Peptides for the treatment of psoriasis vulgaris or psoriatic arthritis

Abstract

This invention relates to pharmaceutical compositions comprising a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.1), for use in a method of treating psoriasis vulgaris. In a second aspect, this invention relates to pharmaceutical compositions comprising a peptide for use in a method of treating psoriatic arthritis.

Description

Technical Field

[0001] In a first aspect, the present invention relates to pharmaceutical compositions comprising peptides for use in methods of treating psoriasis vulgaris. In a second aspect, the present invention relates to pharmaceutical compositions comprising peptides for use in methods of treating psoriatic arthritis. Background Technology

[0002] Psoriasis vulgaris (Ps) is a common autoimmune-mediated inflammatory disease in adults and children. The relapsing course of psoriasis negatively impacts patients' quality of life. This condition is associated with social isolation, anxiety, and depression, and can impair interpersonal relationships and employment. Skin involvement is the most prominent symptom of the disease; however, psoriasis is a chronic, multisystemic inflammatory disease. Patients with mild to moderate psoriasis primarily manage their condition with topical medications or phototherapy. For patients with moderate to severe disease, first-line therapies include methotrexate, acitretin, apremilast, and biologics. All of these treatments require close monitoring (Kessler, 2022). There is a continuing need for alternative therapies for psoriasis vulgaris.

[0003] Psoriatic arthritis (PsA) is a complex inflammatory musculoskeletal and skin disease. Up to 30% of people with psoriasis may develop PsA during their lifetime. Musculoskeletal manifestations of PsA include peripheral arthritis, spondylitis, dactylitis (inflammation of the entire finger / toe), and enthesitis (inflammation where tendons, ligaments, or joint capsules insert into the bone). Skin manifestations of PsA include psoriasis (which has many phenotypes, but the most common types associated with PsA are plaque psoriasis or common psoriasis) and nail diseases. In addition to musculoskeletal and skin features, people with PsA experience fatigue, limited physical function, sleep disturbances, and decreased work capacity and social participation. Treatments for PsA include conventional or standard disease-modifying antirheumatic drugs (DMARDs), biologic therapies such as TNF inhibitors (TNFi), IL-17 inhibitors (IL-17i), IL-12 / 23 inhibitors (IL-12 / 23i), and novel targeted oral agents, including phosphodiesterase-4 inhibitors and Janus kinase (JAK) / signal transducer and activator of transcription (STAT) inhibitors (Ogdie, 2020). There remains a continuing need for alternative treatments for psoriatic arthritis. Summary of the Invention

[0004] Aspect A

[0005] In aspect A, the present invention relates to a pharmaceutical composition comprising the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or a pharmaceutically acceptable salt thereof, the composition being used in a method of treating psoriasis vulgaris (Ps), wherein the pharmaceutical composition is administered in a peptide dose equivalent to about 0.15 mg to about 1.5 mg of the peptide on a molar basis (e.g., a peptide dose equivalent to about 0.45 mg and about 0.9 mg of the peptide on a molar basis).

[0006] In an embodiment of aspect A, the pharmaceutical composition is applied three times a week, twice a week, or once a week.

[0007] In an embodiment of aspect A, the pharmaceutical composition is administered twice weekly.

[0008] In an embodiment of aspect A, the pharmaceutical composition is administered subcutaneously, intramuscularly, or intravenously.

[0009] In an embodiment of aspect A, the pharmaceutical composition is administered subcutaneously.

[0010] In an embodiment of aspect A, the pharmaceutical composition is administered for 3 to 8 weeks.

[0011] In the implementation of aspect A, the pharmaceutical composition is administered for 4 weeks.

[0012] In an embodiment of aspect A, the pharmaceutical composition is administered to a subject suffering from Ps with a Psoriasis Area and Severity Index (PASI) score of <10.

[0013] In an embodiment of aspect A, the pharmaceutical composition is administered to a subject suffering from Ps with a Psoriasis Area and Severity Index (PASI) score of ≥10.

[0014] In an embodiment of aspect A, administration of the pharmaceutical composition results in an improvement in the Ps-related parameter, wherein the Ps-related parameter is the Psoriasis Area and Severity Index (PASI) score, and administration of the pharmaceutical composition according to the invention results in a reduction of the Psoriasis Area and Severity Index (PASI) score by at least 20%, optionally at least 50%, from baseline.

[0015] Aspect B

[0016] In aspect B, the present invention relates to a pharmaceutical composition comprising the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or a pharmaceutically acceptable salt thereof, the composition being used in a method of treating psoriatic arthritis (PsA), wherein the pharmaceutical composition is administered in a peptide dose equivalent to about 0.15 mg to about 1.5 mg of the peptide on a molar basis (e.g., a peptide dose equivalent to about 0.45 mg and about 0.9 mg of the peptide on a molar basis).

[0017] In the implementation of aspect B, the pharmaceutical composition is applied three times a week, twice a week, or once a week.

[0018] In the implementation of aspect B, the pharmaceutical composition is administered twice weekly.

[0019] In an embodiment of aspect B, the pharmaceutical composition is administered subcutaneously, intramuscularly, or intravenously.

[0020] In an embodiment of aspect B, the pharmaceutical composition is administered subcutaneously.

[0021] In the implementation scheme of aspect B, the pharmaceutical composition is administered for 3 to 8 weeks.

[0022] In the implementation scheme of aspect B, the pharmaceutical composition is administered for 4 weeks.

[0023] In an embodiment of aspect B, the pharmaceutical composition is administered to a subject with PsA who has a Psoriasis Area and Severity Index (PASI) score of <10.

[0024] In an embodiment of aspect B, the pharmaceutical composition is administered to a subject with PsA having a Psoriatic Area and Severity Index (PASI) score of ≥10.

[0025] In an embodiment of aspect B, administration of the pharmaceutical composition results in an improvement in the PsA-related parameter, wherein the PsA-related parameter is the Psoriasis Area and Severity Index (PASI) score, and administration of the pharmaceutical composition according to the invention results in a reduction of the Psoriasis Area and Severity Index (PASI) score by at least 20%, optionally at least 50%, from baseline. Attached Figure Description

[0026] Figure 1 For the 450 μg and 900 μg dose levels, exemplary responders had a reduced atopic dermatitis score (SCORAD) relative to baseline.

[0027] Figure 2For dose levels of 450 μg and 900 μg, the exemplary responders had a reduction in affected body surface area (BSA) relative to baseline.

[0028] Figure 3 A blinded data analysis of 29 psoriasis patients revealed the first efficacy signal. Normalized PASI values ​​for the 29 subjects in the study are shown. Detailed Implementation

[0029] Peptide Si-544 (corresponding to “ctgx 544” as described in WO 2015 / 169901 A1) is a blocker of voltage-gated Kv1.3 potassium channels. 25 years of research has linked an increasing number of diseases, including autoimmune diseases such as Alzheimer's disease (AD), to chronically activated Kv1.3-dependent effector memory T cells (T cells). EM This is linked to (Chandy, 2017; Hu, 2017). Typically, T... EM In activation and subsequent calcium (Ca 2+ Following influx, ion homeostasis is restored by recruiting the only two potassium channels expressed in human T cells, Kv1.3 and KCa3.1. In some cases, T... EM It becomes chronically activated, for example by self-antigens, and is driven to an exclusive Kv1.3-dependent state, where KCa3.1 is no longer expressed at relevant levels. This contrasts with normal, primary activated T cells. EM In comparison, these Kv1.3-dependent, disease-related T... EM Sensitive to Kv1.3 blockade because KCa3.1 no longer compensates for the inhibited Kv1.3 channel (Chiang 2017). Therefore, Kv1.3 is a target for novel therapies in autoimmune diseases. Kv1.3 inhibition selectively targets chronically activated, disease-associated T cells. EM It does not cause systemic immunosuppression, as seen in subjects receiving conventional therapy.

[0030] The inventors of this invention found in a multicenter, phase 1b, double-blind, placebo-controlled, single-dose and multiple escalation-dose study in adults with atopic dermatitis that doses up to 900 μg of the acetate of a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) were safe and tolerable. Furthermore, high plasma levels were achieved at doses of 450 µg and 900 µg, resulting in near-complete target engagement. In light of these results, the following assumption appears acceptable: the pharmaceutical composition according to the invention is safe, tolerable, and effective in patients with psoriasis vulgaris (Ps) and psoriatic arthritis (PsA). Analysis of blinded data from 29 psoriasis patients further supports this, revealing initial efficacy signals.

[0031] A phase 1b trial investigating another inhibitor of voltage-gated Kv1.3 potassium channel peptide, dalazatide (a 37-amino acid peptide, formerly known as ShK-186 and SL5), in patients with plaque psoriasis described a maximum dose of 60 µg (Tarcha, 2017). Based on published results (Tarcha, 2017), plasma levels of dalazatide can be calculated; these levels are sufficient to achieve approximately 15-20% target (Kv1.3) engagement. The inventors of this invention have found that significantly higher plasma levels (>20 ng / ml) can be safely achieved with si-544, resulting in at least >85% target engagement.

[0032] As used in the specification and claims, unless the context clearly indicates otherwise, the singular forms “a” and “an” also include the corresponding plural forms.

[0033] In the context of this invention, the term "about" refers to a range of precision that, as will be understood by those skilled in the art, still ensures the technical effect of the features in question. This term typically indicates a deviation from the indicated value of ±10%, and more preferably ±5%.

[0034] It should be understood that the term "comprising" is not restrictive. For the purposes of this invention, the term "consisting of" is considered a preferred embodiment of the term "comprising". If a group is defined below as including at least a certain number of embodiments, this also means covering a group that preferably consists only of these embodiments.

[0035] As used in this article, the term "si-544" refers to 38 non-specific... A peptide composed of modified native amino acids. The peptide consists of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1). The peptide can be prepared using techniques known in the art. For example, the peptide can be synthesized using solid-phase Fmoc chemistry. Such synthesis can be performed, for example, on an automated peptide synthesizer. Once synthesized, the sequence can be verified using an automated peptide sequencer. Notably, the peptide contains eight cysteine ​​residues forming four disulfide bonds and therefore may require active folding to the native state to achieve optimal activity. Activity can be further enhanced by purifying the fully folded peptide. Folding can be achieved by subjecting the synthesized peptide to oxidation to achieve disulfide bonds between the cysteine ​​residues. This can be accomplished by incubating the peptide in a phosphate buffer at, for example, pH 8.0, in the presence of atmospheric oxygen, as described in WO 2015 / 169901 A1 (“ctgx 544” corresponds to “si-544”). Folding can be followed up by mass spectrometry, as the folded peptide will show a slight decrease in mass corresponding to the loss of hydrogen atoms during disulfide bridge formation. Purification of fully folded peptides can be achieved by methods known in the art, such as HPLC purification. Suitable methods are described in WO 2015 / 169901 A1 (“ctgx 544” corresponds to “si-544”).

