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EP-4741501-A1 - DOSING OF OLIGONUCLEOTIDE DRUGS TARGETING MIR-21 FOR INHALATION

EP4741501A1EP 4741501 A1EP4741501 A1EP 4741501A1EP-4741501-A1

Abstract

The present invention relates to a formulation comprising an oligonucleotide drug which is an antagonist of microRNA-21 as an active agent for administration to a human subject in need thereof by inhalation.

Inventors

  • Rabe, Klaus F.
  • Groth, Espen E.
  • FRISCHMUTH, Thomas
  • ENGELHARDT, STEFAN
  • SCHMIDT, JOHANNES

Assignees

  • RNATICS GmbH
  • Technische Universität München, in Vertretung des Freistaates Bayern

Dates

Publication Date
20260513
Application Date
20241111

Claims (15)

  1. A formulation comprising an oligonucleotide drug as an active agent for administration to a human subject in need thereof by inhalation wherein the oligonucleotide drug is an antagonist of miR-21.
  2. The formulation of claim 1 for the use of claim 1, which is a liquid formulation.
  3. The formulation of claim 1 or 2 for the use of claim 1, wherein the formulation is an aqueous formulation, particularly an aqueous isotonic solution.
  4. The formulation of any one of claims 1-3 for the use of claim 1 wherein the oligonucleotide drug comprises an oligonucleotide having the nucleotide sequence (SEQ ID NO.1): 5'-TCAGTCTGATAAGCT-3' wherein each indicated nucleotide building block is a deoxyribonucleotide building block or a modified nucleotide building block.
  5. The formulation of any one of claims 1-4 for the use of claim 1, wherein the oligonucleotide drug comprises an oligonucleotide having the nucleotide sequence (SEQ ID NO. 2): 5'-TCaGtCtGaTaAgCt -3' wherein a capital letter represents a locked nucleic building block, a lower case letter represents a deoxyribonucleotide building block, every capital C denotes 5-methyl cytosine, and all internucleosidic linkages are phosphorothioate linkages.
  6. The formulation of any one of claims 1-5 for the use of claim 1, wherein the oligonucleotide drug is conjugated to a macrophage-targeting moiety, particularly to a trimannose moiety.
  7. The formulation of any one of claims 1-6 for the use of claim 1, wherein the oligonucleotide drug is RCS-21 or a physiologically acceptable salt thereof: wherein the capital letters T, C, A and G in the oligonucleotide moiety represent nucleotide building blocks comprising the nucleobases thymine, 5-methyl cytosine, adenine, and guanine, respectively, the lower-case letter s represents a phosphorothioate internucleosidic bond between two nucleotide building blocks, the lower-case letter b after a capital letter denotes a locked nucleotide building block having a 2'-O-CH 2 -4' bridge, and the lower-case letter d before a capital letter denotes a 2'-deoxyribonucleotide building block.
  8. The formulation of any one of claims 1-7 for the use of claim 1, wherein the formulation is administered by oral inhalation.
  9. The formulation of any one of claims 1-7 for the use of claim 1 or 8, wherein the formulation is administered once daily, each second day, twice weekly or once weekly.
  10. The formulation of any one of claims 1-7 for the use of claim 1, 8 or 9, wherein the oligonucleotide drug is administered in a body weight dependent dosing regimen. For example, the oligonucleotide is administered in a dose of 0.001 mg/kg body weight to 10 mg/kg body weight, in a dose of 0.005 mg/kg body weight to 5 mg/kg body weight or in a dose of 0.01 mg/kg body weight to 2.5 mg/kg body weight per application.
  11. The formulation of any one of claims 1-7 for the use of claim 1, 8 or 9, wherein the oligonucleotide drug is administered in a fixed dose of 0.06 mg to 700 mg, 0.2 mg to 200 mg, in a fixed dose of 0.5 mg to 150 mg, or in a fixed dose of 1 mg to 50 mg per application.
  12. The formulation of any one of claims 1-7 for the of any one of claims 1 or 8-10, wherein the formulation is administered for a time period of at least one week and up to 1 year or longer.
  13. The formulation of any one of claims 1-7 for the of any one of claims 1 or 8-12, wherein the human subject suffers from a disorder selected from pulmonary fibrosis, pneumonia, ARDS, COPD, a viral or bacterial pulmonary infection, e.g. an infection by a coronavirus such as SARS-CoV-2 or influenza virus, a cancer of the respiratory tract, e.g., a lung cancer, and an inflammatory lung disease.
  14. The formulation of any one of claims 1-7 for the use of any one of claims 1 or 8-13, for use in the selective delivery of the active agent to lung macrophages.
  15. A method of treating a human subject in need thereof, comprising administering to said subject a therapeutically effective amount of a formulation by inhalation, wherein the formulation comprises an oligonucleotide drug as an active agent wherein the oligonucleotide drug is an antagonist of miR-21.

