Dosage regimens for camlipixant in treating chronic cough

Abstract

The invention relates to the use of camlipixant in the treatment of cough, in particular chronic cough, and drug-drug interactions when administered with a CYP2C8 inhibitor.

Description

[0001] BEL00023W001

[0002] CAMLIPIXANT DRUG-DRUG INTERACTIONS

[0003] FIELD OF THE INVENTION

[0004] The invention relates to methods of administering camlipixant for treatment in various diseases, in particular chronic cough, such as refractory chronic cough or unexplained chronic cough.

[0005] BACKGROUND TO THE INVENTION

[0006] P2X3 antagonists are useful in the treatment of various diseases, particularly in the treatment of refractory chronic cough. One particular P2X3 antagonist in development is known as camlipixant, disclosed in WO 2014 / 117274.

[0007] Camlipixant is an investigational new drug and it is important to establish if it has any interactions with other drugs so that treatment can be modified or avoided as and when necessary.

[0008] SUMMARY OF THE INVENTION

[0009] In a first aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first AU Co-inf or AUCo-t, and wherein following administration of camlipixant said patient is administered a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP2C8 inhibitor and camlipixant, wherein the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo-t.

[0010] In a second aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first Cmax, and wherein following administration of camlipixant said patient is administered a CYP2C8 inhibitor for a non-chronic cough related indication, wherein said patient has a second Cmax following administration of a CYP2C8 inhibitor and camlipixant, wherein the second Cmax is about 105 to about 200% higher than the first Cmax.

[0011] In a third aspect, there is provided a method of administering camlipixant therapy to a patient in need thereof, wherein said patient is receiving a CYP2C8 inhibitor, the method comprising

[0012] (a) first, discontinuing administration of the CYP2C8 inhibitor;

[0013] (b) second, administering to the patient a therapeutically effective amount of camlipixant. BEL00023W001

[0014] In a fourth aspect, there is provided a method of treatment of chronic cough in a patient in need thereof, comprising administration of a therapeutically effective amount of camlipixant to the patient in need thereof, wherein coadministration with a CYP2C8 inhibitor is avoided.

[0015] In a fifth aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, the method comprising

[0016] (i) administration of camlipixant for the treatment of chronic cough; and

[0017] (ii) administration of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf or AllCo-t in the range of about 2500 to about 7500 h*ng / mL on treatment with camlipixant alone and an AUCo-inf or AUCo-t in the range of about 7000 to about 18000 h*ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor, or wherein the patient has a Cmax in the range of about 500 to about 1500 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 800 to about 2000 ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0018] In a sixth aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf or AUCo-t in the range of about 7000 to about 18000 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non-chronic cough related indication has an AUCo-inf or AUCo-t in the range of about 2500 to about 7500 h*ng / mL.

[0019] In a seventh aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has a Cmax in the range of about 800 to about 2000 ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non-chronic cough related indication has a Cmax in the range of about 500 to about 1500 ng / mL. BEL00023W001

[0020] BRIEF DESCRIPTION OF THE FIGURES

[0021] Figure 1 is a schematic illustrating the study design for the drug-drug interaction study disclosed herein.

[0022] Figure 2 is a graph showing camlipixant plasma concentration over time and camlipixant + gemfibrozil plasma concentration over time (linear scale).

[0023] Figure 3 is a graph showing camlipixant plasma concentration over time and camlipixant + gemfibrozil plasma concentration over time (semilog scale).

[0024] Figure 4 is a summary of descriptive statistics of plasma PK parameters of camlipixant and camlipixant + gemfibrozil.

[0025] Abbreviations: AUCo-inf=Area under the concentration-time curve from time zero to infinity (extrapolated); AUCo-t=Area under the concentration-time curve from time zero until the last observed concentration; Cmax=Maximal observed concentration; CL / F=Apparent clearance, calculated as Dose / AUCo-inf; CV%=Coefficient of variation (percent); Kei=Terminal elimination rate constant; Max= Maxi mum; Min=Minimum; N=Number of participants in the population; PK=Pharmacokinetic(s); Residual area= Percentage of AUCo-inf due to extrapolation from the time of the last observed concentration to infinity, calculated as [1- (AUCo-t / AUCo-inf)]x1OO; SD=Standard deviation; Tmax=Time when the maximal concentration is observed; T%ei=Terminal elimination half-life, calculated as ln(2) / Kei; Vd / F=Apparent volume of distribution, calculated as Dose / KeixAUCo-inf).

[0026] Figure 5 is a summary of geometric LSM for each study intervention, LSM ratios (camlipixant + gemfibrozil versus camlipixant), the 90% geometric Cl, intra-subject CV% and p-values for AUCo-inf, AUCo-t and Cmax.

[0027] Abbreviations: ANOVA=Analysis of variance; CI=Confidence interval; CV%=Coefficient of variation (percent); DDI=Drug-drug interaction; df=Degrees of freedom; exp=Exponential; LSM=Least square means; n=Number of participants included in the analysis; PK=Pharmacokinetic(s); p-value=Probability value; SE=Standard error; vs=Versus; > / =Square root.

[0028] [a] The geometric LSM ratio (camlipixant + rifampin / camlipixant) is calculated using LSM according to the following formula: exp(DIFFERENCE) * 100.

[0029] [b] The 90% geometric Cl is calculated according to the following formula: exp(DIFFERENCE ± t(dfResidual)* SEDIFFERENCE) * 100.

[0030] [c] The ratio of geometric means (camlipixant + rifampin / camlipixant) and 90% Cis for the ratio of geometric means, based on least squares means from the repeated measure BEL00023W001

[0031] ANOVA of the In transformed AUCO-t, AUCO-inf, and Cmax must be within 80% to 125% to demonstrate no DDL

[0032] [d] Calculated according to formula: (exp (residual variance) - 1) * 100.

[0033] [e] Calculated according to formula: (exp (subject variance) - 1) * 100.

[0034] Figure 6 is a table providing values of AUCo-inf for camlipixant alone and camlipixant + gemfibrozil.

[0035] Figure 7 is a table providing values of AllCo-t for camlipixant alone and camlipixant + gemfibrozil.

[0036] Figure 8 is a table providing values of Cmax for camlipixant alone and camlipixant + gemfibrozil.

[0037] DETAILED DESCRIPTION OF THE INVENTION

[0038] Definitions

[0039] The term “treatment” refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject.

[0040] The term “therapeutically effective amount” refers to the quantity of a compound of the invention, which will elicit the desired biological response in a human body. It may vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.

[0041] The term “refractory chronic cough” refers to a cough lasting >8 weeks despite adequate treatment and investigation for cough-related aetiologies.

[0042] The term “non-chronic cough related indication” refers to an indication which is not defined as chronic cough or refractory chronic cough.

[0043] Reference to “camlipixant” is a reference to a compound having the following structure BEL00023W001 pharmaceutically acceptable salt thereof.

[0044] Camlipixant has the chemical name methyl (2S)-2-({2-[2,6-difluoro-4- (methylcarbamoyl)phenyl]-7-methylimidazo[1 ,2-a]pyridine-3-yl}morpholine-4-carboxylate and is also referred in the literature as BLU-5937.

[0045] It should be noted that “AUCo-inf” and “AUCo-t” refer to relevant AUC parameters after a single dose administration. Following repeat dose administration, as would be the case in a therapeutic setting, the relevant AUC parameters may be referred to as AUCo-tau orAUCo-12 based on twice daily dosing of camlipixant.

[0046] Statement of Invention

[0047] In one aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first AUCo-inf or AUCo-t, and wherein following administration of camlipixant said patient is administered a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP2C8 inhibitor and camlipixant, wherein the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AU Co-inf or AUCo-t, for example about 150 to about 250% higher, particularly about 220% higher.

[0048] In other words, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first AUCo-inf or AUCo-t, and wherein following administration of camlipixant said patient is administered a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP2C8 inhibitor and camlipixant, BEL00023W001 wherein the second AUCo-inf or AllCo-t is about 1.4- to 3.2-fold higher than the first AUCo-inf or ALICo-t, for example about 1.5- to about 2.5-fold higher than the first, particularly about 2.2-fold higher.

[0049] In one embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first AUCo-inf or AUCo-t, and wherein following administration of camlipixant said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a CYP2C8 inhibitor, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP2C8 inhibitor and camlipixant, wherein the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo-t, for example about 150 to about 250% higher, particularly about 220% higher; or wherein the second AUCo-inf or AUCo-t is about 1.4- to 3.2-fold higher than the first AUCo-inf or AUCo-t, for example about 1.5- to about 2.5-fold higher than the first, particularly about 2.2-fold higher.

[0050] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof wherein, said patient has a first AUCo-inf or AUCo-t, and wherein following administration with camlipixant said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a CYP2C8 inhibitor, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP2C8 inhibitor and camlipixant, wherein the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo-t, for example about 150 to about 250% higher, particularly about 220% higher; or wherein the second AUCo-inf or AUCo-t is about 1.4- to 3.2-fold higher than the first AUCo-inf or AUCo-t, for example about 1.5- to about 2.5-fold higher than the first, particularly about 2.2-fold higher. BEL00023W001

[0051] In an embodiment, the second AUCo-inf or AllCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo-t.

[0052] In an embodiment, the second AUCo-inf or AUCo-t is about 150 to about 250% higher than the first AUCo-inf or AUCo-t.

[0053] In an embodiment, the second AUCo-inf or AUCo-t is about 220% higher than the first AUCo- inf or AUCo-t.

[0054] In an embodiment, the second AUCo-inf or AUCo-t is about 1.4- to 3.2-fold higher than the first AUCo-inf or AUCo-t.

[0055] In an embodiment, the second AUCo-inf or AUCo-t is about 1.5- to about 2.5-fold higher than the first AUCo-inf or AUCo-t.

[0056] In an embodiment, the second AUCo-inf or AUCo-t is about 2.2-fold higher than the first AUCo- inf or AUCo-t.

[0057] In an embodiment, the first AUCo-inf or AUCo-t is in the range of from about 2500 to about 7500 h*ng / mL.

