Methods for reducing pulmonary exacerbations in patients with respiratory disease

Abstract

To provide methods of reducing pulmonary exacerbations and methods of treating cystic fibrosis, including methods of reducing pulmonary inflammation, comprising administration of an LTA4h inhibitor.SOLUTION: The present invention provides a method of treating cystic fibrosis in a patient in need thereof and / or reducing pulmonary exacerbations in a cystic fibrosis patient, wherein the patient has a FEV1pp greater than or equal to about 65% at baseline, the method comprising orally administering to the patient acebilustat at a total daily dose of about 100 mg or less.SELECTED DRAWING: None

Description

[Background technology]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 678,964, filed May 31, 2018, and U.S. Provisional Application No. 62 / 702,038, filed July 23, 2018, the entire contents of which are incorporated herein by reference.

[0002] Cystic fibrosis (CF) lung pathology is characterized by high levels of inflammation that lead to pulmonary exacerbations, reduced lung function, and associated morbidity and mortality. Inflammatory lung injury is evident early in life, and increased neutrophil elastase in bronchoalveolar lavage fluid is clearly associated with risk of developing structural lung damage (including bronchiectasis) in the first 3 months of life in children with CF [Sly et al., 2013]. Inflammation-induced injury can occur in the absence of detectable infection [Tirouvanziam et al., 2002; Verhaeghe et al., 2007]. Inflammation also persists despite high standards of care and novel therapies such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators [Rowe et al., 2014]. Chronic inflammation in the CF lung is driven by persistent recruitment of immune cells, primarily neutrophils, to the airways [Downey et al., 2009]. Modulation of inflammatory mediators that drive neutrophil influx may provide a viable therapeutic pathway to reduce lung inflammation [Cantin et al., 2015].

[0003] Despite the recognition that treating chronic lung inflammation is an unmet need in CF care, research into anti-inflammatory drugs has yielded mixed results. At high doses, the nonsteroidal anti-inflammatory drug ibuprofen slows the decline of patients' lung function and improves survival in children with CF [Konstan et al., 1995; Konstan et al., 2018, Lands et al., 2007, Lands et al., 2016]. Yet, despite evidence of efficacy, high doses of ibuprofen are rarely used to treat inflammation in CF due to concerns about gastrointestinal and renal toxicity, as well as the need for pharmacokinetic-based dosing [Chmiel et al., 2015; Balfour-Lynn et al., 2007]. A clinical trial of the anti-inflammatory drug BIIL 284 (amelubant), an antagonist of the BLT1 receptor, in patients with stable CF lung disease was terminated early due to an increase in severe respiratory adverse events characterized by increased symptom presentation associated with pulmonary exacerbations [Konstan et al. 2014]. This trial has been described as a "cautionary tale" for administering anti-inflammatory compounds in CF, as it may suppress the inflammatory response and increase the risk of infection [Konstan et al. 2014]. Doring et al. (2014) suggested a mechanism for this increased risk by demonstrating that administration of BIIL 284 to mice (at doses of 0.3-100 mg / kg) significantly downregulated Mac-1 (CR3) and reduced the number of neutrophils in the lungs and airways of mice infected with P. aeruginosa.

[0004] The target of the BLT1 receptor, BIIL 284, is the primary receptor for leukotriene B4 (LTB4). LTB4 is an immune cell chemoattractant and activator implicated in the initiation of cytokine and chemokine cascades that amplify and perpetuate inflammation via neutrophil swarming behavior [Lammerman et al., 2013; Afonso, et al., 2012; Sadik and Luster, 2012]. LTB4 is generated from leukotriene A4 (LTA4) by the enzyme leukotriene A4 hydrolase (LTA4-h). LTA4-h is a monomeric, soluble, 69 kD zinc metalloenzyme that catalyzes two reactions: a stereospecific epoxide hydrolase reaction that converts LTA4 to leukotriene B4 (LTB4), and an aminopeptidase cleavage of small peptide substrates. Inhibition of LTA4-h may reduce the production of LTB4 and decrease neutrophil influx and release of neutrophil-derived enzymes such as neutrophil elastase (Figure 1) [Woolhouse et al., 2002; Tirouvanziam 2006].

[0005] LTA4-h inhibitors are described, for example, in U.S. Patent Nos. 7,737,145, 9,820,974, and U.S. Patent Publication No. 20100210630A1, the contents of each of which are incorporated herein by reference. A particular LTA4-h inhibitor described in these patent publications is 4-{[(1S,4S)-5-({4-[4-oxazol-2-yl-phenoxy]phenyl}methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl}benzoic acid (also referred to herein as CTX-4430, whose international nonproprietary name is acebilustat). Acebilustat is an oral therapy that regulates LTB4 production and targets the inflammatory process in CF [Elborn et al., 2017a]. In two phase I trials, acevirstat reduced LTB4 production and other inflammatory markers in healthy volunteers and CF patients [Elborn et al., 2017a, Elborn et al., 2017b].

[0006] There remains a need in the art for safe and effective anti-inflammatory treatments for cystic fibrosis.Therefore, it would be advantageous to develop additional methods to reduce lung inflammation in cystic fibrosis patients, and / or prevent or reduce loss of lung function, and / or reduce pulmonary exacerbations in CF patients.In addition, given that there is no clear precedent for successfully developing anti-inflammatory treatments for cystic fibrosis, it is also important to identify the appropriate treatment population and / or clinical outcomes. Summary of the Invention [Means for solving the problem]

[0007] The present invention relates to methods of treating cystic fibrosis and other respiratory diseases, including methods of reducing pulmonary exacerbations, including reducing the risk of pulmonary exacerbations and / or reducing the rate (such as annualized rate or annualized rate), number or frequency of pulmonary exacerbations, increasing the time to first pulmonary exacerbation, and / or reducing pulmonary exacerbations such that the patient does not experience any pulmonary exacerbations for at least one year (after starting treatment with acevirstat). In certain embodiments, the methods include orally administering acevirstat to a patient with cystic fibrosis or other respiratory disease at a total daily dose of about 100 mg or less, about 50 mg or less, about 50 mg to about 100 mg, about 100 mg, or about 50 mg. The methods also include methods of reducing pulmonary inflammation in cystic fibrosis patients and methods of treating chronic pulmonary inflammation.

[0008] The primary effect of acebilstat treatment was found to be a reduction in pulmonary exacerbations, including a reduction in the rate (e.g., number or frequency) of pulmonary exacerbations and / or an increase in the time to first pulmonary exacerbation. In addition, acebilstat treatment resulted in an increase in the proportion of patients who were exacerbation-free (did not experience a pulmonary exacerbation) after starting acebilstat treatment over the 48-week study. Acebilstat treatment was found to have the greatest effect in cystic fibrosis patients with a phenotype characterized by mild pulmonary disease (e.g., patients with an FEV1pp of greater than about 65% at the time of starting treatment or at baseline) compared to patients with more severe pulmonary disease. Specifically, anti-inflammatory treatments including acebilstat reduced the rate of pulmonary exacerbations and increased the time to first pulmonary exacerbation in cystic fibrosis patients with mild pulmonary disease phenotypes compared to patients treated with placebo or patients with moderate or severe pulmonary disease. This effect was observed regardless of whether the patients were receiving concomitant treatment with a CFTR modulator therapy. Notably, the greatest benefit of acevirstat treatment was observed in patients with a mild lung disease phenotype and receiving CFTR modulator therapy, although benefit was also observed in patients with mild disease not receiving CFTR modulator therapy. Furthermore, the benefit of acevirstat treatment observed in patients receiving concomitant CFTR modulator therapy was observed regardless of lung disease phenotype, with a greater effect on pulmonary exacerbations in this population with a wide range of lung disease severity than in patients not receiving CFTR modulator therapy.

[0009] Thus, in certain embodiments, the present invention relates to a method of reducing pulmonary exacerbations, including reducing the rate (e.g., number or frequency) of pulmonary exacerbations or increasing the time to first pulmonary exacerbation, in a patient in need thereof, comprising orally administering acevirstat to the patient at a total daily dose of about 100 mg or less. The patient in need of treatment may be a patient suffering from a respiratory disease characterized by the occurrence of pulmonary exacerbations. Such respiratory conditions include, for example, cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, and interstitial lung disease. In certain embodiments, the present invention relates to a method of reducing pulmonary exacerbations, including reducing the number or frequency of pulmonary exacerbations or increasing the time to first pulmonary exacerbation, in a cystic fibrosis patient, comprising orally administering acevirstat to the patient at a total daily dose of about 100 mg or less. In certain embodiments, the patient, such as a cystic fibrosis patient, does not experience any pulmonary exacerbations for at least one year after starting oral administration of acevirstat. Acevirstat can also be administered to patients, such as cystic fibrosis patients, at a total daily dose of, for example, about 50 mg or less, or about 100 mg, or about 50 mg, about 50 mg to about 100 mg. In yet further embodiments, the total daily dose of acevirstat is 100 mg. In certain embodiments, the patient, such as a cystic fibrosis patient, has a mild pulmonary disease phenotype, for example, the patient has an FEV1pp of greater than about 65% at baseline, greater than about 68% at baseline, greater than about 70% at baseline (CF Community Standard definition of "mild" CF disease), or greater than about 75% at baseline. In still further embodiments, the patient, such as a cystic fibrosis patient, has an FEV1pp of greater than about 65% at baseline, greater than about 68% at baseline, greater than about 70% at baseline, or greater than about 75% at baseline. In certain embodiments, the method includes measuring the patient's FEV1pp, e.g., by spirometry (at baseline or prior to initiation of treatment), and administering acevirstat to the patient (at a total daily dose of about 100 mg or less, as described herein) if the patient has an FEV1pp of about 65% or greater, about 68% or greater, or about 70% or greater, or about 75% or greater.In further embodiments, the patient does not experience a pulmonary exacerbation for at least 48 weeks after initiating treatment with acevirstat. In some embodiments, the patient is a cystic fibrosis patient receiving concomitant treatment with a CFTR modulator, such as a CFTR corrector and / or a CFTR enhancer. In further aspects, the patient is not receiving concomitant treatment with a CFTR modulator, e.g., the patient is not receiving concomitant treatment with a CFTR corrector and / or a CFTR enhancer.

[0010] The invention also includes a method of treating cystic fibrosis in a patient in need of treatment thereof and / or a method of reducing pulmonary exacerbations and / or a method of reducing pulmonary inflammation in a cystic fibrosis patient, wherein the patient is, for example, a patient with a mild pulmonary disease phenotype having an FEV1pp of greater than about 65% at baseline, and the method includes orally administering acevirstat to the patient at a total daily dose of about 100 mg or less. A patient with a mild pulmonary disease phenotype may, for example, have an FEV1pp of greater than about 68%, greater than about 70%, or greater than about 75% at baseline. In yet additional embodiments, the patient may, for example, have an FEV1pp of greater than about 65%, greater than about 68%, greater than about 70%, or greater than about 75% at baseline. In additional embodiments, acevirstat is administered to the patient at a total daily dose of less than about 50 mg, between about 50 mg and about 100 mg, about 100 mg, or about 50 mg. In certain aspects, the total daily dose of acevirstat is 100mg. In some embodiments, the cystic fibrosis patient with mild pulmonary disease phenotype is receiving concomitant treatment with a CFTR modulator, such as a CFTR corrector and / or a CFTR enhancer. In a further aspect, the patient is not receiving concomitant treatment with a CFTR modulator, e.g., the patient is not receiving concomitant treatment with a CFTR modulator, such as a CFTR corrector and / or a CFTR enhancer. In yet a further aspect, the patient experiences a reduction in the number or frequency of pulmonary exacerbations in 12 months after starting treatment with acevirstat. In a further aspect, the patient does not experience pulmonary exacerbations for at least 48 weeks, e.g., at least 1 year, after starting treatment with acevirstat. In certain embodiments, the method includes measuring the patient's FEV1pp, e.g., by spirometry (at baseline or prior to initiation of treatment), and administering acevirstat to the patient (at a total daily dose of about 100 mg or less, as described herein) if the patient has an FEV1pp of about 65% or greater, about 68% or greater, or about 70% or greater, or about 75% or greater.

[0011] The invention further includes a method of treating cystic fibrosis in a patient in need of such treatment, comprising orally administering to the patient acevirstat at a total daily dose of about 100 mg or less, about 50 mg or less, about 100 mg, about 50 mg, or about 50 mg to about 100 mg, whereby the patient's lung inflammation is reduced but the risk of lung infection is not increased. In certain aspects, the total daily dose of acevirstat administered to the cystic fibrosis patient is 100 mg. In some embodiments, the patient has a mild pulmonary disease phenotype, e.g., FEV1pp greater than about 65% at baseline, FEV1pp greater than about 68% at baseline, FEV1pp greater than about 70%, or greater than about 75% at baseline. In still further aspects, the patient may have, e.g., FEV1pp greater than about 68% at baseline, greater than about 70% at baseline, or greater than about 75% at baseline. In certain embodiments, the method includes measuring the patient's FEV1pp (at baseline or before starting treatment), for example by spirometry, and administering acevirstat to the patient (at a total daily dose of about 100 mg or less, as described herein) when the patient has an FEV1pp of about 65% or more, about 68% or more, or about 70% or more, or about 75% or more. In certain embodiments, the cystic fibrosis patient is receiving concomitant treatment with a CFTR modulator, such as a CFTR corrector and / or a CFTR enhancer. In further embodiments, the patient is not receiving concomitant treatment with a CFTR modulator, e.g., the patient is not receiving concomitant treatment with a CFTR corrector and / or a CFTR enhancer. In yet further embodiments, the patient experiences a reduction in pulmonary exacerbation rate for 12 months after starting treatment with acevirstat. In further embodiments, the patient does not experience a pulmonary exacerbation for at least 48 weeks, e.g., at least one year, after starting treatment with acevirstat.

