Dosing regimen for the treatment of FAP-mediated conditions

Abstract

The present disclosure relates to methods and dosage regimen for treating or preventing a FAP-mediated condition, comprising administering to the subject a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof.

Description

[0001] DOSING REGIMEN

[0002] The present application claims priority from US provisional patent Application No. 63 / 726,725 filed on 2 December 2024, the contents of which are incorporated by reference.

[0003] Field

[0004] The present disclosure relates to methods of treating or preventing a FAP-mediated condition.

[0005] Background

[0006] Fibroblast activation protein (FAP) is a membrane-bound S9B protease in the same protein family as dipeptidyl peptidase 4 (DPP4). FAP levels are elevated during fibrogenesis in multiple diseases (Fitzgerald 2020). The expression of FAP in the healthy liver is nearly undetectable, but is increased markedly in the fibrotic liver and desmoplastic stroma of hepatic tumours. FAP expression and activity has a positive relationship with liver fibrosis severity (Keane 2014, Levy 1999) and co-locates with areas of expanding fibrotic septae (Yang 2023). Moreover, this is true across liver fibrosis etiologies from steatotic diseases like alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatohepatitis (MASH), to viral hepatitides as well as autoimmune conditions such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) (Keane 2014, Yang 2023). FAP is also present in a soluble, active form and is raised in the serum of patients with fibrotic liver diseases (Keane 2014, Williams 2015). It is well established that fibrosis severity determines outcome in chronic liver disease (CLD) (Taylor 2020, Ekstedt 2015, Angolo 2015, Sanyal 2021),

[0007] FAP has a consensus cleavage motif after Gly-Pro and exhibits both endopeptidase and exopeptidase activity. Known enzymatic activities include cleavage of collagens (Levy 1999), a2-antiplasmin (a2AP) (Lee 2004), and fibroblast growth factor 21 (FGF21) (Zhen 2016). FAP activity at the cell surface of activated fibroblasts (including cleavage of collagens) generates a pro-fibrotic environment. FAP cleavage of a2AP gives a more efficient cross-linking of a2AP to fibrin and results in reduced fibrin clearance. FAP cleavage of FGF21 inactivates FGF21 metabolic effects (Zhen 2016). All these activities are associated with a worsening of liver disease and inhibiting FAP has the potential to treat CLD and other conditions by affecting multiple mechanisms.

[0008] Inhibition of FAP activity is a presently unexploited therapeutic approach for treating CLD and other diseases associated with such activity. No approved pharmacological agents that inhibit FAP activity generally, or that inhibit FAP activity specifically, are currently available. Accordingly, there is a need for FAP inhibitors, particularly FAP inhibitors that have pharmacologically appropriate selectivity and bioavailability and therefore are suitable for administration to a subject in need of such treatment.

[0009] Examples of compounds that inhibit FAP are taught in WO2022 / 130270, including (((R)- / V-(2-(4- cyanothiazolidin-3-yl)-2-oxoethyl)-6-morpholinoquinoline-4-carboxamide with the structure shown below, referred to as a "Compound of Formula I” or “Compound 1”: Compound 1 is also known

[0010] The synthesis of Compound 1 is described in W02022 / 130270 (example 67).

[0011] WO2023 / 247487 discloses crystalline forms of compound 1.

[0012] To deliver Compound 1 to patients, dosing regimens need to be developed with the aim of providing an efficacious treatment with an acceptable safety profile.

[0013] Summary

[0014] In some embodiments, disclosed is a method of treating or preventing a FAP-mediated condition, in a subject suffering from or susceptible to the FAP-mediated condition, the method comprising administering to the subject, a compound of Formula (I):

[0015] (also known as “Compound 1”) or a pharmaceutically acceptable salt thereof, in a daily dose of from 5 mg to 320 mg of the free base.

[0016] In some embodiments, disclosed is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a FAP-mediated condition, wherein said treatment or prevention comprises the administration of the compound of Formula (I) or pharmaceutically acceptable salt thereof, in a daily dose of from 5 mg to 320 mg of the free base.

[0017] In some embodiments, disclosed is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a FAP- mediated condition, wherein said treatment or prevention comprises administering to the patient of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a daily dose of from 5 mg to 320 mg of the free base.

[0018] In embodiments, disclosed is the use of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, at a quantity of from 5 mg to 320 mg of the free base, in the manufacture of a medicament for the treatment or prevention of a FAP-mediated condition. The present disclosure includes the combination of the aspects, embodiments and certain features described except where such a combination is clearly impermissible or expressly avoided.

[0019] Summary of the Figures

[0020] Figure 1A shows FAP activity in male monkeys treated with 10 mg / kg of Compound 1 once daily.

[0021] Figure 1B shows % change in Met a2-AP in male monkeys treated with 10 mg / kg of Compound 1 once daily.

[0022] Figure 2 shows the change in various measured characteristics in male monkeys treated with 10 mg / kg of Compound 1 once daily.

[0023] Figure 3 shows geometric mean plasma concentrations of Compound 1 following a single oral dose.

[0024] Figure 4 shows mean FAP plasma inhibition following a single oral dose of Compound 1 .

[0025] Figure 5 shows geometric mean plasma concentrations of Compound 1 following repeated oral doses.

[0026] Figure 6 shows mean FAP plasma inhibition following repeated oral doses of Compound 1.

[0027] Figure 7 shows average percentage of FAP cleaved a2-antiplasmin (%Asn-a2AP) relative to total a2- antiplasmin following repeated oral doses of Compound 1, split by a2AP genotype (RR, RW, WW). Figure 8A shows the geometric mean plasma concentrations of Compound 1 following once daily dosing of 120mg, at day 1 and day 28 (semi-logarithmic scale + / -gSD).

[0028] Figure 8B shows mean FAP plasma inhibition following once daily dosing of 120 mg of Compound 1 vs placebo, at day 1 and day 28.

[0029] Figure 8C shows the average percentage of FAP cleaved a2-antiplasmin (Asn-a2AP (%)) relative to total a2-antiplasmin following repeated oral doses of Compound 1 vs placebo.

[0030] Figure 9 shows the validation of Compound 1 liver target engagement using Positron Emitting Tomography (PET) imaging.

[0031] Figure 10 shows geometric mean plasma concentration of Compound 1 over time (semi-logarithmic scale).

[0032] Figure 11 shows the mean FAP plasma inhibition following a single dose of Compound 1 + quinidine vs Compound 1 alone.

[0033] Figure 12 shows the geometric mean plasma concentration of Compound 1 over time (semi-logarithmic scale (+ / - gSD)).

[0034] Figure 13 shows median PK / PD predictions, based on phase 2a data, indicating ED50 at 29 mg and ED80 at 90 mg for trough FAP inhibition.

[0035] Detailed Description

[0036] Aspects and embodiments will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0037] Numeric ranges disclosed herein are inclusive of the numbers defining the range. The ranges and / or individual values disclosed herein can be combined to obtain further subranges, which form part of the present disclosure. Salt and Crystalline Form

[0038] In some embodiments, Compound 1 is administered to a subject. In some embodiments, a pharmaceutically acceptable salt of Compound 1 is administered to a subject. In some embodiments, crystalline Compound 1 or a pharmaceutically acceptable salt of Compound 1 is administered to a subject.

[0039] For example, “pharmaceutically acceptable salts” are salts that are suitable for use in mammals, particularly humans, and include salts with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid that are suitable for use in mammals, particularly humans.

[0040] Compound 1 may form acid addition salts. In general, an acid addition salt can be prepared using various inorganic or organic acids. Such salts can typically be formed by, for example, mixing the compound with an acid (e.g. a stoichiometric amount of an acid) using various methods known in the art. This mixing may occur in water, an organic solvent (e.g. ether, ethyl acetate, ethanol, methanol, isopropanol, or acetonitrile), or an aqueous / organic mixture. In another aspect, the acid addition salts are, for example, trifluoroacetate, formate, acetate or chloride. The skilled person will be aware of the general principles and techniques of preparing pharmaceutical salts, such as those described in, for example Berge 1977. Examples of pharmaceutically acceptable salts are also described in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2011 ).

[0041] In some embodiments, Compound 1 may be in crystalline form, such as the crystalline forms described in WO2023 / 247487. In some of these embodiments, Compound 1 is in crystalline form A. In other of these embodiments, Compound 1 is in crystalline form B.

[0042] Pharmaceutical compositions

[0043] The present disclosure includes, in at least one embodiment, pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable excipient. In embodiments of the methods and uses described herein, the pharmaceutical composition may be administered to the subject.

[0044] The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Ninth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian, ISBN: 0857113755. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition. The compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing. The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0045] In embodiments, provided herein is a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, at a quantity of from 5 mg to 320 mg of the free base. In further embodiments, provided herein is the use of a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof at a quantity of from 5 mg to 320 mg of the free base, in the manufacture of a medicament for the treatment or prevention of a FAP-mediated condition. The quantity of Compound 1 present in the composition may be as described herein in the context of daily doses, once daily doses, or twice daily doses.

[0046] Dose

[0047] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0048] In some embodiments Compound 1, is administered to the subject at least once per day. In some embodiments, Compound 1 may be administered to the subject once daily. In some embodiments, Compound 1, may be administered to the subject twice daily.

[0049] In some embodiments where Compound 1 is administered twice daily, the dosages are spaced from 8 to 16 hours. In some embodiments, the dosages are spaced from 10 to 14 hours. In some embodiments, the dosages are spaced from 11 hours 30 minutes to 12 hours 30 minutes.

[0050] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from 5 mg to 320 mg of the free base.

[0051] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from 5 mg to 275 mg of the free base.

[0052] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from 5 mg to 225 mg of the free base.

[0053] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from 5 mg to 200 mg of the free base.

[0054] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 30 mg to about 200 mg of the free base. In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 40 mg to about 200 mg of the free base.

[0055] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 50 mg to about 150 mg of the free base.

[0056] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 60 mg to about 140 mg of the free base.

[0057] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 70 mg to about 130 mg of the free base.

[0058] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 80 mg to about 120 mg of the free base.

[0059] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 10 mg to about 80 mg of the free base.

[0060] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 20 mg to about 70 mg of the free base.

[0061] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 30 mg to about 60 mg of the free base.

[0062] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg or about 200mg of the free base.

[0063] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 30 mg of the free base.

[0064] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 40 mg of the free base.

[0065] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 50 mg of the free base.

[0066] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 60 mg of the free base.

[0067] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 70 mg of the free base.

[0068] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of 80 mg of the free base.

[0069] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of 85 mg of the free base.

[0070] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of 120 mg of the free base. In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of 150 mg of the free base.

[0071] “Daily dose” refers to the total amount of the compound administered in a 24-hour period, for example in one single dose or in multiple separate doses.

[0072] In some embodiments, Compound 1 is administered once a day (od). “od” is an abbreviation meaning once a day and is commonly used in drug dosing instructions.

[0073] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from 5 mg to 320 mg of the free base once per day.

[0074] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from 5 mg to 275 mg of the free base once per day.

[0075] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from 5 mg to 225 mg of the free base once per day.

[0076] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from 5 mg to 200 mg of the free base once per day.

[0077] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 30 mg to about 200 mg of the free base once per day.

[0078] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 40 mg to about 200 mg of the free base once per day.

[0079] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 50 mg to about 150 mg of the free base once per day.

[0080] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 60 mg to about 140 mg of the free base once per day.

[0081] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 70 mg to about 130 mg of the free base once per day.

[0082] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 80 mg to about 120 mg of the free base once per day.

[0083] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 10 mg to about 80 mg of the free base once per day.

[0084] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 20 mg to about 70 mg of the free base once per day.

[0085] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 30 mg to about 60 mg of the free base once per day.

[0086] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg or about 200mg of the free base once per day.

[0087] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 5 mg of the free base once per day.

[0088] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 30 mg of the free base once per day.

[0089] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 40 mg of the free base once per day.

[0090] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 50 mg of the free base once per day.

[0091] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 60 mg of the free base once per day.

[0092] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 70 mg of the free base once per day.

[0093] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 80 mg of the free base once per day.

[0094] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 85 mg of the free base once per day.

[0095] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 120 mg of the free base once per day.

[0096] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 150 mg of the free base once per day.

[0097] In some embodiments, Compound 1 is administered twice a day (bid), “bid” is an abbreviation meaning two times a day and is commonly used in drug dosing instructions.

[0098] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 2.5 mg to about 160 mg of the free base twice per day.

[0099] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 5 mg to about 112.5 mg of the free base twice per day.

[0100] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 20 mg to about 160 mg of the free base twice per day.

[0101] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 20 mg to about 100 mg of the free base twice per day.

[0102] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 20 mg to about 90 mg of the free base twice per day.

[0103] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 25 mg to about 80 mg of the free base twice per day. In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 30 mg to about 70 mg of the free base twice per day.

[0104] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 35 mg to about 65 mg of the free base twice per day.

[0105] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 40 mg to about 60 mg of the free base twice per day.

[0106] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 5 mg to about 40 mg of the free base twice per day.

[0107] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 10 mg to about 35 mg of the free base twice per day.

[0108] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of from about 15 mg to about 30 mg of the free base twice per day.

[0109] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg of the free base twice per day.

[0110] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 15 mg of the free base twice per day.

[0111] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 20 mg of the free base twice per day.

[0112] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 30 mg of the free base twice per day.

[0113] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 40 mg of the free base twice per day.

[0114] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 42.5 mg of the free base twice per day.

[0115] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 60 mg of the free base twice per day.

[0116] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 70 mg of the free base twice per day.

[0117] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 80 mg of the free base twice per day.

[0118] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 100 mg of the free base twice per day.

[0119] In some embodiments, Compound 1 , optionally in the form of a pharmaceutically acceptable salt, is administered in a dose of about 160 mg of the free base twice per day. Aspects and embodiments describing a dose (i.e. a weight in milligrams) of Compound 1 or a pharmaceutically acceptable salt thereof in the context of “the free base” refer to the specified dose of Compound 1 (i.e. the free base of Compound 1 , as depicted in Formula (I)) or an equivalent molar amount of a pharmaceutically acceptable salt of Compound 1.

[0120] In some embodiments the above dosages of Compound 1 are provided in the form of a pharmaceutically acceptable salt.

[0121] Methods

[0122] The language “treat,” “treating” and “treatment” includes the inhibition of FAP in a subject, amelioration of one or more symptoms of a FAP-mediated condition, or the slowing or delaying of progression of diseases or conditions in which inhibition of FAP is beneficial in a subject.

[0123] The language “preventing” and “prevention” includes the inhibition of FAP in a subject to delay or forestall the onset of a FAP-mediated condition and / or a symptom related thereto.

[0124] The language “inhibit”, “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0125] The term “subject” means human. In some embodiments, the subject is suffering from diseases or conditions in which inhibition of FAP is beneficial.

[0126] In some embodiments the FAP-mediated condition is selected from liver disease, diseases of insulin resistance including diabetes mellitus (e.g. type 2) and polycystic ovary syndrome, cardiovascular conditions, cerebrovascular conditions (e.g. stroke), pancreatic disease (e.g. lgG4 disease), inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), lung disease (e.g. pulmonary fibrosis, chronic obstructive pulmonary disorder (COPD) or acute respiratory distress syndrome (ARDS)), kidney disease, obesity, obesity-related conditions, fibrosis, keloid disorder, inflammatory or autoimmune conditions (e.g. rheumatoid arthritis or systemic sclerosis), cancer, and thrombotic conditions (e.g. deep vein thrombosis (DVT) or portal vein thrombosis (PVT)), or combinations thereof.

[0127] In some embodiments, the FAP-mediated condition is liver disease.

[0128] In some of these embodiments, the liver disease is chronic liver disease. In some of these embodiments, there is hepatic fibrosis (e.g. advanced fibrosis, including cirrhosis). In other of these embodiments, there is no hepatic fibrosis. In some embodiments, the subject has compensated cirrhosis. In other embodiments, the subject has decompensated cirrhosis. Liver fibrosis, advanced fibrosis and cirrhosis can be defined histologically (with fibrosis stages or collagen proportionate areas), or through imaging techniques including but not limited to elastographic methods, or through non-invasive circulating biomarkers (including but not limited to ELF, FIB4).

[0129] Liver disease severity can be defined through combinations of clinical biomarkers with or without clinical assessment (such as MELD or Child Pugh scoring), invasive vascular pressure measurements (such as hepatic venous pressure gradient), imaging methods such as elastography, and via circulating biomarkers.

