Treatment of psoriasis using a small molecule inhibitor of tumor necrosis factor alpha.

Description

1 / 70 “TREATMENT OF PSORIASIS USING A SMALL MOLECULE INHIBITOR OF TUMOR NECROSIS FACTOR ALPHA”

[001] The present invention relates to a treatment for psoriasis in which patients are administered a defined amount of a soluble small molecule inhibitor of tumor necrosis factor alpha. This is based on the results of a clinical trial that demonstrated that treatment with the inhibitor for 28 days was effective, safe, and well tolerated by participants with mild to moderate psoriasis. Background

[002] Tumor necrosis factor alpha (TNFα) is a cytokine with pleiotropic effects in pathological and homeostatic processes. TNFα is believed to have a fundamental pathophysiological role in psoriasis (e.g., Mease, Ann Rheum Dis (2004) 63:755-758), and TNFα antagonists have become a mainstay in modern psoriasis treatment.

[003] TNFα is a member of the TNF cytokine superfamily. It is produced by various cell types, most notably inflammatory cells. It is initially expressed as a transmembrane protein, also known as membrane-bound TNFα (mTNFα). At the cell surface, mTNFα can be cleaved by TNFα-converting enzyme to generate soluble TNFα (sTNFα). Structurally, both mTNFα and sTNFα exist as homotrimers that can bind to three cognate receptors. This trimeric involvement is critical for receptor multimerization and subsequent signal transduction.sTNFα signals primarily through the tumor necrosis factor receptor 1 (TNFR1), which is expressed on most cell types. In contrast, mTNFα interacts primarily with the tumor necrosis factor receptor 2 (TNFR2). TNFR2 is expressed mainly on neurons, endothelial cells, and immune cells, with particular enrichment in certain subpopulations of regulatory T cells (Tregs).

[004] Functionally, sTNFα and mTNFα play different roles in pathological and homeostatic processes. The involvement of sTNFα Petition 870250089906, dated 02 / 10 / 2025, page 7 / 95 2 / 70 with TNFR1 leads to the activation of pro-inflammatory and pro-apoptotic pathways, which play essential roles in the effect of TNFα in certain autoimmune conditions. Conversely, mTNFα signaling contributes to a variety of homeostatic functions, including tissue regeneration and cell survival. From an inflammatory standpoint, mTNFα has been shown to enhance the function and proliferation of specific subsets of suppressor Tregs. TNFR2 agonism has also been shown to promote the death of autoreactive CD8+ T cells. It is worth noting that mTNFα mice, which express only a non-cleavable form of TNFα, were generated to study the specific effects of mTNFα. In models of respiratory tuberculosis infection, several studies have demonstrated reduced mortality and bacterial load in mTNFα mice compared to TNFα knockout mice.Similar results have been demonstrated in murine infection models with Listeria monocytogenes, Mycobacterium bovis Calmette-Guérin bacillus, and Leishmania major.

[005] An asymmetric, naturally occurring trimeric form of sTNFα, which is normally a transient intermediate, exhibits impaired ability to interact with TNFR1 (as, for example, O'Connell et al., Nat Commun (2019) 10:5795-5806). O'Connell et al. used size exclusion analysis to demonstrate the impaired ability of sTNFα; they further demonstrated that UCB-9260, a molecule with a trisubstituted benzimidazole structure, stabilizes the asymmetric trimer of sTNFα and impairs TNFR1 signaling in vitro. In this study, Jurkat cells were treated with sTNFα, sTNFα pre-incubated with UCB-9260, or sTNFα pre-incubated with etanercept. TNFR1 signaling, measured by Western Blot analysis of kinases, ubiquitination of receptor-interacting protein kinase 1 (RIP-1), and phosphorylation of nuclear factor kappa B (NF-κB), was impaired in samples treated with etanercept and UCB-9260 compared to samples treated with sTNFα alone.

[006] The compound used in the treatments of this disclosure is Petition 870250089906, dated 02 / 10 / 2025, page 8 / 95 3 / 70 (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7dihydro-7,14-methanebenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one. The structure of this compound, Compound 1, is shown below and has a pentacyclic central structure: Compound 1

[007] The synthesis of Compound 1 is described in international patent application no. PCT / EP2018 / 060489 (published as WO 2018 / 197503), which also describes the compound as belonging to a class of modulators of human TNFα activity, useful for the treatment and / or prevention of various conditions, including a range of inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, eye disorders and oncological disorders.

[008] Psoriasis is a T-cell mediated disease with autoimmune features modulated by genetic susceptibility, along with environmental triggers. Inflammatory pathways marked by the overproduction of the cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23) drive the differentiation of pathogenic T-cell responses, resulting in the production of TNF and interleukin-17 (IL-17). These cytokines are an integral part of the TNF / IL23 / IL-17 axis, responsible for maintaining inflammation in psoriatic skin (as, for example, Bergen et al., Scand J Immunol. (2020) 92(4):e12946). It is estimated that psoriasis affects 1% to 3% of the world's population.

[009] Historically, psoriasis has been treated with topical formulations (e.g., creams and ointments, which may have only an emollient effect, or which may include active agents such as steroids and / or analogues of Petition 870250089906, dated 02 / 10 / 2025, page 9 / 95 4 / 70 vitamin D), phototherapy, and systemic therapeutic treatments (e.g., treatment with oral anti-inflammatory drugs such as methotrexate or immunosuppressants such as cyclosporine). More recently, biological therapies that inhibit TNFα, such as etanercept (Enbrel®, authorized in the EU for the treatment of conditions including moderate to severe plaque psoriasis), have been developed. Biological therapies can be highly effective but carry the risk of immunogenicity and the development of neutralizing antidrug antibodies, as well as side effects, some of which can be serious; they are also usually administered by injection and may require medical supervision or monitoring. There is, therefore, a pressing need for new treatments for psoriasis that are effective, have an acceptable safety profile, and offer advantages in terms of ease of manufacture, storage, and suitability for oral administration.

[0010] This disclosure presents the results of a clinical trial in which Compound 1 was administered orally to patients with psoriasis. The results suggest that the treatment described in the present invention is not only effective in reducing clinical symptoms but also in reducing the levels of inflammatory mediators implicated in disease progression. No serious adverse effects were identified during the course of the trial, nor were there any safety concerns based on vital signs, ECG, or laboratory results, nor any signs of risk in liver function tests. No indication of risk of QTc interval prolongation was observed. This is believed to be the first successful clinical trial of a small molecule TNFα inhibitor in patients with psoriasis. Summary of the Invention

[0011] In a first aspect, the disclosure provides a compound for use in a method of treating psoriasis in a human individual, wherein the compound is (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanebenzimidazo[1,2] Petition 870250089906, dated 10 / 02 / 2025, page 10 / 95 5 / 70 b ][2,5]benzodiazocin-5(14 H)-one (Compound 1): or a pharmaceutically acceptable salt thereof, wherein the individual has mild to moderate psoriasis, and wherein the method comprises administering to the individual a daily dose of approximately 400 mg of the compound (calculated as free base).

[0012] In some forms, psoriasis is plaque psoriasis, for example, chronic plaque psoriasis.

[0013] In some modalities, the severity of psoriasis in the individual is assessed using the PASI score, and the individual has a total PASI score < 16.

[0014] In some modalities, the individual presents a score PASI total > 10.

[0015] In some modalities, the individual presents at least two lesions with a TLS score > 4 (excluding the scalp).

[0016] In some forms, the compound is administered to the individual orally.

[0017] In some embodiments, the compound is administered in the form of an oral pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the oral pharmaceutical composition is a tablet.

[0018] In some embodiments, the method involves administering to the individual a dose of approximately 200 mg of the compound (calculated as the free base) twice a day.

[0019] In a further aspect, disclosure provides a method of Petition 870250089906, dated 02 / 10 / 2025, p. 11 / 95 6 / 70 treatment of psoriasis as defined above, wherein a therapeutically effective amount of Compound 1 (or a pharmaceutically acceptable salt thereof) is administered to a human individual in need, and wherein the therapeutically effective amount is a daily dose of approximately 400 mg (calculated as the free base).

[0020] In another aspect, the disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in the production of a medicament for treating mild to moderate psoriasis, according to a method as previously defined, wherein the medicament is adapted to provide a daily dose of about 400 mg of the compound (calculated as the free base).

[0021] Additional features and advantages of the compositions and methods disclosed in the present invention will become apparent from the detailed description that follows. Brief Description of the Drawings

[0022] Figure 1 shows the mean change (± SEM) in TLS score from baseline over 2 and 4 weeks of treatment in human subjects with psoriasis. The solid line with filled circles represents the placebo treatment arm, and the dashed line with hollow circles represents the Compound 1 treatment arm.

[0023] Figure 2 shows the mean change (± SEM) in total PASI score from baseline over 2 and 4 weeks of treatment in human subjects with psoriasis. The solid line with filled circles represents the placebo treatment arm, and the dashed line with hollow circles represents the Compound 1 treatment arm.

[0024] Figure 3 shows the ratio from baseline over time for serum levels of IL-17A, a systemic biomarker of psoriasis (data represent geometric mean (χ / +) geometric SEM). The light gray line (top) represents the placebo treatment arm, and the dark gray line (bottom) represents the Compound 1 treatment arm. * Petition 870250089906, dated 02 / 10 / 2025, p. 12 / 95 7 / 70 P < 0.05; ** P = 0.0001; *** P < 0.0001.

[0025] Figure 4 shows the ratio from baseline over time for serum levels of IL-17F, a systemic biomarker of psoriasis (data represent geometric mean (χ / +) geometric SEM). The light gray line (top) represents the placebo treatment arm, and the dark gray line (bottom) represents the Compound 1 treatment arm. * P < 0.05; ** P = 0.0001; *** P < 0.0001.

[0026] Figure 5 shows the ratio from baseline over time for serum levels of IL-22, a systemic biomarker of psoriasis (data represent geometric mean (χ / +) geometric SEM). The light gray line (top) represents the placebo treatment arm, and the dark gray line (bottom) represents the Compound 1 treatment arm. * P < 0.05; ** P = 0.0001; *** P < 0.0001.

[0027] Figure 6 shows the percentage of patients who achieved a static Researcher Global Assessment (sIGA) score category (determined as described in the present invention) at baseline, week 2, and week 4. Each sIGA category has paired bars, in which the proportion of patients in the placebo arm (N = 12) is shown in the left bar (gray), and the proportion of patients in the treatment arm (Compound 1,200 mg BID; N = 25) is shown in the right bar (white). Definitions

[0028] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described in this invention may be used in the practice or testing of the present disclosure, exemplary methods, devices and materials will now be described. All technical and patent publications cited in this invention are incorporated herein by reference in their entirety.

[0029] The practice of this disclosure will employ, unless otherwise indicated in Petition 870250089906, dated 02 / 10 / 2025, p. 13 / 95 8 / 70 Conversely, conventional techniques of tissue culture, immunobiology, molecular biology, microbiology, cell biology, and recombinant DNA are within the technician's knowledge in the subject. For example, Michael R. Green and Joseph Sambrook, Molecular Cloning (4th ed., Cold Spring Harbor Laboratory Press 2012); the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., NY); MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Handbook; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition; Gait ed. (1984) Oligonucleotide synthesis; US Patent No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds.(1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, Londres); Herzenberg et al. eds (1996) Weir’s Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3aedição (Cold Spring Harbor Laboratory Press (2002)); Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press).

[0030] All numerical designations, for example, pH, temperature, time, concentration, molecular weight, etc., including ranges, are approximations that vary (+) or (-) in increments of, for example, 0.1 or 1.0, when appropriate. It should be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”, which is used to denote a conventional level of variability. For example, a numerical designation that is “about” a given value may vary by ± 10% of that value; alternatively, the variation may be Petition 870250089906, dated 02 / 10 / 2025, p. 14 / 95 9 / 70 of ± 5%, ± 2% or ± 1% of the value. For example, an amount of Compound 1 or a pharmaceutically acceptable salt thereof that is defined as being “about 400 mg (calculated as the free base)” may be an amount that is between 360 mg and 440 mg (calculated as the free base), i.e., 400 mg ± 10%; alternatively, the variation may be ± 5%, ± 2% or ± 1% of the value. It should also be understood, although not always explicitly stated, that the reagents described in the present invention are merely illustrative, and that equivalents thereof are known in the art.

[0031] As used in the descriptive report and claims, the singular forms “a”, “an” and “the”, “the” include plural references, unless the context clearly dictates otherwise. For example, the term “an inhibitor” includes a plurality of inhibitors, including mixtures thereof. Unless specifically stated or obvious from the context, as used in the present invention, the term “or” is understood to be inclusive. The term “including” is used in the present invention to mean, and is used indiscriminately with, the phrase “including, but not limited to”.

[0032] As used in the present invention, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the enumerated elements, but do not exclude others. “Essentially consisting of,” when used to define compositions and methods, means the exclusion of other elements of any essential significance for the stated purpose. Thus, a composition consisting essentially of the elements as defined in the present invention would not exclude residual contaminants from the isolation and purification method and pharmaceutically acceptable carriers such as phosphate-buffered saline, preservatives, and the like. “Consisting of” means the exclusion of more than residual elements from other ingredients and method steps substantial to the administration of the compositions of this disclosure or process steps to produce a composition or achieve an intended result.The modalities defined by each of these transitional terms fall within the scope of this [the agreement]. Petition 870250089906, dated 02 / 10 / 2025, page 15 / 95 10 / 70 disclosure. The use of the term “comprising” in the present invention is intended to encompass both “essentially consisting of” and “consisting of”.

