WO2016066687A1 - Losmapimod for treating copd - Google Patents
Losmapimod for treating copd Download PDFInfo
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- WO2016066687A1 WO2016066687A1 PCT/EP2015/074983 EP2015074983W WO2016066687A1 WO 2016066687 A1 WO2016066687 A1 WO 2016066687A1 EP 2015074983 W EP2015074983 W EP 2015074983W WO 2016066687 A1 WO2016066687 A1 WO 2016066687A1
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- copd
- nicotinamide
- methyl
- responder
- cyclopropylcarbamoyl
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/12—Pulmonary diseases
- G01N2800/122—Chronic or obstructive airway disorders, e.g. asthma COPD
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Definitions
- This invention relates to methods of treating sub-populations of COPD patients with compounds which are known in the art as p38 kinase inhibitors. More specifically this invention relates to the use of a nicotinamide derivative in such methods.
- COPD Chronic Obstructive Pulmonary Disease
- exacerbations represent an important event in the natural history of COPD and continue to be a major healthcare problem as they largely determine the morbidity, healthcare burden and mortality of COPD.
- Patent application WO03/068747 discloses a series of nicotinamide derivatives that are p38 inhibitors and are said to be useful in the treatment of a number of disorders, including COPD.
- the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide that is to say, the compound having the formula
- a method for treating a sub population of COPD patients who are at risk of exacerbations which comprises administration of a p38 MAP kinase inhibitor.
- a p38 MAP kinase inhibitor for use in the above methods.
- a method for treating COPD patients at risk of exacerbations which comprises: a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
- COPD patients at risk of exacerbations are defined by GOLD (Global Initiative for Chronic Obstructive Lung Disease (2014)) in which it states: "There are three methods assessing exacerbation risk. One is a population-based method using GOLD spirometric classification, with GOLD 3 or GOLD 4 categories indicating high risk. The second based on the individual patient's history of exacerbations, with two or more exacerbations in the preceeding year indicating high risk. The third is a history of hospitalization due to an exacerbation in the preceeding year, (if there is a discrepancy between these criteria, the assessment pointing to the highest risk should be used)."
- a COPD patient at risk of exacerbations is a COPD patient who has experienced two or more exacerbations in the preceding year.
- a method for reducing the incidences and/or severity of exacerbations of COPD in a patient which comprises:
- the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof may be prepared according to procedures described in patent application WO03/068747 (as example 36).
- salts of the compound 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide are non toxic salts and include examples described in patent application
- the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide is in the form of a free base.
- 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof Whilst it is possible for the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof to be administered as the raw chemical it would typically be administered in the form of a pharmaceutical composition. 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt may therefore be formulated for administration in any suitable manner that is known to those skilled in the art.
- composition may, for example, be formulated for topical administration, transdermal administration, administration by inhalation, oral administration or parenteral administration (e.g. intravenously, intravascularly or subcutaneously).
- parenteral administration e.g. intravenously, intravascularly or subcutaneously.
- Suitable methods for formulating 6-(5-cyclopropylcarbamoyl-3- fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt include those described in patent application WO03/068747 and / or the methods that are familiar to those skilled in the art, which are described in Remington: The Science and Practice of Pharmacy, 21 st Edition 2006.
- the pharmaceutical composition is adapted for oral administration e.g. a tablet.
- 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof is administered orally with a dosage in the range 1 mg twice per day (bid) to 30 mg twice per day (bid), particularly 7.5mg twice per day (bid) or more particularly 15mg twice per day (bid).
- the term "therapeutically effective amount” means that amount of a compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
- the term "responder” refers to a COPD patient who through analysis has been identified as someone who will benefit from treatment with the compound or a pharmaceutical composition comprising said compound. A responder will also have a greater response to and derive greater benefit from treatment than a COPD patient who has been identified as a "non-responder".
- a COPD patient is classified as a responder when they have a measured blood eospinophil count at a defined level.
- a blood eosinophil count calculated as a percentage can be converted to an eosinophil/ ⁇ value and vice versa. Moreover, either expression of the eosinophil count can be calculated and/or referred to as part of the uses and methods of the present invention.