[0058] In an embodiment, the first AUCo-inf or AUCo-t is in the range of from about 3000 to about 7000 h*ng / mL.

[0059] In an embodiment, the first AUCo-inf is in the range of from about 3071 to about 6995 h*ng / mL.

[0060] In an embodiment, the first AUCo-t is in the range of from about 3030 to about 6590 h*ng / mL.

[0061] In an embodiment, the second AUCo-inf or AUCo-t is in the range of from about 7000 to about 18000 h*ng / mL.

[0062] In an embodiment, the second AUCo-inf or AUCo-t is in the range of from about 7200 to about 17000 h*ng / mL.

[0063] In an embodiment, the second AUCo-inf is in the range of from about 7497 to about 16964 h*ng / mL.

[0064] In an embodiment, the second AUCo-t is in the range of from about 7457 to about 16833 h*ng / mL.

[0065] In an embodiment, the first AUCo-inf or AUCo-t is in the range of from about 2500 to about 7500 h*ng / mL and the second AUCo-inf or AUCo-t is in the range of from about 7000 to about 18000 h*ng / mL. BEL00023W001

[0066] In an embodiment, the first AUCo-inf or AUCo-t is in the range of from about 3000 to about 7000 h*ng / mL and the second AUCo-inf or AUCo-t is in the range of from about 7200 to about 17000 h*ng / mL.

[0067] In an embodiment, the first AUCo-inf is in the range of from about 3071 to about 6995 h*ng / mL and the second AUCo-inf is in the range of from about 7497 to about 16964 h*ng / mL.

[0068] In an embodiment, the first AUCo-t is in the range of from about 3030 to about 6590 h*ng / mL and the second AUCo-t is in the range of from about 7457 to about 16833 h*ng / mL.

[0069] In an embodiment, the first AUCo-inf or AUCo-t is about 2500 to about 7500 h*ng / mL and the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo- t, for example about 150 to about 250% higher, particularly about 220% higher, such that the values may be about those indicated in the table below.

[0070] In an embodiment, the first AUCo-inf or AUCo-t is about 3000 to about 7000 h*ng / mL and the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo- t, for example about 150 to about 250% higher, particularly about 220% higher, such that the values may be about those indicated in the table below.

[0071] In an embodiment, the first AUCo-inf is about 3071 to about 6995 h*ng / mL and the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo-t, for example about 150 to about 250% higher, particularly about 220% higher, such that the values may be about those indicated in the table below.

[0072] In an embodiment, the first AUCo-t is about 3030 to about 6590 h*ng / mL and the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo-t, for BEL00023W001 example about 150 to about 250% higher, particularly about 220% higher, such that the values may be about those indicated in the table below.

[0073] In a second aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first Cmax, and wherein following administration of camlipixant said patient is administered a CYP2C8 inhibitor for a non-chronic cough related indication, wherein said patient has a second Cmax following administration of a CYP2C8 inhibitor and camlipixant, wherein the second Cmax is about 105 to about 200% higher than the first Cmax, for example about 115 to 160% higher or about 115 to about 140% higher, particularly about 125% higher or about 120% higher.

[0074] In other words, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first Cmax, and wherein following administration of camlipixant said patient is administered a CYP2C8 inhibitor for a non-chronic cough related indication, wherein said patient has a second Cmax following administration of a CYP2C8 inhibitor and camlipixant, wherein the second Cmax is about 1 .05- to about 2-fold higher than the first Cmax, for example about 1.15 to 1.6-fold higher or about 1.15 to about 1.4-fold higher, particularly about 1 .25-fold higher or about 1 .20-fold higher.

[0075] In another embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first Cmax, and wherein following administration of camlipixant said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a CYP2C8 inhibitor, wherein said patient has a second Cmax following administration of a CYP2C8 inhibitor and camlipixant, BEL00023W001 wherein the second Cmax is about 105 to about 200% higher than the first Cmax, for example about 115 to 160% higher or about 115 to about 140% higher, particularly about 125% higher or about 120% higher.

[0076] In another embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first Cmax, and wherein following administration of camlipixant said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a CYP2C8 inhibitor, wherein said patient has a second Cmax following administration of a CYP2C8 inhibitor and camlipixant, wherein the second Cmax is about 1 .05- to about 2-fold higher than the first Cmax, for example about 1.15 to 1.6-fold higher or about 1.15 to about 1.4-fold higher, particularly about 1 .25-fold higher or about 1 .20-fold higher.

[0077] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof wherein, said patient has a first Cmax, and wherein following administration said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a CYP2C8 inhibitor, wherein said patient has a second Cmax following administration of a CYP2C8 inhibitor and camlipixant, wherein the second Cmax is about 105 to about 200% higher than the first Cmax, for example about 115 to 160% higher or about 115 to about 140% higher, particularly about 125% higher or about 120% higher.

[0078] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof wherein, said patient has a first Cmax, and wherein following administration said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a CYP2C8 inhibitor, BEL00023W001 wherein said patient has a second Cmax following administration of a CYP2C8 inhibitor and camlipixant, wherein the second Cmax is about 1 .05- to about 2-fold higher than the first Cmax, for example about 1.15 to 1.6-fold higher or about 1.15 to about 1.4-fold higher, particularly about 1 .25-fold higher or about 1 .20-fold higher.

[0079] In an embodiment, the second Cmax is about 105 to about 200% higher than the first Cmax.

[0080] In an embodiment, the second Cmax is about 115 to 160% higher than the first Cmax.

[0081] In an embodiment, the second Cmax is about 115 to about 140% higher than the first Cmax.

[0082] In an embodiment, the second Cmax is about 125% higher than the first Cmax.

[0083] In an embodiment, the second Cmax is about 120% higher than the first Cmax.

[0084] In an embodiment, the first Cmax is in the range of from about 500 to about 1500 ng / mL.

[0085] In an embodiment, the second Cmax is in the range of from about 800 to about 2000 ng / mL.

[0086] In an embodiment, the first Cmax is in the range of from about 677 to about 1450 ng / mL.

[0087] In an embodiment, the second Cmax is in the range of from about 886 to about 1920 ng / mL.

[0088] In an embodiment, the first Cmax is in the range of from about 500 to about 1500 ng / mL and the second Cmax is in the range of from about 800 to about 2000 ng / mL.

[0089] In an embodiment, the first Cmax is in the range of from about 677 to about 1450 ng / mL and the second Cmax is in the range of from about 886 to about 1920 ng / mL.

[0090] In an embodiment, the first Cmax is about 500 to about 1500 ng / mL and the second Cmax is about 105 to about 200% higher than the first Cmax, for example about 115 to 160% higher or about 115 to about 140% higher, particularly about 125% higher or about 120% higher.

[0091] In an embodiment, the first Cmax is about 677 to about 1450 ng / mL and the second Cmax is about 105 to about 200% higher than the first Cmax, for example about 115 to 160% higher or about 115 to about 140% higher, particularly about 125% higher or about 120% higher. BEL00023W001

[0092] In another aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf or AllCo-t in the range of about 7000 to about 18000 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has an AUCo-inf or AUCo-t in the range of about 2500 to about 7500 h*ng / mL.

[0093] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof, wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf in the range of about 7000 to about 18000 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non- chronic cough related indication has an AUCo-inf in the range of about 2500 to about 7500 h*ng / mL.

[0094] In another aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 ihibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-t in the range of about 7000 to about 18000 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non- chronic cough related indication has an AUCo-t in the range of about 2500 to about 7500 h*ng / mL. BEL00023W001

[0095] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof, wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AllCo-t in the range of about 7000 to about 18000 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has an ALICo-t in the range of about 2500 to about 7500 h*ng / mL.

[0096] In an embodiment, the patient has an AUCo-inf or ALICo-t in the range of about 7200 to about 17000 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non-chronic cough related indication has an AUCo-inf or AUCo-t in the range of about 3000 to about 7000 h*ng / mL.

[0097] In an embodiment, the patient has an AUCo-inf in the range of about 7497 to about 16964 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non-chronic cough related indication has an AUCo-inf in the range of about 3071 to about 6995 h*ng / mL.

[0098] In an embodiment, the patient has an AUCo-t in the range of about 7457 to about 16833 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non-chronic cough related indication has an AUCo-t in the range of about 3030 to about 6590 h*ng / mL.

[0099] In another aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has a Cmax in the range of about 800 to about 2000 ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non- chronic cough related indication has a Cmax in the range of about 500 to about 1500 ng / mL. BEL00023W001

[0100] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof, wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has a Cmax in the range of about 800 to about 2000 ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has a Cmax in the range of about 500 to about 1500 ng / mL.

[0101] In an embodiment, the patient has a Cmax in the range of about 886 to about 1920 ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non-chronic cough related indication has a Cmax in the range of about 677 to about 1450 ng / mL.

[0102] In an embodiment, the patient is administered a therapeutically effective amount of camlipixant.

[0103] In an embodiment, the patient is administered a therapeutically effective amount of a CYP2C8 inhibitor.

[0104] In one embodiment, there is provided a method of administering camlipixant therapy to a patient in need thereof, wherein said patient is also in need of a CYP2C8 inhibitor, the method comprising

[0105] (a) administering to the patient a therapeutically effective amount of camlipixant; and

[0106] (b) avoiding co-administration of said CYP2C8 inhibitor.

[0107] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough, wherein the treatment comprises avoidance or discontinuation of concomitant or coadministration of a CYP2C8 inhibitor, to avoid increased exposure or effectiveness of camlipixant.

[0108] In another embodiment, there is provided a method of administering camlipixant therapy to a patient in need thereof, wherein said patient is receiving a CYP2C8 inhibitor, the method comprising

[0109] (a) first, discontinuing administration of the CYP2C8 inhibitor; and

[0110] (b) second, administering to the patient a therapeutically effective amount of camlipixant. BEL00023W001

[0111] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof, wherein the patient is receiving a CYP2C8 inhibitor, wherein administration of the CYP2C8 inhibitor is discontinued prior to administration of camlipixant.