[0033] “Subject”, “individual” or “patient” are used interchangeably in the present invention and refer to a human being.

[0034] “Administering” is defined herein as a means of delivering an agent (e.g., active ingredient) or a composition containing the agent to an individual in such a way that the agent is within the individual’s body. Such administration may be by any route, including, without limitation, oral administration. Pharmaceutical preparations are, of course, administered in forms suitable for each route of administration. The compositions and methods of this disclosure are usually directed to enteral administration, for example, oral administration.

[0035] “Treating” or “treatment” of a disease includes: (1) inhibiting the disease, that is, interrupting or reducing the development of the disease or its clinical symptoms; and / or (2) alleviating the disease, that is, causing regression of the disease or its clinical symptoms. “Preventing” or “prevention” of a disease includes causing the clinical symptoms of the disease not to develop in a patient who may be predisposed to the disease but does not yet suffer from or show symptoms of the disease.

[0036] The term “suffering,” in relation to the term “treatment,” refers to a patient or individual who has been diagnosed with the disease. The term “suffering,” in relation to the term “prevention,” refers to a patient or individual who is predisposed to the disease. A patient may also be considered “at risk of suffering” from a disease due to a history of diseases in their family lineage or the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the pathologies characteristic of the disease.

[0037] An “effective amount” or “therapeutically effective amount” is an amount sufficient to produce beneficial or desired results. An effective amount may be administered in one or more administrations. Petition 870250089906, dated 02 / 10 / 2025, page 16 / 95 11 / 70 applications or dosages. Such delivery depends on a number of variables, including the length of time during which the individual dosage unit will be used, the bioavailability of the therapeutic agent, and the route of administration. It is understood, however, that the specific dose levels of the therapeutic agents in this disclosure for any particular individual depend on a variety of factors, including, for example, the activity of the specific compound employed, the age, body weight, general health, sex and diet of the individual, the time of administration, the severity of the specific disorder being treated, and the route of administration. Typically, dose-effect relationships from in vitro and / or in vivo tests can initially provide useful guidance on appropriate doses for administration to the patient.In general, the aim is to administer an amount of the compound that is effective in achieving a serum level consistent with concentrations considered effective in vitro. Determining these parameters is within the competence of those skilled in the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and described in conventional textbooks. In accordance with this definition, as used in the present invention, the term "therapeutically effective amount" is an amount sufficient to treat (e.g., improve) one or more symptoms associated with a disease or disorder described in the present invention, ex vivo, in vitro, or in vivo.

[0038] As used in the present invention, the term “pharmaceutically acceptable excipient” encompasses any of the conventional pharmaceutical excipients, including carriers such as phosphate-buffered saline, water and emulsions such as oil-in-water or water-in-oil emulsions, and various types of wetting agents. Pharmaceutical compositions may also include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).

[0039] As used in the present invention, the term “salt Petition 870250089906, dated 02 / 10 / 2025, page 17 / 95 "12 / 70 pharmaceutically acceptable" means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that can be administered without any resulting substantial undesirable biological effects or any resulting deleterious interactions with any other component of a pharmaceutical composition in which it may be contained.

[0040] A mass quantity (e.g., a dosage quantity) of Compound 1 referred to in this invention corresponds, unless expressly stated otherwise, to a mass of the compound calculated as the free base. For example, a dose of 400 mg of the compound refers to a quantity of 400 mg of the free base of Compound 1, or to a quantity of a salt of Compound 1 that provides an equivalent molar quantity of Compound 1; this is referred to in the present invention as a quantity “calculated as the free base”.

[0041] The enumeration of an embodiment for a variable or aspect described in the present invention includes that embodiment as any single embodiment or in combination with any other embodiments or parts thereof.

[0042] Any compositions or methods provided in the present invention may be combined with one or more of the other compositions and methods provided in the present invention.

[0043] The following abbreviations are used in the present invention: ADL activities of daily living AE adverse events AESI adverse events of particular interest ALT (alanine aminotransferase) aPTT (activated partial thromboplastin time) AST aspartate aminotransferase BID twice a day (dosage) BMI body mass index Petition 870250089906, dated 02 / 10 / 2025, page 18 / 95 13 / 70 BSA body surface area CI confidence interval CK creatine kinase COVID-19 coronavirus disease 2019 (also SARS-CoV-2; severe acute respiratory syndrome coronavirus-2) CPK creatine phosphokinase (e)CRF case report form (electronic) (hs)CRP (high sensitivity) C-reactive protein CYP cytochrome P450 DBP diastolic blood pressure deoxyribonucleic acid DNA ECG electrocardiogram ELISA enzyme-linked immunosorbent assay EOS / EoSfim study FSH follicle-stimulating hormone GGT gamma-glutamyl transferase (β-)HCG (β-)human chorionic gonadotropin HCV hepatitis C virus hERG human ether-a-go-related gene HIV1 / HIV2 human immunodeficiency virus 1 / 2 HR heart rate HRT hormone replacement therapy ICF informed consent form IL interleukin (e.g. IL-17A, IL-17F, IL-22) IMP experimental drug INR International Standard Ratio LSm least squares means MMRM mixed model for repeated measurements NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events Petition 870250089906, dated 02 / 10 / 2025, page 19 / 95 14 / 70 NIMP non-experimental drug P-gp P-glycoprotein PASI psoriasis area and severity index (the following abbreviations are used in connection with the PASI score: head (h), upper extremities (u), trunk (t), lower extremities (l), numerical score (A), erythema (E), thickness / hardness (I), and scaling / flaking (D), so that “Eh” would mean erythema of the head, “It” would mean hardness of the trunk, etc.) PCR polymerase chain reaction PCSA potentially clinically significant abnormalities PCT procalcitonin PD pharmacodynamics PK pharmacokinetics PT preferred term QFT Test QuantiFERON-TB Gold QTcF Fridericia-corrected QT interval (QT interval = the time between the beginning of the QRS complex and the end of the T wave) RNA ribonucleic acid RT retention time SAE serious adverse event SBP systolic blood pressure SD standard deviation SE standard error Without standard error of the mean, sIGA global static evaluation by the researcher. SOC class of organ systems SPF sun protection factor TB (tuberculosis) TEAE treatment-emergent adverse event TLS(S) target injury severity (score) Petition 870250089906, dated 02 / 10 / 2025, page 20 / 95 15 / 70 TNF(a) tumor necrosis factor (alpha) mTNFα membrane-bound TNFα sTNFα soluble TNFα TNFR1 / TNFR2 tumor necrosis factor receptor 1 / 2 ULN upper limit of normal XPhos 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl Detailed Description of the Invention

[0044] Although specific embodiments of the present disclosure are now described with reference to preparations and schemes, it should be understood that such embodiments are only by way of example and merely illustrative of only a small number of the many possible specific embodiments that may represent applications of the principles of the present disclosure. Various alterations and modifications will be obvious to those skilled in the art, given the benefit of this disclosure, and are considered within the spirit and scope of this disclosure, as defined in the appended claims.

[0045] This disclosure describes a clinical study conducted to evaluate the impact of Compound 1 in patients with mild to moderate psoriasis. Oral administration of 400 mg of Compound 1 per day was shown to be effective in improving clinical parameters in human patients, including the Psoriasis Area and Severity Index (PASI) score and the Target Lesion Severity (TLS) score. Improvements in biomarkers for psoriasis were also observed, including serum levels of IL-17A, IL-17F, and IL-22. No serious or severe adverse events were observed during the study, nor was any significant impact on cardiac (e.g., QTcF interval) or hepatic (e.g., AST, ALT, or bilirubin levels) parameters observed.

[0046] Thus, a first aspect of the present disclosure provides a compound for use in a method of treating psoriasis in a human individual, wherein the compound is (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5 Petition 870250089906, dated 02 / 10 / 2025, page 21 / 95 16 / 70 yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2b ][2,5]benzodiazocin-5(14 H)-one (i.e. Compound 1): or a pharmaceutically acceptable salt thereof, wherein the individual has mild to moderate psoriasis, and wherein the method comprises administering to the individual a daily dose of approximately 400 mg of the compound (calculated as the free base).

[0047] A related aspect provides a method of treating psoriasis in a human individual in need, wherein the individual has mild to moderate psoriasis, and wherein the method comprises administering a therapeutically effective amount of (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanebenzimidazo[1,2b][2,5]benzodiazocin-5(14H)-one (i.e., Compound 1): or a pharmaceutically acceptable salt thereof to the individual, wherein the therapeutically effective amount is a daily dose of approximately 400 mg (calculated as the free base).

[0048] Another related aspect provides a compound for use in the production of a medicament for the treatment of psoriasis in a human individual, wherein the compound is (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanebenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (i.e., Compound 1): Petition 870250089906, dated 02 / 10 / 2025, page 22 / 95 17 / 70 or a pharmaceutically acceptable salt thereof, wherein the individual has mild to moderate psoriasis, and wherein the medication is tailored to provide the individual with a daily dose of approximately 400 mg of the compound (calculated as the free base).

[0049] In some forms, psoriasis is plaque psoriasis. In some forms, psoriasis is chronic plaque psoriasis.

[0050] In some embodiments, the individual has mild psoriasis. Viewed in this aspect, the disclosure provides a compound for use in a method of treating mild psoriasis in a human individual, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the individual a daily dose of about 400 mg of the compound (calculated as the free base). In other embodiments, the individual has moderate psoriasis. Viewed in this aspect, the disclosure provides a compound for use in a method of treating moderate psoriasis in a human individual, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof, and wherein the method comprises administering to the individual a daily dose of about 400 mg of the compound (calculated as the free base).

[0051] In some embodiments, the severity of psoriasis in the individual is assessed using the PASI score, for example, as described in the present invention (see also, for example, the EMA Guidelines on clinical investigation of medicinal products indicated for the treatment of psoriasis, dated November 18, 2004). The individual may be classified as having mild to moderate psoriasis by virtue of having a total PASI score that is <16. Thus, in one embodiment, the individual has a Petition 870250089906, dated 02 / 10 / 2025, page 23 / 95 18 / 70 total PASI score that is < 16. The individual can be classified as having mild psoriasis by virtue of having a total PASI score that is < 10. Thus, in one modality, the individual has a total PASI score that is < 10. The individual can be classified as having moderate psoriasis if they have a total PASI score > 10. Thus, in one modality, the individual has a total PASI score that is > 10.

[0052] Viewed from this latter perspective, the disclosure provides a compound for use in a method of treating psoriasis in a human individual, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof, wherein the individual has a total PASI score > 10, and wherein the method comprises administering to the individual a daily dose of approximately 400 mg of the compound (calculated as the free base). In some embodiments, the individual has a total PASI score that is > 10 and < 16.

[0053] In another aspect, the disclosure provides a compound for use in a method of treating psoriasis in a human individual, wherein the compound is Compound 1 or a pharmaceutically acceptable salt thereof, wherein the individual has a total PASI score < 10, and wherein the method comprises administering to the individual a daily dose of approximately 400 mg of the compound (calculated as the free base).

[0054] In some modalities, treatment results in a reduction in the total PASI score (e.g., compared to baseline, which can be assessed immediately before treatment begins). In some modalities, the reduction is at least 1 point, for example, a reduction of about 1.5 points. In other modalities, the reduction is at least 2 points, for example, a reduction of about 3 points. In some modalities, the reduction in the total PASI score is at least 15%, for example, a reduction of at least 25% or at least 35%. In some modalities, the reduction is effected over a period of at least 2 weeks or at least 4 weeks. In some modalities, treatment results in a reduction in the PASI score. Petition 870250089906, dated 02 / 10 / 2025, page 24 / 95 19 / 70 total of approximately 1.5 points over a period of approximately 2 weeks. In some modalities, treatment results in a reduction in the total PASI score of approximately 17% over a period of approximately 2 weeks. In some modalities, treatment results in a reduction in the total PASI score of approximately 3 points over a period of approximately 4 weeks. In some modalities, treatment results in a reduction in the total PASI score of approximately 35% over a period of approximately 4 weeks. In some modalities, the individual has a total PASI score < 10 and treatment results in a reduction in the total PASI score of approximately 21% over a period of approximately 2 weeks and / or a reduction in the total PASI score of approximately 34% over a period of approximately 4 weeks.In some modalities, the individual has a total PASI score > 10, and treatment results in a reduction in the total PASI score of approximately 9% over a period of about 2 weeks and / or a reduction in the total PASI score of approximately 33% over a period of about 4 weeks.

[0055] In some embodiments, the presence (or severity) of psoriasis in the individual is assessed using the TLS score, for example, as described in this invention (see also, for example, Fredriksson et al., Dermatologica (1978) 157(4):238-244; as well as Czarnowicki et al., J Am Acad Dermatol. (2014) 71(5):954-959.e1). In some embodiments, the individual has at least two lesions with a TLS score > 4 (excluding the scalp). In some embodiments, the individual has at least two lesions with a TLS score > 4 (excluding the scalp) and also has a total PASI score < 16.