- the blood eosinophil count can be manually or automatically calculated by methods well known in the art. Typically, a sample of blood is taken from a peripheral vein and analysed by an instrument (e.g. Automated Analyser) that provides the total number of white blood cells. All the white blood cell types can be provided as an absolute number per litre or percentage. A complete blood count with differential count also provides how many cells are eosinophils as an absolute value (cells/L or cells/ ⁇ of blood) or percentage of total white blood cells.
- a responder is a COPD patient who has a blood eosinophil level (i.e. a percentage of white blood cells, also known as leukocytes, in a blood sample that are eosinophils) of ⁇ 3% such as ⁇ 2.5%, ⁇ 2.0%, ⁇ 1.5% or ⁇ 1.0%.
- a blood eosinophil level i.e. a percentage of white blood cells, also known as leukocytes, in a blood sample that are eosinophils
- ⁇ 3% such as ⁇ 2.5%, ⁇ 2.0%, ⁇ 1.5% or ⁇ 1.0%.
- 6-(5-Cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide and the other therapeutically active agent(s) may be administered together or separately and, when administered separately, this may occur simultaneously or sequentially in any order.
- the amounts of 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
- the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient.
- the therapeutic ingredients may be used in optically pure form.
- a p38 MAP kinase inhibitor for use in the above methods. Also provided is a p38 MAP kinase inhibitor for use in the manufacture of a medicament for use in the above methods.
- Suitable p38 inhibitor compounds are know in the art and can be administered as a free base or in the form of a pharmaceutically acceptable salt thereof.
- Suitable p38 inhibitor compound include PH-797804 In one embodiment the p38 inhibitor is 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin- 1 (2H)-yl)-N,4-dimethylbenzamide or a pharmaceutically acceptable salt thereof.
- the p38 inhibitor compound is 6-methyl-4'-(4H-[1 ,2,4]triazol-3- yl)-biphenyl-3-carboxylic acid cyclopropylamide or a pharmaceutically acceptable salt thereof.
- a responder is a COPD patient who has a blood eosinophil level of ⁇ 3% such as ⁇ 2.5%, ⁇ 2.0%, ⁇ 1.5% or ⁇ 1.0%.
- a safety and efficacy study relating to losmapimod in the treatment of frequently exacerbating COPD patients The utility of losmapimod in the treatment of frequently exacerbating COPD patients can be evaluated in a randomised, double-blind, parallel-group, multi-centre study evaluating the effects on patients receiving 15 milligram (mg) twice daily (bid) of losmapimod versus placebo, in addition to their standard of care (SoC).
- the primary objective of this study is to explore the therapeutic potential of losmapimod as a treatment to reduce the rate of exacerbations in the subset of participants with moderate-to-severe COPD who are at high risk of exacerbation i.e. having experienced two or more moderate/severe exacerbations in the preceding 12 months.
- a moderate COPD exacerbation is one which requires new prescription for treatment with antibiotics and/or systemic corticosteroids.
- a severe COPD exacerbation requires hospitalisation or leads to death.
- the duration of the treatment period is variable but will be at least 26 weeks and up to a maximum of 52 weeks.
Abstract
The use of p38 kinase inhibitors in the treatment of sub-populations of COPD patients.
Description
LOSMAPIMOD FOR TREATING COPD
Field of the Invention
This invention relates to methods of treating sub-populations of COPD patients with compounds which are known in the art as p38 kinase inhibitors. More specifically this invention relates to the use of a nicotinamide derivative in such methods.
Background of the Invention
Chronic Obstructive Pulmonary Disease (COPD) is a common, debilitating lung disease, characterized by progressive airflow limitation and punctuated by episodes of acute exacerbations. These exacerbations can induce acute worsening of symptoms, causing patients to experience paroxysms of cough, sputum production, and shortness of breath and to seek urgent medical care. As chronic obstructive pulmonary disease progresses, exacerbations increase in frequency and severity. Repeated episodes of COPD exacerbations impair lung tissues and lead to an accelerated rate of decline in FEV^ since many patients do not return to their baseline lung function after the exacerbation. As a consequence patients functional capacity becomes gradually compromised ultimately leading to disability and significant decrements in the overall quality of life. Despite the advances in care, exacerbations represent an important event in the natural history of COPD and continue to be a major healthcare problem as they largely determine the morbidity, healthcare burden and mortality of COPD. There is a clear unmet need for more effective therapeutic strategies aimed at reducing the risk for exacerbations in COPD. Such strategies will improve clinical outcomes and long term will prevent the relentless progression of this disease.