[0012] The present invention further includes a method of reducing pulmonary exacerbations, including reducing the rate (e.g., number or frequency) of pulmonary exacerbations or increasing the time to first pulmonary exacerbation in a cystic fibrosis patient, comprising orally administering acevirstat to the patient at a total daily dose of about 100 mg or less, wherein the patient is a cystic fibrosis patient receiving concomitant treatment with a CFTR modulator, such as a CFTR corrector and / or a CFTR enhancer. In certain embodiments, the patient does not experience any pulmonary exacerbation for at least one year after initiating oral administration with acevirstat. Acevirstat can be administered, for example, at a total daily dose of about 50 mg or less, or about 100 mg, or about 50 mg, about 50 mg to about 100 mg. [Brief description of the drawings]

[0013] [Figure 1] Figure 1 shows the mode of action of acevirstat (CTX-4430). In many inflammatory diseases, the neutrophil signaling pathway governed by the potent inflammatory mediator leukotriene B4 (LTB4) and the recovery mediator lipoxin A4 (LXA4) becomes unbalanced, resulting in neutrophil hyperactivation accompanied by persistent inflammation and tissue damage. Acevirstat modulates this pathway, thereby regulating the response of overactive neutrophils. [Diagram 2] Figure 2 is a flow chart illustrating the Phase IIb study design. Randomization was stratified by baseline FEV1 percent predicted (50-75% and >75%), number of pulmonary exacerbations in the 12 months prior to screening (1 or >1), and use of CFTR modulating therapies such as ivacaftor or lumacaftor and ivacaftor (yes / no). [Diagram 3] Figures 3A and 3B are bar graphs showing adjusted means (95% confidence intervals) of annualized rates of pulmonary exacerbations (PEx) for patients receiving 100 mg, 50 mg acevirstat, combination therapy, or placebo (left to right) for the full analysis set (FAP) (Figure 3A) and per-protocol (PP) population (Figure 3B) for all pulmonary phenotypes. [Figure 4]Figures 4A and 4B are Kaplan-Meier plots showing the proportion of patients remaining exacerbation-free as a function of time (proportion of 364) for patients receiving acevirstat 100 mg, 50 mg, combination therapy, or placebo in the full analysis set (FAP) (Figure 4A) and in the per-protocol (PP) (Figure 4B) for all pulmonary phenotypes studied. [Diagram 5] Figures 5A and 5B are bar graphs showing the percentage of acevirstat- or placebo-treated patients who were progression-free over 48 weeks for all pulmonary phenotypes in the full analysis set (FAP) (Figure 5A) and per protocol (PP) (Figure 5B). [Figure 6] Figures 6A and 6B are bar graphs showing the percentage of patients treated with 100 mg acevirstat, 50 mg acevirstat, or placebo who were progression-free over 48 weeks for all pulmonary disease phenotypes in the full analysis set (FAP) (Figure 6A) and in the per-protocol (PP) (Figure 6B). [Figure 7] Figures 7A and 7B are bar graphs showing adjusted means (95% confidence intervals) of annualized rates of pulmonary exacerbations (PEx) in patients treated with 100 mg, 50 mg acevirstat, or placebo (left to right) for patients with a mild pulmonary disease phenotype characterized by a pooled median FEV1pp >68% at baseline (Figure 7B), and for patients with a more severe pulmonary disease phenotype with a pooled median FEV1pp ≤68% (Figure 7A). [Figure 8] Figures 8A and 8B are bar graphs showing adjusted means (95% confidence intervals) of annualized rates of pulmonary exacerbations (PEx) in patients treated with 100 mg, 50 mg acevirstat, combination, or placebo (left to right) for patients with an FEV1pp >75% at baseline for the full analysis set (Figure 8A) and the per-protocol population (Figure 8B). [Figure 9]Figures 9A and 9B are bar graphs showing adjusted means (95% confidence intervals) of annualized rates of pulmonary exacerbations (PEx) in patients treated with 100 mg, 50 mg acevirstat, or placebo (left to right) for patients with FEV1pp >75% (Figure 9A) and patients with FEV1pp ≤75% at baseline (Figure 9B) for the full analysis set (FAP). [Figure 10] 10A and 10B are Kaplan-Meier plots showing the proportion of patients who remained progression-free (as a proportion of 364) as a function of time for patients with FEV1pp>75% at baseline who received 100 mg, 50 mg acevirstat, combination treatment, or placebo for the full analysis set (FAP) (FIG. 10A) and for the per-protocol (PP) (FIG. 10B). [Figure 11] FIG. 11 is a bar graph showing the percentage of patients with an FEV1pp>75% at baseline treated with acevirstat or placebo who were progression-free over 48 weeks for the full analysis set (FAP). [Figure 12] Figures 12A and 12B are bar graphs showing adjusted means (95% confidence intervals) of annualized rates of pulmonary exacerbations (PEx) in patients receiving CFTR modulator therapy receiving 100 mg, 50 mg acevirstat, combination therapy, or placebo (left to right) for the full analysis set (FAP) (Figure 12A) and per protocol (PP) (Figure 12B). [Figure 13] Figures 13A and 13B are Kaplan-Meier plots showing the proportion of patients who remained progression-free as a function of time (as a proportion of 364) for patients receiving CFTR modulator therapy at baseline, receiving 100 mg, 50 mg acevirstat, the combination arm, or placebo, for the full analysis set (FAP) (Figure 13A) and for the per-protocol (PP) (Figure 13B). [Figure 14]FIG. 14 is a forest plot showing the difference in pulmonary exacerbation rates for acevirstat treatment groups (50 mg and 100 mg combination) versus placebo for patients with FEV1pp 50-75% at baseline, patients with FEV1pp 75% or greater at baseline, patients with 1 exacerbation in the year prior to screening, patients with 2 or more exacerbations in the year prior to screening, patients using CFTR modulator therapy, patients not receiving CFTR modulator therapy, patients with 2 or fewer pulmonary exacerbations in the year prior to screening, patients with 2 or more pulmonary exacerbations in the year prior to screening, patients using azithromycin, and patients not treated with azithromycin for the adherence to protocol analysis set. [Figure 15] Figures 15A and 15B are bar graphs showing the effect of acevirstat on adjusted mean annualized rates of pulmonary exacerbations in patients with baseline FEV1pp>70% (the CF Community Standard definition of "mild" CF disease; Figure 15A) compared with patients with baseline FEV1pp>75% (the prespecified definition of "mild" CF used in clinical studies; Figure 15B). [Figure 16] Figures 16A and 16B are bar graphs showing the effect of acevirstat on adjusted mean annualized rate of pulmonary exacerbations in populations receiving concomitant CFTR modulator therapy ("on"; Figure 16A) and not receiving concomitant CFTR modulator therapy ("off"; Figure 16B). [Figure 17] Figures 17A, 17B, and 17C are bar graphs showing the percentage of progression-free patients (treated with acevirstat or placebo) over 48 weeks of treatment in patients with mild CF (Figure 17A) and those "on" or "off" CFTR modulator therapy (Figures 17B and 17C, respectively). [Figure 18]Figures 18A and 18B are bar graphs showing the percentage of progression-free patients treated with 100 mg acevirstat, patients treated with 50 mg acevirstat, and placebo for 48 weeks of treatment for patients with baseline FEV1pp>75% for the full analysis set (FAP) (Figure 18A) and for patients per protocol (PP) (Figure 18B). [Figure 19] Figures 19A and 19B are bar graphs showing the estimated effect of 100 mg acevirstat and CFTR modulator therapy (KALYDECO®, SYMDEKO®, and ORKAMBI®) on percent reduction in pulmonary exacerbation rate (Figure 19A) and percent reduction in pulmonary exacerbation risk (Figure 19B). [Figure 20] FIG. 20 is a bar graph showing the effect of acevirstat (50 and 100 mg) on ​​the adjusted mean annualized rate of pulmonary exacerbations requiring hospitalization in patients with a baseline FEV1pp>75% for the full analysis set (FAP). [Figure 21] FIG. 21 is a bar graph showing the effect of acevirstat (50 and 100 mg) on ​​adjusted mean annualized rate of pulmonary exacerbations requiring intravenous (IV) antibiotics in patients with baseline FEV1pp>75% for the full analysis set (FAP). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] A description of a preferred embodiment of the present invention follows.

[0015] As used herein, the terms "a" and "an" mean one or more, unless otherwise specified. For example, the term "additional therapeutic agent" encompasses both a single additional therapeutic agent and a combination of two or more additional therapeutic agents.

[0016] When a range of doses or amounts of a drug or active ingredient (e.g., acevirstat, and / or a CFTR modulator, such as a CFTR potentiator and / or a CFTR corrector, and / or an additional therapeutic agent) is described as "between" the lower limit of the range and "between" the upper limit of the range, the range is understood to mean to include both the lower limit and the upper limit as well as the dose between the lower limit and the upper limit. For example, in the case of a "dose between about 50 mg and about 100 mg," the range is understood to include the lower limit of the range, about 50 mg, and the upper limit of the range, about 100 mg, as well as doses in between, e.g., about 75 mg. In addition, a "dose of about 50 mg or less" is intended to include a dose of less than about 50 mg as well as a dose of about 50 mg.

[0017] As used herein, the term "about" with respect to a numerical value or range allows for a degree of variability of the value or range, for example, within 10%, within 5%, or within 4%, or within 2% of the value or range.

[0018] The method of the present invention involves administering to a human patient an effective oral dose of 4-{[(1S,4S)-5-({4-[4-oxazol-2-yl-phenoxy]phenyl}methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl}benzoic acid (CTX-4430; acevirstat). This compound and its method of preparation are described in detail in U.S. Patent Nos. 7,737,145, 9,820,974, and U.S. Patent Publication No. 20100210630A1, the contents of each of which are incorporated herein by reference. The chemical structure of acevirstat is: [ka]

[0019] The invention encompasses a method of treating pulmonary inflammation and / or reducing chronic pulmonary inflammation and / or reducing pulmonary inflammation and / or reducing pulmonary exacerbations in a cystic fibrosis patient in need thereof, as well as a method of reducing pulmonary exacerbations in a patient in need thereof, comprising oral administration, e.g., chronic oral administration (e.g., over an extended period of time and / or throughout treatment of the patient), of about 100 mg of acebilstat to the patient. The invention also encompasses a method of treating pulmonary inflammation and / or reducing chronic pulmonary inflammation and / or reducing pulmonary exacerbations in a cystic fibrosis patient in need thereof, as well as a method of reducing pulmonary exacerbations in a patient in need thereof, comprising chronic oral administration, e.g., chronic oral administration (e.g., over an extended period of time and / or throughout treatment of the patient), of about 50 mg of acebilstat to the patient. Acebilstat may be administered, for example, at a dose of about 50 mg every 12 hours or every 24 hours (i.e., once or twice a day), or at a dose of about 100 mg every 24 hours (i.e., once a day). The present invention additionally encompasses methods of treating pulmonary inflammation and / or reducing chronic pulmonary inflammation and / or reducing pulmonary inflammation and / or reducing pulmonary exacerbations in cystic fibrosis patients, as well as methods of reducing pulmonary exacerbations in patients in need thereof, including chronic oral administration, e.g., chronic oral administration (e.g., over an extended period of time and / or throughout treatment of the patient), of about 100 mg or less, or 50 mg or less, of acebilstat to the patient. The total daily dose of acebilstat may be at a dose of 50 mg or less, e.g., about 25 mg, about 15 mg, about 10 mg, or about 5 mg. The total daily dose of acebilstat may also be about 50 mg to about 100 mg, e.g., about 75 mg. In certain embodiments, the dose of acevirstat is about 25 mg administered twice daily or about 25-50 mg administered twice daily. Acevirstat can be administered with or without food.

[0020] The primary effect of acebilstat treatment is a reduction in pulmonary exacerbations or a reduction in the rate of pulmonary exacerbations, including a higher proportion of patients who are exacerbation-free (i.e., no pulmonary exacerbations) after starting acebilstat treatment (compared to placebo). In certain embodiments, the rate or frequency of pulmonary exacerbations is reduced compared to that before starting acebilstat treatment. Pulmonary exacerbations, a clinical marker of lung inflammation, are serious events that lead to acute decompensation and chronic decline in lung function, and are strongly associated with reduced survival. The rate of pulmonary exacerbations is reduced when the number of pulmonary exacerbations in a given period (e.g., 48 weeks or more or one year or more) is less than the number of pulmonary exacerbations in the same period before starting treatment and / or compared to without acebilstat (e.g., as may be expected from placebo-treated or untreated groups, and / or previous medical history). The rate of pulmonary exacerbations can be, for example, the annualized rate of pulmonary exacerbations or the annualized rate of pulmonary exacerbations. A reduction in the rate, proportion or frequency of pulmonary exacerbations includes, for example, a reduction of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, and at least about 95%. In certain embodiments, the rate, number or frequency of pulmonary exacerbations is reduced by at least about 15%, or at least about 20%, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%. Administration of acevirstat concomitantly with a CFTR modulator can reduce the rate, number, or frequency of pulmonary exacerbations by at least about 15%, or at least about 20%, or at least about 25%, compared to the CFTR modulator without acevirstat.As described herein, when acevirstat is administered concomitantly with a CFTR modulator to a patient with a mild pulmonary disease phenotype, the rate, number, or frequency of pulmonary exacerbations can be reduced by, for example, at least about 15%, at least about 20%, at least about 25%, at least about 35%, at least about 40%, or at least about 50% compared to using a CFTR modulator without acevirstat.

