WO2023133476A1 - Methods of treating idiopathic pulmonary fibrosis with deupirfenidone - Google Patents

Methods of treating idiopathic pulmonary fibrosis with deupirfenidone Download PDF

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Publication number
WO2023133476A1
WO2023133476A1 PCT/US2023/060185 US2023060185W WO2023133476A1 WO 2023133476 A1 WO2023133476 A1 WO 2023133476A1 US 2023060185 W US2023060185 W US 2023060185W WO 2023133476 A1 WO2023133476 A1 WO 2023133476A1
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WIPO (PCT)
Prior art keywords
subject
treatment
lyt
pirfenidone
tid
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PCT/US2023/060185
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English (en)
French (fr)
Inventor
Michael C. Chen
Eric Elenko
Heather A. PADEN
Christopher C. KORTH
Paul Andrew FORD
Julie S. KROP
Camilla S. GRAHAM
Liza C. MICIONI
Simon John HATCH
Varun Garg
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Puretech LYT 100 Inc
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Puretech LYT 100 Inc
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Publication date
Priority to IL314022A priority Critical patent/IL314022A/en
Priority to JP2024540710A priority patent/JP2025502023A/ja
Priority to AU2023205787A priority patent/AU2023205787A1/en
Priority to CA3239301A priority patent/CA3239301A1/en
Priority to CN202380016192.2A priority patent/CN118510510A/zh
Priority to KR1020247022244A priority patent/KR20240131352A/ko
Priority to EP23737759.3A priority patent/EP4460305A4/en
Application filed by Puretech LYT 100 Inc filed Critical Puretech LYT 100 Inc
Priority to MX2024008476A priority patent/MX2024008476A/es
Publication of WO2023133476A1 publication Critical patent/WO2023133476A1/en
Priority to US18/758,783 priority patent/US20240358690A1/en
Anticipated expiration legal-status Critical
Priority to US18/982,798 priority patent/US20250114341A1/en
Priority to US18/982,735 priority patent/US20250114340A1/en
Priority to US19/299,954 priority patent/US20250375431A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Such dose-limiting side effects and/or toxicity typically require, and are therefore managed by, one or more of the following treatment options: administration of lower, less efficacious doses, periodic reduction(s) of efficacious dose, periodic or permanent cessation of drug (treatment interruption or discontinuation), and/or inability to maintain patients on a sustained treatment program or long- term maintenance dose (e.g., without treatment interruption).
  • administration of lower, less efficacious doses periodic reduction(s) of efficacious dose, periodic or permanent cessation of drug (treatment interruption or discontinuation), and/or inability to maintain patients on a sustained treatment program or long- term maintenance dose (e.g., without treatment interruption).
  • a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject in need thereof comprising administering to the subject a total daily dose from about 1650 mg to about 2500 mg of a deuterium-enriched pirfenidone having the structure: wherein the IPF is treated in the subject.
  • IPF Idiopathic Pulmonary Fibrosis
  • a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject in need thereof comprising administering to the subject a total daily dose of 1650 mg to 2475 mg of a deuterium-enriched pirfenidone having the structure: wherein the IPF is treated in the subject.
  • IPF Idiopathic Pulmonary Fibrosis
  • a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject in need thereof comprising administering to the subject a total daily dose of 1650 mg of a deuterium-enriched pirfenidone having the structure: wherein the IPF is treated in the subject.
  • IPF Idiopathic Pulmonary Fibrosis
  • a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject in need thereof comprising administering to the subject a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure: wherein the IPF is treated in the subject.
  • IPF Idiopathic Pulmonary Fibrosis
  • a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject in need thereof comprising administering to a subject a total daily dose from about 825 mg to about 2500 mg of a deuterium-enriched pirfenidone having the structure: wherein the IPF is treated in the subject.
  • IPF Idiopathic Pulmonary Fibrosis
  • a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject in need thereof comprising administering to a subject a total daily dose of 825 mg of a deuterium-enriched pirfenidone having the structure: wherein the IPF is treated in the subject.
  • IPF Idiopathic Pulmonary Fibrosis
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is the same or about the same as the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about l.lx to about 1.9x the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 1.25x to about 1.75x the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 administered achieves a systemic exposure that is 1.25x - 1.75x the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg.
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 1.4x to 1.6x the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is 1.4x to 1.5x the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 1.5x the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 85% to about 125% the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is 125% to 175% the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is 140% to 160% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is 140% to 150% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 150% of the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 10% to about 90% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 25% to about 75% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is 25% to 75% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is 40% to 60% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is 40% to 50% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 50% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 is 550 mg TID.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a Cmax of LYT-100 in the subject which is the same or about the same as the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the administering is at a dose that achieves a Cmax of LYT-100 in the subject which is equivalent to the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a Cmax of LYT-100 in the subject which is about 105% to about 125% of the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a Cmax of LYT-100 in the subject which is about 110% to about 120% of the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the administering is at a dose that achieves a Cmax of LYT-100 in the subject which is about 115% of the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 is 825 mg TID.
  • the administration of LYT-100 is three times daily.
  • the method comprises administering a total daily dose of 825 mg LYT-100 administered in three equal administrations of 275 mg each.
  • the method comprises administering a total daily dose of 1650 mg LYT-100 administered in three equal administrations of 550 mg each.
  • the method comprises administering a total daily dose of 2475 mg LYT- 100 administered in three equal administrations of 825 mg each.
  • each dose is administered with approximately 6 hours between each dose.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a total daily dose of 825 mg of a deuterium-enriched pirfenidone having the structure: wherein the LYT-100 is administered in in three equal administrations of 275 mg each and wherein IPF is treated in the subject.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a total daily dose of 1650 mg of a deuterium-enriched pirfenidone having the structure: wherein the LYT-100 is administered in in three equal administrations of 550 mg each and wherein IPF is treated in the subject.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure: wherein the LYT-100 is administered in in three equal administrations of 825 mg each and wherein IPF is treated in the subject.
  • the LYT-100 is administered without regard to food. In some embodiments, the LYT-100 is administered without food. In some embodiments, the LYT-100 is administered with food.
  • the LYT-100 is administered orally without food in three daily doses of 275 mg each. In some embodiments, the LYT-100 is administered orally with food in three daily doses of 275 mg each. In some embodiments, the LYT-100 is administered orally without food in three daily doses of 550 mg each. In some embodiments, the LYT-100 is administered orally with food in three daily doses of 550 mg each. [0029] In some embodiments, the LYT-100 is administered orally without food in three daily doses of 825 mg each. In some embodiments, the LYT-100 is administered orally with food in three daily doses of 825 mg each.
  • the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period and a second total daily maintenance dose of 1650 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 1650 mg for a first period and a second total daily maintenance dose of 2475 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period, a second total daily dose of 1650 mg for a second period, and then a total maintenance dose of 2475 mg.
  • the method comprises administering LYT- 100 at a first total daily dose of 825 mg for a first period of about 7 days and a second total daily maintenance dose of 1650 mg. In some embodiments, the method comprises administering LYT- 100 at a first total daily dose of 1650 mg for a first period of about 7 days and a second total daily maintenance dose of 2475 mg. In some embodiments, the method comprises administering LYT- 100 at a first total daily dose of 825 mg for a first period of about 7 days, a second total daily dose of 1650 mg for a second period of about 7 days, and then a total maintenance dose of 2475 mg.
  • the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of about 14 days and a second total daily maintenance dose of 1650 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 1650 mg for a first period of about 14 days and a second total daily maintenance dose of 2475 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of about 14 days, a second total daily dose of 1650 mg for a second period of about 14 days, and then a total maintenance dose of 2475 mg.
  • the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of 7-14 days and a second total daily maintenance dose of 1650 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 1650 mg for a first period of 7-14 days and a second total daily maintenance dose of 2475 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of 7-14 days, a second total daily dose of 1650 mg for a second period of 7-14 days, and then a total maintenance dose of 2475 mg.
  • the method comprises administering LYT-100 in three daily doses of 275 mg each for a first period and in three daily doses of 550 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 in three daily doses of 550 mg each for a first period and in three daily doses of 825 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 in three daily doses of 275 mg each for a first period, in three daily doses of 550 mg each for a second period, and then in three daily doses of 825 mg each for a maintenance dose.
  • the method comprises administering LYT-100 in three daily doses of 275 mg each for a first period of about 7 days and in three daily doses of 550 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 in three daily doses of 550 mg each for a first period of about 7 days and in three daily doses of 825 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 in three daily doses of 275 mg each for a first period of about 7 days, in three daily doses of 550 mg each for a second period of about 7 days, and then in three daily doses of 825 mg each for a maintenance dose.
  • the method comprises administering LYT-100 in three daily doses of 275 mg each for a first period of about 14 days and in three daily doses of 550 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 in three daily doses of 550 mg each for a first period of about 14 days and in three daily doses of 825 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 in three daily doses of 275 mg each for a first period of about 14 days, in three daily doses of 550 mg each for a second period of about 14 days, and then in three daily doses of 825 mg each for a maintenance dose.
  • the method comprises administering LYT-100 in three daily doses of 275 mg each for a first period of 7-14 days and in three daily doses of 550 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 in three daily doses of 550 mg each for a first period of 7-14 days and in three daily doses of 825 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 in three daily doses of 275 mg each for a first period of 7-14 days, in three daily doses of 550 mg each for a second period of 7-14 days, and then in three daily doses of 825 mg each for a maintenance dose.
  • the LYT-100 is administered orally without food. In any of the above embodiments, the LYT-100 is administered orally with food. In any of the above embodiments, the LYT-100 is administered orally without regard to food. In any of the above embodiments, the total daily dose, e.g., 825 mg, 1650 mg or 2475 mg may be adjusted to lower daily dose, for example, as described elsewhere in the specification.
  • the method comprises administering the LYT-100 at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 140% to about 160% of the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the method comprises administering the LYT-100 at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 150% of the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 is 825 mg TID.
  • the adverse events are similar to or about the same as the AEs observed when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the incidence, occurrence, or frequency of adverse events is similar to or about the same as the incidence, occurrence, or frequency of AEs observed when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the safety and tolerability profile is similar to or about the same as the safety and tolerability profile observed when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 that achieves the systemic exposure of LYT-100 in the subject which is about 150% of the systemic exposure of pirfenidone (administered at a total daily dose of 2403 mg) achieves a Cmax of LYT-100 in the subject which is about the same as the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 that achieves the systemic exposure of LYT-100 in the subject which is about 150% of the systemic exposure of pirfenidone (administered at a total daily dose of 2403 mg) achieves a Cmax of LYT-100 in the subject which is equivalent to the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 that achieves the systemic exposure of LYT-100 in the subject which is about 150% of the systemic exposure of pirfenidone (administered at a total daily dose of 2403 mg) achieves a Cmax of LYT-100 in the subject which is about 105% to about 125% of the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 that achieves the systemic exposure of LYT-100 in the subject which is about 150% of the systemic exposure of pirfenidone (administered at a total daily dose of 2403 mg) achieves a Cmax of LYT-100 in the subject which is about 110% to about 120% of the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 that achieves the systemic exposure of LYT- 100 in the subject which is about 150% of the systemic exposure of pirfenidone (administered at a total daily dose of 2403 mg) achieves a Cmax of LYT-100 in the subject which is about 115% of the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 is 825 mg TID.
  • the adverse events are similar to or about the same as the AEs observed when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the incidence, occurrence, or frequency of adverse events is similar to or about the same as the incidence, occurrence, or frequency of AEs observed when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • gastrointestinal-related adverse events associated with the administration LYT-100 are similar to gastrointestinal-related adverse events associated with the administration pirfenidone, optionally wherein the total daily dose of pirfenidone is administered at a total daily dose of 2403 mg, and optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the safety and tolerability profile is similar to or about the same as the safety and tolerability profile observed when pirfenidone is administered at a total daily dose of 2403 mg, optionally wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the method of treating prevents, delays, or slows the progression of impaired respiratory function or IPF in the subject.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of a deuterium-enriched pirfenidone having the structure: wherein the LYT-100 administration prevents, delays, or slows the progression of impaired respiratory function in the subject.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of a deuterium-enriched pirfenidone having the structure: wherein the LYT-100 administration prevents, delays, or slows the progression of impaired respiratory function in the subject.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of a deuterium-enriched pirfenidone having the structure: wherein the LYT-100 administration prevents, delays, or slows the progression of impaired respiratory function in the subject.
  • the method of treating prevents, delays, or slows the progression of impaired respiratory function or IPF in the subject.
  • progression of IPF is delayed, slowed or arrested.
  • Respiratory function e.g., impaired respiratory function
  • the respiratory function is determined by measuring Forced Vital Capacity (FVC) in the subject.
  • the progression of impaired respiratory function in the subject is determined by measuring a change in FVC over a period of treatment.
  • the period of treatment for measuring change in FVC is from baseline to a treatment period selected from: at least 26 weeks, at least 52 weeks, at least 78 weeks, or at least 104 weeks.
  • the period of treatment for measuring change in FVC is at least 26 weeks.
  • the change in FVC is measured from baseline to at least 26 weeks of treatment.
  • the period of treatment for measuring change in FVC is at least 52 weeks. In some embodimens, the change in FVC is measured from baseline to at least 52 weeks of treatment.
  • the change in FVC is measured as a rate of decline in FVC (mL).
  • a method of treating Idiopathic Pulmonary Fibrosis (IPF) comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the rate of decline in FVC (mL) is lower relative to a subject who has not received LYT-100.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the the rate of decline in FVC (mL) is lower relative to a subject who has not received LYT-100.
  • a method of treating Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the rate of decline in FVC (mL) is lower relative to a subject who has not received LYT-100.
  • the period of treatment for measuring the rate of decline in FVC (mL) is at least 26 weeks. In some embodiments, the rate of decline in FVC (mL) is measured from baseline to at least 26 weeks of treatment. In some embodiments, the period of treatment for measuring the rate of decline in FVC (mL) is at least 52 weeks. In some embodimens, the rate of decline in FVC (mL) is measured from baseline to at least 52 weeks of treatment. In some embodiments, the rate of decline in FVC (mL) over at least a 26-week treatment period is a value less than the rate of decline exhibited by a subject who has not received LYT-100. In some embodiments, the rate of decline in FVC (mL) over at least a 52-week treatment period is a value less than the rate of decline exhibited by a subject who has not received LYT-100.
  • the change in FVC is measured as a change in FVC% predicted (FVCpp). In some embodiments, the change in FVC is measured as a decline in FVC% predicted (FVCpp).
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the the rate of decline in FVCpp is lower relative to a subject who has not received LYT-100.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the the rate of decline in FVCpp is lower relative to a subject who has not received LYT-100.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the rate of decline in FVCpp is lower relative to a subject who has not received LYT-100.
  • the period of treatment for measuring the rate of decline in FVCpp is at least 26 weeks.
  • the rate of decline in FVCpp is measured from baseline to at least 26 weeks of treatment. In some embodiments, the rate of decline in FVCpp over at least a 26-week treatment period is a value less than the rate of decline exhibited by a subject who has not received LYT- 100. In some emboidments, the decline in FVCpp in the treated subject is less than 5% when measured over 26 weeks of treatment. In any of the treatment methods described herein, a delayed progression of IPF or slower rate of progression of IPF is demonstrated in a subject exhibiting a decline in FVCpp of less than 5% when measured over 26 weeks of treatment, e.g., measured from baseline to week 26 of treatment.
  • the period of treatment for measuring the rate of decline in FVCpp is at least 52 weeks. In some embodimens, the rate of decline in FVCpp is measured from baseline to at least 52 weeks of treatment. In some embodiments, the rate of decline in FVCpp over at least a 52-week treatment period is a value less than the rate of decline exhibited by a subject who has not received LYT-100. In some emboidments, the decline in FVCpp in the treated subject is less than 10% when measured over 52 weeks of treatment.
  • a delayed progression of IPF or slower rate of progression of IPF is demonstrated in a subject exhibiting a decline in FVCpp of less than 10% when measured over 52 weeks of treatment, e.g., measured from baseline to week 52 of treatment.
  • the treatment of IPF is demonstrated or exhibited by a delay in the time to progression of IPF in the subject. In some embodiments, the treatment of IPF is demonstrated or exhibited by a slower rate of progression of IPF in the subject. In any of the methods disclosed herein, the length of time to IPF progression is longer (increased, greater) in the subject treated with LYT-100 relative to a subject who has not received LYT-100. IPF progression can be determined using various methods, including by measuring the change in FVC, e.g., a decline in FVC mL or FVCpp. In some embodiments, IPF progression is determined by a decline in FVCpp of 5% or greater.
  • IPF progression is determined by a decline in FVCpp of 10% or greater.
  • the length of time to IPF progression is longer (increased, greater) in the subject treated with LYT-100 relative to a subject who has not received LYT-100.