[0056] In some modalities, treatment results in a reduction in the TLS score of one or more lesions (e.g., compared to baseline, which can be assessed immediately before treatment begins). In some modalities, the TLS score is calculated as the average score of 2 lesions. In some modalities, the reduction is a reduction of Petition 870250089906, dated 02 / 10 / 2025, p. 25 / 95 20 / 70 at least 1 point. In some modalities, the reduction is a reduction of approximately 1 point. In other modalities, the reduction is a reduction of at least 1.5 points, for example, a reduction of approximately 2.5 points. In some modalities, the reduction is a reduction of at least 15%, for example, a reduction of at least 35%. In some modalities, the reduction is effected over a period of at least 2 weeks or at least 4 weeks. In some modalities, treatment results in a reduction in the TLS score of approximately 1 point over a period of approximately 2 weeks. In some modalities, treatment results in a reduction in the TLS score of approximately 17% over a period of approximately 2 weeks. In some modalities, treatment results in a reduction in the TLS score of approximately 2.5 points over a period of approximately 4 weeks.In some modalities, treatment results in a reduction in the TLS score of approximately 38% over a period of approximately 4 weeks. In some modalities, the individual has a total PASI score < 10 and treatment results in a reduction in the TLS score of approximately 21% over a period of approximately 2 weeks and / or a reduction in the TLS score of approximately 37% over a period of approximately 4 weeks. In some modalities, the individual has a total PASI score > 10 and treatment results in a reduction in the TLS score of approximately 11% over a period of approximately 2 weeks and / or a reduction in the TLS score of approximately 40% over a period of approximately 4 weeks.

[0057] In some embodiments, the presence (or severity) of psoriasis in an individual is assessed using the sIGA score, for example, as described in the present invention (see also, for example, Langley et al., J Dermatolog. Treat. (2015) 26(1):23-31). An individual may be classified as having mild to moderate psoriasis by virtue of having an average sIGA score (for example, the average calculated from the score for erythema, induration and scaling, as described below) of less than 4.5. Thus, Petition 870250089906, dated 02 / 10 / 2025, page 26 / 95 21 / 70 in one modality, the individual presents an average sIGA score > 0.0 and < 4.5, for example, an average sIGA score > 1.5 and < 3.5. In some modalities, the individual presents an average sIGA score > 0.0 and < 2.5, for example, an average sIGA score > 1.5 and < 2.5 (for example, the individual is classified as having mild psoriasis). In some modalities, the individual presents an average sIGA score > 2.5 and < 4.5, for example, an average sIGA score > 2.5 and < 3.5 (for example, the individual is classified as having moderate psoriasis). The sIGA score can also be used in conjunction with other assessment measures, for example, those described in the present invention.Thus, in some modalities, the individual has a mean sIGA score < 4.5 and has: (i) at least two lesions with a TLS score > 4 (excluding the scalp); (ii) a total PASI score < 16; or (iii) at least two lesions with a TLS score > 4 (excluding the scalp) and a total PASI score < 16. In some modalities, the individual has a mean sIGA score < 3.5, for example, a mean sIGA score < 2.5. The individual may be classified as having mild to moderate psoriasis based on an overall sIGA score (e.g., a sIGA score translated, as described below, into an integer from 0 to 5). Thus, in one modality, the individual presents an overall sIGA score of 1, 2, 3, or 4. In some modalities, the individual presents an overall sIGA score of 1 or 2, for example, an overall sIGA score of 2 (for example, the individual is classified as having mild psoriasis).In some modalities, the individual presents an overall sIGA score of 3 or 4, for example, an overall sIGA score of 3 (for example, the individual is classified as having moderate psoriasis).

[0058] In some modalities, treatment results in a reduction in the average sIGA score (e.g., compared to baseline). In some modalities, the reduction is effected over a period of at least about 2 weeks or at least about 4 weeks. In some modalities, treatment results in a reduction in the average sIGA score. Petition 870250089906, dated 02 / 10 / 2025, page 27 / 95 22 / 70 of at least about 0.3, for example, a reduction of at least about 0.6; 1.0; 1.3 or 1.6. In some modalities, treatment results in a reduction in the average sIGA score of up to about 2.0, for example, a reduction of up to about 1.7, 1.4 or 1.0. In some modalities, the reduction is a reduction of about 0.3 to about 1.7. In some modalities, treatment results in a reduction in the average sIGA score of about 0.3 to about 1.7, for example, from about 0.6 to about 1.4, such as about 1.0, over a period of about 2 weeks. In some modalities, treatment results in a reduction in the average sIGA score of approximately 0.3 to approximately 1.7, for example, from approximately 0.6 to approximately 1.4, such as approximately 1.0, over a period of approximately 4 weeks. In some modalities, the individual has an average sIGA score of less than 3.5 after treatment, for example, an average sIGA score of less than approximately 2.5 or 1.5 after treatment.In some modalities, the individual has an average sIGA score of 0 to about 2.5, for example, from 0 to about 1.5, after treatment over a period of at least about 2 weeks or at least about 4 weeks.

[0059] In some modalities, treatment results in a reduction in the overall sIGA score (e.g., compared to baseline). In some modalities, the reduction is effected over a period of at least 2 weeks or at least 4 weeks. In some modalities, treatment results in a reduction in the overall sIGA score of at least 1 point, for example, a reduction in the overall sIGA score of 1 point or more. In some modalities, the reduction is 1 point. In some modalities, treatment results in a reduction in the overall sIGA score of 1 point over a period of approximately 2 weeks. In some modalities, treatment results in a reduction in the overall sIGA score of 1 point over a period of approximately 4 weeks. In some modalities, the individual has an overall sIGA score > 3 after treatment, for example, an overall sIGA score > 2 or > 1 after treatment. In some modalities, Petition 870250089906, dated 02 / 10 / 2025, page 28 / 95 23 / 70 The individual presents an overall sIGA score of 1 or 2 after treatment over a period of at least approximately 2 weeks. In some modalities, the individual presents an overall sIGA score of 1 or 2 after treatment over a period of at least approximately 4 weeks. In some modalities, the individual presents an overall sIGA score of 1 after treatment over a period of at least 4 weeks.

[0060] In some modalities, treatment results in a reduction in the level of one or more psoriasis biomarkers in the individual, for example, a reduction in the level of IL-17A, IL-17F, and / or IL-22 in the individual's blood (e.g., serum). In some modalities, treatment results in a reduction in the level of IL-17A, for example, a reduction in the level of IL-17A in the individual's blood (e.g., serum). In some modalities, treatment results in a reduction in the serum level of IL-17A of at least about 0.05 pg / mL (e.g., compared to baseline, which can be assessed immediately before the start of treatment), for example, a reduction of at least about 0.15 pg / mL. In some modalities, treatment results in a reduction in the serum level of IL-17A of about 0.06 pg / mL in 2 weeks. In some modalities, treatment results in a reduction in serum IL-17A levels of approximately 0.18 pg / mL within 4 weeks.In some modalities, treatment results in a reduction in serum IL-17A levels of at least about 10% (e.g., compared to baseline, which can be assessed immediately before treatment initiation), for example, at least about 25%. In some modalities, treatment results in a reduction in serum IL-17A levels of about 8% in 2 weeks. In some modalities, treatment results in a reduction in serum IL-17A levels of about 28% in 4 weeks. In some modalities, treatment results in a reduction in IL-17F levels, for example, a reduction in the individual's blood (e.g., serum) IL-17F levels. In some modalities, treatment results in a reduction in serum IL-17F levels of at least about 1.0 pg / mL (e.g., compared to baseline). Petition 870250089906, dated 02 / 10 / 2025, p. 29 / 95 24 / 70 baseline, which can be assessed immediately before treatment initiation), for example, a reduction of at least about 1.2 pg / mL. In some modalities, treatment results in a reduction in serum IL-17F levels of about 1.0 pg / mL in 2 weeks. In some modalities, treatment results in a reduction in serum IL-17F levels of about 1.3 pg / mL in 4 weeks. In some modalities, treatment results in a reduction in serum IL-17F levels of at least about 35% (e.g., compared to baseline, which can be assessed immediately before treatment initiation), for example, at least about 50%. In some modalities, treatment results in a reduction in serum IL-17F levels of about 39% in 2 weeks. In some modalities, treatment results in a reduction in serum IL-17F levels of approximately 52% within 4 weeks.In some modalities, treatment results in a reduction in IL-22 levels, for example, a reduction in IL-22 levels in the individual's blood (e.g., serum). In some modalities, treatment results in a reduction in serum IL-22 levels of at least about 1.0 pg / mL (e.g., compared to baseline, which can be assessed immediately before treatment initiation), for example, a reduction of at least about 1.5 pg / mL. In some modalities, treatment results in a reduction in serum IL-22 levels of about 1.2 pg / mL within 2 weeks. In some modalities, treatment results in a reduction in serum IL-22 levels of about 1.6 pg / mL within 4 weeks. In some modalities, treatment results in a reduction in serum IL-22 levels of at least about 30% (for example, compared to baseline, which can be assessed immediately before treatment initiation), for example, at least about 40%.In some modalities, treatment results in a reduction in serum IL-22 levels of approximately 34% in 2 weeks. In some modalities, treatment results in a reduction in serum IL-22 levels of approximately 43% in 4 weeks.

[0061] In some modalities, the individual, at the beginning of treatment, Petition 870250089906, dated 02 / 10 / 2025, p. 30 / 95 25 / 70 meets one or more criteria (e.g., all) selected from: (a) male or female (e.g., male) and age between 18 and 65 years inclusive; (b) confirmed diagnosis of chronic plaque psoriasis, diagnosed at least 6 months prior to screening, with mild to moderate severity, defined as PASI < 16; (c) at least two lesions with a TLS score > 4 (excluding the scalp); (d) in good health (except for psoriasis), for example, as assessed by a physician based on medical history, physical examination, vital signs, ECG, laboratory tests, and urinalysis; (e) women and postmenopausal (e.g., absence of menstruation for 12 months without an alternative medical cause - a high FSH level in the postmenopausal range is used to confirm a postmenopausal state in women not using hormonal contraception or HRT) or sterilized (e.g., bilateral surgical oophorectomy not associated with a history of cancer);(f) laboratory parameters within the normal range, for example, liver enzymes (ALT, AST) and GGT not exceeding the ULN and total bilirubin value up to 1.5 ULN if associated with a normal value of conjugated bilirubin; (g) normal vital signs after at least 10 minutes of rest in the supine position during screening, for example, 90 mmHg < systolic blood pressure (SBP) < 140 mmHg, 45 mmHg < diastolic blood pressure (DBP) < 90 mmHg and 50 beats per minute (bpm) < heart rate (HR) < 100 bpm; (h) standard 12-lead ECG parameters after 10 minutes of rest in the supine position, for example, in the following ranges: PR < 220 ms, QRS < 120 ms, QTcF < 450 ms, 50 bpm < HR < 100 bpm and normal ECG tracing; (i) BMI between 18.0 and 35.0 kg / m2, inclusive (body weight not less than 50.0 kg); and (j) male sex, and use of contraception and agreement not to donate sperm from the start of treatment until 2.5 months after the last dose.

[0062] In some modalities, the individual, at the start of treatment, does not meet any (e.g., all) of the criteria selected from: (a) pre-existing signs of skin atrophy, telangiectasia, or striae in the affected area; (b) current evidence of non-plaque forms of psoriasis (e.g., Petition 870250089906, dated 02 / 10 / 2025, page 31 / 95 26 / 70 erythrodermic, guttate, or pustular) or psoriatic arthritis; (c) current or suspected evidence of drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis by beta-blockers, calcium channel blockers, or lithium); (d) presence or history of drug hypersensitivity or allergic disease diagnosed and treated by a physician; (e) opportunistic infections within 6 months of the intended treatment start date; (f) any prior gastrointestinal surgery or recent history (within 3 months prior to the intended treatment start date) of gastrointestinal disease that may affect the absorption of Compound 1; (g) history of drug or alcohol abuse within 12 months prior to the intended treatment start date;(h) evidence of any clinically significant, serious or unstable, acute or chronically progressive, uncontrolled infection or medical condition (including proven ongoing SARS-CoV-2 infection and recurrent infection) or any condition that may affect the participant's safety (e.g., not being adequately vaccinated against SARS-CoV-2); (i) blood donation (any volume) within 2 months prior to the intended treatment start date; (j) known allergy to local anesthetics; (k) use of systemic immunosuppressants within 4 weeks of the intended treatment start date;(l) use within 4 weeks prior to the intended start date of treatment of any non-biological systemic therapy for psoriasis (including, but not limited to, psoralens and ultraviolet A therapy, cyclosporine, methotrexate, azathioprine, corticosteroids, apremilast, tofacitinib, oral retinoids, mycophenolate mofetil, sirolimus), or phototherapy (including ultraviolet B or self-treatment with tanning beds or therapeutic sunbathing), or topical psoriasis therapy with psoralens; (m) use of topical corticosteroid preparations (except 1% ​​hydrocortisone), topical calcineurin inhibitors, or other topical preparations with immunomodulatory properties within 2 weeks prior to the intended start date of treatment; (n) prior use of any biological products for the treatment of psoriasis; (o) receipt of any live vaccination within; Petition 870250089906, dated 02 / 10 / 2025, page 32 / 95 27 / 70 months, any non-live initial vaccination within 30 days or non-live booster vaccination within 14 days of the intended treatment start date; (p) use of any anticoagulant within 3 months of the intended treatment start date, or of acetylsalicylic acid within 2 weeks before the intended treatment start date; (q) use of sensitive substrates of P-gp, CYP3A4, CYP1A1 or CYP1A2, respectively, with a narrow therapeutic window or high-risk indication; (r) use of strong or moderate inducers or inhibitors of CYP3A4 or P-gp within 30 days or 5 half-lives from the intended treatment start date, whichever is longer (this also includes consumption of grapefruit, grapefruit juice or grapefruit-containing products within 72 hours of the intended treatment start date;(s) use of strong or moderate CYP1A1 / CYP1A2 inducers within 30 days or 5 half-lives from the intended treatment start date, whichever is longer (this also includes excessive consumption of beverages containing xanthine bases, for example, more than 4 cups or glasses per day); (t) enrollment in or participation in any clinical study involving an IMP or any other type of medical research and still being within the exclusion period according to applicable regulations; (u) history of tuberculosis and / or a positive QuantiFERON-TB Gold (QFT) test; (v) positive for hepatitis B surface antigen and / or hepatitis B core antibody, or positive for human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab); (w) positive antibody for hepatitis C, unless successfully treated or, if never treated, negative for hepatitis C virus (HCV) RNA by PCR;(x) positive urine drug test result (e.g., for amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, or opiates); (y) procalcitonin (PCT) greater than 0.5 ng / ml (equivalent to greater than 0.5 μg / L) with clinically evident signs and symptoms of infection; and (z) positive alcohol test.