[0021] The present invention encompasses methods of reducing pulmonary exacerbations, including reducing the number or frequency of pulmonary exacerbations in a patient in need thereof. A patient in need of such treatment may, for example, be a patient suffering from a respiratory disease characterized by the occurrence of pulmonary exacerbations. Respiratory diseases include diseases associated with pathology of the upper airways, bronchi, bronchioles, alveoli, pleura, and / or pleural space. Non-limiting examples of respiratory diseases characterized by pulmonary exacerbations include cystic fibrosis, chronic obstructive pulmonary disease (COPD), bronchiectasis, and interstitial lung disease. In certain specific embodiments, the patient suffers from cystic fibrosis. In certain other embodiments, the patient suffers from bronchiectasis, including but not limited to forms of non-cystic fibrosis bronchiectasis, such as primary ciliary dyskinesia or idiopathic bronchiectasis. In yet further aspects, the patient suffers from COPD. In further aspects, the patient suffers from interstitial lung disease.

[0022] In the Phase IIb study described herein, acevirstat treatment was shown to reduce pulmonary exacerbations in cystic fibrosis patients with a mild pulmonary disease phenotype (e.g., having an FEV1pp greater than about 65% at baseline) compared to a corresponding population receiving placebo and compared to that of acevirstat-treated patients with more severe pulmonary disease. Patients with a "mild pulmonary disease phenotype" can also be described as a subpopulation of CF patients with mild pulmonary disease. The terms "mild pulmonary disease phenotype," "mild CF disease," "mild CF," and "mild disease" in relation to CF patients are used interchangeably herein. The terms "FEV1pp" and "ppFEV1," used interchangeably, refer to percent forced expiratory volume in 1 second predicted and can be measured using spirometry. The severity of pulmonary disease in cystic fibrosis patients is conventionally classified according to the FEV1pp value. For example, in the literature, mild lung disease is classified as FEV1pp ≥ 70%, moderate lung disease as FEV1pp 40-69%, and severe lung disease as FEV1pp < 40% (Cystic Fibrosis Patient Registry. 2016. Cystic Fibrosis Foundation. Available upon request from https: / / www.cff.org / Research / Researcher-Resources / Tools-and-Resources / Patient-Registry-Data-Requests / ; Davies et al, (2009), Respiratory Care 54(5):606-617). Additionally, the severity of lung disease has been classified in the literature as follows: mild disease is classified as FEV1 ≥ 70% predicted; moderate disease is classified as FEV1 60-69% predicted; moderate to severe lung disease is classified as FEV1 50-59% predicted; severe lung disease is classified as FEV1 35-49% predicted; and very severe lung disease is classified as FEV1 < 35% predicted. (Morrow et al. (2008), Jornal de Pediatria 84(5):403-409).In the clinical study described herein, the median FEV1pp of the study population was 68% at baseline, and it was observed that acevirstat-treated patients with FEV1pp greater than the median experienced a decrease in pulmonary exacerbation rate and an increase in time to first pulmonary exacerbation. It was also observed that acevirstat-treated patients with a baseline FEV1pp greater than 65% experienced a decrease in pulmonary exacerbation rate and an increase in time to first pulmonary exacerbation (see Table 1 below).

[0023] As used herein, a CF patient with a mild pulmonary disease phenotype has a baseline FEV1pp of about 65% or more. A patient with a mild pulmonary disease phenotype may have, for example, a baseline FEV1pp of about 68% or more, a baseline FEV1pp of about 70% or more, or a baseline FEV1pp of about 75% or more. Thus, in certain embodiments, the method includes treating a patient with an FEV1pp of about 65% or more at baseline with acevirstat at a dose of about 100 mg or less or about 50 mg or less, for example, a daily dose of about 100 mg or a daily dose of about 50 mg. In certain embodiments, the patient has a baseline FEV1pp of about 68% or more, about 70% or more, or about 75% or more at baseline. In certain additional embodiments, the patient may have an FEV1pp of more than about 70% or more than about 75% at baseline. The method of the invention may also include measuring the patient's baseline FEV1pp (at baseline or before treatment is started), for example by spirometry, and administering acebilstat to the patient when the patient has an FEV1pp of about 65% or more, or about 68% or more, or about 70% or more, or about 75% or more. Baseline FEV1pp is FEV1pp measured before treatment, for example, before or just before the first dose of acebilstat, or in other words, before the start of acebilstat treatment, or is FEV1pp when or at the start of treatment.

[0024] Acevirstat can be administered to patients, such as cystic fibrosis patients (regardless of disease phenotype), in addition to their current treatment regimen or in addition to standard of care. Standard of care for treating cystic fibrosis patients includes, but is not limited to, mucolytics, antibiotics, and CFTR modulators, or combinations thereof. Standard of care for treating chronic obstructive pulmonary disease (COPD) includes, but is not limited to, bronchodilators, beta agonists, anticholinergics, glucocorticoids, or combinations thereof. Standard of care for treating interstitial lung disease includes, but is not limited to, glucocorticoids, cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil, or combinations thereof. Standard of care for treating bronchiectasis includes, but is not limited to, bronchiectasis, steroids, and antibiotics such as penicillin antibiotics, and inhaled antibiotics including tobramycin and aztreonam, and any combinations thereof. The additional therapeutic agent(s) that may comprise a patient's treatment regimen are described in more detail below. Acevirstat can be administered simultaneously to a cystic fibrosis patient with additional therapeutic agents, including, for example, a CFTR modulator and / or a CFTR amplifier. As used herein, the term "CFTR modulator" includes an agent or compound that modulates (e.g., increases) the activity of CFTR, and in certain specific embodiments, a CFTR modulator increases the activity of the CFTR protein. The increased activity resulting from a CFTR modulator includes, but is not limited to, a compound that modulates, enhances, stabilizes, and / or amplifies CFTR. Thus, as used herein, the term "CFTR modulator" includes CFTR correctors, CFTR enhancers, CFTR stabilizers, and CFTR amplifiers. A CFTR corrector is an agent or compound that increases the amount of functional CFTR protein on the cell surface, enhancing ion transport. A CFTR enhancer is an agent or compound that enhances the channel activity of the CFTR protein on the cell surface, thereby promoting ion transport. A CFTR stabilizer prolongs the presence of CFTR in the epithelial cell membrane.CFTR amplifiers are agents that enhance the effects of CFTR enhancers, correctors, and / or stabilizers. Given the number of cystic fibrosis patients currently being treated with CFTR modulators, and the likely increase in the number of cystic fibrosis patients eligible to be treated with new CFTR modulators in the coming years, it is important that acevirstat provides benefit when used in combination with a CFTR modulator.

[0025] Concomitant treatment or administration of acebilstat and a CFTR modulator, including but not limited to a CFTR enhancer and / or a CFTR corrector, or any other additional therapeutic agent, is intended to mean administration of acebilstat and the additional therapeutic agent at such times that would have a therapeutic effect and / or simultaneous administration of the agents, for example, as part of the same treatment regimen. Such simultaneous administration may include administration at the same time (i.e., at the same time), prior to, or subsequent to administration of acebilstat with respect to the administration of the additional therapeutic agent. For example, the initiation of acebilstat treatment may occur after the initiation of treatment with a CFTR modulator, such as a CFTR corrector and / or a CFTR enhancer, for example, a patient may have been undergoing treatment with a CFTR modulator for weeks, months, or years before initiating treatment with acebilstat. It is understood that when acebilstat is co-administered with at least one additional therapeutic agent (e.g., a CFTR enhancer and / or a CFTR corrector and / or another therapeutic agent), the compound may be administered at the same time, prior to, or subsequent to administration of one or more other therapeutic agents. Such combination therapy includes administration of a single pharmaceutical dosage form containing acevirstat and one or more additional active agents, as well as administration of acevirstat and each active agent in its own separate pharmaceutical dosage form. For example, acevirstat and other therapeutic agents can be administered to a patient together in a single oral dosage composition, such as a tablet or capsule, or each agent can be administered in a separate oral dosage formulation. When separate dosage formulations are used, acevirstat and one or more additional active agents can be administered essentially at the same time, i.e., simultaneously, or at different staggered times, i.e., consecutively, and / or during the same treatment session, and / or as part of the same treatment regimen; and / or in a daily administration of acevirstat and a daily administration of one or more additional active agents. It is understood that combination therapy and combined administration include all of these regimens.

[0026] As described in more detail below, the Phase IIb study was designed to provide the first proof of concept of an anti-inflammatory therapy (acevirstat) designed to prevent or reduce progressive loss of lung function by reducing pulmonary exacerbations in patients with cystic fibrosis (CF). The primary analysis was based on analysis of variance (ANOVA), comparing the mean change from baseline in FEV1pp at week 48 for the two acevirstat doses with the mean for the placebo group. The ANOVA model included separate terms for each dose group and the mean of the two acevirstat doses created by averaging the parameter estimates from the ANOVA model. In addition to the treatment group terms, the ANOVA included stratification of factors used for randomization. For example, stratified factors included baseline lung function, frequency of pulmonary exacerbations in the previous year, and concomitant use of CFTR modulators. Analysis of differences in pulmonary exacerbations may include contrast analysis using confidence intervals, simple mean t-tests, Poisson regression, and most preferably negative binomial regression.

[0027] Furthermore, a specific subset of the general cystic fibrosis (CF) population was deemed to be at high risk for rapid lung function decline, and this subset would provide a study population that is subject to active inflammation and experiences declines large enough to detect clinical benefit over a 48-week interval. Such a subset was identified through studies of the Cystic Fibrosis Patient Registry (CFPR) and based on knowledge of the expected rate of decline in FEV1pp, and the frequency of pulmonary exacerbations in this subpopulation. For example, a previous pulmonary exacerbation is one of the strongest predictors of a future pulmonary exacerbation [Block et al., 2006; VanDevanter et al., 2016]. Moreover, it has been speculated that up to half of lung function declines are associated with pulmonary exacerbations, [Waters et al., 2012], and exacerbations are clear indicators of inflammation driven by active neutrophils (see, for example, Ngan et al. (2012), BMC Pulmonary Medicine 12:3; Wojewodka et al. (2014), PLOS One 9(2), e88567). Susceptibility to annual declines in lung function is greatest during adolescence and early adulthood and weakens once patients reach approximately 30 years of age [Liou et al., 2010]. In addition, patients with higher baseline lung function may be more susceptible to larger declines in FEV1pp [Konstan et al., 2012]. Furthermore, CF patients aged 15–30 years are more likely to experience pulmonary exacerbations [CFF Registry Report, 2017].

[0028] Based on these published observations, data from the CFPR [Cystic Fibrosis Foundation, 2014] were analyzed for various age ranges (12–17 years, 18–30 years, 31–35 years, or 36–39 years); baseline FEV1pp (50–59%, 60–79%, 80–99%, or ≥100%), and number of pulmonary exacerbations requiring IV antibiotic use in the previous year (0 or ≥1). The registry data supported the notion that patients aged 12–30 years who had at least one pulmonary exacerbation in the previous year are at highest risk for rapid lung function decline. Within this subgroup, the registry data provided further evidence that patients with a higher FEV1pp at baseline are likely to experience the most rapid decline in FEV1pp. Within the subgroup of CF patients aged 18–30 years who had at least one pulmonary exacerbation in the previous year, the rate of decline in the current year is estimated to be 3.47 percentage points per year. To detect differences in the rate of decline in FEV1pp of around 3 percentage points per year, observation over at least 48 weeks is required. Therefore, the patient population in this study was enriched based on optimal patient age, FEV1pp, and exacerbation history to detect changes in FEV1 decline rate and exacerbation rate over the 48-week period of the Phase II study compared to placebo. This population and study period are consistent with published guidance from the Cystic Fibrosis Foundation (CFF) [Torphy et al., 2015]. Therefore, patients for the Phase IIb study were selected based on strict inclusion criteria (age 18-30 years, FEV1pp ≥ 50, and at least one exacerbation in the past year). This enriched the study population of patients most susceptible to pulmonary exacerbations and annual decline in lung function. This patient population is also likely to achieve greater benefit from acevirstat treatment in terms of reduced lung function decline than other populations.

[0029] As discussed above, patients most likely to benefit from acevirstat treatment, including concomitant treatment with a CFTR enhancer and / or CFTR corrector, are believed to include patients aged 30 years or younger (e.g., from about 12 to about 30 years of age), and / or patients who have had at least one pulmonary exacerbation in the year prior to their first dose of acevirstat, and / or patients with an FEV1pp ≧about 50%, as described in more detail below.

