Camlipixant in combination with CYP3a4 and / or CYP2c8 inducers for use in the treatment of 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 CYP3A4 inducer and / or CYP2C8 inducer.

Description

[0001] BEL00022W001

[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 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, wherein said patient has a second AUCo-inf or AUCo-t following administration of a

[0010] CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second AUCo-inf or AUCo-t is about 30 to about 90% lower than the first AUCo-inf or AUCo-t.

[0011] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, wherein said patient has a second Cmax following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second Cmax is about 20 to about 70% lower than the first Cmax.

[0012] In a third 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, the method comprising BEL00022W001

[0013] (i) administration of camlipixant for the treatment of chronic cough; and

[0014] (ii) administration of a CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the patient has an AllCo-t or AUCo-inf in the range of about 1500 to about 7500 h*ng / mL on treatment with camlipixant alone and an ALICo-t or AUCo-inf in the range of about 150 to about 5250 h*ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer, or wherein the patient has a Cmax in the range of about 400 to about 1200 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 120 to about 960 ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0015] In a fourth 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a nonchronic cough related indication, wherein the patient has an AUCo-inf or AUCo-t in the range of about 150 to about 5250 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-inf or AUCo-t in the range of about 1500 to about 7500 h*ng / mL.

[0016] 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 administered camlipixant, and wherein said patient is also receiving a CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non- chronic cough related indication, wherein the patient has a Cmax in the range of about 120 to about 960 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a Cmax in the range of about 400 to about 1200 ng / mL.

[0017] BRIEF DESCRIPTION OF THE FIGURES

[0018] Figure 1 is a schematic illustrating the study design for the drug-drug interaction study disclosed herein. BEL00022W001

[0019] Figure 2 is a graph showing camlipixant plasma concentration over time and camlipixant + rifampin plasma concentration over time (linear scale).

[0020] Figure 3 is a graph showing camlipixant plasma concentration over time and camlipixant + rifampin plasma concentration over time (semilog scale).

[0021] Figure 4 is a summary of descriptive statistics of plasma PK parameters of camlipixant and camlipixant + rifampin.

[0022] Figure 5 is a summary of geometric LSM for each study intervention, LSM ratios (camlipixant + rifampin versus camlipixant), the 90% geometric Cl, intra-subject CV% and p-values for AUCo-inf, AllCo-t and Cmax.

[0023] Figure 6 is a table providing values of AUCo-inf for camlipixant alone and camlipixant + rifampin.

[0024] Figure 7 is a table providing values of AUCo-t for camlipixant alone and camlipixant + rifampin.

[0025] Figure 8 is a table providing values of Cmax for camlipixant alone and camlipixant + rifampin.

[0026] DETAILED DESCRIPTION OF THE INVENTION

[0027] Definitions

[0028] 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.

[0029] 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.

[0030] The term “refractory chronic cough” refers to a cough lasting >8 weeks despite adequate treatment and investigation for cough-related aetiologies.

[0031] The term “non-chronic cough related indication” refers to an indication which is not defined as chronic cough or refractory chronic cough.

[0032] Reference to “camlipixant” is a reference to a compound having the following structure BEL00022W001 pharmaceutically acceptable salt thereof.

[0033] 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.

[0034] 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 or AUCo-12 based on twice daily dosing of camlipixant.

[0035] Statement of Invention

[0036] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second AUCo-inf or AUCo-t is about 30 to about 90% lower than the first AUCo-inf or AUCo-t, for example about 40 to about 70% lower, for example about 55 to about 65% lower, particularly about 60% lower.

[0037] In an embodiment, the second AUCo-inf or AUCo-t is about 50 to about 75% lower than the first AUCo-inf or AUCo-t, for example about 55 to about 70% lower.

[0038] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic BEL00022W001 cough related indication, the method further comprising administration of a CYP3A4 inducer and / or CYP2C8 inducer, wherein said patient has a second AUCo-inf or AllCo-t following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second AUCo-inf or AUCo-t is about 30 to about 90% lower than the first AUCo-inf or AUCo-t, for example about 40 to about 70% lower, for example about 55 to about 65% lower, particularly about 60% lower.

[0039] In an embodiment, the second AUCo-inf or AUCo-t is about 50 to about 75% lower than the first AUCo-inf or AUCo-t, for example about 55 to about 70% lower.

[0040] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, the method further comprising administration of a CYP3A4 inducer and / or CYP2C8 inducer, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second AUCo-inf or AUCo-t is about 30 to about 90% lower than the first AUCo-inf or AUCo-t, for example about 40 to about 70% lower, for example about 55 to about 65% lower, particularly about 60% lower.ln an embodiment, the second AUCo-inf or AUCo-t is about 40 to about 70% lower than the first AUCo-inf or AUCo-t.

[0041] In an embodiment, the second AUCo-inf or AUCo-t is about 50 to about 75% lower than the first AUCo-inf or AUCo-t.

[0042] In an embodiment, the second AUCo-inf or AUCo-t is about 55 to about 70% lower than the first AUCo-inf or AUCo-t.

[0043] In an embodiment, the second AUCo-inf or AUCo-t is about 55 to about 65% lower than the first AUCo-inf or AUCo-t.

[0044] In an embodiment, the second AUCo-inf or AUCo-t is about 60% lower than the first AUCo-inf or AUCo-t. BEL00022W001

[0045] In an embodiment, the first AUCo-inf or AUCo-t is in the range of from about 1500 to about 7500 h*ng / mL.

[0046] In an embodiment, the first AU Co-inf or AUCo-t is in the range of from about 1800 to about 6700 h*ng / mL.

[0047] In an embodiment, the first AU Co-inf is in the range of from about 1861 to about 6620 h*ng / mL.

[0048] In an embodiment, the first AUCo-t is in the range of from about 1852 to about 6591 h*ng / mL.

[0049] In an embodiment, the second AUCo-inf or AUCo-t is in the range of from about 700 to about 2500 h*ng / mL.

[0050] In an embodiment, the second AUCo-inf is in the range of from about 723 to about 2364 h*ng / mL.

[0051] In an embodiment, the second AUCo-t is in the range of from about 720 to about 2359 h*ng / mL.

[0052] In an embodiment, the first AUCo-inf or AUCo-t is in the range of from about 1800 to about 6700 h*ng / mL and the second AUCo-inf or AUCo-t is in the range of from about 700 to about 2500 h*ng / mL.

[0053] In an embodiment, the first AUCo-inf is in the range of from about 1861 to about 6619 h*ng / mL and the second AUCo-inf is in the range of from about 723 to about 2364 h*ng / mL.

[0054] In an embodiment, the first AUCo-t is in the range of from about 1851 to about 6591 h*ng / mL and the second AUCo-t is in the range of from about 720 to about 2359 h*ng / mL.

[0055] In an embodiment, the first AUCo-inf or AUCo-t is about 1500 to about 7500 h*ng / mL and the second AUCo-inf or AUCo-t is about 30 to about 90% lower than the first AUCo-inf or AUCo-t, for example about 40 to about 70% lower, for example about 55 to about 65% lower, particularly about 60% lower, such that the values may be about those indicated in the table below.

[0056] In an embodiment, the first AUCo-inf or AUCo-t is about 1500 to about 7500 h*ng / mL and the second AUCo-inf or AUCo-t is about 50 to about 75% lower than the first AUCo-inf or AUCo-t, for example about 55 to about 70% lower, such that the values may be about those indicated in the table below. BEL00022W001

[0057] In an embodiment, the first AUCo-inf or AllCo-t is about 1800 to about 6700 h*ng / mL and the second AUCo-inf or AUCo-t is about 30 to about 90% lower than the first AUCo-inf or AUCo-t, for example about 40 to about 70% lower, for example about 55 to about 65% lower, particularly about 60% lower, such that the values may be about those indicated in the table below.

[0058] In an embodiment, the first AUCo-inf or AUCo-t is about 1800 to about 6700 h*ng / mL and the second AUCo-inf or AUCo-t is about 50 to about 75% lower than the first AUCo-inf or AUCo-t, for example about 55 to about 70% lower, such that the values may be about those indicated in the table below.

