WO2025163212A2 - Succinic acid or a pharmaceutically acceptable salt thereof for use in the treatment of chronic rhinosinusitis - Google Patents

Abstract

The present disclosure relates to succinic acid or a pharmaceutically acceptable salt thereof for use in the treatment of chronic rhinosinusitis.

Description

P28812PC00 04.06.2025 1/9 SUCCINIC ACID OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF FOR USE IN THE TREATMENT OF CHRONIC RHINOSI- NUSITIS TECHNICAL FIELD The present invention is in the field of medicine and refers to succinic acid or a pharmaceutical salt thereof for use in the treatment of chronic rhinosinusitis (CRS). BACKGROUND ART Chronic rhinosinusitis is one of the most common chronic inflammatory diseases of the upper respiratory airways. It affects the respiratory and often also the ol- factory epithelium lining the nasal cavity and/or the paranasal sinuses. Current pharmacological treatment modalities include various options depending on the severity and disease subtype. The armamentarium includes irrigations, alpha-2 adrenergic decongestants, corticosteroids and other more specific immunomod- ulatory interventions as well as, in case of infective and allergic etiologies, anti- infectives and antihistamines. Chronic rhinosinusitis is a heterogeneous condition with different pathophysiologies. The sinonasal mucosa is a complex immune or- gan that protects the organism not only against microbes but also against other noxious stimuli by the formation of a physical barrier provided with a mucociliary self-clearance mechanism. This multifunctional epithelial barrier is impaired in patients with chronic rhinosinusitis. Kato A et al. J Allergy Clin Immunol.2022, 149: 1491-1503. Succinate is a common metabolite which plays a central role in cellular respiration as donor of electrons in the respiratory complex II and in mitochondrial metabo- lism as intermediate of the tricarboxylic acid cycle. In addition to these roles in mitochondria succinate has more recently been recognized as an important me- diator of a variety of responses. It plays a role in reactive oxygen species signal- ing which enables neuronal insulin and IGF receptor activation. Persiyantseva N A et al. J Molec Signaling 2013, 8: 11. It is further a mediator of the hypoxic re- sponse by stabilizing HIF-1-α. Corcoran S E and O’Neill L A J. J Clin Invest 2016, 126: 3699-3707 and of post-translational protein modification through succinyla- tion. Weyh M et al. Nature Chem.2024, 16: 913-921. In addition, extracellularly released succinate acts as intercellular messenger by interacting with a cell sur- face receptor called GPR91 or succinate receptor (SUCNR1). He W et al. Nature P28812PC00 04.06.2025 2/9 2004, 429: 188-193. This G-protein coupled receptor is widely expressed in many tissues. The pharmacology of SUCNR1 stimulation is complex and not fully un- derstood yet. Not only vary the signal transduction systems between cell types but the effects of succinate seem to depend also on the pathophysiological state. Relevant in the current context is the experimental finding that activating SUCNR1 has more frequently pro-inflammatory and less frequently anti-inflam- matory effects. Fernandez-Veledo S et al. Diabetologia 2024, 67: 430-442. In the intestine of pigs succinate seems in addition to play an important role in the reg- ulation of the epithelial barrier function. Connors J et al. Nutrients 2019, 11: 25. Choline succinate salt 2:1 is a pharmaceutically acceptable salt of succinic acid that is useful in the treatment of insulin resistance, cerebral ischemia and other diseases of the central nervous system. Storozheva Z I et al. BMC Pharmacol. 2008, 8:1. RU2228174C2, RU2281765C1, RU2281766C1, EA017094B, EA016274B1, EA019584B1, US7666908B2, US6521665B1, US8673977B2, EP1156795B1, JP3944393B2, CN101801368В, CN102223883В. However, nothing is known about the use of choline succinate salt 2:1 in the intranasal treatment of chronic rhinosinusitis. In summary: Chronic rhinosinusitis is a severe, tissue damaging inflammatory disease of the upper airways, succinate a signaling metabolite orchestrating stress response with mostly pro-inflammatory effects. Wu, K K. Int J Mol Sci 2023, 24: 11165. The finding that intranasal administration of succinate improves the clinical symptoms of chronic rhinosinusitis could therefore not be expected. DISCLOSURE OF INVENTION The present invention provides succinic