[0030] The results of the study are shown in Figures 3-21 and described in the Examples. The primary effect of acevirstat was found to be a reduction in pulmonary exacerbation (PEx) rate compared to placebo, and a reduction in the risk of progression to a pulmonary exacerbation. These benefits were most pronounced in patients receiving CFTR modulator therapy, alongside patients with milder disease phenotypes (e.g., FEV1pp greater than 75 at baseline). Patients with less severe impairment of pulmonary function or milder pulmonary disease phenotypes (specifically, FEV1pp greater than 75) achieved the greatest benefit from acevirstat therapy in the analysis of data from the combination arms of the 50 mg and 100 mg doses compared to placebo, achieving an approximately 35% reduction in PEx rate versus placebo (48% reduction in risk at the 100 mg dose), an approximately 43% reduction in risk of experiencing a first exacerbation versus placebo (48% reduction in risk at the 100 mg dose), and an approximately 96% higher proportion of patients who were exacerbation-free after 48 weeks of treatment (100% higher at the 100 mg dose). Furthermore, regardless of disease severity phenotype, patients treated with CFTR modulator therapy in combination with acevirstat showed a 20% reduction in clinically meaningful PEx rate (14% reduction at 100 mg dose), a 29% increase in time to first exacerbation (27% increase at 100 mg dose), and a 47% higher proportion of exacerbation-free patients (51% higher at 100 mg dose) compared to patients treated with CFTR modulator and placebo. In addition, a 15% higher proportion of exacerbation-free patients was observed in patients not receiving CFTR modulator therapy. Furthermore, patients with FEV1pp above 75 treated with CFTR modulator therapy in combination showed a 54% reduction in pulmonary exacerbation rate (65% reduction at 100 mg dose) and a 165% higher proportion of exacerbation-free patients at 48 weeks compared to patients treated with placebo instead of acevirstat.

[0031] For the purposes of clinical trials, a pulmonary exacerbation is defined as the requirement for oral, inhaled, or intravenous antibiotics for four or more signs or symptoms according to the modified Fuchs criteria (change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38°C; loss of appetite or weight loss; sinus pain or tenderness; change in sinus drainage; change in physical chest exam; absolute decrease of ≥10% in FEV1pp from previously recorded value; radiographic changes indicating pulmonary infection) [Fuchs et al., 1994], together referred to as the extended Fuchs criteria (antibiotics and four or more signs and symptoms). A pulmonary exacerbation may be defined according to Fuchs criteria, extended Fuchs criteria, or other criteria known in the art (including, for example, the need for additional treatment indicated by recent changes in clinical parameters) and / or according to the physician's judgment or decision [Bilton et al. (2011), Journal of Cystic Fibrosis 10(Suppl 2):S79-S81; Dakin et al. (2001), Pediatr Pulmonol. 31:436-442, the contents of each of which are expressly incorporated herein by reference]. A pulmonary exacerbation typically accompanies subsequent treatment of a CF or other respiratory disease patient with a course of antibiotics. For purposes of clinical trials and the methods described herein, the date that a pulmonary exacerbation began may be defined as the first day of antibiotic use or the date of onset of symptoms.

[0032] In certain embodiments, the method includes identifying cystic fibrosis patients who have had at least one pulmonary exacerbation in the previous year (in other words, in about 12 months or about 52 weeks prior to initiation of treatment) and treating such patients with a total daily oral dose of acevirstat of about 50 mg to about 100 mg, or about 100 mg or less, or about 50 mg or less, or about 100 mg, or about 50 mg. The method can also include identifying cystic fibrosis patients who have had at least one pulmonary exacerbation in the previous year and treating such patients with a total daily oral dose of acevirstat of about 50 mg to about 100 mg, or about 100 mg or less, or about 50 mg or less, or about 100 mg, or about 50 mg. Further, the method may include identifying patients who have had two or more pulmonary exacerbations in the past year, or three or more pulmonary exacerbations, and treating such patients with a total daily oral dose of acevirstat of about 50 mg to about 100 mg, or about 100 mg or less, or about 50 mg or less, or about 100 mg, or about 50 mg. In certain additional embodiments, the method includes identifying cystic fibrosis patients who have had at least one pulmonary exacerbation within the past two years, within the past three years, within the past four years, or within the past five years, and treating such patients with a total daily oral dose of acevirstat of about 50 mg to about 100 mg, or about 100 mg or less, or about 50 mg or less, or about 100 mg, or about 50 mg. The methods include identifying cystic fibrosis patients who have had at least one pulmonary exacerbation, two or more pulmonary exacerbations, or three or more pulmonary exacerbations within the past year, within the past two years, within the past three years, within the past four years, or within the past five years, and treating such patients with a total daily oral dose of acevirstat of about 50 mg to about 100 mg, or up to about 100 mg, or up to about 50 mg, or about 100 mg, or about 50 mg.

[0033] The Phase 2b study will include stratification based on concomitant CFTR modulators. This is important because approximately half of cystic fibrosis patients in the United States are currently treated with CFTR modulators. Stratification based on concomitant CFTR modulators may also be important because neutrophil elastase has been shown to downregulate CFTR [Le Gars et al., 2013], and acevirstat, which has been shown to reduce neutrophil elastase [Elborn et al., 2017], was thought to potentially have synergistic effects with CFTR modulators, including CFTR potentiators and / or CFTR correctors.

[0034] The method includes orally administering acevirstat to a cystic fibrosis patient at a total daily dose of about 100 mg or less, about 50 mg or less, or about 50 mg to about 100 mg, or at a total daily dose of about 100 mg or about 50 mg. As described herein, a patient treated with acevirstat can receive a CFTR modulator combination therapy (regardless of pulmonary disease phenotype) in which a therapeutically effective amount of a CFTR enhancer and / or a CFTR corrector is administered to the patient simultaneously. A preferred CFTR enhancer is ivacaftor (KALYDECO®). Preferred CFTR correctors are lumacaftor and tezacaftor. In certain embodiments, one CFTR enhancer and at least one CFTR corrector are administered. For example, a combination including ivacaftor can be administered, for example, a combination of ivacaftor and lumacaftor, preferably ORKAMBI® (lumacaftor / ivacaftor). The method includes administering at least two CFTR correctors, or at least one CFTR corrector and at least one CFTR enhancer. For example, a combination of ivacaftor and lumacaftor can be administered, preferably ORKAMBI® (lumacaftor / ivacaftor). In another example, two CFTR correctors can be administered, optionally with a CFTR enhancer, and the combination can include, for example, ivacaftor. As described above, acevirstat can be administered, for example, at a dose of about 50 mg every 12 hours or every 24 hours (i.e., once or twice a day), or at a dose of about 100 mg every 24 hours (i.e., once a day). Acevirstat can also be administered in a total daily dose of 50 mg or less, where the acevirstat is administered once or multiple times daily. If the treatment includes administration of ivacaftor, an exemplary oral dose is 150 mg every 12 hours (or twice daily) and / or a total daily dose of about 300 mg. For patients aged 2 to 6 years, an exemplary oral dose of ivacaftor is 50 mg or 75 mg twice daily.When the treatment includes administration of lumacaftor / ivacaftor (e.g., ORKAMBI® combination), the total daily dose of lumacaftor administered is about 800 mg, and the total daily dose of ivacaftor is about 500 mg for patients aged 12 years or older. For patients aged 6-11 years treated with ORKAMBI®, the total daily dose of lumacaftor is 400 mg, and the total daily dose of ivacaftor is about 500 mg. Certain triple combination regimens including ivacaftor, tezacaftor, and another corrector, have also been described for the treatment of cystic fibrosis. Thus, the present invention encompasses administration of acevirstat in combination with a triple combination regimen, as described herein, optionally including ivacaftor. In certain embodiments, the invention relates to methods comprising administering acevirstat and a triple combination regimen, for example, such triple combination can include tezacaftor and ivacaftor, and one of the following: VX-445, VX-659, VX-440, or VX-152. In other embodiments, the triple combination can be comprised of other CFTR modulators. In yet other embodiments, the combination can be comprised of four or more such CFTR modulators.

[0035] Cystic fibrosis is caused by loss-of-function mutation(s) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is a membrane protein and chloride channel. There are over 1,800 mutations discovered in the CFTR gene, which are characterized into five classes. The most frequent mutation is the class II mutation F508del (deletion of phenylalanine at position 508), which causes the CFTR protein to not reach the cell surface due to misfolding. As will be understood, humans either carry the F508del mutation in one allele and another mutation in the other allele (heterozygous) or carry the F508del mutation in both alleles (homozygous). Other mutations include class III mutations such as G551D and S549N, which allow CFTR to reach the cell surface but impair channel function. Patients treated by the described methods can, for example, have an F508del mutation (either heterozygous or homozygous) and / or have a CFTR functional mutation (classes III-VI or III-VI, depending on the classification system used) or have a non-F508del mutation. Exemplary mutations in addition to F508del are E56K, P67L, R74W, D110E, D110H, R117C, R117H, E193K, L206W, R347H, R352Q, A455E, D579G, S945L, S977F, F1052V, K1060T, A1067T, G1069R, R1070Q, R1070W, F1074L, D1152H, D1270N, G551D, G178R, S549R, S549N, G551S, G1244E, S1251N, S1255P, and G1349D. CFTR correctors increase the amount of functional CFTR protein on the cell surface and enhance ion transport. CFTR enhancers are compounds that increase the channel activity of CFTR at the cell surface (e.g., in patients with gating mutations). For example, CFTR corrective agents can target patients with F508del mutations. Methods of treatment can include treating patients with F508del mutations and treating patients who are not F508del.

[0036] In yet further embodiments, the present invention relates to a method of treating cystic fibrosis or reducing pulmonary inflammation or treating chronic pulmonary inflammation and / or reducing pulmonary exacerbations in a cystic fibrosis patient in need thereof, comprising administering to the patient a total daily dose of about 100 mg or less, or about 50 mg or less, or about 50 mg to about 100 mg, or about 100 mg, or about 50 mg of acevirstat, wherein the patient is not receiving concomitant treatment with a CFTR modulator, such as a CFTR corrector and / or a CFTR enhancer and / or a CFTR amplifier. Such patients include, but are not limited to, patients with mild pulmonary disease phenotypes as described herein. In certain aspects, the patient is not receiving concomitant treatment with a CFTR corrector. In further aspects, the patient is not receiving concomitant treatment with a CFTR enhancer. In still further aspects, the patient is not receiving concomitant treatment with either a CFTR corrector or a CFTR enhancer, or a combination thereof. In a further embodiment, the total daily dose of acevirstat administered to a cystic fibrosis patient not treated with a CFTR corrector and / or CFTR enhancer is about 50 mg. In an additional embodiment, the total daily dose of acevirstat administered to a cystic fibrosis patient not treated with a CFTR corrector and / or CFTR enhancer is about 100 mg. In yet an additional embodiment, the total daily dose of acevirstat administered to a cystic fibrosis patient not treated with a CFTR corrector and / or CFTR enhancer is about 50 mg or less. In a further embodiment, the total daily dose of acevirstat administered to a cystic fibrosis patient not treated with a CFTR corrector and / or CFTR enhancer is about 100 mg or less.

[0037] In additional embodiments, the methods include administering acevirstat to a cystic fibrosis patient, wherein the patient is 30 years of age or younger. In further embodiments, the patient is 2 years of age or older, 6 years of age or older, 12 years of age or older, 18 years of age or older, about 6 to 12 years of age, about 12 to about 30 years of age, or about 18 to about 30 years of age. In yet further embodiments, the patient is over 30 years of age. In further embodiments, the patient is 18 years of age or older.

[0038] The invention encompasses methods of reducing pulmonary inflammation and / or reducing a pulmonary exacerbation in a cystic fibrosis patient in need thereof comprising administering to the patient a therapeutically effective amount of acevirstat as described herein, wherein the patient is over 6 years of age, 2 years or older, 6 years or older, 12 years or older, 18 years or older, 30 years or older, about 6 to 12 years of age, about 6 to about 30 years of age, about 12 to about 30 years of age, or about 18 to about 30 years of age, and has experienced at least one pulmonary exacerbation in the year prior to the first administration of acevirstat. The invention further encompasses a method of treating cystic fibrosis, reducing pulmonary inflammation, and / or treating chronic pulmonary inflammation, and / or reducing pulmonary exacerbations in a cystic fibrosis patient in need thereof comprising administering to the patient a therapeutically effective amount of acebilstat as described herein, wherein the patient is 6 years of age or older, 2 years of age or older, 6 years of age or older, 12 years of age or older, 18 years of age or older, 30 years of age or older, about 6 to 12 years of age, about 12 to about 30 years of age, or about 18 to about 30 years of age, and has experienced no more than two pulmonary exacerbations in the year prior to the first administration of acebilstat. In a further aspect, the patient is about 6 years of age or older, 2 years of age or older, 6 years of age or older, 12 years of age or older, 18 years of age or older, 30 years of age or older, about 6 to 12 years of age, about 12 to about 30 years of age, or about 18 to about 30 years of age, and has an FEV1pp of about 65% or greater, about 68% or greater, about 70% or greater, or about 75% or greater.

[0039] The invention also encompasses a method of reducing pulmonary inflammation and / or reducing a pulmonary exacerbation in a cystic fibrosis patient in need thereof comprising administering to the patient a therapeutically effective amount of acebilstat, wherein the patient is 30 years of age or older and has experienced at least one pulmonary exacerbation in the year prior to the first administration of acebilstat. In certain embodiments, the patient is 30 years of age or older and has experienced no more than two pulmonary exacerbations in the year prior to the first administration of acebilstat. In further embodiments, the patient is 30 years of age or older and has an FEV1pp of greater than about 65%, greater than about 68%, greater than about 70%, greater than about 75%, 65% or greater, 68% or greater, about 70% or greater, or about 75% or greater.

