then. The total daily dose of compound (I) used in Part 2 (MAD qd regimen) and Part 4 (Multiple dose bid regimen) did not exceed the highest SAD dose level explored. Moreover, the total daily dose of Part 4 did not exceed the total daily dose of Part 2.
  • Standard safety monitoring was used throughout all study parts. A dedicated assessment of potential skin bruising events were included. All vital signs, physical examination and subject history, ECGs, adverse events, and laboratory safety parameters (blood chemistry, hematology and urinalysis) up to 96 hours post last dose as well as PK data from the previous dose group (if available) up to 48 hours post last dose were to be reviewed in a blinded fashion for each cohort before dose escalation. Summary safety reports of reported adverse events, clinical safety laboratory parameters, QTc and heart rate were provided to Novartis after completion of each dose level. In Parts 1, 2 and 4, each subject participated in a 28-day Screening period (Days -29 to -2), a Baseline period, a Treatment period and a Follow-up period that included an End-of-Study evaluation.
  • Part 3 was an open-label, randomized, two-way cross-over, single dose study to assess food effects.
  • each subject participated in a 28 day screening period (Day -29 to -2), 2 baseline (Day -1) and 2 treatment periods, each consisting of a single dose administration on Day 1 followed by safety and PK assessment up to Day 5.
  • Treatment period 2 consisted of a follow- up visit and an end of study evaluation on Day 22 and 40, respectively.
  • the two treatment periods were separated by a wash-out period of at least 18 days (+/- 1 day).
  • BMI body mass index
  • Any clinically significant abnormalities in any of the standard coagulation tests including the prothrombin time (PT), partial thromboplastin time (PTT), or International Normalized Ratio (INR) at screening and/or baseline.
  • PT prothrombin time
  • PTT partial thromboplastin time
  • INR International Normalized Ratio
  • Subjects were assigned to one of the following 10 cohorts. In each cohort, 8 subjects were randomized to either compound (I) or matching placebo in an overall 6:2 ratio. The first sub- cohort was randomized in a 1 : 1 ratio as one subject on compound (I) and one on matching placebo. The remaining 6 subjects per cohort, dosed after a 48-hour observation period of the initially dosed 2 subjects, were randomized in a 5: 1 ratio.
  • Subjects were assigned to one of the following 6 cohorts. In each cohort, 8 subjects were randomized to either compound (I) or matching placebo in a 6:2 ratio.
  • Subjects were assigned to one of the following cohorts. In each cohort, 8 subjects were randomized to either Compound (I) or matching placebo in a 6:2 ratio.
  • Cohort 1 multiple oral doses of 100 mg Compound (I) or matching placebo in a bid regimen
  • Cohort 2 multiple oral doses of 200 mg Compound (I) or matching placebo in a bid regimen
  • Pharmacokinetic samples were obtained in blood and evaluated in all subjects at all dose levels. The samples from placebo subjects were not analyzed. The samples for PK assessments from subjects were collected at time points defined in the study. Compound (I) concentrations were determined in blood by a validated LC -MS/MS method.
  • Compound (I) was rapidly absorbed with time to reach Cmax of about 1-1.5 hr across all doses.
  • the absorption phase was characterized by a single distinct absorption peak in most subjects.
  • Drug disposition displayed a bi-exponential decline. Most of the drug was eliminated under the initial distribution phase suggesting substantial drug clearance may occur prior to reaching whole-body tissue equilibrium.
  • the distribution phase demonstrated a dominant dose-independent T1/2 of ⁇ 1 h.
  • the calculated geometric mean of oral blood clearance after single dose administration (CL/F) ranged from 250 to 506 L/h across SAD cohorts, with an estimate of about 383 L/h across all cohorts.
  • Table 1-1 Summary of PK parameters of compound (I) at multiple ascending doses of 10 - 600 mg, q.d. dosing
  • blood concentrations at 24 hours post last dose were typically below 1 ng/ml, except for a few subjects at 100 mg and above indicating near-complete washout of compound (I) within two consecutive doses. The latter also suggests that steady state is reached within a few doses.
  • PD Pharmacodynamics
  • Compound of formula (I) is an irreversible inhibitor of BTK, the extent and duration of BTK occupancy were determined.
  • the PD effect of compound (I) was assessed by measuring both free BTK (not bound) and total BTK in whole blood by enzyme-linked immunosorbent assay (ELISA) on Meso Scale Diagnostics (MSD) platform in two separate assays.