[0059] In an embodiment, the first AUCo-inf is about 1861 to about 6619 h*ng / mL and the second AUCo-inf is about 30 to about 90% lower than the first AUCo-inf, for example about 40 to about 70% lower, for example about 55 to about 65% lower, particularly about 60% lower, such that the values may be about those indicated in the table below.

[0060] In an embodiment, the first AUCo-inf is about 1861 to about 6619 h*ng / mL and the second AUCo-inf is about 50 to about 75% lower than the first AUCo-inf, for example about 40 to about 70% lower, for example about 55 to about 65% lower, particularly about 60% lower, such that the values may be about those indicated in the table below. BEL00022W001

[0061] In an embodiment, the first ALICo-t is about 1861 to about 6619 h*ng / mL and the second ALICo-t is about 30 to about 90% lower than the first ALICo-t, for example about 40 to about 70% lower, for example about 55 to about 65% lower, particularly about 60% lower, such that the values may be about those indicated in the table below.

[0062] In an embodiment, the first AllCo-t is about 1861 to about 6619 h*ng / mL and the second ALICo-t is about 50 to about 75% lower than the first ALICo-t, for example about 55 to about 65% lower, such that the values may be about those indicated in the table below.

[0063] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, wherein said patient has a second Cmax following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second Cmax is about 20 to about 70% lower than the first Cmax, for example about 30 to about 50% lower, particularly about 40% lower.

[0064] In an embodiment, the second Cmax is about 20 to about 65% lower than the first Cmax, for example about 30 to about 65% lower, or about 20 to about 60% lower.

[0065] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, the method further comprising administration of a CYP3A4 inducer and / or CYP2C8 inducer, wherein said patient has a second Cmax following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, BEL00022W001 wherein the second Cmax is about 20 to about 70% lower than the first Cmax, for example about 30 to about 50% lower, particularly about 40% lower.

[0066] In an embodiment, the second Cmax is about 20 to about 65% lower than the first Cmax, for example about 30 to about 65% lower, or about 20 to about 60% lower.

[0067] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, the method further comprising administration of a CYP3A4 inducer and / or CYP2C8 inducer, wherein said patient has a second Cmax following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second Cmax is about 20 to about 70% lower than the first Cmax, for example about 30 to about 50% lower, particularly about 40% lower.

[0068] In an embodiment, the second Cmax is about 20 to about 65% lower than the first Cmax.

[0069] In an embodiment, the second Cmax is about 30 to about 65% lower than the first Cmax.

[0070] In an embodiment, the second Cmax is about 20 to about 60% lower than the first Cmax.

[0071] In an embodiment, the second Cmax is about 30 to about 50% lower than the first Cmax.

[0072] In an embodiment, the second Cmax is about 40% lower than the first Cmax.

[0073] In an embodiment, the first Cmax is in the range of from about 400 to about 1200 ng / mL.

[0074] In an embodiment, the first Cmax is in the range of from about 450 to about 1100 ng / mL.

[0075] In an embodiment, the second Cmax is in the range of from about 300 to about 1000 ng / mL.

[0076] In an embodiment, the first Cmax is in the range of from about 484 to about 1090 ng / mL.

[0077] In an embodiment, the second Cmax is in the range of from about 336 to about 887 ng / mL.

[0078] In an embodiment, the first Cmax is in the range of from about 450 to about 1100 ng / mL and the second Cmax is in the range of from about 300 to about 1000 ng / mL.

[0079] In an embodiment, the first Cmax is in the range of from about 484 to about 1090 ng / mL and the second Cmax is in the range of from about 336 to about 887 ng / mL. BEL00022W001

[0080] In an embodiment, the first Cmax is about 400 to about 1200 ng / mL and the second Cmax is about 20 to about 70% lower than the first Cmax, for example about 30 to about 50% lower, particularly about 40% lower, such that the values may be about those indicated in the table below.

[0081] In an embodiment, the first Cmax is about 400 to about 1200 ng / mL and the second Cmax is about 20 to about 65% lower than the first Cmax, for example about 30 to about 65% lower, or about 20 to about 60% lower, such that the values may be about those indicated in the table below.

[0082] In an embodiment, the first Cmax is about 450 to about 1100 ng / mL and the second Cmax is about 20 to about 70% lower than the first Cmax, for example about 30 to about 50% lower, particularly about 40% lower, such that the values may be about those indicated in the table below.

[0083] In an embodiment, the first Cmax is about 450 to about 1100 ng / mL and the second Cmax is about 20 to about 65% lower than the first Cmax, for example about 30 to about 65% lower, or about 20 to about 60% lower, such that the values may be about those indicated in the table below.

[0084] In an embodiment, the first Cmax is about 484 to about 1090 ng / mL and the second Cmax is about 20 to about 70% lower than the first Cmax, for example about 30 to about 50% lower, BEL00022W001 particularly about 40% lower, such that the values may be about those indicated in the table below.

[0085] In an embodiment, the first Cmax is about 484 to about 1090 ng / mL and the second Cmax is about 20 to about 65% lower than the first Cmax, for example about 30 to about 65% lower, or about 20 to about 60% lower, such that the values may be about those indicated in the table below.

[0086] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a nonchronic cough related indication, wherein the patient has an AUCo-inf in the range of about 150 to about 5250 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-inf in the range of about 1500 to about 7500 h*ng / mL.

[0087] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf in the range of about 150 to about 5250 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-inf in the range of about 1500 to about 7500 h*ng / mL. BEL00022W001

[0088] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a nonchronic cough related indication, wherein the patient has an AllCo-t in the range of about 150 to about 5250 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an ALICo-t in the range of about 1500 to about 7500 h*ng / mL.

[0089] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the patient has an ALICo-t in the range of about 150 to about 5250 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an ALICo-t in the range of about 1500 to about 7500 h*ng / mL.

[0090] In an embodiment, the patient has an AUCo-inf or ALICo-t in the range of about 700 to about 2500 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-inf or AUCo-t in the range of about 1800 to about 6700 h*ng / mL.

[0091] In an embodiment, the patient has an AUCo-inf in the range of about 723 to about 2364 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-inf in the range of about 1861 to about 6619 h*ng / mL. BEL00022W001

[0092] In an embodiment, the patient has an AllCo-t in the range of about 720 to about 2359 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an ALICo-t in the range of about 1851 to about 6590 h*ng / mL.

[0093] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a nonchronic cough related indication, wherein the patient has a Cmax in the range of about 120 to about 960 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a Cmax in the range of about 400 to about 1200 ng / mL.

[0094] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the patient has a Cmax in the range of about 120 to about 960 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a Cmax in the range of about 400 to about 1200 ng / mL.

[0095] In an embodiment, the patient has a Cmax in the range of about 300 to about 1000 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a Cmax in the range of about 450 to about 1100 ng / mL.

[0096] In an embodiment, the patient has a Cmax in the range of about 336 to about 887 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer or CYP2C8 inducer; and BEL00022W001 wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a Cmax in the range of about 484 to about 1090 ng / mL.

[0097] In an embodiment, the patient is administered a therapeutically effective amount of camlipixant.

[0098] In an embodiment, the patient is administered a therapeutically effective amount of a CYP3A4 inducer and / or CYP2C8 inducer.

[0099] 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 CYP3A4 inducer and / or CYP2C8 inducer, the method comprising

[0100] (a) administering to the patient a therapeutically effective amount of camlipixant; and

[0101] (b) avoiding co-administration of said CYP3A4 inducer and / or CYP2C8 inducer.

[0102] In an embodiment, there is provided camlipixant for use in the treatment of chronic cough, wherein the treatment comprises avoidance or discontinuation concomitant or coadministration of a CYP3A4 inducer and / or CYP2C8 inducer, to avoid reduced exposure or effectiveness of camlipixant.

