Soluble guanylate cyclase activators for treatment of systemic sclerosis

Abstract

The present invention relates to a method for treating a patient suffering from systemic sclerosis comprising administering to a patient in need thereof a therapeutically effective amount of a soluble guanylate cyclase (sGC) activator of formula (I): wherein R1-R7 and A are as defined herein, or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the use of specific soluble guanylate cyclase activators for the treatment of systemic sclerosis. Background Art

[0002] Systemic sclerosis is a destructive disease of unknown etiology. It is a rare, chronic, heterogeneous connective tissue disease with vascular, inflammatory, and fibrotic features, and it mainly affects women. The estimated worldwide prevalence of SSc is 17.6 / 100,000, ranging from 6.8 / 100,000 in Asia to 25.9 / 100,000 in North America. (M. Bairkdar et al., “Incidence and prevalence of systemic sclerosis globally: a comprehensive systematic review and meta-analysis”, Rheumatology 2021; 60(7): 3121-3133.) It is considered a rare disease, with a prevalence of approximately 50 to 300 / million in the United States, 20 to 50 / million in Asia, and 100 to 200 / million in Europe. (See, for example, J. Barnes et al., “Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers”, Curr Opin Rheumatol 2012; 24(2): 165-170 and A. Gabrielli et al., N Engl J Med 2009; 360(19): 1989-2003.) The disease progression is variable and unpredictable, with an estimated cumulative survival rate of 74.9% from diagnosis to 5 years and 62.5% from diagnosis to 10 years. (B. Thoreau et al., “Treatment of systemic sclerosis”, Presse Med (Paris) 2021: 50(1): 104088.) In systemic sclerosis-associated interstitial lung disease (SSc-ILD), the median survival is 5 to 8 years. (E. L. Herzog et al., “Interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct?”, Arthritis and Rheumatology, 2014. pp. 1967-1978.)

[0003] Systemic sclerosis is characterized by potentially extensive and progressive skin fibrosis and vascular abnormalities, with early development of Raynaud phenomenon (RP), and may affect the musculoskeletal, gastrointestinal, pulmonary, cardiac, renal, neuromuscular, and urogenital systems. Clinical features are heterogeneous and cover a wide range of disease severity and manifestations. Raynaud phenomenon is a common initial manifestation, followed by joint and muscle pain, fatigue, skin tightening, calcinosis, and DU. Patients with these symptoms have difficulty managing their daily lives and may be stigmatized due to their facial appearance and limb deformities. These external features are associated with internal organ involvement, including gastrointestinal disorders, renal failure, and lung disease, with interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) being the most common causes of death.

[0004] Due to the heterogeneity of clinical manifestations and organ involvement, current disease management involves individually tailored organ-based symptomatic therapies. Symptomatic treatment of SSc-related organ complications may include immunosuppressants, dihydropyridine calcium antagonists, endothelin receptor antagonists, the soluble guanylate cyclase (sGC) stimulator riociguat, prostacyclin analogs, and PDE-5 inhibitors. (O. Kowal-Bielecka et al., “Update of EULAR recommendations for the treatment of systemic sclerosis”, Ann Rheum Dis 2017; 76:1327-1339). Immunosuppressive and anti-fibrotic therapies have been proposed for the treatment of SSc, but controlled data are limited. Nintedanib and tocilizumab have been approved for SSc ILD. Currently, there is no disease-modifying therapy to address underlying vascular lesions and prevent organ damage caused by vascular lesions. Summary of the Invention

[0005] The present invention relates to a method for treating a patient suffering from systemic sclerosis, which comprises administering to the patient a pharmaceutically effective amount of a soluble guanylate cyclase (sGC) activator or a pharmaceutically acceptable salt thereof.

[0006] In another embodiment, the present invention relates to a method for treating a patient suffering from diffuse cutaneous systemic sclerosis (dcSSc) and vascular lesions, which comprises administering to the patient a therapeutically effective amount of an sGC activator or a pharmaceutically acceptable salt thereof.

[0007] The present invention also relates to an SGC activator or a pharmaceutically acceptable salt thereof for treating a patient suffering from dcSSc and vascular lesions.

[0008] In another embodiment, the present invention relates to a method for treating a patient suffering from early progressive dcSSc and vasculopathy, which comprises administering to the patient a therapeutically effective amount of an sGC activator or a pharmaceutically acceptable salt thereof.

[0009] The present invention also relates to an sGC activator or a pharmaceutically acceptable salt thereof for treating a patient suffering from early progressive dcSSc and vasculopathy.

[0010] WO 2014 / 039434 and WO 2020 / 011804 describe oral small molecule activators of sGC (“sGC activators of the present invention”) suitable for the methods of the present invention.

[0011] In one embodiment of the present invention, the sGC activator for use in the method of the present invention is a compound of formula (I)

[0012]

[0013] Wherein:

[0014] A is a 5- to 7-membered saturated heterocyclic group containing one nitrogen and optionally one oxygen, wherein one carbon in the heterocyclic group is optionally substituted by one or two groups selected from C 1-3 alkyl and oxo;

[0015] R 1 is C 1-4 alkyl optionally substituted by methoxy;

[0016] R 2 is selected from H, F, Cl, C 1-3 alkyl, -CN, -OMe and -CF3;

[0017] R 3 is selected from H and -CH3;

[0018] R 4 is selected from H, F, -CH3 and -OMe;

[0019] R 5 is selected from H, Cl, -CH3, -CH2CH3, -CF3, F and -OMe;

[0020] R 6 is bonded to the nitrogen on A and is selected from H, C 1-6 alkyl, -(CH2) n C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -(CH2) n heterocyclic group, -(CH2) nAryl, -(CH2) n Heteroaryl, -SO2aryl, SO2C 1-6 Alkyl, wherein said C 1-6 Alkyl, -(CH2) n Heterocyclic group, -(CH2) n Cycloalkyl, -(CH2) n Aryl and -(CH2) n Heteroaryl is optionally substituted with one to four groups independently selected from C 1-3 Alkyl, halogen, C 1-3 Alkoxy, -CF3, -OH, oxo, -(CH2) 1-3 O(CH2) 2-3 OH and -SO2CH3;

[0021] R 7 Is selected from H, -CH3, -CH2CH3, -CF3, F and -CN;

[0022] n is 0, 1 or 2

[0023] Or a salt thereof.

[0024] Unless otherwise specified herein, the terms "compound of formula (I)", "sGC activator of the present invention" and "compound of the present invention" are used interchangeably.

[0025] In another embodiment, the present invention relates to the method described in the above embodiments, wherein:

[0026] A is a 5- to 7-membered saturated heterocyclic group containing one nitrogen, wherein one carbon in the heterocyclic group is optionally substituted with one or two C 1-3 Alkyl substitution;

[0027] R 1 Is C 1-3 Alkyl;

[0028] R 2 Is selected from H, F, Cl, C 1-3 Alkyl, -CN, -OMe and -CF3;

[0029] R 3 Is selected from H and -CH3;

[0030] R 4 Is selected from H and F;

[0031] R 5 Is selected from H, Cl and -CH3;

[0032] R 6 Is bonded to the nitrogen on A and is selected from H, C 1-6 Alkyl, -(CH2)n C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl, -(CH2) n Heterocyclic group, -(CH2) n Aryl and -(CH2) n Heteroaryl, wherein the C 1-6 Alkyl, -(CH2) n Heterocyclic group, -(CH2) n Cycloalkyl, -(CH2) n Aryl and -(CH2) n Heteroaryl is optionally substituted by one to four groups independently selected from C 1-3 Alkyl, halogen, C 1-3 Alkoxy, -CF3, -OH and -SO2CH3;

[0033] R 7 is H;

[0034] and

[0035] n is 0, 1 or 2;

[0036] or a salt thereof.

[0037] In another embodiment, the present invention relates to the method described in any of the above embodiments, wherein:

[0038] R 1 is methyl, ethyl or isopropyl; and

[0039] group

[0040] is selected from:

[0041]

[0042] or a salt thereof.

[0043] In another embodiment, the present invention relates to the method described in any of the above embodiments, wherein:

[0044] R 2 is selected from -CH3, F, Cl and -CF3; and

[0045] R 6 is selected from H, C 1-6 Alkyl, -(CH2) n C 3-6 Cycloalkyl, -C(O)C 1-6 Alkyl and -(CH2) n Heterocyclic group, wherein the C 1-6 Alkyl, -(CH2) n Cycloalkyl and -(CH2)n The heterocyclic group is optionally substituted by one to four groups independently selected from C 1-3 alkyl, halogen, C 1-3 alkoxy, -CF3, -OH, and -SO2CH3;

[0046] or a salt thereof.

[0047] In another embodiment, the present invention relates to the method as described in any of the above embodiments, wherein R 6 The heterocyclic group mentioned therein is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxabicyclo[3.2.0]heptanyl, [1,4]dioxanyl, 8-oxabicyclo[3.2.1]octanyl, 1-oxaspiro[4.5]decanyl, and pyrrolidin-2-one; R 6 The heteroaryl group mentioned therein is selected from imidazolyl, isoxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, thiazolyl, and 4,5,6,7-tetrahydrobenzothiazolyl;

[0048] And R 6 The aryl group mentioned therein is phenyl;

[0049] or a salt thereof.

[0050] In another embodiment, the present invention relates to the method as described in any of the above embodiments, wherein:

[0051] R 6 is -(CH2) n heterocyclic group, wherein the heterocyclic group is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2-oxabicyclo[3.2.0]heptanyl, [1,4]dioxanyl, 8-oxabicyclo[3.2.1]octanyl, and 1-oxaspiro[4.5]decanyl;

[0052] or a salt thereof.

[0053] In another embodiment, the present invention relates to the method as described in any of the above embodiments, wherein:

[0054] R 2 is -CH3;

[0055] R 3 is H;

[0056] R 4 is H or -CH3;

[0057] R 5 is H or -CH3;

[0058] R 7 is located at R 5Para-position and is H, -CH3 or -CH2CH3;

[0059] or a salt thereof.

[0060] In another embodiment, the present invention relates to the method described in any of the above embodiments, wherein:

[0061] The group

[0062] is

[0063]

[0064] or a salt thereof.

[0065] In another embodiment, the present invention relates to the method described in any of the above embodiments, wherein:

[0066] R 3 is H; and

[0067] R 4 is H;

[0068] or a salt thereof.

[0069] Table 1 shows representative compounds of the present invention that can be used according to the method of the present invention.

[0070] Table 1

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099] In one embodiment, the sCG activator for use in the method of the present invention is selected from any one of the compounds depicted in Table 1 above and their pharmaceutically acceptable salts.

[0100] In another embodiment, the sCG activator for use in the method of the present invention is selected from the group consisting of Compound Nos. 1, 2, 3, 4, 5, 7, 8, 9, 12, 15, 16, 18, 21, 27, 28, 30, 31, 35, 36, 39, 41, 42, 44, 45, 46, 47, 48, 57, 59, 62, 68, 77, 78, 79, 80, 82, 83, 84, 85, 86, 88, 92, 93 and 94 and their pharmaceutically acceptable salts, which are depicted in Table 1.

[0101] In another embodiment, the sCG activator for use in the methods of the present invention is selected from the group consisting of Compound Nos. 95, 97, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 136, 137, 139, 140, 141, 142, 145, 146, 152, 153, 154, 155, 157, 158, 159, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 184, 185, 186, 187, 188, 189, 191, 193, 194, 195, 196, 197, 198, 199, 201, 202, 203, 204, 205, 206, 207, 208, 210, 211, 212, 213, 214, 215, 216, 220, 222, 223, 224, 225, 227, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257 and their pharmaceutically acceptable salts, and these compounds are depicted in Table 1.

[0102] In one embodiment, the sCG activator for use in the methods of the present invention is Compound No. 114. BRIEF DESCRIPTION OF THE DRAWINGS

[0103] In the drawings, “Ex 114” refers to Compound 114; “Ninte” or “Nin” refers to nintedanib; “bleo” refers to bleomycin; and “EX637” or “EX 76637” refers to riociguat.

[0104] Figure 1 Shows hypoxia-induced TGFb2 production by Compound 114 in primary human microvascular endothelial cells.

[0105] Figures 2A to 2C Shows the dermal thickness of bleomycin-induced skin fibrosis ( Figure 2A ), reduced myofibroblast count ( Figure 2B ), and lower hydroxyproline content ( Figure 2C) The effects on the P-value less than 0.05 are considered statistically significant; the p-values are represented as follows: 0.05 > p > 0.01 as *; 0.01 > p > 0.001 as **, 0.001 > p > 0.0001 as *** and p < 0.0001 as ****.

[0106] Figures 3A to 3C Shows the effects of bleomycin-induced pulmonary fibrosis on the Ashcroft score ( Figure 3A ), the collagen coverage area ( Figure 3B ), and the hydroxyproline content ( Figure 3C ). The p-value less than 0.05 is considered statistically significant; the p-values are represented as follows: 0.05 > p > 0.01 as *; 0.01 > p > 0.001 as **, 0.001 > p > 0.0001 as *** and p < 0.0001 as ****; non-significant differences are marked as ns.

[0107] Figure 4 Shows that the ADP-induced CXCL4 secretion is reduced by compound 114 (Ex 114).

[0108] Figure 5 Shows that the sGC activator compound 114 (Ex 114) significantly reduces ADP-induced CXCL4 production in a dose-dependent manner. Figure 5 Also shows that compound 114 is more potent / effective than nintedanib (Nin), mycophenolate mofetil (MMF), and riociguat (EX637).

[0109] Figure 6 Shows the overall trial design, including randomization, placebo control, double-blind, parallel-group efficacy, and safety comparison between two groups (treatment group and placebo group) within 48 weeks. Detailed implementation

[0110] Table 2. Abbreviations.

[0111]

[0112]

[0113]

[0114]

[0115] Unless otherwise specified, throughout this specification and the appended claims, a specified chemical formula or name shall encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures of any of the foregoing forms in which such isomers and enantiomers are present, and salts (including pharmaceutically acceptable salts thereof) and solvates (such as hydrates), including solvates of the free compound or solvates of the salt of the compound.

[0116] Some compounds of formula (I) may exist in more than one tautomeric form. The present invention includes methods using all such tautomers.

[0117] The present invention includes pharmaceutically acceptable derivatives of the compounds of formula (I). "Pharmaceutically acceptable derivatives" means any pharmaceutically acceptable salt or ester, or any other compound which, when administered to a patient, is capable of (directly or indirectly) providing a compound suitable for use in the present invention or its pharmacologically active metabolite or pharmacologically active residue. A pharmacologically active metabolite will be understood to mean any compound of the present invention that can be metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of formula (I).