  • the length of time to IPF progression is longer (increased, greater) in the subject treated with LYT- 100 relative to a subject who has not received LYT-100.
  • the subject exhibits a longer period of time to hospitalization due to impaired respiratory function relative to a subject who has not received LYT- 100.
  • the longer length of time to hospitalization is a longer length of time for an initial hospitalization due to impaired respiratory function.
  • the longer lengthof time to hospitalization is not an initial hospitalization, e.g., it is a longer length of time for subsequent hospitalization(s) due to impaired respiratory function.
  • the subject has less frequent hospitalizations due to impaired respiratory function relative to a subject who has not received LYT-100.
  • the subject has a lower number of hospitalizations due to impaired respiratory function relative to a subject who has not received LYT-100.
  • the subject has a shorter duration of hospitalization time(s) due to impaired respiratory function relative to a subject who has not received LYT-100.
  • the number of hospitalizations and/or the duration of hospitalization time(s) due to impaired respiratory function is measured over at least a 26-week treatment period, e.g., baseline to week 26 of treatment. In some embodiments, the number of hospitalizations and/or the duration of hospitalization time(s) due to impaired respiratory function is measured over at least a 52-week treatment period, e.g., baseline to week 52 of treatment.
  • the subject exhibits a longer period of time to mortality due to impaired respiratory function relative to a subject who has not received LYT-100. In any of the methods disclosed herein, the subject exhibits a longer period of time to mortality due to IPF relative to a subject who has not received LYT-100. In some embodiments, the time to mortality due to impaired respiratory function or IPF is measured over at least a 26-week treatment period. In some embodiments, the time to mortality due to impaired respiratory function or IPF is measured over at least a 52-week treatment period.
  • the subject has a change in one or more serum biomarker(s) related to impaired respiratory function relative to a subject who has not received LYT-100.
  • the serum biomarker is collagen type 4.
  • the change in serum biomarker(s) related to impaired respiratory function is measured over at least a 26-week treatment period. In some embodiments, the change in serum biomarker(s) related to impaired respiratory function is measured over at least a 52-week treatment period.
  • the subject is treated as determined by one or more of: King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score; Saint George Respiratory Questionnaire (SGRQ-I) domain score; EuroQol 5-Dimensional (EQ5D) Questionnaire score; and Cough visual analog scale (VAS), relative to a subject who has not received LYT-100.
  • K-BILD King's Brief Interstitial Lung Disease Questionnaire
  • SGRQ-I Saint George Respiratory Questionnaire
  • EQ5D EuroQol 5-Dimensional
  • VAS Cough visual analog scale
  • the subject is treated without any dose reduction in the administered daily dose over the course of treatment. In any of the methods disclosed herein, the subject is treated without any interruption in treatment or temporary stoppage in treatment over the course of treatment. In any of the methods disclosed herein, the subject is treated without any discontinuation in treatment over the course of treatment. In some embodiments, the course of treatment is at least 26 weeks. In some embodiments, the course of treatment is at least 52 weeks.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a reduced number of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • AE adverse event
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits a reduced number of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • AE adverse event
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a reduced number of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • AE adverse event
  • a method for reducing the number of one or more adverse event(s) (AE) in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a reduced number of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method forreducing the number of one or more adverse event(s) (AE) in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits a reduced number of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for reducing the number of one or more adverse event(s) (AE) in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a reduced number of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a shorter duration of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • AE adverse event
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits a shorter duration of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • AE adverse event
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a shorter duration of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • AE adverse event
  • a method for reducing the duration of one or more adverse event(s) (AE) in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a shorter duration of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for reducing the duration of one or more adverse event(s) (AE) in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits a shorter duration of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for reducing the duration of one or more adverse event(s) (AE) in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a shorter duration of one or more adverse event(s) (AE) relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • the one or more adverse event(s) is a gastrointestinal-related adverse event selected from nausea, vomiting, abdominal pain or distension, dyspepsia, diarrhea, decreased appetite, and constipation.
  • the one or more adverse event(s) is a nervous system-related adverse event selected from headache, dizziness, and somnolence.
  • the one or more adverse event(s) is selected from fatigue, drug intolerance, and photosensitivity.
  • the one or more adverse event(s) is selected from increased AST, ALT, GGT, and liver toxicity.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to first dose reduction in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to first dose reduction in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to first dose reduction in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying e.g., increasing, extending the time to first dose reduction in the administered daily dose in the treatment of IPF, the method comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a longer (lengthened) time to first dose reduction relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying e.g., increasing, extending the time to first dose reduction in the administered daily dose in the treatment of IPF, the method comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subj ect exhibits a longer (lengthened) time to first dose reduction relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying e.g., increasing, extending
  • the time to first dose reduction in the administered daily dose in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT- 100, wherein the subject exhibits a longer (lengthened) time to first dose reduction relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) dose reduction(s) in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) dose reduction(s) in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) dose reduction(s) in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for reducing (e.g., decreasing) the number of dose reductions in the administered daily dose in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) dose reduction(s) in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for reducing (e.g., decreasing) the number of dose reductions in the administered daily dose in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) dose reduction(s) in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for for reducing (e.g., decreasing) the number of dose reductions in the administered daily dose in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) dose reduction(s) in the administered daily dose relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to first treatment interruption or temporary stoppage in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF the method comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-
  • IPF the method comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to first treatment interruption or temporary stoppage in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying (e.g., increasing, extending) the period of time to first treatment interruption or temporary stoppage in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to first treatment interruption or temporary stoppage in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying e.g., increasing, extending
  • the time to first treatment interruption or temporary stoppage in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to first treatment interruption or temporary stoppage in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying e.g., increasing, extending
  • the time to first treatment interruption or temporary stoppage in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to first treatment interruption or temporary stoppage in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) treatment interruptions or temporary stoppages in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) treatment interruptions or temporary stoppages in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) treatment interruptions or temporary stoppages in treatment relative to a subj ect who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for reducing the frequency (e.g., decreasing the number) of treatment interruptions or temporary stoppages in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) treatment interruptions or temporary stoppages in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for reducing the frequency (e.g., decreasing the number) of treatment interruption or temporary stoppage in treatment in the treatment of IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits less frequent (e.g., a lower number of) treatment interruptions or temporary stoppages in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for for reducing the frequency (decreasing the number) of treatment interruptions or temporary stoppages in treatment of IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT- 100, wherein the subject exhibits less frequent (e.g., a lower number of) treatment interruptions or temporary stoppages in treatment relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to treatment discontinuation relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subj ect exhibits a longer (e.g., lengthened) period of time to treatment discontinuation relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to treatment discontinuation relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying (e.g., increasing, extending) the period of time to treatment discontinuation of IPF treatment comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to treatment discontinuation relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying (e.g., increasing, extending) the time to treatment discontinuation of IPF treatment comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to treatment discontinuation relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for delaying (e.g., increasing, extending) the time to treatment discontinuation of IPF treatment comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits a longer (e.g., lengthened) period of time to treatment discontinuation relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • a method for improving the treatment for IPF, relative to treatment with pirfenidone is provided.
  • the improvement in treatment is an improved tolerability.
  • the improved tolerability is due to a decrease in the frequency, incidence, or number of adverse events and/or the duration of adverse events.
  • a method for improving the treatment for IPF comprising administering to a subject in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100, wherein the subject exhibits an improvement in treatment, relative to a subject which has been treated with 801 mg TID pirfenidone.
  • a method for improving the treatment for IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100, wherein the subject exhibits an improvement in treatment, relative to a subject which has been treated with 801 mg TID pirfenidone.
  • a method for improving the treatment for IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100, wherein the subject exhibits an improvement in treatment, relative to a subject which has been treated with 801 mg TID pirfenidone.
  • the improvement in treatment relative to a subject which has been treated with 801 mg TID pirfenidone is a reduced number of one or more adverse event(s) (AEs) and/or a shorter duration of one or more adverse event(s) (AEs).
  • the one or more AEs is selected from nausea, vomiting, abdominal pain or distension, dyspepsia, diarrhea, decreased appetite, constipation, headache, dizziness, somnolence, fatigue, drug intolerance, increased AST, ALT, and/or GGT, and liver toxicity.
  • the improvement in treatment relative to a subject which has been treated with 801 mg TID pirfenidone is selected from a delayed progression of impaired respiratory function, a slower rate of progression of impaired respiratory function, and/or a longer length of time to impaired respiratory function.
  • the improvement in treatment is selected from a delayed progression of IPF, a slower rate of progression of IPF, and/or a longer length of time to IPF proression.
  • IPF progression is determined by measuring a decline in FVC (mL). In some embodiments, the improvement is a lower rate of decline in FVC (mL).
  • IPF progression is measured over at least a 26-week treatment period.
  • the rate of decline in FVC (mL) over at least a 26-week treatment period is a value less than the rate of decline in FVC (mL) exhibited by a subject which has been treated with 801 mg TID pirfenidone.
  • IPF progression is determined by measuring a decline in FVCpp.
  • the improvement is a lower rate of decline in FVCpp.
  • IPF progression is measured over at least a 26-week treatment period.
  • the rate of decline in FVCpp over at least a 26-week treatment period is a value less than the rate of decline in FVCpp exhibited by a subject which has been treated with 801 mg TID pirfenidone.
  • IPF progression is determined by a decline in FVCpp of 5% or greater.
  • IPF progression is measured over at least a 52-week treatment period.
  • the rate of decline in FVCpp over at least a 52-week treatment period is a value less than the rate of decline in FVCpp exhibited by a subject which has been treated with 801 mg TID pirfenidone.
  • IPF progression is determined by a decline in FVCpp of 10% or greater.
  • the improvement in treatment relative to a subject which has been treated with 801 mg TID pirfenidone is selected from a longer period of time to hospitalization due to impaired respiratory function, less frequent (a lower number of) hospitalizations due to impaired respiratory function, and/or a shorter duration of hospitalization time(s) due to impaired respiratory function.
  • the length of time to hospitalization, the number of hospitalizations and/or the duration of hospitalization time(s) due to impaired respiratory function is measured over at least a 26-week treatment period, e.g., baseline to week 26 of treatment.
  • the length of time to hospitalization, the number of hospitalizations and/or the duration of hospitalization time(s) due to impaired respiratory function is measured over at least a 52-week treatment period, e.g., baseline to week 52 of treatment.
  • the improvement in treatment relative to a subject which has been treated with 801 mg TID pirfenidone is a longer period of time to mortality due to impaired respiratory function.
  • the subject exhibits a longer period of time to mortality due to IPF relative to a subject which has been treated with 801 mg TID pirfenidone.
  • the time to mortality due to impaired respiratory function or IPF is measured over at least a 26-week treatment period. In some embodiments, the time to mortality due to impaired respiratory function or IPF is measured over at least a 52-week treatment period.
  • the improvement in treatment relative to a subject which has been treated with 801 mg TID pirfenidone is an improved change in one or more serum biomarker(s) related to impaired respiratory function, e.g., collagen type 4.
  • the change in serum biomarker(s) related to impaired respiratory function is measured over at least a 26-week treatment period.
  • the change in serum biomarker(s) related to impaired respiratory function is measured over at least a 52-week treatment period.
  • the improvement in treatment relative to a subject which has been treated with 801 mg TID pirfenidone is an improvement in one or more of: King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score; Saint George Respiratory Questionnaire (SGRQ-I) domain score; EuroQol 5-Dimensional (EQ5D) Questionnaire score; and Cough visual analog scale (VAS), relative to a subject who has not received LYT-100.
  • K-BILD King's Brief Interstitial Lung Disease Questionnaire
  • SGRQ-I Saint George Respiratory Questionnaire
  • EQ5D EuroQol 5-Dimensional
  • VAS Cough visual analog scale
  • a method of improving the treatment for IPF, relative to treatment with pirfenidone comprising administering to a subject in need thereof a total daily dose from 825 mg to 2475 mg of a deuterium-enriched pirfenidone having the structure:
  • the method comprises administering to a subj ect in need thereof a total daily dose of 825 mg administered in three equal doses of 275 mg each of LYT-100. In some embodiments, the method comprises administering to a subject in need thereof a total daily dose of 1650 mg administered in three equal doses of 550 mg each of LYT-100. In some embodiments, the method comprises administering to a subject in need thereof a total daily dose of 2475 mg administered in three equal doses of 825 mg each of LYT-100. In some embodiments, the treatment with pirefenidone is a total daily dose of 2403 mg pifendione, administered in three eual doses of 801 mg each.
  • the improvement in treatment, relative to treatment with pirfenidone is an improved tolerability, as determined by a reduction in the incidence of one or more gastrointestinal AE(s) and/or a reduction in the duration of one or more gastrointestinal AE(s).
  • the one or more gastrointestinal AE(s) is selected from: nausea, vomiting, loss of appetite, and abdominal pain or distension.
  • the incidence of one or more gastrointestinal AE(s) is reduced by at least 30%.
  • the improvement in treatment, relative to treatment with pirfenidone is an improved tolerability, as determined by a reduction in the incidence of one or more nervous system AE(s) and/or a reduction in the duration of one or more nervous system AE(s).
  • the one or more nervous system AE(s) is selected from: fatigue, headache, dizziness, and somnolence.
  • the incidence of one or more nervous system AE(s) is reduced by at least 30%.
  • the improvement in treatment, relative to treatment with pirfenidone is a selected from: a lower incidence or frequency of dose reduction in the administered daily dose, a longer time to first dose reduction in the administered daily dose, a lower incidence of interrupted treatment or temporary stoppage of treatment, a longer time to first treatment interruption or temporary stoppage in treatment, and a reduction in the incidence of discontinuation of treatment.
  • the improvement in treatment is measured over at least 26 weeks of treatment. In some embodiments, the improvement in treatment is measured over at least 52 weeks of treatment. In any of the described methods, the improvement in treatment is relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • the improvement in treatment, relative to treatment with pirfenidone is selected from: a slower or delayed progression of impaired respiratory function, a slower or delayed progression of IPF, a lower rate of decline in FVC (mL), a lower rate of decline in FVCpp, a longer period of time to hospitalization due to impaired respiratory function, a lower number of hospitalizations due to impaired respiratory function, a shorter duration of hospitalization time(s) due to impaired respiratory function, and a longer period of time to mortality due to impaired respiratory function.
  • the improvement in treatment is measured over at least 26 weeks of treatment. In some embodiments, the improvement in treatment is measured over at least 52 weeks of treatment. In any of the described methods, the improvement in treatment is relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • the improvement in treatment relative to treatment with pirfenidone is determined in one or more of: King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score; Saint George Respiratory Questionnaire (SGRQ-I) domain score; EuroQol 5-Dimensional (EQ5D) Questionnaire score; and Cough visual analog scale (VAS)._In some embodiments, the improvement in treatment is measured over at least 26 weeks of treatment. In some embodiments, the improvement in treatment is measured over at least 52 weeks of treatment. In any of the described methods, the improvement in treatment is relative to a subject who has been treated with 801 mg TID pirfenidone over the same treatment period.
  • K-BILD King's Brief Interstitial Lung Disease Questionnaire
  • SGRQ-I Saint George Respiratory Questionnaire
  • EQ5D EuroQol 5-Dimensional
  • VAS Cough visual analog scale
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 1650 mg of a deuterium-enriched pirfenidone having the structure: wherein the LYT-100 is administered in three equal doses of 550 mg each for a period of time and wherein the total daily dose may be reduced for one or more subsequent period(s) of time.
  • the total daily dose of 1650 mg is an initial dose.
  • the total daily dose of 1650 mg is not an initial daily dose.
  • the total daily dose of 1650 mg may be reduced in increments of 275 mg.
  • the total daily dose of 1650 mg may be reduced to a total daily dose of 825 mg, optionally administered in three equal doses of 275 mg each. In some embodiments, the total daily dose may be reduced to 825 mg for about 1 week to about one month. In some embodiments, the total daily dose may be reduced to 825 mg for longer than one month. In some embodiments, the total daily dose may be reduced to 825 mg as a daily maintenance dose.
  • a method of treating IPF comprising administering to a subject in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure: wherein the LYT-100 is administered in three equal doses of 825 mg each for a period of time and wherein the total daily dose may be reduced for one or more subsequent period(s) of time.
  • the total daily dose of 2475 mg is an initial dose.
  • the total daily dose of 2475 mg is not an initial daily dose.
  • the total daily dose of 2475 mg may be reduced in increments of 275 mg.
  • the total daily dose of 2475 mg may be reduced to a total daily dose of 1650 mg, optionally administered in three equal doses of 550 mg each. In some embodiments, the total daily dose may be reduced to 1650 mg for about 1 week to about one month. In some embodiments, the total daily dose may be reduced to 1650 mg for longer than one month. In some embodiments, the total daily dose may be reduced to 1650 mg as a daily maintenance dose. In some embodiments, the total daily dose of 1650 mg may be further reduced in increments of 275 mg. In some embodiments, the total daily dose of of 1650 mg may be further reduced to a total daily dose of 825 mg, optionally administered in three equal doses of 275 mg each.
