WO2022106621A1

WO2022106621A1 - Selexipag for use via intracolonic administration

Info

Publication number: WO2022106621A1
Application number: PCT/EP2021/082307
Authority: WO
Inventors: Sven Erik SÖDERLIND; Elise VAES; Annelien VAN DROOGENBROECK
Original assignee: Actelion Pharmaceuticals Ltd
Priority date: 2020-11-20
Filing date: 2021-11-19
Publication date: 2022-05-27

Abstract

The present disclosure provides methods for treating pulmonary hypertension, including pulmonary arterial hypertension. The methods comprise administering a therapeutically effective amount of selexipag to a patient in need thereof, wherein at least one dose of selexipag is in an intracolonic form. Also provided are pharmaceutical drug products comprising a therapeutically effective amount of selexipag in an intracolonic form; and instructions for using selexipag via intracolonic administration for the treatment of pulmonary hypertension, including pulmonary arterial hypertension.

Description

SELEXIPAG FOR USE VIA INTRACOLONIC ADMINISTRATION

TECHNICAL FIELD

[0001] The present invention relates to methods of treating pulmonary hypertension, including pulmonary arterial hypertension.

BACKGROUND

[0002] Prostacyclin (PGI2) is a member of the prostaglandin family, which are endogenous, oxygenated fatty acid metabolites deriving from arachidonic acid. PGI2 is a potent vasodilator, inhibitor of platelet aggregation, and inhibitor of smooth muscle cell proliferation. These effects are mediated via the PGI2 receptor (IP receptor). The IP receptor is a G-protein-coupled receptor that activates adenylate cyclase, leading to increased cyclic adenosine monophosphate levels in the target cells, which in turn mediates the cellular effects of PGI2. The predominant cardiovascular actions of PGI2 are vasodilation, inhibition of smooth muscle cell proliferation, and pro-fibrotic pathways in fibroblasts. Thus, PGI2 contributes to the maintenance of vascular homeostasis; its decrease leads to vasoconstriction and proliferation of vascular smooth muscle cells. As PAH is associated with vasoconstriction, proliferation, and thrombosis, restoration of IP receptor signaling using IP receptor agonists is an effective strategy in the treatment of the disease. Selexipag has been approved in Europe, the United States, Canada, and other countries for the treatment of adults with PAH.

[0003] Selexipag immediate release (IR) is the first selective orally available nonprostanoid prostacyclin receptor (IP receptor) agonist approved for the treatment of pulmonary arterial hypertension (PAH). Selexipag IR is approved in eight dose strengths of 200, 400, 600, 800, 1,000, 1,200, 1,400, and 1,600 pg intended for twice daily (bid) dosing at the patient's individual maximum tolerated dose.

SUMMARY

[0004] The present disclosure provides methods of treating pulmonary hypertension, including pulmonary arterial hypertension. These methods comprise administering a therapeutically effective amount of selexipag to a patient in need thereof, wherein at least one dose of selexipag is in an intracolonic form. [0005] The present disclosure also provides pharmaceutical drug products comprising a therapeutically effective amount of selexipag in an intracolonic form. The pharmaceutical drug product also comprises instructions for using selexipag via intracolonic administration for the treatment of pulmonary hypertension, including pulmonary arterial hypertension.

[0006] The present disclosure also provides pharmaceutical compositions comprising about 25 or about 50 pg of selexipag and methods for treating pulmonary hypertension using these compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 is an overview of the study design. For Treatment A [Period 1] and Treatment B [Period 2], further administration of the study drug will be paused until the first two participants within each treatment have completed their 24-hour postdose safety assessments. Upon evaluation of the safety data obtained from the first two participants during Treatment A and Treatment B, respectively, study drug administration to the remaining B participants can be initiated if no safety concerns are identified based on the judgment of the investigator.

[0008] FIG. 2 is a photograph of a Bioperm device.

[0009] FIG. 3 is photograph of a disassembled capsule utilized in the Bioperm device.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0010] In the present disclosure the singular forms “a”, “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

[0011] When a value is expressed as an approximation by use of the descriptor “about” or “substantially” it will be understood that the particular value forms another embodiment. In general, use of the term “about” or “substantially” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about” or “substantially”. In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” or “substantially” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0012] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0013] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiments and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself.

Methods / Uses

[0014] The present disclosure provides methods for treating pulmonary hypertension, including, without limitation, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension (CTEPH) or sarcoidosis-associated pulmonary hypertension (SAPH). In some embodiments, the present disclosure provides methods for treating PAH. In other embodiments, the present disclosure provides methods for treating CTEPH. In further embodiments, the present disclosure provides methods for treating SAPH. In these methods, a therapeutically effective amount of selexipag is administered to a patient in need thereof, wherein at least one dose of selexipag is in an intracolonic form. In other embodiments, a therapeutically effective amount of selexipag is administered to a patient in need thereof, wherein at least one dose of selexipag is in an oral form.

[0015] The terms “pulmonary arterial hypertension” and “PAH” are interchangeable and define a condition of pulmonary hypertension where the patient has high blood pressure in the lungs. PAH occurs when the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs. In some embodiments, the underlying cause of the narrowing is not known, /.< ., idiopathic pulmonary hypertension. PAH also is classified into subgroups including (i) familial, or heritable PAH, (ii) PAH caused by drugs or toxins, (iii) PAH associated with other conditions such as connective tissue diseases (scleroderma or lupus), congenital heart problems, high blood pressure in the liver, HIV, infections (schistosomiasis), and sickle cell anemia, (iv) PAH caused by rare blood conditions (pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis, or (v) PAH in babies (persistent pulmonary hypertension of the newborn).

[0016] The terms “sarcoidosis-associated pulmonary hypertension” and “SAPH” are interchangeable and define the condition in which a patient has pulmonary hypertension and sarcoidosis. Typically, SAPH is classified by the World Health Organization (WHO) using a functional classification of pulmonary hypertension as described below. The methods described herein may include a determination that the patient has SAPH. Typically, that determination is made by an attending physician. A diagnosis or determination of SAPH may be performed using techniques known by those of skill in the art. For example, a rightheart catheterization may be conducted to confirm pulmonary hypertension in a patient with sarcoidosis.

[0017] The terms “chronic thromboembolic pulmonary hypertension” and “CTEPH” are interchangeable and define the condition in which a patient has pulmonary hypertension caused by old blood clots in the lungs, i.e., pulmonary emboli. In some embodiments, CTEPH does not respond to the use of prescribed blood thinners to restore blood flow to the lungs and prevent development of CTEPH. In other embodiments, CTEPH develops when large blood vessels in the lungs are obstructed by old blood clots. In further embodiments, CTEPH develops via changes in the small blood vessels in the lungs that are similar to PAH, i.e., small blood vessels become increasingly narrow and stiff. In yet other embodiments, CTEPH develops from multiple small clots over a long period of time. In still further embodiments, CTEPH develops from one or two large blood clots in the lungs.

[0018] Prior to being administered intracolonic selexipag, the patient will desirably have a body mass index (BMI) of about 18.0 to about 28.0 kg/m². In some embodiments, the patient has a BMI of about 18 to about 28, about 18 to about 26, about 18 to about 24, about 18 to about 22, about 18 to about 20, about 20 to about 28, about 20 to about 26, about 20 to about 24, about 20 to about 22, about 22 to about 28, about 22 to about 26, about 22 to about 24, about 24 to about 28, about 24 to about 26, or about 26 to about 29 kg/m².

[0019] The patient, also, desirably, will have a body weight of not less than about 50.0 kg. In some embodiments, the patient has a body weight of not less than about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, or about 60 kg-

[0020] Prior to administration of selexipag, the patient preferably has a blood pressure of about 90 to about 145 mmHg systolic and/or about 90 mmHg or less diastolic. In some embodiments, the patient has a blood pressure of about 90 to about 140, about 90 to about 130, about 90 to about 120, about 90 to about 110, about 90 to about 100, about 100 to about 140, about 100 to about 130, about 100 to about 120, about 100 to about 110, about 110 to about 140, about 110 to about 130, about 110 to about 120, about 120 to about 140, about 120 to about 130, or about 130 to about 140 mmHg systolic. In other embodiments, the patient has a blood pressure of about 90, about 85, about 80, about 75, about 70, about 65, or about 60 mmHg or less diastolic. In further embodiments, the patient has a blood pressure of about 59 to about 90, about 50 to about 85, about 50 to about 80, about 50 to about 75, about 50 to about 70, about 50 to about 65, about 50 to about 60, about 60 to about 90, about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 60 to about 65, about 65 to about 90, about 65 to about 85, about 65 to about 80, about 65 to about 75, about 65 to about 70, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 70 to about 75, about 75 to about 90, about 75 to about 85, about 75 to about 80, about 80 to about 90, about 80 to about 85, or about 85 to about 90 mmHg diastolic. Desirably, such measurements are made after the patient is supine for about 5 minutes. [0021] The patient, further, desirably has a resting 12-lead electrocardiogram (ECG) that is consistent with normal cardiac conduction, normal cardiac function, and/or normal sinus rhythm prior to administration of selexipag. Certain parameters that may be measured include, without limitation, the pulse/heart rate, QTc interval, QRS interval, and PR interval, or combinations thereof.

[0022] In some embodiments, the patient has a pulse rate of about 45 to about 90 bpm. In some aspects, the patient has a pulse rate of about 45 to about 80, about 45 to about 75, about 45 to about 70, about 45 to about 65, about 45 to about 60, about 45 to about 55, about 45 to about 50, about 50 to about 90, about 50 to about 85, about 50 to about 80, about 50 to about 75, about 50 to about 70, about 50 to about 65, about 50 to about 60, about 50 to about 55, about 55 to about 90, about 55 to about 85, about 55 to about 80, about 55 to about 75, about 55 to about 70, about 55 to about 65, about 55 to about 60, about 60 to about 90, about 60 to about 85, about 60 to about 80, about 60 to about 75, about 60 to about 70, about 60 to about 65, about 65 to about 90, about 65 to about 85, about 65 to about 80, about 65 to about 75, about 65 to about 70, about 70 to about 90, about 70 to about 85, about 70 to about 80, about 70 to about 75, about 75 to about 90, about 75 to about 85, about 75 to about 80, about 80 to about 90, about 80 to about 85, or about 85 to about 90 bpm. In other aspects, the patient has a pulse rate of about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, or about 90 bpm.

[0023] In yet further embodiments, the patient has a QTc interval of about 400 to about 500, about 400 to about 475, about 400 to about 450, 400 to about 425, about 425 to about 500, about 425 to about 475, about 425 to about 450, about 450 to about 500, about 450 to about 475, or about 475 to about 500 ms. In some aspects, the patient has a QTc interval of about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, or about 500 ms. In other aspects, the patient has a QTc interval of about 450 ms.

[0024] In further embodiments, the patient has a QRS interval of about 110 ms or less. In some aspects, the patient has a QRS interval of about 70 to about 110, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 75 to about 110, about 75 to about 100, about 75 to about 90, about 75 to about 85, about 75 to about 80, about 80 to about 110, about 80 to about 100, about 80 to about 90, about 85 to about 110, about 85 to about 100, about 85 to about 90, about 85 to about 95, about 90 to about 110, about 90 to about 100, about 95 to about 110, about 95 to about 100, or about 100 to about 110 ms. In other aspects, the patient has a QRS interval of about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, or about 110 ms.

[0025] In yet other embodiments, the patient has a PR interval of about 200 ms or less. In some aspects, the patient has a PR interval of about 100 to about 200, about 100 to about 180, about 100 to about 160, about 100 about 140, about 100 to about 120, about 120 to about 200, about 120 to about 180, about 120 to about 160, about 120 to about 140, about 140 to about 200, about 140 to about 180, about 140 to about 160, about 160 to about 200, about 160 to about 200, or about 180 to about 200 ms.

[0026] In still further embodiments, the patient has two or more of (i) a pulse rate of about 45 to about 90 bpm, (ii) a QTc interval of about 450 ms, (iii) a QRS interval of about 110 ms or less, or (iv) a PR interval of about 200 ms or less.