[0103] In another embodiment, there is provided a method of administering camlipixant therapy to a patient in need thereof, wherein said patient is receiving a CYP3A4 inducer and / or CYP2C8 inducer, the method comprising

[0104] (a) first, discontinuing administration of the CYP3A4 inducer and / or CYP2C8 inducer; and

[0105] (b) second, administering to the patient a therapeutically effective amount of camlipixant.

[0106] 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 CYP3A4 inducer and / or CYP2C8 inducer, wherein administration of the CYP3A4 inducer and / or CYP2C8 inducer is discontinued prior to administration of camlipixant.

[0107] 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 CYP3A4 inducer and / or CYP2C8 inducer, the method comprising

[0108] (a) first, discontinuing administration of the CYP3A4 inducer and / or CYP2C8 inducer; BEL00022W001

[0109] (b) second, administering to the patient a therapeutically effective amount of camlipixant; and

[0110] (c) third, administering to the patient an alternative to the CYP3A4 inducer and / or CYP2C8 inducer.

[0111] In another aspect, there is provided a method of increasing the effectiveness of camlipixant therapy by avoiding decreased exposure to camlipixant in a patient in need of camlipixant therapy and receiving a CYP3A4 inducer and / or CYP2C8 inducer, the method comprising

[0112] (a) administration to said patient a therapeutically effective amount of camlipixant; and

[0113] (b) avoidance of administration of the CYP3A4 inducer and / or CYP2C8 inducer.

[0114] In another embodiment, there is provided a method of increasing the effectiveness of camlipixant in a patient in need thereof, by avoiding decreased exposure to camlipixant in a patient in of camlipixant therapy and receiving a CYP3A4 inducer and / or CYP2C8 inducer, the method comprising

[0115] (a) administration to said patient a therapeutically effective amount of camlipixant; and

[0116] (b) avoidance of administration of the CYP3A4 inducer and / or CYP2C8 inducer.

[0117] In an embodiment, there is provided a method of increasing the exposure of camlipixant in a patient in need thereof, wherein said patient is receiving a CYP3A4 inducer and / or CYP2C8 inducer, the method comprising

[0118] (a) administration to said patient a therapeutically effective amount of camlipixant; and

[0119] (b) avoidance of administration of the CYP3A4 inducer and / or CYP2C8 inducer.

[0120] In an embodiment, there is provided a method of increasing the exposure of camlipixant in a patient in need thereof, wherein said patient is receiving a CYP3A4 inducer and / or CYP2C8 inducer, the method comprising

[0121] (a) first, discontinuing administration of the CYP3A4 inducer and / or CYP2C8 inducer; and

[0122] (b) second, administering to the patient a therapeutically effective amount of camlipixant for the treatment of chronic cough.

[0123] In an embodiment, increasing the effectiveness of camlipixant or increasing the exposure of camlipixant is defined as maintenance of the same AllCo-t, AUCo-inf and / or Cmax value as when camlipixant is administered alone. BEL00022W001

[0124] In an embodiment, the AUCo-inf of a patient on treatment with camlipixant alone is in the range of from about 1500 to about 7500 h*ng / mL.

[0125] In an embodiment, theAUCo-t of a patient on treatment with camlipixant alone is in the range of from about 1500 to about 7500 h*ng / mL.

[0126] In an embodiment, the AUCo-inf of a patient on treatment with camlipixant alone is in the range of about 1800 to about 6700 h*ng / mL.

[0127] In an embodiment, the AUCo-t of a patient on treatment with camlipixant alone is in the range of about 1800 to about 6700 h*ng / mL.

[0128] In an embodiment, the AUCo-inf of a patient on treatment with camlipixant alone is in the range of about 1861 to about 6619 h*ng / mL.

[0129] In an embodiment, theAUCo-t of a patient on treatment with camlipixant alone is in the range of about 1851 to about 6590 h*ng / mL.

[0130] In an embodiment, the Cmax of a patient on treatment with camlipixant alone is in the range of about 400 to about 1200 ng / mL.

[0131] In an embodiment, the Cmax of a patient on treatment with camlipixant alone is in the range of about 450 to about 1100 ng / mL.

[0132] In an embodiment, the Cmax of a patient on treatment with camlipixant alone is in the range of about 484 to about 1090 ng / mL.

[0133] In an embodiment, the AUCo-inf of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 150 to about 5250 h*ng / mL.

[0134] In an embodiment, the AUCo-t of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 150 to about 5250 h*ng / mL.

[0135] In an embodiment, the AUCo-inf of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 700 to about 2500 h*ng / mL.

[0136] In an embodiment, the AUCo-t of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 700 to about 2500 h*ng / mL. BEL00022W001

[0137] In an embodiment, the AUCo-inf of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 722 to about 2364 h*ng / mL.

[0138] In an embodiment, the AllCo-t of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 720 to about 2359 h*ng / mL.

[0139] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 300 to about 1000 ng / mL.

[0140] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 336 to about 887 ng / mL.

[0141] In an embodiment, the AUCo-inf or AUCo-t of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 30 to about 90% lower than when the same patient is receiving treatment with camlipixant alone, for example about 40 to 70% lower than when the same patient is receiving treatment with camlipixant alone, particularly about 55 to 65% lower.

[0142] In an embodiment, the AUCo-inf or AUCo-t of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 50 to about 75% lower than when the same patient is receiving treatment with camlipixant alone, for example about 55 to 70% lower than when the same patient is receiving treatment with camlipixant alone.

[0143] In an embodiment, the AUCo-inf or AUCo-t of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 60% lower than when the same patient is receiving treatment with camlipixant alone.

[0144] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 20 to 70% lower than when the same patient is receiving treatment with camlipixant alone.

[0145] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 20 to 65% lower than when the same patient is receiving treatment with camlipixant alone.

[0146] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 30 to 65% lower than when the same patient is receiving treatment with camlipixant alone. BEL00022W001

[0147] In an embodiment, the Cmax of a patient receiving treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 20 to 60% lower 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 CYP3A4 inducer and / or CYP2C8 inducer is about 30 to 50% lower 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 CYP3A4 inducer and / or CYP2C8 inducer is about 40% lower than when the same patient is receiving treatment with camlipixant alone.

[0150] In an embodiment, the patient has chronic cough.

[0151] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-cough related indication, the method comprising

[0152] (c) first, discontinuing administration of the CYP3A4 inducer and / or CYP2C8 inducer; and

[0153] (d) second, administering to the patient a therapeutically effective amount of camlipixant for the treatment of chronic cough.

[0154] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-cough related indication, the method comprising

[0155] (a) first, discontinuing administration of the CYP3A4 inducer and / or CYP2C8 inducer;

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

[0157] (c) third, administering to the patient an alternative to the CYP3A4 inducer and / or CYP2C8 inducer for the treatment of the non-cough related indication.

[0158] In an alternative embodiment, there is provided a method of increasing the effectiveness of camlipixant therapy, wherein said patient is receiving treatment with a CYP3A4 inducer and / or CYP2C8 inducer for a non-cough related indication, the method comprising

[0159] (a) first, discontinuing administration of the CYP3A4 inducer and / or CYP2C8 inducer;

[0160] (b) second, administering to the patient a therapeutically effective amount of camlipixant for the treatment of chronic cough; and BEL00022W001

[0161] (c) third, administering to the patient an alternative to the CYP3A4 inducer and / or CYP2C8 inducer for the treatment of the non-cough related indication.

[0162] In an embodiment, the therapeutically effective amount of camlipixant is a twice daily dose of 25 mg or 50 mg per day.

[0163] In an embodiment, the therapeutically effective amount of camlipixant is a twice daily dose of 50 mg per day.

[0164] In an embodiment, the therapeutically effective amount of camlipixant is a twice daily dose of 25 mg per day.

[0165] 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:

[0166] (a) identifying a patient in need of treatment with camlipixant;

[0167] (b) determining that the patient is also receiving therapy with a CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication; and

[0168] (c) administering camlipixant to the patient in need thereof wherein (i) exposure of camlipixant based on AUCo-inf or AllCo-t is reduced by about 30 to about 90%, for example about 40 to about 70%; or (ii) AUCo-inf or AUCo-t is in the range of about 700 to about 2500 h*ng / mL; or Cmax is in the range of about 300 to about 1000 ng / mL.