  • the total daily dose may be further reduced to 825 mg for about 1 week to about one month. In some embodiments, the total daily dose may be further reduced to 825 mg for longer than one month. In some embodiments, the total daily dose may be further reduced to 825 mg as a daily maintenance dose. In some embodiments, the total daily dose of 2475 mg may be reduced to a total daily dose of 825 mg, optionally administered in three equal doses of 275 mg each. In some embodiments, the total daily dose of 2475 mg may be reduced to 825mg for about 1 week to about one month. In some embodiments, the total daily dose of 2475 mg may be reduced to 825 mg for longer than one month. In some embodiments, the total daily dose of 2475 mg may be reduced to 825 mg as a daily maintenance dose.
  • the treatment with LYT-100 may be interrupted or temporarily stopped, for one or more periods of time, as needed.
  • the subject has one or more of the following: Idiopathic Pulmonary Fibrosis as diagnosed by a physician based on ATS/ERS/JRS/ALAT 2018 guidelines or based on high resolution computed tomography (HRCT) performed within 12 months of initiating treatment, a clinically significant decline in DLCO corrected for hemoglobin >30% predicted of normal prior to initiating treatment, and an FVC > 45% predicted prior to initiating treatment.
  • the subject has not received prior treatment for IPF.
  • the subj ect has received prior treatment for IPF.
  • the prior treatment for IPF is nintedanib.
  • the prior treatment for IPF is pirfenidone.
  • the subject has received less than 6 months prior exposure to nintedanib or pirfenidone.
  • FIG. 1A is a graphical illustration of the low rates of treatment and poor tolerability with current antifibrotics (pirfenidone and nintedanib) for IPF.
  • FIG. IB is a graphical depiction of the high rate of discontinuation of pirfenidone therapy over time in the treatment of IPF.
  • FIG. 2 is a graphical illustration of a crossover clinical trial study design according to a non-limiting embodiment of the disclosure.
  • FIG. 3 is a graphical illustration of another crossover clinical trial study design according to a non-limiting embodiment of the disclosure.
  • FIG. 4 is a table showing the extrapolated steady-state exposures (AUCi4ss) and steady-state Cmax values of LYT-100 for 450 mg - 550 mg TID dosing based on PK data from two separate cohorts (12 A and 12B) and a pooled dataset.
  • the pharmacokinetic parameters were calculated using steady state AUC0-24 after administration of LYT-100 dosed at 1000 mg BID or pifenidone dosed at 801 mg TID.
  • the data demonstrates that a dose of 550 mg TID LYT-100 has a steady-state exposure (AUC) that is calculated to be equivalent to 98.5% of the steady-state exposure (AUC) of pirfenidone dosed at 801 mg TID, and a Cmax that is calculated to be equivalent to 67.4% of the Cmax of pirfenidone dosed at 801 mg TID.
  • AUC steady-state exposure
  • AUC steady-state exposure
  • FIG. 5 is a table showing the extrapolated steady-state exposures (AUCi4ss) and steady-state Cmax values of LYT-100 for 700 mg - 1000 mg BID dosing (1400 mg - 2000 mg daily dose) versus 450 mg - 850 mg TID dosing (1350 mg - 2550 mg daily dose).
  • AUC steady-state exposure
  • AUC steady-state exposure
  • a dose of 550 mg TID LYT-100 (1650 mg daily dose) has a steady-state exposure (AUC) that is calculated to be equivalent to 98.5% of the steady-state exposure (AUC) and 67.4% of the steady-state Cmax of pirfenidone dosed at 801 mg TID.
  • FIG. 6A is a summary of the pharmacokinetic and tolerability results of a Phase 1 cross-over study conducted in healthy adults dosed with 850 mg BID LYT-100.
  • FIG. 6B is a table showing the incidence of treatment-emergent adverse events (TEAEs) in a cross-over study of healthy older adults comparing LYT-100850 mg BID versus pirfenidone 801 mg TID.
  • TEAEs treatment-emergent adverse events
  • FIG. 7 is a graphical depiction of side effects encountered in a healthy older patient population for LYT-100 at 550 mg TID and pirfenidone at 801 mg TID.
  • FIG. 8A is a graphical depiction of time versus exposure for LYT-100 for a dose of 550 mg TID.
  • FIG. 8B is a graphical depiction of time versus exposure for LYT-100 for a dose of 824 mg TID.
  • FIG. 8C is a graphical depiction of time versus exposure for the major metabolite for a dose of 550 mg TID.
  • FIG. 8D is a graphical depiction of time versus exposure for the major metabolite for a dose of 824 mg TID.
  • FIG. 9 is a table showing the pharmacokinetic parameters for LYT-100 and the major metabolite for doses of 550 mg TID and 824 mg TID.
  • FIG. 10A is a graphical depiction of time versus exposure for LYT-100 for doses of 550 mg TID and 824 mg TID in the crossover study of Example 1 and two prior dosing studies.
  • FIG. 10B is a graphical depiction of time versus exposure for the major metabolite for doses of 550 mg TID and 824 mg TID in the crossover study of Example 1 and two prior dosing studies.
  • FIG. 11 is a graphical illustration of the mean plasma concentrations over time for pirfenidone dosed at 801 mg TID, and for LYT-100 dosed at 550 mg TID and 824 mg TID.
  • FIG. 12 is a graphical illustration of the mean plasma concentrations of the major metabolite over time for pirfenidone dosed at 801 mg TID, and for LYT-100 dosed at 550 mg TID and 824 mg TID.
  • FIG. 13 is a graphical depiction of plasma concentration versus time for pirfenidone at 550 mg TID and LYT-100 at 824 mg TID following day 3 in the crossover study of Example 1.
  • FIG. 14A is a graphical depiction of subject weight versus exposure for LYT-100 for 550 mg TID and 824 mg TID doses in the crossover study of Example 1 and in three prior dosing studies.
  • FIG. 14B is a graphical depiction of subject weight versus exposure for the major metabolite for 550 mg TID and 824 mg TID doses in the crossover study of Example 1 and in three prior dosing studies.
  • FIG. 15A is a graphical depiction of subject age versus exposure for LYT-100 normalized to 550 mg TID in the crossover study of Example 1 and in three prior dosing studies.
  • FIG. 15B is a graphical depiction of subject age versus exposure for the major metabolite of LYT-100 normalized to 550 mg TID in the crossover study of Example 1 and in three prior dosing studies.
  • FIG. 16A is a graphical summary of exposure versus dose in the crossover study of Example 1 and a prior dosing study demonstrating the achievement of bioequivalence to 801 mg TID pirfenidone for 550 mg TID LYT-100.
  • FIG. 16B is a graphical summary of exposure versus dose in the crossover study of Example 1 and a prior dosing study demonstrating the achievement of bioequivalence to 801 mg TID pirfenidone for 550 mg TID LYT-100.
  • FIG. 16C is a graphical summary of exposure versus dose in the crossover study of Example 1 and a prior dosing study demonstrating the achievement of bioequivalence to 801 mg TID pirfenidone for 550 mg TID LYT-100.
  • FIG. 16D is a graphical summary of exposure versus dose in the crossover study of Example 1 and pooled data from a prior dosing study demonstrating the achievement of bioequivalence to 801 mg TID pirfenidone for 550 mg TID LYT-100.
  • FIG. 17 is a graphical summary of exposure versus dose for pooled data from the crossover study of Example 1 and three prior dosing studies and demonstrating the achievement of bioequivalence to 801 mg TID pirfenidone for 550 mg TID and 687 mg TID LYT-100.
  • FIG. 18 is a table showing the predicted bioequivalence for various LYT-100 TID doses using data from the crossover study of Example 1 and three prior dosing studies.
  • FIG. 19A is a graphical cartoon illustration of predicted plasma concentrations over time for pirfenidone at 801 mg TID, LYT-100 at 550 mg TID, and LYT-100 at 825 mg TID.
  • FIG. 19B is a table showing the ratio of predicted plasma concentrations for pirfenidone at 801 mg TID versus LYT-100 dosed at 550 mg TID and 825 mg TID.
  • FIG. 20 is a table showing a summary of baseline demographic characteristics with respect to age and sex for subjects in the COVID-19 clinical study of Example 3.
  • FIG. 21 is a table showing a summary of baseline demographic characteristics with respect to ethnicity, race, and time from COVID diagnosis for subjects in the COVID-19 clinical study of Example 3.
  • FIG. 22 is a table showing a summary of subject disposition for the enrolled population in the COVID- 19 clinical study of Example 3.
  • FIG. 23 is a table showing a summary of treatment emergent adverse events judged to be at least possibly related to LYT-100 in the COVID-19 clinical study of Example 3.
  • FIG. 24A is a high-level graphical illustration of the IPF clinical trial study design of Example 4 according to anon-limiting embodiment of the disclosure.
  • FIG. 24B is a graphical illustration of the double-blind portion of the IPF clinical trial study of Example 4 according to a non-limiting embodiment of the disclosure.
  • FIG. 24C is a graphical illustration of the open label portion of a the IPF clinical trial study of Example 4 according to a non-limiting embodiment of the disclosure.
  • FIG. 24D is a summary of recent protocol amendments to the IPF clinical trial study of Example 4 according to a non-limiting embodiment of the disclosure.
  • FIG. 25A is an example of a patient reported assessment of IPF symptoms survey according to a non-limiting embodiment of the disclosure.
  • FIG. 25B is an example of a patient reported assessment of side effect survey according to a non-limiting embodiment of the disclosure.
  • FIG. 26 is an example of a patient reported satisfaction survey according to a non- limiting embodiment of the disclosure.
  • FIG. 27 is a table showing the metabolism of pirfenidone and LYT-100 in the presence of individual CYP isozymes in the assay of Example 5.
  • FIG. 28 is a graphical depiction of activity results for LYT-100 and pirfenidone in the BioMap Fibrosis Panel of Example 6.
  • FIG. 29 is a graphical depiction of percent change in body weight over time for rats in Phase I of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 30A is a graphical depiction of lung weight to body weight percentage over time for rats in Phase I of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 30B is a graphical depiction of lung weight to body weight percentage over time for rats in Phase I of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 31A is a graphical depiction of body weight over time for rats in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 31B is a graphical depiction of percent change in body weight over time for rats in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 32A is a graphical depiction of lung weight over time for rats in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 32B is a graphical depiction of lung weight over time for rats in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 33A is a graphical depiction of lung weight to body weight percentage over time for rats in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 33B is a graphical depiction of lung weight to body weight percentage over time for rats in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 34A is a graphical depiction of hydroxyproline content in left lung tissue for rats in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 34B is a graphical depiction of hydroxyproline content in left lung tissue for rats in Phase II of the bleomycin induced lung fibrosis model of Example 76.
  • FIG. 35 is a table showing the hydroxyproline content in left lung tissue across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 36A is a graphical depiction of hydroxyproline content in lung tissue across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 36B is a graphical depiction of hydroxyproline content in lung tissue across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 37 is a table showing the hydroxyproline content in lung tissue across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 38A is a graphical depiction of mean lung fibrosis score across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 38B is a graphical depiction of mean lung fibrosis score across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 38C is a graphical depiction of median lung fibrosis score across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 38D is a graphical depiction of median lung fibrosis score across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • FIG. 39 is a graphical depiction of frequency of lung fibrosis scores across the various treatment groups in Phase II of the bleomycin induced lung fibrosis model of Example 7.
  • IPF Idiopathic Pulmonary Fibrosis
  • the method generally comprises administering to a subject in need thereof the deuterated pirfenidone LYT-100.
  • This method is expected to provide significantly increased efficacy, tolerability, and patient compliance in these subjects, as compared to treatment with pirfenidone.
  • the features of the method are disclosed further herein below.
  • the term “about” used throughout this specification is used to describe and account for small fluctuations.
  • the term “about” can refer to greater than, less than or equal to ⁇ 10%, such as greater than, less than or equal to ⁇ 5%, greater than, less than or equal to ⁇ 2%, greater than, less than or equal to ⁇ 1%, greater than, less than or equal to ⁇ 0.5%, greater than, less than or equal to ⁇ 0.2%, greater than, less than or equal to ⁇ 0.1% or greater than, ess than or equal to ⁇ 0.05%. All numeric values herein are modified by the term "about,” whether or not explicitly indicated. A value modified by the term “about” of course includes the specific value. For instance, "about 5.0" must include 5.0.
  • Adverse Event refers to any event, side-effect, or other untoward medical occurrence that occurs in conjunction with the use of a medicinal product in humans, whether or not considered to have a causal relationship to this treatment.
  • An AE can, therefore, be any unfavourable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
  • AE AE's may have a causal relationship with the treatment, may be possibly related, or may be unrelated.
  • Severity of AEs may be graded as one of: Mild (Grade 1): A type of AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living; Moderate (Grade 2): A type of AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant; Severe (Grade 3): A type of AE that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention; Life-threatening (Grade 4): A type of AE that places the participant at immediate risk of death; Death (Grade 5): Events that result in death.
  • the term "clinically effective amount,” “clinically proven effective amount,” and the like, refer to an effective amount of an API as shown through a clinical trial, e.g., a U.S. Food and Drug Administration (FDA) clinical trial.
  • FDA Food and Drug Administration
  • deuterium enrichment when used to describe a given variable position in a molecule or formula, or the symbol "D," when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium.
  • deuterium enrichment is of no less than about 1%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 98%, or in some embodiments no less than about 99% of deuterium at the specified position.
  • the deuterium enrichment is above 90% at each specified position.
  • the deuterium enrichment is above 95% at each specified position.
  • the deuterium enrichment is about 99% at each specified position.
  • deuterium enrichment refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non- enriched starting materials is about 0.0156%. The deuterium enrichment can be determined using conventional analytical methods, such as mass spectrometry and nuclear magnetic resonance spectroscopy.
  • fibrosis refers to the deposition of extracellular matrix components, excessive fibrous connective tissue, or scarring within an organ or tissue.
  • Idiopathic pulmonary fibrosis refers to a type of lung disease that results in scarring of the lungs (pulmonary fibrosis) for which the origin of the disease state may be unknown.
  • Prevent refers to prophylactic or preventative measures that obstruct, delay and/or slow the development of a targeted pathologic condition or disorder or one or more symptoms of a targeted pathologic condition or disorder.
  • those in need of prevention include those at risk of or susceptible to developing the disorder.
  • subject and “patient” refers to a mammalian subject, including a human subject. In some embodiments, the patient is human subject.
  • Terms such as “treating” or “treatment” or “to treat” refer to therapeutic measures that avoid, delay, and/or slow the occurrence of, avoid, delay, and/or slow the progression of, prevent, cure, ameliorate or lessen one or more symptoms of a pathologic condition or disorder; and/or that avoid occurrence of, prevent, cure, ameliorate, slow progression of, and/or halt progression of, a pathologic condition or disorder.
  • treatment may be administered after one or more symptoms have developed.
  • those in need of treatment include those already with the disorder (e.g., IPF).
  • treatment may be administered after one or more symptoms have developed.
  • a subject is successfully "treated" for a disease or disorder according to the methods provided herein if the patient shows, e.g., total, partial, or transient alleviation or elimination of one or more symptoms associated with the disease or disorder (e.g., IPF) or if the patient shows, e.g., partial or transient delay in the progression of one or more symptoms associated with the disease or disorder (e.g., IPF) and/or if the patient shows, e.g., partial, or transient decrease (reduction, lessening) in the rate of progression of one or more symptoms associated with the disease or disorder, e.g., IPF, including, for example, impaired respiratory function and pulmonary fibrosis, as well as other knowm symptoms of IPF.
  • subject and “patient” refers to a mammalian subject, including a human subject. In some embodiments, the patient is human subject.
  • the methods disclosed herein comprise administering a deuterium-enriched pirfenidone which is LYT-100.
  • LYT-100 is a selectively deuterated form of pirfenidone.
  • LYT-100 is the deuterium-enriched pirfenidone, 5-(methyl-d3)-l-phenylpyridin-2- (1H)-one (CAS# 1093951-85-9) which may alternatively be referred to as deupirfenidone or 2(1H)-Pyridinone, 5-(methyl- ⁇ d3)- 1 -phenyl.
  • LYT-100 has the following structure:
  • Reference to "LYT-100" herein further includes any hydrate, solvate, crystalline polymorph, amorphous form, or the like, of 5-(methyl-d3)-l-phenylpyridin-2-(1H)-one.