[0027] A therapeutically effective amount of selexipag in intracolonic form, on a daily basis, is about 100 to about 500 pg. In some aspects, the therapeutically effective amount of selexipag, on a daily basis, is about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, or about 500 pg. In other aspects, the therapeutically effective amount of selexipag, on a daily basis, is about 100 to about 500, about 100 to about 450, about 100 to about 400, about 100 to about 350, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 500, about 150 to about 450, about 150 to about 400, about 150 to about 350, about 150 to about 300, about 150 to about 250, about 150 to about 200, about 200 to about 500, about 200 to about 450, about 200 to about 400, about 200 to about 350, about 200 to about 300, about 200 to about 250, about 250 to about 500, about 250 to about 450, about 250 to about 400, about 250 to about 350, about 250 to about 300, about 300 to about 500, about 300 to about 450, about 300 to about 400, about 300 to about 350, about 350 to about 500, about 350 to about 450, about 350 to about 400, about 400 to about 500, or about 450 to about 500 pg. Unless otherwise noted, the amounts of selexipag described herein are set forth on a free base basis. That is, the amounts indicate that amount of the selexipag molecule administered, exclusive of, for example, counterions (such as in pharmaceutically acceptable salts). [0028] In some embodiments, at least one dose of selexipag is in an intracolonic form. The term “intracolonic form” or "intracolonic dose" as used herein refers to a form or dose that is targeted to the colon, and, preferably, where the first point of absorption of the selexipag is in the colon. In contrast, an "oral dose" of selexipag, as used herein, is not targeted to the colon, and, includes, for example, an immediate release formulation, or other oral forms where the first point of absorption of selexipag is other than the colon. In some embodiments, the intracolonic form is the same as the oral form. In other embodiments, the intracolonic form is different than the oral form. Desirably, the intracolonic form is delivered by using a device. Thus, the intracolonic form may be a solution, suspension, and/or solid dosage form. For solid dosage forms that are encompassed within the device, the form is typically designed to fit within the device.

[0029] Oral doses of selexipag may also be administered to the patient as determined by one skilled in the art. In some embodiments, the oral doses are administered independent of the intracolonic form. In other embodiments, the oral doses may be administered in combination with the intracolonic form as disclosed herein. In further embodiments, the methods comprise administering one dose of selexipag in an intracolonic form. In other embodiments, the methods comprise administering selexipag in two intracolonic doses. In further embodiments, the methods comprise administering selexipag in one intracolonic dose and one oral dose. In still other embodiments, the methods comprise administering selexipag in two intracolonic doses and one oral dose.

[0030] The therapeutically effective amount of selexipag may be administered once daily, twice daily, or thrice daily. In some embodiments, the therapeutically effective amount of selexipag is administered in one intracolonic dose. In other embodiments, the therapeutically effective amount is administered in two intracolonic doses. In further embodiments, the therapeutically effective amount of selexipag is administered in one intracolonic dose and one oral dose. In still other embodiments, the therapeutically effective amount of selexipag is administered in two intracolonic doses and one oral dose.

[0031] As used herein, the term “selexipag” refers to 2-{4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide of formula (I) in its free base form.

[0032] As used herein, “selexipag” also refers to amorphous or crystalline forms of selexipag, such as polymorphs thereof. In some embodiments, the selexipag is a crystalline form, such as a polymorph. In other embodiments, the selexipag is an amorphous form. In other embodiments, the selexipag is the Form I as described in U.S. Patent Nos. 8,791,122 and 9,284,280, Form II as described in U.S. Patent No. 9,340,516, or Form III as described in U.S. Patent No. 9,440,931, all of which are incorporated by reference herein. The crystallinity may be determined by those skilled in the art using one or more techniques such as, e.g., single crystal x-ray diffraction, powder x-ray diffraction, differential scanning calorimetry, melting point, among others.

[0033] “Selexipag” as used herein also includes anhydrous or hydrates thereof. In certain embodiments, the selexipag is an anhydrous form. In other embodiments, the selexipag is a hydrate thereof.

[0034] “Selexipag” as used herein further also refers to solvates thereof. Such solvates include a molecule of a solvent bound through intermolecular forces or chemical bonds to one or more locations of the selexipag molecule.

[0035] The term “selexipag” may also include pharmaceutically acceptable salts thereof, which may readily be selected by those skilled in the art. A “pharmaceutically acceptable salt” is intended to mean a salt of selexipag that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, e.g., Berge, “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002, which are incorporated herein by reference. Selexipag can be used in the form of a free base or acid, but can also be used after forming into a pharmaceutically acceptable salt by a known method. When the selexipag is basic, examples of “salt” include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid, and salts of organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid. When the selexipag is acidic, examples of “salt” include alkali metal salts such as sodium salt and potassium salt, and alkali earth metal salts such as calcium salt.

[0036] Geometrical isomers (Z form and E form) of selexipag or mixtures thereof are also contemplated.

[0037] Selexipag is commercially available as understood to those skilled in the art. See, e.g., U.S. Patent No. 7,205,302, which is incorporated by reference herein. For example, selexipag is available as Uptravi® and also is known as ACT-293987 or NS-304. Selexipag is an agonist of the prostacyclin receptor and may be prepared according to a process as disclosed in U.S. Patent No. 7,205,302.

[0038] The present disclosure also contemplates the administration of selexipag metabolites or salts thereof. Desirably, the selexipag metabolite is the metabolically active compound. Thus, in certain embodiments, the selexipag metabolite is of formula Ml. Ml is also known under the code name ACT-333679 or MRE-269.

[0039] As used herein, unless otherwise noted, the terms “treating”, “treatment” and the like, shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder. The terms “treating” and “treatment” also include the administration of the compounds or pharmaceutical compositions as described herein to (a) alleviate one or more symptoms or complications of the disease, condition or disorder; (b) prevent the onset of one or more symptoms or complications of the disease, condition or disorder; and/or (c) eliminate one or more symptoms or complications of the disease, condition, or disorder. [0040] As used herein, unless otherwise noted, the terms “preventing”, “prevention” and the like, shall include (a) reducing the frequency of one or more symptoms; (b) reducing the severity of one or more symptoms; (c) delaying, slowing or avoiding of the development of additional symptoms; and/or (d) slowing, or avoiding the development of the disorder or condition to a later stage or more serious form.

[0041] One skilled in the art will recognize that, wherein the present disclosure is directed to methods of prevention, a patient in need thereof shall include a patient who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Further, a patient in need thereof may additionally be a patient who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the patient may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the patient's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like.

[0042] The terms “subject” and “patient” are interchangeably used herein to refer to a human who has been the object of treatment, observation or experiment. Preferably, the patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject is an adult patient. In other embodiments, the subject is a pediatric patient.

[0043] In the methods described herein, the therapeutically effective amount of selexipag is safe, effective, or safe and effective. As used herein, unless otherwise noted, the term “safe” shall mean without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. Similarly, unless otherwise noted, the term “effective” means the efficacy of treatment has been demonstrated for the treatment of patients with pulmonary arterial hypertension when dosed in a therapeutically effective dose. In certain embodiments, the methods described herein are safe. In other embodiments, the methods described herein are effective. In further embodiments, the methods described herein are safe and effective. In yet other embodiments, the therapeutically effective amount of selexipag, in intracolonic and/or oral doses, is safe. In still further embodiments, the therapeutically effective amount of selexipag, in intracolonic and/or oral doses, is effective. In other embodiments, the therapeutically effective amount of selexipag, in intracolonic and/or oral doses, is safe and effective.

[0044] As used herein, unless otherwise noted, the term “clinically proven” (used independently or to modify the terms “safe” and/or “effective”) shall mean that proof has been proven by a Phase III or IV clinical trial that are sufficient to meet approval standards of U.S. Food and Drug Administration or similar study for market authorization by EMEA. Preferably, an adequately sized, randomized, double-blinded controlled study is used to clinically prove the effects of selexipag as compared to a placebo with the patient’s condition assessed by techniques described herein.

[0045] As used herein, unless otherwise noted, the term “clinically proven effective” means the efficacy of treatment has been proven by a Phase III or IV clinical trial as statistically significant, /.< ., the results of the clinical trial are not likely to be due to chance with an alpha level less than 0.05 or the clinical efficacy results are sufficient to meet approval standards of U.S. Food and Drug Administration or similar study for market authorization by EMEA. For example, selexipag was clinically proven effective for the treatment of patients with pulmonary arterial hypertension in a therapeutically effective dose as described herein, and as specifically set forth in the examples.

[0046] As used herein, unless otherwise noted, the term “clinically proven safe” means the safety of treatment has been proven by a Phase III or IV clinical trial by analysis of the trial data and results establishing that the treatment is without undue adverse side effects and commensurate with the statistically significant clinical benefit (e.g., efficacy) sufficient to meet approval standards of U.S. Food and Drug Administration or similar study for market authorization by Europe, the Middle East, and Africa (EMEA). For example, selexipag was clinically proven safe for the treatment of patients with pulmonary arterial hypertension when dosed in a therapeutically effective dose as described herein, and as specifically set forth in the examples.

[0047] In certain aspects, methods of selling a drug product comprising selexipag are also provided. The terms “sale” or “selling” as used herein refers to transferring a drug product, e.g., a pharmaceutical composition or a dosage form, from a seller to a buyer. Thus, the methods include selling a drug product comprising selexipag, wherein the method comprises selling the drug product. In some embodiments, a drug product label for a reference listed drug for the drug product includes instructions for treating pulmonary arterial hypertension via intracolonic administration of selexipag. The methods also include offering for sale a drug product comprising selexipag. The term “offering for sale,” as used herein, refers to the proposal of a sale by a seller to a buyer for a drug product, e.g., a pharmaceutical composition or a dosage form. These methods comprise offering the drug product for sale.

[0048] The present also disclosure provides pharmaceutical drug products comprising selexipag. In some embodiments, the pharmaceutical drug products comprises a therapeutically effective amount of selexipag in an intracolonic form and instructions for using selexipag via intracolonic administration for the treatment of pulmonary hypertension, such as pulmonary arterial hypertension. As disclosed herein, the intracolonic form is in a solid form or is a solution or suspension. In some embodiments, the intracolonic form in the pharmaceutical drug product is a solution or suspension. In other embodiments, the intracolonic form in the pharmaceutical drug product is a solid form.

[0049] The pharmaceutical drug product may also comprise a device for intracolonically administering the selexipag. The device is suitably one that may be swallowed by the patient, thereby passing through the gastrointestinal system to reside in the colon. In some embodiments, the device is a capsule that contains the selexipag, preferably a capsule with a hollow interior. In other embodiments, the device is a capsule that contains the solid form of selexipag. In further embodiments, the device is a capsule that contains a solution or suspension comprising selexipag. In yet other embodiments, the device is an empty capsule where a solution comprising selexipag may be delivered to the capsule. In further embodiments, the device is an empty capsule that does not retain the selexipag solution or suspension, but is instead adapted to deliver a solution or suspension containing selexipag to the colon using the thin tube as described below. In still further embodiments, the selexipag is intracolonically administered to the patient using the Bioperm method. See, Example 1. In other embodiments, the selexipag is administered during a colonoscopy.

[0050] The capsule utilized in the device desirably may be monitored using X-ray radiography. Thus, the capsule comprises a means for detecting the device by X-rays. In some embodiments, the capsule comprises a means that is an X-ray visible tube or is inserted into an X-ray visible tube. In other embodiments, the capsule comprises an X-ray visible screw fastened to the capsule.

[0051] The capsule also may be attached to a thin tube which serves several purposes. In some embodiments, the location of the capsule in the gastrointestinal tract can be fixed by directing the track of the capsule within the gastrointestinal tract using the thin tube. In order to do so, one end of the thin tube is attached to the capsule and the other end of the thin tube is retained outside of the patient’s body. In some embodiments, the thin tube may be attached to a reel, from which the thin tube may be released. A variety of techniques and equipment may be utilized to attach the thin tube to the reel. In some embodiments, the thin tube is attached using a fitting such as a Luer-loc fitting. In further embodiments, once the capsule is suspected to have reached the colon, further progression of the capsule along the gut is prevented by, for example, taping the tube to the cheek of the patient. In other embodiments, the fitting resides within the reel. The thin tube may also have regular measurement marks, e.g., in centimeter or inch gradients, which may be used to estimate the location of the capsule from the nose to the gastrointestinal system. Once the capsule is at the intended location within the gastrointestinal tract, the thin tube may also be utilized to deliver a solution or suspension comprising the selexipag, preferably by injecting the solution or suspension into the tube using a syringe. In embodiments where the capsule carries the selexipag dose, the thin tube allows the location of the capsule in the colon to be measured, thus permitting release of the selexipag dose from the capsule.

[0052] For embodiments where the capsule contains a solid form of selexipag, the hollow interior of the capsule is equipped with a thin elastic membrane. The solid form of selexipag is placed within the elastic membrane. The elastic membrane is designed to retract, thereby forming a sac to enclose the solid form of selexipag. In order to release the solid form of selexipag, the distal part of the capsule is sealed with a lid. The lid is designed to be released from the capsule, z.e., pop off, when air is pressed through the thin tube. For example, air may be pushed into the thin tube using a syringe filled with air and pushing that air into the thin tube. After air enters the capsule, the elastic membrane moves forward within the capsule, the lid dislodges, the capsule opens, and the solid form of selexipag is expelled into the gastrointestinal tract. [0053] In some embodiments, the pharmaceutical product comprises an effective amount of selexipag, wherein the pharmaceutical product is packaged and wherein the package includes a label that identifies selexipag as a regulatory approved chemical entity and includes instructions for colonic use of selexipag for the treatment of pulmonary arterial hypertension. In further embodiments, the present disclosure provides pharmaceutical drug products comprising a therapeutically effective amount of selexipag and instructions for colonic use of selexipag for the treatment of pulmonary arterial hypertension. In other embodiments, the present disclosure provides methods of treating pulmonary arterial hypertension, comprising intracolonically administering to a patient in need thereof an approved drug product comprising selexipag in an amount described in a drug product label for said drug product.