Description

Field of the Invention The present invention relates to a formulation comprising an oligonucleotide drug which is an antagonist of microRNA-21 as an active agent for administration to a human subject in need thereof by inhalation. Background of the Invention Oligonucleotide drugs that inhibit the activity of microRNAs, e.g. microRNA-21 (miR-21), are presently under clinical development. WO 2009/106477, the content of which is herein incorporated by reference, discloses systemic inhibitors of miR-21, called antimiR-21 for the prevention of tissue fibrosis. Based on these findings, a clinical program to develop antimiR-21 against kidney fibrosis was initiated by Regulus Therapeutics (Carlsbad, California) together with Sanofi/Genzyme. Till date, a phase 1 trial has been successfully concluded and a press release had been issued. In 2016, a phase 2 clinical trial in Alport syndrome was approved by the FDA (HERA trial). As listed on ClinicalTrials.gov 14, the trial was a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, efficacy, pharmacodynamics, and pharmacokinetics of Lademirsen (antimiR-21, SAR339375). AntimiR-21 was administered systemically (s.c., 1,5 mg per injection) every week for a total of 48 weeks. According to ClinicalTrials.gov the results of the futility analysis led to the trial termination in 2022. WO 2021/205032, the content of which is herein incorporated by reference, discloses inhibitors of miR-21 which may be administered by inhalation. These inhibitors may comprise an oligonucleotide drug, e.g., an antisense molecule directed against miR-21 conjugated to a targeting moiety for delivery to lung macrophages. No specific formulations for inhalation are described. The publication by Beck et al. (Nature Communications (2023) 14: 4564; doi.org/10.1038/s41467-023-40185-1), the content of which is herein incorporated by reference, discloses a trimannose-conjugated antisense inhibitor of microRNA-21, designated RCS-21, as a therapeutic agent against hyperinflammation and fibrosis. No specific formulations for inhalation are described. It was an objective of the present invention to provide a safe and effective dosing regimen for administering an oligonucleotide drug to a human subject by inhalation. Summary of the Invention A first aspect of the present invention is a formulation comprising an oligonucleotide drug as an active agent for administration to a human subject in need thereof by inhalation wherein the oligonucleotide drug is an antagonist of miR-21. In certain embodiments, the oligonucleotide drug is a conjugate comprising an oligonucleotide moiety and a targeting moiety for delivering the oligonucleotide moiety to a predetermined target cell, e.g., a macrophage. In certain embodiments, the targeting moiety is a carbohydrate moiety, e.g., a trimannose moiety. In even more particular embodiments, the oligonucleotide drug is compound RCS-21 or a physiologically acceptable salt thereof: wherein the capital letters T, C, A and G in the oligonucleotide moiety represent nucleotide building blocks comprising the nucleobases thymine, 5-methyl cytosine, adenine, and guanine, respectively,the lower-case letter s represents a phosphorothioate internucleosidic bond between two nucleotide building blocks,the lower-case letter b after a capital letter denotes a locked nucleotide building block having a 2'-O-CH2-4' bridge, andthe lower-case letter d before a capital letter denotes a 2'-deoxyribonucleotide building block. A further aspect of the present invention relates to a method of treating a human subject in need thereof, comprising administering to said subject a therapeutically effective amount of a formulation by inhalation, wherein the formulation comprises an oligonucleotide drug as an active agent wherein the oligonucleotide drug is an antagonist of miR-21. Detailed description The present inventors have developed a dosing regimen for administering an oligonucleotide drug to a human subject by inhalation wherein the oligonucleotide drug is an antagonist of miR-21. At present, a phase 1 clinical trial based on the dosing regimen of the present invention is planned. The term "antagonist of miR-21" as used herein relates to an oligonucleotide drug which is capable of reducing and/or blocking the physiological activity of miR-21, e.g., by acting as an antisense molecule and/or by RNA interference. In certain embodiments, the oligonucleotide drug comprises an oligonucleotide having the nucleotide sequence (SEQ ID NO.1):         5'-TCAGTCTGATAAGCT-3' wherein each indicated nucleotide building block is a deoxyribonucleotide building block or a modified nucleotide building block. In certain embodiments, the modified nucleotide building block may be a 2'-modified ribonucleotide wherein the 2'-OH substituent of ribose moiety is replaced by halo, e.g., F, -C1-C5 alkyl, -O-C1-C5 alkyl, e.g. -OCH3, -S-C1-C5 alkyl, -C2-C5 alkenyl, -O-C2-C5 alkenyl, -S-C2-C5 alkenyl, -C2