[0036] The pharmaceutical compositions according to the invention can be administered orally, for example in the form of inhalable powder pellets, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. Administration can also be made intranasally, sublingually or buccally. Other suitable forms of administration are, for example, transdermal or topical application (e.g., in the form of ointments, tinctures, sprays or transdermal treatment systems), or inhalation as nasal sprays or aerosol mixtures.

[0037] Preferably, the pharmaceutical composition according to the invention can be administered subcutaneously, intramuscularly, or intravenously, for example, using a standard needle and syringe or a pen delivery device. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices typically utilize a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there is no replaceable cartridge. Instead, the disposable pen delivery device is pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the pharmaceutical composition in the reservoir is emptied, the entire device is discarded. According to some embodiments, the pharmaceutical composition according to the invention is administered subcutaneously.

[0038] Typically, pharmaceutical compositions according to the invention may contain a variety of pharmaceutically acceptable excipients, selected based on the function the composition is intended to achieve. In the context of this invention, a "pharmaceutically acceptable excipient" can be any substance used to prepare a pharmaceutical dosage form, including coating materials, film-forming materials, fillers, disintegrants, release modifiers, carriers, diluents, binders, and other adjuvants. Typical pharmaceutically acceptable excipients include substances such as sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricants such as magnesium stearate, disintegrants, and buffers.

[0039] The term "carrier" refers to a pharmaceutically acceptable organic or inorganic carrier substance to which the active ingredient is combined to facilitate application. Suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohols, oils (preferably vegetable oils), polyethylene glycol, gelatin, lactose, amylose, magnesium stearate, surfactants, essential oils, monoglycerides and diglycerides of fatty acids, petroleum ether fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, etc. The pharmaceutical composition may be sterilized and, if desired, mixed with adjuvants that do not react adversely with the active compound, such as lubricants, preservatives, stabilizers, humectants, emulsifiers, salts that affect osmotic pressure, buffers, colorants, flavoring agents, and / or aromatic substances.

[0040] The pharmaceutical composition according to the invention can be administered in a peptide dose equivalent to about 0.15 mg to about 1.5 mg of peptide acetate on a molar basis. According to some embodiments, the pharmaceutical composition according to the invention is administered in a peptide dose equivalent to about 0.15 mg to about 0.75 mg of peptide acetate on a molar basis, such as a 0.45 mg peptide acetate. According to some embodiments, the pharmaceutical composition according to the invention is administered in a peptide dose equivalent to about 0.75 mg to about 1.5 mg of peptide acetate on a molar basis, such as a about 0.9 mg peptide acetate. In some embodiments, the pharmaceutical composition according to the invention can preferably be administered in a dose of about 0.15 mg to about 1.5 mg of peptide. According to some embodiments, the pharmaceutical composition according to the invention can preferably be administered in a dose of about 0.15 mg to about 0.75 mg of peptide (such as a 0.45 mg peptide). According to some embodiments, the pharmaceutical composition according to the invention can preferably be administered in a dose of about 0.75 mg to about 1.5 mg of peptide (such as about 0.9 mg peptide).

[0041] According to certain embodiments, the pharmaceutical composition according to the invention is administered at a frequency of about four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less, as long as a therapeutic response is achieved. In some embodiments, the pharmaceutical composition according to the invention is administered three times a week, twice a week, or once a week, optionally twice a week. In some embodiments, it may be preferred that the pharmaceutical composition according to the invention is administered subcutaneously twice a week.

[0042] According to certain embodiments, the pharmaceutical composition according to the invention is administered for 3 to 8 weeks, 3 to 6 weeks, or 3 to 4 weeks, optionally for 3, 4, 6, or 8 weeks. In some embodiments, it may be preferred to administer the pharmaceutical composition according to the invention for 4 weeks.

[0043] The Psoriasis Area and Severity Index (PASI) score is a tool used to measure the severity and extent of psoriasis (Fredriksson 1978, https: / / dermnetnz.org / topics / pasi-score). A representative area of ​​psoriasis is selected for each body region (head and neck; upper extremities; trunk; lower extremities). The intensity of redness (erythema), thickness (induration), and peeling (scaling) of psoriasis is assessed as none (0), mild (1), moderate (2), severe (3), or very severe (4). The three intensity scores for each of the four body regions are summed to give subtotals A1 (head and neck), A2 (upper extremities), A3 (trunk), and A4 (lower extremities). Each subtotal is multiplied by the body surface area represented by that region: A1 x 0.1 = B1; A2 x 0.2 = B2; A3 x 0.3 = B3; and A4 x 0.4 = B4.

[0044] Assess the percentage of body area affected by psoriasis in four regions. In each region, the area is expressed as zero (0), 1–9% (score 1), 10–29% (score 2), 30–49% (score 3), 50–69% (score 4), 70–89% (score 5), or 90–100% (score 6). Multiply each body area score by the affected area: B1 x (0–6) = C1; B2 x (0–6) = C2; B3 x (0–6) = C3; and B4 x (0–6) = C4. The PASI score is C1 + C2 + C3 + C4. The maximum score is 72. A score <10 indicates mild psoriasis, and a score ≥10 indicates moderate to severe psoriasis.

[0045] According to certain embodiments of aspect A, the pharmaceutical composition according to the invention is administered to subjects suffering from mild Ps, i.e., subjects suffering from Ps with a Psoriasis Area and Severity Index (PASI) score of <10. According to certain embodiments, the pharmaceutical composition according to the invention is administered to subjects suffering from moderate to severe Ps, i.e., subjects suffering from Ps with a Psoriasis Area and Severity Index (PASI) score of ≥10.

[0046] The Psoriasis Area and Severity Index (PASI) score is an example of the “Ps-related parameter” according to this disclosure. “Improvement of the Ps-related parameter” means a reduction from baseline. As used herein, the term “baseline” with respect to the Ps-related parameter means the value of the subject’s Ps-related parameter before or at the time of application of the pharmaceutical composition of the present invention. To determine whether the Ps-related parameter has been “improved,” the parameter is quantified at one or more time points after baseline and after application of the pharmaceutical composition of the present invention. For example, it may be quantified on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, and 85 after initial treatment with the pharmaceutical composition of the present invention; or during treatment with the pharmaceutical composition of the present invention. The Ps-related parameter is measured at the end of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or longer after initial treatment with the pharmaceutical composition of the invention. The difference between the parameter value at a specific time point after the start of treatment and the parameter value at baseline is used to determine whether the Ps-related parameter has been “improved” (e.g., reduced). According to some embodiments, the “Ps-related parameter” is the Psoriasis Area and Severity Index (PASI) score, and the pharmaceutical composition of the invention results in a reduction of the Psoriasis Area and Severity Index (PASI) score from baseline of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0047] According to certain embodiments of aspect B, the pharmaceutical composition according to the invention is administered to subjects suffering from mild PsA, i.e., subjects suffering from PsA with a Psoriasis Area and Severity Index (PASI) score of <10. According to certain embodiments, the pharmaceutical composition according to the invention is administered to subjects suffering from moderate to severe PsA, i.e., subjects suffering from PsA with a Psoriasis Area and Severity Index (PASI) score of ≥10.

[0048] The Psoriasis Area and Severity Index (PASI) score is an example of the “PsA-related parameter” according to this disclosure. “Improvement of the PsA-related parameter” means a reduction from baseline. As used herein, the term “baseline” with respect to the PsA-related parameter means the value of the subject’s PsA-related parameter before or at the time of application of the pharmaceutical composition of the present invention. To determine whether the PsA-related parameter has been “improved,” the parameter is quantified at one or more time points after baseline and after application of the pharmaceutical composition of the present invention. For example, it may be quantified on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, and 85 after initial treatment with the pharmaceutical composition of the present invention; or during treatment with the pharmaceutical composition of the present invention. The PsA-related parameter is measured at the end of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or longer after initial treatment with the pharmaceutical composition. The difference between the parameter value at a specific time point after the start of treatment and the parameter value at baseline is used to determine whether the PsA-related parameter has been “improved” (e.g., reduced). According to some embodiments, the “PsA-related parameter” is the Psoriasis Area and Severity Index (PASI) score, and the pharmaceutical composition according to the invention results in a reduction of the Psoriasis Area and Severity Index (PASI) score from baseline of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0049] The preferred embodiment of aspect B1 of the present invention relates to:

[0050] 1. A pharmaceutical composition comprising a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or a pharmaceutically acceptable salt thereof, the composition being used in a method of treating psoriatic arthritis (PsA), wherein the pharmaceutical composition is administered in a peptide dose equivalent to about 0.15 mg to about 1.5 mg of the acetate of said peptide on a molar basis.

[0051] 2. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is administered in a peptide dose equivalent to about 0.45 mg of the acetate of the peptide on a molar basis.

[0052] 3. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is administered in a peptide dose equivalent to about 0.9 mg of the acetate of the peptide on a molar basis.

[0053] 4. The pharmaceutical composition for use according to any one of items 1 to 3, wherein the pharmaceutical composition is applied three times a week, twice a week, or once a week.

[0054] 5. The pharmaceutical composition for use according to any one of items 1 to 3, wherein the pharmaceutical composition is applied twice a week.

[0055] 6. The pharmaceutical composition for use according to any one of items 1 to 5, wherein the pharmaceutical composition is administered subcutaneously, intramuscularly or intravenously.

[0056] 7. The pharmaceutical composition for use according to any one of items 1 to 5, wherein the pharmaceutical composition is administered subcutaneously.

[0057] 8. The pharmaceutical composition for use according to any one of items 1 to 7, wherein the pharmaceutical composition is administered for 3 to 8 weeks.

[0058] 9. The pharmaceutical composition for use according to any one of items 1 to 7, wherein the pharmaceutical composition is administered for 4 weeks.

[0059] 10. The pharmaceutical composition for use according to any one of items 1 to 9, wherein the pharmaceutical composition is administered to a subject suffering from PsA with a Psoriasis Area and Severity Index (PASI) score of <10.

[0060] 11. The pharmaceutical composition for use according to any one of items 1 to 9, wherein the pharmaceutical composition is administered to a subject suffering from PsA with a Psoriatic Area and Severity Index (PASI) score of ≥10.

[0061] 12. The pharmaceutical composition for use according to any one of items 1 to 11, wherein administration of the pharmaceutical composition results in improvement of the PsA-related parameter, wherein the PsA-related parameter is the Psoriasis Area and Severity Index (PASI) score, and administration of the pharmaceutical composition according to the invention results in a reduction of the Psoriasis Area and Severity Index (PASI) score from baseline by at least 20%, optionally at least 50%.

[0062] Example

[0063] In the following sections, specific examples illustrating various embodiments and aspects of the invention are given. However, the invention is not limited to the scope of the exemplary embodiments, which are intended only to illustrate a single aspect of the invention, and functionally equivalent methods are within the scope of the invention. In fact, various modifications to the invention beyond those described herein will become apparent to those skilled in the art from the foregoing description.