[0054] The term “drug product” refers to a product that contains an active pharmaceutical ingredient that has been approved for marketing by a governmental authority, e.g., the Food and Drug Administration or the similar authority in other countries. In some embodiments, the drug product comprises selexipag.

[0055] Similarly, “label” or “drug product label” refers to information provided to a patient which provides relevant information regarding the drug product. Such information includes, without limitation, one or more of the description of the drug, clinical pharmacology, indications (uses for the drug product), contraindication (who should not take the drug product), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use in pregnancy, use in nursing mothers, use in children and older patients, how the drug is supplied, safety information for the patient, or any combination thereof. In certain embodiments, the label or drug product label provides instructions for treating pulmonary arterial hypertension via intracolonic administration of selexipag. In further embodiments, the label or drug product label identifies selexipag as a regulatory approved chemical entity.

[0056] The term “reference listed drug” or “RLD” as used herein refers to a drug product to which new generic versions are compared to show that they are bioequivalent. It is also a medicinal product that has been granted marketing authorization by a member state of the European Union or by the Commission on the basis of a completed dossier, /.< ., with the submission of quality, pre-clinical and clinical data in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC and to which the application for marketing authorization for a generic/hybrid medicinal product refers, by demonstration of bioequivalence, usually through the submission of the appropriate bioavailability studies.

[0057] In certain embodiments, the drug product is an ANDA drug product, a supplemental New Drug Application drug product, or a 505(b)(2) drug product. In the United States, a company seeking approval to market a generic equivalent must refer to the RLD in its Abbreviated New Drug Application (ANDA). For example, an ANDA applicant relies on the FDA’s finding that a previously approved drug product, /.< ., the RLD, is safe and effective, and must demonstrate, among other things, that the proposed generic drug product is the same as the RLD in certain ways. Specifically, with limited exceptions, a drug product for which an ANDA is submitted must have, among other things, the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and (with certain permissible differences) labeling as the RLD. The RLD is the listed drug to which the ANDA applicant must show its proposed ANDA drug product is the same with respect to active ingredient(s), dosage form, route of administration, strength, labeling and conditions of use, among other characteristics. In the electronic Orange Book, there is a column for RLDs and a column for reference standards. In the printed version of the Orange Book, the RLDs and reference standards are identified by specific symbol.

[0058] In Europe, Applicants identify in the application form for its generic/hybrid medicinal product, which is the same as an ANDA or supplemental NDA (sNDA) drug product, the reference medicinal product (product name, strength, pharmaceutical form, marketing authorization holder (MAH, first authorization, Member State/Community), which is synonymous with a RLD, as follows:

[0059] 1. The medicinal product that is or has been authorized in the European Economic Area (EEA), used as the basis for demonstrating that the data protection period defined in the European pharmaceutical legislation has expired. This reference medicinal product, identified for the purpose of calculating expiry of the period of data protection, may be for a different strength, pharmaceutical form, administration route or presentation than the generic/hybrid medicinal product.

[0060] 2. The medicinal product, the dossier of which is cross-referred to in the generic/hybrid application (product name, strength, pharmaceutical form, MAH, marketing authorization number). This reference medicinal product may have been authorized through separate procedures and under a different name than the reference medicinal product identified for the purpose of calculating expiry of the period of data protection. The product information of this reference medicinal product will, in principle, serve as the basis for the product information claimed for the generic/hybrid medicinal product.

[0061] 3 The medicinal product (product name, strength, pharmaceutical form, MAH, Member State of source) used for the bioequivalence study(ies) (where applicable).

[0062] The different abbreviated approval pathways for drug products under the Food, Drug, and Cosmetics (FD&C) Act are the abbreviated approval pathways described in sections 505(j) and 505(b)(2) of the FD&C Act (21 U.S.C. 355(j) and 21 U.S.C. 355(b)(2), respectively).

[0063] According to the FDA (“Determining Whether to Submit an ANDA or a 505(b)(2) Application Guidance for Industry,” U.S. Department of Health and Human Services, October 2017, pp. 1-14, the contents of which is incorporated herein by reference), ND As and ANDAs can be divided into the following four categories:

[0064] (1) A “stand-alone NDA” is an application submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference or use.

[0065] (2) A section 505(b)(2) application is an NDA submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use.

[0066] (3) An ANDA is an application for a duplicate of a previously approved drug product that was submitted and approved under section 505(j) of the FD&C Act. An ANDA relies on the FDA’s finding that the previously approved drug product, /.< ., the reference listed drug (RLD), is safe and effective. An ANDA generally must contain information to show that the proposed generic product (a) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and (b) is bioequivalent to the RLD. An ANDA may not be submitted if studies are necessary to establish the safety and effectiveness of the proposed product.

[0067] (4) A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient) and for which FDA has determined, in response to a petition submitted under section 505(j)(2)(C) of the FD&C Act (suitability petition), that studies are not necessary to establish the safety and effectiveness of the proposed drug product.

[0068] A scientific premise underlying the Hatch-Waxman Act is that a drug product approved in an ANDA under section 505(j) of the FD&C Act is presumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions specified in the labeling. In contrast to an ANDA, a section 505(b)(2) application allows greater flexibility as to the characteristics of the proposed product. A section 505(b)(2) application will not necessarily be rated therapeutically equivalent to the listed drug it references upon approval.

Formulations / Compositions

[0069] Pharmaceutical compositions containing selexipag as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. As used herein, the terms “composition” and “formulation” are used interchangeably and encompass a product comprising the specified ingredients in the specified amounts, as well as any product, such as a pharmaceutical product, which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. A summary of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0070] Selexipag may be administered to a patient neat or in a mixture with a pharmaceutically acceptable non-toxic inert carrier, for example, as a pharmaceutical composition containing the compound at a level of 0.1% to 99.5wt%, preferably 0.5% to 90%, based on the total weight of the composition. As a carrier, one or more of auxiliary agents for formulations such as solid, semi-solid and liquid diluent, filler and other auxiliary agents for drug formulations may be used. It is desirable that a pharmaceutical composition is administered as a unit dosage form.

[0071] The pharmaceutical compositions may be administered by a number of routes as determined by those skilled in the art. Preferably, the pharmaceutical compositions are administered by route that is suitable for selexipag. In some embodiments, the pharmaceutical compositions are administered orally, parenterally, or any combination thereof. In other embodiments, the pharmaceutical compositions are administered orally. In further embodiments, the pharmaceutical compositions are administered parenterally such as intravenously.

[0072] For intracolonic administration of selexipag, the form may be a solid, liquid, or a solid form suspended in a liquid, i.e., a suspension. In some embodiments, the intracolonic form of selexipag as described herein is a solid form. In other embodiments, the intracolonic form of selexipag as described herein is a liquid such as a solution. In further embodiments, the intracolonic form of selexipag as described herein is in a suspension. For oral doses of selexipag, the form is desirably a solid form.

[0073] Examples of solid formulations include, for example, pastilles, thin films, pastes, lozenges, granules, powders, capsules, pills such as caplets, gelcaps, tablets such as minitablets, capsules, beads, and pellets (each including immediate release, timed release and sustained release pills). In some embodiments, the intracolonic compositions are administered as tablets, i.e., desirably, the pharmaceutical product comprises a tablet. If desired, tablets or caplets may be sugar coated or enteric coated by standard techniques or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For preparing solid compositions such as tablets, the principal active ingredient e.g., selexipag) is mixed with a pharmaceutical carrier/additive such as starches, sweeteners such as sugars, diluents, coloring agents, granulating agents, preservatives, lubricants, flavoring agents, binders, disintegrating agents and the like. For tablets, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, ethanol, glycerol, or the like, may be used. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrating agents include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. In some embodiments, the intracolonic solid form comprises D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), hypromellose, propylene glycol, titanium oxide, iron oxide red, and carnauba wax. In further embodiments, the intracolonic solid form comprises D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), Aquapolish® P Red, and carnauba wax. In other embodiments, the oral solid form comprises D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), Aquapolish® P Yellow, and carnauba wax. In still further embodiments, the oral solid form comprises D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), hypromellose, propylene glycol, titanium oxide, yellow iron oxide, and carnauba wax.

[0074] In other embodiments, the intracolonic compositions are administered as liquids, solutions, or suspensions, i.e., desirably, the pharmaceutical product is a solution or suspension. The liquid forms in which the compositions of the present disclosure may be incorporated for intracolonic administration include, aqueous solutions or suspensions, syrups, aqueous or oil suspensions, and emulsions with oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. The intracolonic preparations contain selexipag and one or more of suitable carriers/additives such as water, glycols, oils, alcohols, preservatives, stabilizers, coloring agents and the like. In some embodiments, one intracolonic solution or suspension comprises glycine, polysorbate 20, phosphoric acid, and sodium hydroxide.

[0075] The solid, intracolonic form of selexipag comprises about 100 to about 500 pg of selexipag. In some aspects, the solid, intracolonic form of selexipag comprises about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, or about 500 pg of selexipag. In other aspects, the solid, intracolonic form of selexipag comprises about 100 to about 500, about 100 to about 450, about 100 to about 400, about 100 to about 350, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 500, about 150 to about 450, about 150 to about 400, about 150 to about 350, about 150 to about 300, about 150 to about 250, about 150 to about 200, about 200 to about 500, about 200 to about 450, about 200 to about 400, about 200 to about 350, about 200 to about 300, about 200 to about 250, about 250 to about 500, about 250 to about 450, about 250 to about 400, about 250 to about 350, about 250 to about 300, about 300 to about 500, about 300 to about 450, about 300 to about 400, about 300 to about 350, about 350 to about 500, about 350 to about 450, about 350 to about 400, about 400 to about 500, or about 450 to about 500 pg of selexipag. In further aspects, the solid, intracolonic form of selexipag comprises about 200 pg of selexipag.

[0076] The intracolonic form of selexipag in solution form comprises about 100 to about 500 pg of selexipag. In some aspects, the intracolonic form of selexipag in solution form comprises about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, or about 500 pg of selexipag. In other aspects, the intracolonic form of selexipag in solution form comprises about 100 to about 500, about 100 to about 450, about 100 to about 400, about 100 to about 350, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 500, about 150 to about 450, about 150 to about 400, about 150 to about 350, about 150 to about 300, about 150 to about 250, about 150 to about 200, about 200 to about 500, about 200 to about 450, about 200 to about 400, about 200 to about 350, about 200 to about 300, about 200 to about 250, about 250 to about 500, about 250 to about 450, about 250 to about 400, about 250 to about 350, about 250 to about 300, about 300 to about 500, about 300 to about 450, about 300 to about 400, about 300 to about 350, about 350 to about 500, about 350 to about 450, about 350 to about 400, about 400 to about 500, or about 450 to about 500 pg of selexipag. In further aspects, the intracolonic form of selexipag in solution form comprises about 200 pg of selexipag.

[0077] The intracolonic form of selexipag in suspension form comprises about 100 to about 500 pg of selexipag. In some aspects, the intracolonic form of selexipag in suspension form comprises about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, or about 500 pg of selexipag. In other aspects, the intracolonic form of selexipag in suspension form comprises about 100 to about 500, about 100 to about 450, about 100 to about 400, about 100 to about 350, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 500, about 150 to about 450, about 150 to about 400, about 150 to about 350, about 150 to about 300, about 150 to about 250, about 150 to about 200, about 200 to about 500, about 200 to about 450, about 200 to about 400, about 200 to about 350, about 200 to about 300, about 200 to about 250, about 250 to about 500, about 250 to about 450, about 250 to about 400, about 250 to about 350, about 250 to about 300, about 300 to about 500, about 300 to about 450, about 300 to about 400, about 300 to about 350, about 350 to about 500, about 350 to about 450, about 350 to about 400, about 400 to about 500, or about 450 to about 500 pg of selexipag. In further aspects, the intracolonic form of selexipag in suspension form comprises about 200 pg of selexipag.

[0078] In some embodiments, the oral dose of selexipag is administered at a starting dose and is increased to determine an individual maximum tolerated dose (iMTD). The term "iMTD" as used herein refers to the maximum amount of selexipag that may be administered to a patient per day, without resulting in adverse physical and/or pharmacological effects. Thus, the iMTD is typically evaluated for each patient on an individual basis. In some aspects, the starting dose of selexipag is the same as the iMTD. In further aspects, the starting dose of selexipag is lower than the iMTD.