[0112] In an alternative embodiment, there is provided a method of administering camlipixant therapy to a patient in need thereof, wherein said patient is receiving a CYP2C8 inhibitor, the method comprising

[0113] (a) first, discontinuing administration of the CYP2C8 inhibitor;

[0114] (b) second, administering to the patient a therapeutically effective amount of camlipixant; and

[0115] (c) third, administering to the patient an alternative therapy to the CYP2C8 inhibitor.

[0116] In another aspect, there is provided a method of ensuring the desired effectiveness of camlipixant therapy by avoiding increased exposure to camlipixant in a patient in need of camlipixant therapy and receiving a CYP2C8 inhibitor, the method comprising

[0117] (a) administration to said patient a therapeutically effective amount of camlipixant; and

[0118] (b) avoidance of administration of the CYP2C8 inhibitor.

[0119] In another embodiment, there is provided a method of ensuring the desired effectiveness of camlipixant in a patient in need thereof, by avoiding increased exposure to camlipixant in a patient in need of camlipixant therapy and receiving a CYP2C8 inhibitor, the method comprising

[0120] (a) administration to said patient a therapeutically effective amount of camlipixant; and

[0121] (b) avoidance of administration of the CYP2C8 inhibitor.

[0122] In an embodiment, there is provided a method of ensuring the desired effectiveness of camlipixant in a patient in need thereof, wherein said patient is receiving a CYP2C8 inhibitor, the method comprising

[0123] (a) administration to said patient a therapeutically effective amount of camlipixant; and

[0124] (b) avoidance of administration of the CYP2C8 inhibitor.

[0125] In an embodiment, there is provided a method of ensuring or ensuring the desired effectiveness of camlipixant in a patient in need thereof, wherein said patient is receiving a CYP2C8 inhibitor, the method comprising

[0126] (a) first, discontinuing administration of the CYP2C8 inhibitor; and BEL00023W001

[0127] (b) second, administering to the patient a therapeutically effective amount of camlipixant for the treatment of chronic cough.

[0128] In an embodiment, maintaining or ensuring the desired effectiveness of camlipixant or maintaining or ensuring the desired exposure of camlipixant is defined as maintenance of the same AllCo-t, AUCo-inf and / or Cmax value as when camlipixant is administered alone or as the provision of an ALICo-t, AUCo-inf and / or Cmax value as when camlipixant is administered alone. The same is true for the phrase “avoiding increased exposure or effectiveness of camlipixant”.

[0129] In an embodiment, the AUCo-inf of a patient on treatment with camlipixant alone is in the range of from about 2500 to about 7500 h*ng / mL.

[0130] In an embodiment, theAUCo-t of a patient on treatment with camlipixant alone is in the range of from about 2500 to about 7500 h*ng / mL.

[0131] In an embodiment, the AUCo-inf of a patient on treatment with camlipixant alone is in the range of about 3000 to about 7000 h*ng / mL.

[0132] In an embodiment, theAUCo-t of a patient on treatment with camlipixant alone is in the range of about 3000 to about 7000 h*ng / mL.

[0133] In an embodiment, the AUCo-inf of a patient on treatment with camlipixant alone is in the range of about 3071 to about 6995 h*ng / mL.

[0134] In an embodiment, theAUCo-t of a patient on treatment with camlipixant alone is in the range of about 3030 to about 6590 h*ng / mL.

[0135] In an embodiment, the Cmax of a patient on treatment with camlipixant alone is in the range of about 500 to about 1500 ng / mL.

[0136] In an embodiment, the Cmax of a patient on treatment with camlipixant alone is in the range of about 677 to about 1450 ng / mL.

[0137] In an embodiment, the AUCo-inf of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is in the range of about 7000 to about 18000 h*ng / mL.

[0138] In an embodiment, the AUCo-t of a patient receiving treatment with both camlipixant and a inhibitor is in the range of about 7000 to about 18000 h*ng / mL.

[0139] In an embodiment, the AUCo-inf of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is in the range of about 7200 to about 17000 h*ng / mL. BEL00023W001

[0140] In an embodiment, the AllCo-t of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is in the range of about 7200 to about 17000 h*ng / mL.

[0141] In an embodiment, the AUCo-inf of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is in the range of about 7497 to about 16964 h*ng / mL.

[0142] In an embodiment, the ALICo-t of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is in the range of about 7457 to about 16833 h*ng / mL.

[0143] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is in the range of about 800 to about 2000 ng / mL.

[0144] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is in the range of about 886 to about 1920 ng / mL.

[0145] In an embodiment, the AUCo-inf or AUCo-t of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is about 140% to about 320% higher than when the same patient is receiving treatment with camlipixant alone, for example about 150% to about 250% higher than when the same patient is receiving treatment with camlipixant alone, particularly about 220% higher.

[0146] In an embodiment, the AUCo-inf or AUCo-t of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is about 1.4 to about 3.2-fold higher than when the same patient is receiving treatment with camlipixant alone, for example about 1 .5- to about 2.5-fold higher than when the same patient is receiving treatment with camlipixant alone, particularly about 2.2-fold higher.

[0147] In an embodiment, the AUCo-inf or AUCo-t of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is about 220% higher than when the same patient is receiving treatment with camlipixant alone.

[0148] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is about 105% to about 200% higher than when the same patient is receiving treatment with camlipixant alone.

[0149] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is about 115% to about 160% higher than when the same patient is receiving treatment with camlipixant alone.

[0150] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is about 125% higher than when the same patient is receiving treatment with camlipixant alone. BEL00023W001

[0151] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP2C8 inhibitor is about 120% higher than when the same patient is receiving treatment with camlipixant alone.

[0152] In an embodiment, the patient has chronic cough.

[0153] In an embodiment, the patient has refractory chronic cough.

[0154] In another embodiment, there is provided a method of treatment of chronic cough in a patient in need thereof, wherein said patient is receiving treatment with a CYP2C8 inhibitor for a non-cough related indication, the method comprising

[0155] (c) first, discontinuing administration of the CYP2C8 inhibitor; and

[0156] (d) second, administering to the patient a therapeutically effective amount of camlipixant for the treatment of chronic cough.

[0157] In an alternative embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is receiving treatment with a CYP2C8 inhibitor for a non-cough related indication, the method comprising

[0158] (a) first, discontinuing administration of the CYP2C8 inhibitor;

[0159] (b) second, administering to the patient a therapeutically effective amount of camlipixant for the treatment of chronic cough; and

[0160] (c) third, administering to the patient an alternative to the CYP2C8 inhibitor for the treatment of the non-cough related indication.

[0161] In an alternative embodiment, there is provided a method of ensuring the desired effectiveness of camlipixant therapy, wherein said patient is receiving treatment with a CYP2C8 inhibitor for a non-cough related indication, the method comprising

[0162] (a) first, discontinuing administration of the CYP2C8 inhibitor;

[0163] (b) second, administering to the patient a therapeutically effective amount of camlipixant for the treatment of chronic cough; and

[0164] (c) third, administering to the patient an alternative to the CYP2C8 inhibitor for the treatment of the non-cough related indication.

[0165] In an embodiment, the therapeutically effective amount of camlipixant is a twice daily dose of 25 mg or 50 mg per day.

[0166] In an embodiment, the therapeutically effective amount of camlipixant is a twice daily dose of 50 mg per day.

[0167] In an embodiment, the therapeutically effective amount of camlipixant is a twice daily dose of 25 mg per day. BEL00023W001

[0168] In an embodiment, there is provided a method of treating chronic cough in a patient in need thereof, the method comprising administration of camlipixant and comprising the following steps:

[0169] (a) identifying a patient in need of treatment with camlipixant;

[0170] (b) determining that the patient is also receiving therapy with a CYP2C8 inhibitor for a non-chronic cough related indication; and

[0171] (c) administering camlipixant to the patient in need thereof wherein (i) exposure of camlipixant based on AUCo-inf or AllCo-t is increased by about 140 to about 320%, for example about 150 to about 250%; or (ii) AUCo-inf or AUCo-t is in the range of about 7000 to about 18000 h*ng / mL; or (iii) Cmax is increased by about 105 to about 200%, for example about 115 to about 160%; or (iv) Cmax is in the range of about 800 to about 2000 ng / mL.

[0172] In another aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, the method comprising

[0173] (i) administration of camlipixant for the treatment of chronic cough; and

[0174] (ii) administration of a CYfP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf in the range of about 2500 to about 7500 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 7000 to about 18000 h*ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0175] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof, wherein the patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough indication, wherein the patient has an AUCo-inf or AUCo-t in the range of about 2500 to about 7500 h*ng / mL on treatment with camlipixant alone and an AUCo-inf or AUCo-t in the range of about 7000 to about 18000 h*ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0176] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is also in need of a CYP2C8 inhbitor for the treatment of a non-chronic cough related indication, the method comprising

[0177] (i) administration of a therapeutically effective amount of camlipixant for the treatment of chronic cough; and BEL00023W001

[0178] (ii) administration of a therapeutically effective amount of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AllCo-t in the range of about 2500 to about 7500 h*ng / mL on treatment with camlipixant alone and an ALICo-t in the range of about 7000 to about 18000 h*ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0179] In an embodiment, the patient has an AUCo-inf or ALICo-t in the range of about 3000 to about 7000 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 7200 to about 17000 h*ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0180] In an embodiment, the patient has an AUCo-inf in the range of about 3071 to about 6995 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 7497 to about 16964 h*ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0181] In an embodiment, the patient has an AUCo-t in the range of about 3030 to about 6590 h*ng / mL on treatment with camlipixant alone and an AUCo-t in the range of about 7457 to about 16833 h*ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0182] In another aspect, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, the method comprising

[0183] (i) administration of camlipixant for the treatment of chronic cough; and

[0184] (ii) administration of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has a Cmax in the range of about 500 to about 1500 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 800 to about 2000 ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0185] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof, wherein the patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough indication, wherein the patient has a Cmax in the range of about 500 to about 1500 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 800 to about 2000 ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

[0186] In an embodiment, the patient has a Cmax in the range of about 677 to about 1450 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 886 to about 1920 ng / mL on treatment with camlipixant and a CYP2C8 inhibitor. BEL00023W001

[0187] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, the method comprising

[0188] (i) administration of camlipixant for the treatment of chronic cough; and

[0189] (ii) administration of a CYP2C8 inhibitor for the treatment of a non-cough related indication, wherein the patient has a first AUCo-inf or AllCo-t on treatment with camlipixant alone and a second AUCo-inf or ALICo-t on treatment with both camlipixant and of a CYP2C8 inhibitor, wherein the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo- t, for example about 150 to about 250% higher than the first AUCo-inf or AUCo-t, for example about 220% higher.