[0118] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the invention in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include (but are not limited to) inorganic or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and the like. By way of example, such salts include acetate, ascorbate, benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, bromide / hydrobromide, edetate, camphorsulphonate, carbonate, chloride / hydrochloride, citrate, edisylate, ethanedisulphonate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycollylarsanilates, hexylresorcinol, hydrabamine, hydroxyfumarate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulphonate, methylbromide, methylnitrate, methylsulphate, mucate, naphthalenesulphonate, nitrate, oxalate, pamoate, pantothenate, phenylacetate, phosphate / diphosphate, pectinate, propionate, salicylate, stearate, subacetate, succinate, sulphamide, sulphate, tannate, tartrate, teoclate, toluenesulphonate, triethyl iodide, ammonium salts, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, glucamine and procaine. Other pharmaceutically acceptable salts may be formed from cations of metals such as aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (See also Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).

[0119] The pharmaceutically acceptable salts of the invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or free base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or mixtures thereof.

[0120] In addition to those mentioned above, salts of other acids (e.g., trifluoroacetate) suitable for purifying or isolating the compounds of the invention also form part of the invention.

[0121] In addition, the use of prodrugs of the compounds of formula (I) is within the scope of the present invention. Prodrugs include those compounds that are modified upon simple chemical transformation to produce the compounds of the present invention. Simple chemical transformations include hydrolysis, oxidation, and reduction. Specifically, when a prodrug is administered to a patient, the prodrug can be converted to the compounds disclosed above, thereby imparting the desired pharmacological effect.

[0122] The compounds of the present invention are only those compounds that would be considered "chemically stable" as would be understood by one of ordinary skill in the art. For example, compounds having "dangling valences" or "carbanions" are not the compounds contemplated by the methods of the present invention disclosed herein.

[0123] For all compounds disclosed above in this application, in the event of a conflict between the nomenclature and the structure, it should be understood that the compound is defined by the structure.

[0124] Unless otherwise indicated, all terms used in this specification should be understood to have their ordinary meanings as known in the art. For example, "C 1-4 alkyl" is a saturated aliphatic hydrocarbon monovalent group containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, or tert-butyl; "C 1-4 alkoxy" is a C 1-4 alkyl having a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy. Unless otherwise specified, all alkyl, alkenyl, and alkynyl groups should be understood to be structurally capable of being branched or unbranched, cyclic or acyclic. Other more specific definitions are as follows:

[0125] The term "C 1-n alkyl" (where n is an integer from 2 to n), alone or in combination with another group, denotes an acyclic saturated branched or straight-chain hydrocarbon group having 1 to n C atoms. For example, the term C 1-5 alkyl encompasses the groups H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)-, and H3C-CH2-CH(CH2CH3)-.

[0126] The term "C 1-n"-alkylene" alone or in combination with another group means an acyclic straight or branched chain divalent alkyl group containing from 1 to n carbon atoms. By way of example, the term C 1-4 -alkylene includes -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C(CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CHCH(CH3)2)- and -C(CH3)(CH2CH3)-.

[0127] The term "C 3-n -cycloalkyl" alone or in combination with another group means a cyclic saturated unbranched hydrocarbon group containing from 3 to n carbon atoms. By way of example, the term C 3-7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0128] As used herein, the term "heteroatom" is to be understood to mean an atom other than carbon, such as O, N, S and P.

[0129] In all alkyl or carbon chains, one or more carbon atoms may optionally be replaced by the following heteroatoms: O, S or N, it being understood that if N is unsubstituted, it is NH, and it is further understood that the heteroatom may replace a terminal or internal carbon atom within a branched or unbranched carbon chain. Such groups may be substituted by groups (such as oxo) as described above to give definitions such as, but not limited to, alkoxycarbonyl, acyl, amido and thioxo.

[0130] As used herein, the term "aryl" alone or in combination with another group denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be further fused to a second 5- or 6-membered carbocyclic group, which carbocyclic group may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl and dihydronaphthyl.

[0131] The term "heteroaryl" means an aromatic 5- to 6-membered monocyclic heteroaryl or an aromatic 7- to 11-membered heteroaryl bicyclic ring (at least one ring of which is aromatic), wherein the heteroaryl ring contains 1 to 4 heteroatoms such as N, O and S. Non-limiting examples of 5- to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and purinyl. Non-limiting examples of 7- to 11-membered heteroaryl bicyclic heteroaromatic rings include benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl, and benzothiazolyl.

[0132] The term "heterocyclyl" means a stable non-aromatic 4- to 8-membered monocyclic heterocyclic group or a stable non-aromatic 6- to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic group. The 5- to 11-membered heterocyclic ring consists of carbon atoms and one or more (preferably one to four) heteroatoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring may be saturated or partially unsaturated. Non-limiting examples of non-aromatic 4- to 8-membered monocyclic heterocyclic groups include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1λ 6 -Thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl and aza Azepinyl. Non-limiting examples of non-aromatic 6- to 11-membered fused bicyclic groups include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothienyl. Non-limiting examples of non-aromatic 6- to 11-membered bridged bicyclic groups include 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl, and 3-azabicyclo[3.2.1]octyl. Non-limiting examples of non-aromatic 6- to 11-membered spirocyclic heterocyclic groups include 7-aza-spiro[3,3]heptyl, 7-spiro[3,4]octyl, and 7-aza-spiro[3,4]octyl. The term "heterocyclyl" is intended to include all possible isomeric forms.

[0133] The term "halogen" as used in this specification is understood to mean bromine, chlorine, fluorine or iodine. Definitions "halogenated", "partially or completely halogenated", "partially or completely fluorinated", "substituted with one or more halogen atoms" include, for example, mono-, di- or tri-halogen derivatives on one or more carbon atoms. For alkyl, non-limiting examples would be -CH2CHF2, -CF3, etc.

[0134] Each alkyl, cycloalkyl, heterocycle, aryl or heteroaryl group or the like described herein is understood to be optionally partially or fully halogenated.

[0135] As used herein, "nitrogen" or N and "sulfur" or S include any oxidized form of nitrogen and sulfur and any quaternized form of any basic nitrogen. By way of example, unless otherwise specified, for -S-C 1-6 alkyl, this is to be understood to include -S(O)-C 1-6 alkyl and -S(O)2-C 1-6 alkyl, and likewise, when R a is phenyl and m is 0, 1 or 2 therein, -S-R a can be represented as phenyl-S(O) m -.

[0136] General synthesis method

[0137] The compounds of formula (I) for use in the methods of the present invention can be prepared by the methods and examples described in WO 2014 / 039434.

[0138] Method for therapeutic use

[0139] For therapeutic use, the compounds of formula (I) can be administered in any conventional pharmaceutical dosage form, in any conventional manner, via a pharmaceutical composition. Conventional dosage forms generally include pharmaceutically acceptable carriers suitable for the particular dosage form selected. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intra-articular, by infusion, sublingual, transdermal, oral, topical or by inhalation. Preferred modes of administration are oral and intravenous.

[0140] The compounds of formula (I) can be administered alone or in combination with adjuvants (including other active ingredients), which enhance the stability of the inhibitor, promote, in certain embodiments, the administration of the pharmaceutical composition containing it, provide increased dissolution or dispersion, increase inhibitory activity, provide adjuvant therapy and the like. By way of example, in one embodiment, multiple compounds of the present invention can be administered. Advantageously, such combination therapies use lower doses of conventional therapeutic agents and thus avoid the possible toxicities and adverse side effects incurred when these agents are used as monotherapies. The compounds of the present invention can be physically combined with conventional therapeutic agents or other adjuvants in a single pharmaceutical composition. Advantageously, the compounds can then be administered together in a single dosage form. In some embodiments, the pharmaceutical composition containing such a combination of compounds contains at least about 5%, but more preferably at least about 20%, of the compound of formula (I) (w / w) or a combination thereof. The optimal percentage (w / w) of the compounds of the present invention can vary and is within the scope of those skilled in the art. Alternatively, the compounds of the present invention and conventional therapeutic agents or other adjuvants can be administered separately (sequentially or simultaneously). Separate administration provides greater flexibility in the dosing regimen.

[0141] As mentioned above, the dosage forms of the compounds of formula (I) of the present invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable for such dosage forms. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffering substances, water, salts or electrolytes, and cellulose-based substances. Preferred dosage forms include tablets, capsules, cachets, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstitutable powders, granules, suppositories, and transdermal patches. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th Edition, Lea and Febiger (1990)). Specific dosages and treatment regimens will depend on factors such as the general health profile of the patient, the nature or the severity and course of the patient's condition, and the judgment of the treating physician.

[0142] In this context, "combination" or "combined" within the meaning of the present invention may include, but is not limited to, fixed and non-fixed (e.g., free) forms (including kits, or other administrations, administrations or dosage forms) and uses, such as simultaneous, sequential or separate use of an sGC activator as described herein and another therapeutic agent or concomitant therapy.

[0143] The combined administration or administration of the present invention can be carried out by co-administering the therapeutic components, such as by simultaneous administration in a single formulation or two separate formulations. Alternatively, the administration can be carried out by sequential administration of the therapeutic components, such as by sequential administration of two separate formulations.

[0144] For the combination therapy of the present invention, the therapeutic components can be administered separately (which implies their separate formulation) or formulated together (which implies their formulation in the same preparation). Thus, the administration of one component of the combination of the present invention can be before, simultaneous with, or after the administration of another component of the combination.

[0145] Non-limiting examples of another therapeutic agent include cyclophosphamide, mycophenolate mofetil, tocilizumab, nintedanib, and prednisone.

[0146] In one embodiment, the method of the present invention comprises administering to a patient a daily amount of from 0.1 mg to about 50 mg of an sGC activator of the present invention or a pharmaceutically acceptable salt thereof.

[0147] In another embodiment, the method of the present invention comprises administering to a patient a daily amount of from 1 mg to about 30 mg of an sGC activator of the present invention or a pharmaceutically acceptable salt thereof.

[0148] In another embodiment, the sGC activator of the present invention or a pharmaceutically acceptable salt thereof is administered to a patient in a daily amount of 0.1 to 100 mg; or 1 to 25 mg; or 1 to 10 mg; or 2 to 5 mg, or a pharmaceutically acceptable salt thereof.

[0149] In another embodiment, the sGC activator of the present invention or a pharmaceutically acceptable salt thereof is administered to a patient in an amount selected from the group consisting of: 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, and 10 mg.

[0150] In another embodiment, the SGC activator of the present invention or a pharmaceutically acceptable salt thereof is administered to a patient in an amount selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg.

[0151] In another embodiment, the method of the present invention comprises administering to a patient up to 3 mg of the SGC activator of the present invention or a pharmaceutically acceptable salt thereof.

[0152] In another embodiment, the method of the present invention comprises administering to a patient 1 mg of the SGC activator of the present invention or a pharmaceutically acceptable salt thereof.

[0153] In another embodiment, the method of the present invention comprises administering to a patient 2 mg of the SGC activator of the present invention or a pharmaceutically acceptable salt thereof.

[0154] In another embodiment, the method of the present invention comprises administering to a patient 3 mg of the SGC activator of the present invention or a pharmaceutically acceptable salt thereof.

[0155] Vasodilation by the sGC activator can cause orthostatic disorders and episodes of hypotension. Titration of the sGC activator can allow for further increases in the total daily exposure of the sGC activator while avoiding peak concentrations.

[0156] In one embodiment, the present invention relates to a method for preventing or reducing the severity of orthostatic disorders caused by, attributable to, or associated with the administration of an sGC activator or a pharmaceutically acceptable salt thereof, the method comprising administering to a patient a daily dose of the sGC activator QD, BID, or TID.

[0157] In another embodiment, the sGC activator is administered to the patient QD.

[0158] In another embodiment, the sGC activator is administered to the patient BID.

[0159] In another embodiment, the sGC activator TID is administered to a patient.

[0160] In another embodiment, the method of the invention comprises administering to a patient up to 3 mg of the sGC activator of the invention or a pharmaceutically acceptable salt thereof twice daily.

[0161] In another embodiment, the method of the invention comprises administering to a patient 3 mg of the sGC activator of the invention or a pharmaceutically acceptable salt thereof twice daily to provide a total daily dose of 6 mg of the sGC activator.

[0162] In another embodiment, the method of the invention comprises administering to a patient 2 mg of the sGC activator of the invention or a pharmaceutically acceptable salt thereof twice daily to provide a total daily dose of 4 mg of the sGC activator.

[0163] In another embodiment, the method of the invention comprises administering to a patient 1 mg of the sGC activator of the invention or a pharmaceutically acceptable salt thereof twice daily to provide a total daily dose of 2 mg of the sGC activator.

[0164] In another embodiment, the method of the invention comprises administering to a patient up to 3 mg of the sGC activator of the invention or a pharmaceutically acceptable salt thereof in a TID dosing regimen.

[0165] In another embodiment, the method of the invention comprises administering to a patient 3 mg of the sGC activator of the invention or a pharmaceutically acceptable salt thereof in a TID dosing regimen to provide a total daily dose of 9 mg of the sGC activator.

[0166] In another embodiment, the method of the invention comprises administering to a patient 2 mg of the sGC activator of the invention or a pharmaceutically acceptable salt thereof in a TID dosing regimen to provide a total daily dose of 6 mg of the sGC activator.

[0167] In another embodiment, the method of the invention comprises administering to a patient 1 mg of the sGC activator of the invention or a pharmaceutically acceptable salt thereof in a TID dosing regimen to provide a total daily dose of 3 mg of the sGC activator.

[0168] In another embodiment, the invention relates to a method of initiating treatment of a patient with an sGC activator. Non-limiting examples of initial treatment include escalating the amount administered to the patient from a low dose to a target dose.

[0169] In one embodiment, the initial treatment of a patient comprises:

[0170] administering the sGC activator of the invention at a dose of 1 mg TID for two weeks (the first and second weeks of treatment),

[0171] Administer the sGC activator at a dose of 2 mg TID for two weeks (weeks 3 and 4), and

[0172] Administer the sGC activator at a dose of 3 mg TID after week 4.