[0079] The starting dose or the iMTD, on a daily basis, is at least about 10 pg. In some embodiments, the starting dose or the iMTD, on a daily basis, is at least about 25, about 50, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, about 2500, about 2600, about 2700, about 2800, about 2900, about 3000, about 3100, about 3200, about 3300, about 3400, or about 3500 pg. In other embodiments, the starting dose or the iMTD, on a daily basis, is about 25 pg. In other embodiments, the starting dose or the iMTD, on a daily basis, is about 50 pg. The daily dose may be administered once daily, twice daily, or thrice daily, preferably twice daily.

[0080] Desirably, the iMTD does not exceed about 1600 pg twice daily, i.e., 3200 pg per day. In some embodiments, the iMTD, twice daily, is about 100 to about 3500 pg, about 200 to about 3200, about 200 to about 3000, about 200 to about 2800, about 200 to about 2600, about 200 to about 2400, about 200 to about 2200, about 200 to about 2000, about 200 to about 1800, about 200 to about 1600, about 200 to about 1400, about 200 to about 1200, about 200 to about 1000, about 200 to about 800, about 200 to about 600, about 200 to about 400, about 400 to about 3200, about 400 to about 3000, about 400 to about 2800, about 400 to about 2600, about 400 to about 2400, about 400 to about 2200, about 400 to about 2000, about 400 to about 1800, about 400 to about 1600, about 400 to about 1400, about 400 to about 1200, about 400 to about 1000, about 400 to about 800, about 400 to about 600, about 600 to about 3200, about 600 to about 3000, about 600 to about 2800, about 600 to about 2600, about 600 to about 2400, about 600 to about 2200, about 600 to about 2000, about 600 to about 1800, about 600 to about 1600, about 600 to about 1400, about 600 to about 1200, about 600 to about 1000, about 600 to about 800, about 800 to about 3200, about 800 to about 3000, about 800 to about 2800, about 800 to about 2600, about 800 to about 2400, about 800 to about 2200, about 800 to about 2000, about 800 to about 1800, about 800 to about 1600, about 800 to about 1400, about 800 to about 1200, about 800 to about 1000, about 1000 to about 3200, about 1000 to about 3000, about 1000 to about 2800, about 1000 to about 2600, about 1000 to about 2400, about 1000 to about 2200, about 1000 to about 2000, about 1000 to about 1800, about 1000 to about 1600, about 1000 to about 1400, about 1000 to about 1200, about 1200 to about 3200, about 1200 to about 3000, about 1200 to about 2800, about 1200 to about 2600, about 1200 to about 2400, about 1200 to about 2200, about 1200 to about 2000, about 1200 to about 1800, about 1200 to about 1600, about 1200 to about 1400, about 1400 to about 3200, about 1400 to about 3000, about 1400 to about 2800, about 1400 to about 2600, about 1400 to about 2400, about 1400 to about 2200, about 1400 to about 2000, about 1400 to about 1800, about 1400 to about 1600, about 1600 to about 3200, about 1600 to about 3000, about 1600 to about 2800, about 1600 to about 2600, about 1600 to about 2400, about 1600 to about 2200, about 1600 to about 2000, about 1600 to about 1800, about 1800 to about 3200, about 1800 to about 3000, about 1800 to about 2800, about 1800 to about 2600, about 1800 to about 2400, about 1800 to about 2200, about 1800 to about 2000, about 2000 to about 3200, about 2000 to about 3000, about 2000 to about 2800, about 2000 to about 2600, about 2000 to about 2400, about 2000 to about 2200, about 2200 to about 3200, about 2200 to about 3000, about 2200 to about 2800, about 2200 to about 2600, about 2200 to about 2400, about 2400 to about 3200, about 2400 to about 3000, about 2400 to about 2800, about 2400 to about 2600, about 2600 to about 3200, about 2600 to about 3000, about 2600 to about 2800, about 2800 to about 3200, about 2800 to about 3000, or about 3000 to about 3200 pg. In further embodiments, the iMTD, on a twice daily basis, is about 200 to about 1600 pg. In yet other embodiments, the iMTD, on a twice daily basis, is about 100 pg. In further embodiments, the iMTD, on a twice daily basis, is about 200 pg.

[0081] To prepare pharmaceutical compositions of the present disclosure, selexipag, as the active ingredient, may be intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g., oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain, the disclosure of which is hereby incorporated by reference.

[0082] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc., the disclosures of which are hereby incorporated by reference.

[0083] The preparation of selexipag is described in WO-2002/088084 (incorporated herein by reference). The preparation of polymorphic forms, i.e., the crystalline forms I, II, and III of the free base is disclosed in WO-2010/150865 (incorporated herein by reference); polymorphic forms of pharmaceutically acceptable salts are disclosed in WO-2011/024874 (incorporated herein by reference).

Aspects

[0084] Aspect 1. A method for treating pulmonary hypertension, comprising administering a therapeutically effective amount of selexipag to a patient in need thereof, wherein at least one dose of selexipag is in an intracolonic form.

[0085] Aspect 2. The method of Aspect 1, wherein before administration of selexipag, the patient is in a fasted state for at least about 10 hours.

[0086] Aspect 3. The method of Aspect 1 or 2, wherein before administration of selexipag, the patient has a body mass index of about 18.0 to about 28.0 kg/m² and a body weight of not less than about 50.0 kg.

[0087] Aspect 4. The method of any one of the preceding Aspects, wherein before administration of selexipag, the patient has a blood pressure, after the patient is supine for about 5 minutes, of about 90 to about 145 mmHg systolic and about 90 mmHg or less diastolic.

[0088] Aspect 5. The method of any one of the preceding Aspects, wherein before administration of selexipag, the patient has a resting 12-lead ECG consistent with normal cardiac conduction, cardiac function, and sinus rhythm, a pulse rate of about 45 to about 90 bpm, a QTc interval of about 450 ms, a QRS interval of about 110 ms or less, or a PR interval of about 200 ms or less, or combinations thereof.

[0089] Aspect 6. The method of any one of the preceding Aspects, wherein the therapeutically effective amount of selexipag is about 100 to about 500 pg.

[0090] Aspect 7. The method of any one of the preceding Aspects, wherein the intracolonic form is a solid form.

[0091] Aspect 8. The method of Aspect 7, wherein the solid form is a tablet.

[0092] Aspect 9. The method of Aspect 7 or 8, wherein the solid form comprises D- mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), hypromellose, propylene glycol, titanium oxide, iron oxide red, and carnauba wax.

[0093] Aspect 10. The method of any one of Aspects 1 to 6, wherein the intracolonic form is a solution.

[0094] Aspect 11. The method of Aspect 10, wherein the solution comprises glycine, polysorbate 20, phosphoric acid, and sodium hydroxide

[0095] Aspect 12. The method of any one of Aspects 1 to 7, comprising administering two intracolonic forms.

[0096] Aspect 13. The method of Aspect 12, wherein one intracolonic dose is a solid form and one intracolonic dose is a solution.

[0097] Aspect 14. The method of Aspect 13, wherein the intracolonic solution comprises about 200 pg of selexipag.

[0098] Aspect 15. The method of any one of Aspects 7, 8, or 13, wherein the intracolonic solid form comprises about 200 pg of selexipag.

[0099] Aspect 16. The method of any one of the preceding Aspects, further comprising administering an oral dose of selexipag.

[00100] Aspect 17. The method of Aspect 16, wherein the oral dose is in a solid form.

[00101] Aspect 18. The method of Aspect 17, wherein the solid form further comprises D- mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), hypromellose, propylene glycol, titanium oxide, yellow iron oxide, and carnauba wax.

[00102] Aspect 19. The method of Aspect 16 or 17, wherein the oral dose comprises about 10 to about 500 pg of selexipag.

[00103] Aspect 20. The method of any one of Aspects 16 to 19, wherein the oral dose comprises about 200 pg of selexipag. [00104] Aspect 21. The method of any one of the preceding Aspects, wherein intracolonic administration of selexipag is performed using a device comprising a thin tube and a capsule comprising the selexipag, and a means for detecting the device by X-rays.

[00105] Aspect 22. The method of Aspect 21, wherein the capsule is an X-ray visible tube or the capsule comprises an X-ray visible screw fastened to the capsule.

[00106] Aspect 23. The method of any of the preceding Aspects, wherein the pulmonary hypertension is pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, or sarcoidosis-associated pulmonary hypertension.

[00107] Aspect 24. The method of Aspect 23, wherein the pulmonary hypertension is pulmonary arterial hypertension.

[00108] Aspect 25. A pharmaceutical drug product comprising:

[00109] a therapeutically effective amount of selexipag in an intracolonic form; and

[00110] instructions for using selexipag via intracolonic administration for the treatment of pulmonary hypertension.

[00111] Aspect 26. The pharmaceutical drug product of Aspect 25, wherein the intracolonic form is a solution.

[00112] Aspect 27. The pharmaceutical drug product of Aspect 25, wherein the intracolonic form is a solid form.

[00113] Aspect 28. The pharmaceutical drug product of Aspect 27, further comprising a device for intracolonically administering the selexipag.

[00114] Aspect 29. The pharmaceutical drug product of Aspect 28, wherein the device comprises a capsule.

[00115] Aspect 30. The pharmaceutical drug product of Aspect 29, wherein the capsule comprises and X-ray visible tube. [00116] Aspect 31. The pharmaceutical drug product of Aspect 29, wherein the capsule comprises an X-ray visible screw fastened to the capsule.

[00117] Aspect 32. The pharmaceutical drug product of any one of Aspects 29 to 31, wherein the device comprises a thin tube that is attached to the capsule.

[00118] Example 1

[00119] This colonic absorption study is conducted to support the development of a selexipag sustained SR formulation. For example, the bioavailability and conversion of selexipag into its active metabolite following colonic administration will be assessed. During the course of the study, all participants will receive three single doses of selexipag 200 pg administered either intracolonically (solid and solution formulation) or orally (film-coated tablets, IR) on Day 1 of each treatment period.

[00120] Details on the timing of the treatment and assessments are given in Table 1.

Table 1: Time and Events Schedule

SUBSTITUTE SHEET (RULE 26)

SUBSTITUTE SHEET (RULE 26)

SUBSTITUTE SHEET (RULE 26)

SUBSTITUTE SHEET (RULE 26) ^a Early withdrawal other than withdrawal of consent. If a participant withdraws due to withdrawal of consent, he retains the option to participate in the safety follow-up procedures and will strongly be advised to do so. ^bSigning of the ICF needs to be done before the first study -related activity. Tf multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence: ECG, vital signs (blood pressure, heart rate, tympanic body temperature), blood draws (for PK or laboratory measurements), weight, and physical examination.. Blood collections for PK assessments should be kept as close to the specified time as possible. Other measurements may be done earlier than specified time points, if needed. ^dCalculated by the CKD-EPI formula. ^eSerology includes HIV-1 and HIV-2 antibodies, hepatitis A antibody IgM, HBsAg and HCV antibody. ^fStudy drug will be administered/delivered in colon following an overnight fast of at least 10 hours. ^gIf a participant's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the study drug is administered in Period 1 such that he no longer meets all eligibility criteria, then the participant should be excluded from participation in the study. ^hAn X-ray may be performed to confirm colonic positioning of the capsule on Day -1 or Day 1 as deemed appropriate for the individual participant. ‘A safety follow-up phone call will be conducted for all participants 30 to 32 days after the last study drug administration. 'The intracolonic delivery device must be swallowed whole and not chewed. A standard meal will be provided 2 hours after the intracolonic delivery device have been swallowed. The location of the capsule, in terms of centimeters from the tip of the nose, will be determined regularly, approximately every 30 minutes (from the color marks on the tube) until the target area of 300 cm from the tip of the nose has been reached. The date and time for when the capsule has been excreted from the body should also be noted. ^kIf needed, the participant can obtain the sample materials from the site and conduct the sample collection at home. 'Can be obtained on Day -2 or Day -1. ^mA hemoccult test for occult blood in the stool is assessed 12 to 24 hours after each study drug administration/delivery.

[00121] A. Objectives

[00122] The primary objective of the study is to assess the PK of selexipag and its active metabolite following intracolonic administration of selexipag as 200 pg solid dose and 200 pg solution relative to oral administration of UPTRAVI® 200 pg, IR formulation, under fasted conditions.

[00123] The secondary objectives of the study are:

[00124] (i) To assess the PK of selexipag and its active metabolite following intracolonic administration of selexipag as 200 pg solid dose relative to 200 pg solution, under fasted conditions.

[00125] (ii) To assess the safety and tolerability of selexipag following intracolonic administration of selexipag as 200 pg solid dose and 200 pg solution, as well as oral administration, under fasted conditions.

[00126] (iii) To assess the safety and tolerability of the intracolonic delivery device when used to facilitate intracolonic administration of selexipag.

[00127] B. Overview of Study Design

SUBSTITUTE SHEET (RULE 26) [00128] This is a single center, open-label, fixed single sequence, 3 -period crossover study in healthy participants to assess the PK of selexipag and its active metabolite following intracolonic administration of selexipag as single-dose 200 pg solid dose and 200 pg in solution relative to oral administration of UPTRAVI® 200 pg, IR formulation.