[0169] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, the method comprising

[0170] (i) administration of camlipixant for the treatment of chronic cough; and

[0171] (ii) administration of a CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-inf in the range of about 1500 to about 7500 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 150 to about 5250 h*ng / mL on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0172] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough indication, wherein the patient has an AUCo-inf or AUCo-t in the range of about 1500 to about

[0173] 7500 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 150 BEL00022W001 to about 5250 h*ng / mL on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0174] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, the method comprising

[0175] (i) administration of a therapeutically effective amount of camlipixant for the treatment of chronic cough; and

[0176] (ii) administration of a therapeutically effective amount of a CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the patient has an AllCo-t in the range of about 1500 to about 7500 h*ng / mL on treatment with camlipixant alone and an ALICo-t in the range of about 150 to about 5250 h*ng / mL on treatment with both camlipixant and a CYP3A4 inducer or CYP2C8 inducer.

[0177] In an embodiment, the patient has an AUCo-inf orAUCo-t in the range of about 1800 to about 6700 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 700 to about 2500 h*ng / mL on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0178] In an embodiment, the patient has an AUCo-inf in the range of about 1861 to about 6619 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 723 to about 2364 h*ng / mL on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0179] In an embodiment, the patient has an AUCo-t in the range of about 1851 to about 6590 h*ng / mL on treatment with camlipixant alone and an AUCo-t in the range of about 720 to about 2359 h*ng / mL on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0180] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, the method comprising

[0181] (i) administration of camlipixant for the treatment of chronic cough; and

[0182] (ii) administration of a CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein BEL00022W001 the patient has a Cmax in the range of about 400 to about 1200 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 120 to about 960 ng / mL on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0183] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough indication, wherein the patient has a Cmax in the range of about 400 to about 1200 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 120 to about 960 ng / mL on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0184] In an embodiment, the patient has a Cmax in the range of about 450 to about 1100 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 300 to about 1000 ng / mL on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0185] In an embodiment, the patient has a Cmax in the range of about 484 to about 1090 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 336 to about 887 ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0186] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, the method comprising

[0187] (i) administration of camlipixant for the treatment of chronic cough; and

[0188] (ii) administration of a CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-cough related 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 CYP3A4 inducer and / or CYP2C8 inducer, wherein the second AUCo-inf or AUCo-t is about 30 to about 90% lower than the first AUCo-inf or AUCo-t, for example about 40 to about 70% lower than the first AUCo-inf or AUCo-t, for example about 55 to about 65% lower, particularly about 60% lower.

[0189] In an embodiment, the second AUCo-inf or AUCo-t is about 50 to about 75% lower than the first AUCo-inf or AUCo-t, for example about 55 to about 70% lower than the first AUCo-inf or AUCo-t.

[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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough indication, BEL00022W001 wherein the patient has a first AUCo-inf or AllCo-t on treatment with camlipixant alone and a second AUCo-inf or AUCo-t on treatment with both camlipixant and of a CYP3A4 inducer and / or CYP2C8 inducer, wherein the second AUCo-inf or AUCo-t is about 30 to about 90% lower than the first AUCo-inf or AUCo-t, for example about 40 to about 70% lower than the first AUCo-inf or AUCo-t, for example about 55 to about 65% lower, particularly about 60% lower.

[0191] In an embodiment, the second AUCo-inf or AUCo-t is about 50 to about 75% lower than the first AUCo-inf or AUCo-t, for example about 55 to about 70% lower than the first AUCo-inf or AUCo-t.

[0192] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, the method comprising

[0193] (i) administration of camlipixant for the treatment of chronic cough; and

[0194] (ii) administration of a CYP3A4 inducer and / or CYP2C8 inducer 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 CYP3A4 inducer and / or CYP2C8 inducer, wherein the second Cmax is about 20 to about 70% lower than the first Cmax, for example about 30 to about 50% lower than the first Cmax, particularly about 40% lower.

[0195] In an embodiment, the second Cmax is about 20 to about 65% lower than the first Cmax, for example about 30 to about 65% lower than the first Cmax, or about 20 to about 60% lower than the first Cmax.

[0196] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough 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 CYP3A4 inducer and / or CYP2C8 inducer, wherein the second Cmax is about 20 to about 70% lower than the first Cmax, for example about 30 to about 50% lower than the first Cmax, particularly about 40% lower.

[0197] In an embodiment, the second Cmax is about 20 to about 65% lower than the first Cmax, for example about 30 to about 65% lower than the first Cmax, or about 20 to about 60% lower than the first Cmax.

[0198] In an embodiment, the patient is administered a therapeutically effective amount of camlipixant. BEL00022W001

[0199] In an embodiment, the patient is administered a therapeutically effective amount of a CYP3A4 inducer and / or CYP2C8 inducer.

[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 AUCo-inf or AllCo-t in the range of about 1800 to about 6700 h*ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP3A4 inducer or CYP2C8 inducer for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP3A4 inducer or CYP2C8 inducer, wherein said patient has an AUCo-inf or AUCo-t in the range of about 700 to about 2500 h*ng / mL following administration of both a CYP3A4 inducer or CYP2C8 inducer 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 an AUCo-inf in the range of about 1861 to about 6619 h*ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP3A4 inducer or CYP2C8 inducer for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP3A4 inducer or CYP2C8 inducer, wherein said patient has an AUCo-inf in the range of about 723 to about 2364 h*ng / mL following administration of a CYP3A4 inducer or CYP2C8 inducer 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 an AUCo-t in the range of about 1851 to about 6591 h*ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP3A4 inducer or CYP2C8 inducer for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP3A4 inducer or CYP2C8 inducer, wherein said patient has an AUCo-t in the range of about 720 to about 2359 h*ng / mL following administration of both a CYP3A4 inducer or CYP2C8 inducer 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 a therapeutically effective amount of camlipixant and has a Cmax in the range of about 450 to about 1100 ng / mL, BEL00022W001 and wherein following administration said patient is determined to be in need of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP3A4 inducer and / or CYP2C8 inducer, wherein said patient has a Cmax in the range of about 300 to about 1000 ng / mL following administration of both a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant.

[0204] In an embodiment, the Cmax of a patient following administration of both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is in the range of about 300 to about 900 ng / mL.

[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 a therapeutically effective amount of camlipixant and has a Cmax in the range of about 484 to about 1090 ng / mL, and wherein following administration said patient is determined to be in need of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, the method further comprising administration of a therapeutically effective amount of a CYP3A4 inducer and / or CYP2C8 inducer, wherein said patient has a Cmax in the range of about 336 to about 887 ng / mL following administration of both a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant.

[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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non- chronic cough related indication, wherein the patient has an AUCo-inf orAUCo-t in the range of about 700 to about 2500 h*ng / mL or Cmax in the range of about 300 to about 1000 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication, the patient has an improvement in AUCo-inf, AUCo-t or 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non- chronic cough related indication, BEL00022W001 wherein the patient has an AUCo-inf in the range of about 722 to about 2364 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication, the patient has an improvement in AUCo-inf.

[0208] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a nonchronic cough related indication, wherein the patient has an AUCo-t in the range of about 720 to about 2359 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication, the patient has an improvement in AUCo-t.

[0209] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non- chronic cough related indication, wherein the patient has a Cmax in the range of about 336 to about 887 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication, the patient has an improvement in Cmax.

[0210] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non- chronic cough related indication, wherein the patient has a first AUCo-inf or AUCo-t while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and BEL00022W001 wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a second AUCo-inf orAUCo-t, wherein the second AUCo-inf or AUCo-t is higher and / or improved relative to the first AUCo-inf or AUCo-t.

[0211] In an embodiment, the first AUCo-inf orAUCo-t is about 30 to about 90% lower than the second AUCo-inf or AUCo-t.

[0212] In an embodiment, the first AUCo-inf orAUCo-t is about 50 to about 75% lower than the second AUCo-inf or AUCo-t.