  • the LYT-100 as disclosed herein can be prepared by methods known to one of skill in the art and routine modifications thereof, and/or procedures found in Esaki et al., Tetrahedron 2006, 62, 10954-10961, Smith et al., Organic Syntheses 2002, 78, 51-56, U.S. Pat. No. 3,974,281, U.S. Pat. No. 8,680,123, W02003/014087, WO 2008/157786, WO 2009/035598, WO 2012/122165, or WO 2015/112701; the entirety of each of which is hereby incorporated by reference; and references cited therein and routine modifications thereof.
  • Pirfenidone is indicated for the treatment of idiopathic pulmonary fibrosis (IPF) and pirfenidone treatment is associated with clinical benefits.
  • IPF idiopathic pulmonary fibrosis
  • pirfenidone treatment is associated with clinical benefits.
  • phase 3 studies used for US registration Noble 2016 et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J. 2016;47(l):243-253): 1
  • the mean change from baseline to 1 year in FVC was -216 ml. in the pirfenidone group and -363 ml. in the placebo group (absolute difference 148 mL, relative difference 40.7%; p ⁇ 0.001.
  • Pirfenidone reduced the risk of death or disease progression (defined as a confirmed >10% decline in FVC % predicted or a confirmed >50 m decline in 6MWD) at 1 year by 38% compared with placebo (hazard ratio 0.62, 95% CI 0.51-0, 75; p ⁇ 0.001),
  • the unmet medical needs for patients living with IPF include dose-limiting adverse events and toxicity associated with gastrointestinal intolerability (e.g., nausea, vomiting, diarrhea, dyspepsia, anorexia, and other GI events), dizziness, fatigue, rash and photosensitivity rash, as well as other adverse side-effects, which limits current treatment for IPF (Noble, 2016).
  • Management of these adverse events includes dose reductions and discontinuations of pirfenidone, associated with a lost opportunity for the full clinical benefits when full dose pirfenidone is maintained.
  • Pirfenidone is associated with poor tolerability in a population of patients with IPF that is older and typically has multiple comorbidities.
  • patients receiving pirfenidone had a 31.5% rate of permanent dose reducti ons and a 15.2% rate of treatment discontinuation, compared to 20.8% and 12.7% for placebo, respectively (Nathan et al.
  • Patients on placebo also had dose reductions and discontinuations, but at a lower rate than with pirfenidone.
  • Pirfenidone dose reductions are associated with lower efficacy than full dose pirfenidone.
  • Nathan and colleagues compared patients who were able to maintain >90% of their pirfenidone dose (dose intensity) with those who had ⁇ 90% dose intensity for the frequency of IPF progression, defined as a decline >10% in %FV C or death over 52 weeks.
  • the method generally comprises administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: wherein the IPF is treated in the subject.
  • the dose and frequency of dosing may vary based on the severity of the IPF.
  • the total daily dose is from about 825 mg to about 2550 mg of LYT-100.
  • the total daily dose is about 1650 to about 2475 mg of LYT-100, such as about 1650, about 1700, about 1750, about 1800, about 1850, about 1900, about 1950, about 2000, about 2050, about 2100, about 2150, about 2200, about 2250, about 2300, about 2350, about 2400, about 2450, about 2475, about 2500, or about 2550 mg.
  • the total daily dose is 1650 mg.
  • the total daily dose is 2475 mg.
  • the toal daily dose in 825 mg.
  • Improved tolerability of the current clinically efficacious dose of pirfenisone (801 mg TID) can improve IPF patient outcomes due to increased compliance with a sustained clinically efficacious dose (e.g., by reducing the frequency of dose reductions, treatment interruptions, and/or temporary or permanent discontinuations currently experienced with the use of pirfenidone).
  • PK modeling data incorporated the results of various MAD PK studies to reduce variability inherent in multiple studies of small sample size.
  • a dose of 825 mg TID had a systemic exposure (AUC) of about 139-148% (average about 143%) of the AUC achieved with pirfenidone (2403 mg dose, 801mg TID) and a Cmax of about 109 - 121% (average about 115%) of the Cmax achieved with pirfenidone (2403 mg dose, 801mg TID).
  • AUC systemic exposure
  • Pirfenidone has not been tested for clinical efficacy above doses of 801 mg TID due to poor tolerability.
  • the dose of LYT-100 was optimized to achieve similar systemic exposure (AUC ) to pirfenidone 801 mg TID.
  • the dose of LYT-100 was also optimized to achieve similar Cmax to pirfenidone 801 mg TID while maximizing exposure (AUC).
  • Table A summarizes the pharmacokinetic results of a cross-over study administering a dose of LYT-100 550 mg TID versus pirfenidone 801 mg TID.
  • the results are expressed as Mean (SD), and shows that at the 550 mg TID dose, the AUC of LYT-100 is similar to that of pirfenidone dosed at the 801 mg TID dose while the Cmax is lower.
  • the major metabolite of both pirfenidone and LYT-100, 5-carboxypirfenidone showed lower Cmax and AUC0-24 after LYT-100 dosing at 550 mg TID compared to pirfenidone 801 mg TID.
  • the reduced Cmax of the parent and the 5-carboxypirfenidone with LYT-100 may be responsible for lowering the gastric side effects of pirfenidone while the similar level of total exposure (AUC) is expected to maintain the efficacy in IPF.
  • Similar results were also seen on Day 4 or 14 after a single 550 mg dose of LYT-100 or 801 mg of pirfenidone was administered in the fasted state (Table B).
  • the Cmax of the parent and the 5-carboxy metabolite were increased to a smaller extent after LYT-100 dosing than after pirfenidone dosing.
  • Table A Pharmacokinetic Parameters of LYT-100, Pirfenidone, and 5-Carboxypirfenidone after the 3 Days of Dosing in the Fed State
  • Table B Pharmacokinetic Parameters of LYT-100, Pirfenidone, and 5-Carboxy-pirfenidone after the 3 Days of Dosing in the Fed State Followed by a Single Dose in the Fasted State on Day 4/14
  • PK studies were performed to determine dosing frequency and dose amounts that were associated with improved tolerability (compared to the currently approved treatment of IPF, e.g., pirfenidone 801 mg TID).
  • the dose that minimized AEs with a similar overall exposure level (AUC) to pirfenidone 801 mg TID was LYT-100 550 mg TID.
  • LYT-100550 mg TID and pirfenidone 801 mg TID PK and AE data were compared in the fed and fasted states (LYT- 100-2021 -103 Part 2).
  • 550 mg TID e.g., similar drug exposure level to approved 801 TID pirfenidone
  • lower AEs were observed with LYT-100 in both the fed and fasted states compared with pirfenidone.
  • LYT-100 550 mg TID was associated with improved tolerability compared to pirfenidone, including a 50% reduction in gastrointestinal-related AEs and a 45% reduction in CNS-related AEs (see Example 1 and Results for LYT-100-2021-103 Part 2 shown in Table C).
  • Table D summarizes the pharmacokinetic results and shows that at the 550 mg TID dose, the PK parameters of LYT-100 and the metabolite, 5-carboxypirfenidone were similar to those seen in Part 2 of the study at the 550 mg TID dose of LYT-100.
  • the AUCo -24 and Cmax were higher than those seen with pirfenidone; however, the corresponding parameters of the metabolite 5-carboxypirfenidone were similar/slightly lower.
  • the adverse event data shows that even at the 824 mg TID dose, the frequency of the most common adverse events was very low. The higher exposures combined with low frequency of adverse events provide the rationale for using the 825 mg TID dose of LYT-100 in the treatment of IPF.
  • Table D Pharmacokinetic Parameters of LYT-100, Pirfenidone, and 5-Carboxypirfenidone after the 3 Days of Dosing in the Fed State
  • Pirfenidone has not been tested for clinical efficacy above doses of 801 mg TID due to poor tolerability, including gastrointestinal adverse effects, nausea, weight loss, and photosensitive skin rash (among other AEs). Although some studies have been performed using higher doses of pirfenidone, well-controlled efficacy studies have not yet been done with pirfenidone doses higher than 2403 mg daily dose.
  • LYT-100 The dose of LYT-100 was optimized to achieve similar Cmax to pirfenidone 801 mg TID while maximizing drug exposure (AUC).
  • Study LYT-100-2021-103 Part 3 was a randomized, double-blinded, parallel arm, placebo-controlled study conducted in healthy older adults to evaluate the safety and tolerability of titrated high dose LYT-100 compared to placebo under fed conditions.
  • Table E summarizes the pharmacokinetic results and shows that at the 550 mg TID dose, the PK parameters of LYT-100 and the metabolite, 5-carboxypirfenidone were similar to those seen in Part 2 of the study at the 550 mg TID dose of LYT-100.
  • the AUCo -24 and Cmax were higher than those seen with pirfenidone 801 mg TID; however, the corresponding parameters of the metabolite 5-carboxypirfenidone were similar or slightly lower.
  • the adverse event data shows that even at the 824 mg TID dose, the frequency of the most common adverse events was very low. The higher exposures combined with low frequency of adverse events provide the rationale for using the 825 mg TID dose of LYT-100 in future trials of IPF.
  • Table E Pharmacokinetic Parameters of LYT-100, Pirfenidone, and 5-Carboxypirfenidone after the 3 Days of Dosing in the Fed State
  • LYT-100 824 mg TID achieved approximately 25% higher AUC with a modestly higher Cmax compared to historic pirfenidone PK values. Surpisingly, as shown in Table F, this high dose of LYT-100 (825 mg TID) was well-tolerated. Prior to completing the tolerability study shown in Table F, it was not known such high dose - 825 mg TID LYT-100 which is the equivalent of about 120-150 % exposure of 801 TID prifenidone) - could be sufficienty tolerated to be included in a clinical efficacy study.
  • LYT-100 The 550 mg TID and 825 mg TID doses of LYT-100 were optimized to key PK parameters and demonstrated to improve tolerability as compared with 2304 mg daily dose (801 mg TID) pirfenidone, surpisingly even at a higher systemic drug exposure.
  • This improved tolerability of LYT-100 relative to pirfenidone was unexpected and may significantly improve clinical efficacy outcomes for IPF patients due to improved compliance with a sustained high efficacious dose (e.g., by reducing the frequency of dose reductions, treatment interruptions, and/or temporary or permanent discontinuations currently experienced with the use of pirfenidone).
  • LYT-100 550 mg TID had much lower AUC but similar Cmax compared to Part 2 LYT-100 824 mg TID had lower AUC than predicted; Cmax was 17% higher than with pirfenidone
  • the 5- carboxy Metabolite/Parent Ratio was consistently lower with LYT-100 compared to pirfenidone (i.e., the 5-carboxy metabolite exposures are lower when comparing the same doses of LYT-100 and pirfenidone)
  • the total daily dose is administered in three equal administrations.
  • the LYT-100 is administered in three equal doses of 550 mg each (550 mg TID).
  • the LYT-100 is administered in three equal doses of 825 mg each (825 mg TID).
  • the LYT-100 is administered in three equal doses of 275 mg each (275 mg TID).
  • the LYT-100 is administered without regard to food. In some embodiments, the LYT-100 is administered without food. In some embodiments, the LYT-100 is administered with food.
  • the LYT-100 is administered orally without food in three daily doses of 550 mg each. In some embodiments, the LYT-100 is administered orally with food in three daily doses of 550 mg each.
  • the LYT-100 is administered orally without food in three daily doses of 825 mg each. In some embodiments, the LYT-100 is administered orally with food in three daily doses of 825 mg each.
  • the LYT-100 is administered orally without food in three daily doses of 275 mg each. In some embodiments, the LYT-100 is administered orally with food in three daily doses of 275 mg each.
  • the LYT-100 is administered with dose escalation, as described previously above. In some embodiments, the LYT-100 is administered without dose escalation. [0190] In some embodiments, LYT-100 administered in a total daily dose of 1650-2475, in three daily doses, results in increased tolerability as compared with pirfenidone administered at 801 mg TTD. In some embodiments, the increased tolerability is due to a reduction in one or more adverse events or side effects. In some embodiments, the one or more adverse events are nervous system side effects. In some embodiments, the one or more adverse events are gastrointestinal events. In some embodiments, the LYT-100 is administered in three daily doses of 550 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in a lower steady-state Cmax as compared with pirfenidone administered at 801 mg TID.
  • the LYT-100 is administered in three daily doses of 550 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in a steady-state exposure (AUC) of LYT-100 which is the same or about the same as the steady-state exposure (AUC) of pirfenidone achieved when pirfenidone is administered at 801 mg TID.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in a steady-state exposure (AUC) of LYT-100 which is bioequivalent to the steady-state exposure (AUC) of pirfenidone when pirfenidone is administered at 801 mg TID.
  • the LYT-100 is administered in three daily doses of 550 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in the same or about the same steady-state exposure (AUC) of LYT-100 achieved for pirfenidone when pirfenidone is administered at 801 mg TID, and results in a lower steady-state Cmax of LYT-100 achieved for pirfenidone when pirfenidone is adminsitered at 801 mg TID.
  • AUC steady-state exposure
  • the steady-state exposure of LYT-100 is about 90% of the AUC of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, and wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the lower steady-state Cmax of LYT-100 is about 75-80% of the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, and wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the LYT-100 has an increased or improved tolerability that is due to a reduction in one or more adverse events or side effects as compared with pirfenidone administered at 801 mg TID. In some embodiments, the LYT-100 is administered in three daily doses of 550 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in the same or about the same steady-state exposure (AUC) as compared with pirfenidone administered at 801 mg TID and increased or improved tolerability as compared with pirfenidone adminsitered at 801 mg TID.
  • AUC steady-state exposure
  • the increased or improved tolerability is due to a reduction in one or more adverse events or side effects.
  • LYT-100 is administered in three daily doses of 550 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in a higher steady-state exposure (AUC) as compared with pirfenidone administered at 801 mg TID.
  • the LYT-100 is administered in three daily doses of 825 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in the same or about the same steady-state Cmax as compared with pirfenidone administered at 801 mg TID.
  • the LYT-100 is administered in three daily doses of 825 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in a higher steady-state exposure (AUC) as compared with pirfenidone administered at 801 mg TID and the same or about the same steady-state Cmax as compared with pirfenidone administered at 801 mg TID.
  • the LYT-100 is administered in three daily doses of 825 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in a higher steady-state exposure (AUC) as compared with pirfenidone administered at 801 mg TID and has the same or about the same tolerability (e.g., the incidence of adverse events is not significantly different) as compared with pirfenidone administered at 801 mg TID.
  • AUC steady-state exposure
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in a higher steady-state exposure (AUC) as compared with pirfenidone administered at 801 mg TID and has an increased or improved tolerability that is due to a reduction in one or more adverse events or side effects.
  • the LYT-100 is administered in three daily doses of 825 mg each.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in the same or about the same steady-state Cmax as compared with pirfenidone administered at 801 mg TID and has the same or about the same tolerability (e.g., the incidence of adverse events is not significantly different) as compared with pirfenidone administered at 801 mg TID.
  • LYT-100 administered in a total daily dose of 1650-2475, in three daily doses results in the same or about the same steady-state Cmax as compared with pirfenidone administered at 801 mg TID and has an increased or improved tolerability that is due to a reduction in one or more adverse events or side effects.
  • the LYT-100 is administered in three daily doses of 825 mg each.
  • the LYT-100 is administered at a dose that achieves a systemic exposure of LYT-100 in the subject which is about 85-125% of the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, and wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the dose of LYT-100 that achieves the systemic exposure of LYT-100 in the subject which is about 85-125% of the systemic exposure of pirfenidone is 825 mg TID.
  • the dose of LYT-100 that achieves the systemic exposure of LYT-100 in the subject which is about 85-125%of the systemic exposure of pirfenidone also achieves a Cmax of LYT-100 in the subject which is about 115 - 125% of the Cmax of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, and wherein the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).
  • the LYT-100 has the same or about the same tolerability (e.g., the incidence of adverse events is not significantly different) as compared with pirfenidone administered at 801 mg TID. In some embodiments, at this dosing, the LYT-100 has an increased or improved tolerability that is due to a reduction in one or more adverse events or side effects as compared with pirfenidone administered at 801 mg TID. In some embodiments, the LYT-100 is administered in three daily doses of 825 mg each.
  • Impaired respiratory function may be determined by one or more of oximetry, reduced forced expiratory volume in one second (FEV1), reduced forced vital capacity (FVC), and reduced FEV1/FVC ratio.
  • the terms “reduced blood oxygen saturation”, “reduced forced expiratory volume in one second (FEV1)”, “reduced forced vital capacity (FVC)”, or “reduced FEV1/FVC ratio” mean, respectively, a blood oxygen saturation, a forced expiratory volume in one second (FEV1), a forced vital capacity (FVC), or a FEV1/FVC ratio that is reduced or lower than that found in a subject with normal or healthy lungs.
