WO2022238375A1 - Méthodes de traitement de l'hypertension pulmonaire - Google Patents

Méthodes de traitement de l'hypertension pulmonaire Download PDF

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Publication number
WO2022238375A1
WO2022238375A1 PCT/EP2022/062583 EP2022062583W WO2022238375A1 WO 2022238375 A1 WO2022238375 A1 WO 2022238375A1 EP 2022062583 W EP2022062583 W EP 2022062583W WO 2022238375 A1 WO2022238375 A1 WO 2022238375A1
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imtd
selexipag
dose
weeks
patient
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PCT/EP2022/062583
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English (en)
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Carol ZHAO
Veena NARAYAN
Sandeep SAHAY
Karim EL-KERSH
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Actelion Pharmaceuticals Ltd
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Publication of WO2022238375A1 publication Critical patent/WO2022238375A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to methods of treating pulmonary hypertension, comprising administering to a patient in need thereof a therapeutically effective amount of selexipag, wherein the selexipag is administered at a starting dose and is increased to determine a first individual maximum tolerated dose (iMTD), and the patient undergoes a further titration of selexipag to a second iMTD.
  • iMTD individual maximum tolerated dose
  • the patient undergoes the further titration to the second iMTD in the absence of disease progression.
  • Pulmonary arterial hypertension is a serious chronic disorder of the pulmonary circulation of diverse etiologies and pathogeneses. It is characterized by an elevation of pulmonary artery pressure, progressive increase in pulmonary vascular resistance (PVR) resulting in decrease of cardiac output (CO) and right ventricular failure which ultimately leads to death.
  • PVR pulmonary vascular resistance
  • CO cardiac output
  • the complex pathogenesis of PAH involves dysfunction in three key pathways: the prostacyclin, endothelin, and nitric oxide pathways.
  • PAH is defined hemodynamically as a resting mean pulmonary artery pressure of > 20 mmHg with normal pulmonary artery wedge pressure (or left ventricular end-diastolic pressure) of ⁇ 15 mmHg and PVR ⁇ 3 Wood units (or 240 dyn. sec/cm 5 ).
  • the invention relates to methods of treating pulmonary hypertension. These methods comprise administering to a patient in need thereof a therapeutically effective amount of selexipag.
  • the selexipag is administered at a starting dose and is increased to determine a first individual maximum tolerated dose (iMTD), and the patient undergoes a further titration of the first iMTD to a second iMTD.
  • iMTD individual maximum tolerated dose
  • the patient undergoes the further titration to the second iMTD in the absence of disease progression.
  • the invention relates to selexipag for use in a method for treating pulmonary hypertension in a patient.
  • the method includes administering selexipag at a starting dose and is increased to determine a first individual maximum tolerated dose (iMTD) and the patient undergoes a further titration from the first iMTD to a second iMTD.
  • iMTD individual maximum tolerated dose
  • the patient undergoes the further titration to the second iMTD in the absence of disease progression.
  • the invention relates to use of selexipag in the preparation of a medicament for treating pulmonary hypertension in a patient.
  • Selexipag is administered at a starting dose and is increased to determine a first individual maximum tolerated dose (iMTD), and, the patient undergoes a further titration from the first iMTD to a second iMTD.
  • iMTD individual maximum tolerated dose
  • the patient undergoes the further titration to the second iMTD in the absence of disease progression.
  • FIG. 1 is bar graph showing PAH-specific therapies at the time of selexipag initiation.
  • FIG. 2 is a bar graph showing risk as measured by REVEAL 2.0.
  • A Baseline Risk
  • B Change from Baseline to Month 12
  • C Change from Baseline to Month 18. Numbers may not add up to 100% due to rounding.
  • FIG. 3 is a scatter pot showing survival (A) for all patients and (B) for newly initiated patients. Numbers may not add up to 100% due to rounding.
  • 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.
  • 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.
  • 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.
  • amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of one or more symptoms of the disease or disorder being treated.
  • disease progression is categorized by a number of factors as would be understood by one skilled in the art, and may be determined by a physician or other healthcare provider.
  • a disease has progressed if a patient is hospitalized for worsening of PAH.
  • a disease is considered as progressing if the patient has clinical worsening or a worsening of functional class.
  • Other examples of disease progression include an increased risk of death, a decrease in 6-minute walk distance (6MWD), by for example about 15%, and/or a need to initiate parental PAH treatment.