[0040] The methods described herein are useful for treating chronic pulmonary inflammation and / or reducing pulmonary inflammation in cystic fibrosis patients. In certain embodiments, chronic pulmonary inflammation is treated and / or reduced when there is a reduction in the number of pulmonary exacerbations and / or an attenuation in the rate of decline in pulmonary function. With respect to the reduction in pulmonary exacerbations in CF or other respiratory disease patients, the reduction in pulmonary exacerbations can also be a reduction in the annualized rate of pulmonary exacerbations. In addition, the number of pulmonary exacerbations experienced by CF or other respiratory disease patients in a period of 6 months, 12 months, 24 months, 36 months, or 48 months after the start of treatment (including acevirstat) can be reduced compared to a period of 6 months, 12 months, 24 months, 36 months, or 48 months before the start of treatment, respectively. For example, if a patient has two pulmonary exacerbations in the 12 months before starting treatment, the reduction in chronic pulmonary inflammation or pulmonary inflammation can be evidenced by a reduction in the number of pulmonary exacerbations in the 12 months after the start of treatment (e.g., only one or no pulmonary exacerbations). In certain embodiments, a CF or other respiratory disease patient is progression-free for 6 months, 12 months, 24 months, 36 months, or 48 months after initiating treatment (including acevirstat). In certain specific embodiments, a CF patient is progression-free for 6 months, 12 months, 24 months, 36 months, or 48 months after initiating treatment (including acevirstat).

[0041] Additionally, if the rate of decline in lung function is attenuated after initiation of treatment (including acevirstat) compared to before initiation of treatment, chronic pulmonary inflammation is treated and / or pulmonary inflammation is alleviated.

[0042] Acebilstat treatment is "initiated" upon the first administration of acebilstat, so, for example, a 6-month period after initiating treatment is a 6-month period from the day or date on which the first dose of acebilstat is administered, and a 6-month period before initiating treatment is a 6-month period prior to the day or date on which the first dose of acebilstat is administered.

[0043] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount of a compound or drug that, when administered to a mammal, preferably a human, is sufficient to effect treatment of a disease or condition of interest in the mammal, preferably a human, as defined below. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" or "effective amount" varies depending, for example, on the activity of the particular compound employed; the metabolic stability and length of action of the compound; the age, weight, general health, sex, and diet of the patient; the mode and time of administration; excretion rate; drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy, but can be routinely determined by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0044] As used herein, "treat, treating" or "treatment" includes treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, including, for example, (i) inhibiting or reducing the severity of the disease or condition, or one or more symptoms thereof, i.e., arresting or slowing the onset or progression of the disease or condition, and / or ameliorating one or more symptoms; (ii) palliating the disease or condition, i.e., causing regression of the disease or condition, or one or more symptoms thereof; and / or (iii) stabilizing the disease or condition. Additionally, in the context of cystic fibrosis, "treat, treating" or "treatment" can include treating chronic pulmonary inflammation and / or reducing pulmonary inflammation, such as by reducing pulmonary exacerbations (e.g., reducing the rate, number or frequency of pulmonary exacerbations or increasing the time to first pulmonary exacerbation), attenuating the decline in pulmonary function, increasing pulmonary function, reducing inflammation (including reducing neutrophil-induced inflammation), reducing neutrophil influx, increasing FEV1pp, and / or slowing the decline in FEV1pp, or combinations thereof, as described herein. In the context of treating a respiratory disease characterized by pulmonary exacerbations, "treat, treating" or "treatment" can include reducing pulmonary exacerbations (e.g., reducing the rate, number or frequency of pulmonary exacerbations, or increasing the time to first pulmonary exacerbation).

[0045] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular illness or condition may not have a known causative agent (i.e., the etiology has not yet been elucidated) and therefore is not yet recognized as a disease, but only as an undesirable state or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

[0046] "Pharmaceutical composition" refers to a formulation of a compound described herein, e.g., acevirstat and / or a CFTR modulator, and a medium generally accepted in the art for the delivery of a biologically active compound to a mammal, e.g., a human. Such a medium includes any pharma- ceutically acceptable carrier, diluent, or excipient.

[0047] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0048] "Pharmaceutically acceptable excipients" include, but are not limited to, adjuvants, carriers, fillers, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifying agents, which are approved, for example, by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0049] The administration of the compounds or drugs described herein includes the administration of pharmaceutically acceptable salts of the compounds or drugs, for example, the administration of pharmaceutically acceptable salts of acevirstat or CFTR modulators. The administration of the compounds or drugs described herein (such as acevirstat, CFTR modulators or other additional therapeutic agents), or their pharmaceutically acceptable salts, in pure form or in suitable pharmaceutical compositions, can be carried out via any of the accepted administration modes of drugs to provide similar utility. As described herein, the preferred mode of administration of acevirstat is oral administration. The pharmaceutical compositions described herein can be prepared by combining the compounds or drugs with suitable pharmaceutically acceptable carriers, diluents or excipients, and can be formulated into preparations in the form of solids, semi-solids, liquids or gases, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical compositions of the present invention are formulated so that the active ingredients contained therein are bioavailable when the composition is administered to a patient. The composition administered to a subject or patient may take the form of one or more dosage units, for example, a tablet may be a single dosage unit and a container of the compound of the present invention in aerosol form may hold multiple dosage units. Actual methods of preparing such dosage forms will be known or will be apparent to those skilled in the art: see, for example, The Science and Practice of Pharmacy, 2000, pp. 111-115, 2000; th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound or drug, or a pharma- ceutically acceptable salt thereof, for treating the disease or condition of interest according to the teachings of this invention.

[0050] The pharmaceutical composition may be in solid or liquid form. In one embodiment, the carrier(s) are particulate, so that the composition is, for example, in tablet or powder form. In one embodiment, the composition may be in encapsulated powder or granule form. In another embodiment, the encapsulated powder or granule formulation may be opened and sprinkled on food or administered by gastric intubation. The carrier(s) may be liquid, so that the composition is, for example, an oral syrup, an injectable liquid, or an aerosol, which is useful, for example, in inhalation administration. When intended for oral administration, the pharmaceutical composition may be in either solid or liquid form, and semi-solid, semi-liquid, suspension, and gel forms are included in the forms considered as either solid or liquid herein.

[0051] As a solid composition for oral administration, the pharmaceutical composition can be formulated in the form of powder, granules, compressed tablets, pills, capsules, chewing gum, wafers, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavorings such as peppermint, methyl salicylate, or orange flavor; and colorings.

[0052] When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

[0053] The pharmaceutical composition may be in the form of a liquid, such as an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, the composition may contain, in addition to the compound, one or more of sweeteners, preservatives, dyes / colorants and flavor enhancers. In a composition intended to be administered by injection, one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and isotonic agents may be included.

[0054] The liquid pharmaceutical composition of the present invention, whether in solution, suspension or other similar form, may contain one or more of the following adjuvants: water for injection, saline solution, preferably physiological saline, Ringer's solution, sterile diluent such as isotonic sodium chloride or physiological saline, fixed oils such as synthetic mono- or diglycerides that may serve as a solvent or suspending medium, polyethylene glycol, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes or multiple dose vials. Saline is the preferred adjuvant. Injectable pharmaceutical compositions are preferably sterile.

[0055] The present invention includes a method of administering acevirstat together with an additional therapeutic agent that is part of the standard of care for the respiratory disease that the patient suffers from, including, for example, cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, and interstitial lung disease. The present invention specifically includes a method in which acevirstat is administered together with an additional therapeutic agent (e.g., part of the standard of care for cystic fibrosis), or a combination of acevirstat and a CFTR enhancer and / or CFTR corrector is co-administered with an additional therapeutic agent. The additional therapeutic agent may be, for example, a drug used in the treatment of cystic fibrosis, including, but not limited to, a bronchodilator, an antibiotic, a mucolytic agent, a surfactant, a pancreatic enzyme replacement drug, a CFTR modulator, or a combination thereof. In a further aspect, the present invention includes a method in which acevirstat or a combination of acevirstat and a CFTR modulator, such as a CFTR enhancer and / or CFTR corrector, is combined with an airway clearance technique. Such airway clearance techniques include coughing or huffing, and can also include clapping or vibration. In additional embodiments, the combination of acevirstat or acevirstat with a CFTR modulator, such as a CFTR enhancer and / or CFTR corrector, is combined with gene therapy (including administration of agents used in gene therapy, such as retroviral vectors or genome editing reagents), and gene editing techniques, such as using the CRISPR / Cas9 system.

[0056] In some embodiments, the additional therapeutic agent used to treat CF or other respiratory diseases is a beta agonist. Exemplary beta agonists are albuterol, salbutamol, levalbuterol, formoterol, fenoterol, salmeterol, bambuterol, brocaterol, clenbuterol, terbutaline, tulobuterol, epinephrine, isoprenaline, and hexoprenaline. In another embodiment, the additional therapeutic agent is an anticholinergic. Exemplary anticholinergic agents are tiotropium, oxitropium, ipratropium, and glycopyrrolate. In a further embodiment, the additional therapeutic agent is a mucolytic agent and / or a surfactant. Exemplary mucolytic agents and surfactants are saline, acetylcysteine, ambroxol, carbocysteine, tyloxapol, dipalmitoylphosphatidylcholine, recombinant surfactant protein, and DNase. In one embodiment, the additional therapeutic agent is an antibiotic. Exemplary antibiotics include beta-lactam antibiotics including amoxicillin, piperacillin; cephalosporins including cefaclor, cefazedone, cefuroxime, cefoxitin, cefodizime, cefsulodin, cefodixime, and cefixime; carbapenems such as imipenem and cilastatin; monobactams such as aztreonam; aminoglycosides including streptomycin, neomycin, paromomycin, kanamycin, gentamicin, amikacin, tobramycin, and spectinomycin; tetracyclines such as doxycycline and minocycline; erythromycin, clarithromycin, roxithromycin, and roxithromycin. macrolides including thromycin, azithromycin, josamycin, and spiramycin; gyrase inhibitors such as ciprofloxacin, ofloxacin, levofloxacin, pefloxacin, lomefloxacin, fleroxacin, clinafloxacin, sitafloxacin, gemifloxacin, balofloxacin, trovafloxacin, and moxifloxacin; or quinolones, metronidazole, tinidazole), sulfonamides and nitroimidazoles including chloramphenicol, lincomycin, clindamycin, and fosfomycin; and glycopeptides such as vancomycin and teicoplanin.In yet further embodiments, the additional therapeutic agent is an anti-inflammatory agent. Exemplary anti-inflammatory agents include ibuprofen, dornase alfa, BIIL 284, ajulemic acid, PDE4 inhibitors (e.g., roflumilast), lomoglycate, and nedocromil. In yet further aspects, the additional therapeutic agent is azithromycin. In further aspects, acevirstat is co-administered with a corticosteroid. Exemplary corticosteroids are beclomethasone, betamethasone, budesonide, ciclesonide, flunisolide, fluticasone, icomethasone, mometasone, rofleponide, and triamcinolone. In yet another aspect, the additional therapeutic agent is a bradykinin, a prostaglandin, a leukotriene, and a platelet activating factor antagonist. The present invention encompasses the administration of one or more additional therapeutic agents, or combinations thereof, simultaneously with acevirstat. In certain additional embodiments, the invention encompasses the administration of one or more additional therapeutic agents, or combinations thereof, in combination with acevirstat to patients with cystic fibrosis.

[0057] The invention is illustrated by the following non-limiting examples.

[0058] Example 1: EMPIRE-CF: A Phase II, Randomized, Placebo-Controlled Trial of Once-Daily Oral Acevirstat in Adult Patients with Cystic Fibrosis - Study Design, Patient Demographics, and Outcomes Acevirstat is a novel synthetic small molecule leukotriene A4 hydrolase inhibitor being developed as a once-daily oral therapy to modulate LTB4 production and target inflammatory processes in CF [Elborn et al., 2017a]. In two Phase I trials, acevirstat reduced LTB4 production and other inflammatory markers in healthy volunteers and CF patients [Elborn et al., 2017a, Elborn et al., 2017b]. Based on these promising data, a Phase IIb trial, EMPIRE CF (Evaluation of the modulation of the pulmonary inflammatory response in CF), was designed and completed to determine the dose, duration, and endpoints of future clinical trial(s). The study was the first demonstration of a novel anti-inflammatory therapy designed to prevent progressive loss of lung function and / or attenuate pulmonary exacerbations in CF patients. The study design, rationale, and results are described below. The demographics of the study population are also presented and their significance to the study findings is discussed.

[0059] method Design Considerations Previous short-term trials (treatment for 12 weeks or less) have shown that anti-inflammatory medications, despite their potential to be effective treatments, may not produce rapid changes in forced expiratory volume in 1 second percent predicted (FEV1pp) or even changes in biomarkers of inflammation [Elborn et al., 2012; Moss et al., 2013; Chmiel et al., 2015]. Longer-term studies are more likely to show a reduction in exacerbations, along with attenuation of the annual rate of decline in lung function. For example, a 4-year high-dose ibuprofen study showed a reduced rate of decline in FEV1 in a general CF population, but no more rapid evidence of benefit [Konstan et al., 1995]. This phase II trial cannot be conducted over such a period. Based on this, a 48-week treatment period was considered in this study, and a larger sample size was used to detect changes over a shorter observation period (see box below).