  • ELISA enzyme-linked immunosorbent assay
  • MSD Meso Scale Diagnostics
  • BTK occupancy was dertermined for single ascending doses ranging 0.5 to 400 mg, for q.d. multiple ascending doses ranging from of 10 mg and 400 mg, and for b.i.d. multiple ascending doses of 100 mg and 200 mg.
  • Compound of Formula (I) exhibited a clear dose-dependent increase in both extent and duration of peripheral blood BTK occupancy.
  • Peak target occupancy was generally seen as early as 0.5 h post dose, indicating rapid onset with no relevant hysteresis in drug effect relative to peak drug exposure.
  • target occupancy was sustained well beyond its disposition from the systemic circulation, indicating a non-equilibrium PK-PD relationship. Accordingly, duration of BTK occupancy is expected to be governed by the rate of de novo synthesis of BTK.
  • ex vivo inhibition of basophil activation was used as distal mechanistic biomarker to test downstream PD effects of compound (I).
  • whole blood was stimulated ex vivo with anti-IgE. Degranulation was evaluated by percentage of CD63+ and CD203+ basophils by flow cytometry. After single ascending doses of compound (I), data indicate a dose-dependent inhibition of FceR1 -mediated basophil activation.
  • Ex-vivo blood basophil activation as measured by CD63 was near-completely inhibited (>89%) at doses of 60 mg and reached close to a 100% inhibition at higher doses 24 h post dose.
  • maximum inhibition of CD203c 24 h after a single dose of compound (I) was only achieved with 200 mg compound (I).
  • SPT skin prick test
  • the dose-levels of this invention were derived from the following analyses (BTK occupancy, inhibition of basophil activation (monitored by CD63 and CD203c up-regulation) in healthy volunteers; and impact on skin prick tests (SPT) in asymptomatic atopic healthy volunteers - a proxy for mast cell and basophil inhibition within the skin.
  • Compound of Formula (I) inhibits BTK by covalent binding. While BTK occupancy in blood is > 24 hours (h), fast BTK turnover in tissue (example given approximately 5 hours in the spleen of rodents) may require b.i.d. administration of compound (I) to reach maximal efficacy. Doses of 10 mg, 25 mg and 100 mg compound (I) b.i.d., respectively, accurately describe the dose-response curves of compound (I) when given twice a day.
  • Safety assessment of the FIH study in healthy volunteers does not reveal significant safety concerns at dosing up to 600mg.
  • Example 3 Efficacy and Safety Data in Subjects with Asthma
  • COMPOUND (I) designed to establish safety and efficacy and characterize the dose-response of COMPOUND (I)in subjects with moderate to severe asthma to allow further development of the compound for treatment of this disease.
  • a non-confirmatory, multi-center, randomized, placebo-controlled, subject- and investigator-blinded, parallel-group study is conducted to evaluate the efficacy of COMPOUND (I) in patients with inadequately controlled asthma. All subjects receive a standardized background therapy of budesonide 80mg/formoterol 4.5 mg one inhalation b.i.d.. This study enrolls approximately 75 subjects in order to achieve 65 completers for the primary analysis (subjects having week 12 FEV1 assessment). However, in case of a higher dropout rate than assumed (10% over 12 weeks), or a higher variability of the primary endpoint in interim analyses than expected up to 154 subjects may be randomized.
  • budesonide/formoterol may vary between countries.
  • EOS End of Study
  • Screening period After signing informed consent, subjects complete safety assessments, pulmonary function tests, and the ACQ-5 to assess eligibility. All subjects must demonstrate FEV1 reversibility for study eligibility. If reversibility is not demonstrated at the screening visit, then two additional attempts are permitted up to and including at the time of the run-in visit. Subjects are provided with an electronic peak expiratory flow (ePEF)/eDiary device in which they record their PEF, daytime and nighttime asthma symptoms, and the use of rescue medication. Subjects are instructed on eDiary completion and how to use the device for the assessment of peak flow. Subjects perform PEF measurements twice daily (morning and evening) beginning the evening of the screening visit through the EOS visit.
  • ePEF electronic peak expiratory flow
  • a short acting b2-agonists (SABA; salbutamol, known also as albuterol) is provided to all subjects as rescue medication.
  • SABA short acting b2-agonists
  • the investigator checks that the vaccination status of the subject is complete and there are no vaccinations planned during the study period.
  • a complete vaccination status for an asthma patient to be considered for this study includes vaccination against influenza, diphtheria, pertussis and pneumococci.
  • Run-in period Subjects return to the study site for the run-in visit on Day -21 for safety assessments and pulmonary function tests to assess eligibility.