[0173] In another embodiment, the present invention relates to a method of treating a patient with systemic sclerosis, including patients with diffuse cutaneous systemic sclerosis (dcSSc) and vasculopathy, wherein the treatment results in improvement in the following aspects:

[0174] The rate of decline of FVC (mL) within 48 weeks compared to placebo,

[0175] The change in mRSS at week 48 relative to baseline,

[0176] The CRISS score at week 48 (improvement of ≥20% is achieved from baseline to week 48 in at least 3 of 5 core measures, excluding improvement in the percentage predicted FVC of ≥5%),

[0177] The change in HAQ-DI score at week 48 relative to baseline,

[0178] The change in PGA VAS at week 48 relative to baseline,

[0179] The change in CGA VAS at week 48 relative to baseline,

[0180] The composite measure of RP activity at week 48,

[0181] The change in DU net burden at week 48 relative to baseline, and / or

[0182] The time to treatment failure, defined as the time of the first occurrence of any of the following events during weeks 48 and the extended treatment period, which events are selected from:

[0183] Death,

[0184] An absolute decline in the percentage predicted FVC of ≥10% relative to baseline,

[0185] An increase in mRSS of ≥25% and an increase in mRSS > 5 points, and

[0186] Initiation of or a change in the dose of immunomodulatory / immunosuppressive therapy due to a clinically significant worsening of dcSSc.

[0187] In another embodiment, the present invention relates to a method of treating a patient with systemic sclerosis, including patients with diffuse cutaneous systemic sclerosis (dcSSc) and vasculopathy, wherein the treatment results in improvement in the following aspects:

[0188] Absolute change in the FACIT-Fatigue Scale score at Week 48 relative to baseline,

[0189] Absolute change in the SSPRO score at Week 48 relative to baseline,

[0190] Absolute change in the EQ-5D-5L score at Week 48 relative to baseline,

[0191] Absolute change in the Worst Pain NRS score at Week 48 relative to baseline,

[0192] Absolute change in the scores of six individual domains of SHAQ (pain, bowel problems, respiratory problems, RP, finger ulcers, disease severity) at Week 48 relative to baseline,

[0193] PGIC score at Week 48,

[0194] Change in the predicted percentage of DLCO at Week 48 relative to baseline,

[0195] Overall graded composite score (GRCS) at the end of the extension treatment period or at the end of the 48-week primary assessment treatment period, compared to patients who did not participate in the extension treatment period,

[0196] Annual decline rate of FVC (mL) during the primary assessment treatment period and the extension treatment period,

[0197] Change in the presence or absence of crepitus relative to baseline at Week 48,

[0198] Change in joint involvement (tender and swollen joint count - 28) at Week 48 relative to baseline, and / or

[0199] Absolute change in RCS at Week 48 relative to baseline.

[0200] Patients treated with the sCG activator of the present invention may be treated with one or more other therapeutic agents. Non-limiting examples of such one or more other therapeutic agents include cyclophosphamide, mycophenolate mofetil, tocilizumab, nintedanib, and prednisone.

[0201] Clinical trial protocol

[0202] Clinical trials

[0203] The following describes a clinical trial protocol related to the treatment of patients with early progressive dcSSc and vasculopathy. The trial will evaluate the efficacy, safety, and tolerability of the compounds of the present invention compared to placebo in the context of local standard of care (SOC) therapy for adult patients with early progressive dcSSc and vasculopathy.

[0204] Diffuse cutaneous systemic sclerosis (dcSSc) is a subtype of systemic sclerosis (scleroderma) and is characterized by skin hardening (fibrosis) and problems in many organs of the body. Symptoms include Raynaud's phenomenon; skin fibrosis that begins in the fingers and face and quickly becomes systemic; "spider veins" (telangiectasias) on the chest, face, lips, tongue, and fingers; gastroesophageal reflux; and difficulty swallowing (dysphagia), as well as weight loss, vomiting, diarrhea, or constipation. Dry mouth and dental involvement may occur. Joint pain (arthralgia), muscle pain, weakness, abdominal pain, and destruction of the tips of the fingers or toes (acroosteolysis) are common. More serious problems involving the lungs and kidneys may also occur. The exact cause of the condition is unknown.

[0205] Trial Objectives and Endpoints

[0206] Primary Objective: This trial will evaluate the efficacy, safety, and tolerability of 3 mg TID Compound 114 compared to placebo in the context of local SOC therapy in adult patients with early progressive dcSSc and vasculopathy.

[0207] The primary objective is to demonstrate the superiority of 3 mg TID target dose of Compound 114 compared to placebo based on the mean difference in the annual rate of decline of FVC over 48 weeks. The primary treatment effect of interest will be based on all randomized patients, including the effect of any treatment changes, i.e., a treatment policy strategy will be used.

[0208] The secondary objectives are to demonstrate the superiority of Compound 114 compared to placebo in terms of the absolute change from baseline in mRSS, FVC (% predicted), patient and physician global assessments, HAQ-DI, RP activity, and net burden of DU at Week 48, ACR-CRISS, modified CRISS, and time to treatment failure. Additional objectives are to evaluate safety, PK, PD, and exploratory biomarkers.

[0209] Primary Measure: The primary measure is the rate of decline of FVC (mL) over 48 weeks.

[0210] Key Secondary Measures Include:

[0211] ● The absolute change in mRSS from baseline at Week 48

[0212] ● The modified CRISS score at Week 48 (improvement ≥ 20% from baseline to Week 48 in at least 3 of the 5 core domain measures, except for % predicted FVC ≥ 5%)

[0213] ● The absolute change in HAQ-DI score from baseline at Week 48

[0214] Secondary Measures are as follows:

[0215] ● ACR-CRISS score at Week 48

[0216] ● Absolute change in FVC (% predicted) at Week 48 relative to baseline

[0217] ● Absolute change in PGA VAS score at Week 48 relative to baseline

[0218] ● Absolute change in CGA VAS score at Week 48 relative to baseline

[0219] ● Composite measure of RP activity at Week 48

[0220] ● Absolute change in DU net burden at Week 48 relative to baseline

[0221] ● Time to treatment failure is defined as the time of the first (whichever comes first) of the following events occurring during Week 48 and the extended treatment period:

[0222] ○ Death,

[0223] ○ Absolute decrease in FVC percent predicted relative to baseline ≥ 10%,

[0224] ○ mRSS increase ≥ 25% and increase in mRSS > 5 points,

[0225] ○ Initiation of immunomodulatory / immunosuppressive therapy or change in dose for clinically significant worsening of dcSSc as outlined herein.

[0226] Other objectives and other endpoints

[0227] Other objectives: Other objectives include the efficacy, PK, and changes in biomarkers in adults with early dcSSc compared to placebo after 48 weeks of treatment with Compound 114.

[0228] Other endpoints: Other endpoints are as follows:

[0229] Efficacy:

[0230] ● Absolute change in FACIT-Fatigue Scale score at Week 48 relative to baseline

[0231] ● Absolute change in SSPRO score at Week 48 relative to baseline

[0232] ● Absolute change in EQ-5D-5L score at Week 48 relative to baseline

[0233] ● Absolute change in worst pain NRS at Week 48 relative to baseline

[0234] ● Absolute change in six individual SHAQ domain scores (pain, bowel problems, respiratory problems, RP, finger ulcers, disease severity) at Week 48 relative to baseline

[0235] ● PGIC score at week 48

[0236] ● Absolute change in percent predicted DLCO at week 48 relative to baseline

[0237] ● Total Grade of Response Composite Score (GRCS) at the end of the 48-week primary evaluation period or at the end of the 48-week primary evaluation period for patients not participating in the extension period

[0238] ● Proportion of patients who experienced treatment failure (as defined above) or discontinued treatment (non-responders) during the 48-week and extension periods

[0239] ● Annual decline rate of FVC (mL) during the primary evaluation period and extension period

[0240] ● Change relative to baseline in the presence or absence of friction rub at week 48

[0241] ● Change in joint involvement (tender and swollen joint count - 28) at week 48 relative to baseline

[0242] ● Absolute change in RCS at week 48 relative to baseline

[0243] Pharmacokinetics:

[0244] Other PK parameters will be calculated at week 36 if feasible and may include but are not limited to:

[0245] ● Cmax (maximum measured concentration of the analyte in plasma)

[0246] ● tmax (time from dosing to maximum measured concentration of the analyte in plasma)

[0247] ● AUCt1-t2 (area under the concentration-time curve of the analyte in plasma over the time interval t1 to t2)

[0248] Biomarkers:

[0249] ● Changes in blood biomarkers, including but not limited to changes in KL-6, CRP, CCL18, ProC3, C3M, ProC6, C6M, CXCL4, 8-isoprostane, 8-hydroxy dG, sICAM-1, endothelin-1, endostatin, connective tissue growth factor (CTGF), CXCL9, CXCL10 from baseline until week 48

[0250] ● Changes in gene expression in skin biopsies and blood from baseline until week 48 (see RNA gene expression sub-study, section 5.4.1)

[0251] ● Changes in the number of SMA-positive fibroblasts, skin thickness, and other histopathological parameters in skin biopsies from baseline up to week 48, based on immunohistochemical analysis (see RNA gene expression study, section 5.4.1).

[0252] ● Digital artery volume index Changes in a novel quantitative MRI-based score for assessing blood flow in arteries from baseline up to week 48 (see MRA sub-study, section 5.4.1).

[0253] More details and additional other metrics can be defined in the Trial Statistical Analysis Plan (TSAP).

[0254] Description of the design and trial population

[0255] Overall trial design

[0256] This is a multi-center, multi-country, prospective, randomized, placebo-controlled, double-blind, parallel-group, Phase II clinical trial to study the efficacy and safety of orally administered compound 114 at a target dose of 3 mg TID in adult patients with early progressive dcSSc and vasculopathy.

[0257] After the patient signs the informed consent form, they will be enrolled in the trial and screened for eligibility. The screening period is up to 5 weeks. Eligible patients will proceed to a 48-week treatment period. After the screening period, compound 114 and placebo will be randomly assigned in a 1:1 ratio.

[0258] The treatment period includes a 4-week up-titration of compound 114 from 1 mg TID to 3 mg TID: 1 mg of compound 114 will be given TID for 2 weeks. If tolerated, 2 mg of compound 114 will be given TID for 2 weeks, and then increased to 3 mg TID. If a patient develops symptomatic orthostatic hypotension at 2 mg TID, they must stop the study drug and contact the site for dose adjustment. After the up-titration from 2 mg TID to 3 mg TID, the same procedure will be followed. Each dose adjustment will require the patient to be seen at the site. It is expected that approximately 10% of patients may not be fully titrated to the 3 mg TID dose.

[0259] The primary efficacy analysis will be evaluated at week 48. After completion of the first 48 weeks of treatment, patients may continue to receive their assigned study treatment during an extended treatment period until the last patient completes the treatment period. Patients will then enter a 4-week follow-up period, which does not include study treatment, to continue collecting safety and efficacy data. When the patient completes their last scheduled visit (i.e., EOS 4 weeks after EOT), the patient's participation in the trial is complete.

[0260] An overview of the overall trial design is shown in Figure 6In.

[0261] Compound 114 will be in the IR formulation and will be up - titrated during the primary evaluation treatment period according to tolerance, from 1 mg TID to 2 mg TID after two weeks, and then from 2 mg TID to 3 mg TID after an additional two weeks. It is expected that approximately 10% of patients may not be able to fully titrate to the 3 mg TID dose.

[0262] Discussion of the trial design, including the selection of the control group

[0263] This will be a randomized, placebo - controlled, double - blind trial. The rationale for the blinded placebo control group is that SSc patients can have variable symptoms and signs. Therefore, the benefit of the experimental treatment must be determined based on the apparent response (or lack of response) in the placebo group. To minimize bias, patients must be randomly assigned to placebo or investigational drug, and neither the patients nor the researchers should know the assignment. Except as noted herein, individuals involved in data acquisition, cleaning, programming, and analysis will remain unaware of the treatment assignment until all patients have completed the trial.

[0264] One of the most difficult aspects of studying SSc is the lack of validated metrics. A variety of metrics have been used in previous clinical trials, including reduction in skin thickness measured by mRSS, slowing of the decline in lung function demonstrated by FVC, and composite metrics including mRSS, FVC, patient and physician global assessments, and HAQ - DI. Although changes in lung function have been used to register products for the treatment of SSc patients with interstitial lung disease, none of these products have been successfully used to register products for the broad indications of SSc.

[0265] Based on this, FVC has been selected as the primary metric, and it should be understood that demonstrating efficacy in non - lung metrics (secondary metrics) is also important. In the absence of a reliable composite metric, we propose including multiple secondary metrics, including but not limited to RCS, reduction in the number of digital ulcers (net ulcer burden), skin thickening assessment (mRSS), and patient and clinician global assessments, as well as patient - reported outcomes such as HAQ - DI, FACIT, and SSPRO. These metrics are selected based on publications demonstrating their ability to detect meaningful changes in SSc patients.

[0266] In addition, the trial will use currently available composite indices, including ACR-CRISS, modified CRISS, and GRCS. (See, e.g., D Khanna et al., “The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis”, Arthritis Rheumatol 2016;68(2):299-311; D. Khanna et al., “New composite endpoint in early diffuse cutaneous systemic sclerosis: revisiting the provisional American College of Rheumatology Composite Response Index in Systemic Sclerosis”, Ann Rheum Dis 2021;80:641-650; and K.M. Sullivan et al., “Myeloablative autologous stem-cell transplantation for severe scleroderma”, N Engl J Med 2018;378(1):35-47.)

[0267] The primary assessment treatment period duration of 48 weeks was selected to allow time for titration to 3 mg TID and to allow evaluation of the efficacy, safety, and tolerability of 3 mg TID compound 114 compared to placebo in the context of local SOC therapy in adult patients with early progressive dcSSc and vasculopathy. An extended treatment period was included to provide continued therapy and evaluation to trial patients and to collect further efficacy and safety assessments.

[0268] Data cleaning, central medical review, and quality review and reporting of the data will be conducted in a blinded manner.

[0269] The trial will include an external DMC to review blinded and unblinded safety data quarterly at the interim and final analyses throughout the duration of the trial.

[0270] Selection of the trial population

[0271] A total of approximately 200 patients with early progressive diffuse cutaneous systemic sclerosis will be enrolled in the trial. Approximately 150 sites are planned in approximately 30 countries. Approximately one to two patients will be randomized at each site. Additional sites may be recruited if enrollment is delayed.

[0272] Patient screening for this trial is competitive, meaning that once a sufficient number of patients have been screened, trial screening will stop simultaneously at all sites. Investigators will be informed that screening is complete and that no additional patients will be allowed to be screened. Patients who have been screened at this point will continue to be randomized if eligible.

[0273] One retest is permitted during the Screening Period (eg, if the investigator determines that a failed laboratory test is the result of error or extenuating circumstances, the test may be repeated without rescreening the patient).

[0274] Rescreening is also permitted once if the cause of screening failure is reversible and resolved, based on the investigator's judgment. Patients are considered "rescreeners" if they were initially ineligible for the trial and subsequently rescreened, undergo the informed consent process a second time, receive a new unique patient number, and repeat the screening period assessments.

[0275] The records of all patients enrolled in the trial (ie, who have signed the informed consent) will be maintained in the ISF, regardless of whether they have been treated with the investigational drug.