  • disease progression may be assesses by a risk score as disclosed herein, with progression indicated by an increased score resulting in a change in category from a lower risk to a higher risk, such as a change from a low risk score to an intermediate risk score.
  • the present disclosure provides methods of treating pulmonary hypertension in a patient in need thereof.
  • the present disclosure provides methods for treating PAH.
  • the methods tailor long-term selexipag doses to patients who respond to selexipag and have PAH.
  • patients with low or intermediate risk scores are candidates for the methods of treatment disclosed herein.
  • those patients with a high risk score or those with disease progression that results in a high risk score category require initiation of other therapy, such as parental PAH treatment.
  • those in a higher functional class e.g., functional class IV as noted below, may require initiation of other therapy, such as parental PAH treatment, as opposed to the further titration of selexipag described herein.
  • pulmonary hypertension and “PH” are interchangeable and define a general condition where a patient has high blood pressure in the lungs. PH occurs when the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs.
  • the underlying cause of the narrowing is not known, i. e. , idiopathic pulmonary hypertension.
  • PH is classified into subgroups including (i) pulmonary arterial hypertension (PAH), (ii) PH due to left heart disease, (iii) PH due to lung disease, (iv) PH due to chronic blood clots (CTEPH), or (v) PH due to miscellaneous diseases.
  • PAH pulmonary arterial hypertension
  • CTEPH chronic blood clots
  • the methods desirably treat PAH.
  • PAH pulmonary arterial hypertension
  • PAH also is classified into subgroups including (i) idiopathic PAH, (ii) heritable PAH, (iii) PAH caused by drugs or toxins, (iv) PAH associated with other conditions such as connective tissue diseases, congenital heart problems, high blood pressure in the liver, HIV, infections (schistosomiasis) (v) PAH in long-term responders to calcium channel blockers (vi) PAH caused by rare blood vessels conditions (e.g.
  • PAH in babies (persistent pulmonary hypertension of the newborn). Severity of PAH symptoms in a patient is generally evaluated by a classification system, i.e ., the World Health Organization (WHO) class system. See, Table 1.
  • WHO World Health Organization
  • a higher functional class indicates a more severe disease state and/or greater urgency for a patient to be accurately diagnosed and started on PAH therapy.
  • the methods reduce the risk of a patient progressing from a lower functional class to a higher functional class.
  • the methods reduce the risk of a PAH patient progressing from a functional class I to a functional class II, functional class I to a functional class III, functional class I to a functional class IV, functional class II to a functional class III, functional class II to a functional class IV, or functional class III to a functional class IV.
  • the methods may also, or in addition, reduce PAH disease progression by preventing or limiting PAH-related hospitalization, clinical worsening of PAH, initiation of an agent to reduce worsening of PAH, or death.
  • the methods reduce the risk of patient hospitalization, e.g., for worsening of PAH.
  • the methods reduce the risk of clinical worsening of PAH.
  • the methods reduce the risk of patient death.
  • the methods avoid having to initiate administration of an agent to reduce worsening of PAH, such as a parental prostacyclin, prostacyclin analog, or prostacyclin receptor agonist.
  • the patient is treatment naive for PAH, however, patients previously or currently on a treatment regimen for PAH may also benefit from the methods disclosed herein.
  • treatment naive refers to a patient who has not been treated for PAH prior to initiating treatment according to the methods described herein.
  • the patient hasn’t taken selexipag prior to initiating treatment according to the methods described herein.
  • the patient is also, or in addition to being treatment naive, newly diagnosed with PAH.
  • an initial PAH diagnosis of the patient is made within about six months of the start of selexipag administration. In some embodiments, the initial PAH diagnosis made within about 6, about 5, about 4, about 3, about 2, or about 1 month of the start of selexipag administration.
  • the stability of a patient’s PAH prior to and during treatment with selexipag may be measured using a “risk score.”
  • the risk score thus, is a valuable assessment that permits physicians to determine prognoses, identify treatment goals, and monitor PAH disease progression.
  • Techniques for determining a risk score for PAH include those developed by the French, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), and the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), version 1.0 and the updated version 2.0.