[0064] Abbreviations

[0065] The following abbreviations may appear in the Implementation Examples section:

[0066] AD Atopic Dermatitis

[0067] ADA anti-drug antibodies

[0068] Adverse drug reactions (ADRs)

[0069] AE adverse events

[0070] AUC (Area Under the Plasma Concentration-Time Curve)

[0071] BSA body surface area

[0072] CA governing body

[0073] Cmax (maximum concentration)

[0074] CNS (Central Nervous System)

[0075] DEC Dosage Elevation Committee

[0076] DLT dose-limiting toxicity ECG

[0077] eCRF Electronic Case Report Form

[0078] FIH in humans for the first time

[0079] ICF Informed Consent Form

[0080] IEC Independent Ethics Committee

[0081] IL interleukin

[0082] IMP Research Drugs

[0083] ISF Researchers Folder

[0084] MAD with multiple escalation doses

[0085] MTD Maximum Tolerable Dose

[0086] NCI-CTCAE - Common Toxicity Criteria for Adverse Events (NCI-CTCAE) (National Cancer Institute)

[0087] NOAEL indicates no visible adverse effects.

[0088] PD pharmacodynamics

[0089] PK Pharmacokinetics

[0090] PP Compliance Solution Set

[0091] SAD single escalation dose

[0092] SAE Serious Adverse Events

[0093] SAF Security Analysis Set

[0094] SAP Statistical Analysis Plan

[0095] SCORAD Atopic Dermatitis Score

[0096] SUSAR suspected unexpected serious adverse reaction

[0097] TCM Central Memory T Cells

[0098] TEM effector memory T cells

[0099] WHO-DD (World Health Organization Drug Dictionary)

[0100] Example 1 - A multicenter, phase 1b, double-blind, placebo-controlled, single-dose and multiple-escalation-dose study evaluating the safety, tolerability, and efficacy of si-544 in adults with atopic dermatitis.

[0101] 1. Non-clinical data for si-544

[0102] toxicology

[0103] Repeated-dose toxicity studies were conducted in rodents (rats) and highly related non-rodent species (cynomolgus monkeys).

[0104] In a 28-day study in Wistar rats, repeated once-daily intravenous or subcutaneous doses of si-544 were tested (data not shown). Clinical symptoms were observed only during treatment and not during the recovery period. All clinical symptoms, except for tail cyanosis and neck crusting, were considered to be associated with the test product and were a result of repeated injections. Overall, the following test product-associated clinical symptoms began shortly after intravenous administration, lasted from 30 minutes to several hours, and were included in the high-dose subcutaneous group: slightly reduced spontaneous activity and piloerection in males, and ataxia, reduced spontaneous activity, prone position, mild swelling (edema) of the mouth and nose, increased salivation, muscle twitching / tremors, and piloerection in females. The histopathologically determined No-Aspect-Effect Level (NOAEL) was 4 mg / kg / day.

[0105] Repeated-dose toxicity studies were conducted to obtain information on the toxicity and toxicokinetics of si-544 in cynomolgus monkeys following repeated intravenous (0.5 mg / kg, 1 mg / kg, and 2 mg / kg) or subcutaneous (2 mg / kg) administration once daily over a 28-day period (data not shown). The first study was terminated early due to an unexpected finding unrelated to si-544. In the second study, although some clinical signs (primarily bizarre behaviors such as scratching, scratching hands, scratching the enclosure walls, open and closed mouths, tick-like movements) and some changes in biochemical parameters (decreases in sodium, albumin, and total protein) and effects on the spleen (lymphoid follicle development) were observed, these changes were not considered adverse reactions, but continuous intravenous or subcutaneous administration of 2 mg / kg / day for 4 weeks could be considered a NOAEL. This is the highest concentration or amount that, experimentally or observationally, does not cause detectable adverse changes in the morphology, functional capacity, growth, development, or lifespan of the target organism under specified conditions.

[0106] The starting dose (15 µg / subject) and maximum dose (900 µg / subject) of the SAD portion were selected based on the results of a 28-day repeated-dose toxicity study in rats and monkeys.

[0107] Although monkeys are considered the species most relevant to humans, a conservative approach was taken, and the safe starting dose was calculated based on rats (1 mg / kg dose in the central nervous system [CNS] function study) because it is the most sensitive species.

[0108] For a target starting dose of 15 µg / subject, a safety margin exceeding 4000-fold based on the mg / kg dose was calculated using the corresponding exposure values ​​derived from the most sensitive safety endpoint (CNS function studies in rats), and a safety margin exceeding 400-fold based on extrapolated human maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) data. Assuming a volume of distribution of 5 L in humans, a dose of 15 µg / subject results in a maximum plasma concentration of 3 ng / mL, reflecting a worst-case scenario, as the blood si-544 curve may be flatter due to the subcutaneous administration route than that of intravenous injection. In rats and monkeys, the Cmax values ​​after intravenous and subcutaneous administration differed by approximately 3-fold.

[0109] The selected highest dose level of 900 µg / subject still resulted in a safety margin of more than 67-fold based on mg / kg dose calculations, and a safety margin of more than 7 to 19-fold based on extrapolated human Cmax and AUC data.

[0110] 2. Summary of human research

[0111] Research Title

[0112] A multicenter, phase 1b, double-blind, placebo-controlled, single-dose and multiple-escalation-dose study evaluating the safety, tolerability, and efficacy of si-544 in adults with atopic dermatitis.

[0113] Clinical stage: Phase 1b

[0114] Research period

[0115] The study consists of two parts: a single-incremental-dose (SAD) part and a multiple-incremental-dose (MAD) part.

[0116] SAD component: Screening (33 days), single treatment, 7-day safety follow-up.

[0117] MAD component: Screening (33 days), treatment period (4 weeks), follow-up (12 weeks)

[0118] Research objectives and endpoints

[0119] This study consists of a single-escalation-dose (SAD) portion and a multiple-escalation-dose (MAD) portion. Efficacy was assessed only in the MAD portion of the study.

[0120] Table 1: Research Objectives and Endpoints

[0121]

[0122] For all endpoints, the baseline was defined as the last measurement taken before the first administration of the study drug.

[0123] a It depends on the immunophenotyping results of T cell subsets.

[0124] The Scoring of Atopic Dermatitis (SCORAD) is a clinical assessment of the severity (e.g., degree or intensity) of atopic dermatitis developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31; https: / / dermnetnz.org / topics / scorad). SCORAD is a composite score of three components: (A) the BSA involved in AD, (B) the severity of six clinical signs, and (C) the subject-reported components assessing pruritus and reduced sleep. The scores for each component are calculated as follows:

[0125] (A) The percentage of BSA affected by AD in each body part, as explained below:

[0126] Head and neck: 9%; upper limbs: 9% each; lower limbs: 18% each; anterior trunk: 18%; back: 18%; and genitals: 1%.

[0127] The scores of each affected area are summed up, and the total possible score of A (i.e., all areas are affected) is 100 (i.e., 100% BSA).

[0128] (B) The severity of eczema was assessed using a 4-point scale, where 0 = none, 1 = mild, 2 = moderate, and 3 = severe, for each clinical sign: erythema, edema / papules, exudation / crusting, desquamation, lichenification, and dryness. The maximum score for B was 18.

[0129] (C) Subjective rating of symptoms on the visual analog scale from 0 to 10, where 0 is asymptomatic and 10 is the worst possible severity for each symptom of itching and reduced sleep. The highest possible score for C is 20.

[0130] The total score is calculated as follows: A / 5 + 7 × B / 2 + C, where the maximum total score is 103. A score <25 indicates mild AD, a score of 25-60 indicates moderate AD, and a score of 1-103 indicates severe AD.

[0131] Methodology

[0132] This is the first human study of mild to severe AD in multicenter, phase 1b, double-blind, placebo-controlled patients with SAD and MAD in patients receiving si-544.

[0133] This study consisted of two parts (SAD and MAD). In both parts, participants received treatment in cohorts and were randomized within each cohort to receive either si-544 or placebo. Initially, two sentinel participants in each cohort were treated (randomized to placebo or si-544). Other participants were treated only if the investigators assessed that no safety issues had occurred.

[0134] In the SAD portion, 20 eligible subjects were treated in 5 dose cohorts, with 4 subjects in each cohort. Dose levels in cohorts 1 through 5 were 15 µg, 50 µg, 150 µg, 450 µg, and 900 µg si-544 or placebo. Subjects received a single dose on day 1 (starting with the lowest dose cohort), and safety and tolerability were assessed on days 4 and 8.

[0135] Each cohort included two sentinel subjects (randomized 1:1 to placebo and si-544) and two subjects treated with si-544.

[0136] In the MAD portion, eligible subjects received treatment twice weekly for 4 weeks (treatment period). Safety, tolerability, and pharmacokinetics (PK) were assessed during the treatment period. A 12-week follow-up visit was conducted after MAD treatment to assess safety, drug-induced phagocytosis (PD), immunogenicity, and efficacy.

[0137] Each cohort included 2 sentinel subjects (randomized 1:1 to placebo and si-544) and 6 additional subjects (randomized 5:1 to si-544 and placebo).

[0138] Evaluate

[0139] The assessment timeline is provided in Table 2 (SAD section) and Table 3 (MAD section) below.

[0140] Table 2: Assessment Timeline - SAD Section

[0141]

[0142]

[0143] Table 3: Assessment Timeline - MAD Section

[0144]

[0145]

[0146]

[0147] Efficacy and immunogenicity assessment

[0148] Efficacy and immunogenicity analyses were performed in the MAD section.

[0149] Atopic dermatitis score

[0150] As arranged in Table 3, the severity of Alzheimer's disease (AD) was assessed using the Scoring Atopic Dermatitis (SCORAD) score. SCORAD is a composite score of three components: (A) the basis of skin acupoints (BSA) involved in AD, (B) the severity of six clinical signs, and (C) the subject-reported components assessing itching and reduced sleep. The scores for each component are calculated as follows:

[0151] The percentage of BSA affected by AD in each body part is explained as follows:

[0152] o Head and neck: 9%

[0153] o Upper limbs: 9% each

[0154] lower limbs: 18% each

[0155] o Anterior torso: 18%

[0156] o Back: 18%

[0157] o Genitals: 1%.

[0158] The scores of each affected area are summed up, and the total possible score of A (i.e., all areas are affected) is 100 (i.e., 100% BSA).

[0159] The severity of eczema was assessed using a 4-point scale, where 0 = none, 1 = mild, 2 = moderate, and 3 = severe, for each clinical sign: erythema, edema / papules, exudation / crusting, desquamation, lichenification, and dryness. The maximum score for B was 18.

[0160] Subjective ratings of symptoms on the visual analog scale range from 0 to 10, where 0 represents no symptoms and 10 represents the worst possible severity for each symptom, such as itching and decreased sleep. The highest possible score for C is 20.