[0190] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof, wherein the patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough indication, wherein the patient has a first AUCo-inf or AUCo-t on treatment with camlipixant alone and a second AUCo-inf or AUCo-t on treatment with both camlipixant and of a CYP2C8 inhibitor, wherein the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo-t, for example about 150 to about 250% higher than the first AUCo-inf or AUCo-t, for example about 220% higher.

[0191] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, the method comprising

[0192] (i) administration of camlipixant for the treatment of chronic cough; and

[0193] (ii) administration of a CYP2C8 inhibitor for the treatment of a non-cough related indication, wherein the patient has a first Cmax on treatment with camlipixant alone and a second Cmax on treatment with both camlipixant and of a CYP2C8 inhibitor, wherein the second Cmax is about 105 to about 200% higher than the first Cmax, for example about 115 to about 160% higher than the first Cmax, for example about 115 to about 140% higher than the first Cmax, particularly about 125% or 120% higher.

[0194] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough in a patient in need thereof, wherein the patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough indication, BEL00023W001 wherein the patient has a first Cmax on treatment with camlipixant alone and a second Cmax on treatment with both camlipixant and of a CYP2C8 inhibitor, wherein the second Cmax is about 105 to about 200% higher than the first Cmax, for example about 115 to about 160% higher than the first Cmax, for example about 115 to about 140% higher than the first Cmax, particularly about 125% or 120% higher.

[0195] In an embodiment, the patient is administered a therapeutically effective amount of camlipixant.

[0196] In an embodiment, the patient is administered a therapeutically effective amount of a CYP2C8 inhibitor.

[0197] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered a therapeutically effective amount of camlipixant and has an AUCo-inf or AllCo-t in the range of about 2500 to about 7500 h*ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP2C8 inhibitor, wherein said patient has an AUCo-inf or AUCo-t in the range of about 7000 to about 18000 h*ng / mL following administration of both a CYP2C8 inhibitor and camlipixant.

[0198] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered a therapeutically effective amount of camlipixant and has an AUCo-inf or AUCo-t in the range of about 3000 to about 7000 h*ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP2C8 inhibitor, wherein said patient has an AUCo-inf or AUCo-t in the range of about 7200 to about 17000 h*ng / mL following administration of both a CYP2C8 inhibitor and camlipixant.

[0199] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered a therapeutically effective amount of camlipixant and has an AUCo-inf in the range of about 3071 to about 6995 h*ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP2C8 inhibitor, wherein said patient has an AUCo-inf in the range of about 7497 to about 16964 h*ng / mL following administration of a CYP2C8 inhibitor and camlipixant. BEL00023W001

[0200] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered a therapeutically effective amount of camlipixant and has an AllCo-t in the range of about 3030 to about 6590 h*ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP2C8 inhibitor, wherein said patient has an ALICo-t in the range of about 7457 to about 16833 h*ng / mL following administration of both a CYP2C8 inhibitor and camlipixant.

[0201] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered a therapeutically effective amount of camlipixant and has a Cmax in the range of about 500 to about 1500 ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP2C8 inhibitor, wherein said patient has a Cmax in the range of about 800 to about 2000 ng / mL following administration of both a CYP2C8 inhibitor and camlipixant.

[0202] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered a therapeutically effective amount of camlipixant and has a Cmax in the range of about 677 to about 1450 ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP2C8 inhibitor, wherein said patient has a Cmax in the range of about 886 to about 1920 ng / mL following administration of both a CYP2C8 inhibitor and camlipixant.

[0203] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf or AUCo-t in the range of about 7000 to about 18000 h*ng / mL or Cmax in the range of about 800 to about 2000 ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and BEL00023W001 wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication, the patient has a reduction in AUCo-inf, AllCo-t or Cmax-

[0204] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf in the range of about 7497 to about 16964 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication, the patient has a reduction in AUCo-inf.

[0205] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-t in the range of about 7457 to about 16833 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non- chronic cough related indication, the patient has a reduction in AUCo-t.

[0206] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has a Cmax in the range of about 886 to about 1920 ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the non- chronic cough related indication, the patient has a reduction in Cmax.

[0207] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, BEL00023W001 wherein the patient has a first AUCo-inf or AllCo-t while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has a second AUCo-inf orAUCo-t, wherein the second AUCo-inf orAUCo-t is lower relative to the first AUCo-inf orAUCo-t.

[0208] In an embodiment, the first AUCo-inf or AUCo-t while on treatment with both camlipixant and a CYP2C8 inhibitor is about 140 to about 320% higher than the second AUCo-inf or AUCo-t following discontinuation of treatment with a CYP2C8 inhibitor.

[0209] In an embodiment, the first AUCo-inf or AUCo-t while on treatment with both camlipixant and a CYP2C8 inhibitor is about 150 to about 250% higher than the second AUCo-inf or AUCo-t following discontinuation of treatment with a CYP2C8 inhibitor.

[0210] In an embodiment, the first AUCo-inf or AUCo-t while on treatment with both camlipixant and a CYP2C8 inhibitor is about 220% higher than the second AUCo-inf or AUCo-t following discontinuation of treatment with a CYP2C8 inhibitor.

[0211] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered a therapeutically effective amount of camlipixant, and wherein said patient is also receiving a therapeutically effective amount of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has a first Cmax while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has a second Cmax, wherein the second Cmax is lower relative to the first AUCo-inf orAUCo-t.

[0212] In an embodiment, the first Cmax while on treatment with both camlipixant and a CYP2C8 inhibitor is about 105 to about 200% higher than the second Cmax following discontinuation of treatment with a CYP2C8 inhibitor.

[0213] In an embodiment, the first Cmax while on treatment with both camlipixant and a CYP2C8 inhibitor is about 115 to about 160% higher than the second Cmax following discontinuation of treatment with a CYP2C8 inhibitor.

[0214] In an embodiment, the first Cmax while on treatment with both camlipixant and a CYP2C8 inhibitor is about 115 to about 140% higher than the second Cmax following discontinuation of treatment with a CYP2C8 inhibitor. BEL00023W001

[0215] In an embodiment, the first Cmax while on treatment with both camlipixant and a CYP2C8 inhibitor is about 125% or about 120% higher than the second Cmax following discontinuation of treatment with a CYP2C8 inhibitor.

[0216] In an embodiment, there is provided a method of treatment of chronic cough in a patient in need thereof, the method comprising administering a therapeutically effective amount of camlipixant, wherein said patient in need thereof is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the AUCo-inf or AllCo-t of said patient is in the range of about 2500 to about 7500 h*ng / mL when on treatment with camlipixant alone; and wherein the AUCo-inf or AUCo-t of said patient is about 140 to about 320% higher when on treatment with both camlipixant and a CYP2C8 inhibitor.

[0217] In an embodiment, the AUCo-inf or AUCo-t of said patient is about 150 to about 250% higher when on treatment with both camlipixant and a CYP2C8 inhibitor.

[0218] In an embodiment, the AUCo-inf or AUCo-t of said patient is about 220% higher when on treatment with both camlipixant and a CYP2C8 inhibitor.

[0219] In an embodiment, there is provided a method of treatment of chronic cough in a patient in need thereof, the method comprising administering a therapeutically effective amount of camlipixant, wherein said patient in need thereof is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the Cmax of said patient is in the range of about 500 to about 1500 ng / mL when on treatment with camlipixant alone; and wherein the Cmax of said patient is about 105 to about 200% higher when on treatment with both camlipixant and a CYP2C8 inhibitor.

[0220] In an embodiment, the Cmax of said patient is about 115 to about 160% higher when on treatment with both camlipixant and a CYP2C8 inhibitor.

[0221] In an embodiment, the Cmax of said patient is about 115 to about 140% higher when on treatment with both camlipixant and a CYP2C8 inhibitor.

[0222] In an embodiment, the Cmax of said patient is about 125% higher when on treatment with both camlipixant and a CYP2C8 inhibitor.

[0223] In an embodiment, the Cmax of said patient is about 120% higher when on treatment with both camlipixant and a CYP2C8 inhibitor. BEL00023W001

[0224] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, the method comprising administration of a therapeutically effective amount of camlipixant, the method further comprising,

[0225] (a) prior to treatment with camlipixant, determination that the patient in need thereof is receiving therapy with a CYP2C8 inhibitor;

[0226] (b) providing a therapeutically effective amount of camlipixant which does not result in increased exposure or effectiveness of camlipixant relative to treatment of a patient with camlipixant alone.

[0227] In an embodiment, the therapeutically effective amount of camlipixant which does not result in increased exposure or effectiveness of camlipixant relative to treatment of a patient with camlipixant alone is an amount of 25 mg twice per day or 50 mg twice per day.

[0228] In an embodiment, the therapeutically effective amount of camlipixant which does not result in increased exposure or effectiveness of camlipixant relative to treatment of a patient with camlipixant alone is an amount of 25 mg twice per day.

[0229] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, the method comprising administration of a therapeutically effective amount of camlipixant, the method further comprising,

[0230] (a) prior to treatment with camlipixant, determination that the patient in need thereof is receiving therapy with a CYP2C8 inhibitor;

[0231] (b) providing a dose of 25 mg twice a day or a total daily dose of 50 mg.

[0232] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of camlipixant, wherein said patient is also receiving treatment with a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein said patient has an AUCo-inf or AllCo-t of about 140 to about 320% of the AUCo-inf or ALICo-t when on treatment with camlipixant alone.

