Use of PPAR-delta agonists in the treatment of disease
Inventors
O′Donnell, Niall • PURKINS, Lynn • Dorenbaum, Alejandro
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11931365-B2
Publication Date
2024-03-19
Expiration Date
Abstract
Described herein is the use sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate in the preparation of pharmaceutical compositions for the treatment of diseases or conditions that would benefit by administration with a PPARδ agonist compound.
Core Innovation
The invention relates to a method for treating primary mitochondrial myopathy (PMM) in a human by orally administering a solid form pharmaceutical composition comprising crystalline sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate (Compound II). The human has at least one mutation or deletion in at least one mitochondrial DNA (mtDNA) gene and/or at least one mtDNA defect and/or at least one mutation or deletion in at least one nuclear DNA (nDNA) gene involved in mitochondrial function, or a combination thereof.
Crystalline Compound II is defined as crystalline Form 1 by an XRPD pattern with peaks at 2.8±0.2° 2-Theta, 7.2±0.2° 2-Theta, 13.4±0.2° 2-Theta, 17.8±0.2° 2-Theta, 19.7±0.2° 2-Theta, 19.9±0.2° 2-Theta, and 20.6±0.2° 2-Theta as measured using Cu Kα radiation. The solid pharmaceutical composition is orally administered to the human with PMM, and the crystalline Form 1 identity is tied to the claimed XRPD peak pattern measured under Cu Kα radiation.
The described clinical context includes PMM patient evaluation using exercise tolerance and symptom-related clinical endpoints, including fatigue and pain, with additional outcome measures and reported tolerability and improvements associated with daily administration of Compound II in a clinical study framework.
Claims Coverage
The independent claim is directed to a method of treating primary mitochondrial myopathy (PMM) using orally administered solid crystalline Compound II (crystalline Form 1) defined by a specific XRPD peak pattern, with treatment applicability to humans having specified mtDNA and/or nDNA alterations or mtDNA defects. The claims coverage centers on 8 inventive features, with dependent refinements describing additional dosage forms and clinical endpoint improvements.
Oral solid form crystalline Compound II treatment of PMM
A method for treating a primary mitochondrial myopathy (PMM) in a human by orally administering a solid form pharmaceutical composition comprising crystalline sodium (E)-2-(4-((3-(4-fluorophenyl)-3-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)allyl)oxy)-2-methylphenoxy)acetate (Compound II).
Patient genetic and defect inclusion criteria for PMM
The human with PMM has at least one mutation or deletion in at least one mitochondrial DNA (mtDNA) gene, at least one mtDNA defect, at least one mutation or deletion in at least one nuclear DNA (nDNA) gene involved in mitochondrial function, or a combination thereof.
Crystalline Form 1 identity by XRPD peak pattern
Crystalline Compound II is characterized as having an XRPD pattern with peaks at 2.8±0.2° 2-Theta, 7.2±0.2° 2-Theta, 13.4±0.2° 2-Theta, 17.8±0.2° 2-Theta, 19.7±0.2° 2-Theta, 19.9±0.2° 2-Theta, and 20.6±0.2° 2-Theta as measured using Cu Kα radiation (crystalline Form 1).
Systemic oral administration in powder, pill, tablet, or capsule form
The solid pharmaceutical composition is a powder, pill, tablet, or capsule form.
Exercise tolerance improvement measured by 12-minute walk test
Increasing the distance walked in a 12-minute walk test by at least about 10–125 meters or more than about 125 meters after specified durations following daily administration of Compound II.
Fatigue reduction measured by Modified Fatigue Impact Scale
Decreasing human fatigue evidenced by a reduction in Modified Fatigue Impact Scale (MFIS) after multiple specified time points following daily administration of Compound II.
Pain reduction measured by Brief Pain Inventory
Decreasing pain by reducing Brief Pain Inventory (BPI) scores by 1, 2, 3, 4, 5, or more than 5 after daily administration of Compound II at various time points.
PMM muscle symptom severity reduction measured by PGIC
Reducing the severity of PMM muscle symptoms assessed by Patient Global Impression of Change (PGIC) score reductions of 1, 2, 3, 4, or more than 4 after specified durations of daily administration of Compound II.
Overall, the claims coverage centers on orally administering a solid form of crystalline Compound II (crystalline Form 1) to treat PMM in humans meeting defined mtDNA/nDNA mutation or defect criteria, with crystalline identity established by a defined Cu Kα XRPD peak pattern. Dependent coverage further specifies oral dosage form factors and links treatment to improvements in 12-minute walk test distance, fatigue, pain scores, and PGIC-based symptom severity over multiple time points.
Stated Advantages
Improvement in exercise tolerance as measured by increased 12-minute walk test distance.
Reduction in human fatigue as measured by Modified Fatigue Impact Scale (MFIS).
Reduction in pain as measured by Brief Pain Inventory (BPI) score decreases.
Reduction in PMM muscle symptom severity as measured by Patient Global Impression of Change (PGIC) score reductions.
Documented Applications
Treating primary mitochondrial myopathy (PMM) in a human by orally administering solid crystalline Compound II (crystalline Form 1) for patients with specified mtDNA/nDNA mutations/deletions and/or mtDNA defects.
Clinical evaluation of PMM using exercise endurance, fatigue, pain, and symptom severity endpoints, including reported tolerability and improvements in the cited PMM study context.
Interested in licensing this patent?