[0161] The total score is calculated as follows: A / 5 + 7 × B / 2 + C, where the maximum total score is 103. A score <25 indicates mild AD, a score of 25-60 indicates moderate AD, and a score of 61-103 indicates severe AD.

[0162] Body surface area index

[0163] The body surface area index was used to assess the percentage of inflamed skin area relative to the total body surface area (BSA), as arranged in Table 3. The assessment of affected BSAs followed the same rules as in (A) of SCORAD above (BSAs involving AD).

[0164] Anti-drug antibodies

[0165] Serum samples of ADA used to assess immunogenicity were obtained as shown in Table 3.

[0166] Pharmacokinetic and pharmacodynamic evaluation

[0167] General information

[0168] PK analysis is performed in queues 4 and 5 of the SAD section, and PK and PD analysis are performed in the MAD section.

[0169] Sample collection

[0170] Blood samples were collected during the visit for PK and PD analysis. For details on SAD, see Table 2, and for details on MAD, see Table 3.

[0171] Blood samples used for PK assessment were collected at:

[0172] • Before administration: Immediately before IMP injection (i.e., no more than 15 minutes)

[0173] • Post-administration: immediately after IMP injection and at 5, 15, 30 minutes, 1, 2, 4, and 8 hours after IMP injection; Sampling window: ±1 minute for ≤1 hour after injection, ±5 minutes for 2 hours, ±15 minutes for 4 hours, and ±30 minutes for 8 hours after injection.

[0174] On the day of administration, blood samples for PD analysis should be collected up to 15 minutes before IMP injection.

[0175] Bioanalytical methods

[0176] Bioanalysis of Si-544 was performed using a validated high-performance liquid chromatography-tandem mass spectrometry method.

[0177] Pharmacokinetic assessment

[0178] The following PK parameters were calculated based on the plasma concentrations of SAD on day 1 and MAD on days 1 and 25:

[0179] · C max

[0180] • Time to reach maximum concentration (T) max )

[0181] • AUC from 0 to 8 hours, AUC 0-8h

[0182] • AUC from time 0 to the last quantifiable concentration, AUC 0-last

[0183] • AUC from time 0 to infinity 0-∞

[0184] • Terminal elimination rate constant, λ z

[0185] • Apparent terminal elimination half-life, T 1 / 2

[0186] Use Phoenix WinNonlin 6.4 or later to calculate PK parameters.

[0187] Pharmacokinetic assessment

[0188] The following PD assessments were performed using fluorescence-activated cell sorting:

[0189] • T cell count: T CM T EM With regulatory T cells

[0190] • Serum cytokine levels: interferon-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17 and tumor necrosis factor-α

[0191] • Immunophenotyping of T cell subsets, including AD-specific markers CD2, CLA, CD4, CD8, CD45RA, CCR7, CD45RO, Ki67, and optionally (depending on the T cell subset immunophenotyping results) Kv1.3 and KCa3.1

[0192] Security assessment

[0193] Adverse events

[0194] definition

[0195] An AE is any adverse medical event in a subject administering the drug and is not necessarily causally related to the treatment. Therefore, an AE can be any adverse or unexpected sign (e.g., including abnormal laboratory findings), symptom, or illness that is temporally associated with drug use, whether or not it is considered related to IMP. Any worsening of the severity or frequency of a concomitant disease or any new disease diagnosed during the study must be recorded as an AE. A worsening of AD is not considered an AE unless the worsening is clinically significant beyond the usual fluctuations of the disease.

[0196] Significant abnormal laboratory findings in clinical practice are considered adverse events (AEs), but if there is no change compared to baseline values, then abnormal laboratory findings may not be considered AEs.

[0197] All adverse events (AEs) occurring between the signing of the informed consent form and the first IMP injection are defined as “pre-treatment events”.

[0198] All adverse events (AEs) occurring after the first IMP injection are defined as adverse events occurring during treatment.

[0199] A serious adverse event (SAE) is any AE that occurs at any dose, as follows:

[0200] • Caused death

[0201] • Life-threatening

[0202] • Requires hospitalization or extension of existing hospital stay

[0203] • Causes persistent or significant disability or loss of function

[0204] • It is a congenital abnormality or birth defect.

[0205] This is a major medical event.

[0206] Adverse drug reactions (ADRs) are any harmful and unintended responses to a drug that are related to any dose. According to ICH Guideline E2A, an ADR is defined as a reasonable likelihood of a causal relationship between the AE and the IMP.

[0207] Unexpected ADRs are adverse reactions whose nature and severity are inconsistent with the applicable reference document (reference safety information in the investigator's manual).

[0208] Reporting additional important information about the specificity or severity of a known, recorded adverse event (AE) constitutes an unexpected AE. Specific examples include: acute renal failure (as a marker AE), followed by a new report of interstitial nephritis or hepatitis, and then a report of fulminant hepatitis.

[0209] Suspected unintended serious adverse reaction (SUSAR) refers to an unexpected and serious suspected adverse reaction related to IMP. SUSARs will be reported expedited by the regulatory authorities. An unintended AE is defined as a report that adds significant information about the specificity or severity of a known, documented AE. A specific example is acute renal failure (as a marker AE), followed by a new report of interstitial nephritis or hepatitis, followed by a report of fulminant hepatitis.

[0210] Adverse event classification

[0211] causation

[0212] The causal relationship between AE and IMP is assessed as follows:

[0213]

[0214] Severity

[0215] The severity of adverse events (AEs) will be graded according to the National Cancer Institute's Common Acute Respiratory Toxicity Criteria (NCI-CTCAE, version 5.0). If not explicitly defined in the NCI-CTCAE, Table 4 will apply.

[0216] Table 4: Severity Classification of Adverse Events

[0217]

[0218] Ending Category

[0219] The outcome of AE at the last observation will be categorized according to the following scale:

[0220]

[0221] Actions against IMP

[0222] The measures taken against IMP will be assigned to one of the following categories:

[0223]

[0224] Recording of adverse events

[0225] Record all adverse events (AEs) that occur from the time the subject signs the informed consent form (ICF) until the subject completes the study. AEs with verbatim records (matching the terminology listed in NCI-CTCAE version 5.0) are graded according to the specific definitions of severity provided in that list. AEs not listed in the NCI-CTCAE grading system are graded according to the 5-point scale provided in Table 4 above.

[0226] Clinical safety laboratory tests

[0227] Biological samples will be collected for clinical safety laboratory testing and pregnancy testing in women of fertility potential, as shown in Tables 2 and 3. All safety laboratory assessments and parameters are detailed in Table 5.

[0228] Table 5: Laboratory parameters for clinical safety

[0229]

[0230] Vital signs, peripheral blood oxygen saturation, physical examination and electrocardiogram

[0231] Perform vital sign measurements, peripheral blood oxygen saturation, physical examination, and ECG as specified in Tables 2 and 3.

[0232] Vital signs include body temperature, heart rate, respiratory rate, and diastolic and systolic blood pressure. Peripheral blood oxygen saturation is measured using the pulse oximetry method with a finger clip.

[0233] Perform a physical examination and assess any clinically significant abnormalities in the following body systems: general appearance; skin; head and neck, eyes, ears, nose and throat; cardiovascular and pulmonary systems; abdomen; musculoskeletal system; extremities; nervous system (see also the section on neurological examination below); and lymph nodes.

[0234] A 12-lead ECG was recorded (PR interval, QRS interval, QT interval, and QTc[F] interval). Height and weight were assessed during screening, and body mass index was calculated. Weight was also assessed during the MAD (Massage and Disorder) phase.

[0235] Neurological examination

[0236] Perform the following neurological assessments as arranged in Tables 2 and 3:

[0237] Hamstrings and pupillary reflex

[0238] • Motor function

[0239] • Sensory test

[0240] • Romberg test (neurological function for balance):

[0241] The subject is asked to stand upright with feet together and arms close to or crossed in front of their body. First, the subject keeps their eyes open while the examiner assesses body movement relative to balance. Second, the subject stands upright with eyes closed while the examiner observes for any loss of balance within one minute. A positive Romberg test occurs when the subject loses balance with their eyes closed. Loss of balance can be defined as increased body swaying, foot movement in the direction of fall, or a fall.

[0242] • Unterberger test (vestibular pathology):

[0243] The subject is asked to close their eyes, extend their arms, and perform high knees while walking in place for one minute. During the examination, no optical or acoustic stimuli (such as bright light or a ticking clock) are allowed to orient themselves within the room. The examiner observes for any rotations of the subject's body.

[0244] Reproducible leftward or rightward rotation is a pathological finding that leads to involvement of the ipsilateral inner ear or cerebellum (ataxia).

[0245] • Heel walking

[0246] • Walking on tiptoe (ball of foot)

[0247] • Walking in a straight line

[0248] Blind walking

[0249] Standing on one leg

[0250] Dose-limiting toxicity

[0251] Toxicity was assessed according to the National Cancer Institute-General Terminology Criteria for Acute Respiratory Disorders (NCI-CTCAE, version 5.0). If not specifically defined in the NCI-CTCAE, AEs were graded according to their severity (mild, moderate, severe, life-threatening, death, Table 4). If occurring during si-544 treatment, the following AEs were defined as DLTs:

[0252] • ≥ Grade 3 sensory abnormalities

[0253] • ≥3 level of sensory impairment

[0254] • Abnormal vital signs ≥ grade 3 (if different from baseline)

[0255] • Abnormal ECG grade ≥ 3 (if different from baseline)

[0256] • DEC considers any related toxicity level ≥3 to be...

[0257] Dosage selection MAD section

[0258] Based on the incidence of DLT and MTD during si-544 treatment in the SAD phase, DEC recommends dose levels for use in the MAD phase (see Table 6 below).

[0259] Table 6: Dosage Selection MAD Section

[0260]

[0261] Study drugs, dosage cohort, and number of participants

[0262] The Si-544 acetate in the 0.9% NaCl solution was injected subcutaneously into the abdomen.

[0263] • SAD component: Single dose

[0264] MAD component: Multiple doses - twice a week for 4 weeks

[0265] Reference

[0266] Placebo (0.9% NaCl solution), volume and administration as described for the test sample.

[0267] Subject population

[0268] Adults with mild to severe AD

[0269] Inclusion criteria

[0270] SAD section and MAD section

[0271] 1. Subjects are of legal capacity to give consent, are informed of the nature, scope, and relevance of the clinical study, voluntarily agree to participate in the study and its regulations, and formally sign an informed consent form approved by the ethics committee before any study-related procedures.

[0272] 2. Men and women aged 18 to 75 years

[0273] 3. Willing and able to comply with the requirements of the plan.

[0274] 4. Deleted

[0275] 5. Women of childbearing potential must:

[0276] a. The pregnancy test (blood) was negative during screening.

[0277] b. Agree to use and adhere to effective contraceptive control measures continuously for 30 days from screening to the last IMP treatment (with an annual failure rate of less than 1% when used consistently and correctly).

[0278] The reliable methods used in this study include:

[0279] i. Combined hormonal contraceptives (including estrogen and progestin) associated with ovulation suppression (oral, vaginal, transdermal).