[0130] Fibrosis and cirrhosis can be defined by the following fibrosis stages:

[0131] F0: no fibrosis

[0132] F1: portal fibrosis

[0133] F2: periportal fibrosis

[0134] F3: bridging fibrosis cF4: compensated cirrhosis

[0135] F4: cirrhosis.

[0136] F3-F4 may collectively be referred to as advanced fibrosis.

[0137] Alternatively, fibrosis and cirrhosis can be defined by the following Ishak stages:

[0138] IO: no fibrosis

[0139] 11: portal fibrosis

[0140] I2: portal fibrosis with short septa

[0141] I3: fibrosis with occasional bridging

[0142] I4: fibrosis with robust bridging

[0143] I5: marked bridging, occasional nodules

[0144] I6: cirrhosis.

[0145] I4-I6 may collectively be referred to as advanced fibrosis.

[0146] In some embodiments, the liver disease is advanced chronic liver disease (ACLD). ACLD includes advanced liver fibrosis and cirrhosis.

[0147] In some embodiments, the liver disease is Steatotic Liver Disease (SLD).

[0148] In some embodiments, the SLD is metabolic dysfunction-associated steatotic liver disease (MASLD).

[0149] In some embodiments, the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0150] In some embodiments, the SLD is alcohol-related liver disease (ALD).

[0151] In some embodiments, the SLD is metabolic dysfunction-related and alcohol-related liver disease (MetALD).

[0152] In some embodiments, the liver disease includes sarcopenia.

[0153] In some embodiments, the liver disease is viral hepatitis, including hepatitis A, B, C, D, and E. In some embodiments, the liver disease is autoimmune liver disease, such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) and lgG4 disease, or a combination thereof.

[0154] In some embodiments, the liver disease is a genetic liver disease, such as genetic haemochromatosis.

[0155] In some embodiments, the liver disease is chronic liver disease with fibrosis (e.g. advanced fibrosis, including cirrhosis). This may include MASLD, MASH, ALD, chronic viral hepatitis (such as chronic viral hepatitis B and C), autoimmune conditions (such as PBC, PSC, AIH) and haemochromatosis (including genetic haemochromatosis).

[0156] Liver disease (e.g. chronic liver disease, e.g. chronic liver disease with fibrosis) may also include or be associated with conditions such as Wilson’s disease, alpha 1 antitrypsin deficiency, Budd-Chiari syndrome, veno-occlusive disease, cardiac cirrhosis, drug-related liver disease (e.g. methotrexate, amiodarone, methyldopa, vitamin A), biliary atresia, biliary strictures, Fontan-associated liver disease, cystic fibrosis, lysosomal acid lipase deficiency, progressive familial intrahepatic cholestasis, tyrosinaemia type 1 , and type IV glycogen storage disease.

[0157] In some embodiments, the subject has normal hepatic function.

[0158] In some embodiments, the subject has mild hepatic impairment (Child-Pugh A classification)

[0159] In some embodiments, the subject has moderate hepatic impairment (Child-Pugh B classification).

[0160] In some embodiments, the subject has severe hepatic impairment (Child-Pugh C classification).

[0161] The level of hepatic impairment may relate to the dose of Compound 1 given. In particular, lower daily doses may be more suitable for subjects with higher levels of hepatic impairment.

[0162] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject for a defined period of time. The duration of the period can vary depending on the individual subject and the desired outcome, for example reducing one or more symptoms of the disease, and / or delaying or preventing progression of the disease, or delaying or preventing onset of the disease. In some embodiments, the dose is administered for a period of at least about 4 months, at least about 6 months, at least about 1 year, at least about 2 years, at least about 5 years, at least about 10 years, or at least about 20 years. In some embodiments, the dose is administered for the lifetime of the subject.

[0163] In some embodiments, wherein Compound 1 or a pharmaceutically acceptable salt thereof is for a method of treating a disease, the dose is administered until progression of the disease is stopped or reversed (e.g. preventing or reversing cirrhosis). In further embodiments, the dose is administered until removal of the initial cause of the disease (e.g. eradication of hepatitis infection or other viral infection) and optionally until a desired fibrosis level is reached (e.g. fibrosis stage 0, 1 , 2 or 3).

[0164] In some embodiments, wherein Compound 1 or a pharmaceutically acceptable salt thereof is for a method of preventing a disease, the dose is administered until removal of a potential cause of disease (e.g. eradication of hepatitis infection or other viral infection).

[0165] In some embodiments, FAP activity in the subject is reduced by up to about 100%, up to about 95%, up to about 90%, or up to about 80% after administration of Compound 1 or a pharmaceutically acceptable salt thereof, as compared to baseline activity. In some of these embodiments, FAP activity is plasma FAP activity.

[0166] In some embodiments, FAP activity in the subject is reduced by at least about 50%, at least about 60%, at least about 70%, or at least about 80% after administration of Compound 1 or a pharmaceutically acceptable salt thereof, as compared to baseline activity. In some of these embodiments, FAP activity is plasma FAP activity.

[0167] In some embodiments, FAP occupancy in the subject is reduced by up to about 100%, up to about 95%, up to about 90%, or up to about 80% after administration of Compound 1 or a pharmaceutically acceptable salt thereof, as compared to baseline FAP occupancy. In some of these embodiments, FAP occupancy is liver FAP occupancy.

[0168] In some embodiments, FAP occupancy in the subject is reduced by at least about 50%, at least about 60%, at least about 70%, or at least about 80% after administration of Compound 1 or a pharmaceutically acceptable salt thereof, as compared to baseline FAP occupancy. In some of these embodiments, FAP occupancy is liver FAP occupancy.

[0169] In some embodiments, the percentage cleaved a2-antiplasmin (%Asn-a2AP) relative to total a2- antiplasmin (a2AP) in the subject is less than about 40%, less than about 30% or less than about 20% after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some of these embodiments, a2AP is plasma a2AP.

[0170] In some embodiments, %Asn-a2AP relative to total a2AP in the subject is reduced after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, %Asn-a2AP relative to total a2AP in the subject is reduced by at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60% after administration of Compound 1 or a pharmaceutically acceptable salt thereof, compared to baseline. In some of these embodiments, a2AP is plasma a2AP.

[0171] In some embodiments, the percentage intact FGF21 relative to total FGF21 in the subject is increased after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, percentage intact FGF21 relative to total FGF21 in the subject is increased by at least about 10%, at least about 20%, at least about 30%, or at least about 40% after administration of Compound 1 or a pharmaceutically acceptable salt thereof, compared to baseline FGF21. In some of these embodiments, FGF21 is plasma FGF21. In some embodiments, the level of Pro-C3 in the subject is decreased after administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the level of Pro-C3 in the subject is decreased by at least about 5%, at least about 10%, at least about 15% or at least about 20% after administration of Compound 1 or a pharmaceutically acceptable salt thereof, compared to baseline. In some of these embodiments, Pro-C3 level is the plasma Pro-C3 level. Preclinical studies

[0172] Precl inical studies

[0173] Mouse study

[0174] This study examines the time-dependent relationship between exposure of Compound 1 and FAP inhibition in different tissue compartments in vivo. A total of 36 C57BL6 / N male mice were treated with either vehicle or Compound 1 at two different doses, 1 or 3mg / kg, via a single oral gavage. Animals were terminated at 2, 8, 15 and 24 hours post dose, 3 animals per timepoint and dose or treatment. At terminations, blood was collected for exposure analysis of Compound 1, and plasma, liver and subcutaneous fat depots were sampled for FAP activity measurements.

[0175] The following findings were observed after treatment with Compound 1 at 3 or 1 mg / kg or vehicle in lean C57BL / 6 male mice; strong in vivo correlation between FAP inhibition in plasma, liver- and adipose tissue was demonstrated - which supports measurements of FAP activity in plasma as a surrogate marker for target engagement (TE) in humans. The onset of maximal FAP inhibition in liver and adipose is < 2 h, while offset of FAP inhibition in liver is slower than in plasma. These data support plasma FAP activity is a reasonable surrogate for onset TE marker in liver. In conclusion, TE measurement in plasma could serve as a conservative measure of TE in liver.

[0176] Non-human primate study

[0177] Male monkeys (Macaca fascicularis, aged 8-20 years) with diet induced, biopsy confirmed MASH (F1 / 2 fibrosis) were randomized based on baseline body weight (BW), FAP levels and fibrosis stage, to orally administered vehicle or Compound 1 (10 mg / kg once daily) for 29 weeks. Baseline characteristics of the Study Cohort are indicated in the table below. Food intake were monitored daily, and BW measured weekly while metabolic parameters measured monthly. FAP activity, Compound 1 exposure, a2-AP, FGF21, and safety were monitored throughout the study. Effects on histology were compared between baseline and end of treatment biopsies from the same animal and scored by an expert pathologist using the NASH CRN scoring criteria.

[0178] Baseline Characteristics of the Study Cohort

[0179] 3Value ± SDbGroup 2 had 26 monkeys from dosing week 1 to 13, and 25 monkeys from dosing week 14 to 29 due to non-treatment related health condition.

[0180] Figures 1A and 1 B show the FAP activity and % change in Met a2-AP, respectively, over the time of the study. Oral administration of Compound 1 was well tolerated without notable safety signals and resulted in complete inhibition of FAP activity (pmol / pl / min ± SEM) during the treatment phase, which returned to baseline after 30-day washout. FAP activity in vehicle group was maintained to the end of the study, after an initial drop in the activity.

[0181] Figure 2 shows the change in various measured characteristics for the both the vehicle and Compound 1. Mean BW was maintained in Compound 1-treated arm compared with vehicle arm, with a slight increase in BW in the treatment arm. Although a2AP has been proposed as a physiological FAP substrate, proteolytic cleavage by FAP is only demonstrated either biochemically or ex vivo in plasma samples. This study confirmed that FAP inhibition concordantly increased N-terminal intact Met-a2AP by 34% in the active arm compared to 6% for vehicle (p<0.0001 ), and intact FGF21 increased as indicated by increased C-terminal intact FGF21 / total FGF21 ratio in the active arm compared to vehicle (p=0.029).

[0182] Compound 1 treatment significantly improved liver histology, resulting in improvement in steatosis (44% improved on active vs 10% improved on vehicle, p=0.04) NAFLD activity score (48% improved on active vs 20% improved on vehicle, p=0.0008) and histological fibrosis (16% improved on active vs 5% improved on vehicle p=0.01). The improvement of the fibrosis score is independent of age and body weight change, as analyzed by ordinal regression modeling. NAFLD is >99% synonymous with MASLD (Hagstrom 2024).

[0183] Pro-C3, a circulating biomarker for fibrosis, was reduced significantly by Compound 1 , supporting the histology finding. Inflammation markers, including ALT & AST were not changed significantly by Compound 1 treatment. Similar is true for the key metabolic parameters, including fasting glucose and insulin as well as triglycerides (TG).

[0184] *** Examples

[0185] Abbreviations

[0186] Kz terminal rate constant

[0187] (d)ECG (digital) electrocardiogram AE adverse event Ae amount of Drug Excreted in Urine

[0188] Ae(t1-t2) individual and cumulative amount of unchanged drug excreted into urine from time t1 to time t2

[0189] ALD alcohol-related Liver Disease

[0190] ALP alkaline phosphatase

[0191] ALT alanine aminotransferase / transaminase

[0192] AST aspartate aminotransferase / aransaminase

[0193] AUCinf area under concentration-time curve from time 0 to infinity

[0194] AUCinf / D dose normalized AUCinf

[0195] AUCIast area under concentration curve from time 0 to the last quantifiable concentration AUCIast / D dose normalized AUCIast AUCtau area under the concentration-time curve in the dose interval AUCtau / D dose normalized AUCtau AUDIT Alcohol Use Disorders Identification Test BBB bundle branch block BCRP breast cancer resistance protein BID twice a day BMI body mass index BP blood pressure BP blood pressure C3F FAP cleavage of type III collagen CAP controlled attenuation parameter

[0196] CK-18 cytokeratin 18

[0197] Clast Time of occurrence of last observed plasma concentration

[0198] CL / F apparent total body clearance

[0199] CLR renal clearance CLss / F apparent total body clearance after oral administration (at steady state) Cmax maximum observed drug concentration

[0200] Cmax / D dose normalized Cmax CSR clinical study report Ctrough observed lowest concentration before the next dose is administered

[0201] CTX-3 fragment of degraded crosslinked type III collagen

[0202] CYP3A4 cytochrome P450 3A4 eGFR estimated glomerular filtration rate ELF enhanced liver fibrosis ET end of treatment

[0203] FAB fibroblast activation protein

[0204] FAP fibroblast activation protein

[0205] Fe fraction of drug excreted in urine fe(t1-t2) individual and cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 FIB4 Fibrosis 4 index

[0206] FGF21 fibroblast growth factor 21

[0207] FSH follicle-stimulating hormone

[0208] GGT gamma-glutamyl transferase

[0209] GLP-1 glucagon-like peptide-1 h hour

[0210] HbA1c haemoglobin A1c

[0211] HbcAb hepatitis B core antibody

[0212] HBsAg hepatitis B surface antigen

[0213] HCV hepatitis C Virus

[0214] HDL high-density lipoprotein

[0215] HIV human immunodeficiency virus hsCRP high-sensitivity C-reactive protein hslL-6 high-sensitivity lnterleukin-6

[0216] IMP investigational medicinal product

[0217] INR international normalized ratio

[0218] IVCD intraventricular conduction delay

[0219] LDL low density lipoprotein

[0220] LLN lower limit of normal

[0221] LSM low density lipoprotein

[0222] MAD multiple ascending dose

[0223] MELD model for end-stage liver disease metALD metabolic and alcohol-related liver disease

[0224] MRTinf mean residence time

[0225] PAI-1 plasminogen activator inhibitor-1

[0226] PD pharmacodynamics

[0227] PEth phosphatidylethanol

[0228] P-gp P-glycoprotein

[0229] PI principal investigator

[0230] PK pharmacokinetics

[0231] PR (PQ) time from the onset of the P wave to the start of the QRS complex PRO-03 N-terminal Type III Collagen Propeptide

[0232] QRS ECG interval measured from the onset of the QRS complex to the J point

[0233] QT ECG interval measured from the onset of the QRS complex to the end of the T wave

[0234] QTcF QT interval corrected for heart rate using Fridericia’s correction Rac AUG accumulation ratio for AUG

[0235] Rac Cmax accumulation ratio for Cmax

[0236] ROTEM-TEG rotational thromboelastometry - thromboelastography

[0237] SAD single ascending dose

[0238] SAE serious adverse event

[0239] SRC Safety Review Committee

[0240] SVR sustained virologic response t! Az terminal elimination half-life

[0241] T2DM type 2 diabetes mellitus

[0242] TBL total bilirubin

[0243] TCP temporal change parameter

[0244] TG triglycerides tlast / Tlast time of last quantifiable concentration tmax / T max time to reach maximum observed concentration

[0245] TSH Thyroid-stimulating Hormone

[0246] UACR urine albumin-to-creatinine ratio

[0247] UACR urine albumin-to-creatinine ratio

[0248] ULN upper limit normal

[0249] VCTE Vibration-controlled Transient Elastography

[0250] VEGF-A vascular endothelial growth factor A

[0251] Vss / F apparent volume of distribution at steady state vWF von Willebrand Factor

[0252] Vz / F apparent volume of distribution based on the terminal phase

[0253] EXAMPLE 1 - Phase 1 clinical trial (NCT06138795)

[0254] This combined SAD and MAD study was designed to assess the safety, tolerability, PK, and target engagement (inhibition of FAP activity) of Compound 1 . Inclusion of placebo in this study allowed appropriate benchmarking of reported adverse events (AEs) for Compound 1.

[0255] This FtiH (First time in Human), randomized, single-blind, placebo-controlled single and multiple ascending dose study in healthy participants (males and females of non-childbearing potential), was performed at a single study centre. The study consists of 2 parts: Part A (SAD including food effect) and Part B (MAD).

[0256] Part A of the study is a SAD study in healthy non-Asian participants (Part A1 ), healthy Japanese participants (Part A2), and healthy Chinese participants (Part A3) to assess the safety and tolerability and characterize the PK and PD effects of Compound 1 , following oral administration of single ascending doses of Compound 1 .

[0257] Part A1 consisted of 6 cohorts, including one food effect cohort, of healthy non-Asian participants, with at least one further cohort planned. Part A2 is planned to consist of 3 cohorts of healthy Japanese participants, and Part A3 is planned to consist of one cohort of healthy Chinese participants.