  • the risk score is calculated using the patient’s WHO Group 1 subgroup, demographics, comorbidities, NYHA/WHO functional class, all- case hospitalizations ⁇ 6months, vital signs, 6-minute walk distance, BNP, echocardiogram, pulmonary function test, and right hear catherization. See, Table 2. Thus, a higher number of points results in a higher REVEAL score.
  • the REVEAL risk score may be ranked according to a low, intermediate, or high risk score. In some embodiments, the REVEAL risk score is “low”, i.e., score of ⁇ 6. In other embodiments, the REVEAL risk score is “intermediate”, i.e., score of 7-8. In further embodiments, the REVEAL risk score is “high”, i.e. score of > 9.
  • the risk score is calculated using the patient’s NYHA functional class, 6-minute walk distance (6MWD), brain natriuretic peptide (BNP), NT-proBNP (N-terminal precursor of brain natriuretic peptide), right atrial pressure (RAP), cardiac index (Cl), and mixed venous saturation (SvO 2 ). See, Table 3. Thus, a higher number of points results in a higher REVEAL score.
  • the COMPERA risk score may be ranked according a low, intermediate, or high risk score.
  • a baseline risk score of the patient is obtained prior to initiating treatment with selexipag according to the methods described herein.
  • the risk score is assessed after establishing the first iMTD and before starting the further titration as described herein.
  • the risk score is calculated using the REVEAL calculation.
  • the risk score is calculated using the COMPERA calculation.
  • the risk score is calculated using the REVEAL and COMPERA calculations.
  • Efficacy of the methods described herein may then be determined by obtaining a risk score of the patient at any point during selexipag treatment, i.e., one or more treatment phase or one or more maintenance phase.
  • the risk score of the patient improves, i.e., decreases, as compared to the baseline risk score of the patient prior to initiating treatment with selexipag or compared to a risk score of the patient after establishing the first iMTD and before starting the further titration.
  • the risk score of the patient remains substantially the same, as compared to the baseline risk score of the patient or compared to a risk score of the patient after establishing the first iMTD and before starting the further titration.
  • the overall survival of the patient improves as compared a patient at the same risk category who isn’t being treated with selexipag.
  • the overall survival of the patient improves as compared to a patient at the same risk category who hasn’t had the first iMTD selexipag dosage further titrated as described herein.
  • the term “selexipag” refers to 2- ⁇ 4- [(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ -N-(methanesulfonyl)acetamide of formula (II).
  • selexipag also refers to amorphous or crystalline forms of selexipag, such as polymorphs thereof.
  • the selexipag is a crystalline form, such as a polymorph.
  • the selexipag is an amorphous form.
  • 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.
  • “Selexipag” as used herein includes anhydrous or hydrates thereof. In certain embodiments, the selexipag is an anhydrous form. In other embodiments, the selexipag is a hydrate thereof. “Selexipag” as used herein further 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.
  • selexipag may also include pharmaceutically acceptable salts thereof, which may readily be selected by those skilled in the art.
  • 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.,
  • salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid
  • 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.
  • selexipag 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. Geometrical isomers (Z form and E form) of selexipag or mixtures thereof are also contemplated.
  • 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.
  • the present disclosure also contemplates the administration of selexipag metabolites.
  • the selexipag metabolite is metabolically active compound.
  • the selexipag metabolite is of formula II-M1, 4-[(5,6-diphenylpyrazin- 2-yl)(isopropyl)amino]butoxy ⁇ acetic acid.
  • II-M1 is also known under the code name ACT- 333679 or MRE-269.
  • 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).
  • the methods of the disclosure comprise administering to a patient in need thereof a therapeutically effective amount of selexipag.
  • the selexipag is administered at a starting dose and is adjusted to determine a first individual maximum tolerated dose (iMTD).
  • the desired dose of selexipag is an amount that elicits the biological or medicinal response resulting in elimination of one or more PAH symptoms or a reduction of one or more PAH symptoms.
  • the selexipag starting dose on a daily basis is at least about 10 ⁇ g.
  • the selexipag starting dose on a daily basis is at least 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 ⁇ g.
  • the selexipag starting dose is about 200 ⁇ g, twice daily.
  • the daily dose may be administered once daily, twice daily, or thrice daily, preferably twice daily.
  • the selexipag dose does not exceed about 1600 ⁇ g twice daily, i.e., 3200 ⁇ g per day.