[0280] ii. Hormonal contraceptives (oral, injectable, implantable) associated with ovulation suppression and progestin-only methods

[0281] iii. Intrauterine device (IUD)

[0282] iv. Intrauterine hormone-releasing system

[0283] v. Bilateral tubal obstruction

[0284] vi. A sexual partner who has undergone a vasectomy (provided that the partner is the only sexual partner of the fertile woman and that a medical evaluation has been conducted to confirm the success of the surgery).

[0285] vii. Sexual abstinence (defined as avoiding heterosexual intercourse throughout the entire risk period associated with the study treatment). Abstinence is only accepted as true abstinence when it aligns with the subject's preferred and usual lifestyle (cyclical abstinence [such as calendar, ovulation, symptom-basometry, post-ovulation methods, and withdrawal] are not acceptable methods of contraception).

[0286] c. Agree to refrain from breastfeeding during the study and for 90 days after the last IMP treatment.

[0287] Postmenopausal women (without menstruation for at least one year without other medical reasons) or women who are surgically infertile (tubal ligation, hysterectomy, or bilateral oophorectomy) are eligible to enroll.

[0288] 6. Men must also practice genuine abstinence or consent to the use of condoms when having sexual contact with pregnant women or women of childbearing potential until at least 90 days after the last IMP treatment, even after a successful vasectomy.

[0289] SAD section only

[0290] 7. Clinical diagnosis of mild to severe AD

[0291] MAD section only

[0292] 8. Clinical diagnosis of mild to severe AD with SCORAD ≥ 15

[0293] Exclusion criteria

[0294] SAD section and MAD section

[0295] 1. Any changes to standard systemic and topical therapy or immunosuppressive medication within 4 weeks prior to screening (i.e., restart, frequency change, or drug substance change) (for biologics such as dupilumab, no changes to therapy within 12 weeks prior to screening), as determined by the investigator.

[0296] 2. Known allergy history to any component or excipient in the IMP drug formulation.

[0297] 3. Uncontrolled hypertension or uncontrolled diabetes

[0298] 4. History of epileptic seizures

[0299] 5. Presence or history of sensory abnormalities or neuropathy

[0300] 6. Clinically significant ECG abnormalities, such as those determined by the investigator.

[0301] 7. Clinically relevant liver, nervous system, lung, ophthalmological, endocrine, kidney, or other major systemic diseases, as determined by the investigator.

[0302] 8. An acute infection within 7 days prior to screening, as determined by the investigator.

[0303] 9. Known or active Mycobacterium tuberculosis infection

[0304] 10. Known or active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus.

[0305] 11. Schedule vaccinations within 2 weeks prior to screening and / or during the treatment period for the SAD or MAD portion of the disease.

[0306] 12. Pregnancy

[0307] 13. Any findings or medical conditions that would prevent inclusion in the study, as determined by the investigator.

[0308] 14. Currently or previously (within 4 weeks prior to screening) participated in another clinical study of the investigational drug or medical device.

[0309] 15. Known or suspected alcoholism, drug abuse, or medical products

[0310] 16. The sponsor's employees, or the researcher's employees or relatives.

[0311] 17. Use of prohibited medications (see previous medications and concomitant medications below)

[0312] 18. Subjects detained in an institution under an order issued by judicial or administrative authorities.

[0313] 19. Lacking legal capacity or having limited legal capacity

[0314] MAD section

[0315] 20. Those who participated in the SAD portion of this study using IMP administration within 3 months prior to the planned first dose of the MAD portion.

[0316] Previous medications and concomitant medications

[0317] As shown, the following medications and therapies are prohibited during both parts of this study:

[0318] • Changes in therapy using certain biologics such as dupilumab from 12 weeks prior to screening and during the treatment period for both SAD and MAD components.

[0319] • Changes in immunosuppressive therapy from 4 weeks prior to screening and during the treatment periods for SAD and MAD.

[0320] • From 4 weeks prior to screening and during both study phases: use of other investigational drugs or medical devices

[0321] • From 2 weeks prior to screening and during the two-part period of the study: any vaccination

[0322] Statistical methods

[0323] Although no formal sample size calculation was performed, it was considered sufficient to determine safety and tolerability and to evaluate the PK, IMP response and efficacy of si-544, given that there were 4 subjects in each of the SAD cohorts 1 to 5 and 8 subjects in each dose of the MAD cohort.

[0324] 3. Research findings in humans

[0325] 3.1 Results Overview

[0326] IMP (si-544) was well tolerated in the SAD cohort (dose levels for cohorts 1 through 5 were 15 µg, 50 µg, 150 µg, 450 µg, and 900 µg si-544 or placebo, administered subcutaneously). Therefore, in the MAD cohort, dose levels of 450 µg and 900 µg si-544 were used (see also Table 6 above for dose selection for the MAD cohort): each patient (12 patients) received 8 subcutaneous (sc) injections over 4 weeks, and 4 additional patients received placebo. No patients discontinued the study. All patients were closely monitored (e.g., ECG, peripheral oxygen saturation, and neurological safety), and no IMP-related changes were observed. Regarding PK, it is noteworthy that high plasma levels were achieved in both cohorts (450 µg and 900 µg si-544), resulting in near-complete target occupancy. No serious adverse events (AEs) related to si-544 were observed, and no dose reductions or temporary / permanent discontinuation due to SAEs / AEs were observed (i.e., no safety signals and no DLT). Observed AEs were at placebo levels (rare, mild, and transient). Blood tests showed that all treated patients maintained full immune function, e.g., no significant changes in blood cell counts, cytokine expression, or blood chemistry.

[0327] Four weeks after treatment, in the MAD cohort (sc), IMP (si-544) at dose levels of 450 µg and 900 µg delivered clear efficacy signals (SCORAD and BSA). High response rates were observed: 9 out of 12 patients treated with si-544 showed significant improvements in SCORAD and BSA relative to baseline. The first signs of efficacy were observed after 2 weeks of dosing. Improvements in SCORAD and BSA persisted at the end of the study on day 106 (D106), indicating a significantly prolonged duration of action beyond the dosing period.

[0328] Regarding SCORAD, it is worth noting that 3 out of 9 patients showed improvement of >50% (and up to 98%). Figure 1 The reduction in SCORAD relative to baseline is shown for exemplary responders at dose levels of 450 μg and 900 μg. Figure 1 As shown, the duration of action is significantly extended beyond the dosing period.

[0329] Regarding BSA, it is worth noting that 4 out of 9 patients showed an improvement of >85% (almost complete skin clearance). Figure 2 The reduction in BSA relative to baseline is shown in exemplary respondents at dose levels of 450 μg and 900 μg. Figure 2 As shown, the duration of action is significantly extended beyond the dosing period.

[0330] 3.2 Detailed Results

[0331] 3.2.1 Study Subjects

[0332] 3.2.1.1 Subject treatment and analysis dataset

[0333] Of the 50 selected participants, 36 were enrolled (i.e., randomized) and treated with the designated IMP (SAD portion: 15 participants received si-544, 5 received placebo; MAD portion: 12 participants received si-544, 4 received placebo). Participants receiving placebo were included in the data analysis.

[0334] One participant was required to attend both study phases (i.e., the first IMP injection in the MAD phase was 3 months after a single IMP injection in the SAP phase), and was treated with 450 µg si-544 in the SAD phase and 900 µg si-544 in the MAD phase. All (36) randomized participants completed their assigned treatments and studies.

[0335] All 36 enrolled subjects (20 in the SAD portion and 16 in the MAD portion) belonged to both the SAF and PP sets and were classified as primary due to no protocol deviation.

[0336] 3.2.1.2 Demographic and other baseline characteristics

[0337] The demographic summary of SAF is provided in Tables 7 and 8.

[0338] In the SAD section (Table 7), only in the 15 µg and 50 µg si-544 treatment groups were women (70%) more than twice as many as men (30%). All participants were white, not Hispanic or Latino. The median age was 31 years, ranging from 19 to 60 years. The median age was significantly higher in the placebo and 15 µg si-544 treatment groups than in the other treatment groups. BMI varied slightly between treatment groups.

[0339]

[0340] In the MAD section (Table 8), the gender distribution was nearly balanced, with 56.3% male and 43.8% female. All participants, except for one, were white and neither Hispanic nor Latino. The median age was 29 years, ranging from 19 to 49 years. Age and BMI were similar across treatment groups. Based on SCORAD at screening, almost all participants (87.5%) had moderate AD.

[0341]

[0342]

[0343] 3.2.1.3 Medical history and concurrent diseases

[0344] Any medical history and complications are summarized in Tables 9 and 10.

[0345] According to the eligibility criteria, all participants in both study groups had Alzheimer's disease (AD). In addition, the most frequently reported condition in both study groups was immune system disorders (various allergies). Besides, in the SAD group, two participants reported migraines, and in the MAD group, four participants each reported depression and asthma. In any treatment group, at most one participant reported all other conditions.

[0346]

[0347]

[0348] 3.2.1.4 Previous and concomitant therapies

[0349] Tables 11 and 12 summarize the prior medications (i.e., those started within 3 months prior to screening) and concomitant medications taken by at least 2 subjects in any treatment group. Unsurprisingly, for underlying conditions, the most frequently taken medications in both study sections were dermatological corticosteroids and other formulations used to treat AD.

[0350]

[0351]

[0352] 3.2.1.5 Treatment adherence and exposure level

[0353] Exposure level

[0354] All subjects (20) in the SAD portion received a single IMP injection as scheduled. In the MAD portion of the study, 13 of the 16 subjects received all 8 IMP injections as scheduled. One subject in the 450 µg si-544 treatment group missed the day 4 IMP dose due to elevated laboratory results, and two subjects in the 900 µg si-544 treatment group each missed one dose due to missed visits (day 8 and day 22). All three subjects received the remaining 7 doses as scheduled.

[0355] One subject participated in both study phases, receiving a single 450 µg si-544 injection in the SAD phase and eight injections of 900 µg si-544 in the MAD phase.

[0356] Dosage adjustment

[0357] No dosage adjustment is required.

[0358] Measurement of compliance

[0359] No adherence calculations were performed. In both study phases, IMP was administered by investigators at the research center. Three subjects failed to receive the scheduled dose; all other subjects received all planned IMP doses.

[0360] 3.2.2 Safety Evaluation

[0361] The first primary endpoint was the type, frequency, severity, and causality of adverse events (AEs), serious AEs, and deep vein thrombosis (DLTs) during the study. The second primary endpoint was the changes in all assessments of clinical laboratory tests, ECG, vital signs, and peripheral oxygen saturation from baseline to the study period.

[0362] 3.2.2.1 Adverse Events

[0363] 3.2.2.1.1. Brief Summary of Adverse Events

[0364] A summary of TEAEs is provided in Tables 13 and 14. In both study portions, the proportion of subjects reporting events increased with increasing si-544 dose. No serious TEAEs or DLTs were reported in either study portion.