[0063] This disclosure contemplates salt forms of Compound 1, for example, Compound 1 in the form of a pharmaceutically acceptable salt. The Petition 870250089906, dated 02 / 10 / 2025, p. 33 / 95 28 / 70 Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. PH Stahl & CG Wermuth, WileyVCH, 2002. In some embodiments, the compound is a pharmaceutically acceptable salt of Compound 1. In some embodiments, the compound is a pharmaceutically acceptable salt of Compound 1 and the method comprises administering to the individual a daily dose of the salt that is equivalent to 400 mg of the free base, for example, equivalent to 200 mg of the free base BID. In other embodiments, the compound is the free base of Compound 1. In some embodiments, the compound is the free base of Compound 1 and the method comprises administering to the individual a daily dose of 400 mg, for example, 200 mg BID.

[0064] In some embodiments, the compound is administered to the individual orally.In some embodiments, the compound is administered in the form of an oral pharmaceutical composition (e.g., dosage form) comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be any excipient known in the art, including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro ed. 1985). The pharmaceutical compositions of the compound may be prepared by conventional means known in the art, including, for example, mixing with one or more pharmaceutically acceptable excipients.For oral administration, the pharmaceutical composition may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium glycolate); or humectants (e.g., sodium lauryl sulfate). Petition 870250089906, dated 02 / 10 / 2025, page 34 / 95 29 / 70

[0065] Tablets can be coated using methods well known in the art. In some embodiments, the oral pharmaceutical composition is a tablet. Preparations for oral administration can be suitably formulated to provide controlled release of the active compound, for example, using formulations of a type known in the art.

[0066] In some embodiments, treatment comprises administering to the individual a dose of approximately 200 mg of the compound (calculated as the free base) twice daily, for example, 200 mg BID of Compound 1. In some embodiments, the compound is administered in tablet form, for example, tablets comprising 50 mg of the compound (calculated as the free base). In some embodiments, treatment comprises administering four tablets, each containing approximately 50 mg of the compound (calculated as the free base), twice daily, for a total daily dose of approximately 400 mg.

[0067] In some embodiments, treatment involves administering the compound or a pharmaceutically acceptable salt thereof to the individual with food, for example, before, during, or immediately after a meal. In some embodiments, treatment involves administering the compound or a pharmaceutically acceptable salt thereof to the individual regardless of meals.

[0068] Thus, in one aspect, the present disclosure also provides a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is adapted to provide a daily dose of about 400 mg of Compound 1 or a pharmaceutically acceptable salt thereof (calculated as the free base). In some embodiments, the pharmaceutical composition is adapted to provide a twice-daily dose of about 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof (calculated as the free base). In some embodiments, the pharmaceutical composition Petition 870250089906, dated 02 / 10 / 2025, p. 35 / 95 30 / 70 provides Compound 1 or a pharmaceutically acceptable salt thereof in one or more (e.g., 1, 2, or 4) unit doses. In some embodiments, the pharmaceutical composition provides a unit dose of approximately 200 mg of Compound 1 or a pharmaceutically acceptable salt thereof (calculated as the free base), for example, for administration of two unit doses per day. In some embodiments, the pharmaceutical composition provides a unit dose of approximately 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof (calculated as the free base), for example, for administration of eight unit doses per day, or for example, for administration of four unit doses twice daily.

[0069] The present disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in methods of treating psoriasis. It will be recognized that the disclosure also provides methods of treating psoriasis, as described in the present invention, in which a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, as described in the present invention, is administered to a human individual in need. It will also be recognized that the disclosure further provides Compound 1 (or a pharmaceutically acceptable salt thereof) for use in the production of a medicament for the treatment of psoriasis, according to the methods disclosed in the present invention.

[0070] Having been described in general terms in this document, the following non-limiting examples are provided to further illustrate the disclosure. Examples Example 1: Synthesis of (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2b][2,5]benzodiazocin-5(14H)-one (Compound 1) Petition 870250089906, dated 02 / 10 / 2025, page 36 / 95 31 / 70

[0071] Compound 1 was prepared in accordance with Example 6 of international patent application No. PCT / EP2018 / 060489 (published as WO 2018 / 197503). In summary, in a first step, N-(cyclobutylidene)-2-methylpropane-2-sulfinamide (Intermediate 13) was prepared by reacting cyclobutanone with 2-methyl-2-propanesulfinamide, followed by titanium (IV) isopropoxide, and purified by flash chromatography. In a second step, 5-bromo2-iodopyrimidine was cooled and treated with n-butyllithium, followed by Intermediate 13, to give N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide (Intermediate 14), which was purified by flash chromatography. In a third step, Intermediate 14 was treated with MeOH / HCl, followed by isopropyl ether / MeOH, to provide 1-(5-bromopyrimidin-2-yl)cyclobutanamine hydrochloride (Intermediate 15).In a fourth step, Intermediate 15 was treated with di-tert-butyl dicarbonate and triethylamine to provide tert-butyl N-[1-(5-bromopyrimidin-2-yl)cyclobutyl]carbamate (Intermediate 16). In a fifth step, (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanebenzimidazo[1,2b][2,5]benzodiazocin-5(14H)-one (prepared according to Example 11 of WO 2016 / 050975) was treated with potassium bis(trimethylsilyl)amide followed by iodomethane to give (7R,14R)-11chloro-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanebenzimidazo[1,2b][2,5]benzodiazocin-5(14H)-one (Intermediate 3), which was purified by flash chromatography.In a sixth step, Intermediate 3 was treated with tris(dibenzylideneacetone)dipalladium(0), XPhos, bis(pinacolate)diboron and potassium acetate, followed by 1,4-dioxane; to Intermediate 16, an aqueous solution of tribasic potassium phosphate was added, followed by additional tris(dibenzylideneacetone)dipalladium(0), XPhos and an aqueous solution of potassium phosphate. Petition 870250089906, dated 02 / 10 / 2025, page 37 / 95 32 / 70 tribasic to provide tert-butyl (1-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo5,6,7,14-tetrahydro-7,14-methanebenzimidazo[1,2-b][2,5]benzodiazocin-11yl]pyrimidin-2-yl}cyclobutyl)-carbamate (Intermediate 17), which was purified by flash chromatography. In a seventh step, Intermediate 17 was treated with HCl in 1,4-dioxane followed by aqueous sodium hydroxide solution to provide the title compound as a white amorphous solid. õh (400 MHz, DMSO-d6) 9.05 (s, 2H), 8.32-8.22 (m, 1H), 7.91-7.66 (m, 3H), 7.62 (dd, J 8.5, 1.8 Hz, 1H), 7.53-7.46 (m, 2H), 6.31 (d, J 7.1 Hz, 1H), 5.26 (d, J 7.2 Hz, 1H), 3.52 (dt, J 14.2, 7.3 Hz, 1H), 3.36 (s, 3H), 2.84 (d, J 13.8 Hz, 1H), 2.63 (dtd, J 11.5; 5.6; 2.5 Hz, 2H), 2.38 (s, 2H), 2.16-2.05 (m, 2H), 2.04-1.91 (m, 1H), 1.87-1.73 (m, 1H). LCMS (ES+APCI) [M-NH2]-486.0, RT 1.66 minutes (Method 2 of WO 2018 / 197503). LCMS (ES+) [M+H]+503.0, RT 1.71 minutes (Method 1 of WO 2018 / 197503). Example 2: Clinical Study of Compound 1 in Patients with Mild to Moderate Psoriasis Study design

[0072] A phase 1, double-blind, randomized, placebo-controlled study was conducted in participants with mild to moderate psoriasis. Study participants were randomized to receive 200 mg twice daily (BID) of Compound 1 or placebo in a 2:1 ratio (approximately 24 in the treatment group and 12 in the placebo group). The study comprised a screening period of up to 4 weeks and a 4-week treatment period with Compound 1 or placebo. An end-of-study visit was conducted 10 ± 3 days after the last administration of the investigational medicinal product (IMP).

[0073] The primary objective of the study was to evaluate the safety, tolerability, and clinical efficacy of Compound 1 at 200 mg BID via oral administration. The clinical effect of Compound 1 compared to placebo was also assessed by the percentage change in PASI and TLS scores from baseline to week 2 and week 4. The percentage change in PASI score in Petition 870250089906, dated 02 / 10 / 2025, page 38 / 95 The relationship between 33 / 70 and baseline up to week 4 was determined. The TLS score was also assessed during the same period. The effect of Compound 1 on psoriasis biomarkers was also evaluated. Blood samples collected at predetermined time points were processed to quantify serum levels of biomarkers, including interleukin (IL)-17A, IL-17F, and IL-22, using highly sensitive methods. IL-17A, IL-17F, and IL-22 are the main cytokines released by Th17 cells. Plasma levels of Compound 1 were measured to assess pharmacokinetics in the study population. Planned Study Population

[0074] Participants were eligible for inclusion in the study only if all of the following inclusion criteria applied: I 01. Male or female participants aged 18 and over, inclusive: I 02. Confirmed diagnosis of chronic plaque psoriasis, diagnosed at least 6 months prior to screening, with mild to moderate severity, defined as PASI < 16. I 03. The participant must present at least two lesions with TLSS > 4 in both screening and baseline assessments, excluding the scalp. I 04. The participant must be in good health (except for psoriasis), as assessed by the Researcher, based on medical history, physical examination, vital signs, ECG, laboratory tests, and urinalysis. I 05. Female participants who are either postmenopausal or sterilized (e.g., post-bilateral surgical oophorectomy not associated with a history of cancer) may be included in the study. A postmenopausal state is defined as the absence of menstruation for 12 months without an alternative medical cause. An elevated FSH level in the postmenopausal range is used to confirm the postmenopausal state in women (according to the local laboratory) who are not using hormonal contraception or HRT. I 06. Laboratory parameters within the normal range during screening (or Petition 870250089906, dated 02 / 10 / 2025, page 39 / 95 34 / 70 (screening threshold defined for the Researcher's site), unless the Researcher considers an abnormality clinically irrelevant for the participants; however, liver enzymes (ALT, AST) and GGT should not exceed the upper limit of the normal range. Total bilirubin value up to 1.5 times the upper limit of normal may be acceptable if associated with a normal value of conjugated bilirubin. I 07. Normal vital signs after at least 10 minutes of rest in the supine position during triage: - 90 mmHg < systolic blood pressure (SBP) < 140 mmHg; - 45 mmHg < diastolic blood pressure (DBP) < 90 mmHg; - 50 beats per minute (bpm) < heart rate (HR) <100 bpm. I 08. Standard 12-lead ECG parameters after 10 minutes of rest in the supine position in the following ranges during screening: PR < 220 ms, QRS < 120 ms, QTcF < 450 ms (Fridericia formula for QT correction; rechecking is not permitted for screening and inclusion), 50 bpm < HR < 100 bpm and normal ECG tracing, unless the Researcher considers an abnormality in the ECG tracing clinically irrelevant. I 09. Participants with a BMI between 18.0 and 35.0 kg / m2, inclusive (body weight not less than 50.0 kg). 10. Male participants must use contraceptive methods consistent with local regulations regarding contraceptive methods for those participating in clinical studies. Male participants agreed not to donate sperm from enrollment until 2.5 months after the last dose.