[00129] A total of 10 healthy male participants between 18 and 55 years of age will be enrolled in the study to have at least 6 participants evaluable for PK. The study consists of 3 phases: a screening phase of approximately 3 weeks (Days -21 to -3) followed by an openlabel treatment phase consisting of 3 sequential single-dose treatment periods and an EOS visit. Within each of the 3 sequential treatment periods, participants will be admitted to the study center from Days -2 to 4 for Treatment Period 1 and Period 2 and Day -1 to 4 for Treatment Period 3. Each treatment period must be separated by a washout period of at least 7 days between dosings (starting on Day 1 of each period). The treatments are as described in Table 2.

[00130] The Bioperm intubation method was chosen for facilitation of the colonic administration of selexipag as this method enables controlled colonic drug administration in a minimally invasive way, without the need for sedation or surgical procedures.

Table 2

[00131] The formulation details of the study drugs are provided in Table 1.

[00132] All 10 participants will receive a single intracolonic dose of selexipag in solid form, 200 pg (Treatment A) in Treatment Period 1, a single intracolonic dose of selexipag in solution, 200 pg (Treatment B) in Treatment Period 2, followed by a single oral dose of UPTRAVI® 200 pg IR (Treatment C) in Treatment Period 3. The intracolonic administration of the study drug will be facilitated by an investigational intracolonic delivery device, such as the Bioperm capsule.

SUBSTITUTE SHEET (RULE 26) [00133] As a safety precaution, intracolonic administrations of study drug will be performed in a staggered manner. See FIG. 1. For Treatment A (Period 1) and Treatment B (Period 2), further administration of the study drug will be paused until the first 2 participants within each treatment have completed their 24-hour postdose safety assessments. Upon evaluation of the safety data obtained from the first 2 participants during Treatment A and Treatment B, respectively, study drug admini strati on/delivery in the colon of the remaining 8 participants can be initiated if no safety concerns are identified.

[00134] After completion of the last study -related procedure on Day 4 of Treatment Period 1 and Period 2, participants will be discharged from the study center and will be instructed to return to the study center for the subsequent treatment periods (Treatment Period 2 and Period 3, respectively). After completion of the last study -related procedure on Day 4 of Treatment Period 3, participants will be discharged from the study center and will be instructed to return to the study center 8 to 12 days after the last dose of study drug administration for the EOS visit/follow-up assessments.

[00135] Treatment periods in each individual participant will be separated by a washout period of at least 7 days. The washout period starts after study drug administration/delivery in one treatment period and ends with study drug administration/delivery in the next treatment period.

[00136] Any participant who withdraws from the study before completion of all planned study procedures, will complete the EOSZEW assessments 8 to 12 days after the last study drug administration. If a participant withdraws due to withdrawal of consent, he retains the option to participate in the safety follow-up procedures.

[00137] Finally, a safety follow-up phone call will be conducted for all participants 30 to 32 days after the last study drug administration/delivery. The phone call is conducted to collect information on new SAEs occurring after the EOS visit and to follow-up on any AEs and SAEs still ongoing at EOS.

[00138] Details on the timing of the treatment and assessments are given in Table 1.

[00139] C. Study Population

SUBSTITUTE SHEET (RULE 26) [00140] (i) General Considerations

[00141] A total of 10 healthy male participants will be included in the study population to ensure that at least 8 participants complete all required assessments in order to obtain at least 6 PK evaluable participants. A participant is considered PK evaluable if the primary PK parameters can be derived for all 3 treatment periods.

[00142] The inclusion and exclusion criteria for enrolling participants in this study are described below.

[00143] (ii) Inclusion Criteria

[00144] Participants must satisfy the following criteria to be enrolled in the study:

1. Male (according to their reproductive organs and functions assigned by chromosomal complement).

2. 18 to 55 years of age, inclusive, at screening.

3. Healthy on the basis of physical examination, medical history, vital signs, and 12- lead ECG performed at screening.

4. Healthy on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel and hematology are outside the normal reference ranges, the participant may be included only if judged that the abnormalities or deviations from normal to be not clinically significant.

5. Must sign an ICF indicating they understand the purpose of, and procedures required for, the study and are willing to participate in the study.

6. Body mass index (BMI; weight [kg]/height² [m]²) between 18.0 and 28.0 kg/m²

(inclusive), and body weight not less than 50.0 kg at screening.

7. Blood pressure (after the participant is supine for 5 minutes) between 90 and 139 mmHg systolic, inclusive, and no higher than 90 mmHg diastolic at screening. If blood pressure is out of range, up to 2 repeated assessments within the screening period are permitted, last assessment being conclusive.

SUBSTITUTE SHEET (RULE 26) 8. A 12-lead ECG (resting) consistent with normal cardiac conduction and function, including sinus rhythm, pulse rate between 45 and 90 bpm, QTc interval p450 ms (corrected cf. Fridericia 1920; ICH E14 2005), QRS interval of <110 ms, PR interval <200 ms, and morphology consistent with healthy cardiac conduction and function.

9. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.

[00145] Retesting of abnormal values that would lead to exclusion will be allowed once without prior approval. Retesting to replace lost samples or broken tubes is permitted.

Retesting will take place prior to the first study drug administration in the first treatment period during the screening window. Participants with a normal value at retest may be included.

[00146] (iii) Exclusion Criteria

[00147] Any potential participants who meet any of the following criteria will be excluded from participating in the study.

1. History of or current clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, coagulation disorders (including any abnormal bleeding or blood dyscrasias), lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease, diabetes mellitus, hepatic or renal insufficiency eGFR below 60 mL/min at screening by using the CKD-EPI formula), thyroid disease, neurologic or psychiatric disease, infection (including active respiratory infections), or any other illness that is considered should exclude the participant or that could interfere with the interpretation of the study results.

2. Clinically significant abnormal values for hematology or clinical chemistry at screening and/or on Day -2 or Day -1 of Treatment Period 1 as deemed appropriate.

3. Known allergies, hypersensitivity, or intolerance to selexipag or its excipients.

SUBSTITUTE SHEET (RULE 26) nown allergies, hypersensitivity, or intolerance to any components of the intracolonic delivery device. istory or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism, or excretion of the study drugs or the swallowing of the intracolonic delivery device (appendectomy and herniotomy allowed, cholecystectomy not allowed), intra-abdominal surgery including hernia repair, swallowing disorders, and participants with pre-existing gastrointestinal diseases such as Crohn's disease, ulcerative colitis, or any food intolerance or malabsorption manifested by diarrhea. Any prior history of gastrointestinal obstruction or ileus. ny clinical evidence of nasal obstruction or nasal congestion. ositive hemoccult test at screening. Hemoccult test to be performed following at least 3 days of adherence to the diet restrictions. revious history of stroke, fainting, collapse, syncope, orthostatic hypotension, vasovagal reactions, and head injury. se of any prescribed medications (including vaccines) or OTC medications

(including herbal medicines such as St John’s Wort, homeopathic preparations, vitamins, and minerals) are forbidden from screening until EOS. Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture). History of drug or alcohol abuse according to DSM-V criteria within 3 years before screening or positive test result(s) for alcohol and/or drugs of abuse (such as hallucinogens [phencyclidine], barbiturates, opiates, opioids, cocaine, cannabinoids, amphetamines, and benzodiazepines) at screening and on Day -2 of Treatment Period 1 and Period 2 and Day -1 of Treatment Period 3. A positive urine drug test and/or alcohol test may be repeated once (as soon as possible and within the screening period/Day -2 of Treatment Period 1 and Period 2 and Day -1

SUBSTITUTE SHEET (RULE 26) of Treatment Period 3) to exclude a technical error. Participants with a negative urine drug and/or alcohol test at retest may be included/proceed with the treatment visit. Previous exposure to selexipag within 3 months prior to screening. Donated blood or blood products or had substantial loss of blood (more than 500 mL) within 3 months before the first administration of study drug or intention to donate blood or blood products during the study. . Active participation in another investigational drug study with EOS visit within 3 months (90 days) prior to screening, screening or treatment with another investigational drug within a period less than 5 times the drug’s half-life, whichever is longer or participation in more than 4 investigational drug studies within 1 year (365 days) prior to screening. . Unable to swallow the intracolonic delivery device (approximately 30 mm in length and 10 mm in diameter) or the oral dosage forms whole with the aid of water (participants may not chew, divide, dissolve, or crush the study drug). Any condition for which participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Current hepatitis A infection (confirmed by hepatitis A antibody IgM), or hepatitis B virus infection (confirmed by HBsAg), or HCV infection (confirmed by HCV antibody) at screening. History of HIV antibody positive, or tests positive for HIV at screening. History of smoking or use of nicotine-containing substances within the previous 2 months. Preplanned surgery or procedures that would interfere with the conduct of the study.

SUBSTITUTE SHEET (RULE 26) [00148] If a participant's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he no longer meets all eligibility criteria, then the participant should be excluded from participation in the study.

[00149] (iv) Prohibitions and Restrictions

[00150] Potential participants must be willing to adhere to the following prohibitions and restrictions during the course of the study to be eligible for participation:

1. May not consume food or beverages containing grapefruit juice and Seville oranges from 72 hours before each PK sample collection day, until after the last PK sample is collected in each period.

2. May not consume alcohol from 24 hours before admission to the study center until after the last PK sample is collected in each period.

3. Must refrain from the use of any methylxanthine-containing products, (e.g., chocolate bars or beverages, energy drinks if it contains methylxanthine, coffee, teas, or colas) from 24 hours before administration of study drug and during confinement, and also must avoid excessive use of caffeine (e.g, no more than approximately 500 mg/day, as contained in 5 cups of tea or coffee or 8 cans of cola) during the entire study (including the screening period).

4. May not consume food containing poppy seeds from 72 hours before screening or

72 hours before admission to study site in each treatment period (in order to avoid false positive urine drug test for codeine).

5. Participants must consume standard institutional meals during confinement to the study site. Excessive food consumption will not be permitted.

6. Must refrain from the use of nicotine-containing substances, including tobacco products (e.g., cigarettes, e-cigarettes, cigars, chewing tobacco, gum, or patch) throughout the study.

SUBSTITUTE SHEET (RULE 26) ust have negative test for drugs of abuse, such as cannabinoids, alcohol, opiates, opioids, cocaine, amphetamines, benzodiazepines, hallucinogens (phencyclidine) or barbiturates on Day -2 of Treatment Period 1 and Period 2 and Day -1 of Treatment Period 3. a participant has a recent febrile illness (>38°C) within 3 days of the scheduled start of study drug administration/delivery, the start of study drug administration/delivery should be postponed until the tympanic body temperature is normal for at least 72 hours. articipants will be advised not to donate blood for at least 2 months after completion of the study or to participate in an investigational drug study for at least 1 month after completion of the study. Must refrain from jogging and strenuous exercise of all types while confined to the study site and 48 hours before admission to the study site. Must refrain from the use of concomitant medications, except for the treatment of AEs, from screening until EOS. Must refrain from the use of medications that could affect the PK of selexipag, even for the treatment of AEs of selexipag) from screening until collection of the last PK sample. Must refrain from the use of acetylsalicylic acid, heparin, glycoprotein Ilb/IIIa inhibitors or non-steroidal anti-inflammatory drugs including Cox -2 inhibitors, selective serotonin reuptake inhibitors, or other medicinal products associated with bleeding risk such as pentoxifylline, even for the treatment of AEs from screening until the last hemoccult test has been performed. Must refrain from the use of OTC medications, including homeopathic preparations, herbal medicines, vitamins, and minerals from screening until EOS. The following diets should be avoided from screening to until the last hemoccult test has been performed: red or rare meat, horseradish, cantaloupe, raw turnips, broccoli, cauliflower, red radishes, and parsnips.

SUBSTITUTE SHEET (RULE 26) 16. The intracolonic delivery device, while ingested, is considered an implant and therefore, participants must refrain from exposure to magnetic resonance imaging during periods where the intracolonic delivery device is located in the gastrointestinal tract, /.< ., from the time of swallowing the intracolonic delivery device until excretion of the capsule part of the device from the body is confirmed.

[00151] Further instructions for food intake or restrictions relating to the timing of study drug administration are provided.

[00152] (v) Participant Completion/Discontinuation

[00153] A participant will be considered to have completed the study if he completed all required assessments up to and including EOS assessments. Participants who prematurely discontinue the study for any reason before completion of the required assessments of the last study visit will not be considered to have completed the study.

[00154] A participant will be withdrawn from the study for any of the following reasons:

• Lost to follow-up

• Withdrawal of consent

• Participant is not in compliance with requirements of the study, including prohibitions and restrictions

• The maximum allowed number of X-rays for an individual participant is reached without completing any of the planned intracolonic delivery of study drug.

• It is believed (e.g., that for safety or tolerability reasons such as an AE) that it is in the best interest of the participant that he be withdrawn from the study.