[0258] Dosing in Parts A2 and A3 will, at the earliest, be initiated after completion of the sentinel dosing at corresponding dose levels in Part A1 . Depending on emerging data, up to 2 additional cohorts of Japanese participants may be added in Part A2, and up to one additional cohort of Chinese participants may be added in Part A3.

[0259] Part A1 (cohorts 1-6) was conducted in 45 participants. Part A2 is planned to be conducted in 24 participants and Part A3 is planned to be conducted in 8 participants.

[0260] Within each cohort of Parts A1 , A2 and A3, 6 participants were, or will be, randomized to receive Compound 1, and 2 participants will be randomized to receive placebo. Randomization was not applied to participants in the food effect cohort, which included 5 participants, due to the open-label design and the absence of a placebo control group. Dosing for each cohort, except the food effect cohort, in Part A1 started, or will start, with 2 participants per sentinel group, consisting of one participant randomized to receive placebo and one participant randomized to receive Compound 1. The safety data from the sentinel participants from at least 24 hours post-dose will be reviewed before the remaining participants in the cohort are dosed. The remaining 6 participants for each cohort will be dosed only after this safety review of sentinel data is complete. No sentinel dosing took place in food effect cohort.

[0261] The food effect cohort in Part A1 assessed the potential impact of concomitant food intake on the PK of Compound 1. This cohort consisted of two periods. During the first period, which was consistent across all SAD cohorts, participants received the first dose of study intervention after an overnight fast of at least 10 hours. In the second period, participants returned to the study centre no sooner than 7 days after the first dose administration and received Compound 1 after intake of a high-calorie, high-fat breakfast. The participants stayed at the study centre until 36 hours post-dose.

[0262] Part A1 of the study comprised, and Parts A2 and A3 of the study will comprise, of: a) A Screening Period of maximum 28 days. b) A Dosing Session during which participants will be resident at the Clinical Unit from Day -1 before study intervention administration and up to at least 36 hours after study intervention administration. c) Participants in the food effect cohort will return to the Clinical Unit no sooner than 7 days after the first dose to receive a second single dose after a high-calorie, high-fat breakfast and will be resident up to at least 36 hours after the second dose. d) A Follow-up period 7 days post-dose (7 days post the second single dose in the food effect cohort) that will consist of 1 Follow-up Visit, covering 5 predicted half-lives of study intervention, for which the participants will return to the Clinical Unit.

[0263] After each dose cohort, the data was, or will be, reviewed to decide on the dose level for the next cohort.

[0264] Part B of the study is a MAD study part in healthy non-Asian participants (Part B1 ) and healthy Japanese participants (Part B2) to assess the safety and tolerability, and characterize the PK and PD of Compound 1, following oral administration of repeated doses of Compound 1.

[0265] Part B1 consisted of 3 cohorts of healthy non-Asian participants (with one further additional cohort planned), and Part B2 is planned to consist of one cohort of healthy Japanese participants. Depending on emerging data up to one additional cohort of Japanese participants may be added in Part B2, if the SRC considers it necessary to repeat a dose level or if additional dose steps within the pre-defined exposure limits are required.

[0266] Part B1 (cohorts 1-3) was conducted in 24 participants. Study Part B2 is planned to be conducted in 8 participants (and in up to 16 participants in case an extra cohort will be needed).

[0267] Within each cohort of Parts B1 and B2, 6 participants will be randomized to receive Compound 1, and 2 participants will be randomized to receive placebo.

[0268] Dosing in Part B2 will begin after the decision on dose escalation to the corresponding dose level in Part B1.

[0269] Part B1 of the study comprised of, and part B2 of the study will comprise of: a) a Screening Period of maximum 28 days. b) a Dosing Session during which the participants will be resident at the Clinical Unit from Day -1 before study intervention administration until at least 48 hours after last study intervention administration (Day 12). The residency period may be adjusted depending on observed PK data in Part A. c) a Follow-up period 7 days post-dose that will consist of 1 Follow-up Visit, for which the participants will return to the Clinical Unit.

[0270] After each cohort, the data will be reviewed to decide the dose levels for the next cohort(s).

[0271] Study Interventions Administered

[0272] Study and Duration:

[0273] Each participant in Part A and Part B of the study will be involved in the study for up to 8 weeks, including a 28-day Screening period.

[0274] Objectives and Endpoints - Part A (SAD) adECG and telemetry do not apply for the food effect cohort.

[0275] Objectives and Endpoints - Part B (MAD) Key Inclusion Criteria

[0276] • Healthy male and female (of non-childbearing potential) participants with suitable veins for cannulation or repeated venipuncture.

[0277] • For the healthy Japanese cohorts (Parts A2 and B2): healthy participants are to be Japanese (e.g., natives of Japan or Japanese Americans), defined as having both parents and 4 grandparents who are Japanese. This includes healthy second and third generation participants of Japanese descent whose parents or grandparents are living in a country other than Japan.

[0278] • For the healthy Chinese cohort (Part A3): healthy participants are to be Chinese defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.

[0279] Key Exclusion Criteria

[0280] • Any clinically important illness, medical / surgical procedure or trauma within 4 weeks of the first administration of IMP.

[0281] • Known or suspected history of alcohol or drug abuse and smokers.

[0282] • Plasma donation within one month of the Screening Visit or any blood donation / blood loss > 500 ml_ during the 3 months prior to the Screening Visit.

[0283] • History of coagulation or bleeding disorders or use of anti-platelets / anti-coagulants during the 3 months prior to the Screening Visit, as judged by the investigator.

[0284] • History of hypersensitivity as judged by the investigator, to drugs with a similar chemical structure or class.

[0285] • History of severe dermatological disorders, eg, bullous pemphigoid or Stevens-Johnson syndrome, or clinically significant new or healing wounds in areas of the body not always covered by clothing such as face, forearm, and lower leg, as judged by the investigator.

[0286] Administration of Study Intervention

[0287] In Part A of the study, each participant will receive a single oral dose of Compound 1 or placebo in the morning of Day 1 with approximately 240 ml_ room temperature water, after an overnight fast of at least 10 hours. Participants in the food effect cohort will return to the Clinical Unit no sooner than 7 days after the first dose to receive the study intervention administered after a high-calorie, high-fat breakfast.

[0288] In Part B of the study, each participant will receive a once-daily oral dose of Compound 1 or placebo in the morning of Day 1 to Day 10 with approximately 240 ml_ room temperature water, after an overnight fast of at least 10 hours.

[0289] Participants will be allowed to drink water to prevent dehydration until 2 hours before dosing.

[0290] Water will be allowed ad libitum from 2 hours after dosing.

[0291] A standard meal will be given 4 hours after dosing on Day 1 in Part A and Days 1 and 10 in Part B. A standard meal will be given 2 hours after dosing on Days 2 to 9 in Part B.

[0292] After dosing, participants will remain semi-supine on their bed or sitting (except when necessary for study procedures) until completion of the 4 hour assessments.

[0293] Discontinuation of Study Intervention

[0294] It may be necessary for a participant to permanently discontinue study intervention. If study intervention is permanently discontinued, the participant should, if at all possible, remain in the study.

[0295] Participants will be discontinued from study intervention in the following situations: a) Any significant and clinically relevant changes in the safety parameters, e.g., ECG, BP, pulse rate, and laboratory assessments, making the continuation of study intervention unjustified. b) Any case of Potential Hy’s Law, which is defined as aspartate aminotransferase / transaminase or ALT > 3 x ULN together with TBL > 2 * ULN at any point during the study following the start of study medication irrespective of an increase in ALP. c) If a participant reports symptoms which are considered unacceptable by the participant or the investigator, they will be discontinued from study intervention. d) Any SAE or severe non-serious AE which in the opinion of the SRC or investigator warrants discontinuation of the participant from the active protocol for their well-being. e) Participant decision. Participants are free at any time to discontinue treatment, without prejudice to further treatment. f) Severe noncompliance to study protocol.

[0296] Measurements

[0297] Physical Examinations

[0298] A complete physical examination will be performed and include assessments of the following: general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal, and neurological systems.

[0299] A brief physical examination will include, at a minimum, an assessment of the general appearance, skin, abdomen, liver and spleen, cardiovascular, and respiratory system.

[0300] Vital Signs

[0301] At specified time points, the following variables will be collected after the participant has rested in the supine position for at least 10 minutes: Systolic BP (mmHg); Diastolic BP (mmHg); Pulse rate (bpm); Body temperature (°C); Respiratory rate (breaths per minute).

[0302] At screening and baseline visits BP will be measured in triplicate (3 measurements within 5 minutes) and the mean value will be used. At other visits, BP will be measured once.

[0303] Electrocardiograms

[0304] Electrocardiograms will be performed at specified time points. Three types of ECGs will be used in this study: a) Safety 12-lead ECGs allow the site investigator to review the ECG tracings at bedside and determine any potential abnormalities and risks. b) Digital 12-lead continuous ECGs are collected and electronically for expert review and reporting of ECG intervals. c) Telemetry is for continuous monitoring of ECG activity as a safety measure.

[0305] Clinical Safety Laboratory Tests

[0306] Blood and urine samples for determination of clinical chemistry, haematology, coagulation, and urinalysis will be taken at specified visits.

[0307] Additional safety samples may be collected if clinically indicated at the discretion of the investigator. The date, time of collection and results (values, units, and reference ranges) will be recorded.

[0308] The clinical chemistry, haematology, coagulation, and urinalysis will be performed at a local laboratory at or near to the investigator site. Sample tubes and sample sizes may vary depending on laboratory method used and routine practice at the site.

[0309] Pharmacokinetic Drug Assays

[0310] Blood samples for determination of Compound 1 concentrations in plasma will be analysed using a validated assay. Additional analyses may be conducted on the biological samples to further investigate the presence and / or identity of drug metabolites.

[0311] Placebo samples will not be analysed, unless there is a need to confirm that correct treatment has been given to study participants.

[0312] Pharmacodynamics

[0313] Blood samples will be collected for measurement of FAP activity, circulating FAP protein analysis, a2- antiplasmin, FGF21 , and C3F at specified time points.

[0314] RESULTS

[0315] Part A - SAD, JSAD and CSAD

[0316] The starting dose of 5mg was chosen based on the no observed adverse effect level (NOAEL) in the most sensitive species, monkey, and scaling to avoid complete inhibition of FAP activity at the starting dose. The dose escalation in the SAD study (A1) was 5 mg, 15 mg, 45 mg, 90 mg, 225 mg and 275 mg. A food effect cohort (70 mg) was also included. The dose escalation in the Part A2 SAD study in healthy Japanese participants (JSAD) was 45 mg, 90 mg and 200 mg. The 200 mg cohort was terminated after the enrolment of two patients. The Part A3 SAD study in healthy Chinese participants (CSAD) was conducted at 200 mg.

[0317] There were no major safety or tolerability concerns associated with the administration of Compound 1 up to the highest dose (275 mg) in the SAD part of study (A1 , A2 and A3). There was one serious adverse event (SAE), which was unrelated to Compound 1, and there were no deaths. Six Adverse Events (AE) were reported for the A1 cohort (for the 5 mg, 15 mg, 45 mg, 90 mg and 225 mg cohorts), all of which were mild or moderate intensity. Of these, only one was classified as be potentially caused by the administration of Compound 1. This AE (mild intensity abdominal pain) resolved itself. There were no clinically relevant trends in 12-lead ECGs or clinical laboratory results, no clinically significant physical examination changes, vital sign changes or changes in body temperature post-dose.

[0318] Other risks watched for included increased bleeding propensity, delayed wound healing and adverse events seen with certain DPP4 inhibitors similar in chemical structure to Compound 1 (such as acute kidney injury, respiratory tract infections, acute pancreatitis, immunological skin reactions such as bullous pemphigoid and Stevens-Johnson syndrome, arthralgias, heart failure, angioedema, and anaphylaxis). None of these were observed.

[0319] Following single-dose administration of oral suspension, Compound 1 was rapidly absorbed with median time to maximum plasma concentrations (Cmax) between 0.5 to 1.5 hours post-dose. Following Cmax, Compound 1 concentrations declined in a biphasic manner.

[0320] The systemic exposure of Compound 1 (AUC and Cmax) appeared to increase proportionally to the dose in the studied dose range of 5 mg to 275 mg. The geometric mean terminal elimination half-life of Compound 1 ranged from 3 hours to 9 hours across the investigated cohorts with a more reliable estimate of half-life between 45 mg and 275 mg due to more measurable plasma concentrations in the terminal phase.

[0321] Geometric mean plasma concentrations of Compound 1 after single doses of 5 mg - 275 mg are shown in Figure 3, in which the following symbols are used:

[0322] Descriptive statistics of the plasma PK parameters for A1 are shown below:

[0323] Descriptive statistics of the plasma PK parameters for A2 (45 mg and 90 mg cohorts) and A3 are shown below:

[0324] Geometric Mean (gCV%); For tmax and tlast Median (Min-Max) presented; [n]=number of participants Food effect cohort (70 mg Compound 1 ): AUC was similar in fed and fasting state; whereas Cmax was 33% lower in fed state compared to fasting state.

[0325] Plasma FAP inhibition was measured to establish target engagement and is shown in Figure 4, in which the following symbols are used:

[0326] The level of FAP inhibition was calculated as a percentage of activity pre-dose for each participant. The data demonstrates an increase in level and time with plasma FAP inhibition with increasing doses.

[0327] Part B - MAD, MAD BID, JMAD

[0328] The starting dose for Part B1 was 40 mg administered orally once daily. The dose escalation was 80 mg, and 200 mg also administered orally once daily for 10 days. The doses are selected based on the review of safety, PK, and target engagement (inhibition of FAP activity in plasma) results in the SAD part A1 . A further B1 cohort was opened, wherein 160 mg Compound 1 was administered orally twice daily (320 mg total daily dose) for 10 days (MAD BID). The dose escalation in the Part B2 MAD study in healthy Japanese participants (JMAD) was 120 mg and 200 mg.

[0329] Compound 1 displayed dose-linear PK and the results do not indicate an expectation of significant accumulation of Compound 1 in plasma upon repeated dosing. The once-daily repeated doses of 40 mg, 80 mg, and 200 mg in the MAD part are selected targeting approximately 50%, 80% and >80% FAP inhibition at trough, the end of a dosing interval, based on target engagement results in the SAD part.

[0330] There were no major safety or tolerability concerns associated with the administration of Compound 1 up to the highest dose (200 mg) in the MAD part of the study (B1 and B2). There were no deaths or any other significant AEs. Ten Adverse Events (AE) were reported for the B1 once daily cohorts, all of which were mild or moderate intensity. Of these, five were classified as be potentially caused by the administration of Compound 1. These AEs (mild intensity constipation x 3, mild intensity headache, mild intensity palpitation) resolved themselves.

[0331] There were no clinically relevant trends in 12-lead ECGs or clinical laboratory results, no clinically significant physical examination changes, vital sign changes or changes in body temperature post-dose. Other risks watched for included increased bleeding propensity, delayed wound healing and adverse events seen with certain DPP4 inhibitors similar in chemical structure to Compound 1 (such as acute kidney injury, respiratory tract infections, acute pancreatitis, immunological skin reactions such as bullous pemphigoid and Stevens-Johnson syndrome, arthralgias, heart failure, angioedema, and anaphylaxis). None of these were observed.

[0332] Following repeated once daily oral administration at 40 mg, 80 mg, 120 mg and 200 mg, and 160 mg twice daily, Compound 1 was rapidly absorbed with median time to maximum plasma concentrations (Cmax) between 0.5 to 1.5 hours post-dose. Following Cmax, Compound 1 concentrations declined in a biphasic manner. The geometric mean terminal half-life of Compound 1 following repeated once daily, or 160 mg twice daily, oral administration for 10 days ranged from 4 hours to 13 hours across the investigated doses.

[0333] The systemic exposure of Compound 1 appeared to increase proportionally to dose after single and repeated dosing. There was no accumulation in plasma Cmax or AUCtau or time-dependency in Compound 1 PK following repeated once daily dosing.

[0334] Geometric mean observed plasma concentrations of Compound 1 following repeated once daily doses of 40 mg, 80 mg, 120 mg and 200 mg, and a twice daily dose of 160 mg, in healthy participants are shown in Figure 5.

[0335] Descriptive statistics of the plasma PK parameters for the once daily B1 cohorts are shown below:

[0336] Descriptive statistics of the plasma PK parameters for the twice daily 160 mg B1 cohort, and the B2 cohorts, are shown below:

[0337] Plasma FAP inhibition was measured to establish target engagement and is shown in Figure 6.

