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EP-4734975-A1 - COMPOSITIONS FOR THE TREATMENT OF CYSTIC FIBROSIS

EP4734975A1EP 4734975 A1EP4734975 A1EP 4734975A1EP-4734975-A1

Abstract

A composition chosen between (4R)-5-(3'-idrossifenil)-γ-valerolactone (MIPV), (4R)-5-(3',4'-diidrossifenil)-γ-valerolactone (DIPV), and mixtures 5 thereof, in the treatment of cystic fibrosis, alone and/or in combination with CFTR protein modulators.

Inventors

  • COZZA, GIORGIO
  • URSINI, FULVIO
  • ARTUSI, Ilaria
  • RUBIN, Michela
  • BOSELLO TRAVAIN, Valentina
  • MORAZZONI, PAOLO
  • SANTINELLO, Sandro

Assignees

  • Distillerie Bonollo Umberto - S.p.A. Con Sigla "U.B. S.p.A."

Dates

Publication Date
20260506
Application Date
20240621

Claims (9)

  1. 1. A composition chosen between (4R)-5-(3’-idrossifenil)-y- valerolactone (MIPV), (4R)-5-(3’,4’-diidrossifenil)-y- valerolactone (DIPV), and mixtures thereof, for use in the treatment of cystic fibrosis.
  2. 2. The composition according to claim 1, wherein said composition is a racemate, a R enantiomer, a S enantiomer, or a salt thereof.
  3. 3. The composition according to claim 2, wherein said composition is a R enantiomer.
  4. 4. The composition according to any of claims 1-3, wherein said medicament comprises metabolic precursors releasing said composition, preferably an extract of Vitis vinifera L. grape seeds.
  5. 5. The composition according to any of claims 1-4, wherein said composition is administered as adjuvant of other medicaments for the treatment of cystic fibrosis.
  6. 6. The composition according to claim 5, wherein said other medicaments are CFTR modulators, in particular Elexacaftor, Tezacaftor, Ivacaftor, or combinations thereof.
  7. 7. The composition according to any of claims 1-6, wherein said composition is in its form with open lactone ring, optionally in the form of an esterified open lactone ring.
  8. 8. Food supplement comprising the composition according to claim 1, and suitable food excipients.
  9. 9. Pharmaceutical or nutraceutical composition comprising the composition according to any of claims 1-8, and at least one physiologically acceptable excipient.

Description

“Compositions for the treatment of cystic fibrosis” * * * * FIELD OF THE INVENTION [0001 ] The present invention relates to a composition for the treatment of cystic fibrosis. In particular, the composition according to the invention comprises (4R)-5-(3’-hydroxyphenyl)-y-valerolactone, and/or (4R)-5-(3’,4’- dihydroxyphenyl)-y-valerolactone for the treatment of cystic fibrosis. BACKGROUND ART [0002] Cystic fibrosis is the most common genetic disorder in Caucasians: it affects over 100.000 people in the world; in Italy, the affected people are about 6.000. [0003] Cystic fibrosis is substantially characterized by chronic inflammation and repeated, persistent infections. [0004] People affected by cystic fibrosis have two defective copies of the gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). [0005] In normal conditions, CFTR protein is produced in the endoplasmic reticulum, matures in the Golgi apparatus and is transferred into cell plasmatic membrane, where it carries out its function. [0006] CFTR is a transmembrane channel positioned inside cell membrane, allowing the passage of CF ions from the inside to the outside of cells. Said ions recall water on the outside surface of cells, so that mucus can have its physiologic consistence. The scarcity of CF ions on cells surface leads to the formation of a particularly viscous mucus, incapable of performing its physiologic functions. [0007] Cystic fibrosis alters the secretion of many organs, which secretions being denser, dehydrated and not enough fluid contribute to the impairment of organs. Generally, the most affected organs are bronchi and lungs. Inside them, mucus tends to stagnate, leading to repeated infections. Another target organ is pancreas, which cannot carry out its normal function of secreting digestive enzymes into the intestine, leading to diarrhoea, food malabsorption, growth retardation in children and malnutrition in adults. Other affected organs are intestine, liver, nasal cavities, and vas deference in males, which can lead to infertility. Usually, sweat glands are compromised. Statistics suggest a median lifespan around 40 years for patients suffering from cystic fibrosis. [0008] Different mutations can lead to an insufficient production of CFTR protein: the mutations known so far, over 2000, have been grouped into five classes: 1. Class 1 : protein production mutations Nonsense and splice mutations. 2. Class 2: protein processing mutations Deletion and missense mutations. This is the most common genetic defect in population (about 70% of mutations), due to a deletion of the phenylalanine in the 508 position of CFTR (F508del), leading to a structural defect making the protein incapable of reaching the plasmatic membrane. For this mutation, on the market there is available a combination of drugs, Elexacaftor/Tezacaftor/Ivacaftor, enabling the correct folding of the channel and the recovery of its function. 3. Class 3: gating mutations Mutations allowing CFTR to reach plasmatic membrane, although the protein shows a defect in the opening of the channel, so preventing the passage of CF ions through the membrane of the epithelial cells. For this class, the drug Ivacaftor is available on the market. 4. Class 4: conduction mutations Specific mutations of CFTR preventing the channel to transfer sufficient quantities of CF ions. 5. Class 5: insufficient protein mutations Splicing and missense mutations leading to the production of an insufficient quantity of functional protein. For this class of mutations, Ivacaftor and a combination of Tezacaftor/Ivacaftor have been approved. [0009] The above-quoted drugs are CFTR protein modulators. A description of such drugs can be found in the application W02021030556A1. [0010] Briefly, there are two main types of CFTR modulators: CFTR correctors, i.e. molecules capable of binding the channel, correcting the defect and increasing the presence of the channel in the plasmatic membrane, and CFTR potentiators, i.e. molecules capable of holding the gate and increasing the efficiency of the transfer of CF ions once the channel is positioned in the membrane. [0011] As of now, drugs for all the classes of mutations are not available, as the current therapy intercepts a CFTR channel with specific mutations, and therefore is mutation-dependent. At present, a pharmacologic therapy is available for about 11% only of cystic fibrosis patients. [0012] Although the degree of involvement is very different among different mutations, all cystic fibrosis patients share an inflammatory condition affecting mainly digestive and respiratory apparatus, accompanied with persistent pulmonary infections tending to markedly worsen their clinic conditions over time. [0013] The article of Mena Pedro et al: "5-(3',4'-Dihydroxyphenyl)- [gamma]valerolactone and its sulphate conjugates, representative circulating metabolites of flavan-3-ols, exhibit anti-adhesive activity against uropathogenic Esche