[0365] In the SAD portion, 23 TEAEs were reported among 9 subjects (45%). Four subjects treated with si-544 had TEAEs assessed as IMP-related, while none of the subjects treated with placebo had TEAEs assessed as IMP-related (Table 13). No serious TEAEs were reported.

[0366]

[0367] In the MAD portion, 160 TEAEs were reported in 14 subjects (88%), including 10 TEAEs reported in 3 subjects in the placebo group. Ten subjects (9 treated with si-544 and 1 treated with placebo) had TEAEs assessed as IMP-related (Table 14). The only serious TEAE (depression, unrelated to IMP) was reported in 1 subject in the 900 µg si-544 treatment group.

[0368]

[0369] 3.2.2.1.2. Adverse Event Display

[0370] An overview of TEAEs listed by system organ classification is provided in Tables 15 and 16.

[0371] In the SAD portion, no TEAEs were reported in subjects receiving 15 µg si-544. In other treatment groups, no TEAEs were reported in more than one subject (Table 15).

[0372]

[0373] In the MAD (Management Ailment) component, infection and invasion, as well as systemic symptoms and administration site conditions, were reported by the highest proportion of subjects in the 450 µg si-544 treatment group (3 out of 6 subjects), and infection and invasion, as well as neurological symptoms, were reported by the highest proportion of subjects in the 900 µg si-544 treatment group (5 out of 6 subjects). In the placebo treatment group, gastrointestinal symptoms and infection and invasion were the only systemic organ categories affected in more than one subject (2 out of 4 subjects; Table 16).

[0374]

[0375] 3.2.2.1.3. Adverse Event Analysis

[0376] Severity

[0377] Most of the TEAEs in the SAD portion of the study were Grade 1, with only a few Grade 2 events (in the 150 µg and 450 µg si-544 treatment groups), and no Grade 3 events (Table 17).

[0378]

[0379] In the MAD section, most TEAEs were Grade 1 across all treatment groups, with very few Grade 2 events (Table 18). In the 450 µg si-544 treatment group, one subject experienced both elevated Grade 3 transaminases and elevated Grade 4 serum creatine phosphokinase. These two events were assessed as unrelated to IMP because the subject had begun strenuous exercise and experienced muscle soreness after a prolonged interruption in the preceding days.

[0380] In the 900 µg si-544 treatment group, one subject experienced two grade 3 depressive events, and another subject developed grade 3 nasopharyngitis. These events were considered unrelated to IMP.

[0381]

[0382] Causal relationship assessment

[0383] The causal assessment of TEAEs in the SAD section is summarized in Table 19. Details of the relevant TEAEs are provided in Table 21.

[0384]

[0385] In the MAD section, most TEAEs in the two si-544 treatment groups and 1 out of 10 TEAEs in the placebo treatment group were assessed as being related to IMP (Table 20). Details of the related TEAEs are provided in Table 22.

[0386]

[0387] Related TEAE

[0388] TEAEs associated with IMP are summarized in Tables 21 and 22. In the SAD section, associated TEAEs were reported only in four subjects across three higher-dose si-544 treatment groups (Table 21).

[0389]

[0390] In the MAD component, the si-544 treatment group (9 out of 12 subjects) reported more IMP-related TEAEs than the placebo treatment group (1 out of 4 subjects).

[0391] The only relevant TEAE in the placebo group was a feeling of fever (1 event, which subsided 1 day after onset). Relevant TEAEs in the si-544 group included systemic organ disorders, gastrointestinal disorders, systemic disorders, administration site reactions (mainly injection site reactions), and neurological disorders (Table 22).

[0392] Most injection site reactions (except for 2 hematoma events and 1 erythema event) subsided within minutes or hours after onset. Sensory disturbances were the most frequently reported event (44 events in 5 subjects). All sensory disturbances subsided within minutes to hours after onset.

[0393]

[0394] ending

[0395] In the SAD portion, three TEAEs in two subjects (450 µg si-544: anemia, unrelated; 900 µg si-544: decreased sensation in the feet and cheeks [both in the same subject], related) had not resolved by the end of the study. Subjects with anemia were advised to consult a general practitioner and urologist if necessary. Follow-up information regarding subjects with decreased sensation showed that both events resolved by the end of the study (communicated with the investigator).

[0396] In the MAD component, five TEAEs (900 µg si-544: pulpitis, depression, and insomnia [all in the same subject], spinal pain; placebo: oral leukoplakia; all unrelated) in four subjects did not resolve by the end of the study. Follow-up information regarding subjects with depression and insomnia indicated that they were receiving treatment and were recovering slowly after the study (in communication with the investigators).

[0397] Actions against IMP

[0398] No TEAE in any part of the study led to subjects withdrawing from continued IMP treatment (if applicable) or withdrawing from the study.

[0399] 3.2.2.2 Death, other serious adverse events, and other major adverse events

[0400] 3.2.2.2.1 Death

[0401] No deaths occurred.

[0402] 3.2.2.2.2 Other serious adverse events

[0403] The only serious TEAE reported was grade 3 depression in one subject in the 900 µg si-544 treatment group in the MAD portion. This event was assessed as unrelated to si-544 treatment.

[0404] 3.2.2.2.3 Other major adverse events

[0405] Dose-limiting toxicity

[0406] No TEAEs defined as DLT occurred in either study component.

[0407] TEAEs that led to withdrawal from IMP and / or research

[0408] No cases of TEAE leading to permanent discontinuation or withdrawal from the study of IMP treatment were reported.

[0409] 3.2.2.3 Clinical Laboratory Evaluation

[0410] 3.2.2.3.1 Changes in laboratory values ​​over time

[0411] 3.2.2.3.1.1 Hematology

[0412] In any of the assessment parameters in both study sections, there were no significant differences in changes from baseline between the si-544 and placebo treatment groups.

[0413] 3.2.2.3.1.2 Clinical Chemistry

[0414] In any of the assessment parameters in both study sections, there were no significant differences in changes from baseline between the si-544 and placebo treatment groups.

[0415] 3.2.2.3.1.2 Coagulation and Urine Analysis

[0416] In any of the assessment parameters in both study sections, there were no significant differences in changes from baseline between the si-544 and placebo treatment groups.

[0417] 3.2.2.3.2 Individual Subject Variations

[0418] All subjects with clinically significant abnormal laboratory values ​​at the post-baseline visit had normal or clinically insignificant values ​​at baseline.

[0419] 3.2.2.3.3 Significant individual clinical abnormalities

[0420] Clinically significant abnormal laboratory values ​​reported in the SAD and MAD sections are shown in Tables 23 and 24, respectively. No clinically significant abnormalities in coagulation parameters were reported.

[0421] In the SAD component, five subjects in the si-544 treatment group and one subject in the placebo treatment group had clinically significant abnormal laboratory values, which were reported as TEAEs in all subjects except one (who already had these values ​​at screening). TEAEs in two subjects in the 150 µg si-544 treatment group were assessed as si-544 treatment-related (Table 23). These events resolved within 2 days (hyperkalemia) or 3 days (lymphopenia, elevated C-reactive protein) after onset.

[0422] The DEC discussed clinically significant abnormal hematological values ​​in one subject on day 1 at a special meeting and awaited day 4 results before administering the drug to the next subject. Since these values ​​were within the normal range, administration was initiated (see the DEC recommendation table).

[0423]

[0424] In the MAD component, four subjects in the si-544 treatment group and one subject in the placebo treatment group had clinically significant abnormal laboratory values, which were reported as TEAEs in all subjects. None of these were assessed as being related to IMP treatment (Table 24).

[0425]

[0426] 3.2.2.4 Electrocardiogram, vital signs, and peripheral blood oxygen saturation

[0427] 3.2.2.4.1 Electrocardiogram

[0428] In either the SAD or MAD portion, no subjects' ECGs were assessed as clinically abnormal.

[0429] 3.2.2.4.2 Vital signs

[0430] In either the SAD or MAD portion, no subjects had clinically significant abnormalities as assessed.

[0431] 3.2.2.4.3 Peripheral blood oxygen saturation

[0432] Table 25 summarizes the absolute values ​​for the SAD portion, and Table 26 summarizes the absolute values ​​for the MAD portion. No significant changes in mean peripheral oxygen saturation were observed before or after IMP injection on day 1 of the SAD portion, or during follow-up, or in the MAD portion from before to after IMP injection on the treatment day, or during follow-up.

[0433]

[0434]

[0435] 3.2.2.5 Other safety parameters

[0436] 3.2.2.5.1 Physical Examination

[0437] In both study portions, most bodily systems were assessed as normal. All subjects presented with clinically significant skin abnormalities due to AD at screening. Most other clinically significant abnormalities were present at screening. Six subjects in the MAD portion had clinically significant findings not present at screening, reported as the following TEAEs: five subjects treated with si-544 had muscle soreness (2 subjects), nasopharyngitis, joint swelling, and ligament sprains; one subject treated with placebo had oral leukoplakia, rhinitis, and bronchitis. None of these events were related to IMP.

[0438] 3.2.2.5.1 Neurological examination

[0439] The only abnormal finding (clinically significant sensory impairment) in one subject in the 900 µg si-544 treatment group for the SAD portion was present at screening.

[0440] 3.2.2.6 Security Summary

[0441] SAD section

[0442] • 23 TEAEs were reported in 9 subjects (45%), 2 TEAEs were reported in 1 subject treated with placebo, and 21 TEAEs were reported in 8 subjects treated with si-544.

[0443] • All TEAEs are either Level 1 or Level 2.

[0444] • Neither DLT nor serious TEAE was reported.

[0445] • In the higher-dose si-544 treatment group, four subjects reported IMP-related TEAEs (two in the 150 µg treatment group, and one each in the 450 µg and 900 µg treatment groups), while no such reports were found in the placebo treatment group.

[0446] • Two subjects in the 150 µg si-544 treatment group had clinically significant abnormal laboratory values, which were reported as TEAEs (hyperkalemia; lymphopenia; elevated C-reactive protein) assessed as being related to si-544 treatment.

[0447] No clinically significant abnormalities were observed in ECG or vital signs. Peripheral oxygen saturation did not change significantly from baseline in either treatment group.

[0448] • No clinically significant abnormalities not present at the time of screening were reported during physical or neurological examination.

[0449] MAD section

[0450] • 160 TEAEs were reported in 14 subjects (88%), 10 TEAEs were reported in 3 subjects treated with placebo, and 150 TEAEs were reported in 11 subjects treated with si544.

[0451] Most treatment-associated adverse events (TEAEs) were Grade 1 or 2; in the 450 µg si-544 treatment group, one subject experienced one Grade 3 event (elevated transaminases) and one Grade 4 event (elevated serum creatine phosphokinase). In the 900 µg si-544 treatment group, two subjects experienced Grade 3 events (depression and nasopharyngitis). Neither Grade 3 nor Grade 4 events were associated with si-544 treatment.