[0213] In an embodiment, the first AUCo-inf orAUCo-t is about 40 to about 70% lower than the second AUCo-inf or AUCo-t.

[0214] In an embodiment, the first AUCo-inf orAUCo-t is about 55 to about 70% lower than the second AUCo-inf or AUCo-t.

[0215] In an embodiment, the first AUCo-inf orAUCo-t is about 55 to about 65% lower than the second AUCo-inf or AUCo-t.

[0216] In an embodiment, the first AUCo-inf or AUCo-t is about 60% lower than the second AUCo-inf orAUCo-t.

[0217] 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 CYP3A4 inducer and / or CYP2C8 inducer 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 CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a second Cmax, wherein the second Cmax is higher and / or improved relative to the first AUCo-inf or AUCo-t.

[0218] In an embodiment, the first Cmax is about 20 to about 70% lower than the second Cmax.

[0219] In an embodiment, the first Cmax is about 20 to about 65% lower than the second Cmax.

[0220] In an embodiment, the first Cmax is about 30 to about 65% lower than the second Cmax. BEL00022W001

[0221] In an embodiment, the first Cmax is about 20 to about 60% lower than the second Cmax.

[0222] In an embodiment, the first Cmax is about 30 to about 50% lower than the second Cmax.

[0223] In an embodiment, the first Cmax is about 40% lower than the second Cmax.

[0224] 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 CYP3A4 inducer and / or CYP2C8 inducer 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 1800 to about 6700 h*ng / mL when on treatment with camlipixant alone; and wherein the AUCo-inf or AUCo-t of said patient is about 30 to about 90% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0225] In an embodiment, the AUCo-inf or AUCo-t of said patient is about 40 to about 70% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0226] In an embodiment, the AUCo-inf or AUCo-t of said patient is about 50 to about 75% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0227] In an embodiment, the AUCo-inf or AUCo-t of said patient is about 55 to about 70% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0228] In an embodiment, the AUCo-inf or AUCo-t of said patient is about 55 to about 65% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0229] In an embodiment, the AUCo-inf or AUCo-t of said patient is about 60% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0230] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the Cmax of said patient is in the range of about 450 to about 1100 ng / mL when on treatment with camlipixant alone; and wherein the Cmax of said patient is about 20 to about 70% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0231] In an embodiment, the Cmax of said patient is about 20 to about 65% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer. BEL00022W001

[0232] In an embodiment, the Cmax of said patient is about 30 to about 65% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0233] In an embodiment, the Cmax of said patient is about 20 to about 60% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0234] In an embodiment, the Cmax of said patient is about 30 to about 50% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0235] In an embodiment, the Cmax of said patient is about 40% lower when on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

[0236] 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,

[0237] (a) prior to treatment with camlipixant, determination that the patient in need thereof is receiving therapy with a CYP3A4 inducer and / or CYP2C8 inducer;

[0238] (b) providing a therapeutically effective amount of camlipixant which does not result in reduced effectiveness of camlipixant relative to treatment of a patient with camlipixant alone.

[0239] In an embodiment, the therapeutically effective amount of camlipixant which does not result in reduced 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.

[0240] In an embodiment, the therapeutically effective amount of camlipixant which does not result in reduced effectiveness of camlipixant relative to treatment of a patient with camlipixant alone is an amount of 50 mg twice per day.

[0241] 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,

[0242] (a) prior to treatment with camlipixant, determination that the patient in need thereof is receiving therapy with a CYP3A4 inducer and / or CYP2C8 inducer;

[0243] (b) providing a dose of 50 mg twice a day or a total daily dose of 100 mg.

[0244] 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, BEL00022W001 wherein said patient is also receiving treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein said patient has an AUCo-inf or AUCo-t of about 30 to about 90% of the AUCo-inf or AUCo-t when on treatment with camlipixant alone.

[0245] In an embodiment, said patient has an AUCo-inf or AllCo-t of about 40 to about 70% of the AUCo-inf or ALICo-t when on treatment with camlipixant alone.

[0246] In an embodiment, said patient has an AUCo-inf or AUCo-t of about 50 to about 75% of the AUCo-inf or AUCo-t when on treatment with camlipixant alone.

[0247] In an embodiment, said patient has an AUCo-inf or AUCo-t of about 55 to about 70% of the AUCo-inf or AUCo-t when on treatment with camlipixant alone.

[0248] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein said patient has a Cmax of about 20 to about 70% of the Cmax when on treatment with camlipixant alone.

[0249] In an embodiment, said patient has a Cmax of about 30 to about 50% of the Cmax when on treatment with camlipixant alone.

[0250] In an embodiment, said patient has a Cmax of about 20 to about 65% of the Cmax when on treatment with camlipixant alone.

[0251] In an embodiment, said patient has a Cmax of about 30 to about 65% of the Cmax when on treatment with camlipixant alone.

[0252] In an embodiment, said patient has a Cmax of about 20 to about 60% of the Cmax when on treatment with camlipixant alone.

[0253] 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, BEL00022W001 the method further comprising selection of a dose of camlipixant resulting in no reduction in effectiveness or exposure to camlipixant.

[0254] In an embodiment, no reduction in effectiveness or exposure to camlipixant is intended to mean that the AUCo-inf, AllCo-t or Cmax remains consistent throughout treatment with camlipixant.

[0255] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, wherein the AUCo-inf or AUCo-t of said patient on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 40 to about 70% of the AUCo-inf or AUCo- t of said patient when on treatment with camlipixant alone; or wherein the Cmax of said patient on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 30 to about 50% of the Cmax of said patient when on treatment with camlipixant alone.

[0256] 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, wherein the AUCo-inf or AUCo-t of said patient on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 30 to about 90% of the AUCo-inf or AUCo- t of said patient when on treatment with camlipixant alone; or wherein the Cmax of said patient on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer is about 20 to about 70% of the Cmax of said patient when on treatment with camlipixant alone.

[0257] 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:

[0258] (a) identifying a patient in need of treatment with camlipixant;

[0259] (b) determination that the patient is receiving therapy with a CYP3A4 inducer and / or CYP2C8 inducer; and BEL00022W001

[0260] (c) administering a dose of camlipixant for the treatment of chronic cough, which is higher than the dose administered to a patient not receiving therapy with a CYP3A4 inducer and / or CYP2C8 inducer.

[0261] 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:

[0262] (a) identifying a patient in need of treatment with camlipixant;

[0263] (b) determination that the patient is receiving therapy with a CYP3A4 inducer and / or CYP2C8 inducer; and

[0264] (c) administering a 100 mg daily dose of camlipixant for the treatment of chronic cough.

[0265] 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:

[0266] (a) identifying a patient in need of treatment with camlipixant;

[0267] (b) determination that the patient is receiving therapy with a CYP3A4 inducer and / or CYP2C8 inducer; and

[0268] (c) administering a 50 mg dose of camlipixant twice daily for the treatment of chronic cough.

[0269] In an embodiment, the CYP3A4 inducer and / or CYP2C8 inducer is a strong CYP3A4 inducer and / or moderate CYP2C8 inducer.

[0270] In an embodiment, the strong CYP3A4 inducer and / or moderate CYP2C8 inducer is a strong CYP3A4 inducer and moderate CYP2C8 inducer.

[0271] In an embodiment, a strong CYP3A4 inducer is selected from the group consisting of apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, St. John’s wort, rifampicin, rifapentine, ivacaftor and avasimibe.

[0272] In an embodiment, the strong CYP3A4 inducer and moderate CYP2C8 inducer is rifampin. It is well understood that rifampin is also known as rifampicin.

[0273] In an embodiment, the chronic cough is refractory chronic cough (RCC).

[0274] In an embodiment, the chronic cough is unexplained chronic cough (UCC). BEL00022W001

[0275] EXAMPLES

[0276] A Phase 1 , open-label, fixed-sequence study evaluating the effect of rifampin on the pharmacokinetics of a single dose of camlipixant (BLU-5937) 50 mg tablet in healthy participants under fasting conditions was performed.