[0233] In an embodiment, said patient has an AUCo-inf orAUCo-t of about 150 to about 250% of the AUCo-inf orAUCo-t when on treatment with camlipixant alone.

[0234] In an embodiment, said patient has an AUCo-inf or AUCo-t of about 220% of the AUCo-inf or AUCo-t when on treatment with camlipixant alone. BEL00023W001

[0235] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of camlipixant, wherein said patient is also receiving treatment with a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein said patient has a Cmax of about 105 to about 200% of the Cmax than when on treatment with camlipixant alone.

[0236] In an embodiment, said patient has a Cmax of about 115 to about 160% of the Cmax than when on treatment with camlipixant alone.

[0237] In an embodiment, said patient has a Cmax of about 115 to about 140% of the Cmax than when on treatment with camlipixant alone.

[0238] In an embodiment, said patient has a Cmax of about 125% of the Cmax than when on treatment with camlipixant alone.

[0239] In an embodiment, said patient has a Cmax of about 120% of the Cmax than when on treatment with camlipixant alone.

[0240] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of camlipixant, wherein said patient is also receiving treatment with a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, the method further comprising selection of a dose of camlipixant resulting in no increase in effectiveness or no increase in exposure to camlipixant.

[0241] In an embodiment, no increase in effectiveness or exposure to camlipixant is intended to mean that the AUCo-inf, AllCo-t or Cmax remains consistent when measured throughout patient treatment with camlipixant, i.e. does not increase or decrease significantly.

[0242] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, the method comprising administering a therapeutically effective amount of camlipixant and wherein said patient is also receiving prior treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, wherein the AUCo-inf or AUCo-t of said patient on treatment with both camlipixant and a CYP2C8 inhibitor is about 140 to about 320% of the AUCo-inf or AUCo-t of said patient when on treatment with camlipixant alone; and / or BEL00023W001 wherein the Cmax of said patient on treatment with both camlipixant and a CYP2C8 inhibitor is about 105 to about 200% of the Cmax of said patient when on treatment with camlipixant alone.

[0243] In an embodiment, there is provided a method for the treatment of chronic cough in a patient in need thereof, the method comprising administering a therapeutically effective amount of camlipixant and wherein said patient is also receiving prior treatment with a CYP2C8 inhibitor for a non-chronic cough related indication, wherein the AUCo-inf or AllCo-t of said patient on treatment with both camlipixant and a CYP2C8 inhibitor is about 150 to about 250% of the AUCo-inf or ALICo-t of said patient when on treatment with camlipixant alone; and / or wherein the Cmax of said patient on treatment with both camlipixant and a CYP2C8 inhibitor is about 115 to about 160% of the Cmax of said patient when on treatment with camlipixant alone.

[0244] In an embodiment, there is provided a pharmaceutical composition comprising camlipixant for use in a method for the treatment of chronic cough, wherein the method comprises the following steps:

[0245] (a) identifying a patient in need of treatment with camlipixant;

[0246] (b) determination that the patient is receiving therapy with a CYP2C8 inhibitor; and

[0247] (c) administering a dose of camlipixant for the treatment of chronic cough, which is lower than the dose administered to a patient not receiving therapy with a CYP2C8 inhibitor.

[0248] In an embodiment, there is provided a pharmaceutical composition comprising camlipixant for use in a method for the treatment of chronic cough, wherein the method comprises the following steps:

[0249] (a) identifying a patient in need of treatment with camlipixant;

[0250] (b) determination that the patient is receiving therapy with a CYP2C8 inhibitor; and

[0251] (c) administering a 50 mg daily dose of camlipixant for the treatment of chronic cough.

[0252] In an embodiment, there is provided a pharmaceutical composition comprising camlipixant for use in a method for the treatment of chronic cough, wherein the method comprises the following steps:

[0253] (a) identifying a patient in need of treatment with camlipixant;

[0254] (b) determination that the patient is receiving therapy with a CYP2C8 inhibitor; and BEL00023W001

[0255] (c) administering a 25 mg dose of camlipixant twice daily for the treatment of chronic cough.

[0256] In an embodiment, the CYP2C8 inhibitor is a strong CYP2C8 inhibitor.

[0257] In an embodiment, the CYP2C8 inhibitor is gemfibrozil.

[0258] In an embodiment, the strong CYP2C8 inhibitor is gemfibrozil.

[0259] In alternative embodiment, the CYP2C8 inhibitor is a moderate CYP2C8 inhibitor.

[0260] In an embodiment, the moderate CYP2C8 inhibitor is selected from the group consisting of clopidogrel, deferasirox, teriflunomide and trimethoprim.

[0261] In a further alternative embodiment, the CYP2C8 inhibitor is a weak CYP2C8 inhibitor.

[0262] In an embodiment, the weak CYP2C8 inhibitor is selected from the group consisting of abiraterone, efavirenz, lapatinib and tucatinib.

[0263] In an embodiment, the chronic cough is refractory chronic cough (RCC).

[0264] In an embodiment, the chronic cough is unexplained chronic cough (UCC).

[0265] EXAMPLES

[0266] The purpose of this study was to assess, in vivo, the potential of camlipixant drug-drug interactions (DDIs) with CYP2C8 inhibitors.

[0267] STUDY OBJECTIVES AND ENDPOINTS

[0268] Objectives

[0269] Primary objective:

[0270] • To assess the effect of repeated oral doses of gemfibrozil, a CYP2C8 inhibitor, on the PK of a single oral dose of camlipixant administered to healthy participants.

[0271] Secondary objective:

[0272] • To evaluate the safety and tolerability of camlipixant when administered alone and in combination with gemfibrozil to healthy participants.

[0273] Endpoints

[0274] Primary endpoints:

[0275] • PK parameters: AUCo-inf, AUCo-t, and Cmax BEL00023W001

[0276] Study Design

[0277] This was a single-center, Phase 1 , open-label, fixed-sequence, DDI study designed to compare the PK of camlipixant when administered with and without gemfibrozil in healthy participants under fasting conditions.

[0278] A total of 16 participants were to be enrolled. Participants received the assigned study intervention (the term “study intervention” is used to describe study treatment, study drug, or co-administration).

[0279] Participants received a single oral dose of 1x50 mg camlipixant tablet on Day 1 , followed by 72 hours of PK and safety assessments. Repeated oral doses of 1x600 mg gemfibrozil tablet were administered BID, every 12 hours, (total daily dose of 1200 mg) on Days 5 to 11 , with co-administration of a single oral dose of 1x50 mg camlipixant tablet with the morning dose of gemfibrozil on Day 9. Administration of camlipixant on Day 9 occurred 1 hour (±2 minutes) after administration of gemfibrozil, followed by 72 hours of PK and safety assessments.

[0280] The study included a screening visit from Day -28 to Day -1. Eligible participants were admitted to the clinical site on Day -1 and were confined until completion of the assessments on Day 12 (Part 1) or Day 13 (Part 2). There was a washout period of at least 4 days between the first dose of camlipixant on Day 1 and the first dose of gemfibrozil on Day 5. A follow-up phone call was performed 7±2 days after discharge (Day 19±2).

[0281] The maximum total duration of study participation for each participant from screening through the follow-up phone call was anticipated to be approximately 7 weeks.

[0282] The study was intended to dose in one group; if, for any reason, the study was dosed in more than one group, all groups were dosed at the same clinical site and the same protocol requirements and procedures were followed within each group.

[0283] Discussion of Study Design

[0284] The purpose of the study was to assess, in vivo, the potential of camlipixant drug-drug interactions (DDIs) with CYP2C8 inhibitors, believed to be involved in the biotransformation of camlipixant. In accordance with the recommendations provided in the FDA Guidance for Clinical Drug Interaction Studies, multiple doses of the CYP inhibitor gemfibrozil were administered to evaluate the effect on the PK of single dose camlipixant. Gemfibrozil is a clinically validated, strong] inhibitor for CYP2C8. BEL00023W001

[0285] Selection of study population

[0286] 9.4.1. Inclusion / exclusion Criteria

[0287] Inclusion Criteria

[0288] Participants were to meet all of the following criteria to be included in the study:

[0289] 1 . Male or female, non-smoker (no use of tobacco or nicotine products within 3 months prior to screening), >18 and <55 years of age, with BMI >18.5 and <30.0 kg / m2 and body weight >50.0 kg.

[0290] 2. Healthy as defined by: a. the absence of CS illness and surgery within 4 weeks prior to dosing. b. the absence of CS history of neurological, endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.

[0291] 3. Female participants of non-childbearing potential must have been: a. post-menopausal (spontaneous amenorrhea for at least 12 months prior to dosing) with confirmation by documented FSH levels >40 mlll / mL; or b. surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) at least 3 months prior to dosing.

[0292] 4. Females of childbearing potential who were sexually active with a non-sterile male partner (sterile male partners were defined as men vasectomized since at least 3 months) must have been willing to use one of the following acceptable contraceptive methods throughout the study and for 90 days after the last study intervention administration: a. Simultaneous use of intrauterine contraceptive device without hormone release system placed at least 4 weeks prior to study intervention administration, and condom for the male partner; b. simultaneous use of diaphragm or cervical cap with intravaginally applied spermicide and male condom for the male partner, started at least 21 days prior to study intervention administration; c. tubal ligation at least 3 months prior to dosing.

[0293] 5. Female participants must have been willing not to donate ova for 90 days after the last dose.

[0294] 6. Male participants who were not vasectomized for at least 3 months prior to dosing and who were sexually active with a female partner of childbearing potential must have been willing to use one of the following acceptable contraceptive methods from the first dose and for 90 days after the last dose: BEL00023W001 a. simultaneous use of condom and hormonal contraceptive (e.g., oral, patch, depot injection, implant, vaginal ring, intrauterine device) or non-hormonal intrauterine device used for at least 4 weeks prior to sexual intercourse for the female partner; b. simultaneous use of condom and a diaphragm or cervical cap with spermicide for the female partner.

[0295] 7. Male participants (including men who had had a vasectomy) with a pregnant partner must have agreed to use a condom from the first dose and for 90 days after the last dose.