• Discontinuation of study drug for any reason. A participant’s study drug will be automatically discontinued if: o It is believed that for safety or tolerability reasons (e.g., AE) that it is in the best interest of the participant to discontinue treatment.

SUBSTITUTE SHEET (RULE 26) o The participant has clinically significant abnormal laboratory findings or AEs that precludes further participation in the study. o The participant requires treatment with any of the disallowed medications as described.

[00155] Participants who withdraw will be replaced.

[00156] D. Study Treatment

[00157] (i) Dosage and Administration

[00158] During three treatment periods, each participant will receive Treatments A, B, and C once. The dose regimens in Treatments A, B, and C are described in Table 3.

Table 3: Treatment Overview

Treatment A: selexipag in solid form, 200 pg. Treatment B: selexipag will be provided as powder for oral solution. 0.9 mL of reconstituted solution will be administered. The actual selexipag dose administered to the participant is considered to be 200 pg. Treatment C: UPTRAVI® 200 pg (IR), clinical image, not debossed tablets will be used Participants will be admitted to the study site on Day -2 of Treatment Period 1 and Period 2, and Day -1 of Period 3.

[00159] (ii) Intracolonic Drug Administration and Absorption

[00160] The Bioperm delivery system (see Figure 2) consists of a small plastic capsule (10) which, while being moved by peristalsis, pulls a thin soft plastic tube (12) to the intended location in the human gut. The capsule (10) for administering solution is approximately 30 mm in length and approximately 10 mm in diameter. The capsule (10) for the solid formulation is 25 mm in length and 10 mm in diameter, but the last 5 mm has a diameter of approximately 12 mm instead of 10 mm.

[00161] The thin soft plastic tube (12) is inserted into and attached to an X-ray visible tube (22) that runs through the length of the capsule (10). Hence an open line to any location in the

SUBSTITUTE SHEET (RULE 26) GI tract, even the distal colon, is created. At the intended destination, the capsule (10) is stopped by fixing the thin soft plastic tube (12) to the cheek of the participant. A syringe (14) is attached to the Luer-loc outer end of the thin soft plastic tube (12) and a capsule (10) is attached to the other end of the thin soft plastic tube (12). Drug solution may then be administered as a bolus dose by a syringe (14). The equipment for administering solutions is shown in FIG. 2.

[00162] In FIG. 3, a disassembled capsule (10) is shown with the X-ray visible tube (22), that runs through the capsule (10), and a silicone seal (24) to keep the capsule water-tight.

[00163] With a modification of the capsule (not shown), solid formulations may be administered. In this case, there is no X-ray visible tube and the thin soft plastic tube is fastened directly to the proximal end of the capsule with an X-ray visible screw. The hollow interior of the capsule is equipped with a thin elastic membrane that is retracted to form a sac in which the solid formulation is placed. The distal part of the capsule is sealed with a lid. When air is pressed through the open line, the membrane moves forward causing the lid to pop off and the capsule to open and the solid drug formulation will be expelled into the gut lumen.

[00164] Before the capsule (10) is attached to the thin soft plastic tube (12), the thin soft plastic tube (12) is passed through the nose of the participant, retrieved from the pharynx out of the mouth, passed through a X-ray visible tube (22), and finally fastened at its distal end with a locking device (not shown) located inside the capsule (10), whereupon the capsule is swallowed by the participant. The end of the thin soft plastic tube (12) outside the body is equipped with a Luer-loc fitting (16). The fitting is residing in a plastic reel (18), from which the tubing is gradually released. The plastic reel (18) is retained, .e.g., kept in a breast pocket, until the time of drug administration/delivery. From marks on the thin soft plastic tube (12), the location of the capsule (10) in the gut, in terms of centimeters from the nose, can be estimated. Once the desired location of the capsule (10) is assumed, the actual location can be verified by X-ray. After the drug has been administered/delivered, the thin soft plastic tube (12) is cut at the nostril and the capsule (10) with the thin soft plastic tube (12) will leave the body via naturalis, through the anus.

[00165] (ii-a) Intracolonic Delivery - Treatment A (Solid) and Treatment B (Solution)

SUBSTITUTE SHEET (RULE 26) [00166] For Treatments A and B, the Bioperm intubation method will be used for intracolonic administration. Participants will be admitted to the study center on Day -2. On Day -1 (one day prior to the planned administration/delivery of the study drug), following an overnight fast of at least 10 hours the intracolonic delivery device will be administered to the participant by a trained clinical staff. The soft tube will be introduced through the nostril (after prior topical anesthesia [e.g., lidocaine spray 10 mg/dose or tetracaine] and administration of anticongestive nasal drops [e.g., Otrivine nasal spray]) of the participant and make it pass through the nose until it is visible in the pharynx. A local anaesthesia of the pharynx, using e.g., lidocaine spray (10 mg/dose) may be given before the procedure. The tube will be retrieved from the pharynx by a pair of tweezers and pulled out of the mouth, whereupon the capsule part of the intracolonic delivery device will be fastened to the tube and swallowed with approximately 240 mL of non-carbonated water. The intracolonic delivery device must be swallowed whole and not chewed. A standard meal will be provided 2 hours after the intracolonic delivery device has been swallowed. The location of the capsule part of intracolonic delivery device, in terms of centimeters from the tip of the nose, will be determined regularly, approximately every 30 minutes (from the color marks on the tube) until the target area of 300 cm from the tip of the nose has been reached. Once the capsule is suspected to have reached the colon (determined by the 300 cm marking on the tube), further progression of the capsule along the gut is prevented by taping the tube to the cheek of the participant. An X-ray may be performed to confirm colonic positioning of the capsule on Day -1 or Day 1 as deemed appropriate for the individual participant. If the X-ray indicates the capsule position to be proximal to the ascending colon the tubing is released from the cheek of the participant to allow for further progression of the capsule. Upon further progression, the X-ray confirmation of the capsule position is repeated until a colonic (preferable ascending or transverse colon) position is confirmed. Guided by the estimated position of the capsule, reassessment of the actual capsule position can be done for every 20 to 50 cm (determined by the markings on the tube). A maximum of 4 X-rays are allowed per participant per treatment period. When the capsule position in the colon is confirmed, further progression of the capsule along the gut is prevented by taping the tube to the cheek of the participant. A final confirmation of the position of the capsule will be done on Day 1 before the solid formulation (Treatment A) or the solution (Treatment B) is administered/delivered

SUBSTITUTE SHEET (RULE 26) directly in the colon as described below (preferably within 2 hours of the confirming X-ray being performed).

[00167] The date and time of each X-ray performed, as well as the actual length of the tube in centimeters from the tip of the nose (based on the tube marking nearest to the nasal tip) at the time of the X-ray will be noted, along with the estimated position of the capsule (/.< ., proximal to colon, ascending colon, transverse colon, or descending colon).

[00168] In the unintended event that the capsule part of the intracolonic delivery device has passed the colon prior to administration/delivery of drug product, the treatment visit will be stopped without administration/delivery of drug product being conducted. Once the capsule has been excreted from the body, the visit can subsequently be rescheduled and reinitiated with administration of a new intracolonic delivery device, as long as the total number of X- rays for a single participant does not exceed 8 over the entire course of the study. A rescheduled visit should preferably occur within 2 weeks of the original visit. If the maximum allowed number of X-rays for an individual participant is reached without completing any of the planned intra colonic administrations/delivery of drug product, the participant will be withdrawn from the study.

[00169] (ii-b) Intracolonic Administration of Solid Formulation (Treatment A)

[00170] The hollow interior of the capsule part of the intracolonic delivery device designed for the solid formulation (Treatment A) is equipped with a thin elastic membrane that is retracted to form a sac in which the solid formulation (Treatment A) is placed. The distal part of the capsule is sealed with a lid. On the day of study drug administration/delivery (Day 1) air will be pressed into the tube, which will cause the lid to pop off and the retracted membrane to invert, thus pushing the solid formulation into the intestinal lumen.

[00171] (ii-c) Intracolonic Administration of Solution (Treatment B)

[00172] For Treatment B (solution), the study drug will be administered through the tube with a small syringe. Once the study drug has been delivered/administered in colon (Treatment A and Treatment B), the tube will be cut at the nostril and the capsule with the tube will leave the body through the anus.

SUBSTITUTE SHEET (RULE 26) [00173] (ii-d) Oral Administration (IR Formulation, Treatment C)

[00174] Treatment C will be taken orally, with approximately 240 mL of non-carbonated water. The IR tablets must be swallowed whole and not chewed, divided, dissolved, or crushed. All study drug administration/delivery of study drug (Treatments A, B, and C) will take place at the study site preferably in the morning, following an overnight fast of at least 10 hours, at approximately the same time within a participant. (For Treatment A and Treatment B, study drug administration/delivery must not be performed until colonic positioning of the BioPerm capsule is confirmed and the participants should remain in fasting state until 4 hours post dosing). Additional water is permitted ad libitum except for 1 hour before and 1 hour after administration of the study drug. No food is allowed for at least 4 hours postdose. Approximately 4 hours after study drug administration/delivery and after the 4-hour PK sampling, a standard lunch will be served at the study site. From approximately 9 hours after study drug administration/delivery in the colon, participants may resume normal diet.

[00175] (iii) Study Drug Information

[00176] Selexipag (Solid Form for Intracolonic Delivery, Treatment A):

• Product: round, red, film-coated tablets (50 pg), diameter of approximately 3.0 mm.

• Excipients: D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), Aquapolish P Red (containing hypromellose, propylene glycol, titanium oxide, iron oxide red), and carnauba wax.

[00177] Selexipag (Solution for Intracolonic Delivery, Treatment B):

[00178] Product: Selexipag 1.8 mg powder for oral solution in a glass vial.

• Each 10 mL glass vial contains 1.8 mg of selexipag powder for oral solution.

Following reconstitution in 8.6 mL 0.9% (w/v) saline, 1 mL of reconstituted solution will contain 225 pg/mL of selexipag. From this reconstituted solution, 0.9 mL of solution will be administered. Although this is a dose of 202.5 pg, based on

SUBSTITUTE SHEET (RULE 26) in-use testing, approximately 1% is lost to tubing adsorption and therefore the actual dose reaching the participant is considered to be 200 pg.

• Excipients: Glycine, Polysorbate 20, Phosphoric acid, and sodium hydroxide.

[00179] Selexipag 200 pg (for Oral Administration, Treatment C):

• Product: Yellow, round, film-coated tablets (200 pg), diameter of approximately 7.2 mm.

• Excipients: D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), Aquapolish® P Yellow (containing hypromellose, propylene glycol, titanium oxide, iron oxide [yellow]), and carnauba wax.

[00180] The intracolonic delivery device (also called Bioperm delivery system) consists of:

• a soft plastic (polyethylene) tube with a Luer-lock at the outer end (to attach a syringe for administration);

• a hard plastic (polyoxymethylene) capsule with a silicone seal;

• an X-ray visible tube (capsule for solution) or an X-ray visible screw (capsule for solid formulation) fastened to the proximal end of the capsule.

[00181] (iv) Concomitant Therapy

[00182] Concomitant medications, including OTC medication (including homeopathic preparations, herbal medicines, vitamins, and minerals), are forbidden from screening until EOS, except for the treatment of AEs. The use of medications that could affect the PK of selexipag is prohibited, even for the treatment of AEs, from screening until collection of the last PK sample.

[00183] The use of acetylsalicylic acid, heparin, glycoprotein Ilb/IIIa inhibitors or nonsteroidal anti-inflammatory drugs including Cox -2 inhibitors, selective serotonin reuptake inhibitors, or other medicinal products associated with bleeding risk such as pentoxifylline,

SUBSTITUTE SHEET (RULE 26) even for the treatment of AEs, from screening until the last hemoccult test has been performed.

[00184] E. Study Evaluations

[00185] (i) Study Procedures

[00186] Table 1 summarizes the frequency and timing of PK and safety measurements applicable to this study. If multiple assessments are scheduled for the same timepoint, it is recommended that procedures be performed in the following sequence: ECG, vital signs (blood pressure, heart rate, tympanic body temperature), blood draws (for PK or laboratory measurements), weight, and physical examination. Blood collections for PK assessments should be kept as close to the specified time as possible. Other measurements may be done earlier than specified time points, if needed. See, Table 4 for collected blood volumes.

Table 4: Volume of Blood to be Collected From Each Participant

a. Calculated as number of samples multiplied by amount of blood per sample, b. Serum chemistry includes serology (HIV, hepatitis). An indwelling intravenous cannula may be used for blood sample collection.

[00187] The maximum amount of blood drawn in this study will not exceed 350 mL. Repeat or unscheduled samples may be taken for safety reasons. If blood samples are collected via an indwelling cannula, an appropriate amount (/.< ., 1 mL) of fluid, slightly greater than the dead space volume of the lock, will be removed from the cannula and discarded before each blood sample is taken. After blood sample collection, the cannula will be flushed with 0.9% pharmaceutical grade for injection sodium chloride and charged with a volume equal to the dead space volume of the lock. Blood samples (3 mL each) for

SUBSTITUTE SHEET (RULE 26) determination of selexipag and ACT-333679 plasma concentrations will be collected at the time points indicated in Table 1.