[0276] If it is retrospectively discovered that a patient was incorrectly randomized (= did not meet all inclusion criteria or met one or more exclusion criteria), the sponsor or commissioner should be contacted immediately. Based on an individual benefit-risk assessment, a decision will be made as to whether continued participation in the trial is possible.

[0277] Primary diagnosis at entry into the trial

[0278] The primary diagnosis of test entry was SSc (according to the American College of Rheumatology / European League of Associations Against Rheumatism [ACR / EULAR] criteria, 2013), with the subtype diffuse cutaneous as defined by LeRoy et al., “Scleroderma (systemic sclerosis): classification, subsets and pathogenesis,” J Rheumatol 1988;15(2):202-205.

[0279] The trial population should be enriched with patients having earlier and more progressive disease. This will be achieved by using criteria related to "active disease" in the medical history, through two clinical (Criterion #6) and biomarker (Criterion #7) inclusion criteria. In addition to the standard biomarkers related to active inflammation such as CRP and ESR, the biomarker criteria have been enhanced by adding KL-6. In several studies, elevated KL-6 (>1000 U / mL) has been associated with active progressive ILD. See M. Kawana et al., "Elevated serum Krebs von den Lungen-6 in early disease predicts subsequent deterioration of pulmonary function in patients with systemic sclerosis and interstitial lung disease", J Rheumatol 2016;43(10):1825-1831; G.A. Salazar et al., "KL-6 but not CCL-18 is a predictor of early progression in systemic sclerosis-related interstitial lung disease", Journal of Rheumatology, online publication on July 1, 2018, doi:10.3899 / jrheum.170518; pages 1153 to 1158 in 2018; and H. Satoh et al., "Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases", J Intern Med 2006;260:429-434.

[0280] Inclusion Criteria

[0281] ● Provide written and dated informed consent in accordance with ICH-GCP and local regulations before being allowed to participate in the trial

[0282] ● Male or female patients aged ≥18 years (or above the legal age, e.g., UK ≥16 years) at the time of consent.

[0283] ● Patients must meet the 2013 ACR / EULAR classification criteria for SSc.

[0284] ● The patient must be diagnosed with diffuse cutaneous SSc (extensive skin fibrosis with skin involvement near the elbows and / or knees) as defined by LeRoy et al., "Scleroderma (systemic sclerosis): classification, subsets and pathogenesis", J Rheumatol 1988; 15(2): 202-205.

[0285] ● The onset of SSc (defined by the first non-RP symptom) must be within 5 years of the first visit.

[0286] ● Evidence of active disease, defined as having at least one of the following:

[0287] ○ New onset of SSc within the last 2 years of the first visit, or

[0288] ○ New skin involvement or worsening in two new body regions within 6 months of the first visit (among the 17 body regions defined by mRSS assessment, recorded in the clinical file), or

[0289] ○ New involvement or worsening in one new body region in the chest or abdomen within 6 months of the first visit, or

[0290] ○ Worsening of skin thickening (≥2 mRSS score) within 6 months of the first visit

[0291] ○ ≥1 tendon friction rub.

[0292] ● Biomarkers elevated at the first visit (screening), defined as having at least one of the following:

[0293] ○ CRP ≥6 mg / L (≥0.6 mg / dL), or

[0294] ○ Erythrocyte sedimentation rate (ESR) ≥28 mm / h, or

[0295] ○ KL-6 ≥1000 U / mL.

[0296] ● Evidence of significant vascular lesions, defined as:

[0297] ○ Active DU at the first visit, or

[0298] ○ Recorded history of DU, or

[0299] ○ RP previously treated with a prostacyclin analogue or ≥ 1 other drug, such other drugs including calcium channel blockers, nitrates, NO donors in any form, including topically; phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil); non-specific PDE5 inhibitors (theophylline, dipyridamole), or

[0300] ○ RP with elevated CRP ≥ 6 mg / L

[0301] If none of the above four criteria are met, in the case of a confirmed diagnosis of ILD, the patient may be entered

[0302] ● Evidence of early fibrosis at the first visit, defined as

[0303] ○ mRSS ≥ 10 points, and

[0304] ○ FVC ≥ 50% of the predicted normal value.

[0305] ● If the patient is receiving concomitant therapy for dcSSc, these therapies need to be at the following stable doses:

[0306] Mycophenolate mofetil / sodium: Stable dose for at least 4 months before randomization

[0307] Methotrexate: Stable dose and route of administration for at least 4 months before randomization; folic acid supplementation according to local SOC should be used before randomization and during the trial

[0308] Azathioprine: Stable dose for at least 4 months before randomization

[0309] Oral corticosteroids (≤ 10 mg / day of prednisone or equivalent): Stable dose for at least 2 weeks before randomization

[0310] NSAID: Stable dose for at least 2 weeks before randomization

[0311] ACE inhibitor: Stable dose for at least 2 weeks before randomization

[0312] Calcium channel blocker: Stable dose for at least 2 weeks before randomization

[0313] ● If the male patient's sexual partner is a woman of childbearing potential (WOCBP), male patients who are able to father children must be willing to use condoms. WOCBP must be ready and able to use highly effective methods of birth control according to ICH M3(R2). Such methods should be used throughout the trial. A list of contraceptive methods meeting these criteria is provided in the patient information and section 4.2.2.3.

[0314] Exclusion criteria

[0315] ● Any known form of pulmonary arterial hypertension.

[0316] ● Lung diseases with FVC < 50% of the predicted value at screening.

[0317] ● Limited skin SSc at screening. Other autoimmune connective tissue diseases, except myofibromyalgia, scleroderma-related myopathy, and secondary Sjogren's syndrome.

[0318] ● Diffusing capacity of carbon monoxide (DLCO) (corrected for hemoglobin) < 40% of the predicted value at screening.

[0319] ● Any history of scleroderma renal crisis within the last 6 months.

[0320] ● Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m2 (CKD-EPI formula) or on dialysis at screening.

[0321] ● Cirrhosis of any Child-Pugh class (A, B, or C) (Appendix 10.9).

[0322] ● Current cholestasis, or ALP > 4 × ULN at screening, or ALP > 2 × ULN and GGT > 3 × ULN.

[0323] ● Known, severe antral telangiectasia (watermelon stomach).

[0324] ● Any history of bronchial artery embolization or massive hemoptysis. (Massive hemoptysis is defined as acute bleeding > 240 mL within a 24-hour period or recurrent bleeding > 100 mL / day over consecutive days).

[0325] ● Active hemoptysis or pulmonary hemorrhage, including events managed by bronchial artery embolization.

[0326] ● Unstable cardiovascular, pulmonary diseases (other than the trial indication) or other diseases (e.g., acute coronary artery disease, heart failure, and pulmonary embolism) within 6 months before the first interview and / or during the screening period.

[0327] ● Systolic blood pressure < 100 mmHg or a known history of moderate or severe symptomatic orthostatic hypotension as judged by the investigator before starting trial treatment.

[0328] ● Sitting heart rate < 50 bpm at screening interview.

[0329] ● Laboratory values: hemoglobin < 9.0 g / dL, white blood cell (WBC) count < 3000 / mm3 (< 3 × 109 / L), platelet count < 100,000 / mm3 (< 100 × 109 / L)

[0330] ● Heart failure with a known left ventricular ejection fraction < 40% prior to screening.

[0331] ● Marked baseline prolongation of the QT / QTc interval demonstrated by at least 2 ECG measurements repeated in 3 repeats or 2 sets of 3 repeats of the QTc interval (male patients > 450 ms and female patients > 470 ms). History of other risk factors for polymorphic ventricular tachycardia (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome)

[0332] ● Use of the following treatments and therapies:

[0333] ○ Any form of nitrate or NO donor (e.g., amyl nitrite), including topical, within 2 weeks prior to randomization; phosphodiesterase (PDE) 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil); and non-specific PDE5 inhibitors (theophylline, dipyridamole)

[0334] ○ Prostaglandin analogs within 2 weeks prior to randomization (beraprost permitted orally for the treatment of digital ulcers / Raynaud's disease, and short-term / intermittent therapy with intravenous prostaglandin analogs for digital / vascular lesions for up to 21 days)

[0335] ○ Nintedanib, pirfenidone, terguride, tyrosine kinase inhibitors (e.g., imatinib, nilotinib, dasatinib), Janus kinase inhibitors within 2 weeks prior to randomization

[0336] ○ sGC-stimulators / activators (other than compound 114) within 4 weeks prior to randomization

[0337] ○ Treatment with clinically relevant OATP1B1 / 3 inhibitors and clinically relevant UGT inhibitors / inducers within 4 weeks prior to randomization

[0338] ○ Drugs with a known risk of polymorphic ventricular tachycardia within 5 half-lives prior to randomization

[0339] ○ Other investigational drugs within 1 month or 5 half-lives (whichever is greater) prior to randomization

[0340] ○Ultraviolet phototherapy within 6 weeks before randomization

[0341] ●Use the following immunomodulatory / immunosuppressive therapies and corticosteroids:

[0342] ○Anakinra within 1 week before randomization

[0343] ○Etanercept within 2 weeks before randomization

[0344] ○Cyclophosphamide, cyclosporine A, hydroxychloroquine, tacrolimus, sirolimus, colchicine, D-penicillamine, mizoribine, and intravenous immunoglobulin within 4 weeks before randomization

[0345] ○Infliximab, certolizumab, golimumab, adalimumab, abatacept, tocilizumab, brodalumab, and leflunomide within 8 weeks before randomization

[0346] ○Rituximab or other anti-CD20 antibodies within 6 months before randomization

[0347] ○Non-investigational or investigational cell depletion therapies, including but not limited to alemtuzumab, anti-CD4, anti-CD5, anti-CD3, anti-CD19 within 18 months before randomization

[0348] ○Previous treatment with chlorambucil, bone marrow transplantation, total lymphoid irradiation, thalidomide

[0349] (thalidomide), antithymocyte globulin, plasmapheresis, or extracorporeal photopheresis

[0350] ○Oral prednisone >10 mg / day or equivalent, intravenous and intramuscular corticosteroids within 2 weeks before randomization

[0351] ●To make patients eligible for the study, local background standard care must not be terminated. Patients with SSc-ILD who, in the opinion of the researchers, require approved treatments not permitted in this trial (where such therapies are available and considered SOC) should not be included in this trial.

[0352] ● Related chronic or acute infections, including but not limited to human immunodeficiency virus (HIV) and viral hepatitis. Corresponding laboratory tests will be conducted during the screening period. If the patient has been treated and cured from the acute infection, the patient may be re-screened.

[0353] ● From screening until randomization, the patient has an active SARS-CoV-2 infection (or known positive test result).

[0354] ● Planned major surgery during the trial (primarily based on the assessment of the researcher).

[0355] ● Any documented history of active or suspected malignant disease or malignancy within 5 years prior to screening, except for appropriately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.

[0356] ● History of clinically relevant allergy / hypersensitivity that would interfere with trial participation, including allergy to the investigational product / placebo or its excipients.

[0357] ● Any other medical condition that, in the opinion of the researcher, poses a safety risk to the patient or would interfere with the trial objectives.

[0358] ● Patients who are expected to not meet the protocol requirements or are not expected to complete the trial as planned (e.g., chronic alcoholism or drug abuse, or any other condition that, in the opinion of the researcher, makes the patient an unreliable trial participant).

[0359] ● Previous randomization / treatment in this trial.

[0360] ● Currently enrolled in another investigational device or drug trial, or less than 1 month or 5 half-lives (whichever is greater) prior to randomization since the end of another investigational device or drug trial or receipt of other investigational treatment.

[0361] ● Pregnant, lactating, or women planning to become pregnant during the trial.

[0362] ● MRA sub-study: MRI contraindications or inability to perform MRI (e.g., implanted medical devices that are contraindicated for MRI and cannot be removed (e.g., cardiac pacemaker, nerve stimulation system), severe claustrophobia).

[0363] ● Patients who are legally committed according to national law.

[0364] Treatment

[0365] The investigational drug in the trial is an sGC activator formulated as an immediate release (IR) formulation.

[0366] Method of assigning patients to treatment groups:

[0367] After evaluating all inclusion and exclusion criteria, each eligible patient will be randomly assigned to the treatment group at a 1:1 ratio according to the randomization plan at the second visit. The randomization codes will be generated by a validated software and kept blinded to the trial team, sites, and patients. The Interactive Response Technology (IRT) system will be used to screen patients, conduct drug allocation, manage initial / resupply orders of drug supplies, and handle emergency event unblinding.

[0368] The researchers will receive all instructions required to access the IRT from the sponsor. The detailed IRT functions and procedures will be documented in the user requirements specification mutually agreed upon by the sponsor and the IRT vendor. It should be noted that the drug number is different from the patient number (the latter is generated during screening via the IRT system).

[0369] Drug allocation and dose administration for each patient:

[0370] Patients will be randomly assigned to either the active treatment group or the placebo control group (Table 3). The dose will be up-titrated from 1 mg TID to 3 mg TID or matched placebo. All patients will start taking the compound 114 at a dose of 1 mg TID or matched placebo. The up-titration will be performed after 14 days and 28 days. For example, patients with up-titration due to orthostatic intolerance should follow the guidance described in this article. These patients will continue to receive 2 mg or 1 mg (or placebo).

[0371] Table 3. Treatment allocation and dosing schedule

[0372]

[0373] It is recommended to take the first dose in the morning, the middle dose at about lunchtime, and the third dose in the evening (take one tablet at each time point). There must be at least a four-hour interval between trial treatment intakes. If a dose is missed, this should not be corrected by taking two doses at the next time point.

[0374] The trial treatment should be taken with a glass of water and can be taken with or without food. To facilitate swallowing, the tablet can be broken or crushed. The crushed tablet can be suspended in tap water. The crushed or suspended tablet must be used within two hours after crushing. The full dose must be determined. The last dose of the trial treatment will be administered on the evening before the EOT visit.

[0375] All trial treatment allocations, including up-titration / down-titration and kit replacement, will be managed through the IRT system. Patients will be informed that the drug can be either the active trial treatment or placebo.

[0376] During the COVID-19 pandemic or a similar pandemic, physical visits to the site may need to be restricted to ensure patient safety. Based on a thorough assessment of the benefits and risks, the researcher may still decide to continue with the trial treatment and, if acceptable under local laws and regulations, deliver the trial treatment to the patient's home.

[0377] The study site may perform potential down-titration (dose reduction). This will be managed through the IRT system. Dose reduction shall not be done by instructing the patient to take less than three daily doses. The patient will be informed that down-titration may be needed, as decided by the researcher. Down-titration will require an (unscheduled) visit to the trial site.