  • the selexipag dose, twice daily is about 100 to about 3500 ⁇ g, 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
  • the selexipag dose, on a twice daily basis is about 200 to about 1600 ⁇ g. In other embodiments, the selexipag dose, on a twice daily basis, is about 200 ⁇ g to about 1600 ⁇ g.
  • the selexipag dose, on a twice daily basis is about 1200 ⁇ g to about 1600 ⁇ g twice daily.
  • the starting, daily amount of selexipag dose is about 400 ⁇ g.
  • This can be administered to the patient in one dose (400 ⁇ g) or, preferably, in two doses (200 ⁇ g/dose).
  • the doses are taken at the same time or staggered.
  • the first 200 ⁇ g dose may be taken in the morning and the second 200 ⁇ g dose is taken in the evening.
  • a 400 ⁇ g starting dose is taken in the morning.
  • a 400 ⁇ g starting dose is taken in the evening.
  • the amount of selexipag is adjusted to provide a first individual maximum tolerable dose (iMTD), as determined by a physician or other healthcare provider, in a first dose adjustment phase.
  • iMTD first individual maximum tolerable dose
  • the period of time for the first dose adjustment phase depends on the time required to provide the first iMTD. In some embodiments, the first dose adjustment phase is about 4 to about 16 weeks.
  • the first dose adjustment phase is about 4 to about 14 weeks, about 4 to about 12 weeks, about 4 to about 10 weeks, about 4 to about 8, about 4 to about 6 weeks, about 6 to about 16 weeks, about 6 to about 14 weeks, about 6 to about 12 weeks, about 6 to about 10 weeks, about 6 to about 8 weeks, about 8 to about 16 weeks, about 8 to about 14 weeks, about 8 to about 12 weeks, about 8 to about 10 weeks, about 10 to about 16 weeks, about 10 to about 14 weeks, about 10 to about 12 weeks, about 12 to about 16 weeks, about 12 to about 14 weeks, or about 14 to about 16 weeks. In other embodiments, the first dose adjustment phase is about 8 to about 12 weeks.
  • the selexipag dose is increased from the initial selexipag dose at usually regular intervals during the first dose adjustment phase until a first iMTD.
  • the regular intervals may be hourly, daily or weekly depending on patient tolerability. In some embodiments, the regular intervals are hourly or portions of a day. In other embodiments, the regular intervals are daily. In further embodiments, the regular intervals are weekly. When the intervals are hourly, they may be every 1 to about 12 hours. In some embodiments, the intervals are every about 4, about 8, or about 12 hours. In further embodiments, the intervals are twice per day, i.e., twice daily.
  • the starting dose may be increased in increments that are suitable for the type of administration of selexipag.
  • selexipag is increased in increments of at least about 100 ⁇ g in the first dose adjustment phase. In other embodiments, selexipag is increased in increments of about 100 to about 600 ⁇ g in the first dose adjustment phase.
  • selexipag is increased in increments of about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 600, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 600, about 300 to about 500, about 300 to about 400, about 400 to about 600, about 400 to about 500, or about 500 to about 600 ⁇ g in the first dose adjustment phase.
  • selexipag is increased in increments of about 200, about 400, or about 600 ⁇ g in the first dose adjustment phase.
  • selexipag is increased in increments of about 200 ⁇ g in the first dose adjustment phase.
  • the first iMTD is that amount and frequency before which the patient experiences adverse pharmacological effects that cannot be tolerated and/or medically managed.
  • the selexipag first iMTD does not exceed about 1600 ⁇ g twice daily, i.e., 3200 ⁇ g per day.
  • the first iMTD, twice daily is about 100 to about 3500 ⁇ g, 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 200 to about 2600, about 200 to about 2400, about 600 to about 2000, about 400 to
  • the selexipag first iMTD on a twice daily basis, is about 200 to about 1600 ⁇ g. In other embodiments, the selexipag first iMTD is about 200 ⁇ g to about 800 ⁇ g twice daily.
  • the selexipag starting dose is increased until the iMTD is reached. This period of increasing the dose may be determined by one skilled in the art.
  • the time to reach the selexipag iMTD is at least about 1 week. In some embodiments, the time to reach the iMTD is at least about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, or about 16 weeks.