  • the method disclosed herein provides an improvement in the rate of decline in Forced Vital Capacity (FVC; in mL) over a period of treatment of 26 weeks, relative to the rate of decline in a subject treated with pirfenidone at 801 mg TID.
  • FVC Forced Vital Capacity
  • the method disclosed herein prevents or delays the progression of or reduces (lessens, slows) the progression of impaired respiratory function in the subject as determined by a minimal decline in Forced Vital Capacity % (FVC%) change over a 26-week treatment period.
  • FVC% Forced Vital Capacity %
  • the decline in FVC% predicted from baseline to week 26 is less than about 10%. In some embodiments, the decline in FVC% predicted from baseline to week 26 is less than about 5%
  • the method disclosed herein increases a time to IPF progression as defined by a decline in FVC% of 5% or greater over a 26-week treatment period. In some embodiments, the method disclosed herein increases a time to IPF progression as defined by a decline in FVC% of 10% or greater over a 52-week treatment period.
  • the method disclosed herein increases a time to hospitalization due to respiratory cause over a 26-week treatment period.
  • the method disclosed herein lengthens a time to mortality due to respiratory cause relative to that in a subject who has not received treatment according to the disclosed method.
  • the treatment efficacy may be evaluated through the King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score. In some embodiments, an improvement in the change from baseline to Week 26 in the K-BILD total score is observed, relative to a subject who has not received treatment according to the disclosed method.
  • the treatment efficacy may be evaluated through the Saint George Respiratory Questionnaire-I (SGRQ-I).
  • SGRQ-I is an idiopathic pulmonary fibrosis disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with interstitial lung disease. There are 34 self-completed items with 3 domain component scores (Symptoms, Activities, and Impacts). Higher scores indicate more limitations.
  • an improvement in the change from baseline to Week 26 in the Saint George Respiratory Questionnaire-I (SGRQ-I) domain score is observed.
  • the treatment efficacy may be evaluated through the EuroQol 5-Dimensional (EQ5D) Questionnaire score.
  • the EQ-5D is an instrument developed in Europe and widely used for evaluation of the generic health-related quality of life.
  • the EQ-5D is a preference-based HRQL measure with one question for each of five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
  • the responses can be converted into EQ-5D utility score anchored at 0 for death and 1 for perfect health.
  • the EQ-5D questionnaire also includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst possible health status) to 100 (the best possible health status).
  • VAS Visual Analog Scale
  • an improvement in the change from baseline to Week 26 in the EQ5D score is observed.
  • an improvement in one or more of the following is observed, relative to a subject who has not received treatment according to the disclosed method:
  • VAS cough visual analog scale
  • the patient experiences, relative to treatment with pirfenidone, one or more of: reduced frequency of dose modifications (reductions and interruptions), time to first dose modification (reduction or interruption), reduced duration of adverse events of special interest, increased time to treatment discontinuation due to an adverse event of special interest, and improvement in a patient reported assessment of symptoms and satisfaction.
  • the subject has Idiopathic Pulmonary Fibrosis based on high resolution computed tomography (HRCT), performed within 12 months of initiating treatment;
  • HRCT high resolution computed tomography
  • the subject does not have any of the following, or none of the following apply, prior to initiating treatment: AST, ALT > 1.5 x ULN; bilirubin > 1.5 x ULN; creatinine clearance ⁇ 30 mL/min calculated by Cockcroft-Gault formula; underlying chronic liver disease (Child Pugh B or C hepatic impairment); prior allergic reaction to pirfenidone; received other investigational therapy within 1 month; significant Pulmonary Arterial Hypertension (PAH) defined by any of the following: a) previous clinical or echocardiographic evidence of significant right heart failure, b) history of right heart catheterization showing a cardiac index ⁇ 2 1/min/m 2 , c) PAH requiring parenteral therapy with epoprostenol/treprostinil; primary obstructive airway physiology (pre-bronchodilator FEV1/FVC ⁇ 0.7); known explanation for interstitial lung disease, including but not limited to radiation,
  • the subject has not used any of the following drugs: strong and moderate CYP1 A2 inhibitors (i.e. ciprofloxacin, fluvoxamine, verapamil, or enoxacin); strong and moderate inducers of CYP1A2 (e.g., St.
  • Johns Wort or phenytoin drugs associated with substantial risk for prolongation of the QTc interval (including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol); warfarin, imatinib, ambrisentan, azathioprine, cyclophosphamide, cyclosporin A, bosentan, methotrexate, sildenafil (except for occasional use), prednisone at steady dose > 10 mg/ day or equivalent; or tobacco products.
  • drugs associated with substantial risk for prolongation of the QTc interval including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol
  • warfarin imatinib, ambrisentan, azathioprine, cyclophosphamide, cyclosporin A, bosentan, methotrexate, sildenafil (except for occasional use), prednisone at steady dose > 10 mg/
  • the subject does not have a current immunosuppressive condition (e.g. human immunodeficient virus).
  • a current immunosuppressive condition e.g. human immunodeficient virus.
  • Idiopathic Pulmonary Fibrosis comprising administering to a subject in need thereof a deuterium-enriched pirfenidone having the structure: at a first total daily dose of 825 mg for a first period, a second total daily dose of 1650 mg for a second period, and a total daily dose of 2475 mg for a maintenance period, wherein IPF is treated in the subject.
  • the first period and the second period are 7 days each.
  • the LYT-100 is administered as 275 mg capsules or tablets.
  • the daily dosage is titrated to the maintenance dosage over a two- week period as follows:
  • the first period, the second period, or both may be extended longer than 1 week.
  • the first period and the second period are each 14 days.
  • adverse events do not increase as the dose increases. In some embodiments, adverse events decrease as the dose increases. In some embodiments, there are no AEs at the maintenance dose. These AEs may be one or more GI AEs, e.g., selected from nausea, vomiting, diarrhea, dyspepsia, abdominal pain, abdominal discomfort, and abdominal distention. These AEs may be nervous system AEs, e.g., headache or dizziness, or both. In some embodiments, IPF is treated with mild or no AEs. In some embodiments, the subject is treated for IPF, and the treatment is not interrupted or discontinued due to adverse events.
  • the method includes temporary dosage reduction, treatment interruption, or discontinuation for management of adverse reactions, drug interactions, or in response to altered liver function (e.g., as determined by a liver function test indicative of hepatic impairment).
  • the dose may be reduced from 2475 mg/day to 1650 mg/day or 825 mg/day.
  • the reduction may be in the form of a titration down over a period of days, e.g., as described above for titration to the maintenance or full dose, but in a reverse order, or dosing may be interrupted entirely.
  • dosing may be interrupted temporarily.
  • dosing may be permanently discontinued.
  • the method includes re- initiating treatment by undergoing the above titration regimen over two weeks, up to the full maintenance dosage.
  • the method includes interrupting dosing, e.g., due to elevated liver enzymes, and thereafter resuming the dosage prior to treatment or re-titrating back up to the maintenance dosage.
  • the method includes reducing the dosage to 825 mg/day or 1650 mg/day, and maintaining this dose as a new maintenance dose.
  • the method comprises obtaining the results of a liver function test for the subject prior to administration of LYT-100. In some embodiments, the method comprises obtaining the results of a liver function test after administering LYT-100 to the subject. In some embodiments, the method includes obtaining the results of liver function tests periodically for the subject.
  • the method includes reducing or interrupting dosing of LYT- 100 due to elevated liver enzymes.
  • a subj ect after being administered LYT- 100, exhibits >3 but ⁇ 5 x the upper limit of normal (ULN) ALT and/or AST without exhibiting symptoms or hyperbilirubinemia, the method including discontinuing confounding medications, excluding other causes, and monitoring the patient closely; repeating liver chemistry tests; and maintaining, reducing, or interrupting dosing, with subsequent re-titration to the maintenance dose or a lower dose.
  • the subject exhibits >3 but ⁇ 5 x ULN ALT and/or AST accompanied by symptoms or hyperbilirubinemia, the method including permanently discontinuing LYT-100. In some embodiments, the subject exhibits >5 x ULN ALT and/or AST, the method including permanently discontinuing LYT-100.
  • IPF a prominent feature of the disease is impaired respiratory function, resulting in reduced blood oxygen saturation.
  • the method disclosed herein prevents or reduces the progression of impaired respiratory function in a subject, including a human subject, having IPF.
  • Impaired respiratory function may be determined by one or more of oximetry, reduced forced expiratory volume in one second (FEV1), reduced forced vital capacity (FVC), and reduced FEV1/FVC ratio.
  • FEV1 reduced forced expiratory volume in one second
  • FVC reduced forced vital capacity
  • FEV1/FVC ratio reduced mean, respectively, a blood oxygen saturation, a forced expiratory volume in one second (FEV1), a forced vital capacity (FVC), or a FEV1/FVC ratio that is reduced or lower than that found in a subject with normal or healthy lungs.
  • the method disclosed herein provides an improvement in the rate of decline in Forced Vital Capacity (FVC; in mL) over a period of treatment of 26 weeks, relative to the improvement in rate of decline in a subject treated with pirfenidone at 801 mg TID.
  • the method disclosed herein prevents the progression of or reduces the progression of impaired respiratory function in the subject as determined by a minimal decline in Forced Vital Capacity % (FVC%) change over a 26-week treatment period.
  • the decline in FVC% predicted from baseline to week 26 is less than about 10%.
  • the decline in FVC% predicted from baseline to week 26 is less than about 5%
  • the method disclosed herein increases a time to IPF progression as defined by a decline in FVC% of 5% or greater over a 26-week treatment period. In some embodiments, the method disclosed herein increases a time to IPF progression as defined by a decline in FVC% of 10% or greater over a 26-week treatment period.
  • the method disclosed herein increases a time to hospitalization due to respiratory cause over a 26-week treatment period.
  • the method disclosed herein lengthens a time to mortality due to respiratory cause relative to that in a subject who has not received treatment according to the disclosed method.
  • the treatment efficacy may be evaluated through the King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score.
  • K-BILD King's Brief Interstitial Lung Disease Questionnaire
  • an improvement in the change from baseline to Week 26 in the K-BILD total score is observed, relative to a subject who has not received treatment according to the disclosed method.
  • the treatment efficacy may be evaluated through the Saint George Respiratory Questionnaire-I (SGRQ-I).
  • SGRQ-I is an idiopathic pulmonary fibrosis disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with interstitial lung disease.
  • an improvement in the change from baseline to Week 26 in the Saint George Respiratory Questionnaire-I (SGRQ-I) domain score is observed.
  • the treatment efficacy may be evaluated through the EuroQol 5-Dimensional (EQ5D) Questionnaire score.
  • the EQ-5D is an instrument developed in Europe and widely used for evaluation of the generic health-related quality of life.
  • the EQ-5D is a preference-based HRQL measure with one question for each of five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
  • the responses can be converted into EQ-5D utility score anchored at 0 for death and 1 for perfect health.
  • the EQ-5D questionnaire also includes a Visual Analog Scale (VAS), by which respondents can report their perceived health status with a grade ranging from 0 (the worst possible health status) to 100 (the best possible health status).
  • VAS Visual Analog Scale
  • an improvement in the change from baseline to Week 26 in the EQ5D score is observed.
  • an improvement in one or more of the following is observed, relative to a subject who has not received treatment according to the disclosed method:
  • VAS cough visual analog scale
  • reduced frequency of dose modifications reductions and interruptions
  • time to first dose modification reduction or interruption
  • reduced duration of adverse events of special interest increased time to treatment discontinuation due to an adverse event of special interest
  • improvement in a patient reported assessment of symptoms and satisfaction are provided.
  • the subject has Idiopathic Pulmonary Fibrosis diagnosed by a physician based on ATS/ERS/JRS/ALAT 2018 guidelines;
  • the subject has Idiopathic Pulmonary Fibrosis based on high resolution computed tomography (HRCT), performed within 12 months of initiating treatment;
  • HRCT high resolution computed tomography
  • the subject has a clinically significant decline in DLCO corrected for hemoglobin >30% predicted of normal prior to initiating treatment.
  • the subject has FVC > 45% predicted prior to initiating treatment.
  • the subject does not have any of the following, or none of the following apply, prior to initiating treatment: AST, ALT > 1.5 x ULN; bilirubin > 1.5 x ULN; creatinine clearance ⁇ 30 mL/min calculated by Cockcroft-Gault formula; underlying chronic liver disease (Child Pugh B or C hepatic impairment); currently treated with nintedanib or pirfenidone; prior allergic reaction to pirfenidone; received other investigational therapy within 1 month; significant Pulmonary Arterial Hypertension (PAH) defined by any of the following: a) previous clinical or echocardiographic evidence of significant right heart failure, b) history of right heart catheterization showing a cardiac index ⁇ 2 1/min/m 2 , c) PAH requiring parenteral therapy with epoprostenol/treprostinil; primary obstructive airway physiology (pre-bronchodilator FEV1/FVC ⁇ 0.7
  • the subject has not used any of the following drugs: strong and moderate CYP1 A2 inhibitors (i.e. ciprofloxacin, fluvoxamine, verapamil, or enoxacin); strong and moderate inducers of CYP1A2 (e.g., St.
  • Johns Wort or phenytoin drugs associated with substantial risk for prolongation of the QTc interval (including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol); warfarin, imatinib, ambrisentan, azathioprine, cyclophosphamide, cyclosporin A, bosentan, methotrexate, sildenafil (except for occasional use), prednisone at steady dose > 10 mg/ day or equivalent; or tobacco products.
  • drugs associated with substantial risk for prolongation of the QTc interval including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol
  • warfarin imatinib, ambrisentan, azathioprine, cyclophosphamide, cyclosporin A, bosentan, methotrexate, sildenafil (except for occasional use), prednisone at steady dose > 10 mg/
  • the subject does not have a current immunosuppressive condition (e.g. human immunodeficient virus).
  • a current immunosuppressive condition e.g. human immunodeficient virus.
  • Examples 1 and 2 provide crossover studies comparing the safety, tolerability, and pharmacokinetics of deupirfenidone (LYT-100) and pirfenidone.
  • Example 3 provides a study exploring tolerability of the deuterated pirfenidone LYT-100 in patients with COVID-19 Respiratory Illness.
  • Example 4 provides a study exploring the efficacy, tolerability and safety of the deuterated pirfenidone LYT-100 in patients with Idiopathic Pulmonary Fibrosis.
  • Example 5 provides the CYP isozyme profile of pirfenidone and LYT-100.
  • Example 6 provides a BioMAP Fibrosis Panel screening study for LYT-100 and pirfenidone across a series of fibrosis biomarkers.
  • Example 7 provides a study exploring the efficacy of LYT-100 in a bleomycin rat model of pulmonary fibrosis.
  • This study waq a double-blind, randomized, two-period crossover study in older, healthy subjects to compare the safety, tolerability, and pharmacokinetics of deupirfenidone (LYT- 100) and pirfenidone.
  • the crossover study was performed at a single Study Center per Part in the United States.
  • Part 1 was a randomized, double-blinded, two period crossover study conducted in healthy older adults to compare the safety, tolerability, and pharmacokinetics of deupirfenidone (LYT-100) with twice daily (BID) dosing of LYT-100 to pirfenidone.
  • LYT-100 deupirfenidone
  • BID twice daily
  • Part 2 was a randomized, double-blinded, two period crossover study conducted in healthy older adults to compare the safety, tolerability, and pharmacokinetics of deupirfenidone (LYT-100) with three times daily (TID) dosing of LYT-100 to pirfenidone.
  • Treatment-emergent adverse events including severity, and relatedness to study drug
  • ECGs Electrocardiograms
  • Clinical laboratory parameters including hematology, serum chemistry, coagulation, and urinalysis
  • Part 1 was a double-blind, randomized, two-period crossover study conducted in older, healthy subjects to determine the safety, tolerability, and PK of LYT-100 administered twice daily (BID) for 3 days (to steady state [Day 1 to Day 3 and Day 11 to Day 13]) compared to pirfenidone administered 3 times daily (TID) for 3 days (to steady state) under fed conditions.
  • BID twice daily
  • TID 3 times daily
  • a final single dose of study drug (LYT 100 or pirfenidone) was administered on the morning of the fourth day in each treatment period (Day 4/Day 14) following an overnight fast of at least 8 hours to determine the effect of food on steady state PK parameters.
  • the initial dose of LYT-100 for this crossover study directly comparing LYT-100 to pirfenidone in healthy adults was 850 mg BID LYT-100 (1700 mg daily dose) vs. 801 mg TID pirfenidone (2403 mg daily dose).
  • the 850 mg BID LYT-100 (1700 mg daily dose) was selected based on the PK results from earlier studies.
  • PK modelling work using data from the multiple ascending dose study and a single-dose crossover study of LYT-100 and pirfenidone indicated that a dose of LYT-100 of approximately 800-850 mg BID (1600-1700 mg daily dose) results in a similar systemic exposure to the marketed dose of pirfenidone (2403 mg daily dose).