[0075] Participants were excluded from the study if any of the following criteria applied: E 01. Pre-existing signs of skin atrophy, telangiectasia, or stretch marks in the affected area. E 02. Current evidence of non-plaque forms of psoriasis (e.g., erythrodermic, guttate, or pustular), psoriatic arthritis. Petition 870250089906, dated 02 / 10 / 2025, page 40 / 95 35 / 70 E 03. Current evidence or suspicion of drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis due to beta-blockers, calcium channel blockers, or lithium). E 04. Presence or history of hypersensitivity to drugs or allergic disease diagnosed and treated by a physician. E 05. Opportunistic infections in the 6 months prior to randomization (Day 1). E 06. Any previous gastrointestinal surgery or recent history (within the 3 months prior to Day 1 of inclusion) of gastrointestinal disease that may affect the absorption of the study drug. E 07. History of drug or alcohol abuse (more than 800 mL of regular beer or an amount equivalent to approximately 40 g of alcohol per day) in the 12 months prior to the dosage. E 08. Evidence of any clinically significant, serious or unstable, acute or chronically progressive and uncontrolled infection or medical condition (including ongoing and biologically proven SARS-CoV-2 infection and recurrent infection) or any condition that may affect the participant's safety, at the Researcher's discretion, including participants who are not adequately vaccinated against SARS-CoV-2 infection, in accordance with local regulations. E 09. Blood donation (any volume) in the 2 months prior to inclusion. E 10. Known allergy to local anesthetics. E 11. Use of systemic immunosuppressants in the 4 weeks prior to study entry and throughout the duration of the study. E 12. Use of any of the following therapies in the 4 weeks prior to baseline (Day 1): non-biological systemic therapies for psoriasis (including, but not limited to): psoralen therapy and ultraviolet A radiation (PUVA), cyclosporine, methotrexate, azathioprine, corticosteroids, apremilast, tofacitinib, oral retinoids, mycophenolate mofetil, sirolimus; or Petition 870250089906, dated 02 / 10 / 2025, p. 41 / 95 Phototherapy 36 / 70 (including ultraviolet B [UVB] radiation or self-treatment with tanning beds or therapeutic sunbathing) or topical therapy for psoriasis with psoralens. E 13. Use of topical corticosteroid preparations (except 1% ​​hydrocortisone), topical calcineurin inhibitors, or other topical preparations with immunomodulatory properties in the 2 weeks prior to randomization (Day 1). E 14. Prior use of any biologics for the treatment of psoriasis. E 15. Participants who received any live vaccination within 3 months, any initial non-live vaccination within 30 days, or a non-live booster vaccination within 14 days of the first administration of the IMP, or who intend to receive any vaccination during the study. E 16. Use of any anticoagulant in the 3 months prior to Day 1 (acetylsalicylic acid in the 2 weeks prior to Day 1) or during the study. E 17. Any participant receiving sensitive substrates of P-gp, CYP3A4, CYP1A1, and CYP1A2, respectively, with a narrow therapeutic window or high-risk indication. E 18. Any participant receiving strong or moderate CYP3A4 and P-gp inducers or inhibitors within 30 days or 5 half-lives after screening, whichever is longer, prior to inclusion. This also includes consumption of grapefruit, grapefruit juice, or grapefruit-containing products within 72 hours of starting Compound 1 administration. E 19. Any participant who is receiving strong or moderate CYP1A1 / CYP1A2 inducers within 30 days or 5 half-lives after screening, whichever is longer, prior to inclusion. This also includes excessive consumption of beverages containing xanthine bases (more than 4 cups or glasses per day). E 20. Any participant enrolled in or who has participated in this or any other clinical study involving an IMP or any other type of medical research and who is still within the exclusion period, according to the Petition 870250089906, dated 02 / 10 / 2025, p. 42 / 95 37 / 70 applicable standards. E 21. History of tuberculosis and / or positive QuantiFERON-TB Gold (QFT) test at screening. E 22. Positive for hepatitis B surface antigen and / or hepatitis B core antibody or positive for human immunodeficiency virus antibodies 1 and 2 (anti-HIV1 and anti-HIV2). E 23. Positive antibodies for hepatitis C, unless the participant has been successfully treated or has never been treated, then the hepatitis C virus (HCV) RNA by polymerase chain reaction (PCR) must be negative (in both cases, eligibility must be considered with supporting documentation). E 24. Positive result in urine drug test (amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates) during screening. E 25. Procalcitonin (PCT) greater than 0.5 ng / ml (equivalent to greater than 0.5 ug / L) with clinically evident signs and symptoms of infection, at the researcher's discretion during screening. E 26. Positive alcohol test during screening.

[0076] Participants were instructed to avoid direct exposure to natural or artificial sunlight during the study treatment and to wear protective clothing, sunscreen, and lip balm with a high sun protection factor (e.g., SPF > 30) when outdoors throughout the study period.

[0077] Regarding food and dietary restrictions, and the consumption of caffeine, alcohol, and tobacco, the following was stipulated: not to consume excessively (more than 4 cups or glasses per day) beverages containing methylxanthine bases (e.g., coffee, tea, cola, chocolate, energy drinks) during participation in the study; not to consume grapefruit, grapefruit juice, or products containing grapefruit in the 72 hours (3 days) prior to inclusion until the end of participation in the study; not to consume foods or beverages containing poppy seeds in the 48 hours prior to screening; participants Petition 870250089906, dated 02 / 10 / 2025, page 43 / 95 38 out of 70 smokers and non-smokers (according to the randomization list) can be included in the study, the restriction is only for smokers who smoke more than 20 cigarettes per day; and not consuming excessive alcohol (i.e., no more than 800 mL of regular beer or an amount equivalent to approximately 40 g of alcohol per day) from screening until the end of participation in the study. Study Interventions

[0078] Two study interventions were used: Compound 1 and placebo. The Compound 1 intervention comprised four 50 mg Compound 1 tablets twice daily, i.e., 200 mg twice daily, for four weeks. The placebo intervention consisted of four placebo tablets twice daily for four weeks. The tablets were administered orally.

[0079] The interventions were used in two arms of the study. Arm 1 was the experimental arm and involved participants who received 200 mg of Compound twice daily for 4 weeks, under fed conditions. Arm 2 was the placebo arm and involved participants who received the corresponding placebo tablets for 4 weeks, under fed conditions. Study Assessments and Procedures

[0080] The planned time points for all effectiveness evaluations are shown in Table A of the Activity Schedule below: Table A Screening Phase D1 Baseline Study observation period End of study W0 W1 W2 W3 W4 W5 / W6 Day of CONSULTATION a D-28 a D-2 D1 D8±2 D15±2 ​​D22±2 D29±1 D38±3 Consultations V01 V02 V03 V04 V05 V06 V07 Time (Hour / minute) b 0H 0H 0H 0H 0H Petition 870250089906, dated 02 / 10 / 2025, page 44 / 95 39 / 70 Informed consent X On-site clinical consultation Xc XXXXXX Overnight stay 0 X Inclusion / exclusion criteria X Xf Participant demographics X Medical history r X d X Previous / concomitant medications < --- - - - - --- > Randomization Xf Daily and Xf XXXX Compliance verification (IMP) XXXX Standard breakfast g X g X g X g X g X g Study Treatment Daily oral administration of compound 1 or placebo tablets (D1-D28) X------------------------------------------------------ --X Petition 870250089906, dated 02 / 10 / 2025, page 45 / 95 40 / 70 Dispensing of Compound 1 tablet vial or placebo XX Return of used or unused tablets / vials XXXX Safety k Physical examination X Xf XXXXX height; X body weight; X Xf XXX Body temperature X Xf Xf Xf Xf XX Vital signs X Xf Xf Xf Xf XX 12-lead ECG q X Xfp Xf Xfp Xf Xfp X Archive blood sample Xf Hematology, biochemistry, coagulation, urinalysis X Xf Xf Xf Xf XX Serological tests X Urine drug test, breathalyzer test X Petition 870250089906, dated 02 / 10 / 2025, page 46 / 95 41 / 70 COVID-19 test h XX s QuantiFERON-TB Gold test Xc Procalcitonin XXX β-HCG blood test (if applicable) XXX Urine pregnancy test X Xf X FSH (if applicable) X Adverse event collection <- - - - - ---> Clinical response 1 Target lesion severity score (TLSS) X Xf Xf X Psoriasis Area and Severity Index (PASI) X Xf Xf X Researcher Global Assessment (static) (sIGA) X Xf Xf X Photographs of psoriasis plaques j Xf X Pharmacokinetics Petition 870250089906, dated 02 / 10 / 2025, page 47 / 95 42 / 70 Blood samples of Compound 1 P01 postdose (3 h ± 1 h) + P02n P03f P04f + P05 postdose (3 h ± 1 h) P06f P07f + P08 postdose (3 h ± 1 h) Blood samples of 4β-hydroxycholesterol Xf Xf Xf DNA (optional) Pharmacogenetic DNA sample for storage Xf Pharmacodynamics Pharmacodynamic blood samples for hsCRP (included in the safety laboratory) Xf Xf Xm Pharmacodynamic blood samples for IL-17A Xf Xf Xm Petition 870250089906, dated 02 / 10 / 2025, page 48 / 95 43 / 70 Pharmacodynamic blood samples for IL-17F Xf Xf X m Pharmacodynamic blood samples for IL-22 Xf Xf X m Skin biopsy (optional) i Xf X m Abbreviations: D = Day, h = hour, V = Visit, W = week a. If the participant discontinues treatment early, they should be evaluated using the safety and clinical response procedure planned for the end-of-treatment study visit at week 4, including the collection of blood samples for pharmacokinetic and pharmacodynamic evaluation, if appropriate. b The time (hour / minute) is expressed in reference to the last administration of Compound 1 (T0H). c. The appointment must be scheduled appropriately, as laboratory results (in particular the QuantiFERON-TB Gold test) from the screening will be released at least 1 week after the blood sample is received at the laboratory. d Including vaccination history and tonsillitis / perichonditis that occurred in the last 4 weeks. and a Diary provided to the study participant on Day 1 and at each visit, then returned and checked by the researcher to verify IMP intake and validate adverse events reported on Day 8±2, Day 15±2, Day 22±2, and Day 29±1. f Pre-dose. Petition 870250089906, dated 02 / 10 / 2025, page 49 / 95 44 / 70 g. Dosing on Day 1, Day 8, Day 15, and Day 22 will be at the study site. A standard hospital breakfast (moderate-fat meal) will be served at the study site before dosing the study drug; that is, the study drug will be administered approximately 5 to 15 minutes after breakfast is finished. However, the study drug can be taken at home, shortly before, during, or immediately after a meal. The study drug should be taken with a glass of water (min. 240 ml). The COVID-19 test may be repeated during the study as needed, according to the researcher's judgment and in accordance with national and local regulations, if applicable. The screening test, such as the nasopharyngeal swab, will be analyzed by PCR. The PCR test may also be performed outside the study site. A new COVID-19 test may be used during the study according to available scientific knowledge and / or recommendation from the local health authority. i Skin biomarkers (RNA analysis) from biopsies (3 mm puncture): before the first dose (Day 1) in lesioned and non-lesioned areas, and at week 4 only in lesioned areas, biopsy is optional for participants who agreed and have visible psoriatic plaque in a region suitable for tissue biopsy. The photograph is optional; more details are provided in the Manual. Photo Reference. k See the Security section (Section 8.2) for detailed security investigations. The TLSS, PASI, and sIGA should always be completed by the same physician for a given participant, if possible, in order to ensure longitudinal comparability and avoid any bias. Pre-dose on day 28 (if the on-site consultation is on day 28); if the on-site consultation is on day 29 or day 30, it should be at the same dosing time as the treatment period. Petition 870250089906, dated 02 / 10 / 2025, p. 50 / 95 45 / 70 n Pre-dose of the nighttime administration of IMP (8 to 12 hours after the morning dose of IMP). Overnight stays are optional from Day -1 to Day 1 and / or from Day 1 to Day 2 for participants who live far from the study location. p ECG post-dose (3h ± 1 h). Digital triplicate ECGs should be recorded within 5 minutes, with at least 1 minute between 2 replicates for all ECGs. The medical history includes, but is not limited to, surgical history / history of psoriasis / history of tonsillitis / periodontitis / smoking status / concomitant disease(s). The Covid-19 test can be performed on Day -1 if the overnight stay is from Day -1 to Day 1. Note: When multiple items are performed simultaneously, the following order must be respected: ECG, vital signs, questionnaires, pharmacodynamics, blood collection, meal (if applicable), drug administration; the exact timing of pharmacokinetic sampling must be respected.

[0081] The TLS score, a validated tool for assessing psoriasis severity, was used to evaluate severity and clinical effectiveness. It consists of a summative score of 3 clinical severity parameters (scaling, erythema, plaque elevation / hardening; each rated on a 5-point severity scale: 0 = clear, 1 = weak, 2 = mild, 3 = moderate, and 4 = severe) with a total score ranging from 0 to 12 points (as per, for example, Czarnowicki et al., J Am Acad Dermatol. (2014) 71(5):954-959.e1). The following assessment was used, in which the TLS score was calculated as the sum of A + B + C (adapted from Fredriksson et al., Dermatologica (1978) 157(4):238-244): Table B A - Desquamation B - Erythema C - Elevated Plaques 0 - Clear: no scaling 0 - No erythema: hyperpigmentation, discoloration 0 - No elevated plaques: no elevation above Petition 870250089906, dated 02 / 10 / 2025, page 51 / 95 46 / 70 Diffuse red or pale pink discoloration of normal skin 1 - Mild desquamation: superficial dryness with some white discoloration 1 - Mild: almost moderate red discoloration, almost defined 1 - Mild: difficult to assess if there is a slight elevation above normal skin 2 - Mild desquamation: thin scales partially or mostly covering the lesions 2 - Mild: almost moderate red discoloration, almost defined 2 - Mild: weak but defined elevation; usually the edges are indistinct or curved 3 - Moderate desquamation: thick, viscous scale covering most or all of the lesions 3 - Moderate: moderate, defined red discoloration 3 - Moderate: moderate elevation, with rough or curved edges 4 - Severe desquamation: thick, viscous scale predominantly covering most or all of the lesions 4 - Severe: very bright, severe red discoloration 4 - Severe: pronounced elevation, usually with hard or sharp edges

[0082] The PASI scoring system assesses psoriasis based on body surface area (BSA) involvement and plaque morphological characteristics (as per, for example, EMA Guidelines on clinical investigation of medicinal products indicated for the treatment of psoriasis, 18 November 2004). BSA estimation was performed using the 'palm' (i.e., the palm of the hand and thumb of the individual together, excluding the fingers). The palm thus defined represented 1% of the total BSA. PASI combines assessments of four body areas: head (h, 10%), upper limbs (u, 20%), trunk (t, 30%), and lower limbs (l, 40%). Using the palm to assess BSA (as described above), the proportion of skin affected by psoriasis in each area received a numerical score (A) representing the proportion involved: 1 (0 to 9%); 2 (10 to 29%); 3 (30 to 49%); 4 (50 to 69%); 5 (70 to 89%) and 6 (90 to 100%).In each area, the severity of three signs, erythema (E), thickness / hardening (I), and scaling / peeling (D), was assessed. Petition 870250089906, dated 02 / 10 / 2025, p. 52 / 95 47 / 70 on a five-point scale: 0, none; 1, mild; 2, moderate; 3, severe; 4, very severe. PASI ranges from 0 to 72 and is calculated using the following formula: PASI = 0.1(Eh + Ih + Dh)Ah + 0.2(Eu + lu + Du)Au + 0.3(Et + It + Dt)At + 0.4(El + Il + Dl)Al

[0083] The sIGA employed in this study is a six-point ordinal scale used to assess the overall severity of the disease in the body as a topography, measured by the overall degree of hardening, scaling, and erythema of an individual's psoriatic lesions. For statistical analysis, the scale was assigned scores from 0 to 5, from “mild” to “very severe,” respectively.