[0378] Rules for titration in case of interruption of trial treatment

[0379] Since the interruption of trial treatment may have an impact on tolerance, the following rules will apply for patient safety:

[0380] ● An interruption of trial treatment is defined as any situation where 4 consecutive doses* or more are not administered (i.e., missed or temporarily interrupted dosing). *One dose refers to an individual time point, e.g., morning dose or mid-dose or evening dose.

[0381] ○ If less than 4 consecutive doses of trial treatment are missed, the next dose of trial treatment should be administered as scheduled.

[0382] ● After an interruption of trial treatment, unless the patient is down-titrated due to an adverse event (see Section 4.1.4.2), the patient should restart with 1 mg TID of Compound 114 / placebo, independent of the previous patient's dose. In this case:

[0383] ○ If they have taken 2 mg / 3 mg of Compound 114 / placebo, they should restart with 1 mg of Compound 114 / placebo.

[0384] ○ If they have taken 1 mg of Compound 114 / placebo, they should restart with 1 mg of Compound 114 / placebo.

[0385] ● Before any up-titration, the patient must have taken the aforementioned dose for at least 10 consecutive days. This applies throughout the treatment period.

[0386] ○ This may mean that a patient who should up-titrate at the 3rd or 4th visit (according to Table 4.1.4:1) maintains their current dose until their next scheduled visit. Once this requirement is met, they may also up-titrate at an unscheduled visit.

[0387] ● If an interruption occurs for any reason after the 4th visit, subsequent up-titration will be allowed at a scheduled or unscheduled visit.

[0388] ● Patients who discontinue Compound 114 2 mg or 3 mg or matching placebo will need to return to the clinic for the next scheduled or unscheduled visit to receive 1 mg Compound 114 / placebo tablets before resuming trial treatment.

[0389] Rules for down-titration in case of intolerance to trial treatment

[0390] If a patient has an AE that the investigator deems potentially related to the trial treatment, the investigator may discontinue the patient's trial treatment (and resume following the above rules) or reduce the patient's dose as described below:

[0391] ● If a patient reports symptomatic orthostatic hypotension between scheduled visits, the investigator should consider discontinuing trial treatment until an unscheduled visit.

[0392] ● If a patient is taking Compound 114 or matching placebo at 1 mg TID, the patient will discontinue trial treatment.

[0393] ● If a patient is taking Compound 114 (or corresponding matching placebo) at 2 mg TID or 3 mg TID and trial treatment is discontinued:

[0394] ○ For < 4 consecutive doses, the patient will then down-titrate one level, i.e.:

[0395] ■ 2 mg TID Compound 114 / placebo switches to 1 mg TID Compound 114 / placebo.

[0396] ■ 3 mg TID Compound 114 / placebo switches to 2 mg TID Compound 114 / placebo.

[0397] ○ For 4 consecutive doses or more, the patient will then down-titrate to 1 mg TID Compound 114 or placebo.

[0398] ● Doses should not be reduced by taking less than three daily doses or by splitting tablets to avoid taking the whole tablet.

[0399] ● If a patient has experienced discontinuation / down-titration due to an AE and experiences a second AE that the investigator deems related and will require further down-titration, the patient should permanently discontinue trial treatment.

[0400] ● In the case of persistent AEs despite dose reduction or serious adverse reactions at any dose, permanent discontinuation of treatment should be considered.

[0401] Up-titration is not permitted for patients who have been down-titrated or discontinued due to a related AE.

[0402] All changes in trial treatment dose will require a scheduled or unscheduled visit to the site and an IRT call.

[0403] Blinding and Unblinding Procedures

[0404] Blinding

[0405] Except in the exceptional circumstances mentioned below, patients, researchers, central reviewers, and everyone involved in the conduct or analysis of the trial or having any other interest in this double-blind trial will remain unaware of the randomized treatment allocation until the database is declared ready for analysis according to the sponsor's standard operating procedures (SOP). Other details regarding the time point at which the database is unblinded for analysis will be recorded in the TSAP.

[0406] The randomization codes will be provided to bioanalysis to exclude placebo samples from PK analysis 48 weeks before the treatment period of the last patient is completed. The randomization codes or their measurement results will not be revealed until the database is locked.

[0407] External independent statisticians will receive the data and treatment codes to generate quarterly safety reports for the DMC. External independent statisticians will also receive the data and treatment codes for the interim analysis, which is planned to be conducted approximately 24 weeks after about 80% of the patients have completed treatment. The DMC and the project team will have access to the aggregated results of the interim analysis.

[0408] To expedite population PK and PK-PD analysis and ensure timely delivery of PK / PD results after database lock, specific data must be unblinded and treatment information must be made available to selected individuals. It should be noted that PK / PD results will not be communicated to the project and trial teams before database lock.

[0409] Before the interim analysis, the logistics and access plan will document the details of data transfer, timeline, and individual functions involved in the interim analysis and population PK and PK-PD analysis.

[0410] Unblinding and Decoding

[0411] Emergency unblinding will be available to researchers via the IRT. It must only be used in emergency situations when the researcher must know the identity of the investigational drug to provide appropriate medical treatment or otherwise ensure the safety of the trial participants. The reason for unblinding must be recorded in the source document and / or the appropriate CRF page.

[0412] Due to the requirement to report suspected unexpected serious adverse reactions (SUSAR), it may be necessary to obtain the randomization code of an individual patient during the trial. The obtaining of this code will only be given to authorized pharmacovigilance representatives for processing in the PV database system and will not be further shared.

[0413] Other Treatments, Emergency Procedures, Restrictions

[0414] Other Treatments and Emergency Procedures

[0415] The following immunomodulatory / immunosuppressive drugs are permitted and should be at a stable dose for at least 4 months prior to randomization and throughout the trial until EOT.

[0416] In special circumstances, dose reduction of concomitant medications may be permitted.

[0417] ● Mycophenolate mofetil / sodium

[0418] ● MTX - Patients using MTX should take folic acid supplements according to local SOC prior to randomization and throughout the trial to minimize the likelihood of MTX - related toxicities. (For MTX, a stable dose means a stable dose of this drug and the route of administration)

[0419] ● Azathioprine - Concomitant use with xanthine oxidase inhibitors such as allopurinol and febuxostat should be avoided. If concomitant use with a xanthine oxidase inhibitor is required, the dose of azathioprine should be reduced to one - quarter of the normal dose, as xanthine oxidase inhibitors reduce the metabolism of azathioprine.

[0420] If these drugs are not used concomitantly but have been used previously, they should be discontinued at least 4 weeks prior to randomization (second visit).

[0421] In addition, the following concomitant drug therapies are permitted and should be at a stable dose for at least 2 weeks prior to randomization and throughout the trial until EOT (dose reduction of these drugs is permitted for safety reasons):

[0422] ● Oral corticosteroids (≤10 mg / day of prednisone or equivalent)

[0423] ● NSAID

[0424] ● ACE inhibitors

[0425] ● Calcium channel blockers

[0426] ● Endothelin receptor antagonists

[0427] During the study, these treatments may also be discretionarily handled by the investigator as new treatments for SSc - specific adverse events (e.g., Raynaud's phenomenon, joint inflammation, new - onset renal crisis).

[0428] For patients receiving corticosteroids and / or NSAIDs, prophylactic treatment with a proton pump inhibitor or histamine - 2 receptor blocker may be added at the discretion of the investigator according to local SOC.

[0429] Analgesics may be used up to the maximum recommended dose as needed for pain. However, patients should be discouraged from using analgesics, including NSAIDs, within 12 hours prior to efficacy assessment during the clinical interview.

[0430] In the case of worsening of dcSSc

[0431] In the case of clinically significant worsening of dcSSc, initiation of therapy or change of immunomodulatory / immunosuppressive therapy and dose of corticosteroids > 10 mg / day of prednisone or equivalent are permitted at or after the 24-week interview. Use of these medications prior to week 24 is not favored, unless in cases of clinically significant worsening. However, if new therapy is initiated to treat significant worsening, the study medication should be interrupted. Use of these medications prior to week 24 is not favored, unless in cases of clinically significant worsening.

[0432] Clinically significant worsening observed at any time during the course of the trial is defined as:

[0433] ● An absolute decrease in the predicted percentage of FVC ≥ 10% since baseline (e.g., if the predicted percentage of FVC changes from 70% at baseline to < 60%, excluding other causes such as respiratory infection), or

[0434] ● A relative change in mRSS ≥ 25% relative to baseline and an absolute change relative to baseline > 5 points, or

[0435] ● Clinically significant worsening of other organ systems or clinical parameters, at the discretion of the investigator.

[0436] Drug treatment is permitted at the sole discretion of the investigator, unless covered by the drug restrictions described herein and as given by the inclusion / exclusion criteria. If unpermitted therapy is initiated, the study medication must be interrupted.

[0437] In the case of severe AE or overdose

[0438] There are no special emergency procedures to follow. Although there is no specific antidote for Compound 114, symptomatic therapy to reverse its effects is widely available and should be applied.

[0439] All concomitant therapies and / or rescue therapies will be recorded on the appropriate pages of the electronic case report form (eCRF).

[0440] Restrictions

[0441] Restrictions on concomitant therapies

[0442] Mitigation of potential risks can be achieved by closely monitoring patients and prohibiting co - administration of drugs with similar mechanism of action (i.e., activators of the NO - sGC - cGMP pathway). Special attention is required when compound 114 is co - administered with NTI and / or sensitive CYP3A4 substrates, as exposure to such drugs may increase in a clinically relevant manner. Additionally, compound 114 should not be co - administered with OATP1B1 / 3 inhibitors and drugs known to inhibit or induce UGT enzymes, as this can affect compound 114 exposure in a clinically relevant manner. A list of relevant drugs can be found in the ISF.

[0443] In addition, therapies with known TdP risk should not be co - administered with compound 114. These restrictions apply from screening (first visit) throughout the entire study period, including the treatment period and the follow - up period until the EOS visit. In the case of temporary concomitant use of such therapies, the trial treatment must be temporarily stopped and can then be restarted at least 5 half - lives after the concomitant therapy with known TdP risk has ceased, provided the interruption rules are followed.

[0444] Table 4 outlines the drugs and therapies that should not be taken within the specified time periods.

[0445] Table 4. Restricted drug therapies

[0446]

[0447]

[0448] 1 Non - SSc - related conditions permitted for treatment at the discretion of the investigator, such as asthma or allergic / anaphylactic reactions.

[0449] 2 In cases of suspected acute coronary syndrome requiring sublingual nitrates, patients need to be closely monitored for blood pressure during trial treatment.

[0450] Diet and lifestyle restrictions

[0451] Starting from the second visit, patients should fast for at least 8 hours before collecting safety laboratory samples.

[0452] Contraception requirements

[0453] WOCBP trial participants, if their sexual partner is a man capable of fathering children, must use highly effective birth control methods throughout the trial and for at least 7 days after the last intake of trial medication. Partners of WOCBP participants do not require contraception.

[0454] An effective method of fertility control according to ICH M3(R2), which has a low failure rate of less than 1% per year when used consistently and correctly, includes (examples depending on the approval status in each country):

[0455] ●Combination hormonal fertility control (oral, intravaginal, transdermal) that prevents ovulation (containing estrogen and progestin).

[0456] ●Progestin-only fertility control that prevents ovulation (oral, injectable, implantable).

[0457] ●Intrauterine device or intrauterine hormone-releasing system.

[0458] ●Bilateral tubal occlusion.

[0459] If the sexual partner of a male trial participant is a WOCBP, the male trial participant must have a vasectomy or use a condom after demonstrating azoospermia until at least 7 days after the last intake of the investigational product.

[0460] The partner of male participants does not require contraception.

[0461] Alternatively, WOCBP participants and male participants who are able to father children must avoid heterosexual intercourse. This is defined as consistent with the preferred and common lifestyle of the patient. For example, periodic abstinence using the calendar, ovulation, symptothermal method, post-ovulation method; declaration of abstinence during the duration of exposure to the investigational product; and withdrawal is unacceptable.

[0462] Assessment

[0463] Efficacy assessment

[0464] Forced vital capacity

[0465] Spirometry will be performed according to the ATS / ERS 2019 guidelines. B.L. Graham et al., “American Thoracic Society, European Respiratory Society. Standardization of spirometry 2019 update: an official American Thoracic Society and European Respiratory Society technical statement”, Am J Respir Crit Care Med 2019; 200(8):e70-e88. FVC will be evaluated using a standardized spirometry device that will provide a supply of pre-calibrated disposable flow sensors at the center. These sensors comply with the International Organization for Standardization (ISO) 26782 standard but have a maximum allowable accuracy error of ±2.5% according to the ATS / ERS technical statement. Therefore, daily calibration is not required before use. Only these spirometers will be used for this test. Spirometry will be performed while the individual is in a sitting position. Preferably, the same trained individual will perform the PFT on the given individual. The best of three efforts will be defined as the highest FVC obtained on any one of three blows that meet the 2019 ATS / ERS standards (up to eight attempts). Predicted normal values will be calculated according to the Global Lung Function Initiative.

[0466] Reference should be made to the baseline measurement (second visit), and efforts should be made to schedule spirometry at approximately the same time of day. During the clinical visit, the patient must avoid strenuous activity for at least 12 hours before the PFT. Smoking should be discouraged throughout the visit (clinical visit) and not permitted during the 30-minute period prior to spirometry. The patient should also avoid cold temperatures, environmental smoke, dust, or areas with strong odors (e.g., perfumes). If on bronchodilator therapy, the clearance of long-acting bronchodilators for 24 hours and short-acting bronchodilators for 8 hours should be observed before spirometry.

[0467] In the case of a (relative) decline in FVC% predicted relative to baseline of ≥15%, this should be confirmed by another FVC test within one month. If an ILD diagnosis has not been established by HRCT at the time of screening, a new HRCT of the chest should be performed to confirm the ILD.

[0468] Spirometry results will be transmitted electronically. To ensure the quality of the primary endpoint measurement, a central spirometry review will be implemented to provide feedback to the study sites and the CRA on the quality of the data received from the sites.

[0469] Other instructions regarding FVC measurement will be provided in the ISF.

[0470] Modified Rodnan skin score

[0471] The mRSS consists of the assessment of the skin thickness of the patient by clinical palpation using a scale of 0 to 3 (0 = normal skin; 1 = mild thickness; 2 = moderate thickness; 3 = severe thickness, where the skin cannot be pinched into a fold), for each of 17 surface anatomic regions of the body: face, anterior chest, abdomen, (left and right respectively) fingers, forearms, upper arms, thighs, calves, dorsum of the hands, and dorsum of the feet. These individual values are added and the sum is defined as the total skin score. D. Khanna et al., “Scleroderma Clinical Trials Consortium, World Scleroderma Foundation. Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis”, J Scleroderma Rel Disord 2017;2(1):11 - 18.