  • the time to reach the iMTD is about 2 to about 16 weeks, about 2 to about 14 weeks, about 2 to about 12 weeks, about 2 to about 10, weeks, about 2 to about 8 weeks, about 2 to about 6 weeks, about 2 to about 4 weeks, about 4 to about 16 weeks, about 4 to about 14 weeks, about 4 to about 12 weeks, about 4 to about 10 weeks, about 4 to about 8 weeks, about 4 to about 6 weeks, about 5 to about 15 weeks, about 5 to about 10 weeks, about 6 to about 16 weeks, about 6 to about 14 weeks, about 6 to about 12 weeks, about 6 to about 10 weeks, about 6 to about 8 weeks, about 8 to about 16 weeks, about 8 to about 14 weeks, about 8 to about 12 weeks, about 8 to about 10 weeks, about 10 to about 16 weeks, about 12 to about 16 weeks, about 12 to about 14 weeks, or about 14 weeks to about 16 weeks.
  • the time to reach the selexipag iMTD dose is about 5 to about 10 weeks.
  • the selexipag dose is increased as determined by one skilled in the art until the iMTD is determined.
  • the selexipag dose is increased daily.
  • the selexipag dose is increased weekly.
  • the selexipag dose is increased monthly.
  • the selexipag dose is increased weekly (based on a 7-day week).
  • the selexipag dose may be administered on the same day each week or within 1 day within the scheduled dosing day.
  • the next dose of selexipag may be administered on Sunday, Monday, or Tuesday of the following week.
  • the selexipag dose may be administered of the same day each month or within 3 days of the next scheduled dosing day.
  • the next dose of selexipag may be administered on February 4 th , 5 th , 6 th , 7 th , 8 th , 9 th , or 10 th .
  • the treatment period of selexipag therapy also includes one or more maintenance phases.
  • the treatment period includes at least one maintenance phase.
  • the treatment period includes at least two maintenance phases.
  • the treatment period includes at least three maintenance phases.
  • the maintenance phases may be determined by a physician or other healthcare provider and typically begins following the first dose adjustment phase.
  • the maintenance phase(s) is performed without dose interruption and/or dose change.
  • the maintenance phase(s) is performed without dose interruption.
  • the maintenance phase(s) is performed without a change in dose of selexipag.
  • the maintenance phase(s) is performed without dose interruption and without dose change.
  • the duration of the first maintenance phase will typically be determined by the attending physician.
  • the first maintenance phase is at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 week, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 17 weeks, about 18 weeks, about 19 weeks, or about 20 weeks. In other embodiments, the first maintenance phase is about 12 to about 28 weeks.
  • the first maintenance phase is about 12 to about 26 weeks, about 12 to about 24 weeks, about 12 to about 22 weeks, about 12 to about 20 weeks, about 12 to about 18 weeks, about 12 to about 16 weeks, about 12 to about 14 weeks, about 14 to about 28 weeks, about 14 to about 26 weeks, about 14 to about 24 weeks, about 14 to about 22 weeks, about 14 to about 20 weeks, about 14 to about 18 weeks, about 14 to about 16 weeks, about 16 to about 28 weeks, about 16 to about 26 weeks, about 16 to about 24 weeks, about 16 to about 22 weeks, about 16 to about 20 weeks, about 16 to about 18 weeks, about 18 to about 28 weeks, about 18 to about 26 weeks, about 18 to about 24 weeks, about 18 to about 22 weeks, about 18 to about 20 weeks, about 20 to about 28 weeks, about 20 to about 26 weeks, about 20 to about 24 weeks, about 20 to about 22 weeks, about 22 to about 28 weeks, about 22 to about 26 weeks, about 22 weeks, about 22 weeks, about 22 weeks, about 22 weeks, about 22 weeks, about 18 to about 20 weeks, about 20 to about 28
  • the maintenance phase is about 12 weeks, about 13, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, or about 28 weeks. In still other embodiments, the maintenance phase is about 14 weeks to about 26 weeks.
  • the amount of selexipag administered to the patient during the maintenance treatment period is the iMTD that is determined during the first treatment phase. Additional Dose Adjustment Phases
  • the patient undergoes a further titration of selexipag.
  • the patient undergoes a further titration of selexipag to a second iMTD during a second dose adjustment phase.
  • the further titration comprises a dose increase from the first iMTD to a second iMTD.
  • the amount of selexipag is adjusted during the second dose adjustment phase to provide a second iMTD, as determined by a physician or other healthcare provider, in a second dose adjustment phase.