[0338] The level of FAP inhibition was calculated as a percentage of FAP activity pre-dose for each participant. These show FAP inhibition >90% at Cmax, 47 % inhibition at trough after 40 mg once daily (QD) for 10 days, 74% inhibition at trough after 80 mg QD for 10 days and 92% inhibition at trough after 200 mg QD for 10 days in B1 , and 66% inhibition at trough after 120 mg QD for 10 days and 74% inhibition at trough after 200 mg QD for 10 days in B2. This data demonstrates an increase in level and time of plasma FAP inhibition with increasing doses.

[0339] Compound 1 reduces cleavage of disease-related biomarker a2-antiplasmin in a dose-dependent manner as shown in Figure 7. Specifically, Figure 7 depicts percentage cleaved a2-antiplasmin (%Asn-a2AP) relative to total a2-antiplasmin (a2AP) for each of the three a2AP genotypes present in the subjects tested (RR, RW, WW). EXAMPLE 2 - Phase 2a clinical trial (D7930C00002)

[0340] This Phase 2a, randomised, single-blind, placebo-controlled study is intended to evaluate the safety, tolerability, and pharmacokinetics and explore the pharmacodynamic effects of Compound 1 in participants with liver fibrosis and compensated cirrhosis.

[0341] Compound 1 will be evaluated in two cohorts, each with a parallel-group design and two arms, with participants blinded to treatment allocation. Cohort A will consist of participants with presumed MASH with fibrosis. Approximately 40% of Cohort A will have advanced fibrosis including compensated cirrhosis (F3-cF4). Cohort B will include participants with underlying SLDs of varying aetiologies (e.g., MetALD, ALD, and treated hepatitis C virus [HCV SVR12]) and have advanced fibrosis including compensated cirrhosis (F3-cF4).

[0342] The total duration of study participation for each participant in Cohorts A and B will be approximately 63 days (9 weeks) and will include an up to 28-day screening period, a 28-day treatment period, and a follow-up visit seven days following completion of treatment, as follows:

[0343] • 1 or 2 screening visits (up to 28 days before treatment)

[0344] • 28 days of treatment including 5 clinic visits

[0345] • Week 1 : 24-hour in-clinic stay (Day 1 )

[0346] • Week 2: Outpatient clinic visit (Day 7)

[0347] • Week 3: Outpatient clinic visit (Day 14)

[0348] • Week 4: T elephone visit (Day 21 )

[0349] • Week 5: 24 to 48-hour in-clinic stay (Day 28)

[0350] • Week 6: Follow-up visit (Day 35)

[0351] Study Interventions Administered

[0352] Objectives and Endpoints Key Inclusion Criteria

[0353] • Males / females aged > 18 years

[0354] • Indications: Presumed MASH with fibrosis (cohort A) OR steatotic liver disease excluding MASH, with advanced fibrosis (cohort B)

[0355] • No significant change in weight over the last 6 months

[0356] • Barrier contraceptives use by males

[0357] • Capable of informed consent

[0358] • Judged to be suitable for study by investigator

[0359] Key Exclusion Criteria

[0360] • A condition that could put the participant at risk, influence the participant’s ability to participate in the trial, interfere with evaluation of the study intervention or affect the interpretation of the results

[0361] • Other causes of liver disease which are not the principal inclusion criteria for each cohort.

[0362] • Significant elevations in liver blood tests or platelets <140 x109 / L

[0363] • Decompensated liver disease, hepatobiliary cancer or listing for liver transplantation

[0364] • Bleeding disorders or major bleeding risk

[0365] • HIV infection or hepatitis B infection

[0366] • Clinically significant cardiovascular (e.g. severe ischaemic heart disease, severe heart failure or cardiac dysrhythmia) or cerebrovascular disease within the past 3 months

[0367] • Stage 2 hypertension

[0368] • eGFR <60ml / min / 1.73m2

[0369] • Clinically significant gastrointestinal disease which can affect the interpretation of pharmacokinetic, safety, and tolerability data

[0370] • Skin disorders or ongoing wound healing

[0371] • Psychiatric disorders which may negatively affect participation in the trial

[0372] • Females of childbearing potential

[0373] Administration of Study Intervention

[0374] The safety profile observed in the MAD study at 40-200 mg, the available data from up to 225 mg in the SAD study, and the absence of significant accumulation or time dependency in plasma PK following repeated dosing, justify the planned Phase 2a study with oral once daily dosing of 120 mg Compound 1 for 28 days.

[0375] This will allow for the assessment of safety, PK, target engagement (FAP inhibition) and exploratory biomarkers, while prioritizing patient safety within the context of the existing safety data from SAD and MAD studies. The proposed main elimination pathway of Compound 1 in humans is hepatic metabolism, predominately mediated by CYP3A4. After administration of single doses of 5 mg to 225 mg in the SAD part of the study, on average 24% of the administered dose was excreted unchanged in urine. Doses of 120 mg Compound 1 or placebo will be administered orally, once daily for 28 days.

[0376] Discontinuation of Study Intervention

[0377] If study intervention is permanently discontinued, the participant should, if possible, remain in the study.

[0378] Platelet Count

[0379] Discontinuation of study intervention will occur if the participant’s platelet count drops to < 75 * 109 / L and is confirmed by taking a second measurement in 5 to 7 days.

[0380] QTc Stopping Criteria

[0381] If a clinically significant finding is identified on or after enrolment, including, but not limited to absolute QTcF > 500 ms, or changes in QTcF > 60 ms from baseline, confirmed with repeated 12-lead ECGs recording within 5 minutes, the investigator or qualified designee will determine if the participant can continue on the study intervention and if any change in participant management is needed. For QTcF, the review of the ECG printed at the time of collection must be documented.

[0382] Summary Schedule of Activities

[0383] Medical and Surgical History

[0384] The investigator will record details of each participant’s medical and surgical history at Screening.

[0385] Demographics Demographic data recorded at Screening will include age, sex, race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White), and ethnicity (Hispanic or Latino or Non-Hispanic or Latino) of participants.

[0386] Concomitant Medications

[0387] The investigator will record details of each participant’s concomitant medications at the timepoints specified.

[0388] Height and Weight

[0389] Height (in cm) and weight will be measured (in kg) at specified timepoints.

[0390] Females of Non-childbearing Potential

[0391] Only females of non-childbearing potential will be included in this study.

[0392] Viral Serology

[0393] Viral serology for hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus antibody; HIV-1 and HIV-2 antibodies will be determined at screening, for eligibility.

[0394] Alcohol and Drugs of Abuse

[0395] Urine for drugs of abuse will be assessed at screening for eligibility. Participants may be included should they test positive for anti-depressants, benzodiazepines, opiates, or cannabinoids where there is evidence of a legal prescription that is appropriately indicated, the participant has been on stable dose for at least 3 months prior to randomisation, and the Principal Investigator is satisfied that the participant is suitable for study inclusion. Where these criteria do not apply, a urine drug screen should be conducted to confirm the result, and if positive, the participant should be excluded. The urine drug screen is for the following: Alcohol; Amphetamine; Antidepressants; Barbiturates; Benzodiazepines; Cannabinoids; Cocaine; Methadone; Opioids; and Phencyclidine. The Study Physician and Medical Monitor should be contacted for questions regarding retest for positive drug test result where there is ambiguity. The AUDIT questionnaire will be utilized as a measure of alcohol dependence during screening. The PEth will be evaluated at the timepoints specified to determine alcohol use, but results are not required for randomisation.

[0396] Efficacy Assessments

[0397] FAP Activity

[0398] Inhibition of FAP activity in plasma will be determined at Days 1, 7, 14, 28, and follow-up (calculated as change and percentage change in FAP activity against baseline) compared to placebo.

[0399] Imaging - FibroScan

[0400] A FibroScan (VCTE) is a non-invasive ultrasound-based method used for the measurement of liver stiffness (LSM), CAP, as well as spleen stiffness (SSM). The SSM is optional. The SSM requires the use of the FibroScan® 630 Expert machine (Echosens, Paris, France), equipped with a spleen- dedicated module. The FibroScan (LSM, CAP, and optional SSM) assessments should be performed in the morning with the participants in a fasted state with at least 4 hours of fasting. The timing of the FibroScan should be kept as consistent as possible at each study visit where these assessments are required. Sites are expected to follow standard procedures as required for FibroScan assessments and quality as provided by the training modules for FibroScan (e.g. , take 10 valid measurements with an interquartile range / median ratio that does not exceed 30%, appropriate-sized probe for body habitus, etc). The FibroScan assessments performed at Screening and pre-dose at Visit 7 can be performed within a ± 2-day window.

[0401] Physical Examinations

[0402] A full physical examination will be performed and include assessments of the following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities), and neurological systems. The full physical examination at screening will include an examination of the participants’ feet to observe skin integrity, circulation (pedal pulses), and presence of any neuropathy (ankle reflex and sensation). A brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).

[0403] Vital Signs

[0404] Participants must abstain from using caffeine products and tobacco products 2 hours before assessment of vital signs. Vital signs measurements should be measured after the participant has rested in the seated position for at least 10 minutes. Days 1 and 28: Recordings should be collected pre-dose, 1 hour, 4 hours post-dose. All other visits should be collected pre-dose.

[0405] Electrocardiograms

[0406] 12-lead safety ECGs will be performed at timepoints as specified and as clinically indicated by the investigator, and will allow the site investigator to review the ECG tracings at bedside to determine any potential abnormalities and risks.

[0407] Ten-second 12-lead safety ECGs will be obtained after the participant has been resting in the supine position for at least 10 minutes whenever it is required by the investigator. The ECGs will be performed in triplicate, with 1 minute between readings. All ECGs will be evaluated with respect to rhythm; heart rate; and PR, RR, QRS, QT, and QTcF intervals from the 12-lead safety ECG, and the investigator will judge the overall interpretation as normal or abnormal. If abnormal, it will be decided whether the abnormality is clinically significant or not, and the abnormality will be recorded. The investigator or delegate will evaluate the safety ECG in real time.

[0408] The date, time, and the physician interpretation (normal, abnormal - clinically not significant, or abnormal - clinically significant) for the safety ECGs will be recorded in the eCRF and stored as source documents.

[0409] Days 1 and 28: ECG recordings should be collected pre-dose, 1 hour, 4 hours post-dose.

[0410] All other visits should be collected pre-dose. The ECG recording should be taken prior to the pharmacokinetic samples for Compound 1 or planned blood sampling at the same timepoint.

[0411] Clinical Safety Laboratory Tests Blood and urine samples for determination of clinical chemistry, haematology, coagulation, and urinalysis will be taken at the visits indicated. Additional safety samples may be collected if clinically indicated at the discretion of the investigator. The clinical chemistry, haematology, and urinalysis will be performed at a central laboratory. The following laboratory variables will be measured:

[0412] Additional Clinical Safety Laboratory Variables

[0413] Liver Enzyme Elevations

[0414] Participants with liver enzyme elevations, including possible DILI or Hy’s Law, should be managed according to FDA Guidance on DILI and IQ DILI consensus frameworks for detection, assessment, and management of suspected acute drug-induced liver injury during clinical trials in participants with CLDs (Regev 2019, T reem 2021 ). The evaluation for other potential causes of liver chemistry elevations of participants with potential DILI will be the same as for Hy’s Law.

[0415] In case a participant shows an AST or ALT > 3 * ULN together with TBL > 2 * ULN, in order to identify cases of potential Hy’s Law, it is important to perform a comprehensive review of laboratory data. As soon as possible after the biochemistry abnormality is initially detected, the Study Clinical Lead will contact the investigator in order to review available data and agree on whether there is an alternative explanation for meeting potential Hy’s Law criteria other than DILI caused by the IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from date potential Hy’s Law criteria was met.

[0416] Discontinuation of treatment should be considered if:

[0417] • ALT or AST >= 8xULN

[0418] • ALT or AST >= 5xULN for more than 2 weeks

[0419] • ALT or AST >3= xULN and (TBL >=2xULN or INR >1 .5)

[0420] • ALT or AST >= 3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%).

[0421] Pharmacokinetics

[0422] Blood and urine samples will be collected for measurement of plasma and urine concentrations of Compound 1 as specified. Plasma and urine samples may be used to analyse the PK of Compound 1 metabolites. Samples collected for analyses of Compound 1 concentration may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the study.

[0423] Determination of Drug Concentration

[0424] Samples for determination of drug concentration in plasma and urine will be assayed using an appropriately validated bioanalytical method.

[0425] Collection of Samples for Pharmacodynamics

[0426] Blood samples will be collected for measurement of plasma FAP activity as specified. Biomarker Sample Collection

[0427] To evaluate their association with the observed clinical responses to Compound 1, samples will be tested for the following biomarkers:

[0428] • Hepatic necroinflammation: CK-18 M30, CK-18 M65, hsCRP

[0429] • Sinusoidal endothelial dysfunction: VEGF-A, vWF (profile), hslL-6, renin activity, PAI-1

[0430] • Mechanistic biomarkers: plasma FAP protein levels, %Asn-a2-antiplasmin, total and intact FGF-21, C3F

[0431] • Pharmacodynamic biomarkers: ELF, PRO-C3, CTX-3, FIB-4 (calculation), FAST (calculation), AGILE 3+ (calculation), ADAPT (calculation)

[0432] • Metabolic and lipid biomarkers: standard lipid panel (HDL, LDL, TG, total cholesterol), fasting glucose and insulin, HOMA-IR (calculation)

[0433] AEs and SAEs

[0434] Adverse Events

[0435] An AE is the development of any untoward medical occurrence in a patient or clinical study participant administered a medicinal product, and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (e.g. , an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease temporally associated with the use of a medicinal product, whether it’s considered related to the medicinal product.

[0436] The term AE is used to include both serious and non-serious AEs and can include a deterioration of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout periods, even if no study intervention has been administered.

[0437] Serious Adverse Events

[0438] An SAE is an AE occurring during any study phase (i.e. , run-in, treatment, washout, follow-up), that fulfils one or more of the following criteria:

[0439] • Results in death.

[0440] • Is immediately life-threatening.

[0441] • Requires inpatient hospitalisation or prolongation of existing hospitalisation.

[0442] • Results in persistent or significant disability or incapacity.

[0443] • Is a congenital anomaly or birth defect.

[0444] • Is an important medical event that may jeopardise the participant or may require medical treatment to prevent one of the outcomes listed above.

[0445] Life-threatening

[0446] ‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it occurred, or it is suspected that use or continued use of the medicinal product would result in the participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might have caused death (e.g., hepatitis that resolved without hepatic failure). Hospitalisation

[0447] Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and / or surgical operations planned before or during a study are not considered AEs if the illness or disease existed before the participant was enrolled in the study, provided that it did not deteriorate in an unexpected way during the study.

[0448] Important Medical Event or Medical Treatment

[0449] Medical and scientific judgement should be exercised in deciding whether a case is serious in situations where important medical events may not be immediately life-threatening or result in death, hospitalisation, disability or incapacity but may jeopardise the participant or may require medical treatment to prevent one or more outcomes listed in the definition of serious. These should usually be considered as serious. Simply stopping the suspect drug does not mean that it is an important medical event; medical judgement must be used.

[0450] Intensity Rating Scale

[0451] • Mild (awareness of sign or symptom, but easily tolerated)

[0452] • Moderate (discomfort sufficient to cause interference with normal activities)

[0453] • Severe (incapacitating, with inability to perform normal activities)

[0454] AEs Based on Examinations and Tests

[0455] Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs should only be reported as AEs if they meet any of the following:

[0456] • fulfil any of the SAE criteria

[0457] • are the reason for discontinuation of the IMP

[0458] • are the reason for other management change ( i.e. , addition of a medication to treat the AE)

[0459] • are clinically relevant as judged by the investigator (which may include but is not limited to consideration as to whether intervention or non-planned visits were required or other action was taken with the IMP, e.g., dose adjustment or drug interruption).

[0460] If deterioration in a laboratory value / vital sign is associated with clinical signs and symptoms, the sign or symptom will be reported as an AE and the associated laboratory result / vital sign will be considered as additional information. Wherever possible, the reporting investigator uses the clinical, rather than the laboratory term (e.g., anaemia vs low haemoglobin value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated parameters should be reported as AE(s).

[0461] Any new or aggravated clinically relevant abnormal medical finding at a physical examination as compared with the baseline assessment will be reported as an AE unless unequivocally related to the DUS (disease under study). AEs Based on Signs and Symptoms

[0462] All signs or symptoms spontaneously reported by the participant or care provider or reported in response to the open question from the study site staff: “Have you had any health problems since the previous visit / you were last asked?” or revealed by observation will be collected and recorded in the eCRF.

[0463] When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.