  • the study is blinded with a placebo mid-day dose for LYT-100 to match TID pirfenidone dosing.
  • the 850 mg BID dose was selected as a match to the exposure for pirfenidone based on the outcome of the earlier PK crossover study, which indicated that an 850 mg BID daily dose of LYT-100 has about 102% of the steady-state systemic exposure of pirfenidone dosed daily at 801 mg TID.
  • Part 2 was a double-blind, randomized, two-period crossover study conducted in older healthy subjects to determine the safety, tolerability, and PK of LYT-100 administered three times daily (TID) for 3 days (to steady state [Day 1 to Day 3 and Day 11 to Day 13]) compared to pirfenidone administered TID for 3 days (to steady state) under fed conditions.
  • TID three times daily
  • a final single dose of study drug (LYT-100 or pirfenidone) was administered on the morning of the fourth day in each treatment period (Day 4 / Day 14) following an overnight fast of at least 8 hours to determine the effect of food on steady state PK parameters. Over-encapsulation was utilized to maintain study blind.
  • FIG. 3 A graphical illustration of the study design for Part 2 is provided as FIG. 3. Dosing is outlined in Table 2.
  • a Pirfenidone AM dose: 3 x 267 mg, mid-day dose: 3 x 267 mg, PM dose: 3 x 267 mg.
  • AM, mid-day, and PM doses are over-encapsulated to maintain study blind.
  • Placebo capsules are administered as needed to match the number of LYT-100 capsules in order to maintain the blind.
  • Each cohort starting concurrently or closely staggered.
  • the LYT-100 dose for this crossover study directly comparing LYT-100 to pirfenidone in healthy adults was 550 mg TID LYT-100 (1650 mg daily dose) vs. 801 mg TID pirfenidone (2403 mg daily dose).
  • the 550 mg TID LYT-100 (1650 mg daily dose) was selected based on the PK results from earlier studies and the PK results obtained in Part 1 of this study.
  • PK modelling work using data from the multiple ascending dose study the single-dose crossover study of LYT-100 and pirfenidone and Part 1 of this study indicated that a dose of LYT-100 550 mg TID (1650 mg daily dose) results in a similar systemic exposure to the marketed dose of pirfenidone (2403 mg daily dose). Particularly, it was predicted that a dose of 550 TID LYT-100 (1650 mg total daily dose) would achieve a steady-state systemic exposure that is about 99% of the steady- state systemic exposure observed for pirfenidone dosed at 801 mg TID.
  • AUC24ss for LYT-100 dosed at 550 TID is 98.5% of the steady-state systemic exposure (AUC24ss) of pirfenidone dosed at 801 mg TID.
  • the Cmax for LYT-100 dosed at 550 mg TID is predicted to be lower than the pirfenidone Cmax resulting from pirfenidone administered at 801 mg TID.
  • FIG. 5 shows that the predicted steady-state Cmax for LYT- 100 dosed at 550 mg TID is 67.4% of the steady-state Cmax for pirfenidone dosed at 801 mg TID.
  • the lower Cmax of LYT-100 may contribute to the enhanced tolerability of LYT-100 relative to pirfenidone.
  • Treatment Period 1 (Day -1 to Day 4) Parts 1 and 2
  • Subjects were admitted to the Clinical Research Unit (CRU) on Day -1 of Treatment Period 1 and were administered their assigned study drug (pirfenidone or LYT-100, with or without matching placebo) every 6 hours for 3 days until steady state (Day 1 to Day 3) under fed conditions. Subjects were then administered a single dose of their randomized treatment (pirfenidone or LYT-100, with or without matching placebo) on the morning of Day 4 following an overnight fast of at least 8 hours. Subjects were discharged on Day 4 following successful completion of all assessments and at the Investigator’s discretion.
  • CRU Clinical Research Unit
  • Treatment Period 2 (Dav 11 to Dav 14) Parts 1 and 2
  • Subjects have a body mass index (BMI) between > 18.0 and ⁇ 35.0 kg/m 2 at screening.
  • BMI body mass index
  • Symptoms of dysphagia at screening or baseline or known difficulty in swallowing capsules Any condition at screening or baseline (e.g., chronic diarrhoea, inflammatory bowel disease or prior surgery of the gastrointestinal tract) that would interfere with drug absorption or any disease or condition that is likely to affect drug metabolism or excretion, at the discretion of the Investigator. History or presence at screening or baseline of cardiac arrhythmia or congenital long QT syndrome. QT interval corrected using Fridericia’s formula (QTcF) > 450 msec. ECG may be repeated30 to 60 minutes apart from the first one collected at screening. If repeat ECG is ⁇ 450 msec, the second ECG may be used to determine patient eligibility.
  • Fridericia formula (QTcF) > 450 msec.
  • LYT-100 (Deupirfenidone) was provided as hard gelatin capsules. LYT-100 was stored at a controlled room temperature of 15°C to 25°C.
  • Pirfenidone (Esbriet) was provided as white to off-white hard gelatin capsules contain 267 mg of pirfenidone.
  • This study included a 28-day Screening period, two treatment periods (each 4 days in duration) with a minimum 7-day washout period between treatment periods, and a 3-day ( ⁇ 1 day) post-last-dose safety follow-up visit. Thus, total duration of study participation for each subject was approximately 50 days. Treatment with double-blind study medication was 4 days for each of the two treatment periods, 8 days in total.
  • Safety and tolerability was assessed by monitoring AEs, physical examination, vital signs, 12-lead ECGs, clinical laboratory values (hematology panel, multiphasic chemistry panel and urinalysis), and review of concomitant treatments/medication use.
  • Subjects provided blood samples prior to treatment, i.e., Day -1 or Day 1 in Treatment Period 1, for the determination of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotype to support exploratory PK analyses. Subjects were required to provide consent for genotyping.
  • Days 3 & 13 0 (pre-morning dose), and 1, 2, 3, 4, 6 (pre-mid-day dose), 7, 8, 9, 10, 12 (pre-evening dose), 13, 14, 15, 16, and 17 hours post-morning dose
  • Plasma PK parameters for steady state dosing included, but are not limited to:
  • T max time to maximum concentration, as reported relative to the beginning of a dosing interval in which maximum concentration occurred
  • Plasma PK parameters for food effect analysis included, but are not limited to:
  • Urine samples for PK were collected for Cohorts 1 and 2 at specified intervals during both treatment periods, as follows: • Days 1 and 11 : pre-dose (subjects instructed to empty their bladders approximately
  • Urine samples for analysis of excretion in urine were collected, separated by specified time interval, and analyzed. The total volume of urine collected in each interval (tl to t2) was noted.
  • the urine PK parameters included, but are not limited to:
  • ECGs Electrocardiograms
  • the Part 1 study was conducted in healthy older adults as relevant age group for IPF. Overall, the head-to-head crossover study of Part 1 was designed at least in part to evaluate the tolerability impact of reducing exposure to the major metabolite. To this end, thirty-seven subjects were randomized in the blinded crossover study to receive 850 mg BID LYT-100 or 801 mg TID pirfenidone with three days of fed dosing and a 4 th day morning fasted dose. With reference to FIG. 6A, the Cmax and AUC of parent drug for 850 mg BID LYT-100 were very similar to that of parent drug for 801 mg TID pirfenidone.
  • the steady-state AUC and with 850 mg BID dosing was 102% AUC compared with the steady-state AUC for pirfenidone dosed at 801 mg TID and the steady-state Cmax achieved was 104% of the Cmax of the steady-state Cmax for pirfenidone dosed at 801 mg TID.
  • Fasting increased the Cmax.
  • the major metabolite (5-carboxypirfenidone) exposure was reduced for 850 mg BID LYT-100 relative to that when pirfenidone was dosed at 801 mg TID.
  • FIG. 6B The adverse events encountered in each treatment group are provided in FIG. 6B, which shows that no serious adverse events occurred in either group, and similar types of AEs were observed across both groups. No clinically meaningful differences between LYT-100 and pirfenidone in overall AE rates.
  • the adverse events in both groups were primarily GI and nervous system, with nervous system AEs including headache and dizziness.
  • fasting increased Cmax and was hypothesized to increase overall GI AE rates.
  • FIG. 6B and with reference to FIG. 6A, the results of this study show that reducing exposure to the major metabolite did not improve tolerability.
  • Part 2 was a double-blind, randomized, two-period crossover study conducted in older healthy subjects to determine the safety, tolerability, and PK of 550 mg of LYT-100 administered three times daily (TID) for 3 days (to steady state [Day 1 to Day 3 and Day 11 to Day 13]) compared to pirfenidone administered 801 mg TID for 3 days (to steady state) under fed conditions.
  • TID three times daily
  • pirfenidone 801 mg TID for 3 days (to steady state) under fed conditions.
  • a final single dose of study drug (LYT-100 or pirfenidone) was administered on the morning of the fourth day in each treatment period (Day 4 / Day 14) following an overnight fast of at least 8 hours to determine the effect of food on steady state PK parameters.
  • the mean age of the overall population was 67.7; the mean age was similar in Cohorts 1 and 2 (68.5 and 66.9 years, respectively). The majority of subjects were female (53.1%; 52.2% in Cohort 1, 53.8% in Cohort 2), predominately white (81.6%), and the average BMI was 27.9 kg/m 2 .
  • the overall mean number of days of dosing with LYT-100 was 4.0 days (4.0 days in Cohort 1, 3.9 days in Cohort 2).
  • the mean number of days of dosing with pirfenidone was 3.9 days (4.0 days in Cohort 1 and 3.9 days in Cohort 2).
  • FIG. 7 provides a graphical illustration of the reduction in GI and nervous system symptoms for LYT-100 at 550 mg TID versus pirfenidone at 801 mg TID in this patient population.
  • fifty percent fewer subjects experienced Gl-related AEs with LYT-100 compared to pirfenidone (17.4% versus 34.0%, respectively), including 50% fewer with nausea (15.2% versus 29.8%).
  • LYT-100-treated subjects who experienced at least 1 TEAE under fed conditions and 8 (17.8%) subjects under fasted conditions. There were 10 (21.3%) pirfenidone-treated subjects under fed conditions and 17 (37.0%) subjects under fasted conditions who experienced at least one TEAE.
  • a summary of the most common TEAEs (>10%) under fed and fasted conditions is provided in Table 7 for each study medication.
  • This study was a double-blind, randomized, two-period crossover study in older, healthy subjects to compare the safety, tolerability, and pharmacokinetics of deupirfenidone (LYT- 100) and pirfenidone.
  • the crossover study was performed at a single Study Center per Part in the United States.
  • This study was a randomized, double-blinded, parallel arm, placebo-controlled study conducted in healthy older adults to evaluate the safety and tolerability compared to placebo of a dose of LYT-100 that provides an exposure of LYT-100 which is approximately 150% of the exposure of pirfenidone when dosed at 801 mg TID and did not exceed 850 mg TID LYT-100. Study Endpoints
  • Treatment-emergent adverse events including severity, and relatedness to study drug
  • ECGs Electrocardiograms
  • Comparison of the key PK parameters (C ma x,ss, Cmin,ss, and AUC 0- 24,ss) between the parent compound (LYT-100 and pirfenidone) and primary metabolite (5- carboxypirfenidone). Other PK parameters will also be derived and compared. Comparison of the key urine PK parameters (Ae t1-t2 , CLR, Fe t1-t2 ) between the parent compound (LYT-100 and pirfenidone) and primary metabolite (5-carboxypirfenidone). Other urine PK parameters may be derived and compared.
  • Subjects have a body mass index (BMI) between > 18.0 and ⁇ 35.0 kg/m 2 at screening.
  • BMI body mass index
  • Symptoms of dysphagia at screening or baseline or known difficulty in swallowing capsules Any condition at screening or baseline (e.g., chronic diarrhoea, inflammatory bowel disease or prior surgery of the gastrointestinal tract) that would interfere with drug absorption or any disease or condition that is likely to affect drug metabolism or excretion, at the discretion of the Investigator. History or presence at screening or baseline of cardiac arrhythmia or congenital long QT syndrome. QT interval corrected using Fridericia’s formula (QTcF) > 450 msec. ECG may be repeated30 to 60 minutes apart from the first one collected at screening. If repeat ECG is ⁇ 450 msec, the second ECG may be used to determine patient eligibility. However, if repeat ECG confirms QTcF remains >450msec, the subject is not eligible. 13. Use of tobacco or nicotine containing products in the previous 3 months prior to dosing or a positive urine cotinine test at Screening or Baseline.
  • Fridericia formula
  • Pirfenidone (Esbriet) was provided as white to off-white hard gelatin capsules contain 267 mg of pirfenidone. The cap of the capsule is printed with “PFD 267 mg” in brown ink. Pirfenidone should be stored at 15°C to 25°C.
  • This study included a 28-day Screening period, a 6-day treatment period consisting of: 3 days of up to 550 mg TID LYT-100 followed directly by 3 days of 824 mg TID LYT-100, or placebo. A 3-day ( ⁇ 1 day) post-last-dose safety follow-up visit occured. Thus, total duration of study participation for each subject was up to 40 days.
  • Safety and tolerability were assessed by monitoring AEs, physical examination, vital signs, 12-lead ECGs, clinical laboratory values (hematology panel, multiphasic chemistry panel and urinalysis), and review of concomitant treatments/medication use.
  • Subjects provided blood samples prior to treatment, i.e., Day -1 or Day 1, for the determination of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotype to support exploratory PK analyses. Subjects were required to provide consent for genotyping. Blood samples for PK were collected at specified times, as follows:
  • Plasma concentration-time data for LYT-100, and its metabolite(s) were analyzed using noncompartmental methods.
  • Plasma PK parameters for steady state dosing included, but were not limited to:
  • T max time to maximum concentration, as reported relative to the beginning of a dosing interval in which maximum concentration occurred
  • Urine samples for PK were collected at specified intervals, as follows:
  • Days 3 and 6 pre-dose (subjects to be instructed to empty their bladders approximately 30 minutes prior to dosing), 0 to 4, 4 to 8, 8 to 12, 12 to 16, and 16 to 24 hours post-AM dose
  • Urine samples for analysis of excretion in urine will be collected, separated by specified time interval, and analyzed. The total volume of urine collected in each interval (t1 to t2) will be noted.
  • ECGs Electrocardiograms
  • Subjects between the ages of 60 and 80 were randomized to receive LYT-100 or placebo. Subjects were administered up to 550 mg LYT-100 TID for 3 days (to steady state [Day 1 to Day 3]) compared to placebo administered TID for 3 days to steady state. On Day 4 to Day 6, subjects were administered 824 mg LYT-100 TID for 3 days compared to placebo TID for 3 days to steady state.
  • Table 9 A summary of the dosing scheme is provided in Table 9.
  • FIG. 8A to FIG. 19B The results for the pharmacokinetic assessments are provide in FIG. 8A to FIG. 19B.
  • the plasma concentrations for both the parent drug (LYT-100; SD-560) and major metabolite (5-carboxypirfenidone; SD-789) were higher for the 824 mg TID dose cohort (FIGS. 8B and 8D) relative to the 550 mg TID dose cohort (FIGS. 8A and 8C).
  • the Cmax, AUC, and T ma x values in the fed state for LYT-100 and the major metabolite at the 550 mg and 824 mg TID doses are provided in FIG. 9.
  • FIG. 9 With reference to FIG.
  • FIG. 11 provides a comparison of plasma concentrations of LYT-100 (dosed at 550 mg and 824 mg TID) and pirfenidone (dosed at 801 mg TID) versus time following the day 3 doses.
  • the concentration peaks for pirfenidone are higher than those for 550 mg LYT-100.
  • FIG. 12 provides a comparison of plasma concentrations of the major metabolite of LYT-100 (dosed at 550 mg and 824 mg TID) and pirfenidone (dosed at 801 mg TID) versus time following the day 3 doses.
  • FIG. 12 provides a comparison of plasma concentrations of the major metabolite of LYT-100 (dosed at 550 mg and 824 mg TID) and pirfenidone (dosed at 801 mg TID) versus time following the day 3 doses.
  • FIG. 13 provides a comparison of plasma concentrations versus time for pirfenidone at 801 mg TID and LYT-100 at 550 mg TID following the day 3 doses.
  • FIG. 14A provides a comparison of AUC0-24 versus body weight for LYT-100 administration across this and previous studies.
  • FIG. 14B provides a comparison of AUC0-24 versus body weight for the major metabolite of LYT-100 across this and previous studies. With reference to FIGS. 14A and 14B, a similar trend for impact of body weight was observed across all three groups, with an apparent exposure difference above and below a threshold of 70-75 kg.