  • the period of time for the second dose adjustment phase depends on the time required to reach the second iMTD. In some embodiments, the second dose adjustment phase is about 4 to about 16 weeks.
  • the second dose adjustment phase is about 4 to about 14 weeks, about 4 to about 12 weeks, about 4 to about 10 weeks, about 4 to about 8, about 4 to about 6 weeks, about 6 to about 16 weeks, about 6 to about 14 weeks, about 6 to about 12 weeks, about 6 to about 10 weeks, about 6 to about 8 weeks, about 8 to about 16 weeks, about 8 to about 14 weeks, about 8 to about 12 weeks, about 8 to about 10 weeks, about 10 to about 16 weeks, about 10 to about 14 weeks, about 10 to about 12 weeks, about 12 to about 16 weeks, about 12 to about 14 weeks, or about 14 to about 16 weeks. In other embodiments, the second dose adjustment phase is about 8 to about 12 weeks.
  • the selexipag dose is increased from the first iMTD at regular intervals during the second dose adjustment phase until a second iMTD.
  • the regular intervals during the second iMTD may be hourly, daily or weekly depending on patient tolerability.
  • the regular intervals are hourly or portions of a day.
  • the regular intervals are daily.
  • the regular intervals are weekly.
  • the intervals are hourly, they may be every 1 to about 12 hours.
  • the intervals are every about 4, about 8, or about 12 hours.
  • the intervals are twice per day, i.e., twice daily.
  • the first iMTD dose may be increased in increments that are suitable for the type of administration of selexipag.
  • selexipag is increased in increments of at least about 100 ⁇ g in the second dose adjustment phase to provide the second iMTD.
  • selexipag is increased in increments of about 100 to about 600 ⁇ g in the second dose adjustment phase.
  • selexipag is increased in increments of about 100 to about 500, about 100 to about 400, about 100 to about 300, about 100 to about 200, about 200 to about 600, about 200 to about 500, about 200 to about 400, about 200 to about 300, about 300 to about 600, about 300 to about 500, about 300 to about 400, about 400 to about 600, about 400 to about 500, or about 500 to about 600 ⁇ g in the first second adjustment phase.
  • selexipag is increased in increments of about 200, about 400, or about 600 ⁇ g in the second dose adjustment phase.
  • selexipag is increased in increments of about 200 ⁇ g in the second dose adjustment phase.
  • the second iMTD is that amount and frequency before which the patient experiences adverse pharmacological effects that cannot be tolerated and/or medically managed. Desirably, the second iMTD does not exceed about 1600 ⁇ g twice daily, i.e., 3200 ⁇ g per day.
  • the second iMTD, twice daily is about 100 to about 3500 ⁇ g, 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 200 to about 2600, about 200 to about 2400, about 600 to about 2000, about 400 to
  • the patient’s response to the treatment may be assessed. This assessment may be performed until the patient is considered by a physician or other healthcare provider to have achieved a suitable response to the therapy.
  • the patient remains on the second iMTD of selexipag as determined by the attending physician.
  • a patient that undergoes a further titration to the second iMTD remains on selexipag treatment longer than a patient that does not undergo the further titration of selexipag to the second iMTD.
  • the first iMTD is about 600 to about 1050 ⁇ g twice daily, and the second iMTD is about 800 to about 1400 ⁇ g twice daily. In other embodiments, the first iMTD is less than about 1000 ⁇ g twice daily and the second iMTD is greater than about 1000 ⁇ g twice daily. In yet other embodiments, the first iMTD is about 200 ⁇ g to about 800 ⁇ g twice daily, and the second iMTD is greater than about 800 ⁇ g iMTD to about 1600 ⁇ g twice daily.
  • the time between the determination of the first iMTD and the start of the further titration to the second iMTD will vary based on the patient assessment by the physician, but can be about 15 to about 40 weeks, about 20 to about 35 weeks, or about 25 to about 30 weeks.
  • the amounts/doses of selexipag are safe, effective, or safe and effective.
  • 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.
  • 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.
  • 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.
  • the therapeutically effective amount of selexipag is safe. In still further embodiments, the therapeutically effective amount of selexipag is effective. In other embodiments, the therapeutically effective amount of selexipag is safe and effective.
  • 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.
  • 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.
  • the term “clinically proven effective” means the efficacy of treatment has been proven by a Phase III or IV clinical trial as statistically significant i. e. , 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.