[0464] Disease Progression

[0465] Disease progression can be considered as a worsening of a participant’s condition attributable to the disease for which the IMP is being studied. It may be an increase in the severity of the DUS and / or increases in the symptoms of the disease. The development of liver-decompensating events, such as ascites, hepatic encephalopathy, variceal bleeding, etc., should be considered as disease progression and not an AE so long as there is not definitive evidence of a drug-induced event.

[0466] Disease Under Study

[0467] Symptoms of DUS are those which might be expected to occur as a direct result of liver fibrosis. Events that are unequivocally due to DUS should not be reported as AEs during the study unless they meet SAE criteria or lead to discontinuation of the IMP.

[0468] RESULTS

[0469] The fibrosis severity and liver stiffness measurement (LSM) in cohorts A and B, including corresponding placebo groups, are as follows:

[0470] * Approximate equivalencies for fibrosis stage and Fibrosis severity: Mild= F0-F1, Moderate= F2-F3, Severe=F3-F4.

[0471] Participants in cohort A (14 active + 8 placebo) had MASH with moderate (n=7) to severe (n=15) liver fibrosis. Participants in cohort B (12 active + 6 placebo) had severe liver fibrosis of various etiologies, predominately MetALD. Overall, there was an overlap in fibrosis severity between the two cohorts. Compound 1 Gmean Cmax was comparable between cohort A and cohort B on Day 1 and Day 28. Gmean AUCO-24 was 1.2-fold and 1.36-fold higher in cohort A on Day 1 and Day 28, respectively.

[0472] It was found that Compound 1 120mg was safe and well tolerated in patients with steatotic liver disease and advanced fibrosis. This is as demonstrated in the following table:

[0473] The primary endpoint of safety and tolerability for orally administered Compound 1 at 120 mg was met. There were no major safety or tolerability concerns associated with the administration of Compound 1 . There were no deaths or any other significant AEs. 7 Adverse Events (AE) were reported, and these were balanced between Compound 1 and placebo arms. All AEs were mild or moderate intensity and distributed predominately across the gastrointestinal, infections, respiratory, and investigations system organ classes.

[0474] There were no clinically relevant trends in 12-lead ECGs or clinical laboratory results, no clinically significant physical examination changes, vital sign changes or changes in body temperature postdose.

[0475] These findings support a favourable tolerability profile for Compound 1 in the target population.

[0476] Figure 8A shows the geometric mean plasma concentrations of Compound 1 following once daily dosing of 120mg, at day 1 and day 28. Figure 8A shows that there was no accumulation in plasma Cmax or AUCtau or time-dependency in Compound 1 PK following once daily dosing for 28 days. Following repeated once daily oral administration at 120 mg, Compound 1 was rapidly absorbed with median time to maximum plasma concentrations (Cmax) 1-hour post-dose.

[0477] Figure 8B shows Mean FAP plasma inhibition following once daily dosing of 120 mg of Compound 1 vs placebo, at day 1 and day 28. The level of FAP inhibition was calculated as a percentage of FAP activity pre-dose for each participant in Cohort A and Cohort B. These show 98% FAP inhibition at trough when measured on day 1 and day 28, for both cohorts.

[0478] Figure 8C shows the average percentage of FAP cleaved a2-anti plasmin (Asn-a2AP (%)) relative to total a2-antiplasmin following repeated oral doses of Compound 1 vs placebo. The PK parameters for Cohort A and B are shown in the following table:

[0479] EXAMPLE 3 - Phase 1 PET trial (D7930C00003) The present trial is designed to provide information on radioligand [68Ga]Ga-FAPI-46 kinetics, examine radioligand reproducibility and to examine Compound 1 occupancy of its target, FAP, in the liver in a limited number of patients with advanced liver fibrosis. [68Ga]Ga-FAPI-46 has the structure: and has the CAS ID of 2374784-98-0. It has been used broadly used in nuclear medicine, and more recently it has been explored in non-malignant disorders, e.g., for the evaluation of fibrotic tissue in lungs, heart and kidney (Siebermair 2021 ; Bergmann 2021; Conen 2022).

[0480] Trial objectives.

[0481] Primary objective

[0482] • To examine target FAP occupancy in the liver by Compound 1 as measured with [68Ga]Ga-FAPI-46 PET.

[0483] Secondary objectives

[0484] • To evaluate plasma PK of Compound 1 after single doses.

[0485] • To evaluate the plasma target engagement of Compound 1 by assessment of plasma FAP inhibition following single oral dosing.

[0486] • To quantify test-retest reproducibility of radioligand [68Ga]Ga-FAPI-46 uptake in the liver.

[0487] • To examine the relationship between target FAP occupancy in the liver (PET examination) and Compound 1 dose and plasma concentration.

[0488] Safety objective

[0489] • To assess the safety and tolerability of Compound 1 following oral administration of single doses.

[0490] Trial endpoints

[0491] • Occupancy, %: percent change from baseline in the uptake of FAP PET radioligand [68Ga]-Ga- FAPI-46 in the liver after a single dose of Compound 1 .

[0492] • Plasma concentrations of Compound 1. The following PK variables will be calculated: o Individual estimate of the terminal plasma elimination rate constant o Area under the plasma concentration vs. time curve (AUC) from 0 to infinity o Dose normalised AUCinf o AUC from 0 to time of last measurable plasma concentration o Dose normalised AUCIast o Apparent total body clearance following extravascular administration o Maximum observed concentration o Dose normalised Cmax o Mean residence time extrapolated to infinity o Elimination half-life o Time of occurrence of last observed plasma concentration o Time of occurrence of Cmax o Volume of distribution following extravascular administration

[0493] • % FAP inhibition compared to baseline in plasma.

[0494] • Absolute test-retest variability, % (aTRV) and intraclass correlation coefficient (ICC) (for radioligand uptake).

[0495] • Descriptive statistic and modelling of relationship between occupancy and drug dose, drug plasma concentration ( / .e., the dose / plasma concentration of Compound 1 required to induce 50% receptor occupancy [IDso, ICso] and radioligand affinity in vivo [K / _pl]).

[0496] Safety endpoints o Frequency, seriousness, and intensity of AEs. o Clinically significant changes in vital signs (blood pressure, pulse rate, body temperature, and respiratory rate), electrocardiograms, safety laboratory measurements (haematology, clinical chemistry, coagulation, and urinalysis), and physical examination findings.

[0497] Trial design

[0498] The trial will consist of up to 3 sequential panels. The design of the trial is adaptive and adjustments in time points and / or number of assessments and samples can be made during the course of the trial.

[0499] The pilot panel (Part A) aims to provide information on radioligand kinetics and to adjust the imaging protocol for the trial. The panel is planned to be conducted in up to 3 participants.

[0500] The main panel (Part B) has 2 aims; to examine radioligand reproducibility (test-retest) and to examine Compound 1 occupancy upon its target, FAP, in the liver. This panel will examine the occupancy of 3 dose levels of Compound 1. Six (6) participants in total are planned to participate in this panel, 2 participants per dose level. Compound 1 dose selection will follow an adaptive design, i.e. the dose level to be explored depends upon the results of the preceding participants / panel. Participants will receive a single dose of Compound 1 and will undergo 3 PET examinations in total with the radioligand [68Ga]- F API-46.

[0501] The initial dose is 35mg which is administered orally as a suspension (the same route is used for the other doses). The initial dose was chosen in light of the results of Example 1. An optional panel (Part C) may be added depending on emerging data in order to further the examination of target occupancy. Up to 3 participants may be included in the optional panel. Participants of the optional panel may receive a Compound 1 dose level that was assessed in the main panel or different dose levels may be examined. Participants in the optional panel may receive 2 single doses of Compound 1 each, the interval period between PET examinations and administration of Compound 1 will be approximately 1 week to allow sufficient wash-out.

[0502] Each participant is expected to take part in the trial for approximately 49 days in Part A (pilot panel) and Part B (main panel), or 51 days in Part C (optional panel), including an up to 35-day screening period.

[0503] The trial flow will be as follows:

[0504] All participants in Part A and Part B, will attend the trial site during Visit 1 (screening). The screening visit will take place from Day -35 to Day -14 and will include an eligibility check and physical examination, as well as the collection of demographic data, medical history, and prior and concomitant medications. Liver stiffness will be measured by VCTE FibroScan and will be performed during the screening period (may be performed as a separate visit). If a historical liver stiffness analysis has been performed within 6 months prior to screening, no additional evaluation is required for inclusion in the trial. The first PET examination (screening period) will be performed at least 5 days before IMP administration (for Part B) and will serve for 2 purposes: 1) to determine participant eligibility according to inclusion / exclusion criteria and 2) as a baseline measurement for further PET examinations.

[0505] In Part A, eligible participants (screening Visit 1) will return to the trial site for pre-assessments, confirmation of eligibility criteria, blood sampling for FAP concentration analysis (at the trial site), and the first PET examination (Visit 2). The participants will perform the PET examination at the PET Centre using the radioligand [68Ga]Ga-FAPI-46. Depending on the results of the initial PET examination, participants of Part A may be invited to continue the trial in Part B. In such a case they will participate in a total of 3 PET examinations, not exceeding predefined radiation exposure limits. If they do not participate further, they will complete the trial with a follow-up visit (Visit 3, telephone call to follow-up on AEs and concomitant medications) 7 days (±2 days) after the PET examination.

[0506] In PartB, eligible participants who completed the screening visit and / or Part A will return to the trial site for blood sampling for FAP concentration analysis and for the second PET examination on Day 1 (Visit 3) using the radioligand [68Ga]Ga-F API-46. At Visit 4, on Day 7 (±2 days), participants will be admitted to the trial site, where they will receive a single oral dose of Compound 1. Standardised meals will be served while the participants are admitted to the trial site. On the day after Compound 1 administration, the third PET examination will be performed at the PET Centre followed by blood sampling for PK analysis and FAP activity, after which the participants will return to the trial site for further follow-up and safety monitoring. Vital signs and ECGs will be checked at regular intervals. The participants will be discharged from the trial site approximately 24 hours post-dose of Compound 1 . At Visit 5 (7 days [±2 days] after the drug administration on Visit 4), a final follow-up visit at the trial site will take place for safety monitoring and follow-up of any AEs. In Part C (optional), participants will attend the trial site during Visit 1 (screening). The screening visit will take place from Day -35 to Day -14 and will include an eligibility check and physical examination, as well as the collection of demographic data, medical history, and prior and concomitant medications. Liver stiffness will be measured by VOTE FibroScan and will be performed during the screening period (may be performed as a separate visit). If a historical liver stiffness analysis has been performed within 6 months prior to screening, no additional evaluation is required for inclusion in the trial.

[0507] The first PET examination (Visit 2) will be performed at the PET Centre at least 5 days before IMP administration on Day 1. Safety assessments and blood sampling for FAP concentration will take place at the trial site.

[0508] At Visit 3 (Day 1 ), participants will be admitted to the trial site for single oral Compound 1 administration. On Day 2, the second PET examination will take place at the PET Centre using the radioligand [68Ga]Ga- F API-46. Blood sampling for PK analysis and FAP activity will be performed. The participants will be discharged from the trial site 24 hours post-dose of Compound 1.

[0509] At Visit 4 (Day 8 [±2 days]), participants will be admitted to the trial site for a second single oral Compound 1 administration. On Day 9, the third PET examination will take place at the PET Centre using the radioligand [68Ga]Ga-FAPI-46 and blood sampling for PK analysis and FAP activity will be performed. The participants will thereafter return to the trial site. Vital signs and ECGs will be checked at regular intervals. The participants will be discharged from the trial site approximately 24 hours post-dose of Compound 1 . At Visit 5, (7 days [±2 days] after the PET examination on Visit 4), a final follow-up visit at the trial site will take place for safety monitoring and follow-up of any AEs.

[0510] If needed, the stay at the trial site for additional safety and PK assessments may be added based on a review of the data from previous panels and participants.

[0511] Number of participants

[0512] Approximately 12 participants will be included in the 3 panels as follows:

[0513] 1. Part A (pilot panel): up to 3 participants.

[0514] 2. Part B (main panel): 6 participants in total including 3 dose levels of Compound 1 , 2 participants per dose level, with starting dose of 35 mg.

[0515] 3. Part C (optional panel): up to 3 participants.

[0516] If a participant withdraws from the trial or if their PET examinations are not considered evaluable (i.e., all PET examinations completed per protocol but not evaluable due to technical reasons), a replacement participant will be assigned to the group of the withdrawn participant.

[0517] PET image analysis

[0518] PET image analysis of radioligand [68Ga]Ga-FAPI-46 uptake (as a measure of FAP expression) in the liver will be performed. The analysis will be performed stepwise. At first, the data will be inspected (visual interpretation), followed by extraction of radioactivity time curves (as SUV over PET examination time), calculation of radioligand binding (SUV ratio to the selected reference region), followed by the primary endpoint calculation (target occupancy).

[0519] The SUV is the radioactivity concentration in the region of interest corresponding to the regional radioactivity concentration normalised for injected radioactivity and body weight.

[0520] Standardised uptake value ratio (SUVR) is a semiquantitative parameter representing total radioligand binding in the region of interest (SUVIiver / SUVreference region). The reference region is a region without FAP expression and will be chosen based on the results of the pilot panel as deemed necessary.

[0521] In addition, quantitative image analysis to determine total and if possible specific radioligand binding using image-derived input function and compartmental, graphical analysis methods will also be explored and compared. The final analysis method for the primary endpoint, target occupancy analysis will be chosen after the pilot panel.

[0522] Target occupancy, as the primary endpoint, will be calculated as the difference in radioligand binding to FAP before and after drug administration.

[0523] RESULTS

[0524] The validation of Compound 1 liver target engagement using Positron Emitting Tomography (PET) imaging is shown in Figure 9.

[0525] FAPi-PET imaging has enabled the visualisation of Compound 1 binding to FAP in the livers of participants with cirrhosis. This is exemplified in Figure 9 with images from one representative participant. The baseline figure shows radioligand ([68Ga]GAF API-46) uptake in the liver due to high FAP expression, while the post-dose figure demonstrates reduced imaging signal 22 hours after a single dose of Compound 1 , proof that Compound 1 is occupying the target. At the first tested dose (n=2), a target occupancy in the liver of >85% was achieved.

[0526] EXAMPLE 4 - Phase 1 Hepatic Impairment trial (D7930C00004)

[0527] This is a Phase I study designed to evaluate the PK profile in addition to safety and tolerability of a single oral dose of Compound 1 (80 mg) in participants with impaired hepatic function as defined by the Child- Pugh (CP) classification.

[0528] Hepatic impairment can adversely affect some pathways of hepatic / gut drug metabolism and its absorption and distribution. Preclinical data suggest that hepatic metabolism accounts for the major part of the systemic clearance of Compound 1. In vitro studies indicate that Compound 1 is metabolised primarily via hepatic CYP3A4, accounting for > 90% of metabolism in liver. Compound 1 is likely to be administered to patients with hepatic impairment as it is being developed for treatment of advanced fibrosis (including cirrhosis). The target population may also include patients with steatotic liver diseases due to various aetiologies including viral and alcoholic liver diseases. Thus, participants enrolled in this study will include participants with varying degrees of hepatic impairment that are representative of the target population.

[0529] The selection of participants in this study will be based on by CP classification to characterise impact of mild, moderate, and severe hepatic impairment on the PK of Compound 1.

[0530] The study is planned to consist of:

[0531] Cohort 1 : Participants with normal hepatic function (sex-, age-, and body mass index [BMI]-matched), up to N = 12

[0532] Cohort 2: Participants with mild hepatic impairment (CP A classification), up to N = 8 (minimum of 6 PK evaluable participants)

[0533] Cohort 3: Participants with moderate hepatic impairment (CP B classification), up to N = 8 (minimum of 6 PK evaluable participants)

[0534] Cohort 4 (Optional): Participants with severe hepatic impairment (CP C classification), up to N = 8 (minimum of 6 PK evaluable participants)

[0535] Safety, tolerability, and available plasma PK data up to 48 hours post-dose from at least 4 participants in each of the mild hepatic impairment (CP Class A) and moderate hepatic impairment (CP Class B) cohorts must have been assessed by the investigator(s), medical monitor, and sponsor prior to the decision to proceed with evaluation / recruitment of participants with severe hepatic impairment (CP Class C). Cohort 1 (normal hepatic function) will be initiated in parallel with Cohorts 2 and 3.