[0472] This assessment should be performed by a physician experienced and trained in skin scoring. For a given patient throughout the trial, it should be attempted that the skin scoring be performed by the same rater to prevent inter - observer variability.

[0473] Other instructions regarding mRSS assessment will be provided in the ISF.

[0474] Diffusing capacity for carbon monoxide

[0475] The site will use its own DLCO equipment and perform all measurements with the same DLCO equipment (e.g., when several devices will be available at the site). Single - breath DLCO will be performed according to ATS / ERS guidelines for DLCO measurement. N. Macintyre et al., “Standardisation of the single - breath determination of carbon monoxide uptake in the lung”, Eur Respir J 2005;26(4):720 - 735. Before starting the test, the operator should demonstrate and carefully instruct the patient.

[0476] The DLCO value will be adjusted for the latest hemoglobin value. For the predicted normal values, different sites may use different prediction formulas based on the method used to measure DLCO. In any case, the calculation method used must comply with the ATS / ERS guidelines for DLCO measurement and the prediction formula appropriate for that method. The original data (gas mixture, equation used for normal value prediction, further adjustment if so carried out) must be traced.

[0477] DLCO assessment should be carried out after FVC assessment and should always start at approximately the same time of day, i.e., the maximum difference between test starts < 90 minutes.

[0478] Other instructions regarding DLCO measurement will be provided in the ISF.

[0479] Oxygen saturation measurement

[0480] The oxygen saturation (SpO2) at rest will be measured by standard pulse oximetry (on unaffected skin of the earlobe or forehead), and the recorded value will be entered into the eCRF.

[0481] Net digital ulcer burden

[0482] The net digital ulcer burden is defined as the total number of "active" and indeterminate digital ulcers at the time of assessment. Digital ulcers are defined according to the proposed World Scleroderma Foundation (WSF) definition: "Loss of epidermal covering where the basement membrane is interrupted (which separates the dermis from the epidermis). It is clinically manifested as visible blood vessels, fibrin, granulation tissue and / or deeper underlying structures (e.g., muscle, ligament, fat) or when it will appear on debridement". Y.A. Suliman et al., "Defining skin ulcers in systemic sclerosis: Systematic literature review and proposed World Scleroderma Foundation (WSF) definition", J Scleroderma Relat Disord 2017; 2(2): 115 - 1204.

[0483] Ulcer counts will ideally be carried out by the same healthcare professional at each visit.

[0484] Other instructions regarding DU assessment will be provided in the ISF.

[0485] Raynaud's attack assessment (composite measure of RP activity)

[0486] Raynaud's attacks will be evaluated using a composite of the following 6 individual outcome measures to minimize measurement variability and placebo response: Raynaud's Condition Score (RCS), patient assessment of RP, physician assessment of RP, attack symptoms, attack duration, and mean number of attacks per day, as described in "Evaluation of test characteristics for outcome measures used in Raynaud's phenomenon clinical trials" by H. Gladue et al., Arthritis Care & Res. 2013:65(4):630 - 636.

[0487] Daily patient self - assessment of RP activity using a 0 - to - 10 ordinal scale from "no difficulty" to "extremely difficult" for the RCS. It incorporates the cumulative frequency, duration, severity, and impact of RP attacks, reflecting the overall extent to which RP has affected the patient's hand use. See P.A. Merkel et al., "Scleroderma Clinical Trials Consortium. Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon", Arthritis Rheum 2002;46(9):2410 - 2420.

[0488] Details of the frequency and duration of Raynaud's attacks and attack symptoms of pain, numbness, and tingling, each represented by a 0 - to - 100 VAS for the RCS, will be incorporated into a daily diary, which will require the patient to complete for 7 consecutive days until the visit.

[0489] Patient and physician assessments will measure the severity of RP in the past week using a 0 - to - 100 VAS at the time of the interview.

[0490] Tendinous friction rub

[0491] Anatomic sites including the hands, wrists, elbows, shoulders, knees, and ankles will be examined for the presence of tendinous friction rubs.

[0492] Tender and swollen joint count

[0493] This physician - reported tool assesses swelling and tenderness of 28 joints. This outcome measure should be performed by the same physician to evaluate the burden of joint disease due to SSc - related polyarthritis and myopathy.

[0494] Questionnaires and derived results

[0495] Before any other trial-related checks, the patient should complete the PRO questionnaire alone in a quiet area / room. Before the patient leaves the site, the site personnel will check the completeness of the patient's responses in the questionnaire, but should not scrutinize the responses to each item. In cases where the patient is unable to give a response or is unable to decide on a response, no response should be recorded. Subsequently, the scores will be transcribed into the eCRF by the designated site personnel.

[0496] Functional Assessment of Chronic Illness Therapy - Fatigue

[0497] The FACIT-Fatigue Scale is a 13-item measure for assessing self-reported fatigue and its impact on daily activities and function. M. Hinchcliff et al., "Validity of two new patient-reported outcome measures in systemic sclerosis: Patient-Reported Outcomes Measurement Information System 29-item Health Profile and Functional Assessment of Chronic Illness Therapy-Dyspnea short form", Arthritis Care Res (Hoboken) 2011; 63(11):1620-1628.

[0498] Health Assessment Questionnaire - Disability Index (HAQ-DI)

[0499] The HAQ is a questionnaire frequently used in rheumatic conditions including systemic sclerosis to assess daily living function / activities, with 20 items in 8 categories, namely dressing and grooming, hygiene, rising, reaching, eating, gripping, walking, and common daily activities. See J. Pope, "Measures of systemic sclerosis (scleroderma)", Arthritis Care Res (Hoboken) 2011; 63(Suppl 11):S98-S111; and B. Bruce et al., "The Health Assessment Questionnaire (HAQ)", Clin Exp Rheumatol 2005; 23(Suppl 39):S14-S18.

[0500] Each category has at least two sub-category questions. Within each category, the patient reports the amount of difficulty they have in performing the specific sub-category items. There are four response options ranging from no difficulty to unable to complete, scored from 0 to 3. The overall score (HAQ Disability Index or HAQ-DI) will be calculated based on the category scores.

[0501] Scleroderma Health Assessment Questionnaire

[0502] The SHAQ includes the HAQ-DI and 6 other VASs relevant to patients with systemic sclerosis. V. D. Steen et al., “The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time”, Arthritis Rheum 1997; 40(11):1984 - 1991.

[0503] The 6 other VASs relevant to patients with systemic sclerosis are pain, patient's overall assessment of limitations, vascular involvement, DU, pulmonary involvement, and gastrointestinal involvement. The scores from these scales are not incorporated into the overall score of the HAQ-DI.

[0504] The SHAQ will be self-administered by the patient during the interview. Detailed additional instructions on the administration of the SHAQ to the patient and scoring are provided in the ISF.

[0505] EuroQol 5-Dimensional Quality of Life Questionnaire

[0506] The EQ-5D was developed by the EuroQol group and is a standardized instrument used as a measure of health outcomes. M. Herdman et al., “Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)”, Qual Life Res 2011; 20:1727 - 1736. The version used in this trial is the new five-level version (EQ-5D-5L).

[0507] The questionnaire basically consists of 2 pages. The first page is a descriptive system with 5 questions about the patient's current health status. Each question captures a health dimension (e.g., mobility, self-care) and has five response levels. The second page records the patient's current self-assessed health status on a vertical graded (0 to 100) visual analogue scale.

[0508] Global assessment of patient and clinician

[0509] This tool incorporates the self-assessment of overall health of the patient (PGA VAS) and clinician assessment (CGAVAS) using an ordinal scale from 0 to 10 in the previous 1 week and ratings of overall SSc-related health transition compared to 1 month ago and 1 year ago.

[0510] Patient-reported outcomes in scleroderma skin

[0511] The SSPRO is a validated PRO measure that assesses health-related quality of life (HRQOL) related to skin involvement in SSc. A. Man et al., “Development and validation of a patient-reported outcome instrument for skin involvement in patients with systemic sclerosis”, Ann Rheum Dis 2017; 76:1374-1380. It has 18 items representing 4 HRQOL scales: physical effects, emotional effects, physical function, and social effects. All items are scored from 0 (preferred) to 6 (worse).

[0512] Worst pain numeric rating scale

[0513] The worst pain NRS is a horizontal line with an eleven-point numeric range. It is labeled from zero to ten, where zero is an example of someone with no pain and ten is the worst possible pain.

[0514] Patient global impression of change (PGI-C)

[0515] The Patient Global Impression Scale (PGI) is the PRO counterpart of the Clinical Global Impression Scale (CGI), which was published by the National Institute of Mental Health (USA) in 1976. It consists of one item based on the CGI and adapted for patients. Used as PGI-C, it primarily measures changes in clinical status.

[0516] Combined response index for systemic sclerosis, ACR-CRISS version and revised version

[0517] CRISS is a two-step composite index that in step 2 includes mRSS, percent predicted FVC, HAQ-DI, the patient's global assessment, and the clinician's global assessment. Step 1 in the ACR-CRISS version consists of no significant worsening of interstitial lung disease, new scleroderma renal crisis, left ventricular failure, or pulmonary arterial hypertension. D Khanna et al., “The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis”, Arthritis Rheumatol 2016;68(2):299-311. In step 1, worsening of ILD is defined as a (relative) decline in percent predicted FVC ≥15%, confirmed by another FVC test within a month, confirmed by HRCT if not confirmed at screening, and FVC < 80% of predicted value. Left ventricular failure is defined as left ventricular ejection fraction ≤45% and requiring treatment. New PAH should be confirmed by right heart catheterization. Patients with any of the above are considered not improved and assigned a probability score of 0.0.

[0518] In step 2 of the ACR-CRISS, a weighted probability score (ranging from 0.0 to 1.0, inclusive) is calculated that incorporates the absolute change from baseline in five core domain measures: mRSS, percent predicted FVC, HAQ-DI, the patient's global assessment, and the clinician's global assessment.

[0519] In the revised version, significant gastrointestinal dysmotility requiring parenteral or enteral nutrition and significant digital ischemia requiring hospitalization, gangrene, or amputation were added to step 1. D. Khanna et al., “New composite endpoint in early diffuse cutaneous systemic sclerosis: revisiting the provisional American College of Rheumatology Composite Response Index in Systemic Sclerosis”, Ann Rheum Dis 2021;80:641-650. These patients are considered not improved and not included in step 2.

[0520] In step 2 of the modified CRISS, the proportion of patients achieving a specified percentage improvement in at least 1, 2, 3, 4, or 5 core domain measures is evaluated.

[0521] Global Ranking Composite Score (GRCS)

[0522] GRCS is a composite score that reflects the hierarchical comparison of trial participants with respect to ordered outcomes: death, event-free survival (survival without respiratory, renal, or cardiac failure), FVC, score on the disability index of the Health Assessment Questionnaire, and modified Rodnan skin score. K.M. Sullivan et al., “Myeloablative autologous stem-cell transplantation for severe scleroderma”, N Engl J Med 2018; 378(1):35-47.

[0523] Example

[0524] Example 1

[0525] Example 1 describes an experiment demonstrating the inhibition of hypoxia-induced TGFβ2 production in primary human microvascular endothelial cells by Compound 114. TGFβ and hypoxia are considered important drivers of vascular remodeling and fibrosis associated with the pathogenesis of SSc.

[0526] Materials and Methods

[0527] The analysis used the following materials and reagents:

[0528] The human dermal microvascular endothelial cell line was obtained from (Lonza, 2543).

[0529] All experiments were performed using cells between passages 4 and 8. Four donors were used in these experiments

[0530] EBM TM -2 (Lonza, 3156 or 00190860)

[0531] EGM TM -2MV Singlequots (Lonza, 4147)

[0532] FBS (Gibco, A4766801)

[0533] Reagent Pack (Lonza, 5034)

[0534] Pen / Strep (Gibco, 15140122)

[0535] Glutamax (Gibco, 35050061)

[0536] T175 flask (Corning, 431466)

[0537] DMSO (Sigma D2650 - 5X5ML)

[0538] Compound 114 (Sample ID 30295026, Batch 5, molar weight 582.689)

[0539] ODQ (Enzo Life sciences, ALX270034M010)

[0540] 96 - well culture plate (Corning Costar 3595)

[0541] Hypoxic chamber (Water - jacketed incubator (Thermo Scientific, 3110) set at 37°C and 1% O2)

[0542] Media preparation: Normal media: EBM - 2 supplemented with EGM - 2MV singlequots, 10% Premium plus FBS, 1% Glutamax and 1% Pen - Strep. Basal media: EBM - 2 supplemented with 2% FBS

[0543] Culturing endothelial cells: Grow dermal endothelial cells from each of the indicated donors in T175 flasks with normal media in a 37°C / 5% CO2 incubator. When the cells reach 80% to 90% confluence, sub - culture the cells for five minutes by trypsinization with trypsin from the reagent pack at 37°C. Count the cells and seed them into new T175s for further expansion or seed them for experiments as described in the following protocol.

[0544] Preparation of compounds: Dissolve 5.2 mg of Compound 114 at a concentration of 20 mM in 446.2 μL of 100% DMSO. Subsequently, dilute the compound solution in 100% DMSO to 10 mM. Subsequently, dilute the 10 mM compound solution in 100% DMSO to 1 mM and 100 mM, and then serially dilute in HEPES - Tyrode BSA buffer to 100 μM, 10 μM and 1 μM to make 10× stock solutions.

[0545] Hypoxia assay:

[0546] Day 0: Trypsinize the cells, count them and seed them so that each well contains 8×103 cells and 100 μl of media and place them in the incubator overnight (37°C)

[0547] Day 1: Aspirate the medium and replace it with basal medium left at 37°C overnight, i.e., for 24 hours.

[0548] Day 2: Replace the basal medium with 90 μL of fresh basal medium.

[0549] Add 10 μL of ODQ (12×) to achieve a final concentration of 10 μM (or 3-fold serial dilution). Incubate the plates at 37°C for 45 minutes. Add an aliquot of the compound solution at 6× concentration, 20 μL / well, to make the final well volume 120 μl.

[0550] After treatment, leave the plates at 37°C in normoxia or 37°C 1% O2 hypoxia for 48 hours. Collect the supernatant and measure the TGFβ2 content using MSD ELISA.

[0551] MSD Elisa: MSD ELISA was performed according to the protocol provided by the manufacturer.