[00188] (ii) Analytical Procedures

[00189] Plasma samples will be analyzed to determine concentrations of selexipag and ACT-333679 using a validated, specific, and sensitive method. If required, a selection of plasma samples may be analyzed to document the presence of circulating metabolites using a qualified research method.

[00190] (iii) Pharmacokinetic Parameters

[00191] Based on the individual concentration-time data, using the actual sampling times (see Table 1), the following PK parameters will be derived for selexipag and ACT-333679 by non-compartmental methods for each treatment period: Ciast, Cmax, tmax, kz, AUCiast, AUC®, and ti/2. The following requirements should be met for an acceptable calculation of 11/2, kz, AUCoo, and related parameters:

(A): at least 3 data points are used in the calculation;

(B): adjusted coefficient of determination (r² _adj) is at least 0.900.

[00192] If requirement (B) is not met, ti/2, k_z, AUG /, and related parameters will be reported as approximations.

[00193] Actual sampling times will be checked for major aberrations. In case a major aberration occurs for an actual sampling time of >20% deviation from the scheduled time, this plasma concentration will be excluded from descriptive statistics in the plasma concentration table.

[00194] (iv) Safety Evaluations

[00195] Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards until the participant’s last study-related activity (ie., EOS visit), or until the participant has been deemed lost to follow-up after demonstration of due diligence of followup efforts. Serious AEs spontaneously reported within 30 days after the last study drug administration/delivery will also be collected. Any clinically significant abnormalities

SUBSTITUTE SHEET (RULE 26) persisting at the EOS/early withdrawal will be followed until resolution or until a clinically acceptable endpoint is reached.

[00196] The study will include the following evaluations of safety and tolerability according to the time points provided in Table 1 : monitoring of AEs, physical examination, body weight, vital signs (including temperature), 12-lead ECG, urine drug testing, and clinical laboratory assessments (hematology and serum chemistry panel).

[00197] (iv-a) Adverse Events

[00198] Adverse events will be reported for the duration of the study. All AEs will be assessed for their relationship to the study drug or intracolonic delivery device.

[00199] (iv-b) Clinical Laboratory Tests

[00200] Blood samples for serum chemistry and hematology will be taken for evaluation of laboratory safety parameters. The following tests will be performed by the local laboratory:

• Hematology Panel: hemoglobin - platelet count, hematocrit, RBC count, WBC count with differential (differential blood count includes basophils, eosinophils, neutrophils, lymphocytes, monocytes).

• Serum Chemistry Panel: sodium, potassium, creatinine, glucose, uric acid, AST,

ALT, GGT, and total and direct bilirubin

• Serology (HIV antibody, hepatitis A antibody IgM, HBsAg, and HCV antibody) at screening only.

• TSH, T4 and T3 at screening only.

• Urine drug screen at screening and at admission to the study site: hallucinogens

(phencyclidine), barbiturates, opiates, opioids, cocaine, cannabinoids, amphetamines, benzodiazepines, and methadone.

• Alcohol breath test at screening and at admission to the study site.

SUBSTITUTE SHEET (RULE 26) • A hemoccult test for occult blood in the stool is assessed at screening, Day -2 or Day -1 and 12 to 24 hours after each drug administration/delivery (or the first bowel movement thereafter). A negative test should be present prior to any dosing. A positive test at screening will lead to exclusion from the study and does not warrant further investigation by colonoscopy. A positive test after an intracolonic study drug administration/delivery should trigger further investigations by colonoscopy for intracolonic bleeds. A positive test at screening or Day -2/Day -1 of each treatment period or after oral drug administration will not trigger further investigations by colonoscopy.

[00201] (iv-c) Electrocardiogram (ECG)

[00202] During the collection of ECGs, participants should be in a quiet setting without distractions (e.g., television, cell phones). Participants should rest in a supine position for at least 5 minutes before ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital sign measurement is scheduled for the same time point as ECG recording, the procedures should be performed in the following order: ECG(s), vital signs, blood draw.

[00203] (iv-d) Vital Signs (blood pressure, heart rate, tympanic body temperature)

[00204] Blood pressure and heart rate will be assessed with a completely automated device consisting of an inflatable cuff and an oscillatory detection system. All blood pressure and heart rate values will be registered on a built-in recorder so that measurements are observerindependent. Blood pressure and heart rate will be measured after 5 minutes rest in supine position. Vital signs measurements, including tympanic body temperature, will be measured at the time points indicated in Table 1.

[00205] (iv-e) Physical Examination

[00206] Physical examinations including height and body weight will be conducted at times indicated in Table 1. Adverse intubation associated events including local bleeding complications, pain and ulcerations (due to connecting line) will be assessed during physical examinations.

SUBSTITUTE SHEET (RULE 26) [00207] F. Statistical Methods

[00208] To investigate the difference between the selexipag administered in the colon vs orally, the PK parameters following selexipag administered as a solid form or in solution in the colon (Treatment A and Treatment B, respectively) (tests) will be compared to that of selexipag IR oral tablets (Treatment C, reference), all administered under fasted conditions. In addition, the difference in the PK following colonic administration of a solid formulation and solution will be evaluated by comparing Treatment A vs Treatment B.

[00209] (i) Sample Size Determination

[00210] Using an estimated intrasubject CV of 23% for the primary PK parameters of selexipag, a sample size of 6 participants would be sufficient for the point estimate of the relative bioavailability of test formulation (Treatment A and Treatment B) with respect to reference formulation (Treatment C) to fall within 75.6% and 132.2% of the true value with 90% confidence. A total of 10 participants will be enrolled in the study to ensure that at least 6 participants will be PK evaluable. If the number of participants completing all planned study assessments decreases to less than 8, additional participants may be enrolled.

[00211] (ii) Initial Participant Characteristics

[00212] For all participants who received at least one dose of study drug, descriptive statistics (mean, SD, median, minimum, and maximum) will be performed for age, BMI, weight, height and renal function. Sex and race will be listed and tabulated.

[00213] (iii) Pharmacokinetic Analyses

[00214] Pharmacokinetic and statistical analysis will be done using Phoenix™ WinNonlin® (Tripos L.P.). Noncompartmental analysis will be applied for the PK analysis. Furthermore, Microsoft Excel® (Microsoft, Redmond, Washington, United States), and SAS (SAS Institute Inc., Cary, NC, US) will be used. Plasma concentrations of selexipag and ACT-333679 will be listed by treatment group (Treatments A, B, and C), participant number, and time point. Pharmacokinetic parameters of selexipag and ACT-333679, will be listed by treatment, and participant number.

SUBSTITUTE SHEET (RULE 26) [00215] For each treatment group, descriptive statistics will be calculated for the plasma concentrations of selexipag and ACT-333679, at each applicable time point specified (see Table 1), and for the derived plasma PK parameters. Statistics include sample size (n), arithmetic mean, geometric mean, minimum, median, maximum, SD, SE, 95% CI of the means, CV, and CV/_n. For tmax only n, median, minimum, and maximum will be reported.

[00216] For each participant and per treatment group, plasma concentration -time data for selexipag and ACT-333679, will be graphically presented. Similarly, graphs of the mean plasma concentration-time profiles and overlay graphs with combined individual plasma concentration-time profiles will be produced for selexipag and ACT -333679. Pharmacokinetic parameters will be evaluated graphically as well.

[00217] The primary PK parameters are Cmax, AUCiast, and AUC® of selexipag and ACT- 333679. In case more than 50% of the individual observations for AUC / are missing for a treatment, AUC / will not be considered as a primary parameter. If a PK parameter of interest is missing or cannot be estimated for a given participant in one or more treatment periods, the participant will not be included in the statistical analysis of that particular PK parameter. The least square means of the log-transformed primary PK parameters for each treatment will be estimated with a mixed-effects model, controlling for treatment as fixed effect, and participant as a random effect. All three pairwise comparisons (Treatment A vs Treatment C, Treatment B vs Treatment C, and Treatment A vs Treatment B) will be included in a single statistical model. A 90% CI will be constructed around the difference between the least square means of each pair of treatment. Geometric means and its 90% CI for the ratio of means will be obtained by back transformation to the original scale. Using the mixed-effects model, intra- and inter-subject CV will also be estimated, tmax will be analyzed using descriptive statistics.

[00218] (iv) Safety Analyses

[00219] All participants who are enrolled and received at least one dose of study drug or who have swallowed an intracolonic delivery device will be included in the safety and tolerability analysis. Safety and tolerability variables will be listed by treatment (Treatments A, B, and C) or intubation period (/.< ., from the time of intubation being initiated until study

SUBSTITUTE SHEET (RULE 26) drug is delivered in colon) and participant number, and will be summarized descriptively by treatment or for the intubation period, as applicable.

[00220] Proportion of participants is calculated for categorical and binary data based on the corresponding population (e.g., by treatment or intubation period for safety parameter analysis).

[00221] Baseline for all laboratory evaluations, vital signs, and ECG measurements will be defined as the last evaluation done before study drug administration/delivery on Day 1 of each treatment period or the last evaluation done before the initiation of the capsule intubation period on Day -1 prior to Treatment Period 1 and Period 2, as applicable.

[00222] (iv-a) Adverse Events

[00223] All reported AEs with onset during the treatment phase or intubation period (/.< ., treatment-emergent AEs and SAEs including AEs associated with the intracolonic delivery device) and AEs that have worsened since baseline will be included in the analysis. For each AE, the percentage of participants who experience at least one occurrence of the given event will be summarized by treatment. Treatment-emergent AEs or worsening since baseline will be tabulated by frequency of the preferred terms and tabulated by primary SOC and frequency of the preferred terms within each SOC. The crude incidence rate of participants who experienced AEs coded with the same preferred term will be tabulated by treatment. Treatment-emergent AEs will also be tabulated by severity and by relationship to study drug (by preferred terms and by SOC).

[00224] (iv-b) Adverse events associated with the intracolonic delivery device

[00225] All AEs considered related to the intracolonic delivery device will be tabulated separately. All AEs or worsening since baseline will also be tabulated by onset time to specifically analyze those that are due to the intracolonic device solely. Serious AEs and reasons for death will be summarized in a similar manner to that used for AEs.

[00226] (iv-c) Clinical Laboratory Tests

[00227] Laboratory data will be listed and summarized by type of laboratory test by treatment. Reference ranges and markedly abnormal results will be used in the summary of

SUBSTITUTE SHEET (RULE 26) laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and at each scheduled time point by arithmetic mean, SD, SE, median, minimum, and maximum. Changes from baseline results will be presented in pre- versus post-treatment, crosstabulations (with classes for below, within, and above normal ranges). A listing of participants with any laboratory results outside the reference ranges will be provided. A listing of participants with any markedly abnormal laboratory results will also be provided. Values outside the normal range will be flagged in the listings and frequency tabulations of the abnormalities will be made.

[00228] (iv-d) Electrocardiogram

[00229] Electrocardiogram results will be listed and evaluated by means of descriptive statistics and frequency tabulations. These tables will include actual observed and computed values and changes from baseline values (the predose or the pre -intubation ECG will be used as baseline, as applicable) to allow detection of clinically relevant changes in individuals. Electrocardiogram data will be summarized by ECG parameter, treatment, and intubation period.

[00230] Descriptive statistics will be calculated at baseline and for observed values and changes from baseline at each scheduled time point. Descriptive statistics will be presented by arithmetic mean, SD, SE, median, minimum, and maximum. Values outside the normal range will be flagged in the listings and frequency tabulations of the abnormalities will be made.

[00231] The ECG variables that will be analyzed are heart rate, PQ/PR interval, QRS interval, RR interval, QT interval, and QTc using the following correction methods:

• QT interval corrected for heart rate according to Bazett's formula (QTcB) and QT interval corrected for heart rate according to Fridericia's formula (QTcF) as described in Bazett, “An analysis of the time relations of electrocardiograms”, Heart. 1920;7:353-370 and Fridericia, “The Duration of Systole in the Electrocardiogram of Normal Subjects and Patients with Heart Disease”, Acta Medica Scandinavia 1920;57:469-486.

SUBSTITUTE SHEET (RULE 26) • All clinically relevant morphologic abnormalities in ECG waveform that are changes from the baseline readings will be reported (e.g., changes in T-wave morphology or the occurrence ofU-waves).

[00232] (iv-e) Vital Signs

[00233] Results will be listed and descriptive statistics of tympanic body temperature, heart rate, and blood pressure (systolic and diastolic) (supine) values and changes from baseline will be summarized at each scheduled time point, by treatment and intubation period. Descriptive statistics will be presented by arithmetic mean, SD, SE, median, minimum, and maximum. The percentage of participants with values beyond clinically important limits will be summarized. Values outside the normal range will be flagged in the listings.