acid or a pharmaceutically acceptable salt thereof for use in the treatment of chronic rhinosinusitis. Another aspect of the present invention relates to a use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic rhinosinusitis. Succinic acid, other names butanedioic acid or 1,4-butanedioic acid, has the for- mula C4H6O4, chemical structure of HOOCCH2CH2COOH, and CAS registry number 110-15-6. A pharmaceutically acceptable salt of succinic acid can be prepared from organic and inorganic bases by known methods. Such bases include, but are not limited to, nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, P28812PC00 04.06.2025 3/9 sodium and potassium hydroxide; ammonium hydroxide and nontoxic organic ba- ses, such as triethylamine, ethanolamine, dimethylethanolamine, butylamine, di- ethanolamine, triethanolamine, or choline. Preferably, the choline salt of succinic acid is the dicholine succinate salt accord- ing to formula (I): Formula (I) The dicholine succinate salt of formula (I) has the formula C14H32N2O6 and the CAS number 109438-15-5 and can be prepared by reaction of choline hydroxide with succinic acid at molar ratio of about 2:1 as disclosed in RU2228174C2. As used herein, the term “chronic rhinosinusitis" (CRS) refers to a group of in- flammatory diseases of the nasal and paranasal cavities either accompanied by polyp formation or without polyps. CRS is thus used herein as an umbrella term including chronic rhinitis (CR). However, in a particular aspect of the present in- vention, chronic rhinitis (CR) can be excluded. As used herein, the term “treatment” refers to any action that improves or bene- ficially changes the symptoms of a specific disease by administration of the prod- uct of the present invention. As used herein the term "intranasal" refers to administration of the product of the present invention to any portion of the nasal and/or paranasal epithelium. As used herein the term "product" refers to any pharmaceutical formulation com- prising succinic acid or a pharmaceutically acceptable salt thereof. In practicing the invention, succinic acid or a pharmacologically acceptable salt thereof is typically administered intranasally as an aqueous solution using a nasal spray or pipette. The dosing is typically done once to ten times daily, but it can also be allowed ad libitum. The concentration of the preparation is preferably slightly hypertonic with a concentration of succinic acid typically between 30 mM and 300 mM. A single dose of succinic acid according to this invention ranges typically from 1.4 mg and 14 mg, if the preparation is administered as nasal spray by applying 2 strokes of 100 μL each per nostril. To adjust for the appropriate tonicity any pharmaceutically acceptable salt can be added. The following example demonstrates the usefulness of the invention. P28812PC00 04.06.2025 4/9 Example This example illustrates the use of the succinic acid salt of formula (I) in the treat- ment of chronic rhinosinusitis. For the clinical testing of the preparation described herein an aqueous solution of the dicholine succinate salt of formula (I) was prepared by reaction of choline hydroxide with succinic acid, as disclosed in RU2228174C2. For drug administra- tion a sterile 7% solution (216 mM) was prepared and filled aseptically into a microbiologically safeguarded dispenser system (nasal spray) with a volume of 10 mL. The average spray volume was 0.10 mL per stroke. A single dose was defined as 2 strokes of 100 μL per each nostril, corresponding to 28 mg of the salt of formula (I). To test for the therapeutic effects of succinate, single case studies were carried out in patients with chronic rhinosinusitis. All patients used a nasal spray of 7% dicholine succinate of formula (I) as described. The patients were allowed to use the spray ad libitum but had to use it at least twice a day, once in the morning and once in the evening. The spray bottles were weighed before and after the treatment to calculate the average number of doses administered. As primary endpoint for clinical testing the SNOT-22 questionnaire (Sino-Nasal Outcome Test with 22 questions) allowing theoretically for scores from 0 to 110 was used. Hopkins C et al. Clin Otolaryngol 2009, 34: 447-454. This clinically validated questionnaire measures the subjective symptoms of chronic rhinosinus- itis. Clinical response to dicholine succinate of formula (I) was assessed by re- cording for each