[0084] A score was assigned to an individual on a scale of 0 to 5 for each erythema, induration, and desquamation; an average sIGA score was calculated as the average of these individual scores, and this was translated into an overall sIGA score (an integer between 0 and 5), as described in Tables C and D below: Table C 01 2 3 Normal (post-inflammatory hyperpigmentation may be present) Normal to pink coloration Pink to light red coloration Erythema 4 Dull to bright red, clearly perceptible erythema 5 Bright red to intense dark red coloration Intense dark red coloration 01 None 2 No thickening Hardening 3 Only slight thickening detectable 4 Clearly perceptible to moderate thickening 5 Severe (pronounced) thickening with hard borders Very severe thickening with hard borders 01 No scaling Desquamation 2 Minimal or no focal desquamation 3 Predominantly fine desquamation 4 Moderate desquamation (mild to coarse) Petition 870250089906, dated 02 / 10 / 2025, page 53 / 95 48 / 70 5. Severe (thick) scaling covering almost all lesions. Very severe (very thick) scaling covering all lesions. Table D Overall Score Calculation Detailed Description 0 (Clear) 0 for all three No signs of psoriasis Post-inflammatory hyperpigmentation may be present 1 (Almost clear / Minimal) 0 < average > 1.5 No thickening Normal pink coloration Minimal or no focal scaling 2 (Mild) 1.5 < average > 2.5 Only mild thickening detectable Pink to light red coloration Predominantly fine scaling 3 (Moderate) 2.5 < average > 3.5 Clearly perceptible to moderate thickening Dull to bright red, clearly perceptible erythema Moderate scaling (mild to thick) 4 (Severe) 3.5 < average > 4.5 Severe (pronounced) thickening with hard borders Bright red to intense dark red coloration Severe (thick) scaling covering almost all lesions 5 (Very severe) 4.5 < average Very severe thickening with hard borders Intense dark red coloration Very severe (very thick) scaling covering all lesions.

[0085] The planned time points for all safety assessments are described in the activity table above.

[0086] The physical examination included, at a minimum: cardiac and respiratory auscultation; Petition 870250089906, dated 02 / 10 / 2025, page 54 / 95 49 / 70 peripheral arterial pulse; pupillary, knee, heel, and plantar reflexes; examination of peripheral lymph nodes and abdomen.

[0087] Vital signs (HR, SBP and DBP measured after at least 10 minutes in supine position at rest and after approximately 3 minutes standing) and ear temperature were measured.

[0088] The following electrocardiogram data were recorded: • Standard 12-lead ECGs (safety ECGs) were recorded after at least 10 minutes in the supine position, using an electrocardiographic device. The electrodes were positioned in the same location for each ECG recording throughout the study (e.g., the lead attachment sites were visualized on transparent paper); • Triplicate ECGs were recorded within 5 minutes, with at least 1 minute between 2 replications for all ECGs; • Each ECG consisted of a 10-second recording of all 12 leads simultaneously, resulting in: - A single 12-lead ECG printout (50 mm / s, 10 mm / mV) with automatic correction assessment of heart rate, PR, QRS, QT, and QTc (by the ECG device), including date, time, and participant number, signature of the investigating physician, and at least 3 complexes for each lead. The investigating physician's opinion and the automatic values ​​were recorded on the eCRF. This printout was kept on-site. A second printout was also performed if necessary; - a digital storage that allows for later readings by a central ECG laboratory: each digital file will be identified by theoretical time (day and time Dxx Txx Hxx), actual date and time (recorder time), sponsor study code, participant number (i.e., 3 digits), and location and country numbers, if applicable. Digital recording, storage, and transmission of data (whenever requested) must comply with all applicable regulatory requirements (i.e., FDA Code of Federal Regulations [CFR] 21, Part 11). Petition 870250089906, dated 02 / 10 / 2025, page 55 / 95 50 / 70

[0089] Laboratory tests (at least 10 hours fasting for blood samples) included: • Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with differential count (neutrophils, eosinophils, basophils, monocytes and lymphocytes), platelets; • Biochemistry: - Plasma / serum electrolytes: sodium, potassium, chloride, calcium; - Liver function: AST, ALT, alkaline phosphatase, GGT, total and conjugated bilirubin; - Kidney function: urea, creatinine; - Metabolism: glucose, albumin, total proteins, total cholesterol, triglycerides; - potential for muscle toxicity: CK; - International normalized ratio (INR) and activated partial thromboplastin time (aPTT); - C-reactive protein; CRP levels were assessed by an independent investigator not involved in the study to protect against blinding. CRP values ​​were provided by the independent investigator to the researcher in case of medical need; - Procalcitonin at screening, week 2, and end of pregnancy; • QuantiFERON-TB Gold test (QFT).

[0090] If the participant was female, serum β-HCG testing was required at screening, Day 1, and Day 29 ±1, and a urine pregnancy test was performed at screening, Day 1, and Day 29 ±1. In postmenopausal women, plasma or serum FSH was tested only at screening.

[0091] Urinalysis included specific gravity, proteins, glucose, blood, bilirubin, urobilinogen, leukocytes, ketone bodies, nitrite, and pH: • If any parameter on the reagent strip was abnormal, a quantitative urine analysis was performed. If positive for proteins and / or red blood cells, microscopic analysis was performed by the local laboratory. Petition 870250089906, dated 02 / 10 / 2025, page 56 / 95 51 / 70

[0092] Urine drug screening was performed for amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates (screening only).

[0093] Serological tests included hepatitis B antigen, antinuclear hepatitis B antibodies (anti-HBc Ac), antibodies against hepatitis C, and anti-HIV1 and anti-HIV2 antibodies.

[0094] A 15 mL blood sample (or three 5 mL samples) was collected in a dry red-topped tube, held upright at room temperature for 30 minutes, and then centrifuged at approximately 1,500 g for 10 minutes at 4°C; the serum was then transferred to 3 storage tubes, which were immediately capped and frozen upright at -20°C. This sample was to be used in case of any unexpected safety issue, in order to ensure that a pre-administration baseline value was available for previously unassessed parameters (e.g., serology). If this sample was not used, the investigator would destroy it after sponsor approval.

[0095] A COVID-19 test could be repeated during the study as needed, according to the researcher's judgment and in accordance with national and local regulations, if applicable. The screening test was a nasopharyngeal swab analyzed by PCR.

[0096] Other assessments included body weight (kg), ear body temperature and blood alcohol test (screening only).

[0097] Note: When vital signs, ECG, blood samples, and skin biopsies on Day 1 are scheduled for the same time as IMP administration and / or a meal, they are performed before IMP ingestion and / or the meal. Additionally, blood PK samples collected at scheduled appointments (Day 1, Day 15±2, and Day 29±1) are collected before dose administration, as well as 3 hours after dosing. All other safety, pharmacodynamic, and clinical response assessments scheduled for weeks 2 and 4 are performed close to dosing time (before or after). Petition 870250089906, dated 02 / 10 / 2025, page 57 / 95 52 / 70

[0098] Adverse events (AEs) were reported by the participant or observed by the researcher, and were defined as follows: • An adverse event (AE) is any undesirable medical occurrence in a patient or clinical study participant, temporarily associated with the use of the study intervention, regardless of whether or not it is considered related to the study intervention; • Note: an AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporarily associated with the use of the study intervention.

[0099] Events that meet the definition of AE: • Any abnormal results from laboratory tests (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological examinations, vital sign measurements), including those that worsen from baseline, considered clinically significant in the Researcher's medical and scientific judgment (i.e., not related to the progression of the underlying disease), for example: - Symptomatic; and / or - requiring corrective treatment or consultation; and / or - which lead to discontinuation of IMP or modification of dosage; and / or - that meet a severity criterion; and / or - defined as an AESI; • Exacerbation of a pre-existing chronic or intermittent condition, including an increase in the frequency and / or intensity of the condition; • a new condition detected or diagnosed after administration of the study intervention, even if it may have been present before the start of the study; • signs, symptoms or clinical sequelae of a suspected drug interaction; Petition 870250089906, dated 02 / 10 / 2025, p. 58 / 95 53 / 70 • signs, symptoms or clinical sequelae of a suspected overdose of any study intervention or concomitant medication; • Lack of efficacy or failure of the expected pharmacological action will not, by itself, be reported as an adverse event (AE) or adverse drug reaction (ADR). Such occurrences will be recorded in efficacy assessments. However, signs, symptoms, and / or clinical sequelae resulting from the lack of efficacy will be reported as an adverse event (AE) or adverse drug reaction (ADR) if they meet the definition of an AE or ADR.

[00100] Events that do NOT meet the definition of EA: • any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless the Investigator considers them to be more severe than expected for the participant's condition; • the disease / disorder under study or the expected progression, signs or symptoms of the disease / disorder under study, unless they are more severe than expected for the participant's condition; • medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is AE; • situations in which no adverse medical event occurred (social and / or convenience hospitalization in a hospital); • Predicted daily fluctuations in one or more pre-existing diseases or conditions, present or detected at the start of the study, that do not worsen.

[00101] A serious adverse event (SAE) is any adverse medical occurrence that, at any dose, meets one or more of the following criteria: A) results in death; B) presents a risk to life; Note: The term "life-threatening" in the definition of "serious" refers to an event in which the participant was at risk of death at the time of the event; it does not refer to an event that hypothetically could have caused death if it had been more serious. Petition 870250089906, dated 02 / 10 / 2025, page 59 / 95 54 / 70 C) requires hospitalization of the patient or prolongation of existing hospitalization; - In general, hospitalization means that the participant was admitted (usually involving at least one overnight stay) to the hospital or emergency room for observation and / or treatment that would not have been appropriate in a doctor's office or outpatient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or meets any other serious criteria, the event is considered serious. If there is doubt as to whether hospitalization occurred or was necessary, the AE should be considered serious; Hospitalization for elective treatment of a pre-existing condition that has not worsened from baseline is not considered an adverse event. D) results in persistent or significant impotence / disability; - the term disability means a substantial interruption of a person's ability to perform their normal vital functions; - This definition is not intended to include experiences of relatively minor medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, flu, and accidental trauma (e.g., ankle sprain) that may interfere with or prevent daily life functions but do not constitute a substantial disruption; E) It is a congenital anomaly / birth defect; F) is a clinically important event: Medical and scientific judgment should be exercised when deciding whether rapid notification is appropriate in other situations, such as major medical events that may not pose a risk to life or result in death or hospitalization, but may put the participant at risk or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above; Note: Examples of such events include intensive emergency room or home treatment for allergic bronchospasm, blood dyscrasias, seizures, ALT > 3 x ULN + total bilirubin > 2 x ULN or increased Petition 870250089906, dated 02 / 10 / 2025, page 60 / 95 55 / 70 asymptomatic ALT > 10 χ ULN, development of drug dependence or abuse, suicide attempt or any event suggestive of suicide, syncope, loss of consciousness (except if documented as a consequence of blood collection) or bullous skin eruptions.

[00102] The researcher would assess the intensity of each AE and SAE reported during the study and assign them to one of the following categories (according to NCICTCAE): • Grade 1: mild; asymptomatic or with mild symptoms; only clinical or diagnostic observations; intervention not indicated; • Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADLs). Instrumental ADLs refer to preparing meals, buying groceries or clothes, using the telephone, managing money, etc. • Grade 3: severe or clinically significant, but not immediately life-threatening; hospitalization or prolonged hospitalization is indicated; disabling; limiting ADLs (Activities of Daily Living) of self-care. ADLs of self-care refer to bathing, dressing and undressing, feeding oneself, using the toilet, taking medication, and not being bedridden; • Grade 4: life-threatening consequences; urgent intervention indicated; • Grade 5: death related to aegypti.

[00103] An event was defined as “serious” when it reached at least 1 of the predefined outcomes, as described in the SAE definition, and not when it was classified as serious.

[00104] Whenever possible, the diagnosis or isolated syndrome was reported instead of the symptoms. The researcher would specify the onset date, intensity, action taken regarding the IMP, corrective treatment / therapy administered, additional investigations carried out (e.g., in the case of dermatological lesions where photographs were necessary), the outcome, and the researcher's opinion on the reasonable possibility that the AE was caused. Petition 870250089906, dated 02 / 10 / 2025, page 61 / 95 56 / 70 by IMP.

[00105] All AEs (serious or non-serious) were collected from the signing of the informed consent form (ICF) until the end of the study, at the time points specified in the Activity Schedule above. All SAEs and SAEs were recorded and reported to the Sponsor or designated person immediately and, under no circumstances, after 24 hours. The Researcher sent any updated SAE data to the Sponsor within 24 hours of its availability. Researchers were not required to actively seek information on AEs or SAEs after the conclusion of study participation. However, if the Researcher became aware of any SAE, including a death, at any time after the participant's discharge from the study, and considered the event reasonably related to the intervention or participation in the study, the Researcher was required to notify the Sponsor immediately.