[0060] Measuring significant changes in lung function decline and frequency of exacerbations is only possible if the correct patient population is enrolled. We hypothesized that a certain subset of the general CF population may be at high risk for rapid lung function decline, and that this subset may provide a study population that is affected by active inflammation and experiences declines large enough to detect clinical benefit over a 48-week interval. Such a subset was identified through the Cystic Fibrosis Patient Registry (CFPR) study and based on knowledge of the expected rate of decline in FEV1pp, and the frequency of pulmonary exacerbations in this subpopulation. For example, a previous pulmonary exacerbation is one of the strongest predictors of future pulmonary exacerbations [Block et al., 2006; VanDevanter et al., 2016]. Moreover, it has been estimated that up to half of the decline in lung function is associated with a pulmonary exacerbation [Waters et al., 2012], and it is speculated that exacerbations are a clear indicator of active neutrophil-driven inflammation. The susceptibility to annual declines in lung function is greatest during adolescence and early adulthood and weakens once patients reach approximately age 30 [Liou et al., 2010]. In addition, patients with higher baseline lung function may be more susceptible to larger declines in FEV1pp [Konstan et al., 2012].

[0061] Based on these published observations, data from the CFPR (Cystic Fibrosis Foundation, 2014) were analyzed for various age ranges (12–17 years, 18–30 years, 31–35 years, or 36–39 years); baseline FEV1pp (50–59%, 60–79%, 80–99%, or ≥100%), and number of pulmonary exacerbations requiring IV antibiotic use in the previous year (0 or ≥1). The registry data strongly supported the notion that patients aged 12–30 years who had at least one pulmonary exacerbation in the previous year are at highest risk for rapid lung function decline. Within this subgroup, the registry data provided further evidence that patients with a higher FEV1pp at baseline are likely to experience the most rapid decline in FEV1pp. Within the subgroup of CF patients aged 18–30 years who had at least one pulmonary exacerbation in the previous year, the current-year rate of decline is estimated to be 3.47 percentage points per year. To detect a difference in the rate of decline in FEV1pp relative to placebo of about 3 percentage points per year, observation for at least 48 weeks is required. Therefore, to detect differences in the rate of decline in FEV1pp relative to placebo and differences in exacerbation rates over the 48-week period of the Phase II study, the patient population was enriched based on optimal patient age, FEV1pp, and exacerbation history (see section 2.4). This population and study period are consistent with the guidance published by the Cystic Fibrosis Foundation (CFF) [Torphy et al., 2015].

[0062] We used this Phase II study as a pivotal trial in our research design while establishing proof of concept that leukotriene A4 hydrolase (LTA4H) is a therapeutic target in CF. Up-front baseline stratification based on lung function (as FEV1pp), number of exacerbations in the previous year, and concomitant use of a CFTR modulator ensured that patient characteristics were balanced between treatment arms, allowing us to identify the most appropriate patient population for future clinical trials. Given the evolving standard of care that may soon include the use of CFTR modulator regimens across a broad range of CF populations, including the use of a CFTR modulator as a stratification criterion is also important.

[0063] Overall Research Plan EMPIRE-CF was a Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study (NCT02443688) to evaluate the efficacy and safety of acevirstat in adult patients with CF. The study consisted of a 48-week treatment period and a 4-week follow-up visit after completion of treatment. The screening visit occurred up to 21 days prior to the first study drug dose (Figure 2).

[0064] patient Patients were enrolled from 69 centers across the United States, Canada, and Europe. All centers were involved in CF treatment and clinical trial implementation. Inclusion and exclusion criteria are shown in Table 2. Briefly, adult women and men aged 18-30 years with a documented diagnosis of CF, FEV1pp ≥ 50% at screening, and at least one pulmonary exacerbation in the previous year were enrolled. Baseline demographics are shown in the following columns.

[0065] Overall, 284 patients were screened, 200 patients were enrolled, 199 patients (FAP) received at least one dose of study drug (acevirstat 100 mg, n = 66; acevirstat 50 mg, n = 67; placebo, n = 66), and one patient in the placebo group was randomized but discontinued before receiving study drug. Overall, 32 patients (16%) discontinued the study before the 48-week visit, of which 21 (15.8%) were in the acevirstat treatment group and 11 (16.7%) in the placebo group. The most common reasons for discontinuation were withdrawal of informed consent (5%) and non-compliance with study drug (3%). The per-protocol (PP) analysis included 162 patients (acevirstat 100 mg, n = 54; acevirstat 50 mg, n = 54; placebo, n = 54). Mean compliance with study drug was 93% in the acevirstat 100 mg group, 96% in the acevirstat 50 mg group, and 96% in the placebo group.

[0066] intervention Patients were randomized 1:1:1 to receive either acevirstat 50 mg or 100 mg (Celtaxsys, Atlanta, GA, USA) or placebo delivered as a capsule once daily. The two acevirstat doses were selected based on the level of reduction in serum LTB4 production seen in a phase I study. The 100 mg dose produced near-maximal reduction in LTB4 (86% reduction), whereas the 50 mg dose showed a peak reduction in LTB4 production of approximately 75% [Elborn et al., 2017b].

[0067] results Primary endpoints were absolute change from baseline in FEV1pp and safety outcomes. Secondary endpoints included pulmonary exacerbation rate and time to first pulmonary exacerbation, and effects on biomarkers of pulmonary and systemic inflammation. Analyses are described in the section entitled "Analysis."

[0068] Pulmonary exacerbations were defined as the requirement for oral, inhaled, or intravenous antibiotics for 4 or more signs or symptoms according to the modified Fuchs criteria (change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue, tiredness, or lethargy; temperature above 38°C; loss of appetite or weight loss; sinus pain or tenderness; change in sinus drainage; change in physical chest exam; absolute decrease in FEV1pp of 10% or more from the previously recorded value; radiographic changes indicating pulmonary infection) [Fuchs et al., 1994], together referred to as the extended Fuchs criteria (antibiotics and 4 or more signs and symptoms). The day a pulmonary exacerbation began was defined as the first day of antibiotic use.

[0069] evaluation The patient's medical condition At the screening visit, the investigator recorded a full medical history and performed a complete physical and laboratory examination to determine eligibility for the study. At the screening visit, demographic and disease characteristics, concomitant CF medications (including use of CFTR modulators such as ivacaftor or lumacaftor, dornase alfa and chronic azithromycin use), history of Pseudomonas aeruginosa colonization, and CFTR genotype were recorded. The number of pulmonary exacerbations in the past 12 months and the date of the last pulmonary exacerbation were also recorded at screening.

[0070] Spirometry Spirometry data were recorded at screening and baseline, and all other spirometry measurements at subsequent visits were ideally recorded within ±1 hour of the baseline visit measurement. All studies met the American Thoracic Society / European Respiratory Society criteria for quality (acceptability, reproducibility, and study termination criteria) [Miller et al., 2005]. To ensure consistency of measurements, spirometry was ideally performed by the same investigator, and patients were instructed to exert maximum effort on all attempts. Patients were allowed to take all their concomitant medications according to the regular schedule, but patients were to refrain from using short-acting bronchodilators within 4 hours of the scheduled spirometry time, and from using long-acting bronchodilators within 12-24 hours of the scheduled spirometry time.

[0071] safety Treatment-emergent adverse events (TEAEs), including serious adverse events, were collected at each visit and summarized by MEDRA system organ class and preferred term, severity, and relationship to study drug.An independent data monitoring committee monitored safety and study conduct at approximately 8-week intervals.

[0072] Treatment Adherence Assessment of adherence to treatment with the study drug was based on capsule counts by the investigator at visits 3, 5–9, 11, 13, and 15. To ensure accuracy of adherence assessments, patients were asked if they had lost or destroyed any capsules.

[0073] Determining sample size It was assumed that the primary endpoint would require a sample size of 156 patients in the largest analysis population (FAP, n=52 acevirstat 50 mg: n=52 acevirstat 100 mg: n=52 placebo), however, to ensure an adequate sample size for the per-protocol (PP) analysis (based on 80% of patients included in the PP population), the number of randomized patients with FAP was 195, i.e., n=65 in each treatment group.

[0074] Sample size calculations were based on the primary efficacy endpoint of absolute change from baseline in FEV1pp. The calculations were based on the following assumptions: a 1:1:1 ratio of patients receiving 50 mg acevirstat vs 100 mg acevirstat vs placebo, and a mean treatment effect difference of at least 3.5 units between active treatment (both doses of acevirstat) vs placebo at week 48. With a standard deviation of 7 units, the study had at least 90% power with a one-sided alpha of 0.05 to detect a difference of 3.5 units in the mean treatment effect (change from baseline in FEV1pp) between active treatment (both doses of acevirstat) vs placebo at week 48.

[0075] Randomization and blinding Eligible patients were randomized to active treatment by an interactive web-based randomization system (IWRS). Randomization was stratified by baseline FEV1pp (50-75% and >75%), number of pulmonary exacerbations in the 12 months before screening (1 or >1), and use of CFTR-modulating therapy with ivacaftor or ivacaftor + lumacaftor (yes / no). All patients, investigators with direct contact with patients, and others, as well as sponsor and contract research institution staff, were blinded to treatment assignment.

[0076] analysis Primary endpoint The primary analysis was based on analysis of variance (ANOVA), comparing the mean change from baseline at week 48 in FEV1pp for the two acevirstat doses with the mean for the placebo group. The ANOVA model included separate terms for each dose group and the mean of the two acevirstat doses, which were created by averaging the parameter estimates from the ANOVA models. In addition to terms for treatment group, the ANOVA included stratification for the factors used for randomization. If the primary analysis (total acevirstat effect) reached the 0.05 level of significance (one-sided), individual acevirstat doses would be compared with the placebo group using Dunnett's procedure at the 0.05 (two-sided) alpha level.

[0077] Secondary endpoints Pulmonary exacerbations were analyzed as both time to first pulmonary exacerbation and pulmonary exacerbation rate. Time to first protocol-defined pulmonary exacerbation was analyzed using a Cox proportional hazards model. The number of protocol-defined pulmonary exacerbations reported through the week 48 / early termination visit was annualized (a year was defined as 52 weeks) and analyzed using negative binomial regression. The two effective doses were compared to placebo individually and pooled together using a contrast statement similar to that used for the primary analysis. Point estimates, standard errors, and 95% CIs for the mean number of pulmonary exacerbations were presented. Mean differences from placebo between each CTX-4430 group were presented with standard errors and 95% CIs. Spirometry-based endpoints were analyzed using the same methods as the primary endpoint. Analyses of sputum DNA and elastase, and serum high-sensitivity C-reactive protein were based on descriptive statistics by treatment group.

[0078] Exploratory endpoints Sputum bacterial density (total and densities of P. aeruginosa, Burkholderia cepacia complex, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, and Staphylococcus aureus (including methicillin-resistant S. aureus and small-colony variants of S. aureus)) and analyses of health-related quality of life (using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) quality of life scale [Quittner et al., 2000]) were based on descriptive statistics by treatment group.

[0079] Baseline characteristics A total of 200 patients were enrolled in the study. The mean age of patients was 23.7 years, and the mean FEV1pp at baseline was 70.6% overall. Nearly one-third of patients were concomitantly using a CFTR modulator. The mean number of exacerbations in the previous year was two Nearly half of all patients had one exacerbation in the previous year, compared with 28.5% having two and 25% having three or more exacerbations.

[0080] result In this Phase IIb study, patients with cystic fibrosis (CF) were enrolled into one of three treatment arms: placebo, 50 mg acevirstat, or 100 mg acevirstat (Figure 2). Patients were prospectively stratified across treatment arms by three criteria: baseline lung function (measured as FEV1 percent predicted, FEV1pp), number of pulmonary exacerbations in the year prior to enrollment, and use of concomitant treatment with CFTR modulator therapy. Enrolled patients were followed for 48 weeks of treatment and an additional 4 weeks post-treatment. Over the course of the study, patients were monitored for changes in lung function and occurrence of pulmonary exacerbations to assess treatment efficacy.

[0081] Although this phase 2 study was not powered to detect statistically significant changes in pulmonary exacerbations, pulmonary exacerbations were an important secondary endpoint because anti-inflammatory therapy is expected to be beneficial in pulmonary exacerbations compared with changes in spirometry. Annualized rates of pulmonary exacerbations were calculated by standard methods for each treatment group. Two main populations were examined across the full analysis set (FAP), consisting of any patients receiving at least one treatment, and the per-protocol population (PP), consisting of patients who met all inclusion / exclusion criteria, adhered to at least 80% of the treatment regimen, and were also evaluated at week 48.