  • DPI turbohaler or equivalent device if turbohaler not available
  • all subjects must have received a minimum of 3 weeks budesonide 80mg/formoterol 4.5mg one inhalation b.i.d. as background therapy.
  • the run-in period may be extended by up to two weeks.
  • the run-in period will end with the baseline visit.
  • the baseline visit assessments occur between Day -3 and Day 1 to allow for flexibility and to ensure all data required is available for randomization. All baseline assessments are completed and eligibility confirmed prior to randomization on Day 1. If required, to adjust for the subjects (e.g. holiday, family or work) needs the run in period are extended by up to two weeks.
  • Treatment period On Day 1 of the treatment period, after completion of all pre-dose
  • Subjects take their first dose in the clinic on Day 1. For the remainder of the 12 week treatment period, subjects take their daily dose in the morning at approximately the same time. There are a total of 5 visits during the treatment period (Day 1, 15, 29, 57 and Day 85). Each visit is scheduled in the morning at approximately the same time, so that pre-dose FEV1 assessments are performed between 6 AM and 10 AM +/- 1 hour. On visit days, subjects take their dose in the clinic after completion of efficacy and safety assessments. Subjects on visit days also take their standardized background therapy morning dose after the efficacy and safety measurements. Subjects will complete dosing on Day 85.
  • Budesonide 80mg/formoterol 4.5mg was selected because it ensures that subjects receive an ICS/LABA as recommended in the applicable guidelines for treating patients with asthma.
  • the ICS-component is administered at a low dose level to make the study sensitive for the anti-inflammatory effects resulting from BTK-inhibition.
  • the standardization of the background therapy minimizes the variation that would be observed if patients enrolled in the study on variable doses or variable asthma control therapy. All subjects receive a minimum of 3 weeks background therapy of budesonide 80mg/formoterol 4.5mg prior to randomization so that all have the same treatment and are in steady state condition for the baseline assessments. In addition, subjects can manage their symptoms with short acting b2-agonists as rescue medication when required.
  • COMPOUND (I) is administered as 100 mg q.d.
  • the treatment duration of 12 weeks is covered by pre-clinical data and is considered sufficient to allow assessment of anti inflammatory effects resulting in lung function improvement and symptom control in patients with asthma.
  • the pre-clinical toxicity profile of COMPOUND (I) was assessed in 13-weeks studies in dogs and rats.
  • NOAEL no-observed-adverse-effect-level
  • margins of safety (19 fold in female, 13 -fold in male) versus the exposure of 100 mg COMPOUND (I) q.d.
  • a NOAEL was established at the highest dose tested of 1000 mg/kg/d with margins of safety (108-fold in female, 9.8-fold in male).
  • COMPOUND (I) in single ascending dose cohorts (SAD; up to 600 mg COMPOUND (I)) and in multiple ascending dose cohorts (MAD; up to 600 mg COMPOUND (I) q.d. and up to 200 mg COMPOUND (I) b.i.d. for 12 days).
  • SAD single ascending dose cohorts
  • MAD multiple ascending dose cohorts
  • COMPOUND (I) was well tolerated and there was no serious or severe adverse event related to COMPOUND (I) intake in any of the cohorts completed.
  • Observed adverse events (AEs) did not appear to be dose dependent, the majority were single events, and were generally mild in nature. Thus, preclinical and clinical safety information support the doses selected for this proof-of-concept study.
  • COMPOUND (I) Since COMPOUND (I) is covalently bound to its target, it provides sustained coverage based on the target engagement over 24h despite its relatively short elimination half-life. Thus a once daily dosing regimen is considered appropriate. Recurrence of BTK related disease activity requires resynthesis of BTK in sufficient amounts to reactivate the pathway. Sufficient resynthesis of BTK is not expected to occur within one day.
  • Placebo is chosen as the comparator for this study in order to demonstrate that
  • COMPOUND (I) adds a significant improvement in efficacy to background ICS/LABA therapy in moderate to severe asthmatic patients.
  • the primary endpoint in the study, FEV1 is an effort dependent measurement.
  • the secondary endpoints (ACQ-5, patient diary) are patient reported outcomes.
  • the placebo control arm is essential to account for effects not mediated by BTK inhibition (placebo effects).
  • the placebo arm is also expected to control for potential bias in safety assessments in this study.

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Abstract

La présente invention concerne des procédés de traitement de l'asthme à l'aide d'un composé de formule (I). L'invention concerne également un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, pour le traitement de patients asthmatiques, ainsi que des médicaments, des schémas posologiques, des formulations pharmaceutiques, des formes posologiques, et des kits destinés à être utilisés dans les utilisations et les procédés décrits.
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