[0536] Each participant with normal hepatic function (Cohort 1) enrolled in the study will be demographically matched by sex, age (± 10 years), and BMI (± 20% kg / m2; data obtained at screening) to an enrolled participant with hepatic impairment. Participants with normal hepatic function cannot be matched to more than one participant with hepatic impairment within an impairment cohort; however, participants with normal hepatic function may be matched to 1 participant from more than 1 hepatic impairment cohort.

[0537] Potential participants will be screened to assess their eligibility to enter the study within 21 days prior to administration of study intervention. Participants who meet the study entry criteria will report to the clinic on Day -1 for assessment of continued eligibility and baseline safety assessments. Each participant will receive a single oral dose of 80 mg Compound 1 , on Day 1 , under fasted conditions. Participants will remain resident in the clinic for 48 hours post-dose for the completion of PK, biomarker, target engagement, and safety assessments. Participants will attend the safety follow-up visit approximately 1 week after the last PK sample. Each participant will be involved in the study for approximately 4.5 weeks

[0538] Objectives and Endpoints

[0539] Child-Pugh Classification (Tsoris and Marlar 2024) aGrade 0: normal consciousness, personality, neurological examination, electroencephalogram. Grade 1: Restless, sleep disturbed, irritable / agitated, tremor, impaired handwriting, 5 cps waves. Grade 2: lethargic, time disoriented, inappropriate, asterixis, ataxia, slow triphasic waves. Grade 3: Somnolent, stuporous, place disoriented, hyperactive reflexes, rigidity, slower waves. Grade 4: unrousable coma, no personality / behaviour, decerebrate, slow 2 to 3 cps delta activity.bAbsent: No detectable ascites by manual investigation. Mild: Ascites palpitation doubtful. Moderate: Ascites detectable by palpitation. Severe: Necessity of paracentesis. Does not respond to medication.cEither prothrombin time and / or International Normalised Ratio may be used. If both are calculated, the parameter with the highest points scored will be used.

[0540] The severity of hepatic impairment is then calculated as follows:

[0541] • Child-Pugh A: 5 to 6 points

[0542] • Child-Pugh B: 7 to 9 points

[0543] • Child-Pugh C: 10 to 15 points

[0544] Dose level

[0545] A dose of 80 mg Compound 1 (to be administered orally as one single dose) was selected for this study based on the review of safety, PK, and target engagement data from Example 1, and matches the dose of the second cohort in the MAD part of that study. The proposed main elimination pathway of Compound 1 in human is hepatic metabolism, predominately mediated by CYP3A4. The predicted fraction excreted in urine is 30%. Based on pre-clinical studies, plasma protein binding of Compound 1 in humans is 44%.

[0546] EXAMPLE 5 - a Phase 1 study investigating the pharmacokinetics of Compound 1 when administered alone and in combination with guinidine (D7930C00006)

[0547] This is an open-label, randomized, cross-over, single dose study in healthy participants to assess the pharmacokinetics of Compound 1 when administered alone and in combination with quinidine. In pre- clinical studies, Compound 1 was identified as a substrate of the permeability glycoprotein (P-gp) efflux transporter in human-derived cell systems. In vitro, some saturation was observed at increasing concentrations of Compound 1, indicating that efflux of Compound 1 by P-gp transporter may be more pronounced at lower dose levels. Therefore, a clinical drug-drug interaction study with an inhibitor of P-gp transporter is justified to investigate potential impact of inhibition of efflux by this transporter on absorption of Compound 1.

[0548] The primary objective of this study is, therefore, to evaluate the effect of a strong inhibitor of the P-gp transporter, quinidine, on the pharmacokinetics (PK) of Compound 1 in healthy participants (males, and females of non-childbearing potential). The results of this study will support inclusion / exclusion criteria in future clinical studies and support labelling statements about the use of P-gp inhibitors in combination with Compound 1.

[0549] Approximately 16 participants will be enrolled in this study to ensure at least 12 evaluable participants will complete the study.

[0550] Key Inclusion Criteria

[0551] • Provision of signed and dated, written informed consent prior to any study-specific procedures.

[0552] • Healthy male and female (of non-childbearing potential) participants aged 18 to 55 years, inclusive, with suitable veins for cannulation or repeated venipuncture at the time of signing consent.

[0553] • All females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit.

[0554] • Have a BMI between 18 and 32 kg / m2, inclusive, and weigh at least 50 kg at the Screening Visit.

[0555] Key Exclusion Criteria

[0556] • Any clinically important illness, medical / surgical procedure or trauma within 4 weeks of the first administration of IMP.

[0557] • Any laboratory values with the following deviations at the Screening Visit or on admission to the Clinical Unit. Abnormal values may be repeated once at each visit (screening and admission) at the discretion of the investigator: o Aminotransferases ■ ALT > ULN.

[0558] ■ AST > ULN. o TBL > ULN. o Estimated glomerular filtration rate < 80 ml_ / min / 1 .73 m2calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. o Hemoglobin < lower limit of normal.

[0559] • Any positive result on Screening for serum HBsAg, HBcAb, HCV Ab, or HIV.

[0560] • Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead ECG, at screening and / or admission to the Clinical Unit, as judged by the investigator.

[0561] • Known or suspected history of alcohol or drug abuse and smokers.

[0562] • Plasma donation within one month of the Screening Visit or any blood donation / blood loss > 500 mL during the 3 months prior to the Screening Visit.

[0563] • History of coagulation or bleeding disorders or use of anti-platelets / anti-coagulants during the 3 months prior to the Screening Visit, as judged by the investigator.

[0564] • History of hypersensitivity to DPP4 inhibitors, as judged by the investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to DPP4 inhibitors.

[0565] • History of severe dermatological disorders, eg, bullous pemphigoid or Stevens-Johnson syndrome, as judged by the investigator.

[0566] The study will comprise:

[0567] A Screening Period of maximum 28 days.

[0568] Period 1 : single dose administration of compound 1 (80 mg) or compound 1 (80 mg) + quinidine (600 mg) on Day 1 followed by PK sampling of compound 1 for 48 hours (approximately 5 times the predicted plasma half-life). Period 2 will start after a washout period of at least 7 days.

[0569] Period 2: single dose of alternate treatment on Day 8 in Period 2, followed by PK sampling of compound 1 for 48 hours.

[0570] A Follow-up Visit: participants will return to the Clinical Unit for a Follow-up Visit, 7 to 14 days after the last compound 1 PK sample in Period 2.

[0571] Participants will be randomized to one of 2 treatment sequences:

[0572] Sequence 1: Treatment A in Period 1, Treatment B in Period 2.

[0573] Sequence 2: Treatment B in Period 1, Treatment A in Period 2.

[0574] T reatment A: 80 mg Compound 1 .

[0575] Treatment B: 80 mg Compound 1 + 600 mg quinidine.

[0576] Objectives and endpoints

[0577] Dose level

[0578] A dose of 80 mg Compound 1 (to be administered orally as one single dose) was selected for this study based on the review of safety, PK, and target engagement data from Example 1, and matches the dose of the second cohort in the MAD part of that study.

[0579] The Compound 1 dose in this study was selected based on safety, PK, and target engagement results in the first-in-human study D7930C00001 where Compound 1 single doses of up to 275 mg and QD repeated doses of up to 200 mg were well tolerated with no important safety issues. Compound 1 displayed dose-proportional PK with no signs of time-dependency in PK or accumulation in plasma upon repeated dosing for 10 days. The single dose of 80 mg Compound 1 , resulting in approximately 75% inhibition of FAP activity in plasma (Study D7930C00001 ) was selected in this study to mimic what is considered to be a relevant therapeutic exposure at steady state.

[0580] The oral dose of 600 mg quinidine, dosed QD or twice daily are the approved therapeutic doses of quinidine and commonly used in studies where evaluation of potential drug-drug interactions (DDIs) by quinidine is done. Calculation or Derivation of Pharmacokinetic Parameters

[0581] The PK parameters of the concentration data for Compound 1 will be derived using non-compartmental methods in Phoenix® WinNonlin® Version 8.5 or higher (Certara).

[0582] PK analysis will, where data allow, be carried out using actual elapsed times determined from the PK sampling and dosing times recorded in the database. If actual elapsed times are missing, nominal times may be used. Nominal sampling times may be used for any agreed interim PK parameter calculations.

[0583] Where data allow, the following PK parameters for Compound 1 will be derived from concentrations.

[0584] PK Parameters The following diagnostic parameters for plasma PK analysis will be provided:

[0585] Urine Parameters

[0586] Where data allow, the following parameters will be calculated for Compound 1 from the urine data:

[0587] Additional PK parameters may be determined where appropriate.

[0588] RESULTS The results for this study are set out below and in Figures 10 and 11.

[0589] Figure 10 shows the geometric mean plasma concentration (nM) of Compound 1 over time (semi- logarithmic scale). This data shows that following oral administration of a single dose of Compound 1 alone or in combination with quinidine, Compound 1 was rapidly absorbed, with a median tmax of 1.00 hour (range: 0.50, 3.00). Figure 11 shows the mean FAP plasma inhibition following a single dose of Compound 1 + quinidine vs Compound 1 alone.

[0590] Descriptive statistics of the plasma PK parameters are show below ([n]=number of participants):

[0591] Plasma results The geometric mean CL / F for Compound 1 alone and in combination with quinidine was 61.08 L / h and 57.41 L / h, respectively, while the geometric mean Vz / F was 473.6 L and 500.1 L, respectively. The gCV% was moderate for Cmax (-47%) and low for AUCs (-25%).

[0592] Urine Pharmacokinetic parameters of Compound 1 Urine results

[0593] The geometric mean percentage of unchanged Compound 1 excreted in urine over 48 hours (Fe[0-48]) was 27.94% for participants receiving Compound 1 alone and 23.90% for those receiving Compound 1 in combination with quinidine. The corresponding geometric mean renal clearance (CLR) values were 17.14 L / h and 13.78 L / h for Compound 1 alone and Compound 1 in combination with quinidine, respectively.

[0594] Statistical comparison of key pharmacokinetic parameters The geometric mean ratio of Compound 1 when administered along with quinidine, compared to Compound 1 alone, was 0.8023 (90% Cl: 0.6464, 0.9959) for Cmax, 1.0444 (90% Cl: 0.9639, 1.1317) for AUCinf, and 1.0472 (90% Cl: 0.9648, 1.1367) for AUCIast. These results suggest that coadministration with quinidine leads to an approximately 20% reduction in peak plasma concentration of Compound 1, while overall systemic exposure, as measured by AUCinf and AUCIast, remained comparable to Compound 1 administered alone.

[0595] Compound 1 when taken alone or in combination with quinidine was generally safe and well-tolerated in healthy participants. No SAEs, deaths, or AEs leading to discontinuation were reported in the study.

[0596] EXAMPLE 6 - Phase 1 study to assess the effect of Compound 1 on the pharmacokinetics of midazolam, caffeine and bupropion (D7930C00007)

[0597] This is a study to investigate how multiple oral doses of Compound 1 affect the pharmacokinetics of midazolam, caffeine, and bupropion in healthy participants.

[0598] In vitro induction studies showed that Compound 1 has induction potential against midazolam, caffeine, and bupropion. Consequently, there is a risk for interactions with co-administered compounds that act as substrates of midazolam, caffeine, and bupropion.

[0599] The primary objective of this study is, therefore, to evaluate the effect of Compound 1 on the PK of midazolam (CYP3A4), caffeine (CYP1A2), and bupropion (CYP2B6) in healthy participants (males, and females of non-childbearing potential). The results of this study will support inclusion and exclusion criteria in future clinical studies and support labelling statements about the use of CYP1 A2, CYP2B6, and CYP3A4 substrates in combination with Compound 1.

[0600] Objectives and Endpoints

[0601] The study duration will be approximately 8 weeks. Approximately 16 participants will be enrolled in this study. Key inclusion criteria

[0602] • Provision of signed and dated, written informed consent prior to any study-specific procedures.

[0603] • 2 Healthy male and / or female (of non-childbearing potential) participants aged 18 to 55 years (at the time of signing the ICF) with suitable veins for cannulation or repeated venipuncture.

[0604] • All females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit (Day -2).

[0605] • Have a BMI between 18 and 32 kg / m2inclusive and weigh at least 50 kg at Screening.

[0606] Key exclusion criteria

[0607] • History of any clinically important disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, or influence the results or the participant’s ability to participate in the study.

[0608] • Any clinically important illness, medical / surgical procedure or trauma within 4 weeks of the first administration of IMP. • Any laboratory values with the following deviations at the Screening Visit or on admission to the Clinical Unit. Abnormal values may be repeated once at each visit (screening and admission) at the discretion of the investigator: o Aminotransferases

[0609] ■ ALT > ULN.

[0610] ■ AST > ULN. o TBL > ULN. o Estimated glomerular filtration rate < 80 ml_ / min / 1 .73 m2calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. o Hemoglobin < lower limit of normal.

[0611] • Any positive result on Screening for serum HBsAg, HBcAb, HCV Ab, or HIV.

[0612] • Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead ECG, at screening and / or admission to the Clinical Unit, as judged by the investigator.

[0613] • Abnormal vital signs, after 10 minutes supine rest, at the Screening Visit and / or admission to the Clinical Unit (Day -2), defined as any of the following. Abnormal values may be repeated once at the discretion of the investigator.

[0614] • Known or suspected history of alcohol or drug abuse and smokers.

[0615] • Plasma donation within one month of the Screening Visit or any blood donation / blood loss > 500 mL during the 3 months prior to the Screening Visit.

[0616] • History of coagulation or bleeding disorders or use of anti-platelets / anti-coagulants during the 3 months prior to the Screening Visit, as judged by the investigator.

[0617] • History of hypersensitivity to DPP4 inhibitors, as judged by the investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to DPP4 inhibitors.

[0618] • History of severe dermatological disorders, eg, bullous pemphigoid or Stevens-Johnson syndrome, as judged by the investigator.

[0619] The treatment duration will be 17 days. During this time, participants will receive 13 single doses of Compound 1 (120 mg), 2 doses of the combination of midazolam (1 mg) and caffeine (50 mg), and 2 doses of bupropion (75 mg), on different days (Periods 1 to 3).

[0620] Number of visits: 3 visits to the Clinical Unit (1 Screening Visit, 1 residential period, 1 Follow-up Visit) Approximately 16 participants will be enrolled in this study to achieve at least 12 evaluable participants.

[0621] Dose Level

[0622] The Compound 1 dose in this study was selected based on safety, PK, and target engagement results from the first-in-human Study D7930C00001 where Compound 1 single doses of up to 275 mg and multiple doses of up to 200 mg once daily were well tolerated with no important safety issues. Compound 1 displayed dose-proportional and time-independent PK with no accumulation in plasma after repeated dosing for 10 days. Compound 1 demonstrated strong target engagement assessed by inhibition of FAP activity in plasma. After repeated once daily administration of Compound 1 for 10 days, plasma FAP inhibition at trough was 47%, 74%, and 92% for Compound 1 doses of 40 mg, 80 mg and 200 mg, respectively.

[0623] The multiple doses of 120 mg compound 1 to be used in this study have been chosen to represent what is considered to be a relevant therapeutic exposure at steady state and is the same dose as in the currently ongoing Phase Ila study in participants with Liver Fibrosis and Compensated Cirrhosis (Example 2).

[0624] Midazolam 1 mg and caffeine 50 mg doses are the doses used in a clinical study using Geneva cocktail (including midazolam, caffeine and bupropion) to assess the activity of CYP enzymes (3A4, 1 A2 and 2B6) with no mutual interaction between the cocktail components (Bosilkovska 2016). The bupropion dose in the Geneva cocktail was 20 mg. Bupropion dose of 75 mg was selected in this study as it is the lowest commercially available strength of the product in the USA. To minimize risk of mutual interaction with midazolam / caffeine due to higher dose of bupropion in this study, bupropion will be administered on the day after administration of midazolam / caffeine.

[0625] Study Interventions administered

[0626] Administration of study intervention

[0627] Each participant will receive 13 single doses of 120 mg Compound 1, 2 doses of the combination of 1 mg midazolam and 50 mg caffeine, and 2 doses of 75 mg bupropion during the study. Participants will be resident in the Clinical Unit for all periods of the study, and all doses of study interventions are to be taken under supervision at the Clinical Unit.

[0628] On Day 1 (Period 1), each participant will receive a single dose combination of 1 mg midazolam and 50 mg caffeine. Participants will be fasted for at least 10 hours prior to dosing until 4 hours after dosing.

[0629] On Day 2 (Period 1), each participant will receive a single dose of 75 mg of bupropion. Participants will be fasted for at least 10 hours prior to dosing until 4 hours after dosing.