[0452] The only serious TEAE (depression, unrelated to IMP) was reported in one subject in the 900 µg si-544 treatment group.

[0453] • Infections and invasions, as well as systemic symptoms and administration site conditions, were reported by the highest proportion of subjects in the 450 µg si-544 treatment group (3 out of 6 subjects), and infections and invasions, as well as neurological symptoms, were reported by the highest proportion of subjects in the 900 µg si-544 treatment group (5 out of 6 subjects). In the placebo treatment group, gastrointestinal symptoms and infections and invasions were the only systemic organ categories affected in more than one subject (2 out of 4 subjects).

[0454] • Nine out of twelve subjects treated with si-544 and one out of four subjects treated with placebo experienced treatment-associated adverse events (TEAEs) that were assessed as IMP-related. Related TEAEs in the si-544 group included gastrointestinal symptoms, systemic symptoms, and administration site reactions (primarily administration site reactions), as well as neurological symptoms.

[0455] • Sensory abnormalities were the most frequently reported TEAEs following si-544 treatment (44 events in 5 subjects).

[0456] • No subjects had laboratory values ​​that were reported as clinically significant abnormalities in TEAEs assessed as IMP-related.

[0457] No clinically significant abnormalities were observed in ECG or vital signs. Peripheral oxygen saturation did not change significantly from baseline in either treatment group.

[0458] • Six subjects had clinically significant physical findings reported as TEAEs (five subjects received si-544 treatment and one subject received placebo), none of which were related to IMP.

[0459] No clinically significant abnormalities were reported during neurological examination.

[0460] 3.2.3 Pharmacokinetics, pharmacodynamics, efficacy and other evaluations

[0461] 3.2.3.1 Pharmacokinetics and Pharmacodynamics

[0462] 3.2.3.1.1 Relationship between drug dosage, drug concentration, and response

[0463] 3.2.3.1.1.1 Plasma concentration of free Si-544

[0464] In the SAD portion, plasma concentrations of free si-544 were measured on day 1 in the 450 µg and 900 µg si-544 treatment groups, and in the MAD portion, on day 1 and day 25 in both si-544 treatment groups.

[0465] In both study portions, free si-544 concentrations were below the limit of quantitation (5 ng / mL) both before and after administration. A small number of subjects (1 in the SAD portion and 2 in the MAD portion) achieved first detectable concentrations at 5 minutes post-administration, but the detectable concentration window was generally short for most subjects. Table 27 summarizes the free si-544 plasma concentrations at 15 minutes post-administration.

[0466] In the SAD component, the mean si-544 plasma concentration in both treatment groups was highest 1 hour after injection.

[0467] In the MAD (Multiple Injections of si-544) component, on Day 1, the mean si-544 plasma concentration was highest 30 minutes post-injection in the 450 µg group and highest 1 hour post-injection in the 900 µg group. On Day 25 (i.e., after multiple si-544 injections), the mean si-544 plasma concentration was highest 1 hour post-injection in the 450 µg group and highest 30 minutes post-injection in the 900 µg treatment group.

[0468]

[0469] 3.2.3.1.1.2 Pharmacokinetic parameters

[0470] PK parameters are summarized in Table 28. In both study sections, the geometric mean Cp in the 450 µg si-544 treatment group was...max The C in the approximately 900 µg si-544 treatment group max Half of the median T values ​​across all treatment groups and all assessment time points. max Approximately 1 hour. Total Si-544 exposure (AUC) in the 900 µg treatment group. 0-last The efficacy was 3-4 times that of the 450 µg treatment group.

[0471]

[0472]

[0473] 3.2.3.1.1.3 Dosage Proportionality

[0474] In the SAD section, use approximately 1 AUC. 0-last and C max The slope and dose proportionality can be calculated (Table 29).

[0475]

[0476] 3.2.3.1.2 Pharmacodynamics

[0477] 3.2.3.1.2.1 T cell subsets

[0478] A summary of CD2+ lymphocyte and T cell subsets is shown in Table 30. No significant changes in CD2+ lymphocyte counts from baseline were observed, with no significant differences between treatment groups.

[0479] For the following T cell subsets and time points, differences in mean and median between si-544 and placebo treatments were observed:

[0480] The si-544 treatment group showed an increase from baseline, while the placebo treatment group showed a decrease from baseline.

[0481] Day 29: CD2+ CD4- CD8+ CCR7+ CD45RA+

[0482] Day 106:

[0483] o CD2+ CD4+ CD8-

[0484] o CD2+ CD4+ CD8- CCR7+ CD45RA+

[0485] The si-544 treatment group showed a decrease from baseline, while the placebo treatment group showed an increase or no change from baseline.

[0486] Day 29

[0487] o CD2+ CD4- CD8+ CCR7- CD45RA- (450 µg si-544 only; 900 µg si-544: no change from baseline)

[0488] o CD2+ CD4- CD8+ Ki-67+ (placebo showed no change from baseline)

[0489] Day 106

[0490] o CD2+ CD4- CD8+

[0491] o CD2+ CD4- CD8+ CCR7- CD45RA+

[0492] o CD2+ CD4- CD8+ Ki-67+

[0493] o CD2+ CD45RO+ CLA+

[0494] However, only two subjects in the placebo group had available day 1 data to calculate the change from baseline.

[0495]

[0496]

[0497]

[0498] 3.2.3.1.2.2 Serum cytokines

[0499] Biomarkers were assessed only in the MAD portion of the study. Table 31 summarizes descriptive statistics of baseline serum cytokine levels and changes from baseline for measurable parameters in >1 subjects. IL-8 and TNF-α were the only parameters in which all subjects had values ​​above LLOQ at all visits.

[0500] IL-1β, IL-2, IL-4, IL-12, IL-13, and IL-17A are undetectable (i.e. below LLOQ) in most (IL-1β) or all subjects (IL-2, IL-4, IL-12, IL-13, and IL-17A).

[0501] Compared with baseline, median IFN-γ levels were decreased on day 29 in both the 450 µg and 900 µg si-544 treatment groups, while a slight increase was observed in the placebo group. During follow-up, the decreased median (and mean) IFN-γ levels were maintained in the 450 µg si-544 treatment group.

[0502] In contrast, TNF-α and IL-8 levels were elevated in the 450 µg group and at all post-baseline visits in the 900 µg si-544 treatment group on day 29, but decreased at all post-baseline visits in the placebo group. However, inter-subject variability was high for all parameters.

[0503] No significant trends or differences in IL-6 and IL-10 were observed between treatment groups.

[0504]

[0505]

[0506] 3.2.3.2 Immunogenicity

[0507] Immunogenicity was assessed by anti-drug antibody titers. One subject in the 900 µg si-544 treatment group had a titer of 80 ng / mL on day 29. All other subjects assessed had negative titers on days 1 and 29.

[0508] 3.2.3.3 Efficacy Results

[0509] Secondary efficacy was assessed only in the MAD portion of the study.

[0510] 3.2.3.3.1 Secondary efficacy endpoint

[0511] 3.2.3.3.1.1 Body Surface Area Index

[0512] The inflamed skin area was assessed as a percentage of total BSA using body surface area index (BSA). A summary of BSA is shown in Table 32. At baseline, the mean affected BSA (with approximately 9% BSA) in the 900 µg si-544 group was significantly lower than that in the 450 µg si-544 group and the placebo group (19% and 24%, respectively). After 4 weeks of treatment (day 29), BSA improved in all treatment groups. The improvements in the 450 µg and 900 µg si-544 treatment groups (with BSA reductions of 9% and 12%, respectively) were less than those in the placebo group (a 29% reduction). During follow-up, BSA further decreased to similar levels in both si-544 treatment groups. The highest improvement was observed in the placebo group, which is likely due to pre-existing differences at baseline (e.g., acute exacerbations).

[0513]

[0514] 3.2.3.3.1.2 Severity of Atopic Dermatitis

[0515] The severity of Alzheimer's disease (AD) is assessed using the SCORAD, which includes the following three domains: disease severity assessed using the body surface area index, disease intensity assessed using the eczema severity score, and subjective symptom score.

[0516] Eczema severity scores are summarized in Table 33. At baseline, eczema severity was slightly higher in the 450 µg si-544 treatment group than in the 900 µg si-544 treatment group, with the highest severity observed in the placebo group. After 4 weeks of treatment (day 29), eczema severity decreased in both si-544 treatment groups, and this improvement was maintained throughout the follow-up period. A similar trend was observed in the placebo group.

[0517]

[0518] Total subjective symptom scores are summarized in Table 34. At baseline, the mean subjective symptom score in the 900 µg si-544 treatment group was slightly lower than that in the 450 µg si-544 and placebo treatment groups. During treatment, subjective symptoms improved in all treatment groups, and this improvement was maintained during the follow-up period.

[0519] For individual symptoms, no significant trend of reduced sleep was observed, but itching appeared to improve over time in all treatment groups.

[0520]

[0521] Total SCORAD scores are summarized in Table 35 by absolute score and in Table 36 by category. SCORAD showed improvement in AD severity in all treatment groups. Treatment with 450 µg si-544 showed a higher improvement from baseline of up to 36% compared to treatment with 900 µg si-544 (relative improvement up to 21% from baseline), but no significant difference compared to treatment with placebo (relative improvement up to 41%; Table 35). The proportion of subjects with mild AD increased over time in all three treatment groups (Table 36).

[0522]

[0523]

[0524] 3.2.3.3.2 Subgroup Analysis

[0525] Subgroup analysis was not performed.

[0526] 3.2.3.4 Statistical problems encountered during the analysis

[0527] No statistical problems were found in the study.

[0528] 3.2.3.5 Summary of Pharmacokinetics, Pharmacodynamics, Efficacy and Other Evaluations

[0529] • Free Si-544 plasma concentrations were measurable starting 5 minutes after administration, with median T values ​​in both study portions. max For about 1 hour

[0530] The SAD section shows C max and AUC 0-last Dosage proportionality

[0531] • Partial T-cell subset analysis of MAD showed no significant change in CD2+ lymphocyte count from baseline, with no significant difference between treatment groups.

[0532] • On day 29, IFN-γ levels decreased in both si-544 treatment groups, remained stable during follow-up in the 450 µg si-544 treatment group, while IFN-γ levels increased from baseline in the placebo treatment group.

[0533] Compared with baseline, TNF-α and IL-8 levels were increased at all post-baseline visits in the 450 µg si-544 treatment group and at the post-baseline visit on day 29 in the 900 µg si-544 treatment group, while TNF-α and IL-8 levels were decreased at all post-baseline visits in the placebo treatment group.

[0534] • Cytokine levels varied considerably among subjects, and some cytokines were undetectable (i.e. below LLOQ) in most (IL-1β) or all subjects (IL-2, IL-4, IL-12, IL-13, and IL-17A).

[0535] • All subjects (except one subject in the 900 µg si-544 treatment group on day 29) had negative antidrug antibody titers on both day 1 and day 29.