[0277] The purpose of this study was to assess, in vivo, the potential of camlipixant drug-drug interactions (DDIs) with CYP3A4 and CYP2C8 inducers.

[0278] Rifampin is known to induce drug metabolising enzymes of the liver, especially of the CYP family including CYP3A4 (strong inducer) and CYP2C8 (moderate inducer).

[0279] STUDY OBJECTIVE(S) AND ENDPOINT(S)

[0280] Objectives

[0281] Primary objective:

[0282] • To assess the effect of repeated oral doses of rifampin, a CYP3A4 and CYP2C8 inducer on the PK of a single oral dose of camlipixant, administered to healthy participants.

[0283] Secondary objective:

[0284] • To evaluate the safety and tolerability of camlipixant when administered alone and in combination with rifampin to healthy participants.

[0285] Endpoints

[0286] Primary endpoints:

[0287] • PK parameters: AUCo-inf, AUCo-t, and Cmax

[0288] Study Design

[0289] 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 rifampin in healthy participants under fasting conditions.

[0290] A total of 16 participants were enrolled. All participants received the assigned study intervention (the term “study intervention” is used to describe study treatment, study drug, or co-administration).

[0291] Participants received single oral dose of 1x50 mg camlipixant tablet on Day 1 , followed by 48 hours of PK and safety assessments. Repeated oral doses of 2x300 mg rifampin capsules (total dose 600 mg) were administered once daily on Days 4 to 12, with coadministration of a single oral dose of 1x50 mg camlipixant tablet with rifampin capsules on Day 11. Administration of camlipixant on Day 11 occurred 1 hour (±2 minutes) after administration of rifampin, followed by 48 hours of PK and safety assessments. BEL00022W001

[0292] Discussion of Study Design

[0293] The purpose of the study was to assess, in vivo, the potential of camlipixant drug-drug interactions (DDIs) with CYP3A4 and CYP2C8 inducers. In accordance with the recommendations provided in the Food and Drug Administration (FDA) Guidance for Clinical Drug Interaction multiple doses of the CYP inducer, rifampin, were administered to evaluate the effect on the PK of single dose camlipixant.

[0294] Rifampin was judged to be the optimal choice among CYP inducers for this study, given its ability to induce both CYP3A4 and CYP2C8. It is a clinically validated, strong inducer for CYP3A4, and one of the only clinically validated inducers of CYP2C8 (moderate inducer). Additionally, rifampin does not require an initial up-titration phase, allowing for an overall shorter exposure time to the perpetrator drug and reduces study duration for healthy participants. Moreover, the use of rifampin to induce both CYP3A4 and CYP2C8 represents the worst-case scenario to understand the effect of metabolism induction on camlipixant PK and enables to delineate the relative contributions of the two metabolic pathways in clearance of camlipixant.

[0295] Selection of Study Population

[0296] Inclusion / exclusion Criteria

[0297] Inclusion Criteria

[0298] Participants were to meet all of the following criteria to be included in the study:

[0299] 1. Male or non-childbearing potential 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 for males and >45.0 kg for females.

[0300] 2. Healthy as defined by: a. the absence of clinically significant illness and surgery within 4 weeks prior to dosing. b. the absence of clinically significant history of neurological, endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.

[0301] 3. Female participants of non-child bearing 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.

[0302] 4. Female participants of childbearing potential (Part 2 only) who were sexually active with a non-sterile male partner (sterile male partners were defined as men vasectomized for at BEL00022W001 least 3 months prior to dosing) must have been willing to use one of the following acceptable contraceptive methods throughout the study and for 30 days after the last dose: a. simultaneous use of non-hormonal intrauterine device placed at least 4 weeks prior to dosing and condom for the male partner; b. simultaneous use of diaphragm or cervical cap with spermicide and condom for the male partner, started at least 21 days prior to dosing; c. tubal ligation at least 3 months prior to dosing.

[0303] 5. Female participants must have been willing not to donate ova for 30 days after the last dose.

[0304] 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: 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.

[0305] 7. Male participants (including men who have 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.

[0306] 8. Male participants must have been willing not to donate sperm for 90 days after the last dose.

[0307] 9. Able to understand the study procedures and provide signed informed consent to participate in the study.

[0308] 9.4.1.2. Exclusion Criteria

[0309] Participants were excluded from participating in this study if any of the following criteria were met:

[0310] 1. Any clinically significant abnormal finding at physical examination at screening.

[0311] 2. Clinically significant abnormal laboratory test results or positive serology test results for HBsAg, HCV antibody, or HIV antigen and antibody, at screening.

[0312] 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 1.5x ULN were to be repeated once for confirmation to below ULN.

[0313] 4. Positive pregnancy test or lactating female participant.

[0314] 5. Positive urine drug screen, urine cotinine test, or alcohol breath test.

[0315] 6. Positive test for COVID-19 at admission. BEL00022W001

[0316] 7. Known allergic reactions or hypersensitivity to camlipixant, rifampin or any other rifamycins or other related drugs, or to any excipient in the formulation.

[0317] 8. Clinically significant 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.

[0318] 9. History of drug abuse within 1 year prior to screening or recreational use of soft drugs (such as medicinal or recreational marijuana) within 1 month or hard drugs (such ascocaine, phencyclidine, crack, opioid derivatives including heroin, and amphetamine derivatives) within 3 months prior to screening.

[0319] 10. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 6 months prior to screening that exceeds 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%).

[0320] 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.

[0321] 12. Known Gilbert, Rotor, Crigler-Najjar, or Dubin-Johnson syndrome.

[0322] 13. Medical history of ageusia / hypogeusia / dysgeusia or known presence of a dysfunction in his / her ability to taste.

[0323] 14. History of Clostridium difficile infection and Clostridium difficile-associated diseases.

[0324] 15. Participants in Part 1 only: History of liver cirrhosis, liver tuberculosis, adenocarcinoma of the liver or neoplasm of the biliary tract.

[0325] 16. Participants in Part 1 only: History of coagulation disorders.

[0326] 17. Participants in Part 2 only: History of osteoporosis.

[0327] 18. Participants in Part 2 only: History of subacute cutaneous lupus erythematosus.

[0328] 19. 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 are judged unlikely to affect the PK profile of the study drug 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; 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 vitamins, minerals, amino BEL00022W001 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).

[0329] 20. 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.

[0330] 21. 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.

[0331] 22. Any reason which, in the opinion of the Investigator, would prevent the participant from participating in the study.

[0332] Study Interventions

[0333] Study Interventions and Reference Therapy

[0334] Participants were administered the following study interventions:

[0335] • 1 x 50 mg of camlipixant (BLU-5937) tablet (Patheon, Part of Thermofisher, Whitby, Ontario, Canada) administered under fasting conditions in the morning of Day 1 and Day 11 .

[0336] • 2 x 300 mg capsules of rifampin, total dose 600 mg (Sourced from the Canadian market) administered once daily, in the morning, for 9 consecutive days from Day 4 to Day 12.

[0337] Identification of Study Intervention(s)

[0338] Prior and Concomitant Medications and Non-drug Therapies

[0339] Participants were required to avoid receiving any vaccination (including COVID-19 vaccine) and using prescription medications, OTC medications, and natural health products (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.19 and throughout the study. BEL00022W001

[0340] Hormonal contraception and hormone replacement therapy for female participants were not allowed.

[0341] 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 are judged unlikely to affect the PK profile of the study drug or participant safety (e.g., topical drug products without significant systemic absorption).

[0342] If vaccination was required for any reason, it had first 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 drug or the participant safety.

[0343] 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, were 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.

[0344] Compliance

[0345] 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 a 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 13.

[0346] 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.

[0347] Pharmacokinetic Assessment

[0348] The analytes to be measured included the investigational drug camlipixant as well as rifampin.

[0349] Pharmacokinetic Analyses

[0350] Validated Phoenix WinNonlin software, Version 8.3.4 was used for all PK analyses. BEL00022W001

[0351] Statistical analyses were performed using SAS for Windows software, Version 9.4. Bioanalysis of all samples was completed prior to the initiation of the PK and statistical analyses.