[0630] Bupropion will be administered 24 hours post-dose of midazolam and caffeine on Day 1.

[0631] On Days 5 to 13 (Period 2), each participant will receive a dose of 120 mg of Compound 1 once daily for 9 days. On Days 5 and 13, participants will be fasted for at least 10 hours prior to dosing until 4 hours after dosing.

[0632] On Day 14 (Period 3), each participant will receive a single dose of combination of 1 mg midazolam and 50 mg caffeine co-administered with a single dose of 120 mg of Compound 1. Participants will be fasted for at least 10 hours prior to dosing until 4 hours after dosing.

[0633] On Day 15 (Period 3), each participant will receive a single dose of 75 mg bupropion co-administered with a single dose of 120 mg of Compound 1. Participants will be fasted for at least 10 hours prior to dosing until 4 hours after dosing. Bupropion will be administered 24 hours post-dose of compound 1 on Day 14.

[0634] On Days 16 and 17 (Period 3), each participant will receive a single dose of 120 mg.

[0635] Pharmacokinetics

[0636] Blood sample collection Blood samples for the determination of plasma concentrations of Compound 1, and midazolam, caffeine, and bupropion and their metabolites (1’-hydroxy midazolam, paraxanthine, and hydroxy-bupropion) will be collected for each treatment period.

[0637] Blood samples for determination of Compound 1 , and midazolam, caffeine, and bupropion and their metabolite (1’-hydroxy midazolam, paraxanthine, and hydroxy-bupropion) concentrations in plasma will be analysed by bioanalytical test sites, using validated assays. Additional analyses may be conducted on the biological samples to further investigate the presence and / or identity of drug metabolites.

[0638] Pharmacokinetic Variables

[0639] Calculation or Derivation of Pharmacokinetic Parameters

[0640] The PK parameters of the concentration data for midazolam, caffeine, bupropion, and their respective metabolites (T-OH-midazolam, paraxanthine, and OH-bupropion) alone and in combination with Compound 1, and those of Compound 1 will be derived using non-compartmental methods in Phoenix®WinNonlin®Version 8.5 or higher (Certara).

[0641] PK analysis will, where data allow, be carried out using actual elapsed times determined from the PK sampling and dosing times recorded in the database. If actual elapsed times are missing, nominal times may be used.

[0642] Where data allow, the following PK parameters for midazolam, caffeine, bupropion, and their respective metabolites, and Compound 1 will be derived from concentrations.

[0643] PK Parameters

[0644] 3For midazolam, caffeine, and their respective metabolites.bFor midazolam, caffeine, and bupropion.cOnly for Compound 1

[0645] The following diagnostic parameters for plasma PK analysis will be provided:

[0646] The PK parameters (RCmax, RAUCinf, RAUCIast, RAUCO-24) of midazolam, caffeine, and bupropion and their respective metabolites (T-OH-midazolam, paraxanthine, and OH-bupropion) in the absence and presence of Compound 1 will be analysed using a mixed effects model following a natural logarithmic transformation, with fixed effect for treatment and random effect for participant. Results will be transformed back to be presented as least-squares gmeans (together with 2-sided 95% Cis) for the reference treatment (substrate alone) and test treatment (substrate + Compound 1 ). Ratios of gmeans together with 2-sided 90% Cis of test treatment and reference treatment will also be estimated and presented.

[0647] RESULTS

[0648] The results of this study are set out below and shown in Figure 12.

[0649] Figure 12 shows the geometric mean plasma concentration (n M) of Compound 1 over time (semi- logarithmic scale (+ / - gSD)). The results shown in Figure 12 demonstrate that following daily oral administration of Compound 1, the median tmax was 0.98 hours (range: 0.48, 2.00 hours) on Day 5 and 0.99 hours (range: 0.48, 3.03 hours) on Day 13 and the geometric mean t1 Az for Compound 1 was 4.073 hours on Day 5 and 4.131 hours on Day 13.

[0650] Descriptive statistics of plasma PK parameters of Compound 1 on Day 5 and Day 13 are shown below:

[0651] This data shows that PK parameters for Compound 1 were similar on Day 5 and Day 13. The gCV% for Cmax, AUCO-24, and AUCIast ranged from 22.0% to 40.9%, indicating low to moderate variability across both days.

[0652] Pharmacokinetic Conclusions

[0653] The pharmacokinetic profiles of midazolam, caffeine, bupropion, and their primary metabolites were assessed following oral administration, both alone and in combination with Compound 1. All analytes were rapidly absorbed, with median tmax values generally below one hour for parent drugs (midazolam: 0.53 h; caffeine: 0.52 h; bupropion: 0.97-1.00 h) and slightly longer for metabolites. Elimination half-life (t1 / 2Az), clearance (CL / F), and volume of distribution (Vz / F) were consistent between regimens for each compound.

[0654] Midazolam / 1-Hydroxymidazolam:

[0655] Coadministration with Compound 1 resulted in comparable Cmax for both midazolam (GMR: 1.13; 90% Cl: 1.01-1.27) and its metabolite, 1 -hydroxy midazolam (GMR: 1.13; 90% Cl: 0.99-1.29). AUCinf, AUCIast, and AUCO-24 for midazolam were comparable (GMR: 1.12 for all; 90% Cl ranges: 1.00-1.27), while for 1-hydroxymidazolam, AUCinf increased by 22% (GMR: 1.22; 90% Cl: 1.09-1.35) and AUCIast / AUCO-24 increased by 21% (GMR: 1.21 ; 90% Cl: 1.10-1.34), relative to administration alone. These results suggest that Compound 1 has no effect on CYP3A4. Caffeine / Paraxanthine:

[0656] Coadministration with Compound 1 , caffeine Cmax was similar (GMR: 0.93; 90% Cl: 0.85-1 .01 ) and AUCinf, AUCIast, and AUCO-24 were comparable (AUCinf GMR: 1.18; 90% Cl: 1.11-1.25; AUCIast GMR: 1.13; 90% Cl: 1.05-1.22; AUCO-24 GMR: 1.14; 90% Cl: 1.08-1.20). For paraxanthine, Cmax and AUC parameters were similar (Cmax GMR: 0.97; 90% Cl: 0.93-1.01 ; AUCinf GMR: 1.08; AUCIast GMR: 1.01 ; AUCO-24 GMR: 1.02; all 90% Cl: 0.87-1.18). These results suggest that Compound 1 has no effect on CYP1A2.

[0657] Bupropion / Hydroxy-bupropion:

[0658] Coadministration with Compound 1 resulted in similar Cmax for bupropion (GMR: 1.06; 90% Cl: 0.92- 1.23) and hydroxy-bupropion (GMR: 0.97; 90% Cl: 0.93-1.02). For bupropion, AUCinf, AUCIast, and AUCO-24 were comparable (GMR: 1.15; 90% Cl: 1.08-1.23 for AUCinf, 1.15; 90% Cl: 1.07-1.23 for AUCIast, and 1.12; 90% Cl: 1.06-1.19 for AUCO-24, respectively). For hydroxy-bupropion, AUCinf and AUCIast were similar (GMR: 1.01; 90% Cl: 0.96-1.07 and 0.96-1.06, respectively). These results suggest that Compound 1 has no effect on CYP2B6.

[0659] Variability, as assessed by geometric CV%, was moderate (generally 25-50%) for Cmax and AUC in most analytes, and low (<25%) for Cmax in caffeine and paraxanthine. The elimination half-life (t1 / 2Az) and distributional parameters remained essentially unchanged by Compound 1 in all groups.

[0660] EXAMPLE 7 - A Phase Ila, Randomized. Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Compound 1 in Adult Patients with Steatotic Liver Disease and Advanced Fibrosis

[0661] The prevalence of chronic liver disease (CLD) and cirrhosis is increasing and currently accounts for approximately 2 million deaths per year globally. The chronic cycle of liver inflammation, destruction, and regeneration results in fibrosis and ultimately cirrhosis with deterioration of liver function. Currently, there are no approved therapies for the treatment of advanced hepatic fibrosis that is agnostic to aetiology, leaving a huge unmet need and residual risk, especially in those with cirrhosis. Compound 1 is a potent selective first-in-class small molecule oral inhibitor of FAP and is being developed for the treatment of CLDs with advanced hepatic fibrosis including cirrhosis. FAP is a membrane-bound serine protease and human tissue studies have also demonstrated that FAP is overexpressed in hepatic fibrosis of different aetiologies including steatotic liver disease or SLD (e.g., MASH / NASH, ALD), chronic viral hepatitis, and autoimmune / cholestatic liver diseases. FAP overexpression also correlates with stage of hepatic fibrosis, being most highly expressed in cirrhosis. Membrane bound FAP can also be cleaved to a soluble form, and its circulating levels are highly predictive of adverse liver outcomes. Preclinical data has demonstrated Compound 1 has a beneficial impact on steatosis, inflammation, and fibrosis in an NHP model of MASH / NASH and hepatic fibrosis, and studies of other FAP inhibitors in rodents have shown positive effects on fibrosis in both MASH / NASH and generalised hepatic fibrosis induced by CCI4. The aim of this study is to obtain safety, PK, PD and proof of concept efficacy data prior to initiating a larger, longer-term Phase 2b study. This Phase 2a study will explore the efficacy, safety, and pharmacokinetics of Compound 1 in participants with SLD and advanced fibrosis, when treated over 24 weeks with 150mg of Compound 1 or placebo.

[0662] The study will randomize approximately 104 participants, of whom approximately 50% will have compensated cirrhosis.

[0663] Objectives and Endpoints

[0664] This is a Phase 2a, randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy, safety and pharmacokinetics and explore the pharmacodynamic effects of Compound 1 in participants with SLD and advanced fibrosis. The study population will comprise participants with advanced fibrosis, where approximately 50% will have compensated cirrhosis. Randomization will be stratified by cirrhosis, type 2 diabetes mellitus, and alcohol use.

[0665] Dose Level

[0666] For the Phase 2a study in patients with SLD and advanced fibrosis, a once-daily oral dose of 150 mg Compound 1 was selected, which is supported by PK / PD predictions and current clinical and nonclinical- exposure constraints.

[0667] Median PK / PD predictions, based on D7930C00002 (Example 2) data, indicate ED50 at 29 mg and ED80 at 90 mg for trough FAP inhibition (Figure 13). A 150 mg QD dose is therefore expected to deliver trough inhibition exceeding 80% on the median curve and, given interpatient variability, increase the proportion of subjects achieving high inhibition thresholds (e.g., -90% at trough).

[0668] Safety and exposure constraints were assessed against human PK from Phase I SAD / MAD and D7930C00002. The predicted exposure for 150 mg QD in participants with liver fibrosis and compensated cirrhosis is within the pre-defined geometric mean exposure limits and within the Phase I SAD / MAD and D7930C00002 exposure range, which has been well tolerated with no important safety issues.

[0669] The 150 mg QD regimen was chosen to maximize the duration and depth of FAP inhibition and thereby the probability of achieving the primary endpoint (ELF reduction), while maintaining exposures within established limits and leveraging favourable safety at 120 mg.

[0670] Intervention Groups and Duration

[0671] Arm A will include 52 participants with SLD and advanced fibrosis who will receive oral Compound 1 (150 mg) tablets once daily for 24 weeks.

[0672] Arm B will include 52 participants with SLD and advanced fibrosis who will receive oral placebo tablets once daily for 24 weeks.

[0673] Study details include: 4 weeks (28 days) of screening period before treatment

[0674] 24 weeks (168 days) of treatment

[0675] 4 weeks or 28 days of safety follow-up

[0676] Presentation and analysis of ELF score data (primary endpoint)

[0677] ELF score and absolute change in ELF score from baseline to end of treatment will be summarized using descriptive statistics and presented using tabular and graphical from as appropriate, by treatment. Statistical inference will also be performed: ANCOVA will be conducted, with change from baseline to end of treatment in ELF score as dependent variable, and treatment group, baseline ELF score and relevant stratification factors (cirrhosis, T2DM, alcohol use) as covariates. The analysis of ELF score data will be based on the full analysis set.

[0678] Key inclusion criteria

[0679] • Provision of signed and dated, written informed consent prior to any study specific procedures.

[0680] • Male and female participants aged >18 years based on the date of the screening visit.

[0681] • A diagnosis of SLD defined by hepatic steatosis identified by imaging or biopsy, or by having at least one co-existing or historic metabolic comorbidity:

[0682] • BMI > 25 kg / m2 [23 Asia] OR WC > 94 cm (M) >80 cm (F) OR ethnicity adjusted equivalent,

[0683] • Fasting serum glucose > 5.6 mmol / L [100 mg / dL] OR 2-hour post-load glucose levels > 7.8 mmol / L [>140 mg / dL] OR HbA1c > 5.7% [39 mmol / L] OR type 2 diabetes OR treatment for type 2 diabetes,

[0684] • Blood pressure > 130 / 85 mmHg OR specific antihypertensive drug treatment,

[0685] • Plasma triglycerides > 1.70 mmol / L [150 mg / dL] OR lipid lowering treatment,

[0686] • Plasma HDL-cholesterol < 1.0 mmol / L [40 mg / dL] (M) and < 1.3 mmol / L [50 mg / dL] (F) OR lipid lowering treatment.

[0687] • Advanced fibrosis as defined by 2 of the following criteria:

[0688] • At least NASH CRN stage 3 fibrosis (or at least Ishak stage 4) within the last 1 year of randomization;

[0689] • LSM 10-15 kPa (inclusive) by VOTE;

[0690] • ELF score of 9.8-10.5 inclusive.

[0691] • The cirrhosis population should meet the following criteria: o NASH CRN stage 4 fibrosis (or at least Ishak stage 5) within the last 1 year of randomization; o LSM 15-25 kPa (inclusive) by VCTE; o ELF score of 9.8-11.3 inclusive.

[0692] • No evidence of worsening of ALT and AST (within 50%) measurements at the screening visits 1 and 2.

[0693] • Participants on Vitamin E >400 ILJ / day, resmetirom, thiazolidinediones (e.g. pioglitazone, rosiglitazone, and lobeglitazone), glucagon-like peptide 1 receptor agonists (GLP1RA) or dual agonists (e.g. semaglutide, tirzepatide), or sodium-glucose transport protein 2 (SGLT2) inhibitors (e.g. dapagliflozin, canagliflozin, empagliflozin) must be on a stable dose, defined as no changes in prescribed dose, new medications, or discontinuation for at least 6 months prior to screening.

[0694] • No clinically significant change in body weight (> 5%) over the last 3 months prior to randomization or >10% in the 6 months prior to screening.

[0695] • Female participants should be of non-childbearing potential

[0696] Key exclusion criteria

[0697] • History of, or any existing condition that, in the opinion of the investigator, would interfere with evaluation of the study intervention, put the participant at risk, influence the participant’s ability to participate or affect the interpretation of the results of the study.

[0698] • Positive results for HIV infection.

[0699] • Positive results for hepatitis B surface antigen.

[0700] • Other causes of liver disease including autoimmune diseases (autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, lgG4 or overlap disorders), heritable disorders (haemochromatosis, alphal anti-trypsin deficiency, Wilson’s disease).

[0701] • Prior or planned bariatric surgery (e.g. gastroplasty, Roux-en-Y gastric bypass). Surgery reversal or removal of intragastric balloon >2 years prior to enrolment would be eligible.

[0702] • History of significant pancreatic disorders (acute pancreatitis, chronic pancreatitis, hereditary pancreatitis, pancreatic cancer).

[0703] • History of decompensated liver disease including but not limited to ascites, hepatic encephalopathy, variceal bleeding.

[0704] • For individuals with cirrhosis, Child-Pugh score >A6 (i.e. Class B or C), as determined at screening.

[0705] • Model for End Stage Liver Disease (MELD) score >12, as determined at screening, unless due to therapeutic anti-coagulation.

[0706] • Prior or planned liver transplantation.

[0707] • Current or prior history of hepatocellular carcinoma or cholangiocarcinoma or other malignant liver tumour

[0708] • Poorly controlled hypertension with systolic BP > 160 mmHg and / or diastolic BP > 100 mmHg on the average of 2 supine measurements after being at rest for at least 10 minutes at screening or randomization

[0709] • Clinically significant cardiovascular or cerebrovascular disease within the past 6 months, including but not limited to, myocardial infarction, acute coronary syndrome, unstable angina pectoris, transient ischemic attack, or stroke, or participants who have undergone percutaneous coronary intervention or a coronary artery bypass graft within the past 6 months or who are due to undergo these procedures at the time of screening.