[00234] (iv-f) Physical Examination

[00235] Results of physical examinations (abnormalities) will be listed by treatment.

[00236] G. Adverse Event Report

[00237] (i) Adverse Event

[00238] An adverse event is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An adverse event does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non- investigational) product (definition per ICH). This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities. Adverse events are collected starting with the signing of the ICF.

[00239] (ii) Serious Adverse Event

[00240] A serious adverse event based on ICH is any untoward medical occurrence that at any dose:

SUBSTITUTE SHEET (RULE 26) • Results in death

• Is life-threatening (the participant was at risk of death at the time of the event. It does not refer to an event that hypothetically might have caused death if it were more severe.)

• Requires inpatient hospitalization or prolongation of existing hospitalization

• Results in persistent or significant disability/incapacity

• Is a congenital anomaly/birth defect

• Is a suspected transmission of any infectious agent via a medicinal product

• Is medically important

[00241] (iii) Unlisted (Unexpected) Adverse Event/Reference Safety Information

[00242] An adverse event is considered unlisted if the nature or severity is not consistent with the applicable product reference safety information. In this study with healthy volunteers, reported SARs for study treatment will be assessed as unexpected. Any SAE with a reasonable causal relationship to the intracolonic delivery device will be considered unexpected. The SAEs related to intracolonic delivery device will be set up as an investigational device in safety database.

[00243] (iv) Adverse Event Associated With the Use of the Drug or Intracolonic Delivery Device

[00244] An adverse event is considered associated with the use of the study treatment or with the intracolonic delivery device if the attribution is related or not-related.

[00245] (v) Assessment of Causality

[00246] The causal relationship to study treatment or the intracolonic delivery device is determined. The following selection should be used to assess all AEs. There is a reasonable causal relationship between study drug administration or the intracolonic delivery device and the AE (the relationship to study drug and intracolonic delivery device should be evaluated

SUBSTITUTE SHEET (RULE 26) separately). The term "reasonable causal relationship" means there is evidence to support a causal relationship. There is not a reasonable causal relationship between study treatment administration or the intracolonic delivery device and the AE.

[00247] (vi) Severity Criteria

[00248] An assessment of severity grade will be made using the following general categorical descriptors. See, Table 5.

Table 5

[00249] Clinical judgment is used in assessing the severity of events not directly experienced by the participant (e.g., laboratory abnormalities).

[00250] (vii) Procedures

[00251] (vii-a) All Adverse Events

[00252] All adverse events and special reporting situations, whether serious or non-serious, will be reported from the time a signed and dated ICF is obtained until completion of the participant's last study-related procedure (which may include contact for follow-up of safety). All events that meet the definition of a serious adverse event will be reported as serious adverse events, regardless of whether they are protocol -specific assessments.

[00253] All adverse events, regardless of seriousness, severity, or presumed relationship to study therapy, or the intracolonic delivery device must be noted. Whenever possible, diagnoses should be given when signs and symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory infection”).

SUBSTITUTE SHEET (RULE 26) [00254] (vii-b) Serious Adverse Events

[00255] All SAEs occurring during clinical studies must be reported to within 24 hours of knowledge of the event. Information regarding SAEs will be transmitted within 24 hours. All serious adverse events that have not resolved by the end of the study, or that have not resolved upon discontinuation of the participant's participation in the study, must be followed until any of the following occurs:

• The event resolves

• The event stabilizes

• The event returns to baseline, if a baseline value/status is available

• The event can be attributed to agents other than the study drug or the intracolonic delivery device or to factors unrelated to study conduct

• It becomes unlikely that any additional information can be obtained (participant or health care practitioner refusal to provide additional information, lost to follow-up after demonstration of due diligence with follow-up efforts)

[00256] Suspected transmission of an infectious agent by a medicinal product will be reported as a serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the course of a participant's participation in a clinical study must be reported as a serious adverse event, except hospitalizations for the following:

• Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons such as pending placement in long-term care facility)

• Surgery or procedure planned before entry into the study.

[00257] The cause of death of a participant in a study within 30 days of last dose, whether or not the event is expected or associated with the investigational agent, is considered a serious adverse event.

[00258] All initial reports of pregnancy in female partners of male participants must be reported within 24 hours of their knowledge of the event. Abnormal pregnancy outcomes

SUBSTITUTE SHEET (RULE 26) (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious adverse events and must be reported.

[00259] Example 2

[00260] Mini tablets containing 25 or 50 pg were prepared. See, Tables 6 and 7.

Table 6: Quantitative composition of selexipag film-coated tablets

Ingredient Amount per tablet

Dose strength 25 pg 50 pg 200 pg selexipag 0.025 mg 0.05 mg 0.2 mg

maize starch 6.043 mg 6.043 mg 48.0 mg low substituted hydroxypropylcellulose 0.856 mg 0.856 mg 6.8 mg hydroxypropylcellulose 0.680 mg 0.680 mg 5.4 mg magnesium stearate 0.251 mg 0.251 mg 2.0 mg

Core tablet weight 17.0 mg 17.0 mg 135.0 mg

carnauba wax s.q. s.q. s.q.

Coating weight 0.629 mg 0.629 mg 5.0 mg

Total weight of film-coated tablet 17.629 mg 17.629 mg 140.0 mg s.q. = small quantity

Table 7: Quantitative composition of Aquapolish per tablet

Amount per tablet

11121 edient _ .

Dose strength 25 g 50 g 200 g hypromellose 0.47804 mg 0.47804 mg 3.8 mg propylene glycol 0.08806 mg 0.08806 mg 0.7 mg

0.4505 mg iron oxide yellow 0.00623 mg - 0.0495 mg iron oxide red - 0.01887

SUBSTITUTE SHEET (RULE 26)

Claims

63 What is claimed is:

1. Selexipag for use in a method for treating pulmonary hypertension, wherein a therapeutically effective amount of selexipag is administered to a patient in need thereof and at least one dose of selexipag is in an intracolonic form.

2. Selexipag of claim 1, wherein before administration of selexipag, the patient is in a fasted state for at least about 10 hours.

3. Selexipag of claim 1 or 2, wherein before administration of selexipag, the patient has a body mass index of about 18.0 to about 28.0 kg/m² and a body weight of not less than about 50.0 kg.

4. Selexipag of any one of the preceding claims, wherein before administration of selexipag, the patient has a blood pressure, after the patient is supine for about 5 minutes, of about 90 to about 145 mmHg systolic and about 90 mmHg or less diastolic.

5. Selexipag of any one of the preceding claims, wherein before administration of selexipag, the patient has a resting 12-lead ECG consistent with normal cardiac conduction, cardiac function, and sinus rhythm, a pulse rate of about 45 to about 90 bpm, a QTc interval of about 450 ms, a QRS interval of about 110 ms or less, or a PR interval of about 200 ms or less, or combinations thereof.

6. Selexipag of any one of the preceding claims, wherein the therapeutically effective amount of selexipag is about 100 to about 500 pg.

7. Selexipag of any one of the preceding claims, wherein the intracolonic form is a solid form.

8. Selexipag of claim 7, wherein the solid form is a tablet.

9. Selexipag of claim 7 or 8, wherein the solid form comprises D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), hypromellose, propylene glycol, titanium oxide, iron oxide red, and carnauba wax. 64 Selexipag of any one of claims 1 to 6, wherein the intracolonic form is a solution. Selexipag of claim 10, wherein the solution comprises glycine, polysorbate 20, phosphoric acid, and sodium hydroxide Selexipag of any one of claims 1 to 7, wherein two intracolonic forms are administered to the patient. Selexipag of claim 12, wherein one intracolonic dose is a solid form and one intracolonic dose is a solution. Selexipag of claim 13, wherein the intracolonic solution comprises about 200 pg of selexipag. Selexipag of any one of claims 7, 8, or 13, wherein the intracolonic solid form comprises about 200 pg of selexipag. Selexipag of any one of the preceding claims, wherein an oral dose of selexipag is further administered to the patient. Selexipag of claim 16, wherein the oral dose is in a solid form. Selexipag of claim 17, wherein the solid form further comprises D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), hypromellose, propylene glycol, titanium oxide, yellow iron oxide, and carnauba wax. Selexipag of claim 16 or 17, wherein the oral dose comprises about 10 to about 500 pg of selexipag. Selexipag of any one of claims 16 to 19, wherein the oral dose comprises about 200 pg of selexipag. Selexipag of any one of the preceding claims, wherein intracolonic administration of selexipag is performed using a device comprising a thin tube and a capsule comprising the selexipag, and a means for detecting the device by X-rays. 65 Selexipag of claim 21, wherein the capsule is an X-ray visible tube or the capsule comprises an X-ray visible screw fastened to the capsule. Selexipag of any of the preceding claims, wherein the pulmonary hypertension is pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, or sarcoidosis-associated pulmonary hypertension. Selexipag of claim 23, wherein the pulmonary hypertension is pulmonary arterial hypertension. A pharmaceutical drug product comprising: a therapeutically effective amount of selexipag in an intracolonic form; and instructions for using selexipag via intracolonic administration for the treatment of pulmonary hypertension. The pharmaceutical drug product of claim 25, wherein the intracolonic form is a solution. The pharmaceutical drug product of claim 25, wherein the intracolonic form is a solid form. The pharmaceutical drug product of claim 27, further comprising a device for intracolonically administering the selexipag. The pharmaceutical drug product of claim 28, wherein the device comprises a capsule. The pharmaceutical drug product of claim 29, wherein the capsule comprises and X- ray visible tube. The pharmaceutical drug product of claim 29, wherein the capsule comprises an X- ray visible screw fastened to the capsule. The pharmaceutical drug product of any one of claims 29 to 31, wherein the device comprises a thin tube that is attached to the capsule. 66 The pharmaceutical drug product of any one of claims 25-32, wherein the pulmonary hypertension is pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, or sarcoidosis-associated pulmonary hypertension. The pharmaceutical drug product of claim 33, wherein the pulmonary hypertension is pulmonary arterial hypertension. Use of selexipag in the preparation of a medicament for treating pulmonary hypertension, wherein the medicament comprises a therapeutically effective amount of selexipag and at least one medicament of selexipag is in an intracolonic form. The use of claim 35, wherein before administration of selexipag, the patient is in a fasted state for at least about 10 hours. The use of claim 35 or 36, wherein before administration of selexipag, the patient has a body mass index of about 18.0 to about 28.0 kg/m² and a body weight of not less than about 50.0 kg. The use of any one of claims 35-37, wherein before administration of selexipag, the patient has a blood pressure, after the patient is supine for about 5 minutes, of about 90 to about 145 mmHg systolic and about 90 mmHg or less diastolic. The use of any one of claims 35-38, wherein before administration of selexipag, the patient has a resting 12-lead ECG consistent with normal cardiac conduction, cardiac function, and sinus rhythm, a pulse rate of about 45 to about 90 bpm, a QTc interval of about 450 ms, a QRS interval of about 110 ms or less, or a PR interval of about 200 ms or less, or combinations thereof. The use of any one of claims 35-39, wherein the medicament comprises about 100 to about 500 pg of selexipag. The use of any one of claims 35-41, wherein the intracolonic form is a solid form. The use of claim 41, wherein the solid form is a tablet. 67 The use of claim 41 or 42, wherein the solid form comprises D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), hypromellose, propylene glycol, titanium oxide, iron oxide red, and carnauba wax. The use of any one of claims 35 to 40, wherein the intracolonic form is a solution. The use of claim 44, wherein the solution comprises glycine, polysorbate 20, phosphoric acid, and sodium hydroxide The use of any one of claims 35 to 41, comprising administering two intracolonic forms are administered to the patient. The use of claim 46, wherein one intracolonic dose is a solid form and one intracolonic dose is a solution. The use of claim 47, wherein the intracolonic solution comprises about 200 pg of selexipag. The use of any one of claims 41, 42 or 47, wherein the intracolonic solid form comprises about 200 pg of selexipag. The use of any one of claims 35-49, further comprising administering an oral dose of selexipag is further administered to the patient. The use of claim 50, wherein the oral dose is in a solid form. The use of claim 51, wherein the solid form further comprises D-mannitol, maize starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate (vegetable origin), hypromellose, propylene glycol, titanium oxide, yellow iron oxide, and carnauba wax. The use of claim 50 or 51, wherein the oral dose comprises about 10 to about 500 pg of selexipag. The use of any one of claims 50-53, wherein the oral dose comprises about 200 pg of selexipag. The use of any one of claims 35-54, wherein intracolonic administration of selexipag is performed using a device comprising a thin tube and a capsule comprising the selexipag, and a means for detecting the device by X-rays. The use of claim 55, wherein the capsule is an X-ray visible tube or the capsule comprises an X-ray visible screw fastened to the capsule. The use of any of claims 35-56, wherein the pulmonary hypertension is pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, or sarcoidosis-associated pulmonary hypertension. The use of claim 57, wherein the pulmonary hypertension is pulmonary arterial hypertension.