Patent application WO03/068747 (SmithKline Beecham Corporation) discloses a series of nicotinamide derivatives that are p38 inhibitors and are said to be useful in the treatment of a number of disorders, including COPD. The compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide that is to say, the compound having the formula
is specifically described therein. The statement of non-proprietary name adopted by the USAN Council for this compound is losmapimod.
A reported losmapimod study (MKI 1 13006) was a randomised, double-blind, parallel-group dose ranging study in 602 COPD patients (inclusion criteria being FEV1/FVC <0.70, FEV1 <80%, 6 minute walk test (6MWT) < 350m) in which losmapimod was evaluated at 2.5 mg (n=149), 7.5 mg (n=151 ) and 15 mg (n=149) bid for 24 weeks versus placebo (n=153). It was found that there was no statistical difference between any dose of losmapimod and placebo in the primary end point, that being the 6MWT.
Summary of the Invention
In one aspect there is provided a method for treating a sub population of COPD patients who are at risk of exacerbations which comprises administration of a p38 MAP kinase inhibitor.
In a further aspect there provided a method for reducing the incidences and/or severity of exacerbations in a sub population of COPD patients.
In a yet further aspect there is provided a p38 MAP kinase inhibitor for use in the above methods.
Detailed Description of the Invention
A retrospective (post hoc) analysis of the Phase 2b losmapimod trial
(MKI 1 13006) has identified a COPD sub population with low eosinophils (categorised as ≤2% of blood eosinophils at randomisation (baseline)) which demonstrated a clinically meaningful response to losmapimod treatment. This response was not observed in patients with elevated blood eosinophils at baseline (>2%). Clinically meaningful reductions in the rate of exacerbations and improvements in lung function were particularly observed in the 15 mg bid dose group. For exacerbations a trend to improvement in response was observed with increasing doses of losmapimod (2.5 mg - 10%, 7.5 mg - 29%, 15 mg - 55%).
In one aspect there is provided a method for treating COPD patients at risk of exacerbations which comprises:
a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
b) determining if the COPD patient is a responder; and
c) administering a therapeutically effective amount of 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof to said COPD patient identified as a responder.
Also provided is the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of COPD patients at risk of exacerbations using a method which comprises steps (a), (b) and (c) as outlined above.
Also provided is the use of the compound 6-(5-cyclopropylcarbamoyl-3-fluoro- 2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of COPD patients at risk of exacerbations which comprises steps (a), (b) and (c) as outlined above.
COPD patients at risk of exacerbations are defined by GOLD (Global Initiative for Chronic Obstructive Lung Disease (2014)) in which it states: "There are three methods assessing exacerbation risk. One is a population-based method using GOLD spirometric classification, with GOLD 3 or GOLD 4 categories indicating high risk. The second based on the individual patient's history of exacerbations, with two or more exacerbations in the preceeding year indicating high risk. The third is a history of hospitalization due to an exacerbation in the preceeding year, (if there is a discrepancy between these criteria, the assessment pointing to the highest risk should be used)."
In one embodiment a COPD patient at risk of exacerbations is a COPD patient who has experienced two or more exacerbations in the preceding year.
In a further aspect there is provided a method for reducing the incidences and/or severity of exacerbations of COPD in a patient which comprises:
a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
b) determining if the COPD patient is a responder; and
c) administering a therapeutically effective amount of 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof to said COPD patient identified as a responder.
Also provided is the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in reducing the incidences and/or severity of exacerbations of COPD in a patient which comprises steps (a), (b) and (c) as outlined above.
Also provided is the use of the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-
2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in reducing the incidences and/or severity of exacerbations of COPD in a patient which comprises steps (a), (b) and (c) as outlined above.
The compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof may be prepared according to procedures described in patent application WO03/068747 (as example 36).
Pharmaceutically acceptable salts of the compound 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide are non toxic salts and include examples described in patent application
WO03/068747, the contents of which is incorporated by reference. For a review of suitable pharmaceutically acceptable salts see also Berge et al., J. Pharm. Sci., 66:1- 19, (1977).
In one embodiment the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide is in the form of a free base.