[0552] Plate dermal microvascular endothelial cells from three normal donors and grow them to confluence. Serum-starve the cells and treat them with DMSO / ODQ / compound 114. After adding DMSO / ODQ / compound 114, incubate the cells in a hypoxia chamber (1% O2). After 48 hours, collect the cells and supernatant, and measure the TGFβ2 content by MSD-ELISA. Read the MSD plates using the MSDQuickPlex SQ 120 instrument. Discovery Workbench version 4.0 was used to determine the standard curve and TGF-β2 concentration. Use normoxia as a control for the hypoxia condition.

[0553] TGFβ and hypoxia are considered important drivers of vascular remodeling and fibrosis associated with the pathogenesis of SSc. As Figure 1 shown, compared to the normoxic control condition, elevated TGFβ2 content is produced in primary human microvascular endothelial cells under hypoxic conditions (1% O2). Compound 114 inhibits hypoxia-induced TGFβ2 content in primary human microvascular endothelial cells.

[0554] Using hypoxia (1% O2) as a disease-related stimulus, the results show that elevated TGFβ2 content is produced in primary human microvascular endothelial cells under hypoxic conditions compared to the normoxic control condition. The data also show that in primary human microvascular endothelial cells from 3 donors, sGC activation by compound 114 reduces hypoxia-driven TGFβ2 production in a concentration-dependent manner (see Figure 1)。A statistically significant reduction was achieved with 10 μM compound 114. Thus, compound 114 is expected to provide significant vasoprotective and anti-fibrotic benefits to SSc patients by reducing hypoxia-mediated endothelial cell activation.

[0555] References:

[0556] Yuansheng Gao, J. Usha Raj, fetal neonatal Physiology, 2017

[0557] Pyriochou A, Papapetropoulos A. Soluble guanylyl cyclase: more secrets revealed. Cell Signal. 2005 Apr;17(4):407-13. doi:10.1016 / j.cellsig.2004.09.008. PMID:15601619.

[0558] Kimberly A. Lucas, Giovanni M. Pitari, Shiva Kazerounian, Inez Ruiz-Stewart, Jason Park, Stephanie Schulz, Kenneth P. Chepenik and Scott A. Waldman. Guanylyl Cyclases and Signaling by Cyclic GMP. Pharmacological Reviews September 2000, 52(3)375-414 Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch JP, Gnoth MJ, Seeger W, Grimminger F, Schermuly RT. Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation. 2006 Jan 17;113(2):286-95.

[0559] Beyer C, Reich N, Schindler SC, Akhmetshina A, Dees C, Tomcik M, Hirth-Dietrich C, von Degenfeld G, Sandner P, Distler O, Schett G, Distler JH. Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann Rheum Dis. 2012 Jun;71(6):1019-26.

[0560] Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011 May 24;123(20):2263-73.

[0561] Example 2

[0562] Example 2 demonstrates the therapeutic efficacy of the dual sGC activator in bleomycin-induced pulmonary and dermal fibrosis models.

[0563] Materials and methods

[0564] Compounds and formulations: Compounds: Compound 114 (Sample ID 30295026), Batch 5, and EX00076637 (EX76637 / riociguat), Sample ID 17810950, Batch 5 were all dissolved in methylcellulose solution. The concentrations were 10 mg / kg, 3 mg / kg, and 1 mg / kg, and they were orally administered in a volume of 0.1 ml. Nintedanib ethanesulfonate was freshly prepared every other day. The concentration was 60 mg / kg, and it was orally administered in a volume of 0.1 ml.

[0565] Bleomycin-induced dermal fibrosis

[0566] Dermal fibrosis was induced by subcutaneous injection of bleomycin (2.5 mg / kg) every other day for six weeks. To evaluate the effect of therapeutic administration, fibrosis was first induced by injecting bleomycin for three weeks in the absence of treatment. Subsequently, treatment was initiated while continuing to inject bleomycin. The results were analyzed six weeks after the first injection of bleomycin. Mice injected with 0.9% NaCl (vehicle for bleomycin) served as non-fibrotic controls. The following groups were analyzed, where n = 8 female C57Bl / 6 mice:

[0567] Group 1 is NaCl / vehicle

[0568] Group 2 is bleomycin / vehicle

[0569] Group 3 is bleomycin / nintedanib

[0570] Group 4 is bleomycin / compound 114, 1 mg / kg, twice daily (bid), orally

[0571] Group 5 is bleomycin / compound 114, 3 mg / kg, bid, orally

[0572] Group 6 is bleomycin / compound 114, 10 mg / kg, bid, orally

[0573] Group 7 is bleomycin / EX76637, 1 mg / kg, bid, orally

[0574] Group 8 is bleomycin / nintedanib + compound 114, 3 mg / kg, bid, orally

[0575] Group 9 is bleomycin / nintedanib + compound 114, 10 mg / kg, bid, orally

[0576] Quantification of dermal thickening: A defined area of the upper dorsal skin was excised and then fixed in 4% formalin for 6 h and embedded in paraffin. Skin sections were cut and stained with hematoxylin / eosin. Dermal thickness (measured as the distance between the epidermal-dermal border and the dermal-subcutaneous border in arbitrary units) was quantified at different sites in 4 different sections, with 2 measurements taken for each section, as described in 1, 2, 4 - 7. Analysis was performed in a blinded manner.

[0577] Detection of myofibroblasts: Myofibroblasts were characterized by the expression of α-smooth muscle actin (α-SMA). α-SMA-positive fibroblasts were detected from the upper dorsal in paraffin-embedded coverslips by incubation with a monoclonal anti-αSMA antibody (clone 1A4, Sigma-Aldrich, Steinheim, Germany). The expression was visualized using a horseradish peroxidase-labeled secondary antibody and 3,3-diaminobenzidine tetrahydrochloride (DAB) (Sigma-Aldrich). Monoclonal mouse IgG antibody (Calbiochem, San Diego, CA, USA) was used as a control 4, 8 - 10. The analysis was performed by blinded reviewers, assessing myofibroblasts in four sections of each sample.

[0578] Hydroxyproline analysis: The amount of collagen in skin samples was determined via hydroxyproline analysis. Full-thickness punch biopsies from the upper back were digested in 6M HCl for three hours and then the pH of the samples was adjusted to 6 with 6M NaOH. For the lungs, the middle lobe was analyzed. Subsequently, 0.06M chloramine T was added to each sample and incubated at room temperature for 20 minutes. Next, 3.15M perchloric acid and 20% p-dimethylaminobenzaldehyde were added and the samples were incubated at 60°C for another 20 minutes. Absorbance was determined at 557 nm using a Spectra MAX 190 microplate spectrophotometer with a standard curve generated from purified type I collagen (Sigma-Aldrich). After digestion in 6M HCl for three hours, the pH of the samples was adjusted to 6 with 6M NaOH. For the lungs, the middle lobe was analyzed. Subsequently, 0.06M chloramine T was added to each sample and incubated at room temperature for 20 minutes. Next, 3.15M perchloric acid and 20% p-dimethylaminobenzaldehyde were added and the samples were incubated at 60°C for another 20 minutes. Absorbance was determined at 557 nm using a Spectra MAX 190 microplate spectrophotometer with a standard curve generated from purified type I collagen (Sigma-Aldrich).

[0579] Bleomycin-induced pulmonary fibrosis

[0580] In a bleomycin-induced pulmonary fibrosis model, fibrosis was induced on day 0 by a single intratracheal injection of 50 μl of bleomycin. Mice injected with an equal volume of 0.9% NaCl served as controls. Results were analyzed 28 days later. Treatment was initiated on day 15 after intratracheal instillation of bleomycin and thus at a time point when fibrosis had been pre-established.

[0581] The following groups were analyzed, where n = 8 female C57Bl / 6 mice:

[0582] Group 1 was NaCl / vehicle

[0583] Group 2 was bleomycin / vehicle

[0584] Group 3 was bleomycin / nintedanib

[0585] Group 4 was bleomycin / compound 114, 1 mg / kg, bid, orally

[0586] Group 5 was bleomycin / compound 114, 3 mg / kg, bid, orally

[0587] Group 6 was bleomycin / compound 114, 10 mg / kg, bid, orally

[0588] Group 7 was bleomycin / EX76637, 1 mg / kg, bid, orally

[0589] Group 8 was bleomycin / nintedanib + compound 114, 3 mg / kg, bid, orally

[0590] Group 9 was bleomycin / nintedanib + compound 114, 10 mg / kg, bid, orally

[0591] Two mice (one from Group 3 and the other from Group 9) died during the pre-treatment phase and were thus not available for analysis.

[0592] Histological evaluation of pulmonary fibrosis: The entire lungs were excised, fixed in 4% formalin for 6 h and embedded in paraffin. Five-micron sections were cut and stained with Sirius Red. Images were captured using a Hamamatsu nano sumo S60 slide scanner microscope (Hamamatsu, Herrsching am Ammersee, Germany). Histological changes of pulmonary fibrosis were quantified by Ashcroft scoring. Analysis was performed in a blinded manner. Additionally, all lung sections were stained with Sirius Red (Sigma-Aldrich), and the fibrotic area was determined as the percentage of the total area covered by Sirius Red using ImageJ (V.1.42q, National Institutes of Health, USA).

[0593] Missing samples / values: As outlined above, two mice died in bleomycin-induced pulmonary fibrosis and the samples were thus not available. Additionally, the following values were missing: Ashcroft score: 1 sample in the NaCl group (tissue rinsed with slides); pulmonary hydroxyproline: 1 sample each for compound 114 at 3 mg / kg, compound 114 at 10 mg / kg, and compound 114 at 10 mg / kg + nintedanib (analysis-related issues); dermal thickness: 1 mouse each in compound 114 at 1 mg / kg and compound 114 at 10 mg / kg + nintedanib (not embedded in a fully upright position). Statistics: All data are presented as median ± range, and for non-relevant samples, the Mann-Whitney U non-parametric test was used to test for statistically significant differences between groups.

[0594] Results: The results showed that the therapeutic doses of compound 114 (Cpd 114) and EX76637 improved bleomycin-induced dermal and pulmonary fibrosis. Compared with control mice, mice stimulated with bleomycin (bleomycin / vehicle) for six weeks developed dermal fibrosis. As expected, treatment with nintedanib at a dose of 60 mg / kg qd improved bleomycin-induced dermal fibrosis for the last three weeks, while the dermal thickness decreased ( Figure 2A ), the myofibroblast count decreased ( Figure 2B ) and the hydroxyproline content decreased ( Figure 2C ) compared with bleomycin / vehicle mice. Treatment with compound 114 at a dose of 1, 3 or 5 mg / kg also improved bleomycin-induced dermal fibrosis for the last two weeks ( Figures 2A to 2B)。However, although there were specific trends in dermal thickness and myofibroblast counts, no clear dose-dependence was observed, ultimately because the effects of even the lowest dose were already quite pronounced. These effects were within the range of those observed with nintedanib. EX76637 at a dose of 1 mg / kg also improved bleomycin-induced dermal fibrosis, and these effects were comparable to those of compound 114 ( Figures 2A to 2B )。The combination of nintedanib with compound 114 at doses of 3 or 10 mg / kg bid was well tolerated and demonstrated antifibrotic effects. However, no additive effect of the combination therapy was observed compared to monotherapy with nintedanib or compound 114.

[0595] Intratracheal instillation of bleomycin induces severe pulmonary fibrosis. Consistent with previous reports, treatment with nintedanib starting two weeks after bleomycin instillation until the end of the experiment reduced the Ashcroft score ( Figure 3A ), decreased the collagen coverage area ( Figure 3B ) and reduced the hydroxyproline content ( Figure 3C ). Treatment with compound 114 at doses of 1, 3 or 10 mg / kg also significantly improved the fibrosis readings. Although there was a trend towards a more pronounced effect at higher doses for the Ashcroft score, the difference did not reach statistical significance. Regarding bleomycin-induced dermal fibrosis, EX76637 also improved bleomycin-induced pulmonary fibrosis. The combination therapy of nintedanib and compound 114 did not show enhanced efficacy compared to individual monotherapies.

[0596] The results show that activation of sGC signaling significantly improves bleomycin-induced dermal and pulmonary fibrosis.

[0597] References:

[0598] 1 Gabrielli, A., Avvedimento, E. V. & Krieg, T. Scleroderma. N Engl J Med 360, 1989 - 2003, doi:10.1056 / NEJMra0806188 (2009).

[0599] 2 Varga, J. & Abraham, D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. The Journal of clinical investigation 117, 557 - 567, doi:10.1172 / jci31139 (2007).

[0600] 3Distler, J. H. et al. Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis. Arthritis & rheumatology (Hoboken, N.J.) 69, 257 - 267, doi:10.1002 / art.39865(2017).

[0601] 4Akhmetshina, A. et al. Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nature communications 3, 735, doi:10.1038 / ncomms1734(2012).

[0602] 5Avouac, J. et al. Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis and rheumatism 63, 800 - 809, doi:10.1002 / art.30171(2011).

[0603] 6Avouac, J. et al. Inhibition of activator protein 1 signaling abrogates transforming growth factor beta-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis and rheumatism 64, 1642 - 1652, doi:10.1002 / art.33501(2012).

[0604] 7Weingartner,S.et al.Pomalidomide is effective for prevention andtreatment of experimental skin fibrosis.Annals of the rheumatic diseases 71,1895-1899,doi:10.1136 / annrheumdis-2012-201784(2012).

[0605] 8Dees,C.et al.Platelet-derived serotonin links vascular disease andtissue fibrosis.The Journal of experimental medicine 208,961-972,doi:10.1084 / jem.20101629(2011).

[0606] 9Dees,C.et al.JAK-2as a novel mediator of the profibrotic effects oftransforming growth factor beta in systemic sclerosis.Arthritis andrheumatism 64,3006-3015,doi:10.1002 / art.34500(2012).

[0607] 10Dees,C.et al.Inhibition of Notch signaling prevents experimentalfibrosis and induces regression of established fibrosis.Arthritis andrheumatism 63,1396-1404,doi:10.1002 / art.30254(2011).

[0608] 11Reich,N.et al.Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis.Annals of the rheumatic diseases 71,737-745,doi:10.1136 / annrheumdis-2011-200412(2012).

[0609] 12Chakraborty,D.et al.Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis.Nature communications 8,1130,doi:10.1038 / s41467-017-01236-6(2017).

[0610] 13Palumbo-Zerr,K.et al.Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis.Nat Med 21,150-158,doi:10.1038 / nm.3777(2015).

[0611] Example 3

[0612] Example 3 describes a study for evaluating the in vitro efficacy of compound 114 in reducing platelet activation, as measured by CXCL4 release. CXCL4 is a chemokine highly expressed by platelets. It is increased in the blood and skin of SSc patients and is associated with the worsening of pulmonary fibrosis and pulmonary arterial hypertension. The NO-sGC-cGMP system is the main pathway for platelet quiescence. Dysregulation of this pathway can cause a systemic increase in CXCL4. Therefore, the reduction of human platelet activation measured by CXCL4 release can be used to evaluate the efficacy of treatment regimens.