[0710] • Severe congestive heart failure

[0711] • History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal) or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter or sinus node dysfunction with clinically significant pause or second to third degree AV-block untreated with pacemaker. • Prolonged QT interval (Fridericia-corrected QT interval, QTcF > 470 ms) on ECG at screening (Visit 1 ) or at randomisation (Visit 3), known congenital long QT syndrome, or family history of cardiac sudden death at age < 40 years.

[0712] • Clinically significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery affecting the upper gastrointestinal tract (including bariatric surgery) that may affect gastric emptying or could affect the interpretation of the safety and tolerability data.

[0713] • Clinically significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery affecting the upper gastrointestinal tract (including bariatric surgery) that may affect gastric emptying or could affect the interpretation of the safety and tolerability data.

[0714] • Type 1 diabetes mellitus or T2DM subjects taking insulin.

[0715] • For T2DM subjects, participants must have been on a stable antidiabetic regimen for 3 months prior screening.

[0716] • Known or suspected history of alcohol or drug abuse and smokers.

[0717] • History of psychosis or bipolar disorder. History of major depressive disorder within the past year.

[0718] • History of hypersensitivity such as anaphylaxis requiring carriage of adrenaline / epinephrine, or angioedema.

[0719] • History of hypersensitivity to DPP4 inhibitors, as judged by the investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to DPP4 inhibitors.

[0720] • History of coagulation or bleeding disorders, or blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, or symptoms of increased risk of bleeding (frequent bleeding gums or nosebleeds)

[0721] • History of major bleeding or high-risk of bleeding diathesis

[0722] • Ongoing wound healing / post-surgery in prior 3 months

[0723] • History of dermatological disorders such as bullous pemphigoid, Steven’s Johnson syndrome, or clinically significant new or healing wounds in areas of the body not always covered by clothing

[0724] • Use of strong inhibitors of CYP3A4 and BCRP / OAT3 within 2 weeks or 5 half-lives, whichever is longer

[0725] • Use of moderate to strong inducers of CYP3A4 within 3 weeks or 5 half-lives, whichever is longer

[0726] • Use of warfarin, direct and indirect thrombin inhibitors, factor Xa inhibitors or any antiplatelet therapy other than low-dose aspirin (< 81 mg / day) within one week of screening visit and during the study

[0727] • Participation in another clinical study with an IMP administered in the last 3 months or 5 half-lives of the therapy (whichever is longer) at the time of screening

[0728] References

[0729] Several publications are cited above. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

[0730] For standard molecular biology techniques, see Sambrook, J., Russel, D.W. Molecular Cloning, A Laboratory Manual. 3 ed. 2001 , Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press.

[0731] Numbered Embodiments

[0732] 1. A method of treating or preventing a FAP-mediated condition, in a subject suffering from or susceptible to the FAP-mediated condition, the method comprising administering to the subject, a compound of Formula (I): or a pharmaceutically acceptable salt thereof, in a daily dose of from 5 mg to 320 mg of the free base.

[0733] 2. The method according to embodiment 1 , wherein the FAP-mediated condition is selected from liver disease, diseases of insulin resistance, cardiovascular conditions, cerebrovascular conditions, pancreatic disease, inflammatory bowel disease, lung disease, kidney disease, obesity, obesity-related conditions, fibrosis, keloid disorder, inflammatory and autoimmune conditions, and cancer, or a combination thereof.

[0734] 3. The method according to embodiment 2, wherein the FAP-mediated condition is liver disease.

[0735] 4. The method according to embodiment 3, wherein the liver disease is advanced chronic liver disease (ACLD).

[0736] 5. The method according to embodiment 3 or 4, wherein the liver disease is Steatotic Liver Disease (SLD).

[0737] 6. The method according to embodiment 5, wherein the SLD is metabolic dysfunction-associated steatotic liver disease (MASLD).

[0738] 7. The method according to embodiment 6, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH). 8. The method according to embodiment 5, wherein the SLD is alcohol-related liver disease (ALD).

[0739] 9. The method according to embodiment 5, wherein the SLD is metabolic and alcohol-related liver disease (MetALD).

[0740] 10. The method according to embodiment 3, wherein the liver disease is viral hepatitis.

[0741] 11 . The method according to embodiment 3, wherein the liver disease is autoimmune liver disease.

[0742] 12. The method according to embodiment 3, wherein the liver disease is a genetic liver disease.

[0743] 13. The method according to any one of embodiments 1 to 12, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from 5 mg to 225 mg of the free base.

[0744] 14. The method according to embodiment 13, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 40 mg to about 200 mg of the free base.

[0745] 15. The method according to embodiment 14, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 50 mg to about 150 mg of the free base.

[0746] 16. The method according to embodiment 15, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 60 mg to about 140 mg of the free base.

[0747] 17. The method according to embodiment 16, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 70 mg to about 130 mg of the free base.

[0748] 18. The method according to embodiment 17, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 80 mg to about 120 mg of the free base.

[0749] 19. The method according to embodiment 13, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 10 mg to about 80 mg of the free base. 20. The method according to embodiment 19, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 20 mg to about 70 mg of the free base.

[0750] 21. The method according to embodiment 20, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 30 mg to about 60 mg of the free base.

[0751] 22. The method according to any one of embodiments 1 to 12, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 30 mg of the free base.

[0752] 23. The method according to any one of embodiments 1 to 12, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 40 mg of the free base.

[0753] 24. The method according to any one of claims 1 to 12, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 60 mg of the free base.

[0754] 25. The method according to any one of embodiments 1 to 12, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 80 mg of the free base.

[0755] 26. The method according to any one of embodiments 1 to 12, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 85 mg of the free base.

[0756] 27. The method according to any one of embodiments 1 to 12, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 120 mg of the free base.

[0757] 28. The method according to any one of embodiments 1 to 12, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 150 mg of the free base.

[0758] 29. The method according to any one of embodiments 1 to 28, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once a day (od).

[0759] 30. The method according to any one of embodiments 1 to 28, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day (bid). 31. The method according to any one of embodiments 1 to 12, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg once a day.

[0760] 32. The method according to any one of embodiments 1 to 31 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0761] 33. A compound of Formula (I or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a FAP-mediated condition, wherein said treatment or prevention comprises administration of the compound of Formula (I) or pharmaceutically acceptable salt thereof, in a daily dose of from 5 mg to 320 mg of the free base.

[0762] 34. The compound for use according to embodiment 33, wherein the FAP-mediated condition is selected from liver disease, diseases of insulin resistance, cardiovascular conditions, cerebrovascular conditions, pancreatic disease, inflammatory bowel disease, lung disease, kidney disease, obesity, obesity-related conditions, fibrosis, keloid disorder, inflammatory and autoimmune conditions, and cancer.

[0763] 35. The compound for use according to embodiment 34, wherein the FAP-mediated condition is liver disease.

[0764] 36. The compound for use according to embodiment 35, wherein the liver disease is advanced chronic liver disease (ACLD).

[0765] 37. The compound for use according to embodiment 35 or 36, wherein the liver disease is Steatotic Liver Disease (SLD).

[0766] 38. The compound for use according to embodiment 37, wherein the SLD is metabolic dysfunction- associated steatotic liver disease (MASLD).

[0767] 39. The compound for use according to embodiment 36, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0768] 40. The compound for use according to embodiment 37, wherein the SLD is alcohol-related liver disease (ALD). 41 . The compound for use according to embodiment 37, wherein the SLD is metabolic and alcohol- related liver disease (MetALD).

[0769] 42. The compound for use according to embodiment 35, wherein the liver disease is viral hepatitis.

[0770] 43. The compound for use according to embodiment 35, wherein the liver disease is autoimmune liver disease.

[0771] 44. The compound for use according to embodiment 35, wherein the liver disease is a genetic liver disease.

[0772] 45. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from 5 mg to 225 mg of the free base.

[0773] 46. The compound for use according to embodiment 45, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 40 mg to about 200 mg of the free base.

[0774] 47. The compound for use according to embodiment 46, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 50 mg to about 150 mg of the free base.

[0775] 48. The compound for use according to embodiment 47, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 60 mg to about 140 mg of the free base.

[0776] 49. The compound for use according to embodiment 48, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 70 mg to about 130 mg of the free base.

[0777] 50. The compound for use according to embodiment 49, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 80 mg to about 120 mg of the free base.

[0778] 51. The compound for use according to embodiment 45, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 10 mg to about 80 mg of the free base. 52. The compound for use according to embodiment 51 , wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 20 mg to about 70 mg of the free base.

[0779] 53. The compound for use according to embodiment 52, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 30 mg to about 60 mg of the free base.

[0780] 54. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 30 mg of the free base.

[0781] 55. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 40 mg of the free base.

[0782] 56. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 60 mg of the free base.

[0783] 57. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 80 mg of the free base.

[0784] 58. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 85 mg of the free base.

[0785] 59. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 120 mg of the free base.

[0786] 60. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 150 mg of the free base.

[0787] 61 . The compound for use according to any one of embodiments 33 to 60, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once a day (od).

[0788] 62. The compound for use according to any one of embodiments 33 to 60, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day (bid). 63. The compound for use according to any one of embodiments 33 to 44, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg once a day.

[0789] 64. The compound for use according to any one of embodiments 33 to 63, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0790] 65. Use of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a FAP-mediated condition, wherein said treatment or prevention comprises administering to the patient of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a daily dose of from 5 mg to 320 mg of the free base.

[0791] 66. The use according to embodiment 65, wherein the FAP-mediated condition is selected from liver disease, diseases of insulin resistance, cardiovascular conditions, cerebrovascular conditions, pancreatic disease, inflammatory bowel disease, lung disease, kidney disease, obesity, obesity-related conditions, fibrosis, keloid disorder, inflammatory and autoimmune conditions, and cancer.

[0792] 67. The use according to embodiment 66, wherein the FAP-mediated condition is liver disease.

[0793] 68. The use according to embodiment 67, wherein the liver disease is advanced chronic liver disease (ACLD).

[0794] 69. The use according to embodiment 67 or 68, wherein the liver disease is Steatotic Liver Disease (SLD).

[0795] 70. The use according to embodiment 69, wherein the SLD is metabolic dysfunction-associated steatotic liver disease (MASLD).

[0796] 71. The use according to embodiment 70, wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

[0797] 72. The use according to embodiment 69, wherein the SLD is alcohol-related liver disease (ALD).

[0798] 73. The use according to embodiment 69, wherein the SLD is metabolic and alcohol-related liver disease (MetALD). 74. The use according to embodiment 67, wherein the liver disease is viral hepatitis.

[0799] 75. The use according to embodiment 67, wherein the liver disease is autoimmune liver disease.

[0800] 76. The use according to embodiment 67, wherein the liver disease is a genetic liver disease.

[0801] 77. The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from 5 mg to 225 mg of the free base.

[0802] 78. The use according to embodiment 77, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 40 mg to 160 mg of the free base.

[0803] 79. The use according to embodiment 78, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 50 mg to about 150 mg of the free base.

[0804] 80. The use according to embodiment 79, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 60 mg to about 140 mg of the free base.

[0805] 81. The use according to embodiment 80, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 70 mg to about 130 mg of the free base.

[0806] 82. The use according to embodiment 81 , wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 80 mg to about 120 mg of the free base.

[0807] 83. The use according to embodiment 77, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 10 mg to about 80 mg of the free base.

[0808] 84. The use according to embodiment 83, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 20 mg to about 70 mg of the free base. 85. The use according to embodiment 84, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from about 30 mg to about 60 mg of the free base.

[0809] 86. The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 30 mg of the free base.

[0810] 87. The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 40 mg of the free base.

[0811] 88. The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 60 mg of the free base.

[0812] 89. The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 80 mg of the free base.

[0813] 90. The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 85 mg of the free base.

[0814] 91 . The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 120 mg of the free base.

[0815] 92. The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of about 150 mg of the free base.

[0816] 93. The use according to any one of embodiments 65 to 92, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once a day (od).

[0817] 94. The use according to any one of embodiments 65 to 92, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day (bid).

[0818] 95. The use according to any one of embodiments 65 to 76, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg once a day. 96. The use according to any one of embodiments 65 to 95, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0819] 97. Use of a pharmaceutical composition comprising a compound of Formula (I): or a pharmaceutically acceptable salt thereof, at a quantity of from 5 mg to 320 mg of the free base, in the manufacture of a medicament for the treatment or prevention of a FAP-mediated condition.

[0820] 98. The use according to embodiment 97, wherein the FAP-mediated condition is as described in any of claims 63 to 72.

[0821] 99. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from 5 mg to 225 mg of the free base.

[0822] 100. The use according to embodiment 99, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from about 40 mg to 160 mg of the free base.

[0823] 101. The use according to embodiment 100, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from about 50 mg to about 150 mg of the free base.

[0824] 102. The use according to embodiment 101 , wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from about 60 mg to about 140 mg of the free base.

[0825] 103. The use according to embodiment 102, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from about 70 mg to about 130 mg of the free base.

[0826] 104. The use according to embodiment 103, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from about 80 mg to about 120 mg of the free base.

[0827] 105. The use according to embodiment 99, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from about 10 mg to about 80 mg of the free base. 106. The use according to embodiment 105, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from about 20 mg to about 70 mg of the free base.

[0828] 107. The use according to embodiment 106, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is from about 30 mg to about 60 mg of the free base.

[0829] 108. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is about 30 mg of the free base.

[0830] 109. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is about 40 mg of the free base.

[0831] 110. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is about 60 mg of the free base.

[0832] 111. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is about 80 mg of the free base.

[0833] 112. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is about 85 mg of the free base.

[0834] 113. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is about 120 mg of the free base.

[0835] 114. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is about 150 mg of the free base.

[0836] 115. The use according to embodiment 97 or 98, wherein the quantity of the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is about 150 mg of the free base once daily.

Claims

Claims1. A compound of Formula (Ior a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a FAP-mediated condition, wherein said treatment or prevention comprises administration of the compound of Formula (I) or pharmaceutically acceptable salt thereof, in a daily dose of from 5 mg to 320 mg of the free base.

2. The compound for use according to claim 1 , wherein the FAP-mediated condition is selected from liver disease, diseases of insulin resistance, cardiovascular conditions, cerebrovascular conditions, pancreatic disease, inflammatory bowel disease, lung disease, kidney disease, obesity, obesity-related conditions, fibrosis, keloid disorder, inflammatory and autoimmune conditions, cancer, and thrombotic conditions.

3. The compound for use according to claim 2, wherein the FAP-mediated condition is liver disease.

4. The compound for use according to claim 3, wherein the liver disease is advanced chronic liver disease (ACLD).

5. The compound for use according to claim 3 or 4, wherein the liver disease is Steatotic Liver Disease (SLD).

6. The compound for use according to claim 5, wherein the SLD is alcohol-related liver disease (ALD), metabolic and alcohol-related liver disease (MetALD) or metabolic dysfunction-associated steatotic liver disease (MASLD), optionally wherein the MASLD is metabolic dysfunction-associated steatohepatitis (MASH).

7. The compound for use according to claim 3, wherein the liver disease is viral hepatitis, autoimmune liver disease, or a genetic liver disease.

8. The compound for use according to any one of claims 1 to 7, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from 5 mg to 225 mg of the free base.

9. The compound for use according to claim 8, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of from: a) about 40 mg to about 200 mg of the free base;85b) about 50 mg to about 150 mg of the free base; c) about 60 mg to about 140 mg of the free base; d) about 70 mg to about 130 mg of the free base; e) about 80 mg to about 120 mg of the free base; f) about 10 mg to about 80 mg of the free base; g) about 20 mg to about 70 mg of the free base; or h) about 30 mg to about 60 mg of the free base.

10. The compound for use according to any one of claims 1 to 7, wherein the compound of Formula (I), optionally in the form of a pharmaceutically acceptable salt, is administered in a daily dose of: a) about 5 mg of the free base; b) about 30 mg of the free base; c) about 40 mg of the free base; d) about 60 mg of the free base; e) about 80 mg of the free base; f) about 85 mg of the free base; g) about 120 mg of the free base; or h) about 150 mg of the free base.11 . The compound for use according to any one of claims 1 to 10, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once a day (od).

12. The compound for use according to any one of claims 1 to 10, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day (bid).

13. The compound for use according to any one of claims 1 to 10, wherein the compound of Formula(I) or a pharmaceutically acceptable salt thereof is administered at a dose of from a) about 40 mg to about 200 mg of the free base once a day; or b) about 50 mg to about 150 mg of the free base once a day.

14. The compound for use according to any one of claims 1 to 10, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg once a day.

15. The compound for use according to any one of claims 1 to 14, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered orally.86

Images