[0296] 8. Male participants must have been willing not to donate sperm for 90 days after the last dose.

[0297] 9. Able to understand the study procedures and provide signed informed consent to participate in the study.

[0298] Exclusion Criteria

[0299] Participants were excluded from participating in this study if any of the following criteria were met:

[0300] 1. Any CS abnormal finding at physical examination at screening.

[0301] 2. CS abnormal laboratory test results or positive serology test results for HBsAg, HCV antibody, or HIV antigen and antibody, at screening.

[0302] 3. Any of the following laboratory parameters above the ULN values at screening or baseline (Day -1): AST, ALT, direct bilirubin, indirect bilirubin, and total bilirubin. Only abnormal values up to 1 .5xllLN were to be repeated once for confirmation to below ULN.

[0303] 4. Positive pregnancy test or lactating female participant.

[0304] 5. Positive urine drug screen, urine cotinine test, or alcohol breath test.

[0305] 6. Positive test for COVID-19 (SARS-CoV-2) at admission.

[0306] 7. Known allergic reactions or hypersensitivity to camlipixant, gemfibrozil, or other related drugs, or to any excipient in the formulation.

[0307] 8. CS ECG abnormalities (for example, QTcF >450 ms) or vital signs abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or heart rate less than 50 or over 100 bpm) at screening.

[0308] 9. History of drug abuse within 1 year prior to screening or use of drugs (such as cocaine, PCP, crack, opioid derivatives including heroin, and amphetamine derivatives) within 3 months prior to screening, except for cannabis, hashish, or any products containing either, which were not allowed within 1 month prior to screening.

[0309] 10. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to screening that exceeded 10 units for women or 15 units for men of alcohol per week (1 unit=340 mL of beer 5%, 140 mL of wine 12%, or 45 mL of distilled alcohol 40%). BEL00023W001

[0310] 11. History of gastrointestinal disorders, such as stomach ulcers, IBS, ulcerative or pseudomembranous colitis, intestinal obstruction, previous liver disease, hyperbilirubinemia, jaundice, or elevated liver enzymes.

[0311] 12. Known Gilbert, Rotor, Crigler-Najjar, or Dubin-Johnson syndrome.

[0312] 13. Medical history of ageusia / hypogeusia / dysgeusia or known presence of a dysfunction in his / her ability to taste.

[0313] 14. History of gallbladder disease, including cholelithiasis.

[0314] 15. History of renal dysfunction and those with estimated CrCI less than 60 mL / min.

[0315] 16. Participants in Part 1 only: history of myoglobinuria, myopathy, myalgia, myositis, or rhabdomyolysis.

[0316] 17. Participants in Part 1 only: history of Type I hyperlipoproteinemia.

[0317] 18. Participants in Part 2 only: participants with hemorrhagic manifestations, CS active bleeding, including gastrointestinal bleeding, bleeding diathesis, spontaneous or pharmacological impairment of hemostasis.

[0318] 19. Participants in Part 2 only: participants with lesions, diseases, or procedures at risk of CS bleeding / hemorrhagic risks, such as congenital or acquired coagulations disorders, thrombocytopenia or functional platelet defects, recent cerebral infarction (hemorrhagic or ischemic) within the last 6 months, active ulcerative gastrointestinal disease (including peptic ulcer) with recent gastrointestinal bleeding, bacterial endocarditis, recent biopsy or major trauma, brain, spinal or ophthalmic surgery, prosthetic heart valves, or hemodynamically significant rheumatic heart disease.

[0319] 20. Participants in Part 2 only: history of antiphospholipid disease.

[0320] 21. Participants in Part 2 only: participants having undergone any major surgery within 6 months prior to the start of the study, unless deemed otherwise by the Investigator.

[0321] 22. Participants in Part 2 only: any of the following laboratory parameters outside the normal ranges at screening or baseline (Day -1): prothrombin time and aPTT.

[0322] 23. Use of medications for the timeframes specified below, with the exception of medications exempted by the Investigator on a case-by-case basis because they were judged unlikely to affect the PK profile of the study intervention or participant safety (e.g., topical drug products without significant systemic absorption): a. depot injection or implant within 3 months prior to dosing; b. any drug known to induce or inhibit hepatic drug metabolism, including St. John’s wort, within 30 days prior to dosing or 10 half-lives, whichever was longer; c. prescription medications within 14 days prior to dosing; d. any vaccine, including COVID-19 vaccine, within 14 days prior to dosing; e. OTC medications and natural health products (including herbal remedies, homeopathic and traditional medicines, probiotics, food supplements such as BEL00023W001 vitamins, minerals, amino acids, essential fatty acids, and protein supplements used in sports) within 7 days prior to dosing, with the exception of the occasional use of acetaminophen (up to 2 g daily).

[0323] 24. Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to dosing, administration of a biological product in the context of a clinical research study within 90 days prior to dosing, or concomitant participation in an investigational study involving no drug or device administration.

[0324] 25. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to dosing.

[0325] 26. Any reason which, in the opinion of the Investigator, would prevent the participant from participating in the study.

[0326] Study Interventions

[0327] Study Interventions and Reference Therapy

[0328] Participants were administered the following interventions:

[0329] • 1x50 mg of camlipixant (BLU-5937) tablet (Patheon, Part of Thermofisher, Whitby, Ontario, Canada) administered under fasting conditions in the morning of Day 1

[0330] • 1x600 mg tablet of gemfibrozil (Sourced from the Canadian market) administered BID, every 12 hours (total daily dose 1200 mg) for 7 consecutive days from Day 5 to Day 11. Administration occurred before the morning and evening meals, except for the morning dose on Day 9.

[0331] Identification of Study Intervention(s)

[0332] Prior and Concomitant Medications and Non-drug Therapies

[0333] Participants were required to avoid receiving any vaccination (including COVID-19 vaccine) and using prescription medications, OTC medications, and natural health products BEL00023W001

[0334] (including herbal remedies, homeopathic and traditional medicines, probiotics, food supplements such as vitamins, minerals, amino acids, essential fatty acids, and protein supplements used in sports) for the period of time specified in exclusion criterion no. 23 and throughout the study.

[0335] Hormonal contraception and hormone replacement therapy for female participants were not allowed.

[0336] No concomitant medications were allowed during the study, with the exception of medications required for the medical management of an AE / SAE, and medications exempted by the Investigator on a case-by-case basis that were judged unlikely to affect the PK profile of the study intervention or participant safety (e.g., topical drug products without significant systemic absorption).

[0337] If vaccination was required for any reason, first it had to be discussed with and exempted by the Investigator on a case-by-case basis to ensure that it did not compromise the PK profile of the study intervention or the participant safety.

[0338] Medications taken by participants before dosing were documented as prior medications and medications taken by participants after dosing up to follow-up phone call were documented as concomitant medications. Any prior or concomitant medication use, other than the allowed medications stated above, was reviewed, and evaluated on a case-by-case basis by the Investigator to determine if they affected a participant’s eligibility or continued participation in the study, or for potential impact on the study results.

[0339] Compliance

[0340] Study intervention compliance was ensured as participants were dosed under direct supervision by the site’s staff. Participant identification was verified before dosing, and each participant’s identification was cross-checked with the label on the pre-dispensed medication for that participant. A mouth and hand check were performed to ensure participants had swallowed the study medication. In addition, participants were confined to the clinical facility and were monitored from Day -1 , until discharge on Day 12.

[0341] Individual doses were dispensed according to the fixed-sequence scheme in appropriate containers indicated with at least the project number and the participant number / spare number.

[0342] All study interventions received at the site were inventoried and accounted for throughout the study and the result recorded in the drug accountability record. BEL00023W001

[0343] Pharmacokinetic Assessment

[0344] The analytes to be measured included the study intervention camlipixant, as well as gemfibrozil (total and free).

[0345] A dead-volume IV catheter was used for blood collection to avoid multiple skin punctures to participants. Otherwise, blood samples were collected by direct venipuncture.

[0346] The total volume of blood drawn from each participant in this study did not exceed 250 mL.

[0347] Plasma samples were collected and processed as per the Analytical Methodology Information Sheet as summarized below.

[0348] Blood Samples

[0349] A total of 38 blood samples were drawn from each participant for PK analysis of camlipixant (BLU-5937).

[0350] Blood samples were collected into blood collection tubes (1x3 mL) containing K2EDTA. A total of 5 blood samples were drawn for PK analysis of gemfibrozil prior to the morning dose on Days 5, 6, 7, 8 and 9.

[0351] Sample collections done outside the pre-defined time windows were not considered as protocol deviations since actual post-dose sampling times were used for PK and statistical analyses. Unless otherwise specified or for participant safety, when blood draws and other procedures safety procedures coincided, safety procedures took precedence.

[0352] For all the analytes, blood samples were cooled in an ice / water bath and were centrifuged at 2000±20 g for at least 10 minutes at approximately 4°C (no more than 120 minutes between the time of each blood draw and the start of centrifugation).

[0353] Camlipixant (BLU-5937): Two (2) aliquots of at least 0.5 mL (when possible) of plasma were dispensed into polypropylene cryovials with screw caps as soon as possible. The aliquots were transferred to a -80°C freezer (no more than 180 minutes between the start of centrifugation and aliquots storage), pending analysis / shipment to the analytical facility.

[0354] Gemfibrozil: Two (2) aliquots of at least 0.5 mL (when possible) of plasma were dispensed into polypropylene cryovials with screw caps as soon as possible. Twenty-five (25) microliters of stabilizing agent (phosphoric acid [10% VA / ]) was added to the aliquots (no more than 60 minutes between the end of centrifugation and mixing with the stabilizing agent). The aliquots were transferred to a -80°C freezer (no more than 90 minutes between BEL00023W001 the end of stabilization and aliquots storage), pending analysis / shipment to the analytical facility.

[0355] At the end of the study, all clinical samples were transferred to the bioanalytical facility (within the same site). The plasma aliquots were received at the bioanalytical facility frozen and in good condition.