[00106] Care was taken not to introduce bias in the detection of AEs and / or SAEs. The preferred method for inquiring about occurrences of AE was open-ended verbal questioning not directed at the participant.

[00107] All adverse events (AEs), regardless of severity or relationship to the non-experimental medicinal product (NIMP), from the signing of the informed consent form until the end of the study, as defined by the protocol, were recorded on the corresponding page(s) or screen(s) of the case report form for the included participants. For participants who did not pass screening, recording on the case report form was only performed in the case of an adverse event that occurred during the screening period or in the case of an AE when some screening procedures exposed the participant to safety risks (e.g., any substance administered as pretreatment or for phenotyping, invasive tests performed, or interrupted chronic treatment).

[00108] To ensure the safety of the participants, the Researcher took appropriate measures to monitor all AEs until recovery. Petition 870250089906, dated 02 / 10 / 2025, page 62 / 95 57 / 70 clinical findings were complete and laboratory results returned to normal, or until disease progression stabilized, or until death. This may imply that observations would continue beyond the last consultation planned by the protocol, and that additional investigations could be requested by the monitoring team.

[00109] When treatment was discontinued prematurely, participants were evaluated using the procedure planned for the end-of-study visit, including a pharmacokinetic sample, if appropriate, as defined by the protocol.

[00110] Laboratory, vital sign, or ECG abnormalities were recorded as AEs in the eCRF if: • symptomatic; and / or • requiring corrective treatment or consultation; and / or • leading to discontinuation or dosage modification of IMP / NIMP, and / or meeting a severity criterion, and / or defined as an AESI.

[00111] Pregnancy occurring in a female partner of a male participant included in the study was classified as a SAE only if it met one of the severity criteria. In the case of pregnancy in a female participant, the IMP was discontinued. If pregnancy occurred during the screening phase, it would only be reported if it met one of the severity criteria. Pregnancy follow-up was mandatory until its outcome was determined. If a pregnancy was reported, the Researcher would record the pregnancy information on the appropriate form and send it to the Sponsor within 24 hours of becoming aware of the participant's pregnancy.

[00112] Cardiovascular events were reported if they met the criteria for AE / SAE. Events with fatal outcomes were reported as SAEs.

[00113] An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and medical interest, specific to the IMP or program, for which continuous monitoring and prompt communication from the Researcher to the Sponsor may be appropriate. Such events may require Petition 870250089906, dated 02 / 10 / 2025, page 63 / 95 58 / 70 further investigation to characterize and understand them. AESI can be added, modified, or removed during a study through protocol changes.

[00114] For AESI in this study, the Sponsor should be notified immediately (i.e., within 24 hours), in accordance with SAE notification guidelines, even if a severity criterion was not met, using the corresponding screens in eCRF. • ALT increased > 3 x ULN. • QT prolongation (QTcF > 500 milliseconds [ms]) and / or QTc delta change from baseline > 60 ms (12-lead ECG). In case of QTc interval prolongation (automatic measurement) > 500 ms, confirmed by manual reading by the Researcher or a physician designated by him, using the Fridericia formula for QT correction, the participant was placed under supervision in a specialized environment. Administration of the investigational medicinal product was interrupted, and appropriate blood samples were collected. Subsequent monitoring of the participant's ECG was then performed regularly and clinically responsibly until the QTc interval returned to a safe value, as determined by the Researcher in agreement with the Sponsor. • Photosensitivity (Grade 2 or higher aortic sclerosis due to sun exposure). • Pregnancy. • Symptomatic overdose; - An overdose (accidental or intentional) with IMP is an event suspected by the Researcher or spontaneously reported by the participant (not based on systematic tablet counting) and defined as at least twice the intended dose within the intended therapeutic range, adjusted according to the drug being tested; Note: Asymptomatic overdose should be reported as a standard adverse event.

[00115] After the participant's inclusion in the clinical trial, the following laboratory abnormalities were monitored, documented, and treated: Petition 870250089906, dated 02 / 10 / 2025, pp. 64 / 95 59 / 70 • neutropenia, differentiated as neutrophils < 1,500 / mm3 or according to ethnic group (recorded as AE only if at least 1 of the criteria listed above was met); • thrombocytopenia, differentiated by platelets < 100,000 / mm3, confirmed with or without bleeding (recorded as AE only if at least 1 of the criteria listed above was met); • Increased ALT. Patients were monitored when 3 ULN < ALT < 5 ULN and total bilirubin was < 2 ULN. IMP was discontinued when total bilirubin was > 2 ULN or ALT > 5 ULN; • acute renal failure, differentiated by a persistent increase in creatinine from baseline of 0.3 mg / dL (~26.4 μmol / L) or 30%, whichever is lower (recorded as AE only if at least 1 of the criteria listed above is met); • elevated CPK suspected to be of non-cardiac origin and not related to intense physical activity, identified by muscle symptoms or systematic evaluation and differentiated as CPK > 3 ULN (suspected rhabdomyolysis was recorded as AE only if at least 1 of the criteria listed above was met; elevated CPK was recorded as AE only if at least 1 of the criteria listed above was met).

[00116] Blood samples were processed for analysis of IL-17A, IL-17F, and IL-22 in serum samples using highly sensitive methods. Samples were collected according to the schedule of activities described above. Results - Demographic Data and Baseline Characteristics of Patients

[00117] A total of 38 participants were randomized; 26 were exposed to Compound 1 and 12 to placebo. Thirty-six participants completed the study. Two participants who received Compound 1 at 200 mg BID dropped out of the study due to AEs (one on Day 8 and one on Day 15), and were replaced to complete 36 participants for the pharmacodynamic population. Petition 870250089906, dated 02 / 10 / 2025, pp. 65 / 95 60 / 70 Safety data were available for all 38 participants, clinical response data were available for 37 participants (only one of the two participants who dropped out of the study had a post-baseline PD assessment on Day 15), and biomarker data were available for 38 participants (the two participants who dropped out of the study had post-baseline biomarker assessments on Day 8 and only one on Day 15).

[00118] Thirty-eight male participants with comparable demographic characteristics were included (demographic data are summarized in Table 1 below). The median age was 43 years, more specifically 42.5 (range 21 to 64), with a median BMI of 26.2 kg / m2 (range 21.0 to 32.7). All had a confirmed diagnosis (at least 6 months prior to screening) of chronic plaque psoriasis and presented at least two lesions with a TLS score > 4 at screening and baseline. The mean TLS score (± SD) at baseline was approximately 7.0, more specifically 7.01 (± 1.54), and the mean PASI was 8.6, more specifically 8.58 (± 3.40) at baseline. A total of 13 / 38 (34.2%) participants had a total PASI score > 10 (moderate psoriasis). A total of 25 / 38 (65.8%) participants had a total PASI score < 10 (mild psoriasis).Participants were prohibited from using any systemic or topical therapy for psoriasis, except for the use of topical hydrocortisone up to 1%. Treatment with 1,25-dihydroxyvitamin D analogs could be maintained at a stable dose until the end of the study if initiated 6 months before Day 1. However, none of the participants used permitted treatment during the study. Table 1 - Demographic Data and Baseline Characteristics of Study Participants. Baseline Characteristics Placebo (n = 12) Composite 1 (n = 26) Age, mean (± SD), years 40.5 (12.5) 44.2 (9.7) BMI, mean (± SD), kg / m2 25.98 (2.92) 26.45 (2.97) TLS score, mean (± SD) 7.42 (1.40) 6.83 (1.60) PASI, mean (± SD) 7.86 (2.53) 8.91 (3.73) Petition 870250089906, dated 02 / 10 / 2025, pp. 66 / 95 61 / 70 sIGA score 2.25 (0.45) 2.42 (0.64) PASI score, n (%) < 10 (mild psoriasis) 8 (66.7) 17 (65.4) > 10 (moderate psoriasis) 4 (33.3) 9 (34.6) Results - Clinical Response by TLS Score

[00119] The TLS score was assessed at baseline, at 2 weeks, and at 4 weeks. Table 2 below presents the Least Squares Mean (LSm) ± Standard Error (SE) for each treatment and the difference in Least Squares Mean ^LSm; Composite 1 minus placebo) ± Standard Error (SE) with a 90% confidence interval (CI) in the percentage improvement from baseline in the TLS score (calculated as the average of the TLS score values ​​collected from 2 lesions) at week 2 and week 4. Table 2 - Adjusted Mean % Improvement and 90% CI from Baseline in TLS Score between Composite 1 and Placebo Comparison versus baseline LSm (± SE) for Composite 1 LSm (± SE) for placebo ΔLSm (± SE) 90% CI At week 2 17.06 (3.13) 6.29 (4.68) 10.77 (5.61) (1.29 to 20.26) At week 4 38.18 (4.33) 20.44 (6.18) 17.74 (7.54) (4.98 to 30.49) 00120] The results in Table 2 were obtained using the Mixed Model for Repeated Measures (MMRM).

[00121] Figure 1 shows the mean change (±SEM) in TLS score from baseline over time. The placebo treatment arm (solid line with filled circles) shows a mean reduction of about 1.25 points at week 4, while the treatment arm with Composite 1 (dashed line with empty circles) shows a mean reduction of about 2.5 points over the same period.

[00122] Table 3 below presents the mean percentage (±SEM) improvement from baseline in the TLS score (calculated as the average of TLS score values ​​collected from two lesions) at week 2 and week 4 in the patient population with PASI < 10 (mild) or PASI > 10 Petition 870250089906, dated 02 / 10 / 2025, page 67 / 95 62 / 70 (moderate) at baseline. Table 3 - Mean % (± SEM) Improvement from Baseline in TLS Score in Subpopulations TLS Score Population PASI < 10 (mild) Population PASI > 10 (moderate) Placebo (N = 8) Compound 1 200 mg BID (N = 16) Placebo (N = 4) Compound 1 200 mg BID (N = 9) Week 2 8.5 (4.35) 20.9 (3.61) 0.0 (0.00) (1) 10.9 (6.20) Week 4 22.3 (9.0) 37.0 (6.32) (2) 15.0 (7.97) 39.7 (4.03) 00123] The results in Table 3 are from standard descriptive analysis,(1)N = 3,(2)N = 15

[00124] Based on the observed data, the difference in the mean percentage improvement in TLS score at week 4 between Compound 1 and placebo was estimated at 17.7% (90% CI [5.0%; 30.5%]). Results - Clinical Response by PASI Score

[00125] The PASI score was assessed at baseline, at 2 weeks, and at 4 weeks. Table 4 below presents the LSm (± SE) for each treatment and the ΔLSm (Composite 1 minus placebo) with a 90% confidence interval (CI) for the percentage improvement from baseline in the total PASI score at week 2 and week 4. Table 4 - % Adjusted Mean Improvement and 90% CI from Baseline in Total PASI Score between Composite 1 and Placebo. Comparison versus Baseline LSm (± SE) for Composite 1 LSm (± SE) for placebo ΔLSm (± SE) 90% CI At week 2 17.73 (2.75) 4.12 (4.10) 13.61 (4.92) (5.28 to 21.94) At week 4 35.09 (4.47) 15.71 (6.33) 19.38 (7.75) (6.28 to 32.48)

[00126] The results in Table 4 were obtained using MMRM.

[00127] Figure 2 shows the mean change (± SEM) in total PASI score from baseline over time. The placebo treatment arm (solid line with filled circles) shows a mean reduction of Petition 870250089906, dated 02 / 10 / 2025, pp. 68 / 95 63 / 70 showed a reduction of approximately 1.25 points in week 4, while the treatment arm with Compound 1 (dashed line with empty circles) showed an average reduction of approximately 3.0 points over the same period.

[00128] Table 5 below presents the mean percentage (±SEM) improvement from baseline in total PASI score at week 2 and week 4 in the population of patients with PASI < 10 (mild) or PASI > 10 (moderate) at baseline. Table 5 - Mean % (± SEM) Improvement from Baseline in Total PASI Score in Subpopulations PASI Population PASI < 10 (mild) Population PASI > 10 (moderate) Placebo (N = 8) Compound 1 200 mg BID (N = 16) Placebo (N = 4) Compound 1 200 mg BID (N = 9) Week 2 4.8 (3.89) 21.2 (3.98) 3.5 (1.43)(1) 9.3 (3.60) Week 4 14.3 (11.66) 33.8 (5.34)(2) 19.9 (8.83) 33.2 (4.03) 00129] The results in Table 5 are from standard descriptive analysis,(1)N = 3,(2)N = 15.

[00130] Based on the observed data, the difference in the mean percentage improvement in the total PASI score at week 4 between Compound 1 and placebo was estimated at 19.4% (90% CI [6.3%; 32.5%]). The improvement in the PASI score after 4 weeks of treatment with Compound 1 is clinically significant and consistent with the improvement in the TLS score in mild to moderate psoriasis.