[0613] Materials and methods:

[0614] Compound 114 (Sample ID: 30295026, Lot: 5)

[0615] EX0076637 (Sample ID: 17810950, Lot: 5)

[0616] Nintedanib ethanesulfonate (Boehringer Ingelheim, manufacturing number: 67653, batch number: 1078235)

[0617] EX0000076 (sample ID: 15614118, batch: 1)

[0618] Blood from healthy donor volunteers

[0619] Plastic blood collection tubes with sodium citrate (BD Biosciences, 363083)

[0620] 50 ml conical tubes (Corning, 430828)

[0621] BSA solution, 30% saline solution, fatty acid-free, sterile filled (Sigma, A9205)

[0622] ADP (Sigma, 01905-250MG-F)

[0623] Tyrode buffer (Sigma, T2397)

[0624] HEPES (Gibco, 15630-080)

[0625] DMSO (Sigma, D2650)

[0626] 1 ml deep well culture plates (Thermo Scientific, 260251)

[0627] Sterile 0.22 μm PVDF filter disks (Millipore, MAGVS2210)

[0628] 96-well microculture plates (Thermo Scientific, 249946)

[0629] CXCL4 ELISA kit (Abcam, ab189573 and R&D systems, DPF40)

[0630] Buffer preparation: HEPES-Tyrode BSA buffer: Tyrode buffer supplemented with 0.35% BSA and 5 mM HEPES.

[0631] Generation of platelet-rich plasma (PRP): Blood was collected from healthy donor volunteers into plastic sodium citrate tubes. The first two collection tubes were discarded. The remaining blood was processed within 30 min of blood draw. The blood was poured into 50 ml conical tubes with no more than 35 ml in each tube and centrifuged at 200×g for 16 minutes at room temperature, with the acceleration set at half of the maximum speed and the deceleration turned off. After centrifugation, the top layer (PRP) was carefully transferred to a new tube by avoiding the white blood cell layer. The PRP was allowed to stand at room temperature for 5 to 15 minutes. The PRP was then ready for experiments as described in the following protocol.

[0632] Preparation of compounds: 5.2 mg of compound 114 was dissolved in 446.2 μl of 100% DMSO at a concentration of 20 mM. Subsequently, the compound solution was diluted to 10 mM in 100% DMSO. Subsequently, the 10 mM compound solution was diluted to 1 mM and 100 μM in 100% DMSO, and then serially diluted to 100 μM, 10 μM, and 1 μM in HEPES-Tyrode BSA buffer to prepare 10× stock solutions.

[0633] Preparation of compound 114 and EX 76637: 5.2 mg of compound 114 was dissolved in 446.2 μl of 100% DMSO at a concentration of 20 mM. 2.3 mg of EX 76637 was dissolved in 109 μl of 100% DMSO at a concentration of 50 mM. Subsequently, the compound solution was diluted to 10 mM in 100% DMSO. Subsequently, the 10 mM compound solution was diluted to 1 mM and 100 μM in 100% DMSO, and then serially diluted to 100 μM, 10 μM, and 1 μM in HEPES-Tyrode BSA buffer to prepare 10× stock solutions.

[0634] Preparation of nintedanib: 2.9 mg of nintedanib was dissolved in 446.3 μl of 100% DMSO at a concentration of 10 mM. Subsequently, the compound solution was diluted to 100 μM in 100% DMSO. Subsequently, the 100 μM compound solution was diluted to 1 μM in HEPES-Tyrode BSA buffer to prepare 10× stock solutions.

[0635] Preparation of EX 00000776 (MMF): 2.3 mg of EX 00000776 was dissolved in 530.5 μl of 100% DMSO at a concentration of 10 mM. Subsequently, the compound solution was diluted to 5 mM in 100% DMSO. Subsequently, the 5 mM compound solution was diluted to 50 μM in HEPES-Tyrode BSA buffer to prepare 10× stock solutions.

[0636] Dissolve ADP at a concentration of 100 mM in distilled water. The 100 mM ADP is further diluted to 10 mM in HEPES-Tyrode BSA buffer and then serially diluted to 100 μM in HEPES-Tyrode BSA buffer to prepare a 10× stock solution.

[0637] ADP activates PRP and ELISA detects CXLC4

[0638] Add 80 μl or 40 μl of PRP to the wells in a 1 ml deep well plate containing 560 μl or 280 μl of HEPES-Tyrode BSA buffer. Add 80 μl or 40 μl of the 10× compound solution to each well and incubate at 37 °C / 5% CO2 for 30 min, then add ADP. Add 80 μl or 40 μl of 100 μM ADP to each well and incubate the plate at 37 °C / 5% CO2 for 5 min. After incubating for 5 minutes, transfer 300 μl / well of the stimulated PRP to a sterile 0.22 μm PVDF 96-well filter plate. Place a 96-well microculture plate under the filter plate to collect the supernatant after centrifugation at 1100 rpm for 5 min. Collect the supernatant flowing through and dilute it 1:50 in sample diluent NS from the Abcam CXCL4 ELISA kit or 1:4 in calibration diluent RD6-13 from the R&D systems CXCL4 Quantikine ELISA kit. Perform CXCL4 ELISA according to the supplier's instructions.

[0639] Data analysis

[0640] Generate the raw data with a Victor Nivo plate reader and analyze it using Microsoft Excel 2016. Generate a standard curve by using XLfit5.5.0 model 205. The concentration of CXCL4 in the sample is determined by interpolating the absorbance value relative to the standard curve. Multiply the obtained value by 50 or 4 (dilution factor) to obtain the concentration of CXCL4 in the sample. Calculate the maximum CXCL4 percentage by dividing the concentration value of the sample by the concentration value of DMSO / ADP and then multiplying by 100.

[0641] Results

[0642] Stimulate PRP generated from fresh blood with 10 μM ADP with or without 10 μM, 1 μM, 0.1 μM of compound 114 or DMSO for 5 minutes.

[0643] CXCL4 ELISA for filtering platelets through a filter disc and collecting the supernatant. The maximum CXCL4 percentage was calculated by dividing the value of the sample by the value of DMSO / ADP and multiplying by 100. ADP induced CXCL4 production in all 10 tested donors. Addition of 1 μM and 10 μM of compound 114, an sGC activator, attenuated ADP-induced CXCL4 production in all 10 donors. Low-dose (0.1 μM) of compound 114 also reduced ADP-induced CXCL4 production in 9 out of 10 donors( Figure 4 ). Figure 5 Shows the maximum percentage for all donors compared to ADP / DMSO. The sGC activator compound 114 significantly reduced ADP-induced CXCL4 production in a dose-dependent manner.

[0644] Results showed that very low levels of CXCL4 secretion were observed in PRP without activation. As Figure 4 shown, ADP-induced CXCL4 secretion was reduced by the sGC activator compound 114. Ten PRP donors were stimulated with 10 μM ADP in the presence or absence of 10 μM, 1 μM, or 0.1 μM compound 114 or DMSO. Ex114 = compound 114. As Figure 5 shown, the sGC activator compound 114 significantly reduced ADP-induced CXCL4 production in a dose-dependent manner. In addition, after treatment with riociguat (EX 76637, and designated as EX 637 in the figure) at a dose equivalent to that of compound 114, minimal effects on CXCL4 production were observed. Similarly, treatment with nintedanib or MMF was also ineffective. The maximum CXCL4 percentage was calculated by dividing the value of the variable by the value of DMSO / ADP and then multiplying by 100. All values are expressed as means; error bars represent standard deviations. Paired t-tests were used for statistical analysis.

[0645] Addition of 10 μM ADP (a known platelet agonist) caused a large release of CXCL4. Data indicate that sGC activation by compound 114 inhibited agonist-induced CXCL4 release from PRP of 10 donors in a concentration-dependent manner. Addition of compound 114 significantly and dose-dependently attenuated ADP-induced CXCL4 production in all 10 donors. Minimal to no effects were observed after treatment with riociguat, nintedanib, or MMF, indicating that compound 114 has distinct activity in activating CXCL4 release in human platelets compared to the sGC stimulator riociguat or standard of care.

[0646] Results showed that platelet activation was associated with fibrosis, inflammation, and microvascular damage. CXCL4, which is produced abundantly by activated platelets, was found to be directly associated with SSc disease activity. Inhibition of CXCL4 release was demonstrated in ADP-activated PRP using the sGC activator compound 114.

Claims

1. A method for treating a patient suffering from systemic sclerosis, which comprises administering to the patient a therapeutically effective amount of a soluble guanylate cyclase (sGC) activator of formula (I), wherein: A is a 5- to 7-membered saturated heterocyclic group containing one nitrogen and optionally one oxygen, wherein one carbon in the heterocyclic group is optionally substituted with one or two groups selected from C 1-3 alkyl and oxo; R 1 is an optionally methoxy-substituted C 1-4 alkyl; R 2 selected from H, F, Cl, C 1-3 alkyl, -CN, -OMe and -CF3; R 3 selected from H and -CH3; R 4 selected from H, F, -CH3 and -OMe; R 5 selected from H, Cl, -CH3, -CH2CH3, -CF3, F, and -OMe; R 6 bonded to the nitrogen on A and selected from H, C 1-6 alkyl, -(CH2) n C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -(CH2) n heterocyclic group, -(CH2) n aryl, -(CH2) n heteroaryl, -SO2aryl, SO2C 1-6 alkyl, wherein the C 1-6 alkyl, -(CH2) n heterocyclic group, -(CH2) n cycloalkyl, -(CH2) n aryl and -(CH2) n heteroaryl is optionally substituted by one to four groups independently selected from C 1-3 alkyl, halogen, C 1-3 alkoxy, -CF3, -OH, oxo, -(CH2) 1-3 O(CH2) 2-3 OH and -SO2CH3; R 7 selected from H, -CH3, -CH2CH3, -CF3, F and -CN; n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the patient suffers from early diffuse cutaneous systemic sclerosis (dcSSc) and / or vasculopathy.

3. The method according to claim 1 or 2, wherein the compound of formula (I) is administered to the patient in an amount selected from the group consisting of: 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

4. The method according to any one of claims 1 to 3, wherein the compound of formula (I) is administered to the patient three times a day (TID) of the compound of formula (I).

5. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is administered to the patient in an amount selected from the group consisting of 1 mg, 2 mg and 3 mg.

6. The method according to claim 5, wherein the compound of formula (I) is administered to the patient in an amount of 1 mg TID, or in an amount of 2 mg TID, or in an amount of 3 mg TID.

7. The method according to claim 1 or 2, wherein the treatment comprises an initial treatment, which comprises administering the compound of formula (I) in an amount of 1 mg TID in the first and second weeks; then administering in an amount of 2 mg TID in the 3rd and 4th weeks, and then administering in an amount of 3 mg in the 5th week until the end of the treatment.

8. The method according to any one of the preceding claims, wherein if the patient develops symptomatic orthostatic hypotension, the amount of the compound of formula (I) is reduced.

9. A compound for treating a patient suffering from systemic sclerosis, wherein the compound has formula (I), wherein: A is a 5- to 7-membered saturated heterocyclic group containing one nitrogen and optionally one oxygen, wherein one carbon in the heterocyclic group is optionally substituted by one or two groups selected from C 1-3 alkyl and oxo; R 1 is an optionally methoxy-substituted C 1-4 alkyl group; R 2 selected from H, F, Cl, C 1-3 alkyl, -CN, -OMe and -CF3; R 3 selected from H and -CH3; R 4 selected from H, F, -CH3 and -OMe; R 5 selected from H, Cl, -CH3, -CH2CH3, -CF3, F and -OMe; R 6 bonded to the nitrogen on A and selected from H, C 1-6 alkyl, -(CH2) n C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -(CH2) n heterocyclic group, -(CH2) n aryl, -(CH2) n heteroaryl, -SO2aryl, SO2C 1-6 alkyl, wherein the C 1-6 alkyl, -(CH2) n heterocyclic group, -(CH2) n cycloalkyl, -(CH2) n aryl and -(CH2) n heteroaryl is optionally substituted with one to four groups independently selected from C 1-3 alkyl, halogen, C 1-3 alkoxy, -CF3, -OH, oxo, -(CH2) 1-3 O(CH2) 2-3 OH and -SO2CH3; R 7 selected from H, -CH3, -CH2CH3, -CF3, F, and -CN; n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

10. The method according to any one of the preceding claims, wherein the compound of formula (I) has the following structure: or a pharmaceutically acceptable salt thereof.

11. The method according to any one of the preceding claims, wherein the treatment results in improvement in the following aspects: The rate of decline of FVC (mL) within 48 weeks compared to placebo, The change in mRSS at week 48 relative to baseline, The CRISS score at week 48 (in at least 3 of the 5 core indicators, achieving ≥20% improvement from baseline to week 48, except for improvement in the percentage prediction of FVC ≥5%), The change in HAQ-DI score at week 48 relative to baseline, The change in PGA VAS at week 48 relative to baseline, The change in CGAVAS at week 48 relative to baseline, The composite index of RP activity at week 48, The change in the net burden of DU at week 48 relative to baseline, and / or Time to treatment failure, defined as the time to the first occurrence of any one of the following events during the 48-week and extended treatment periods, selected from: Death, An absolute decrease in the predicted percentage of FVC ≥ 10% relative to baseline, An increase in mRSS ≥ 25% and an increase in mRSS > 5 points, and Initiation or change in the dose of immunomodulatory / immunosuppressive therapy due to a clinically significant worsening of dcSSc.

12. The method according to any one of claims 1 to 10, wherein the treatment results in an improvement in: The absolute change in the FACIT-Fatigue Scale score at week 48 relative to baseline, The absolute change in the SSPRO score at week 48 relative to baseline, The absolute change in the EQ-5D-5L score at week 48 relative to baseline, The absolute change in the Worst Pain NRS score at week 48 relative to baseline, The absolute change in the SHAQ six individual domain scores (pain, bowel problems, respiratory problems, RP, digital ulcers, disease severity) at week 48 relative to baseline, The PGIC score at week 48, The change in the predicted percentage of DLCO at week 48 relative to baseline, The overall graded composite score (GRCS) at the end of the extended treatment period or at the end of the 48-week primary assessment treatment period, compared to patients not participating in the extended treatment period, The annual rate of decline in FVC (mL) during the primary assessment treatment period and the extended treatment period, The change in the presence or absence of tendon friction rubs at week 48 relative to baseline, The change in joint involvement (tender and swollen joint count - 28) at week 48 relative to baseline, and / or The absolute change in RCS at week 48 relative to baseline.

13. The method according to claim 1, wherein the compound of formula (I) has the following structure:

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