  • FIGS. 15A and 15B provide a comparison of AUC0-24 versus subject age for LYT- 100 and the major metabolite, respectively, across this and previous studies. With reference to FIGS. 15A and 15B, age appears to impact AUC, with exposure increasing with age.
  • FIG. 19A An illustrative prediction of plasma concentration over time for theoretical 550 mg TID and 825 mg TID dosing of LYT-100 and 801 mg TID dosing of pirfenidone is provided in FIG. 19A.
  • Cmax maximal plasma concentration
  • AUC exposure
  • TEAEs stratified by onset day 1 to 3 or day 4 to 6 showed that the onset of the COVID-19 events occurred within days 4 to 6; the onset of the headache events occurred within days 1 to 3. Overall, the majority of TEAEs were considered to be mild. There were 13 mild events reported by 8 (26.7%) subjects, 7 (29.2%) in the LYT-100 group and 1 (16.7%) in the placebo group. Two moderate TEAEs were reported by one (3.3%) subject; this subject was in the LYT-100 group. No TEAEs were severe. TEAEs were unrelated for 5 (16.7%) events and possibly related for 6 (13.3%) events. No events were probably related.
  • the AUC of LYT-100 at 824 mg TID is expected to be approximately 150% of the AUC for the approved pirfenidone dose of 801 mg TID.
  • the dose was well tolerated over the 3 treatment days. In this dosage group, the most common TEAE was headache, and the majority of the events were mild.
  • An LYT-100 dose regimen of 825 mg TID is predicted to provide parent drug exposure that is approximately 150% of that following administration of pirfenidone given 801 mg TID.
  • the slower absorption of LYT-100 relative to pirfenidone results in a predicted Cmax for LYT- 100 at a dose of 825 mg TID that is only 15% higher than the corresponding Cmax for pirfenidone at a dose of 801 mg TID.
  • Example 3 LYT-100 Tolerability in Patients with COVID-19 Respiratory Illness
  • a Phase 2 multi-center randomized, double-blind, parallel arm, placebo-controlled trial was performed to evaluate the safety and efficacy of deupirfenidone (LYT-100) compared to placebo in post-acute adult patients with COVID-19 respiratory disease who were treated with supplemental oxygen (including MV, ECMO or any other means of oxygen administration) in the hospital for at least 1 day and have required only low flow nasal oxygen or no oxygen supplementation for at least 72 hours prior to screening.
  • Patients received LYT-100 (deupirfenidone) formulated as powder in 250 mg capsules or matching placebo. Dosing was as provided in Table 12. An initial dosage of 500 mg BID was given the first 3 days of dosing, followed by 750 mg BID thereafter.
  • Patients took LYT-100 study medication, or placebo (in Part A), orally and preferably with food, (solid or nutritional supplements, whenever possible), with approximately 10 to 12 hours between the two daily doses.
  • LYT-100 was well -tolerated in this relatively sick patient population with multiple comorbidities and concomitant medications. There were no drug-related serious adverse events (SAEs) or deaths.
  • SAEs drug-related serious adverse events
  • the treatment emergent AE's occurring in the LYT-100 arm at a frequency greater than or equal to 5% are summarized in Table 13.
  • nausea was the only AE judged to be at least possibly related to LYT-100 with an incidence >5% (8.7% vs 2.4% with placebo).
  • Discontinuation rates due to AEs that were considered at least possibly related to LYT-100 were low in both arms (8.6% with LYT-100 vs. 2.4% with placebo) and the majority of discontinuations in the LYT-100 arm were due to idiosyncratic events and not AEs commonly associated with pirfenidone.
  • a summary of all treatment emergent adverse events judged to at least possibly be related to LYT-100 are provided as FIG. 23.
  • Example 4 LYT-100 Efficacy, Safety, and Dose Response in Idiopathic Pulmonary Fibrosis (IPF)
  • This study is a randomized double-blind, four-arm active and placebo-controlled dose- finding trial to evaluate the efficacy, tolerability, safety, and dose response of LYT-100 in patients with Idiopathic Pulmonary Fibrosis (IPF).
  • IPF Idiopathic Pulmonary Fibrosis
  • FIG. 24A A high-level graphical illustration is provided as FIG. 24A.
  • the Double-blind Treatment Period will be a multicenter, four-arm, active and placebo- controlled, randomized, double-blind, trial comparing the efficacy, tolerability, and safety of LYT- 100 550 mg oral capsules three times a day (TID), LYT-100 825 mg oral capsules TID, pirfenidone 801 mg oral capsules TID, and placebo oral capsules TID over a 26-week treatment period.
  • the primary objective is to determine the dose(s) to carry into Phase 3. This determination will be based on the overall benefit risk profile of LYT-100 via decline in forced vital capacity (FVC, mL), including both efficacy and tolerability outcomes over the 26-week treatment period.
  • FVC forced vital capacity
  • Part A Patients will be randomized to one of the four treatments in a 1 : 1 : 1 :1 ratio and stratified based on prior exposure to nintedanib ( ⁇ 6 months) versus nintedanib -naive patients.
  • Part B Patients who complete the Double-blind Treatment Period (Part A) will be offered participation in the Long-term Extension (Part B).
  • Part B Patients who do not participate in the Part B will have a follow-up visit 4 weeks after their last dose of study medication. For patients who participate in Part B, the follow-up will be conducted at the end of Part B.
  • a graphical illustration of an embodiment of the trial design is provided as FIG. 24B.
  • Part B (long-term extension) will evaluate the tolerability and long-term safety of LYT- 100 in patients who complete the Double-blind Treatment Period.
  • Part B will have two periods. During Part 1 Period 1 , patients will be titrated over a period of 7 to 14 days to the target dose of either 550 or 825 nig LYT-100 TID. followed bv maintenance treatment through Week 52. Patients completing Part B Period 1 may continue maintenance treatment in Part B Period 2 until the study ends. Part B Period 2 will continue at least until all patients who entered Part B Period 1 have had the opportunity to complete Part B Period 1.
  • AEs adverse events
  • ECGs electrocardiograms
  • Efficacy will be assessed by evaluation of pulmonary function and will be monitored by spirometry at regularly scheduled clinic visits.
  • FIG. 24C Recent amendments to the study protocol are summarized in FIG. 24D.
  • the primary objective is to obtain clinical data establishing the efficacy, tolerability, safety, and dosing regimen of LYT- 100 in patients with IPF in order to determine the dose to carry forward into Phase 3.
  • a secondary objective is to obtain point estimates and measures of variability of efficacy endpoints in order to determine sample size for Phase 3 study.
  • Another secondary objective is to assess the relative efficacy of LYT-100 as compared to pirfenidone.
  • the objectives are to assess the safety and tolerability of long-term treatment with LYT- 100 in the IPF population to inform the optimal dosing regimen(s) to carry forward into Phase 3, and to compare the rate of change in F VC through the end of Part B Period 1 to that observed during Part A, by Part A treatment group assignment and by Part B LYT-100 target dose.
  • Part A patients will receive one of two doses of LYT-100 (550 mg or 825 mg) capsules, pirfenidone (801 mg) capsules, or placebo, each TID orally with meals, with approximately 6 hours between each of the three daily doses.
  • LYT-100 550 mg or 825 mg
  • pirfenidone 801 mg
  • dosing will be three times a day (TID) of the indicated dosage (i.e., 550 mg of LYT-100 will be administered three times daily for a total daily dose of 1650 mg; 825 mg of LYT-100 will be administered three times daily for a total daily dose of 2475 mg).
  • Patients will take LYT-100, pirfenidone or placebo, orally and with food (solid or nutritional supplements, whenever possible), with approximately 6 hours between the three daily doses. Doses may be adjusted according to safety and tolerability to avoid toxicity.
  • Table 14 below provides the dosing regimens to be used during the 6-month treatment period. Note that, for all treatment groups, the first 7 days of treatment, one capsule will be taken TID. Day 8 through Day 14 two capsules TID. Day 15 forward 3 capsules TID. Each capsule is 275 mg LYT-100 (e.g., for the 550 mg TID dose at weeks 3-24, two 275 mg capsules of LYT-100 will be administered TID; for the 825 TID dose at weeks 3-24, three 275 mg capsules of LYT-100 will be administered TID).
  • the doses indicated i.e., 550 mg TID and 825 mg TID
  • Patients should be instructed to avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure. Additionally, patients should be instructed to avoid concomitant medications known to cause photosensitivity. Dose reduction may be considered per investigator judgement.
  • Days 8-14 reduction from 2 capsules, TID, to 1 capsule, TID, x 2 days (may be longer if needed)
  • Days 15-182 reduction from 3 capsules, TID, to 2 capsules, TID x 2 days (may be longer if needed); and if reduction from 3 capsules to 2 capsules of study drug TID is not sufficient to address difficulties with tolerability or toxicity, further reduction to one capsule TID is allowed
  • Days 183-189 reduction from 2 tablets, TID, to 1 tablet, TID, x 2 days (may be longer if needed)
  • TID Patients who are unable to tolerate 275 mg (1 tablet) TID should be discontinued from study medication but should remain in the study.
  • the full daily dosage may be maintained, if clinically appropriate, or reduced or interrupted (e.g., until liver chemistry tests are within normal limits).
  • the patient can be re-started on study drug at 1 capsule TID and following the up-titration schedule.
  • the extent of fibrotic changes is greater than the extent of emphysema on the most recent HRCT scan as determined by the investigator
  • PAH Pulmonary Arterial Hypertension
  • interstitial lung disease including but not limited to radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, human immunodeficiency virus (HIV), viral hepatitis, and cancer
  • Cardiovascular diseases any of the following: a. Uncontrolled hypertension within 3 months months of Visit 1 b. Myocardial infarction within 6 months of Visit 1 c. Unstable cardiac angina within 6 months of Visit 1
  • CYPI A2 inhibitors i.e. ciprofloxacin, fluvoxamine, enoxacin, methoxsalen, mexiletine, vemurafenib
  • phenytoin rifampin
  • terifluonmide inducers of CYP1A2
  • Medications associated with substantial risk for prolongation of the QTc interval including but not limited to moxitloxacin, quinidine, procainamide, amiodarone, sotalol).
  • QTc prolongation is not an all / nothing drug effect, and specifically the administration drugs such as hydroxychloroquine do not preclude participation in this trial but does mandate measurement of the QTc every 6 hours until deemed necessary in accordance with investigator judgement c.
  • Immunosuppressant medications such as azathioprine, cyclophosphamide, cyclosporin A, methotrexate, prednisone at steady dose >10 mg/ day or equivalent d.
  • Medications used to treat pulmonary hypertension such as ambrisentan, bosentan, and phosphodiesterase- 5 inhibitors (sildenafil and tadalafil used to treat erectile dysfunction are allowed) e. Warfarin, as it may worsen IPF f.
  • Vaccination with a live vaccine is not permitted during the period from 4 weeks prior to screening to 4 weeks after the last dose; however, adenovirus and mRNA vaccines are allowed
  • a current immunosuppressive condition e.g., human immunodeficient virus
  • Inclusion Criteria - Part B 1. Patient must have completed Part A. of the study, through Day 183 of treatment
  • CYP1 A2 inhibitors ie, ciprofloxacin, fluvoxamine, enoxacin, methoxsalen, mexiletine, vemurafenib
  • phenytoin, rifampin, and teriflunomide inducers of CYP1A2
  • any drug associated with prolongation of the QTc interval including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol.
  • Immunosuppressant medications such as azathioprine, cyclophosphamide, cyclosporin A, methotrexate, and prednisone at steady dose >10mg/day or equivalent
  • Some concomitant medications should be administered with care in combination with pirfenidone and as such clinical judgement should be used to consider discontinuation of a concomitant medication such as in the event of LFT elevation.
  • Investigators should consult the local prescribing information for pirfenidone for their country for additional information on medications to be used with caution in combination with LYT-100 or pirfenidone.
  • Randomization Patients meeting all eligibility criteria will be randomized at Visit 2/Study Day 1.
  • Part B Patients who Participate in Part B will be treated with 550 mg or 825 mg LYT-100 mg TID for at least an additional 6 months (26 weeks).
  • Post-treatment Period A follow up post-treatment completion visit will occur within 28 days of last day of study treatment unless the patient elects to enter Part B, in which case this visit will be performed at the end of Part B.
  • K BILD King's Brief Interstitial Lung Disease Questionnaire
  • SGRQ-I Respiratory Questionnaire - IPF Version
  • Safety endpoints include: Adverse events, concomitant medications, clinical laboratory findings (chemistry, hematology, urinalysis), physical examinations, ECGs, and vital signs. These will be summarized descriptively, where appropriate.
  • Tolerability endpoints include: Frequency of dose modifications (reductions and interruptions), time to first dose modification, (reduction or interruption), duration of adverse events of special interest, time to treatment discontinuation due to an adverse event of special interest and patient reported assessment of IPF symptoms, side-effects, severity, change and satisfaction.
  • Selected endpoints including adverse events of special interest (AESIs) and all-cause mortality are considered efficacy outcomes in the context of the study objectives, the disease being studied, and the expected benefits of LYT-100. These endpoints may be included in the overall discussion (as part of the clinical study report) of the safety and tolerability of LYT-100, where appropriate.
  • AESIs adverse events of special interest
  • a sparse PK sampling strategy will be employed in which all patients will provide pre-dose blood samples for determination of plasma concentrations of LYT-100/pirfenidone and its metabolite(s).
  • an intensive PK sub-study will be conducted in approximately 8 patients per treatment arm in which each patient will provide up to 16 blood samples for PK over a 24-hour period at Study Visits 3, 5 and 8.
  • DLCO diffusing capacity of the lungs for carbon monoxide
  • ECG electrocardiogram
  • eCRF electronic case report form
  • EQ- 5D EuroQol 5-Dimensional Quality of Life Questionnaire
  • FVC forced vital capacity
  • FU follow-up
  • HCRU healthcare resource utilization
  • HRCT high-resolution computed tomography
  • IPF idiopathic pulmonary fibrosis
  • K-BILD King’s Brief Interstitial Lung Disease
  • PGI-C Patient Global Impression - Change
  • PGI-S Patient Global Impression - Severity
  • PK pharmacokinetic
  • SGRQ-I St. George’s Respiratory Questionnaire - IPF Version
  • a serum pregnancy test must also be performed as confirmation. Documentation will be done in patient’s notes. Where required by local regulations, an appropriate pregnancy test may be performed more frequently than this schedule. i. In all patients, PK samples will be obtained immediately prior to drug administration at Visits 3, 5 and 8. Date and exact clock time of drug administration and blood sampling must be recorded on the eCRF. Patients will be provided (Visits 2 and 4) with a PK-card to support the record of the exact clock time of medication intake 3 days preceding PK sampling. Approximately 8 patients per treatment group will participate in the intensive PK substudy at Visits 3, 5 and 8.
  • PK samples will be obtained from these patients immediately prior to dosing and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 15, 18 and 24 hours postdose. Pre-dose sample to be collected within 30 minutes prior to dosing. Acceptable windows for PK sampling are as follows: +/- 2 minutes during 0.5 to 4-hour postdose period, +/- 5 minutes 6-16 h postdose and +/- 10 minutes 24 h postdose. Exact time of each sample collection to be recorded. j .
  • Deoxyribonucleic Acid (DNA) and serum banking samples will be taken from eligible patients at Visit 2 who consent. Participation is voluntary and is not a prerequisite for participation in the trial. Note, the DNA sample may not be taken prior to Visit 2.
  • DNA Deoxyribonucleic Acid
  • Biomarker samples will be taken just before drug administration at Visits 2, 5 and 8. l. Order of lung function measurements: 1. FVC followed by patients rest at Screening (Visit 1), baseline (Visit 2) and weeks 4 (Visit 3), 8 (Visit 4), 16 (Visit 6) and 26 (Visit 8A/ET); 2. DLCO. Measurements at approximately the same time each visit. DLCO will be done at Screening (Visit 1) and Week 26 (Visit 8A/ET) where available at the study site.
  • assessments are being conducted in a pulmonary function lab not in close proximity to the research clinic where other study assessments are performed, the sequence of assessments may be modified to reduce burden on study patients as long as spirometry continues to be performed in the morning.
  • Weekly spirometry is to be performed by patients at home weekly in the am. Site staff will schedule televisits with patients to coach the weekly FVC maneuvers, as needed.
  • home spirometry should not be performed on that same day. Patients may do their weekly home spirometry assessment the following day.
  • the final home spirometry assessment should be performed no later than the day prior to Visit 8A (W eek 26) .
  • Patients will be asked weekly to complete ePROs to assess their symptoms, cough and IPF severity starting during Screening (Visits 1-2) and will continue to assess symptoms and side effects, cough and IPF severity weekly through the 26-week treatment period (Visits 2-8).
  • Patients will also be asked to assess PGI-C Cough and PGI-C IPF Severity at Visit 8A/ET.