[0356] Plasma sample concentrations for camlipixant (BLU-5937), gemfibrozil, were assayed using validated bioanalytical methods.

[0357] Pharmacokinetic Analyses

[0358] Validated Phoenix WinNonlin software, Version 8.3.4 was used for all PK analyses. Statistical analyses were performed using SAS for Windows software, Version 9.4. Bioanalysis of all samples were to be completed prior to the initiation of the PK and statistical analyses.

[0359] All PK concentration and PK parameter analyses were conducted on the PC population and PK parameter population, respectively.

[0360] For the PC population, PK concentrations, actual times, date / time of study intervention administration, and sample collection were listed for the PC population by nominal time for each study part, study day, participant and intervention, and summarized for the PC population for each study part by intervention and timepoint, using descriptive statistics (n, number of BLQs, arithmetic and geometric means, SD, geometric SD, CV%, geometric mean CV%, min, max, and median). Individual, mean (±SD) concentration, and overlay of individual plasma concentration versus time profile were presented for both linear and semi- logarithmic scales for each study part by intervention. For ease of presentation, actual and nominal sampling times were used to present results for individual and mean figures, respectively.

[0361] PK parameters were presented in data listings and summarized in tables for each study part by study day and intervention (or day), using descriptive statistics (n, arithmetic mean, SD, CV%, geometric mean, geometric SD, geometric mean CV%, minimum, median, and maximum).

[0362] PK Parameters Calculation Rules: For all PK analyses, concentration values BLQ that occurred before the first measurable concentration of the study intervention were set to “0.00”; BLQ values that occurred after first measurable concentration were set to “missing”. No imputations were made on BLQ concentrations. BEL00023W001

[0363] Invalid concentration values (due to bioanalytical or clinical issues) that occurred prior to dosing were replaced by “0.00”. Invalid concentration values that occurred after dosing were set to “missing” for tabulation, graphical representation, and calculation purposes.

[0364] The actual clock time for dosing and the actual clock time for each PK sample collection were recorded. For all sampling times, the actual sampling duration was calculated as the difference between the sample collection actual clock time and the actual clock time of dosing. The actual post-dose sampling times, expressed in hours and rounded off to three decimal digits, was used to calculate the PK parameters. Pre-dose sampling times was always reported as zero (0.000), regardless of the time difference. Nominal sampling times were used in concentration tables and mean graphs, while actual sampling times for postdose samples were used in the individual graphs. Actual sampling times for post-dose samples also were used for PK parameter derivation, unless the actual sampling time was missing, in which case, the nominal time was used.

[0365] Data Presentation Rules: Non-measurable values reported in the plasma concentration data (i.e. , values that were BLQ), were entered as zero for the determination of summary statistics with the exception of geometric mean, geometric SD, and geometric CV%, where BLQ values were imputed as half the LLOQ value. This also applied to any concentrations that were defined as PK parameters. Data recorded as “No Result” or “Not Reported”, “Not Calculated” or “No Sample” were handled as missing (i.e., no assumption was made about the actual concentration).

[0366] Pharmacokinetic Parameters: The PK parameters shown below, were calculated, whenever possible, by standard non-compartmental methods for camlipixant.

[0367] AUCo-inf: Area under the concentration-time curve from time zero to infinity (extrapolated).

[0368] Cmax: Maximal observed concentration.

[0369] AllCo-t: Area under the concentration-time curve from time zero until the last observed concentration.

[0370] Residual area: Percentage of AUCo-inf due to extrapolation from the time of the last observed concentration to infinity, calculated as (1-[AUC0-t / AUC0-inf]) x100.

[0371] Tmax: Time when the maximal concentration was observed.

[0372] T 2 el: Terminal elimination half-life, calculated as ln(2) / Kel.

[0373] Kel: Terminal elimination rate constant.

[0374] CL / F: Apparent clearance, calculated as Dose / AUCO-inf. BEL00023W001

[0375] Vz / F Apparent volume of distribution, calculated as Dose / (Kel x AUCO-inf).

[0376] Additional PK parameters could be calculated as deemed necessary.

[0377] The following information was presented for gemfibrozil: pre-dose concentrations on the morning of Days 5, 6, 7, 8, and 9.

[0378] Some PK parameters may not have been calculated for all or some participants, if the concentration data was not deemed to be amenable to evaluation. However, PK parameters were derived for the participants who comprised the PK parameter population.

[0379] Assessment of gemfibrozil effect: The effect of gemfibrozil on the PK of camlipixant was evaluated using the MIXED procedure in SAS. A repeated measures ANOVA was performed on In-transformed ALICO-t, AUCO-inf, and Cmax at the 1 -sided alpha level of 0.05; the model included intervention as a fixed effect, and participants as a random effect to account for the repeated measures.

[0380] The ratio of geometric means (camlipixant + gemfibrozil / camlipixant) and 90% Cl for the ratio of geometric means, based on least squares means from the repeated measure ANOVA of the In-transformed ALICO-t, AUCO-inf, and Cmax were to be within 80% to 125% to demonstrate no DDL A non-parametric assessment to test for central location differences among interventions (camlipixant + gemfibrozil versus camlipixant), was undertaken for Tmax and presented. The Wilcoxon signed-rank test was performed using the SAS Univariate Procedure on the paired intervention differences for Tmax.

[0381] STUDY POPULATION RESULTS

[0382] Disposition of Participants

[0383] A total of 47 healthy participants were screened for this study. Of these, 25 participants were enrolled and a total of 16 participants were dosed.

[0384] All 16 participants who received at least one dose of any study intervention comprised the safety population (N=16). Fifteen (15 [93.8%] participants) of the 16 participants dosed completed the study. One (1 [6.3%]) participant (participant no. 109) did not complete the study due to TEAEs.

[0385] A breakdown by study intervention is presented in Table 1. BEL00023W001

[0386] Table 1

[0387] Abbreviations: n (%)=Number and percent of participants; n=Number of participants; N=Number of participants in the population.

[0388] [a] Percentage is based on the number of screened volunteers.

[0389] [b] Screening failures include volunteers who did not meet study criteria.

[0390] [c] Not enrolled include volunteers who were judged eligible but decided not to participate on study or who were not selected to participate in the study since there was already a sufficient number of volunteers.

[0391] [d] Enrolled includes volunteers who were judged eligible and accepted to participate in the trial after having signed the approved final version of the study informed consent form and those identified as standby who may replace participants who withdraw from the study before dosing.

[0392] [e] Includes all participants who received at least one dose of the study drug within respective treatment phase. Overall number includes all participants dosed in at least one treatment phase.

[0393] [f] Number of participants who completed the respective treatment phase.

[0394] [g] Percentage is based on the number of participants in the population.

[0395] [h] Percentage is based on the number of participants that did not complete the study.

[0396] Note: Participant 109 was withdrawn on Day 11 during the gemfibrozil / camlipixant treatment phase. The overall column includes participants from all treatment groups.

[0397] Treatment sequence: camlipixant 50 mg single dose on Day 1 , gemfibrozil 600 mg BID from Day 5 to Day 11 , with coadministration of camlipixant 50 mg single dose in the morning of Day 9.

[0398] Exposure and Intervention Compliance

[0399] All participants except 2 received all planned doses:

[0400] All the study interventions were administered as per study design.

[0401] All the participants were compliant with respect to study interventions as administration was performed under direct supervision, and participant identification was verified and cross checked with the pre-dispensed study intervention.

[0402] EFFICACY RESULTS

[0403] Efficacy was not an objective for this study. BEL00023W001

[0404] Pharmacokinetic Results

[0405] All plasma PK concentrations and PK parameter summaries / analyses were conducted on the PK concentration population and PK parameter population, respectively.

[0406] The descriptive statistics for all PK parameters for camlipixant are presented in Figures 6-8 according to study intervention and day (camlipixant alone [Day 1] and camlipixant coadministered with gemfibrozil [Day 9]).

[0407] The mean (±SD) plot for untransformed data is presented using both linear-scale and semi- log-scale in Figure 2 and Figure 3, respectively.

[0408] The mean ALICs (ALICO-t and AUCO-inf) of camlipixant were increased (by approximately 2-fold) when camlipixant was administered in combination with gemfibrozil as compared to camlipixant administered alone.

[0409] The mean Cmax of camlipixant was increased (by approximately 20%) when camlipixant was administered in combination with gemfibrozil as compared to camlipixant administered alone.

[0410] The median Tmax for camlipixant was similar when camlipixant was administered alone compared to camlipixant administered in combination with gemfibrozil.

[0411] The mean T1Z> el for camlipixant was approximately 4 hours longer when camlipixant was administered in combination with gemfibrozil (approximately 10 hours) compared to when camlipixant was administered alone (approximately 6 hours).

[0412] Assessment of Gemfibrozil Effect

[0413] The geometric LSM for each study intervention, LSM ratios (camlipixant + gemfibrozil versus camlipixant), the 90% geometric Cl, intra-subject CV%, inter-subject CV%, and p- values for ALICO-t, AUCO-inf, and Cmax are presented in Figures 4 and 5.

[0414] The exposure of camlipixant when administered in combination with gemfibrozil was greater compared to camlipixant administration alone. The GMRs of AUCO-t, AUCO-inf, and Cmax were 217.49%, 217.78% and 120.86%, respectively and the corresponding 90% Cl were not contained within the 80% to 125% range.

[0415] Pharmacokinetic and Statistical Conclusions

[0416] The exposure of camlipixant when co-administered with gemfibrozil was greater (approximately 2-fold increase for AUCs [AUCO-t and AUCO-inf] and 20% increase for BEL00023W001

[0417] Cmax) compared to camlipixant alone. The GMRs of ALICO-t, AUCO-inf, and Cmax, and the corresponding 90% Cl were not contained within the 80% to 125% range.

[0418] Based on the results:

[0419] • When administered with gemfibrozil, an increase of approximately 20% in peak and approximately 2-fold increase in total exposure of camlipixant was observed compared to camlipixant administered alone. These results suggest there is a potential fordrug-drug interaction leading to increase in camlipixant exposures when administered with strong inhibitors of CYP2C8.