  • selexipag was clinically proven effective for the treatment of patients with pulmonary arterial hypertension in therapeutically effective doses as described herein, and as specifically set forth in the examples.
  • 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).
  • EMEA Middle East, and Africa
  • selexipag was clinically proven safe for the treatment of patients with pulmonary arterial hypertension when dosed in therapeutically effective doses as described herein, and as specifically set forth in the examples.
  • 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.
  • the methods include selling a drug product comprising selexipag, wherein the method comprises selling the drug product.
  • a drug product label for a reference listed drug for the drug product includes instructions for treating PAH.
  • the methods also include offering for sale a drug product comprising selexipag.
  • offering for sale 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.
  • the present disclosure provides pharmaceutical drug products comprising clinically proven safe and clinically proven effective amounts of selexipag, wherein the pharmaceutical product is packaged and wherein the package includes a label that identifies selexipag as regulatory approved chemical entities and includes instructions for treating PAH.
  • 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.
  • the drug product comprises selexipag.
  • 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.
  • the label or drug product label provides instructions for treating PAH.
  • the label or drug product label identifies selexipag as regulatory approved chemical entities.
  • RTD reference listed drug
  • 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, i.e., 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.
  • the drug product is an ANDA drug product, a supplemental New Drug Application drug product, or a 505(b)(2) drug product.
  • ANDA Abbreviated New Drug Application
  • an ANDA applicant relies on the FDA’s finding that a previously approved drug product, i.e., 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.
  • 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.
  • 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.
  • 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: 1.
  • EAA European Economic Area
  • 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.
  • 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.
  • the medicinal product (product name, strength, pharmaceutical form, MAH, Member State of source) used for the bioequivalence study(ies) (where applicable).
  • NDAs and ANDAs can be divided into the following four categories:
  • 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.
  • 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.
  • 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, i.e., 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.
  • 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.
  • 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.
  • 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
  • the methods may also comprise, consist of, or consist essentially of placing selexipag into the stream of commerce.
  • selexipag includes a package insert that contains instructions for treating PAH.
  • described herein are methods of selling pharmaceutical compositions, containing selexipag comprising, consisting of, or consisting essentially of placing the pharmaceutical compositions into the stream of commerce.
  • the pharmaceutical composition includes a package insert that contains instructions for treating PAH.
  • described herein are methods of offering for sale selexipag comprising, consisting of, or consisting essentially of offering to place selexipag into the stream of commerce.
  • selexipag includes a package insert that contains instructions for treating PAH.
  • compositions independently 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.
  • compositions 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.
  • 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.
  • selexipag is formulated into a composition as discussed herein.
  • Such compositions 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.
  • 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.
  • 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.
  • Selexipag may be administered by a number of routes as determined by those skilled in the art.
  • selexipag is independently, administered by any suitable route.
  • selexipag is administered orally, parenterally, or any combination thereof.
  • selexipag is administered orally.
  • selexipag is administered orally in the form of one or more tablets.
  • selexipag is administered as injections or infusions such as intravenous injections.
  • selexipag or pharmaceutical product is a sterile solution.
  • injectable suspensions or solutions may be prepared utilizing aqueous carriers along with appropriate additives.
  • the carrier will usually consist of sterile water and other ingredients which increase solubility or preservation.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. Isotonic preparations which may contain suitable preservatives are employed when intravenous administration is desired.
  • the carrier used in intravenous formulations comprises sterile water.
  • each preparation may be solid or liquid.
  • the oral forms of selexipag are solids.
  • solid formulations include, for example, pastilles, thin films, pastes, lozenges, granules, powders, capsules, pills such as caplets, gelcaps, tablets, and capsules (each including immediate release, timed release and sustained release pills).
  • the oral compositions are administered as tablets, i.e., desirably, the pharmaceutical product comprises a tablet.
  • 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.
  • the principal active ingredient 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.
  • 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.
  • 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.
  • liquid forms in which the compositions of the present disclosure may be incorporated for administration by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • suitable carriers/additives such as water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like.
  • selexipag 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).
  • a pharmaceutical 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.
  • a method of treating pulmonary hypertension comprising administering to a patient in need thereof a therapeutically effective amount of selexipag, wherein the selexipag is administered at a starting dose and is increased to determine a first individual maximum tolerated dose (iMTD), and, the patient undergoes a further titration from the first iMTD to a second iMTD.