[00131] Overall, Compound 1 at a dose of 200 mg BID showed a significant improvement in total PASI score at week 2 (17.73% versus 4.12%, p = 0.005) and week 4 (35.09% versus 15.71%, p = 0.009) (mean % improvement from baseline, p-value for a one-tailed test with a significance level of 5%). Consistently, there was a clear improvement in TLS score from baseline through week 2 (17.06% versus 6.29%, p = 0.032) and week 4 (38.18% versus 20.44%, p = 0.012). A separate analysis of patients with mild (PASI < 10) or moderate (PASI > 10) psoriasis Petition 870250089906, dated 02 / 10 / 2025, page 69 / 95 64 / 70 10) showed improvement in week 2 (mild: 20.9%; moderate: 10.9%) and in week 4 (mild: 37.0%; moderate: 39.7%), despite the severity of the disease. Results - Clinical Response by sIGA Score

[00132] The sIGA score was evaluated as described in the present invention. As shown in Table 6 below, the proportion of patients who achieved improvement in at least 1 severity level in the sIGA score measured at week 4, compared with the baseline sIGA measurement, was 58.3% in the treatment arm versus 0% in the placebo group. Table 6 - Percentage of Individuals with Changes in sIGA Score Compared to Baseline Change in sIGA from baseline -1 No change +1 Placebo Week 2 0 10 (90.9%) 1 (9.1%) Week 4 0 10 (83.3%) 2 (16.7%) Compound 1 200 mg BID Week 2 8 (32.0%) 17 (68.0%) 0 Week 4 14 (58.3%) 9 (38.5%) 1 (4.2%)

[00133] Figure 6 shows the severity of psoriasis in patients, measured by the sIGA score in the treatment arm versus the placebo arm at baseline, week 2, and week 4.

[00134] Overall, Compound 1 at 200 mg BID showed a clinically significant change in sIGA score after 4 weeks of treatment compared to placebo. Conclusions regarding the Clinical Response

[00135] Although milder forms of the disease generally lead to more subtle therapeutic changes, Compound 1 showed a rapid and statistically significant improvement in psoriasis severity compared to placebo as early as week 2, and the improvement was maintained through week 4.

[00136] The mean least squares (LS) difference in percentage improvement in TLS score between Composite 1 and placebo was 10.77% at week 2 and 17.74% at week 4, indicating an overall improvement in TLS score with Composite 1 compared to placebo. Comparison of the difference Petition 870250089906, dated 02 / 10 / 2025, pp. 70 / 95 The mean difference in LS scores between the treatment arm and the placebo arm in the percentage improvement in TLS score at week 2 (mild: 20.9%; moderate: 10.9%) and week 4 (mild: 37.0%; moderate: 39.7%) shows an improvement in TLS score, despite disease severity. The mean difference in LS scores in the percentage improvement in total PASI score at week 2 (13.61%) and week 4 (19.38%) also indicates an overall improvement in psoriasis severity with Compound 1 compared to placebo. A greater percentage improvement in PASI score was observed in the Composite 1 group versus the placebo group at week 2 (mild: 21.2% versus 4.8%, more specifically 21.24% versus 4.80%; moderate: 9.3% versus 3.5%, more specifically 9.31% versus 3.54%) and at week 4 (mild: 33.8% versus 14.3%, more specifically 33.83% versus 14.26%; moderate: 33.2% versus 19.9%, more specifically 33.19% versus 19.88%) in both subcategories.

[00137] The treatment arm showed a significant improvement from baseline in total PASI score compared to the placebo arm at Week 2 (17.73% vs. 4.12%, p = 0.005) and Week 4 (35.09% vs. 15.71%, p = 0.009). A clear improvement in TLS score was observed in the treatment arm versus the placebo arm at Week 2 (17.06% vs. 6.29%, p = 0.032) and Week 4 (38.18% vs. 20.44%, p = 0.012). At Week 4, the proportion of patients who achieved improvement in at least 1 severity level on the sIGA was 58.3% in the Composite 1 group versus no effect (0%) in the placebo group. The sIGA score also demonstrated how a greater percentage of patients who received Compound 1 improved from 'moderate' disease at baseline to 'mild' or 'almost clear' at week 2 and week 4, compared to the placebo group. Patients in the placebo group showed an increase in sIGA from 'mild' to 'moderate'. Results - Pharmacokinetics

[00138] The mean pre- and post-dose plasma concentrations of Compound 1 were consistent with analogous values ​​observed at the same dose in a previous study in healthy participants. The mean plasma levels Petition 870250089906, dated 02 / 10 / 2025, page 71 / 95 Pre-dose levels of Compound 1 (66 / 70) were similar from Day 8 to Day 29, indicating that steady state was achieved and maintained. Plasma concentrations of Compound 1 remained below the limit of quantification in the placebo group. Results - Adverse Events

[00139] Treatment-emergent adverse events (TEAEs) were reported in 7 (58.3%) of the 12 participants in the placebo group and in 24 (92.3%) of the 26 participants in the Compound 1 treatment group. There were no serious AEs (SAEs), TEAEs, or serious AEs of special interest (AESI). Two TEAEs led to permanent discontinuation of the study intervention for 2 participants on Compound 1 at 200 mg BID; one participant withdrew on Day 15 due to nausea, assessed by the investigator as drug-related, another participant withdrew on Day 8 due to increased CPK (grade 2), assessed by the investigator as non-drug-related and associated with increased physical activity, the CPK value returned to baseline after 7 days.

[00140] The most frequent AEOs by primary organ system (POS) class were nervous system disorders [4 (33.3%) in the placebo groups and 19 (73.1%) in the Compound 1 groups], gastrointestinal disorders [2 (16.7%) in the placebo groups and 8 (30.8%) in the Compound 1 groups], and infections and infestations [4 (33.3%) in the placebo groups and 4 (15.4%) in the Compound 1 groups]. The most frequent AEOs by preferred term (PT) were dysgeusia [0 (0%) in the placebo groups and 16 (61.5%) in the Compound 1 groups] and headache [4 (33.3%) in the placebo groups and 8 (30.8%) in the Compound 1 groups]. All AEOs were of grade 1 or grade 2 severity, and participants recovered fully.

[00141] There were few potentially clinically significant abnormalities (PCSA) for vital signs, ECG, and laboratory parameters distributed between the placebo and Compound 1 treatment groups. All were considered clinically non-significant by the investigator. There was no change in QTcF from baseline > 60 msec and / or QTcF > 480 msec. Petition 870250089906, dated 02 / 10 / 2025, page 72 / 95 67 / 70 One participant on Compound 1 at 200 mg BID experienced a QTcF > 450 msec (459 msec) on a single occasion on Day 8, with a QTcF change of 33 msec from baseline (baseline QTcF value of 426 msec). There was no PCSA increase for ALT; two participants on Compound 1 at 200 mg BID experienced a total bilirubin increase > 1.5 ULN on a single occasion on Day 8 (1.67 ULN, baseline value of 1.5 ULN) and on Day 15 (1.56 ULN, baseline value of 1.3 ULN), respectively.

[00142] In summary, no serious adverse events, serious TEAEs or AESIs were reported. Conclusions on Pharmacodynamics, Pharmacokinetics, and Safety

[00143] Compound 1, a specific inhibitor of TNFR1 signaling, demonstrated consistent clinical efficacy over a 4-week treatment period. Compound 1 at 200 mg BID over 28 days was safe and well tolerated by participants with mild to moderate psoriasis, with no reports of severe AEs, treatment-emergent severe AEs, or treatment-associated AEs.

[00144] Observed plasma concentrations of Compound 1 were consistent with pharmacokinetic data previously obtained in healthy participants. Based on mean pre-dose plasma concentrations, steady state was achieved in the first week and maintained until the end of treatment. Results - Biomarker Analysis

[00145] As indicated above, peripheral blood samples collected at predetermined time points were processed to quantify serum levels of psoriasis biomarkers, including IL-17A, IL-17F, and IL-22. IL-17A and IL-17F levels were quantified using a single-molecule sandwich immunoassay (SMCxPro™, Millipore - see also Hwang et al., Methods (2019) 158:69-76). IL-22 levels were quantified using a single-molecule array ELISA assay (SIMOA™, Myriad RBM - see also Rissin et al., Anal Chem (2011) 83(6):2279-2285). Statistical analysis was based on the ratio between the geometric mean and the Petition 870250089906, dated 02 / 10 / 2025, page 73 / 95 68 / 70 baseline; a two-sample t-test with a significance level of alpha of 5% was used to calculate the p-values. Table 7 below shows the changes in biomarker levels summarized using descriptive statistics (mean, standard error of the mean [SEM]) by treatment and time point. Table 7 - Change from Baseline Over Time of Systemic Biomarker Levels in Psoriasis Biomarker Treatment Biomarker Levels Geometric Mean (Geometric SE) Ratio to Baseline Geometric Mean (Geometric SE) Baseline Week 2 Week 4 Week 2 Week 4 IL-17A Compound 1 0.62 0.56 0.45 0.92 0.72 (pg / mL) (1.15) (1.13) (1.14) (1.14) (1.17) Placebo 0.69 0.89 0.76 1.30 1.10 (1.16) (1.22) (1.17) (1.12) (1.15) IL-17F Compound 1 2.63 1.65 1.35 0.61 0.48 (pg / mL) (1.19) (1.21) (1.21) (1.13) (1.12) Placebo 2.74 2.39 2.73 0.92 1.00 (1.23) (1.35) (1.29) (1.22) (1.25) IL-22 Compound 1 4.13 2.86 2.49 0.66 0.57 (pg / mL) (1.19) (1.18) (1.15) (1.10) (1.09) Placebo 2.55 2.87 3.06 1.24 1.20 (1.21) (1.18) (1.23) (1.08) (1.12)

[00146] Compared to placebo, Compound 1 achieved a rapid and significant reduction in serum IL-22 levels by week 2 (0.66 versus 1.24; p = 0.0001), which decreased further by week 4 (0.57 versus 1.20; p < 0.0001). IL-17F also decreased substantially in treated patients compared to the placebo group, both by week 2 (0.61 versus 0.92; p = 0.0795) and week 4 (0.48 versus 1.00; p = 0.0025). A gradual decline in IL-17A levels relative to baseline was observed by week 2 (0.92 versus 1.30; p = 0.1066) and by week 4 (0.72 versus 1.10; p = Petition 870250089906, dated 02 / 10 / 2025, p. 74 / 95 69 / 70 0.0859). The evolution of biomarkers from baseline to week 4 (IL-17A, IL-17F, and IL-22) is shown in Figures 3 to 5, respectively. The decrease in cytokine secretion correlated with a statistically significant clinical improvement in PASI in patients treated with Compound 1 compared to placebo at week 2 (17.73% versus 4.12%, p = 0.005) and week 4 (35.09% versus 15.71%, p = 0.009). Conclusion regarding Biomarker Levels

[00147] Serum levels of IL-17A, IL-17F, and IL-22 decreased substantially after treatment with Compound 1 for 4 weeks in patients with mild to moderate psoriasis. The decrease in biomarkers correlated with the clinical improvement observed in patients who received Compound 1. Overall Conclusions of the Clinical Study

[00148] The findings of this phase 1 trial demonstrated that Compound 1, a specific inhibitor of the TNFR1 signal, was safe, well tolerated, and clinically effective, with a sustained clinical response, in mild to moderate psoriasis over a 4-week treatment period. * * * * *

[00149] It should be understood that, although disclosure has been described in conjunction with the above modalities, the preceding description and examples are intended to illustrate, and not limit, the scope of disclosure. Other aspects, advantages, and modifications in the scope of disclosure will be evident to those skilled in the art to which the disclosure belongs.

[00150] Furthermore, when features or aspects are described in terms of Markush groups, those skilled in the art will recognize that such features or aspects are also described in terms of any individual member or subgroup of members of the Markush group.

[00151] All publications, patent applications, patents and other references mentioned in the present invention are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the reference in point 1 shall prevail. Petition 870250089906, dated 02 / 10 / 2025, pp. 75 / 95 70 / 70 present descriptive report, including definitions. Petition 870250089906, dated 02 / 10 / 2025, pp. 76 / 95

Claims

1 / 2 CLAIMS 1. Compound for use in a method of treating psoriasis in a human individual, characterized in that the compound is (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7dihydro-7,14-methanebenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one (Compound 1): or a pharmaceutically acceptable salt thereof, wherein the individual has mild to moderate psoriasis, and wherein the method comprises administering to the individual a daily dose of about 400 mg of the compound (calculated as the free base).

2. Compound for use according to claim 1, characterized in that the psoriasis is plaque psoriasis, for example, chronic plaque psoriasis.

3. Compound for use according to claim 1 or 2, characterized in that the severity of psoriasis in the individual is assessed using the PASI score, and wherein the individual has a total PASI score < 16.

4. A compound for use in accordance with any of claims 1 to 3, characterized in that the individual has a total PASI score > 10.

5. Compound for use in accordance with any of claims 1 to 4, characterized in that the individual has at least two lesions with a TLS score > 4 (excluding the scalp).

6. Compound for use in accordance with any of claims 1 to 5, characterized in that the compound is administered to the individual orally.

7. Compound for use according to any one of claims 1 to 6, characterized in that the compound is administered in the form of an oral pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

8. Compound for use according to claim 7, characterized in that the oral pharmaceutical composition is a tablet.

9. Compound for use in accordance with any one of claims 1 to 8, characterized in that the method comprises administering to the individual a dose of approximately 200 mg of the compound (calculated as the free base) twice daily.

10. A method for treating psoriasis, as defined in any one of claims 1 to 9, characterized in that a therapeutically effective amount of Compound 1 (or a pharmaceutically acceptable salt thereof) is administered to a human individual in need, and wherein the therapeutically effective amount is a daily dose of about 400 mg (calculated as the free base).

11. Compound 1, or a pharmaceutically acceptable salt thereof, for use in the production of a medicament for the treatment of mild to moderate psoriasis, according to a method as defined in any one of claims 1 to 9, characterized in that the medicament is adapted to provide a daily dose of about 400 mg of the compound (calculated as the free base). Petition 870250089906, dated 10 / 02 / 2025, pp. 78 / 95

Images