[0352] All PK concentration and PK parameter analyses were conducted on the PC Population and PK Parameter Population, respectively.

[0353] For the PC Population, PK concentrations, actual times, date / time of study intervention administration and sample collection were listed by nominal time for each study part, study day, participant and study intervention, and summarized for each study part by study 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).

[0354] Individual, mean (±SD) concentration, and overlay of individual plasma concentration versus time profile were presented for both linear and semilogarithmic scales for each study part by study intervention. For ease of presentation, actual and nominal sampling times were used to present results for individual and mean figures, respectively.

[0355] PK parameters were presented in data listings and summarized in tables for each study part by study intervention (or day), using descriptive statistics (n, arithmetic mean, SD, CV%, geometric mean, geometric SD, geometric mean CV%, minimum, median, and maximum).

[0356] PK Parameters Calculation Rules: For all PK analyses, concentration values BLQ that occurred before the first measurable concentration of the study drug were set to “0.00”; BLQ values that occurred after first measurable concentration were set to “missing”. No imputations were made on BLQ concentrations. Invalid concentration values (due to bioanalytical or clinical issues) that occurred prior to dosing were replaced by “0.00”.

[0357] Invalid concentration values that occurred after dosing were set to “missing” for tabulation, graphical representation, and calculation purposes. 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 postdose sampling times, expressed in hours and rounded off to three decimal digits, was used to calculate the PK parameters. Pre-dose sampling times were 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 post-dose samples was used in the individual graphs. Actual sampling times for post-dose samples also was used for PK parameter BEL00022W001 derivation, unless the actual sampling time was missing, in which case, the nominal time was used.

[0358] 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 Reportable”, “Not Calculated” or “No Sample” was handled as missing (i.e., no assumption was made about the actual concentration).

[0359] Pharmacokinetic Parameters: The PK parameters shown below, were calculated, whenever possible, by standard non-compartmental methods for camlipixant.

[0360] AUCo-inf: area under the concentration-time curve from time zero to infinity

[0361] (extrapolated).

[0362] Cmax: Maximal observed concentration.

[0363] AllCo-t: Area under the concentration-time curve from time zero until the last observed concentration.

[0364] 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.

[0365] Tmax: Time when the maximal concentration was observed.

[0366] T 2 el: Terminal elimination half-life, calculated as ln(2) / Kel.

[0367] Kei: Terminal elimination rate constant.

[0368] CL / F: Apparent clearance, calculated as Dose / AUCO-inf.

[0369] Vd / F Apparent volume of distribution, calculated as Dose / (Kel x AUCo-inf).

[0370] Additional PK parameters could be calculated as deemed necessary. The following information was presented for rifampin: pre-dose concentrations on the morning of Days 4, 8, 9, 10, and 11. These data were listed. Any additional PK data was presented as appropriate. Some PK parameters may not have been calculated for all or some participants, at the discretion of the Syneos pharmacokineticist if the concentration data was not deemed to be amenable to evaluation.

[0371] The effect of rifampin on the PK of camlipixant was evaluated using the MIXED procedure in SAS. A repeated measures ANOVA was performed on In-transformed AUCo-t, AUCo-inf, and Cmax at the 1 -sided alpha level of 0.05; the model included treatment as a fixed effect, and subject as a random effect to account for the repeated measures. The ratio of geometric means ([camlipixant + rifampin] versus camlipixant) and 90% Cl for the ratio of geometric BEL00022W001 means, based on least squares means from the ANOVA of the In-transformed data, was calculated for ALICO-t, AUCO-inf, and Cmax and presented. The ratio of geometric means ([camlipixant + rifampin] versus camlipixant) and 90% Cis for the ratio of geometric means, based on least squares means from the repeated measure ANOVA of the In-transformed AllCo-t, AUCo-inf, and Cmax need to be within 80% to 125% to demonstrate no DDL

[0372] A non-parametric assessment to test for central location differences among treatments ([camlipixant + rifampin] versus camlipixant), was undertaken for Tmax and presented. The Wilcoxon signed-rank test was performed using the Univariate Procedure on the paired treatment differences for Tmax.

[0373] Attainment of Steady State: As supportive data, to assess attainment of steady state, descriptive statistics on pre-dose concentrations of rifampin was presented.

[0374] STUDY POPULATION RESULTS

[0375] Disposition of Participants

[0376] A total of 33 healthy participants were screened for this study. Of these, 20 participants were enrolled and a total of 16 participants were dosed. All participants who received at least one dose of any study intervention comprised the Safety Population (N=16). All dosed participants completed the study.

[0377] A breakdown by study intervention is presented in Table 1

[0378] Oamlio xant +

[0379] Camlipixant Rifampin Riiairan Overall

[0380] Category (N=16) (N=16) (N=16) (N=16i

[0381] Table 1

[0382] Abbreviations: n (%)=Number and percent of participants; n=Number of participants; N=Number of participants in the population.

[0383] [a] Percentage is based on the number of screened volunteers.

[0384] [b] Screening failures include volunteers who did not meet study criteria.

[0385] [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.

[0386] [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.

[0387] [e] Includes all participants who received at least one dose of the study drug. BEL00022W001

[0388] [f] Number of participants who completed the respective study treatment phase.

[0389] [g] Percentage is based on the number of dosed participants.

[0390] Note: The overall column includes participants from all study treatment groups.

[0391] Treatment sequence: camlipixant 50 mg SD on Day 1 , rifampin 600 mg once daily from Day 4 to Day 12, with coadministration of camlipixant 50 mg SD on Day 11 .

[0392] Exposure and Study Intervention Compliance

[0393] All the 16 participants received camlipixant 50 mg on Day 1 , rifampin 600 mg from Days 4 to 10 and Day 12, and both camlipixant 50 mg and rifampin 600 mg on Day 11 , as per study design shown in Figure 1.

[0394] EFFICACY RESULTS

[0395] Efficacy was not an objective for this study.

[0396] Pharmacokinetic Results

[0397] All plasma PK concentrations and PK parameter summaries / analyses were conducted on the PK Concentration Population and PK Parameter Population, respectively.

[0398] The descriptive statistics for relevant PK parameters for camlipixant are presented in Figures 6-8 according to study intervention and day (camlipixant alone [Day 1] and camlipixant co-administered with rifampin [Day 11]) and timepoint.

[0399] The mean (±SD) plot for untransformed data is presented using both linear-scale and semi- log-scale in Figure 2 and Figure 3, respectively.

[0400] Overall, the exposure for camlipixant was reduced (approximately 60% reduction in AUCs [AUCo-t and AUCo-inf]) and approximately 40% reduction in Cmax) when camlipixant was administered in combination with rifampin compared to camlipixant administered alone.

[0401] The median Tmax for camlipixant was similar when camlipixant was administered in combination with rifampin compared to camlipixant administered alone.

[0402] The mean T1Z> el for camlipixant was approximately 3 hours shorter when camlipixant was administered in combination with rifampin (approximately 2 h) compared to when camlipixant was administered alone (approximately 5 h).

[0403] Pharmacokinetic and Statistical Conclusions

[0404] The total exposure of camlipixant when co-administered with rifampin was lower (approximately 60% for AUCs and 40% for Cmax) compared to camlipixant alone. The GM Rs of AUCo-t, AUCo-inf, and Cmax, and the corresponding lower and upper bounds of the 90% Cl were outside the 80% to 125% range. BEL00022W001

[0405] Based on the results, when administered with rifampin, reduction in peak and total exposure of camlipixant was observed. The total exposure of camlipixant was reduced by approximately 60% when camlipixant was administered in combination with rifampin as compared to camlipixant administered alone. The Cmax of camlipixant was reduced by approximately 40% when camlipixant was administered in combination with rifampin as compared to camlipixant administered alone.

[0406] DISCUSSIONS AND OVERALL CONCLUSIONS

[0407] The primary objective of the study was to assess the impact of rifampin (a CYP3A4 and CYP2C8) inducer on the exposure of camlipixant in healthy participants. The secondary objective was to assess the safety and tolerability of camlipixant when administered alone or in combination with rifampin.