  • iMTD individual maximum tolerated dose
  • Aspect 2 The method of Aspect 1, wherein the pulmonary hypertension is pulmonary arterial hypertension.
  • Aspect 3 The method of Aspect 1 or 2, wherein the further titration to the second iMTD is in the absence of disease progression.
  • Aspect 4 The method of any one of the preceding Aspects, wherein the starting dose of selexipag is about 200 ⁇ g twice daily.
  • Aspect 5 The method of any one of the preceding Aspects, wherein the starting dose is increased in twice-daily increments of about 200 ⁇ g until the first iMTD is determined in a first dose adjustment phase.
  • Aspect 6 The method of any one of the preceding Aspects, wherein the first iMTD is from about 200 ⁇ g to about 1600 ⁇ g twice daily.
  • Aspect 7 The method of any one of the preceding Aspects, wherein the first dose adjustment phase is from about 8 to about 12 weeks.
  • Aspect 8 The method of any one of the preceding Aspects, wherein the first iMTD does not exceed about 1600 ⁇ g twice daily.
  • Aspect 9 The method of any one of the preceding Aspects, wherein the first iMTD is maintained during a first maintenance phase following the first dose adjustment phase.
  • Aspect 10 The method of Aspect 8, wherein the first maintenance phase is about 14 weeks to about 26 weeks without dose interruption and/or dose change.
  • Aspect 11 The method of any one of the preceding Aspect, wherein the further titration comprises a dose increase from the first iMTD to the second iMTD.
  • Aspect 12 The method of any one of the preceding Aspect, wherein the time between the determination of the first iMTD and the start of the further titration is about 8 to about 35 weeks.
  • Aspect 13 The method of any one of the preceding Aspect, wherein the first iMTD is about 200 ⁇ g to about 800 ⁇ g twice daily, and the second iMTD is greater than about 800 ⁇ g iMTD to about 1600 ⁇ g twice daily.
  • Aspect 14 The method of any one of the preceding Aspect, wherein a risk score of the patient improves or is maintained compared to the risk score of the patient prior to initiating treatment with selexipag or compared to the risk score after determining the first iMTD and before starting the further titration.
  • Eligible patients are followed for up to 18 months after enrollment, with data collected during routine clinic visits. Eligible patients are aged ⁇ 18 years and are either newly initiated on selexipag (i.e., receiving selexipag for ⁇ 60 days) at the time of enrollment, or have already been receiving selexipag (i.e., previously initiated, starting selexipag >60 days before enrollment) and have a documented titration regimen
  • selexipag maintenance dose was defined as the first dose post initiation that was maintained for >14 days without dose interruption and/or dose change. Further titration was defined as patients who reached the first individualized maintenance dose ( ⁇ 1600 ⁇ g BID) and then had a dose increase maintained for ⁇ 14 days (without dose interruption or decrease) for any reason.
  • Baseline data included demographics, clinical characteristics and history; selexipag dosing regimens and titration, safety (based on AEs), and survival status were also assessed. AEs reported as leading to selexipag discontinuation were classified as related or unrelated to PAH progression, per investigator assessment and as adjudicated by an independent medical monitor.
  • Risk assessments were conducted based on the REVEAL 2.0 risk calculator, and on the COMPERA risk assessment strategy.
  • Baseline disease characteristics are shown in Table 5.
  • PAH therapies at selexipag initiation are shown in Fig. 1. The majority of patients in the further titration group and the total group were receiving dual therapy (54.8% and 55.9%, respectively).
  • REVEAL 2.0 risk scores are shown in Fig. 2.
  • Month 12 most patients in the further titration group (66.3%) had improved/stable risk (comprised of 21/116 improved and 57/116 stable, data was missing for 19/116 patients). Fewer patients in the further titration group had missing values at Month 12 (16.4%) compared with the total group (39.3%).

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Abstract

La présente invention concerne des méthodes de traitement de l'hypertension pulmonaire, comprenant l'administration à un patient en ayant besoin d'une quantité thérapeutiquement efficace de sélexipag, le sélexipag étant administré à une dose de départ et étant augmenté pour déterminer une première dose maximale tolérée individuelle (iMTD), le patient étant alors soumis à un autre titrage de sélexipag à une seconde iMTD.
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