Whilst it is possible for the compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof to be administered as the raw chemical it would typically be administered in the form of a pharmaceutical composition. 6-(5-cyclopropylcarbamoyl-3-fluoro-2- methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt may therefore be formulated for administration in any suitable manner that is known to those skilled in the art. It may, for example, be formulated for topical administration, transdermal administration, administration by inhalation, oral administration or parenteral administration (e.g. intravenously, intravascularly or subcutaneously). Suitable methods for formulating 6-(5-cyclopropylcarbamoyl-3- fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt include those described in patent application WO03/068747 and / or the methods that are familiar to those skilled in the art, which are described in Remington: The Science and Practice of Pharmacy, 21 st Edition 2006.
In one embodiment the pharmaceutical composition is adapted for oral administration e.g. a tablet.
In a particular embodiment 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof is administered orally with a dosage in the range 1 mg twice per day (bid) to 30 mg twice per day (bid), particularly 7.5mg twice per day (bid) or more particularly 15mg twice per day (bid).
As used herein, the term "therapeutically effective amount" means that amount of a compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
As used herein, the term "responder" refers to a COPD patient who through analysis has been identified as someone who will benefit from treatment with the compound or a pharmaceutical composition comprising said compound. A responder will also have a greater response to and derive greater benefit from treatment than a COPD patient who has been identified as a "non-responder". In the context of the present invention a COPD patient is classified as a responder when they have a measured blood eospinophil count at a defined level.
It will be appreciated by those skilled in the art that a blood eosinophil count calculated as a percentage can be converted to an eosinophil/μΙ value and vice versa. Moreover, either expression of the eosinophil count can be calculated and/or referred to as part of the uses and methods of the present invention. The blood eosinophil count can be manually or automatically calculated by methods well known in the art. Typically, a sample of blood is taken from a peripheral vein and analysed by an instrument (e.g. Automated Analyser) that provides the total number of white blood cells. All the white blood cell types can be provided as an absolute number per litre or percentage. A complete blood count with differential count also provides how many cells are eosinophils as an absolute value (cells/L or cells/μΙ of blood) or percentage of total white blood cells.
In one embodiment a responder is a COPD patient who has a blood eosinophil level (i.e. a percentage of white blood cells, also known as leukocytes, in a blood sample that are eosinophils) of < 3% such as < 2.5%, < 2.0%, < 1.5% or < 1.0%.
It will be appreciated that 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof may be employed alone or in combination with other therapeutic agents which are suitable for the treatment of patients with COPD.
6-(5-Cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide and the other therapeutically active agent(s) may be administered together or separately and, when administered separately, this may occur simultaneously or sequentially in any order. The amounts of 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredient(s) may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts), or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g. hydrates) to optimise the activity and/or stability and/or physical characteristics (e.g. solubility) of the therapeutic ingredient. It will be clear also that where appropriate, the therapeutic ingredients may be used in optically pure form.
Further provided is a method for treating COPD patients at risk of
exacerbations which comprises:
a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
b) determining if the COPD patient is a responder; and
c) administering a therapeutically effective amount of a p38 MAP kinase inhibitor to said COPD patient identified as a responder.
Also provided is a method for reducing the incidences and/or severity of exacerbations of COPD in a patient which comprises:
a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
b) determining if the COPD patient is a responder; and
c) administering a therapeutically effective amount of a p38 MAP kinase inhibitor to said COPD patient identified as a responder.
Further provided is a p38 MAP kinase inhibitor for use in the above methods. Also provided is a p38 MAP kinase inhibitor for use in the manufacture of a medicament for use in the above methods.
Suitable p38 inhibitor compounds are know in the art and can be administered as a free base or in the form of a pharmaceutically acceptable salt thereof. Suitable p38 inhibitor compound include PH-797804 In one embodiment the p38 inhibitor is 3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin- 1 (2H)-yl)-N,4-dimethylbenzamide or a pharmaceutically acceptable salt thereof. In another embodiment the p38 inhibitor compound is 6-methyl-4'-(4H-[1 ,2,4]triazol-3- yl)-biphenyl-3-carboxylic acid cyclopropylamide or a pharmaceutically acceptable salt thereof. In one embodiment a responder is a COPD patient who has a blood eosinophil level of < 3% such as < 2.5%, < 2.0%, < 1.5% or < 1.0%.
The following examples illustrate the invention. Example 1
A pharmaceutical formulation of 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide (losmapimod) suitable for oral administration
A representative formulation for use in this invention is provided in the table below.