individual patient the change of the SNOT-22 score between baseline and after the treatment period of variable duration. As secondary endpoints four additional outcome measures were assessed be- fore and after the treatment period, if appropriate: i) a Visual Analog Scale (VAS) of nasal discomfort with a range from 0 to 100, ii) a VAS of headache with a range from 0 to 100, iii) the Peak Nasal Inspiratory Flow (PNIF) measured with a PNIF meter from GM Instruments (Irvine, Ayrshire, UK) in L/min to assess nasal ob- struction Araújo‑Martins J et al. Scientific Reports 2020, 10:12674, and iv) a standardized 8-item olfactory test resulting in a score of 0 to 8 correct answers. Briner H R and Simmen D. Rhinology 1999, 37: 145-148. At the end of the treat- ment the patients were asked for their subjective rating of their condition: worse, unchanged, slightly improved, improved or strongly improved, respectively. The outcome of the individual case studies is shown in Table 1 below. P28812PC00 04.06.2025 5/9 Table 1. Outcome of the individual case studies. Case Nr. 01 02 03 04 05 06 07 08 09 10 11 Diagnosis CRS CR CRS CRS CRS CR CRS CR CRS CRS CRS Age 35 39 77 31 31 74 52 67 74 40 72 Sex f m m m m f m f f m f Treatment (days) 14 14 14 15 13 14 14 14 120 14 14 Doses/day 3.5 4.3 2.4 2.7 0.7 3.6 3.0 2.5 4.3 1.9 2.3 SNOT score _before 56 43 39 50 50 49 26 15 75 13 49 SNOT score after 14 27 8 19 36 31 10 12 16 11 34 Δ SNOT score -42 -16 -31 -31 -14 -18 -16 -3 -59 -2 -15 VAS nasal before 56 77 50 92 73 50 38 42 98 31 25 VAS nasal _after 22 75 19 30 60 22 12 2 28 12 17 Δ VAS nasal -34 -2 -31 -62 -13 -28 -26 -40 -70 -19 -8 VAS headache _before 51 2 61 27 15 42 13 2 98 1 83 VAS headache after 6 3 1 18 2 23 3 2 17 0 40 Δ VAS headache -45 +1 -60 -9 -13 -19 -10 0 -81 -1 -43 PNIF before 135 25 70 150 115 110 120 80 20 175 190 PNIF _after 180 35 80 155 122 120 110 80 170 185 190 Δ PNIF +45 +10 +10 +5 +7 +10 -10 0 +150 +10 0 Smell _before 8/8 7/8 7/8 7/8 8/8 2/8 6/8 4/8 0/8 6/8 5/8 Smell _after 8/8 7/8 7/8 8/8 8/8 3/8 7/8 4/8 8/8 6/8 5/8 Δ Smell 0 0 0 +1 0 +1 +1 0 +8 0 0 Subjective s_{elf-assessment} ^{↑↑↑ Ø ↑↑ ↑↑ ↑ ↑ ↑ ↑ ↑↑↑ ↑ ↑↑} Legend: CRS = chronic rhinosinusitis, CR = chronic rhinitis. Δ = change of the related parameter. Self-assessment: unchanged (Ø), slightly improved (↑), im- proved (↑↑), strongly improved (↑↑↑) P28812PC00 04.06.2025 6/9 To calculate the statistical significance (p-value) of the average change of each parameter, the Wilcoxon two-sided signed-rank test was used (Table 2): Table 2. Statistical efficacy evaluation of the case studies. Parameter Average change ± SD P-value (n = 11) S^{NOT-22 score} _{- 22 ±17 0.004} V^{AS nasal} _{- 30 ±21 0.001} V^{AS headache} _{- 25 ±28 0.009} P^{NIF (L/min)} _{+22 ±45 0.040} S^{mell test} _{no meaningful statistical evaluation possible} Chronic rhinosinusitis is associated with several clinical symptoms which are best assessed by the SNOT-22 questionnaire. Nasal and/or paranasal discomfort is common and often strong, while headache, airway obstruction and olfactory im- pairment are more variable and not always pronounced. The case studies show that treatment of chronic rhinosinusitis with the dicholine succinate salt of formula (I) improves the condition of the disease, thus demonstrating the therapeutic po- tential of the preparation described by the present invention.

Claims

P28812PC00 04.06.2025 7/9 PATENT CLAIMS 1. Use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic rhinosinusitis. 2. Use according to claim 1, wherein the pharmaceutically acceptable salt of succinic acid is dicholine succinate according to formula (I). Formula (I) 3. Use according to one of claims 1 or 2, wherein the medicament is an aqueous solution of succinic acid or a pharmaceutically acceptable salt thereof. 4. Use according to claim 3, wherein the concentration of succinic acid or a pharmaceutically acceptable salt thereof in the solution is between 30 mM and 300 mM. 5. Use according to one of claims 3 or 4, wherein the pH of the solution is be- tween 6.5 and 7.5. 6. Use according to one of claims 1 to 5, wherein the medicament is adminis- tered intranasally, in particular as an aqueous solution by using a nasal spray or a pipette. P28812PC00 04.06.2025 8/9 7. Use according to claim 6, wherein a single dose ranges from 1.4 mg to 14 mg succinic acid or succinate. 8. Use according to one of claims 6 or 7, wherein the dosing is done once to ten times daily.