[0082] In FAP, the adjusted mean (95% CI) annualized pulmonary exacerbation rates based on negative binomial regression models were 1.51 (1.26, 1.81) in the acevirstat combination group, 1.57 (1.22, 2.02) in the 100 mg group, 1.46 (1.13, 1.89) in the 50 mg group, and 1.56 (1.21, 2.01) in the placebo group (Figure 3A). The time to first pulmonary exacerbation was numerically longer in patients receiving acevirstat (combination and individual groups) compared with placebo. The hazard ratios (95% CI) versus placebo were 0.87 (0.605, 1.246) in the acevirstat combination group, 0.88 (0.576, 1.339) in the acevirstat 100 mg group, and 0.86 (0.563, 1.308) in the acevirstat 50 mg group (Figure 4A). The proportion of patients who did not experience a pulmonary exacerbation during the study period was also numerically higher in the acevirstat groups (51 / 133 patients [38%] in the acevirstat combination group, 25 / 66 patients [38%] in the 100 mg group, and 26 / 67 patients [39%] in the 50 mg group) than in the placebo group (20 / 66 patients [30%]) (Figures 5A and 6A). In the PP analysis, the difference in pulmonary exacerbation rates between the acevirstat group and placebo was greater than in the FAP (Figure 3B). The time to first pulmonary exacerbation and the proportion of patients who did not experience a pulmonary exacerbation during the study were also numerically higher (Figures 4A, 4B, 5A, 5B, 6A, and 6B). In the FAP and PP analyses, the difference from placebo in pulmonary exacerbations occurred at approximately 4 months.

[0083] Kaplan-Meier analysis was performed based on the proportion of exacerbation-free patients as a function of time (Figures 4A and 4B). The treatment group curves differed from the placebo curve, showing an increased time to first exacerbation for both dose groups in both FAP and PP (Figures 4A and 4B, respectively). At 48 weeks, the hazard ratios for exacerbation risk show a treatment effect for both acevirstat dosing groups, with a reduced exacerbation risk compared to placebo. In addition, the number of patients who did not experience a pulmonary exacerbation during the 48-week treatment period was determined for each treatment group. This analysis shows that the majority of patients treated with acevirstat remained exacerbation-free in both FAP (Figures 5A and 6A) and PP (Figures 5B and 6B).

[0084] In a prespecified analysis, CF patients in the study were classified according to baseline lung function above or below the median FEV1pp for the entire study population, which was found to be 68%. Patients with milder lung disease with baseline FEV1pp higher than the median (>68%) were found to respond to acevirstat treatment as evidenced by lower annualized rates of pulmonary exacerbations versus placebo (Figure 7B). In contrast, patients with baseline FEV1pp below the median (≦68%) did not demonstrate the same level of response to acevirstat treatment (Figure 7A).

[0085] In prespecified analyses, CF patients in the study were classified according to baseline lung function (FEV1pp 50-75, or >75%). Patients with milder lung disease (baseline FEV1pp>75%) were found to respond to acevirstat treatment as evidenced by lower annualized rates of pulmonary exacerbations in both FAP and PP (Figures 8A and 8B, respectively). Specifically, the mean annualized rate of pulmonary exacerbations in patients with baseline FEV1pp>75% was approximately 35% lower in the acevirstat combination group compared to placebo, and this difference was greater than in the overall study population. The adjusted mean (95% CI) annualized rates of pulmonary exacerbations in this prespecified FAP population were 1.04 (0.74, 1.46) in the acevirstat combination group, 0.84 (0.49, 1.44) in the 100 mg group, and 1.28 (0.84, 1.96) in the 50 mg group versus 1.61 (1.07, 2.42) in the placebo group (Figure 9A). The effect of acevirstat versus placebo on time to first pulmonary exacerbation was also more pronounced in this population than in the overall trial population. The hazard ratios (95% CI) versus placebo for FAP were 0.57 (0.307, 1.051) in the acevirstat combination group, 0.52 (0.245, 1.101) in the acevirstat 100 mg group, and 0.62 (0.304, 1.274) in the acevirstat 50 mg group (Figure 9A). Nearly half of the patients with mild disease who received acevirstat did not have a pulmonary exacerbation during the study (23 / 47 patients [49%] in the acevirstat combination group; 11 / 22 patients [50%] in the 100 mg acevirstat group; 12 / 25 patients [48%] in the 50 mg acevirstat group), whereas only 6 / 24 patients (25%) in the placebo group did not have a pulmonary exacerbation (Figures 11, 17A, 18A). Exacerbation rate data for subjects with baseline FEV1pp ≦75% are shown in Table 1 below. These patients showed a numerical benefit in exacerbation rate compared to placebo, but the difference was less pronounced. In contrast to patients with baseline FEV1pp >75% (Figure 9A), patients with FEV1 below 75% (≦75%) did not show the same level of response to acevirstat treatment (Figure 9B).This is evidenced by both the reduction in annualized rate of exacerbation and the reduction in hazard ratio of time to first exacerbation in the population with baseline FEV1pp>75% (Figure 9A), compared with unchanged or increased rates and hazard ratios in the population with FEV1pp below 75% (Figure 9B). Kaplan-Meier analysis of the CF patient population with baseline FEV1pp>75% showed a longer time to first exacerbation and a lower hazard ratio of exacerbation risk for both acevirstat dosing groups, both FAP and PP, compared with placebo (Figures 10A and 10B, respectively). Furthermore, more patients treated with acevirstat in the group with baseline FEV1pp>75% remained free of pulmonary exacerbations during 48 weeks of treatment compared with patients in the placebo group (Figure 11).

[0086] Figures 15A and 15B show the effect of acevirstat on pulmonary exacerbation rates in patients with baseline FEV1pp>70, the CF Community Standard definition of "mild" CF disease, compared to patients with baseline FEV1pp>75 (a pre-specified definition of "mild" CF used in clinical studies). As shown in the figures, acevirstat demonstrates a significant reduction in pulmonary exacerbations in both groups with different definitions of "mild" CF disease.

[0087] In summary, the treatment effect of acevirstat in reducing pulmonary exacerbations is greatest in CF patients with high baseline FEV1pp ("mild CF disease"). Table 1 shows that both the 50 mg and 100 mg doses demonstrated treatment effect in patients with baseline FEV1pp ≥ 65%, with the greatest benefit seen at baseline ppFEV1 > 70%. The 100 mg dose of acevirstat also demonstrated treatment effect > 60% at baseline FEV1pp. The terms "FEV1pp" and "ppFEV1" are used interchangeably. [Table 1]

[0088] Furthermore, patients taking acevirstat in combination with CFTR modulator therapy showed a reduced annualized rate of pulmonary exacerbations and a reduced hazard ratio for exacerbation risk compared to patients taking a placebo in combination with CFTR targeted therapy (Figures 12A and 12B). These effects were evident for both acevirstat doses in both FAP and PP populations (Figures 12A and 12B, respectively). Furthermore, the proportion of exacerbation-free CF patients taking acevirstat in combination with CFTR modulator therapy was lower compared to patients taking a placebo in combination with CFTR targeted therapy (Figures 13A and 13B). This effect persisted until the end of 48 weeks of treatment and was evident for both acevirstat doses in both FAP and PP populations (Figures 13A and 13B, respectively).

[0089] As shown in Figures 16A and 16B, acevirstat-treated patients had lower rates of pulmonary exacerbations in CF patients with mild disease (FEV1pp>75), regardless of whether they were receiving ("on") or not receiving ("off") concomitant CFTR modulator therapy. The greatest effect of acevirstat on pulmonary exacerbations in the entire study (65% lower compared to placebo at a 100 mg dose) was observed in patients with mild disease treated with concomitant CFTR modulator therapy (Figure 16A), suggesting possible mechanistic synergy. In the data shown in Figures 16A and 16B, the corresponding placebo group was matched to the acevirstat-treated group with respect to the use of CFTR modulators, i.e., for patients "on" CFTR modulators, patients taking acevirstat and a CFTR modulator were compared to patients taking only a CFTR modulator.

[0090] As shown in Figures 17A-17C, acevirstat-treated patients had a higher proportion of patients who were exacerbation-free over the course of 48 weeks of treatment (vs. placebo) in patients with mild CF, as well as in the overall study population (Figure 17A), whether or not they were receiving ("on") (Figure 17B) or not ("off") (Figure 17C) a CFTR modulator concomitant therapy. Surprisingly, and consistent with its effect on pulmonary exacerbation rates, the effect of acevirstat in increasing the proportion of exacerbation-free patients was greatest in patients receiving a CFTR modulator concomitant therapy (see Figure 17B).

[0091] Figures 18A and 18B show that both the 100 mg and 50 mg doses of acevirstat had a higher percentage of exacerbation-free patients in the mild (FEV1pp>75%) subgroup. Figures 20 and 21 show that compared to placebo, the 100 mg dose of acevirstat had a lower rate of pulmonary exacerbations requiring hospitalization and a lower rate of pulmonary exacerbations requiring intravenous antibiotics.

[0092] Figures 19A and 19B show the effect of acevirstat (100 mg in the mild population) and CFTR modulator therapy (KALYDECO®, SYMDEKO®, and ORKAMBI®) on the percent difference from placebo in pulmonary exacerbation rate and risk of pulmonary exacerbation, respectively. These figures show that the magnitude of effect of acevirstat (at the 100 mg dose) in the mild CF population is similar to or better than that observed with recently approved CFTR modulator therapy (at the approved dose) in each genetically targeted population, with respect to both annualized rate and risk of pulmonary exacerbation benefit. Although this is data from different studies, it confirms that the level of effect seen with acevirstat in terms of pulmonary exacerbations is considered therapeutically meaningful.

[0093] In summary, the primary benefit of acevirstat is a reduction in pulmonary exacerbation (PEx) rate and a reduction in the risk of progression to a pulmonary exacerbation. In the study, acevirstat demonstrated clinically meaningful improvements in pulmonary exacerbations by reducing the frequency of PEx and increasing the time to the next exacerbation over 48 weeks of treatment. Prospectively identified key subgroups of patients benefited most, including those with mild CF lung disease at baseline and / or those receiving CFTR modulator concomitant therapy. The benefit when used in combination with a CFTR modulator is an important consideration given that the number of CF patients eligible for treatment with CFTR modulators is likely to increase in the coming years. This appropriately addresses an unmet need for optimal treatment of patients with cystic fibrosis to reduce persistent lung inflammation despite CFTR modulator therapy. Patients treated with acevirstat demonstrated an 18% reduction in PEx and a 22% reduction in the risk of progressing to a first PEx compared to placebo. Additionally, 32% more patients treated with acevirstat did not experience a PEx during the study compared with placebo. The benefit of acevirstat on pulmonary exacerbations was evident as early as 4 months after treatment initiation and persisted throughout the 48-week study. Lung function, measured as FEV1 percent predicted (FEV1pp), did not differ from placebo in acevirstat-treated patients over the 48-week treatment period. Previous studies with CFTR modulators have shown that FEV1pp responses do not always correlate with PEx responses on an individual patient basis.

[0094] Patients with less severely impaired lung function (FEV1pp>75) achieved the greatest benefit from acevirstat therapy, reducing their PEx rate by 34%, reducing their risk of experiencing a first exacerbation by 43%, and increasing their likelihood of being exacerbation-free by 96% after 48 weeks of treatment. In addition, patients treated with concomitant CFTR modulator therapy demonstrated an 18% reduction in clinically meaningful PEx, a 29% increase in time to first exacerbation, and a 47% higher likelihood of being exacerbation-free compared to patients treated with a CFTR modulator and placebo. Acevirstat is well tolerated without increasing the risk of infection, a key attribute of any anti-inflammatory drug development candidate to treat CF patients at high risk of infection. Discontinuation rates due to adverse events were low, with the majority of adverse events being mild or moderate in severity.

[0095] Patients treated with acevirstat showed a small improvement in FEV1pp but did not separate from placebo on the primary endpoint. Specifically, FEV1pp was highly variable and did not predict reduction in pulmonary exacerbations (PEx responders). This study provides evidence that reduction in pulmonary exacerbations is a better measure of outcome from anti-inflammatory therapy than FEV1pp.

[0096] Consideration The deleterious effects of chronic inflammation are well recognized in CF. Although CFTR mutations have been implicated in some aspects of inflammation [Rubin 2007; Perez et al., 2007], CFTR modulators have not fully addressed chronic pulmonary inflammation [Rowe et al., 2014], and therapeutics in this area remain a significant unmet need [Torphy et al., 2015].

[0097] Acebilstat, an LTA4 inhibitor, is being developed as an anti-inflammatory therapy for CF and has shown promising results in Phase I trials. In a study of once-daily acebilstat in adult patients with CF, the drug significantly reduced sputum neutrophil levels by up to 65% and sputum elastase levels by up to 58%. Numerical reductions in C-reactive protein were observed in the acebilstat treatment group [Elborn et al., 2017a]. Sputum LTB4 levels were significantly reduced in acebilstat-treated vs. placebo-treated patients [Elborn et al., 2017b]. These Phase I trials highlighted several important PK / PD aspects of acebilstat. Data confirmed that once-daily oral dosing is appropriate [Elborn et al., 2017b]. The C-reactive protein (C-reactive protein) profile of acebilstat was significantly reduced in healthy volunteers and CF patients [Elborn et al., 2017b]. max or AUC 0-24 No significant differences occurred in the AUC 0.01 and AUC 0.02 at steady state in fed and fasted patients. Given the high burden of CF therapy [Harman et al., 2017], a simple dosing regimen for any add-on therapy is important. Furthermore, the AUC 0.01 and AUC 0.02 at steady state in fed and fasted patients were significantly different. 0-24 There were no differences in the CYP3A4 metabolic pathway in patients with CF [Elborn et al., 2017b]. This is relevant given the potential impaired intestinal absorption in patients with CF and their complex dietary needs [Li and Somerset 2014]. Furthermore, acevirstat does not induce CYP3A4, a known metabolizer of the CFTR modulator ivacaftor, and importantly, these data indicate that the two drugs (acevirstat and ivacaftor) can be taken simultaneously [Elborn et al., 2017b]. The adverse event profile of acevirstat was closely monitored in phase I studies. Encouragingly, acevirstat was well tolerated in these trials. The majority of treatment-emergent adverse events (AEs) were mild or moderate in severity, and no drug-related serious AEs occurred in these studies [Elborn et al., 2017a,b].