Example 2
A safety and efficacy study relating to losmapimod in the treatment of frequently exacerbating COPD patients
The utility of losmapimod in the treatment of frequently exacerbating COPD patients can be evaluated in a randomised, double-blind, parallel-group, multi-centre study evaluating the effects on patients receiving 15 milligram (mg) twice daily (bid) of losmapimod versus placebo, in addition to their standard of care (SoC).
Approximately 200 participants in a 1 :1 ratio between patients receiving losmapimod and patients receiving placebo will be randomized to the study.
Patients will undergo a blood eosinophil count screening at initial visit and only those who have been determined to have < 2% of blood eosinophils will be considered suitable for inclusion in this study.
The primary objective of this study is to explore the therapeutic potential of losmapimod as a treatment to reduce the rate of exacerbations in the subset of participants with moderate-to-severe COPD who are at high risk of exacerbation i.e. having experienced two or more moderate/severe exacerbations in the preceding 12 months. A moderate COPD exacerbation is one which requires new prescription for treatment with antibiotics and/or systemic corticosteroids. A severe COPD exacerbation requires hospitalisation or leads to death.
As secondary objectives safety, effects on lung function, quality of life, pharmacokinetic (PK), biomarkers of both disease and inflammation shall be evaluated.
The duration of the treatment period is variable but will be at least 26 weeks and up to a maximum of 52 weeks.
Claims
1. A method for treating COPD patients at risk of exacerbations which comprises:
a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
b) determining if the COPD patient is a responder; and
c) administering a therapeutically effective amount of 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof to said COPD patient identified as a responder.
2. A method for reducing the incidences and/or severity of exacerbations of COPD in a patient which comprises:
a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
b) determining if the COPD patient is a responder; and
c) administering a therapeutically effective amount of 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof to said COPD patient identified as a responder.
3. The compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in the treatment of COPD patients at risk of exacerbations using a method which comprises:
a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
b) determining if the COPD patient is a responder; and
c) administering a therapeutically effective amount of the 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof to said COPD patient identified as a responder.
4. The compound 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2- dimethylpropyl)-nicotinamide or a pharmaceutically acceptable salt thereof for use in
reducing the incidences and/or severity of exacerbations of COPD in a patient which comprises:
a) measuring the blood eosinophil count of a blood sample taken from a COPD patient;
b) determining if the COPD patient is a responder; and
c) administering a therapeutically effective amount of the 6-(5- cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)-N-(2,2-dimethylpropyl)- nicotinamide or a pharmaceutically acceptable salt thereof to said COPD patient identified as a responder.
5. A method according to claim 1 or 2 or a compound for use according to claims 3 and 4 wherein a COPD patient is identified as being a responder when the measured blood eospinophil count is < 3% such as < 2.5%, < 2.0%, < 1 .5% or < 1.0%.
6. The method according to any of claims 1 , 2 or 5 or a compound for use according to claims 3, 4 or 5 in which 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl- phenyl)-N-(2,2-dimethylpropyl)-nicotinamide (losmapimod) is provided in a pharmaceutical composition adapted for oral administration.
7. The method according to claims 1 , 2, 5 or 6 or a compound for use according to claims 3, 4, 5 or 6 in which 6-(5-cyclopropylcarbamoyl-3-fluoro-2-methyl-phenyl)- N-(2,2-dimethylpropyl)-nicotinamide is dosed at 15mg bid.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462072797P | 2014-10-30 | 2014-10-30 | |
| US62/072,797 | 2014-10-30 |
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| WO2016066687A1 true WO2016066687A1 (en) | 2016-05-06 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
| US11291659B2 (en) | 2017-10-05 | 2022-04-05 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
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2015
- 2015-10-28 WO PCT/EP2015/074983 patent/WO2016066687A1/en active Application Filing
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| US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
| US10537560B2 (en) | 2017-10-05 | 2020-01-21 | Fulcrum Therapeutics. Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
| US11291659B2 (en) | 2017-10-05 | 2022-04-05 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
| US11479770B2 (en) | 2017-10-05 | 2022-10-25 | Fulcrum Therapeutics, Inc. | Use of p38 inhibitors to reduce expression of DUX4 |
| EP4159212A1 (en) * | 2017-10-05 | 2023-04-05 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd |
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