  • Patients will be asked at baseline (Visit 2) to assess satisfaction expectations with their study treatment and then access overall satisfaction with study medication weekly beginning on Day 7 through Visit 8A/ET. p.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • DLCO diffusing capacity of the lungs for carbon monoxide
  • ECG electrocardiogram
  • eCRF electronic case report form
  • ET end of treatment
  • FVC forced vital capacity
  • FU follow-up
  • HCRU healthcare resource utilization
  • IPF idiopathic pulmonary fibrosis
  • a serum pregnancy test should be conducted in addition to the urine pregnancy test, (ie, in certain countries, a serum pregnancy test is required at enrollment.) If a urine pregnancy test is positive, a serum pregnancy must also be performed as confirmation.
  • Biomarker samples will be taken just before drug administration at Visit 11 in Period 1, and every 13 weeks during Period 2.
  • j. Vital status check (living/dead) will be done for all patients at Week 26 and at the end of the study for patients who discontinue study medication early and do not complete all study visits.
  • SABA e.g., albuterol or salbutamol
  • SAMA e.g., ipratropium bromide 12 h
  • LABA e.g., formoterol or salmeterol
  • Ultra-LABA (e.g., indacaterol, vilanterol, or olodaterol) 36 h
  • LAMA e.g., tiotropium, umeclidinium, aclidinium, or glycopyrronium 36-48 h Definition of abbreviations'.
  • LABA long-acting P2-agonist
  • LAMA long-acting muscarinic antagonist
  • SAB A short-acting P2-agonist
  • SAMA short-acting muscarinic antagonist.
  • Pulmonary function will be measured in a standardized manner and results should be transmitted electronically during the visit immediately after performing the spirometry and evaluated by a central reader. In case the acceptability and repeatability criteria as specified by ATS/ERS/JRS/ALAT guidelines are not met, a repeat spirometry should be performed during the same visit.
  • the primary efficacy endpoint is the rate of decline in FVC mL over 26 weeks.
  • decline in FVC % predicted from baseline to Week 26 and by > 10% and > 5% will be assessed.
  • the secondary endpoint is comparison of FVC % predicted change from baseline to Week 26.
  • the site will use DLCO equipment available onsite. All measurements at a site will be conducted with the same DLCO device (i.e., if multiple devices are available, select only one for the entire study). Single-breath DLCO measurement will be carried out according to local practice at the time points specified in the Schedule of Assessments. Before beginning the test, the techniques should be demonstrated, and the patient carefully instructed. The DLCO assessment should always be performed after the FVC measurement and following a few minutes of rest.
  • FEV1 (mL) and percent predicted forced expiratory volume in 1 second (FEVl%p) .
  • the '2012 Global Lung Function Initiative Equations' will be used to calculate the predicted values (Quanjer et al, "Multi-ethnic reference values for spirometry for the 3-95 year age range: the global lung function 2012 equations: Report of the Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung Function Reference Values.," Eur Respir J, vol. 40(6), pp. 1324- 1343, 2012).
  • GLI Global Lung Function Initiative
  • ERS Task Force to establish improved Lung Function Reference Values.
  • Exploratory parameters include:
  • K-BILD King's Brief Interstitial Lung Disease Questionnaire
  • K-BILD King's Brief Interstitial Lung Disease Questionnaire
  • the K-BILD is a self-administered health status questionnaire that was developed and validated specifically for patients with ILD.
  • Questionnaire development and validation included a range of ILDs, including the ILD disease types in this study population.
  • the questionnaire consists of 15 items and 3 domains: breathlessness and activities, psychological, and chest symptoms. Possible score ranges from 0-100, with a score of 100 representing the best health status.
  • the efficacy endpoint is the change from baseline to Week 26 in the total score.
  • the EQ-5D was developed by the European Quality of Life Group (EuroQol Group) and is a standardized instrument for use as a measure of health outcome.
  • the version used in this trial is the new five-level version (EQ-5D-5L).
  • the questionnaire consists of 2 sections. The first section is the descriptive system with 5 questions regarding the patient's health state on the day of the assessment. Each question captures one dimension of health (e.g., mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has three levels, which results in a 1 -digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient’s health state) and has five levels to answer.
  • EuroQol Group European Quality of Life Group
  • the second section records the patient's self-rated health status on the day of the assessment on a vertical graduated (0 to 100) visual analogue scale.
  • the EQ VAS records the patient’s self-rated health on a vertical VAS and can be used as a quantitative measure of health outcome that reflects the patient’s own judgment.
  • the SGRQ-I is an idiopathic pulmonary fibrosis disease-specific instrument designed to measure the impact of the disease on overall health, daily life, and perceived well-being in patients with interstitial lung disease.
  • the interviews will be based on an interview guide with open-ended questions that will be used to encourage spontaneous responses and good qualitative data.
  • the interview guide will include non-leading questions such as “What is a bad day like with IPF?”
  • the interview guide will include topics, questions, and probes designed to understand IPF from the patient’s perspective.
  • the interview guide will begin with an overall introduction about the interview and then move into a general discussion about the patient’s experience. During this concept elicitation phase of the interview, the interviewer will listen for terms and wording that are spontaneously voiced by the patient when describing any problems, they may have experienced (with particular reference to respiratory problems). A mix of open-ended and probing questions will be used.
  • Safety laboratory tests (hematology, biochemistry, coagulation, urinalysis, and urine cotinine) will be performed at the time points specified in the Schedule of Assessments (Tables 16 and 17). Additional clinical laboratory tests may be performed at other times if deemed necessary based on the patient’s clinical condition.
  • Each patient will have blood samples taken for hematology, coagulation, biochemistry and as necessary for serum pregnancy and FSH analyses at the time points delineated in the study schedules.
  • urine sample will be taken for urinalysis at the time points delineated in the study schedules.
  • C-reactive protein C-reactive protein
  • Lymphocytes (LYM - collected with hematology biomarkers and at screening)
  • TGF-pi Transforming Growth Factor Beta 1
  • TNF-a Tumor necrosis factor alpha
  • Interleukin 6 (IL-6)
  • Interleukin 1 beta (IL-ip) Interleukin 1 beta
  • PDGF- P Platelet-derived growth factor- p
  • GCSF Granulocyte colony-stimulating factor
  • VEGF Vascular endothelial growth factor
  • Coagulation parameters to be tested are:
  • Disease and/or drug-related biomarkers including, but not limited to, extracellular matrix synthesis and turnover (i.e., neo-epitopes), inflammatory cells, alveolar epithelial and oxidative stress markers, may be assessed in plasma and/or serum, if deemed appropriate.
  • other analytes such as metabolites or endogenous biomarkers might be assessed in plasma and/or serum, if deemed appropriate.
  • Blood samples for potential serum disease-specific biomarker analysis and for potential plasma disease-specific biomarker analysis will be collected before study medication administration at Visits 2, 5 and 8ZET. The details on blood sample collection, handling, storage, and shipment instructions will be provided in a separate laboratory manual.
  • AEs will be reported for all patients from the time of consent until the completion of the Follow-up visit. AEs reported prior to the first dose will be denoted as pre-treatment. SAEs will be reported for all patients (randomized or not) from the time of consent. AEs reported from the time of consent to confinement on Day 0 will be recorded as pre-treatment AEs.
  • Treatment emergent adverse events are defined as an AE that occurs following first dose of study medication and will be evaluated from the first administration of study drug on Day 1 until the Follow-up visit.
  • Adverse Events of Special Interest relate to any specific AE that has been identified at the project level as being of particular concern for prospective safety monitoring and safety assessment within this trial, (e.g., the potential for AEs based on knowledge from other compounds in the same class). AESI need to be reported to the Sponsor’s Pharmacovigilance Department within the same timeframe that applies to SAEs, Adverse Events of Special Interest (AESI)
  • An SAE is an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-up), and at any dose of the study drug (active or placebo), that fulfils one or more of the following:
  • pirfenidone and LYT-100 concentrations decreased by at least 15% during incubation with recombinantly expressed human CYP1A2, CYP2D6 and CYP2C19 isozymes.
  • the ti/2 of pirfenidone following incubation with CYP1A2, CYP2C19 and CYP2D6 was 3.18, 2.13 and 2.30 hours, respectively.
  • the ti/2 of LYT-100 following incubation with CYP1 A2, CYP2C19 and CYP2D6 was 9.08, 3.67 and 2.72 hours, respectively.
  • the DiscoverX BioMAP Fibrosis Panel was used to evaluate LYT-100 and pirfenidone.
  • the panel contains 54 biomarker (cell surface receptors, cytokines, chemokines, matrix molecules and enzymes) readouts that capture biological changes that occur within the physiological context of the particular BioMAP system.
  • LYT-100 and pirfenidone were tested in the BioMAP Fibrosis Panel at various dilutions starting at highest dose of 1700 pM in three cell/stimulus systems (myofibroblast [MyoF] composed of lung fibroblasts treated with TNF-a, and TGF-P, renal proximal tubule epithelial cell (RE)MyoF including renal tubule epithelial cells and lung fibroblasts treated with TNF-a, and TGF- ⁇ , and small airway epithelial cell (SAE)MyoF comprising small airway epithelial cells and lung fibroblasts treated with TNF-a, and TGF- P). Similar results were observed with both compounds in the three systems (FIG. 28).
  • MyoF myofibroblast
  • RE renal proximal tubule epithelial cell
  • SAE small airway epithelial cell
  • Example 7 Evaluation of L YT-100 Efficacy in a Rodent Bleomycin-Induced Fibrosis Model
  • the rodent bleomycin-induced fibrosis model (BLM) is commonly utilized in the preclinical setting as it appears to have clinical relevance as an animal model of human fibrosis (e.g., idiopathic pulmonary fibrosis) based on the observed pulmonary pathophysiology following the bleomycin challenge in rats. See, e.g., Corboz et al., Pumonary Pharm. & Then 49 (2016), 95- 103).
  • Bleomycin is a metabolite of the bacterium Streptomyces verticillus first identified in 1962. Specifically, bleomycin is a non-ribosomal hybrid peptide-poly ketide natural product having the structure:
  • bleomycin While bleomycin possesses antibacterial activity, its toxicity precludes use as an antibiotic. Bleomycin is used as a chemotherapeutic agent in the treatment of various cancers, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, testicular cancer, ovarian cancer, and cervical cancer among others. Bleomycin acts by induction of DNA strand breaks and may also inhibit incorporation of thymidine into DNA strands. DNA cleavage by bleomycin depends on oxygen and metal ions, at least in vitro, though the exact mechanism of DNA strand scission is unresolved.
  • bleomycin chemotherapy include fever, weight loss, vomiting, rash, and a severe type of anaphylaxis.
  • bleomycin induces DNA strand rupture, generates free radicals, and causes oxidative stress tresulting in cell necrosis and/or apoptosis.
  • Bleomycin is normally metabolized by the enzyme bleomycin hydrolase, but the lung is particularly susceptible to bleomycin toxicity by virtue of the scarcity of this enzyme in the lung. Lung inflammation, fibrosis, reductions in lung compliance, and impaired gas exchange are the consequences of a bleomycin challenge.
  • evaluation is generally performed in the phase of established fibrosis, i.e., 10-15 days after the initiation, rather than in the early period of bleomycin-induced inflammation. Conversion of proline into hydroxyproline and incorporation into lung collagen occurs as early as 4 days after bleomycin administration. The switch between inflammation and fibrosis occurs in rats around day 9 after bleomycin administration. It was deemed desirable to evaluate activity of LYT-100 during both the inflammatory and fibrotic stages of the model. Accordingly, LYT-100 was administered starting at day 8 following bleomycin administration.
  • Body weight and lung weight were evaluated over the duration of the study to determine the effects of bleomycin and LYT-100 in the model.
  • Body weight gain was impeded in Groups 2 and 3 that received Bleomycin between Days 1 to 9 (FIG. 29). With continued reference to FIG. 29, from Day 10 and until the end of Phase 1 on Day 14, body weight gain in Groups 2 and 3 resumed at a rate similar to Group 1 that received saline.
  • Body weight gain (expressed as % of body weight compared with Day Minus 1 body weights) weight gain was impeded in Groups 2 and 3 that received Bleomycin between Days 1 to 9. From Day 10 and until the end of Phase 1 on Day 14, body weight gain in Groups 2 and 3 resumed at a rate similar to Group 1 that received saline.
  • Lung weights were heavier in the bleomycin-treated animals (Group 1 vs Group 2 and Group 3 comparisons) as expected from this model.
  • Lung weight ratios (expressed as % of body weight; FIGS. 30A and 30B) were heavier in the bleomycin-treated animals (Group 1 vs Group 2 and Group 3 comparisons) as expected from this model.
  • Phase 1 was performed as per protocol and no deviations were considered to affect the integrity of the Phase’s outcome.
  • LYT-100 was administered at high (400 mg/kg) and low (250 mg/kg) dose levels once daily (QD) from Day 8 until (including) Day 13 in healthy (high dose) and bleomycin-challenged (low and high dose) rats.
  • QD dose levels once daily
  • LYT-100 was well tolerated by all animals and there was not an obvious correlation between dose level and presence of side effects. Any side effects observed were resolved within ⁇ 5 hours after they were noticed and they did not reappear before the following dosing occasions.
  • the tolerability phase determined that LYT-100 administered QD at 400 mg/kg was well-tolerated by both healthy and bleomycin-challenged rats and that this dose levels will be used to examine LYT- 100's therapeutic potential during Phase 2 (Efficacy).
  • Body weight and lung weight were evaluated over the duration of the study to determine the effects of bleomycin and LYT-100 in the model. Body weight gain was impeded between Days 1 to 9 in Groups 5, 6, and 7 that received Bleomycin (FIG. 31A). With continued reference to FIG. 31 A, from Day 10 and until the end of the efficacy Phase on Day 28, body weight gain in Groups 5 (Bleomycin/Vehicle) and 6 (Bleomycin/LYT-100) resumed and at a rate similar to Group 4 that received Saline/Vehicle. Body weight gain in Group 7 (Blemoycin/Nintedanib) showed modest improvement after Day 8 and the rate of body weight gain remained slower compared with the other groups.
  • Body weight gain (expressed as % of body weight compared with Day 1 body weights) was impeded between Days 1 to 9 in Groups 5, 6, and 7 that received bleomycin (FIG. 31B).
  • % of body weight gain in Groups 5 (Bleomycin/Vehicle) and 6 (Bleomycin/LYT-100) resumed and at a rate similar to Group 4 that received Saline/Vehicle.
  • Percent of body weight gain in Group 7 (Bleomycin/Nintedanib) showed modest improvement after Day 8 and the rate of body weight gain remained slower compared with the other groups.
  • LYT-100 treatment did not affect lung weight ratios in the bleomycin-treated rats (Group 5, Bleomycin / vehicle vs Group 6, Bleomycin / LYT-100). There was a trend for lower lung weight ratios in the Nintedanib-treated rats (Group 5 vs Group 7), however this lung ratio remained higher compared with non-challenged rats (Group 7 vs Group 4).
  • Lung hydroxyproline content was measured for all groups (FIGS. 34A, 34B, 35, 36A, 36B, 37). With reference to FIGS. 34A, 34B, 35, 36A, 36B, and 37, total left lung hydroxyproline (pg per left lung) was higher in the bleomycin-treated rats (Group 4, saline vs Group 5, Bleomycin). LYT-100 treatment did not affect total hydroxyproline levels in the bleomycin-treated rats (Group 5, Bleomycin/vehicle vs Group 6, Bleomycin/LYT-100).
  • Lungs from animals treated with Nintedanib had lower levels of total hydroxyproline (Group 7 vs Group 5) but higher than non-challenged rats (Group 7 vs Group 4). Hydroxyproline content (pg per mg of wet lung) was higher in the bleomycin-treated rats (Group 4, saline vs Group 5, Bleomycin). LYT-100 treatment reduced the hydroxyproline content in the bleomycin-treated rats (Group 5, Bleomycin/vehicle vs Group 6, Bleomycin/LYT-100). Nintedanib treatment also reduced hydroxyproline content (Group 7 vs Group 5).
  • Phase 2 was performed as per protocol and no deviations were considered to affect the integrity of the Phase’s outcome.
  • LYT-100 administered QD at 400 mg/kg from Day 8 until (including) Day 27 was well tolerated by all animals and any side-effects observed were resolved within ⁇ 5 hours after they were noticed and did not reappear before the following dosing occasions.
  • Nintedanib administered twice daily (BID) at 60 mg/kg was used as a Reference.
  • LYT-100 did not negatively affect body weight developments, in contrast to Nintedanib.
  • LYT-100 reduced lung hydroxyproline content, suggesting reduced presence of connective tissue in the lungs. Consistent with the latter, lungs from LYT-100-treated rats also had reduced median fibrosis scores compared with vehicle controls.

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