[0408] Following oral administration, camlipixant was rapidly absorbed with median Tmax of 0.75 hours and 1 hour, respectively, when administered in combination with rifampin or alone. Exposure to camlipixant was reduced when it was co-administered with rifampin as compared to administration of camlipixant alone, with AUCs reduced by approximately 60% and Cmax reduced by approximately 40%. The GMRs of AUCo-t, AUCo-inf, and Cmax (37.02%, 36.97% and 63.39%, respectively) and the corresponding 90% Cis were not contained within 80% to 125%.

[0409] The reduction in AUC was likely due to increased clearance of camlipixant, mediated via induction of CYP (CYP3A4 and CYPC8) activity by rifampin. This increased clearance is reflected in the mean T1Z> el of camlipixant which was approximately 3 hours shorter when administered in combination with rifampin as compared to when administered alone.

[0410] The study interventions were well-tolerated overall. The number of drug-related TEAEs and the proportion of participants reporting drug-related TEAEs were similar following the administration of camlipixant alone and the co-administration of camlipixant and rifampin. All TEAEs reported were mild in severity and resolved by the end of the study.

[0411] There were no TEAEs leading to death, SAEs, or TEAEs that led to study withdrawal. No AEMIs of taste disturbance, oral paresthesia or hypoesthesia were reported. There were no clinically significant changes in vital signs, ECGs and physical examination findings. CS changes in biochemistry (ALT increased) were reported by 2 participants; these changes were judged related to rifampin by the Qualified Investigator. No TEAEs related to vital signs, ECG, physical examination abnormalities were reported during the study. BEL00022W001 Conclusions

[0412] When administered with rifampin, reduction in peak and total exposure of camlipixant was observed. The total exposure of camlipixant was reduced by approximately 60% when camlipixant was administered in combination with rifampin as compared to camlipixant administered alone. The Cmax of camlipixant was reduced by approximately 40% when camlipixant was administered in combination with rifampin as compared to camlipixant administered alone.

Claims

BEL00022W001CLAIMS1. 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 CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, wherein said patient has a second AUCo-inf or AUCo-t following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second AUCo-inf or AUCo-t is about 30 to about 90% lower 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 50 to about 75% lower 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 55 to about 65% lower 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 1500 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 1800 to about 6700 h*ng / mL.

6. The method according to any one of the preceding claims, wherein the first AUCo-inf is in the range of about 1861 to about 6619 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 about 1851 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 700 to about 2500 h*ng / mL.

9. The method according to any one of the preceding claims, wherein the second AUCo-inf is in the range of about 723 to about 2364 *ng / mL.

10. The method according to any one of claims 1 to 7, wherein the second AUCo-t is in the range of about 720 to about 2359 *ng / mL.

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

12. 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,44BEL00022W001 and wherein following administration of camlipixant said patient is administered a CYP3A4 inducer and / or CYP2C8 inducer for a non-chronic cough related indication, wherein said patient has a second Cmax following administration of a CYP3A4 inducer and / or CYP2C8 inducer and camlipixant, wherein the second Cmax is about 20 to about 70% lower than the first Cmax.

13. The method according to claim 12, wherein the second Cmax is about 20 to about 65% lower than the first Cmax, for example about 30 to about 65% lower or about 20 to about 60% lower.

14. The method according to claim 12, wherein the second Cmax is about 30 to about 50% lower than the first Cmax, for example about 40% lower.

15. The method according to any one of claims 12 to 14, wherein the first Cmax is in the range of from about 400 to about 1200 ng / mL.

16. The method according to any one of claims 12 to 15, wherein the first Cmax is in the range of from about 450 to about 1100 ng / mL.

17. The method according to any one of claims 12 to 16, wherein first Cmax is in the range of from about 484 to about 1090 ng / mL.

18. The method according to any one of claims 12 to 17, wherein the second Cmax is in the range of from about 300 to about 1000 ng / mL.

19. The method according to any one of claims 12 to 18, wherein second Cmax is in the range of from about 336 to about 887 ng / mL.

20. A method for the treatment of chronic cough in a patient in need thereof, wherein said patient is also in need of a CYP3A4 inducer and / or CYP2C8 inducer 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the patient has an AUCo-t or AUCo-inf in the range of about 1500 to about 7500 h*ng / mL on treatment with camlipixant alone and an AUCo-t or AUCo-inf in the range of about 150 to about 5250 h*ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer, or whereinBEL00022W001 the patient has a Cmax in the range of about 400 to about 1200 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 120 to about 960 ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.21 . The method according to claim 20, wherein the patient has an AllCo-t or AUCo-inf in the range of about 1800 to about 6700 h*ng / mL on treatment with camlipixant alone and an ALICo-t or AUCo-inf in the range of about 700 to about 2500 h*ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer, or wherein the patient has a Cmax in the range of about 450 to about 1100 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 300 to about 1000 ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

22. The method according to claim 20 or claim 21 , wherein the patient has an AUCo-t in the range of about 1851 to about 6591 h*ng / mL on treatment with camlipixant alone and an AUCo-t in the range of about 720 to about 2359 h*ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer, or wherein the patient has an AUCo-inf in the range of about 1861 to about 6619 h*ng / mL on treatment with camlipixant alone and an AUCo-inf in the range of about 723 to about 2364 h*ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer, or wherein the patient has a Cmax in the range of about 484 to about 1090 ng / mL on treatment with camlipixant alone and a Cmax in the range of about 336 to about 887 ng / mL on treatment with camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer.

23. The method according to any one of claims 20 to 22, wherein the patient is administered a therapeutically effective amount of camlipixant and a therapeutically effective amount of a CYP3A4 inducer and / or CYP2C8 inducer.

24. 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 CYP3A4 inducer and / or CYP2C8 inducer 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 150 to about 5250 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; andBEL00022W001 wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-inf or ALICo-t in the range of about 1500 to about 7500 h*ng / mL.

25. A method according to claim 24, wherein the patient has an AUCo-inf or AUCo-t in the range of about 700 to about 2500 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-inf or AUCo-t in the range of about 1800 to about 6700 h*ng / mL.

26. A method according to claim 24 or claim 25, wherein the patient has an AUCo-inf in the range of about 723 to about 2364 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-inf in the range of about 1861 to about 6619 h*ng / mL.

27. A method according to claim 24 or claim 25, wherein the patient has an AUCo-t in the range of about 720 to about 2359 h*ng / mL while on treatment with both camlipixant and a CYP3A4 inducer and / or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has an AUCo-t in the range of about 1851 to about 6590 h*ng / mL.

28. 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 CYP3A4 inducer and / or CYP2C8 inducer for the treatment of a non-chronic cough related indication, wherein the patient has a Cmax in the range of about 120 to about 960 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer or CYP2C8 inducer; and wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a Cmax in the range of about 400 to about 1200 ng / mL.

29. The method according to claim 28, wherein the patient has a Cmax in the range of about 300 to about 1000 ng / mL while on treatment with both camlipixant and a CYP3A4 inducer or CYP2C8 inducer; andBEL00022W001 wherein following discontinuation of treatment with a CYP3A4 inducer and / or CYP2C8 inducer for the non-chronic cough related indication has a Cmax in the range of about 450 to about 1100 ng / mL.

30. The method according to any one of claims 24 to 29, wherein the patient is administered a therapeutically effective amount of camlipixant.

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

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

33. 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.

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

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

36. The method according to any one of claims 33 to 35, wherein the amount is a therapeutically effective amount.

37. The method according to any one of the preceding claims, wherein the CYP3A4 inducer and / or CYP2C8 inducer is a strong CYP3A4 inducer and / or moderate CYP2C8 inducer38. The method according to claim 37, wherein the strong CYP3A4 inducer and / or moderate CYP2C8 inducer is a strong CYP3A4 inducer and moderate CYP2C8 inducer.

39. The method according to claim 36, wherein the strong CYP3A4 inducer and moderate CYP2C8 inducer is rifampin.

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