[0420] DISCUSSIONS AND OVERALL CONCLUSIONS

[0421] The primary objectives of the study were to assess the effect of repeated oral doses of gemfibrozil, a CYP2C8 inhibitor, on the PK of a single oral dose of camlipixant.

[0422] The secondary objective was to evaluate the safety and tolerability of camlipixant when administered alone and in combination with gemfibrozil to healthy participants.

[0423] Following oral administration, camlipixant was rapidly absorbed with median Tmax of 0.760 hour and 0.750 hour, respectively, when administered alone and in combination with gemfibrozil. Exposure to camlipixant was greater when it was co-administered with gemfibrozil as compared to administration of camlipixant alone, with AUCs (AUCO-t and AUCO-inf) increased by 2-fold and Cmax increased by approximately 20%. The GMRs of AUCO-t, AUCO-inf, and Cmax were 217.49%, 217.78% and 120.86%, respectively and the corresponding 90% Cl were not contained within 80% to 125%. The mean T1Z> el of camlipixant which was approximately 4 hours longer when administered in combination with gemfibrozil (9.7 hours) as compared to camlipixant administered alone (5.8 hours).

[0424] The study interventions were well-tolerated overall. Most TEAEs reported were mild in severity. Three (3 [18.8%]) participants reported 4 moderate TEAEs. No severe TEAEs were reported. All except 2 TEAEs (thyroxine free decreased and aphthous ulcer) were recovered / resolved by the end of the study.

[0425] There were no TEAEs leading to death. One (1 [6.3%]) participant each reported 1 AEMI (dysgeusia) and 1 SAE: hepatic enzyme increased. One (1 [6.3%]) participant was discontinued from the study due to 2 TEAEs (CS biochemistry lab findings).

[0426] One (1 [6.3%]) participant reported 2 CS vital sign abnormalities. There were no CS changes in hematology, coagulation and urinalysis laboratory parameters and ECGs. No TEAEs related to ECG abnormalities were reported during the study. BEL00023W001 One (1 [6.3%]) participant reported 1 CS physical examination finding which was reported as a TEAE.

[0427] Conclusions

[0428] When administered with gemfibrozil, an increase of approximately 20% in peak and approximately 2-fold increase in total exposure of camlipixant was observed compared to camlipixant administered alone. These results suggest there is a potential for drug-drug interaction leading to increases in camlipixant exposures when administered with strong inhibitors of CYP2C8.

[0429] Overall, the administration of camlipixant 50 mg alone and in combination with gemfibrozil was well tolerated in healthy participants.

Claims

1. BEL00023W001CLAIMS1 . A method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first AUCo-inf or AUCo-t, and wherein following administration of camlipixant said patient is administered a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP2C8 inhibitor and camlipixant, wherein the second AUCo-inf or AUCo-t is about 140 to about 320% higher than the first AUCo-inf or AUCo-t.

2. The method according to claim 1 , wherein the second AUCo-inf or AUCo-t is about 150 to about 250% higher than the first AUCo-inf or AUCo-t.

3. The method according to claim 1 or claim 2, wherein the second AUCo-inf or AUCo-t is about 220% higher than the first AUCo-inf or AUCo-t.

4. The method according to any one of the preceding claims, wherein the first AUCo-inf or AUCo-t is in the range of from about 2500 to about 7500 h*ng / mL.

5. The method according to any one of the preceding claims, wherein the first AUCo-inf or AUCo-t is in the range of from about 3000 to about 7000 h*ng / mL.

6. The method according to any one of the preceding claims, wherein the first AUCo-inf is in the range of from about 3071 to about 6995 h*ng / mL.

7. The method according to any one of claims 1 to 5, wherein the first AUCo-t is in the range of from about 3030 to about 6590 h*ng / mL.

8. The method according to any one of the preceding claims, wherein the second AUCo-inf or AUCo-t is in the range of from about 7000 to about 18000 h*ng / mL.

9. The method according to any one of the preceding claims, wherein the second AUCo-inf or AUCo-t is in the range of from about 7200 to about 17000 h*ng / mL.

10. The method according to any one of the preceding claims, wherein the second AUCo-inf is in the range of from about 7497 to about 16964 h*ng / mL.BEL00023W00111 . The method according to any one of claims 1 to 9, wherein the second AllCo-t is in the range of from about 7457 to about 16833 h*ng / mL.

12. The method according to any one of the preceding claims, wherein the patient is administered a therapeutically effective amount of camlipixant.

13. A method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant and has a first Cmax, and wherein following administration of camlipixant said patient is administered a CYP2C8 inhibitor for a non-chronic cough related indication, wherein said patient has a second Cmax following administration of a CYP2C8 inhibitor and camlipixant, wherein the second Cmax is about 105 to about 200% higher than the first Cmax.

14. The method according to claim 13, wherein the second Cmax is about 115 to about 160% higher than the first Cmax.

15. The method according to claim 13 or 14, wherein the second Cmax is about 115 to about 140% higher than the first C max-16. The method according to any one of claims 13 to 15, wherein the second Cmax is about 125% higher or about 120% higher than the first Cmax.

17. The method according to claim 13, wherein the first Cmax is in the range of from about 500 to about 1500 ng / mL.

18. The method according to claim 17, wherein the first Cmax is in the range of from about 677 to about 1450 ng / mL.

19. The method according to claim 13, wherein the second Cmax is in the range of from about 800 to about 2000 ng / mL.

20. The method according to claim 19, wherein the second Cmax is in the range of from about 886 to about 1920 ng / mL.

21. A method of administering camlipixant therapy to a patient in need thereof, wherein said patient is receiving a CYP2C8 inhibitor, the method comprising(c) first, discontinuing administration of the CYP2C8 inhibitor;BEL00023W001(d) second, administering to the patient a therapeutically effective amount of camlipixant.

22. The method according to claim 21 , further comprising administering to the patient an alternative therapy to the CYP2C8 inhibitor following administration of camlipixant or following discontinuation of administration of the CYP2C8 inhibitor.

23. A method of treatment of chronic cough in a patient in need thereof, comprising administration of a therapeutically effective amount of camlipixant to the patient in need thereof, wherein coadministration with a CYP2C8 inhibitor is avoided.

24. A method for the treatment of chronic cough in a patient in need thereof, wherein said patient is also in need of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, the method comprising(iii) administration of camlipixant for the treatment of chronic cough; and(iv) administration of a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf or AllCo-t in the range of about 2500 to about 7500 h*ng / mL on treatment with camlipixant alone and an AUCo-inf or AUCo-t in the range of about 7000 to about 18000 h*ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor, or wherein the patient has a Cmax in the range of about 500 to about 1500 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 800 to about 2000 ng / mL on treatment with both camlipixant and a CYP2C8 inhibitor.

25. The method according to claim 24, wherein the patient has an AUCo-t or AUCo-inf in the range of about 3000 to about 7000 h*ng / mL on treatment with camlipixant alone and an AUCo-t or AUCo-inf in the range of about 7200 to about 1700 h*ng / mL on treatment with camlipixant and a CYP2C8 inhibitor.

26. The method according to claim 24 or claim 25, wherein the patient has an AUCo-t in the range of about 3030 to about 6590 h*ng / mL on treatment with camlipixant alone and an AUCo-t in the range of about 7457 to about 16833 h*ng / mL on treatment with camlipixant and a CYP2C8 inhibitor, or wherein the patient has an AUCo-inf in the range of about 3071 to about 6995 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 7497 to about 16964 h*ng / mL on treatment with camlipixant and a CYP2C8 inhibitor, or whereinBEL00023W001 the patient has a Cmax in the range of about 677 to about 1450 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 886 to about 1920 ng / mL on treatment with camlipixant and a CYP2C8 inhibitor.

27. A method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf orAUCo-t in the range of about 7000 to about 18000 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has an AUCo-inf orAUCo-t in the range of about 2500 to about 7500 h*ng / mL.

28. A method according to claim 27, wherein the patient has an AUCo-inf or AUCo-t in the range of about 7200 to about 17000 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has an AUCo-inf orAUCo-t in the range of about 3000 to about 7000 h*ng / mL.

29. A method according to claim 27 or claim 28, wherein the patient has an AUCo-inf in the range of about 7497 to about 16964 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has an AUCo-inf in the range of about 3071 to about 6995 h*ng / mL.

30. A method according to claim 27 or claim 28, wherein the patient has an AUCo-t in the range of about 7457 to about 16833 h*ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has an AUCo-t in the range of about 3030 to about 6590 h*ng / mL.31 . A method for the treatment of chronic cough in a patient in need thereof, wherein said patient is administered camlipixant, and wherein said patient is also receiving a CYP2C8 inhibitor for the treatment of a non-chronic cough related indication,BEL00023W001 wherein the patient has a Cmax in the range of about 800 to about 2000 ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has a Cmax in the range of about 500 to about 1500 ng / mL.

32. The method according to claim 31 , wherein the patient has a Cmax in the range of about 886 to about 1920 ng / mL while on treatment with both camlipixant and a CYP2C8 inhibitor; and wherein following discontinuation of treatment with a CYP2C8 inhibitor for the nonchronic cough related indication has a Cmax in the range of about 677 to about 1450 ng / mL.

33. The method according to any one of the preceding claims, wherein the chronic cough is refractory chronic cough.

34. The method according to any one of claims 1 to 32, wherein the chronic cough is unexplained chronic cough.

35. The method according to any one of the preceding claims, wherein camlipixant is administered in an amount of 25 mg or 50 mg administered twice a day.

36. The method according to any one of the preceding claims, wherein camlipixant is administered in an amount of 25 mg administered twice a day.

37. The method according to any one of the preceding claims, wherein camlipixant is administered in an amount of 50 mg administered twice a day.

38. The method according to any one of claims 35 to 37, wherein the amount is a therapeutically effective amount.

39. The method according to any one of the preceding claims, wherein the CYP2C8 inhibitor is a strong CYP2C8 inhibitor.

40. The method according to claim 39, wherein the strong CYP2C8 inhibitor is gemfibrozil.

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