[0098] Promising data from the Phase I trial led acevirstat to progress into the Phase IIb trial described herein. The trial has been robustly designed, taking into account guidance from the CFF, including recommendations from the 2014 CFF Anti-inflammatory Strategy Group (CFF-ASG) [Torphy et al., 2015]. Study endpoints examined both change from baseline in lung function and pulmonary exacerbations, both of which have real clinical impact. Decline in lung function is a strong predictor of morbidity [Kerem et al., 1992], while pulmonary exacerbations are associated with irreversible loss of lung function and decline in health status in many patients [Sanders et al., 2010].

[0099] It is important to choose a study duration appropriate for the drug being studied. Although CFTR modulators may lead to relatively rapid improvements in lung function [Rowe et al., 2014], longer trials are needed to demonstrate benefits from anti-inflammatory therapy aimed at halting the decline in lung function and / or reducing pulmonary exacerbation rates. The CFF-ASG recommended that phase II trials be at least 3–6 months [Torphy et al., 2015], although 12-month studies may be preferable for more definitive data on anti-inflammatory effects. In the present study, the treatment duration was 48 weeks.

[0100] Enrolling the most relevant patient phenotype is key to assessing clinical outcomes in trials of novel and potential therapies. Patients in EMPIRE-CF were selected based on strict inclusion criteria (age 18–30 years, FEV1pp ≥ 50, and at least one exacerbation in the past year). This enriched the study population of patients most susceptible to pulmonary exacerbations and annual decline in lung function. Enrolled patients had experienced a mean of 2.1 exacerbations in the previous year. Modeling of FEV1pp decline from a similar patient cohort in the CFPR (Cystic Fibrosis Foundation, 2015) suggests that patients eligible for this study may have an annual decline in FEV1pp of 3.5 (standard deviation [SD] 7.9), ranging from 2.7 (SD 7.6) in patients with one exacerbation in the previous year, to 3.7 (SD 7.9) in patients with two, and 5.1 (SD 8.4) in patients with three or more exacerbations [Elborn et al., 2018]. Importantly, the total study population size was calculated to ensure that the study was adequately powered to show a difference in lung function decline from placebo. The size of the study population and duration of the study may have made a benefit in pulmonary exacerbations detectable in this population.

[0101] Ensuring that treatment arms are balanced with respect to patient characteristics helps to identify specific patient populations that are more likely to benefit from acevirstat and may be included in future clinical trials. Therefore, randomization was stratified by baseline FEV1pp, number of pulmonary exacerbations in the past 12 months, and use of CFTR-modulating therapy. Stratification based on concomitant use of CFTR modulators is important because neutrophil elastase has been shown to downregulate CFTR [Le Gars, et al. 2013], and anti-inflammatory agents such as acevirstat that reduce neutrophil elastase may have synergistic effects with CFTR modulators.

[0102] The unique rigorous design elements of the EMPIRE-CF trial were expected to help identify optimal patient populations, doses, durations, and endpoints for future trials to improve understanding of the efficacy of acevirstat in patients with CF. This study provides evidence that pulmonary exacerbations are a better outcome measure of anti-inflammatory therapies such as acevirstat than changes in FEV1pp. No differences were observed between acevirstat and placebo for the primary endpoint, absolute change in ppFEV1 from baseline at week 48. Given the mechanism of action of acevirstat as an anti-inflammatory agent, and previous experience with ibuprofen [Konstan et al. 1995], a sharp increase from baseline in ppFEV1, implying a bronchodilation or mucociliary clearance effect, would not have been expected. In addition, a longer trial, such as was the case in the 4-year high-dose ibuprofen study, may have been necessary to demonstrate a reduction in lung function decline versus placebo [Konstan et al. 1995].

[0103] Importantly, analysis of secondary endpoints showed that acevirstat treatment resulted in a numerical reduction in pulmonary exacerbation rate, an increase in time to first pulmonary exacerbation, and a higher proportion of patients free of pulmonary exacerbations. These differences from placebo were expressed numerically but were internally consistent across several measures of exacerbations. These effects were particularly evident in patients with milder disease (ppFEV1 > 75% at baseline), consistent with previous findings that high-dose ibuprofen treatment in children reduced the rate of FEV1 decline and improved survival in children with evidence of pulmonary disease progression (ppFEV1 < 100) but still in a milder population (ppFEV1 ≥ 60), although no survival benefit was observed in children with advanced pulmonary disease (ppFEV1 < 60) [Konstan et al. 2018]. In addition, the magnitude of acevirstat's effect on pulmonary exacerbations was also more pronounced in patients receiving concomitant CFTR modulators, a group that may more closely resemble those with milder CF lung disease due to partial restoration of CFTR activity.

[0104] Although CFTR modulators have been shown to reduce the rate of lung function decline, they have not consistently shown an effect on markers of airway inflammation, and patients receiving CFTR modulator treatment still experience exacerbations and progressive loss of lung function [Sawicki et al. 2015; Konstan et al. 2017; Hisert et al. 2017; Rowe et al. 2014]. The findings of our study suggest that adding acevirstat to CFTR modulator therapy may further reduce lung exacerbations and potentially further reduce long-term loss of lung function. Longer duration trials are needed to detect the effect of combination treatment on the trajectory of lung function decline.

[0105] Reducing pulmonary exacerbations is an important goal of CF therapy because exacerbations are associated with significant morbidity, decline in lung function, and early death [de Boer et al. (2011); Konstan et al. 2012; Stephenson et al. 2015]. The findings of this study indicate that targeting neutrophil-mediated inflammation in CF with acevirstat may provide clinical benefit by reducing pulmonary exacerbations, particularly in the context of CFTR modulator combination therapy and in patients with milder lung disease. This approach warrants further investigation in these populations.

[0106] Direct targeting of LTB4 inflammatory signaling was investigated in a clinical trial of Amervant (BIIL 284), an antagonist of the BLT1 receptor, but this trial in patients with stable CF lung disease was terminated early due to an increase in severe pulmonary AEs [Konstan et al. 2014]. Amervant at the dose used in the study may have had an overly potent effect on the BLT1 receptor, impairing antibacterial defenses and increasing infection [Chmiel et al. 2007; Dorin et al. 2014]. Its mechanism as a receptor antagonist may also have resulted in an increased presence of LTB4 in the airways as an adverse outcome. Amervant acts to decrease LTB4 synthesis by inhibiting the LTA4H enzyme, and thus may downregulate signaling through the BLT1 receptor rather than blocking signaling. This is reflected in the acceptable safety profile observed for Amervant in this study, which showed that Amervant was safe and well tolerated in patients with CF. Most AEs were mild or moderate in intensity and were judged by the investigators to be unrelated or unlikely to be related to study drug. There were few discontinuations due to AEs.

[0107] Neutrophil elastase is an important inflammatory marker associated with reduced lung function in patients with CF [Mayer et al. (2007)]. In a phase 1 trial of acevirstat, sputum neutrophil DNA and serum high-sensitivity C-reactive protein, alongside sputum levels of neutrophil elastase, were reduced with acevirstat treatment compared to placebo [Elborn et al. (2017)]. We did not observe similar changes in this study. This finding may be due to limitations associated with the collection, processing, and analysis of sputum from multiple clinical sites, including the need to freeze samples to perform centralized analysis, which tends to release intracellular neutrophil elastase. High-sensitivity C-reactive protein, a marker of systemic inflammation, was affected by comorbid illness in this study, where patients had pulmonary exacerbations throughout the trial, although stable at randomization, which may have increased variance and adversely affected the detection of stable changes between groups.

[0108] This trial highlights the challenges in designing clinical trials of anti-inflammatory agents at the phase 2 stage of drug development. The study was based on ppFEV1, which, despite being a more meaningful measure of the activity of anti-inflammatory agents, required a more manageable sample size than conducting such studies based on pulmonary exacerbations. Future clinical trials will need adequate statistical power for the pulmonary exacerbation endpoint, and in this trial, a numerical signal of benefit was seen. This poses a clear challenge for evaluating anti-inflammatory agents early in clinical development, as sputum biomarkers are not necessarily predictive of mid-term benefit. By design, we enrolled a population at risk for future pulmonary exacerbations, which may have been a beneficial design feature that allowed for the detection of the positive trend for pulmonary exacerbations found in this study.

[0109] In summary, although there was no meaningful effect on ppFEV1, a positive clinically relevant trend of acevirstat's effect on the proportion of patients free of pulmonary exacerbations was observed, along with the rate and time to first pulmonary exacerbation, especially in patients with mild disease and those receiving concomitant CFTR modulator therapy. In the future, it is predicted that the majority of people with CF will have mild pulmonary disease (CFF Registry Report, 2017) and be receiving concomitant CFTR modulators. Given the importance of reducing pulmonary exacerbations in the treatment of patients with CF, further clinical investigation of acevirstat is warranted, focusing on these patient populations.

[0110] In conclusion, acebilstat is the first novel anti-inflammatory molecule to prospectively demonstrate benefit in both reducing the frequency of pulmonary exacerbations and extending the time to first exacerbation when added to existing treatment regimens in CF patients in clinical trials. Acebilstat treatment had a significant effect on reducing the rate of pulmonary exacerbations, and this effect was most pronounced in patients with milder lung disease populations (with FEV1pp >75 at baseline) and in patients receiving CFTR modulator therapy. Acebilstat-treated patients had less frequent pulmonary exacerbations, especially as recruited patients had had an exacerbation in the year prior to entering the study and were therefore at higher risk for new exacerbations. It was also observed that a higher proportion of acebilstat-treated patients remained exacerbation-free during the study compared with placebo. These data suggest that the efficacy of anti-inflammatory therapy may be better assessed using clinical events such as pulmonary exacerbations. Pulmonary exacerbations, a clinical marker of uncontrolled pulmonary inflammation, are critical events that lead to acute decompensation and chronic decline in lung function and are strongly associated with reduced survival. Given this, acevirstat may protect patients from the progressive and irreversible damage associated with CF. [Table 2] [Table 3]

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[0112] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as encompassed by the appended claims.

[0113] The patent and scientific literature referred to herein establishes knowledge available to those of skill in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are hereby incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, manuscripts, and scientific literature cited herein are hereby incorporated by reference. The relevant teachings of all patents, published applications, and references cited herein are hereby incorporated by reference in their entirety.

Claims

1. 1. A pharmaceutical composition comprising acevirstat for use in a method of treating cystic fibrosis in a patient in need thereof and / or a method of reducing pulmonary exacerbations in a cystic fibrosis patient, comprising: The pharmaceutical composition, wherein the patient is receiving concomitant treatment with a CFTR modulator and the patient has an FEV1pp of 68% or greater at baseline, and the method comprises orally administering acevirstat to the patient at a total daily dose of 100 mg or less.

2. 2. The pharmaceutical composition of claim 1, wherein acevirstat is administered at a total daily dose of 100 mg.

3. 3. The pharmaceutical composition of claim 2, wherein acevirstat is administered at a total daily dose of 50 mg.

4. 2. The pharmaceutical composition of claim 1, wherein the CFTR modulator is a CFTR enhancer and / or a CFTR corrective agent.

5. The pharmaceutical composition of claim 4, wherein the CFTR modulator is a CFTR enhancer.

6. The pharmaceutical composition of claim 4, wherein the CFTR modulator is a CFTR corrective agent.

7. 10. The pharmaceutical composition of claim 1, wherein the patient is undergoing combination therapy with at least two CFTR correcting agents, or with at least one CFTR correcting agent and at least one CFTR enhancing agent.

8. 8. The pharmaceutical composition of claim 4, 5, or 7, wherein the CFTR enhancer is ivacaftor.

9. 2. The pharmaceutical composition of claim 1, wherein the CFTR correcting agent is lumacaftor or tezacaftor.

10. The pharmaceutical composition of claim 1, wherein the patient has an FEV1pp of 70% or greater at baseline.

11. The pharmaceutical composition of claim 10, wherein the patient has an FEV1pp of 75% or greater at baseline.

12. 2. The method of claim 1, wherein the patient experiences a reduction in the rate, number or frequency of pulmonary exacerbations over a 12-month period following initiation of administration of acevirstat.

13. The pharmaceutical composition of claim 12, wherein the patient does not experience a pulmonary exacerbation for at least 48 weeks after starting administration of acevirstat.

14. 2. The pharmaceutical composition of claim 1, wherein the patient experiences a reduction in the number of pulmonary exacerbations in the 12 months after initiating administration of acevirstat compared to the number of pulmonary exacerbations in the 12 months prior to initiating administration of acevirstat.

15. 2. The pharmaceutical composition of claim 1, wherein the CFTR modulator is ivacaftor or a combination drug comprising ivacaftor.

16. 16. The pharmaceutical composition of claim 15, wherein the combination drug is lumacaftor / ivacaftor.

17. The pharmaceutical composition of claim 15, wherein the combination drug is a triple combination.

18. The above-mentioned triple drug combination is Ivacaftor, Tezacaftor, One selected from the group consisting of VX-445, VX-659, VX-440 and VX-152 20. The pharmaceutical composition of claim 17, comprising:

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