[0536] • Compared with baseline, AD severity assessed by the affected BSA and SCORAD in the MAD section improved in all treatment groups, with no significant difference between si-544 and placebo treatment.

[0537] 3.2.4. Discussion and Overall Conclusion

[0538] Summary and discussion

[0539] This study is a multicenter, phase 1b, double-blind, placebo-controlled, FIH study of mild to severe AD in subjects receiving si544. The target indication is AD, a multifaceted, chronic, relapsing inflammatory skin condition affecting 15% to 20% of children and 1% to 3% of adults worldwide (Bieber, 2008; Berke, 2012; Drucker, 2017; Nutten, 2015; Eichenfield, 2014). A hallmark of the disease is severe itching (Furue, 2015; Tominag, 2014). In addition to pronounced itching and dry skin, eczema is seen across different body surface areas, with other clinical features such as exudation or crusting, and lichenification, where the skin becomes thickened and leathery (Frazier, 2020).

[0540] Current treatment options for Alzheimer's disease (AD) include topical glucocorticoids and calcineurin and phosphodiesterase-4 inhibitors, systemic immunosuppressive therapy or phototherapy, and biologics (Wollenberg, 2018 May; Ferrucci, 2023; Plant 2021).

[0541] The aim of this study was to evaluate the safety and tolerability, PK, PD, immunogenicity and efficacy of si-544 in adults with AD.

[0542] All 36 participants who were randomized to receive either si-544 or placebo completed the trial, with 20 participants in the SAD portion and 16 participants in the MAD portion.

[0543] In the SAD segment, more women (70%) were treated than men (30%), while in the MAD segment, the gender ratio was more balanced (women: 44%, men: 56%). However, since more women are affected by AD, the gender distribution follows the reported gender distribution of AD (Holm, 2004).

[0544] The primary endpoint of this study focused on the safety and tolerability of the treatment. si-544 was demonstrated to be safe and well-tolerated. No dose-related injuries (DLTs) were reported in the SAD portion, and therefore, all dose cohorts were treated as planned. No treatment-associated adverse events (TEAEs) meeting the definition of DLT were reported during the MAD portion following the two highest doses of treatment in the SAD portion (450 µg and 900 µg si-544). All reported TEAEs considered to be related to si-544 treatment were Grade 1 or 2, including those without serious consequences. TEAEs assessed as related to treatment with si-544 were primarily injection site reactions, most of which subsided within minutes or hours of onset.

[0545] In the MAD component, sensory abnormalities were the most frequently reported treatment-related adverse events (TEAEs) assessed as being associated with treatment with si-544 (44 events in 5 subjects). This was also the most common treatment-related AE in a phase 1b trial of another Kv1.3 channel inhibitor, dalazatide, and thus supports the mode of action of si-544 (Tarcha, 2017).

[0546] In the SAD component, two subjects had clinically significant abnormal laboratory values ​​3 days after treatment with 150 µg si-544. All events resolved within 2–3 days of onset and had no effect on dose escalation. No other clinically significant abnormalities were reported in laboratory values, ECG, vital signs, or physical or neurological examinations after treatment in either the SAD or MAD component.

[0547] Secondary endpoint analyses assessing T-cell subsets did not reveal any significant changes from baseline in CD2+- lymphocyte counts across any treatment group.

[0548] Evaluation of IFN-γ showed a decrease from baseline after treatment with si-544, while an increase was observed in the placebo group, suggesting that si-544 may reduce the inflammatory response associated with AD severity by inhibiting IFN-γ (Belpaire, 2022; Kopitar-Jerala, 2017; Zhang, 2007).

[0549] AD severity, assessed by affected BSA and SCORAD, showed improvement in all treatment groups. Because this study was not statistically capable of providing a statistically significant efficacy result, no statistically significant difference was achieved between si-544 and placebo. The primary objective of this Phase 1b study was to demonstrate the safety and tolerability of si-544, which was achieved. Furthermore, it demonstrated initial efficacy signals.

[0550] in conclusion

[0551] Si-544 is safe and well-tolerated.

[0552] · PK data shows C in the SAD section max and AUC 0-last Expected dose proportionality

[0553] • Si-544 showed its first efficacy signal in subjects with Alzheimer's disease (AD).

[0554] Example 2 - A multicenter, phase 1b, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of si-544 in adults with psoriasis vulgaris or psoriatic arthritis.

[0555] Summary of research

[0556] Research period

[0557] Screening (33 days), treatment period (4 weeks), follow-up (12 weeks)

[0558] Table 3: Research Objectives and Endpoints

[0559]

[0560]

[0561] method

[0562] This is an ongoing, multicenter, phase 1b, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of si-544 in adults with mild to severe Ps or PsA.

[0563] Eligible subjects were randomized 3:1 within each indication to receive either 900 µg si-544 or placebo and to receive the investigational drug (IMP) twice weekly for 4 weeks (treatment period). Safety and tolerability, pharmacokinetics (PK), drug-promoting effects (PD), immunogenicity, and efficacy were assessed during treatment. Follow-up visits (FU) were conducted at day 29 (week 5; end of treatment, EoT), week 8, week 12, and week 16 (end of study, EoS) (i.e., 12 weeks after the treatment period) to assess safety, PD, immunogenicity, and efficacy.

[0564] Once a participant is randomized, they are considered enrolled. Participants who terminate their participation before receiving 75% of the planned IMP injection (i.e., before day 18) are replaced. Participants who terminate their participation after receiving at least 75% of the planned IMP injection (i.e., after day 18) are not replaced.

[0565] Test products

[0566] Test sample

[0567] 900 µg of Si-544 acetate in 0.9% NaCl solution was injected subcutaneously into the abdomen.

[0568] Reference

[0569] Placebo (0.9% NaCl solution), administered subcutaneously into the abdomen.

[0570] Subject population

[0571] Adults with mild to severe Ps and / or PsA

[0572] Inclusion criteria

[0573] General inclusion criteria

[0574] 1. Participants must be of legal capacity to consent, be informed of the nature, scope, and relevance of the clinical study, voluntarily agree to participate and the study regulations, and formally sign an informed consent form approved by the ethics committee before any study-related procedures are conducted.

[0575] 2. Men and women aged 18 to 75 years

[0576] 3. Willing and able to comply with the requirements of the plan.

[0577] 4. Women of childbearing potential must:

[0578] a. The pregnancy test (blood) was negative during screening.

[0579] b. Agree to use and adhere to highly effective contraceptive methods continuously from screening to 30 days after the last IMP treatment (with an annual failure rate of less than 1% if used correctly).

[0580] The reliable methods used in this study include:

[0581] i. Combined hormonal contraceptives (including estrogen and progestin) associated with ovulation suppression (oral, vaginal, transdermal).

[0582] ii. Hormonal contraceptives (oral, injectable, implantable) associated with ovulation suppression and progestin-only methods

[0583] iii. Intrauterine device (IUD)

[0584] iv. Intrauterine hormone-releasing system

[0585] v. Bilateral tubal obstruction

[0586] vi. A sexual partner who has undergone a vasectomy (provided that the partner is the only sexual partner of the fertile woman and that a medical evaluation has been conducted to confirm the success of the surgery).

[0587] vii. Abstinence (the condition is defined as avoiding heterosexual intercourse throughout the entire risk period associated with the study treatment) Abstinence is only accepted as true abstinence: when this is consistent with the subject’s preferred and usual lifestyle (cyclical abstinence [such as calendar, ovulation, sympathobasic temperature method, post-ovulation method and withdrawal] is not an acceptable method of contraception).

[0588] c. Agree to discontinue breastfeeding during the study and for 90 days after the last IMP treatment.

[0589] Postmenopausal women (without menstruation for at least one year without other medical reasons) or women who are surgically infertile (tubal ligation, hysterectomy, or bilateral oophorectomy) are eligible to enroll.

[0590] 5. For at least 90 days after the last IMP treatment, even after a successful vasectomy, the man must agree to practice true abstinence or use a condom when having sexual contact with a pregnant woman or a woman of childbearing potential.

[0591] Disease-specific inclusion criteria

[0592] 6. Inadequate response or intolerance to prior or current treatment with conventional disease-modifying antirheumatic drugs (cDMARDs).

[0593] Ps-specific inclusion criteria

[0594] 7. Ps diagnosed at least 3 months prior to screening.

[0595] 8. Active Ps involving ≥3% of body surface area (BSA) and having at least one psoriatic plaque (excluding nail / fingernail changes).

[0596] PsA-specific inclusion criteria

[0597] 7. PsA diagnosed at least 3 months prior to screening.

[0598] 8. Diagnosed as active Pseudomonas aeruginosa with at least one psoriatic plaque (different from nail / fingernail changes).

[0599] 9. Active PsA is defined as...

[0600] a. ≥1 tender joint out of 68 assessed joints, and

[0601] b. ≥1 swollen joint out of 66 assessed joints (digital / toe inflammation is counted as 1 joint each), and

[0602] c. Negative results for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies.

[0603] Exclusion criteria

[0604] Ps specific exclusion criteria

[0605] 1. Drug-induced psoriasis

[0606] PsA-specific exclusion criteria

[0607] 1. Late-stage PsA with joint deformities

[0608] Medical history and comorbidity exclusion criteria

[0609] 2. Known allergy history to any component or excipient in the IMP drug formulation.

[0610] 3. Uncontrolled hypertension or uncontrolled diabetes

[0611] 4. History of epileptic seizures

[0612] 5. Presence or history of sensory abnormalities or neuropathy

[0613] 6. Clinically significant ECG abnormalities, such as those determined by the investigator.

[0614] 7. Clinically relevant liver, nervous system, lung, ophthalmological, endocrine, kidney, or other major systemic diseases, as determined by the investigator.

[0615] 8. Based on the researcher's assessment, an acute infection occurred within 7 days prior to screening and on day 1, as determined by the researcher.

[0616] 9. Known or active Mycobacterium tuberculosis infection and / or positive Tbc-IGRA results at the time of screening.

[0617] 10. Known or active infection with HIV, hepatitis B virus, or hepatitis C virus.

[0618] 11. Any findings or medical conditions that would prevent inclusion in the study, as determined by the investigator.

[0619] 12. Known or suspected alcoholism, drug abuse, or medical products

[0620] Therapy Exclusion Criteria

[0621] 13. Any changes to standard systemic and topical therapy or immunosuppressive drug therapy (i.e., changes in initiation, frequency, or drug substance) of Ps or PsA within 4 weeks prior to screening (for biologics such as Cosentyx and Humira, no changes in therapy within 12 weeks prior to screening), as determined by the investigator.

[0622] 14. Any other indication (such as cardiovascular disease) where the standard systemic therapy is altered (i.e., the start date, frequency, or substance of the medication is changed).

[0623] 15. Vaccinations scheduled within 2 weeks prior to screening and / or during the treatment period.

[0624] 16. Currently or previously (within 4 weeks prior to screening) participated in another clinical study using IMP or a medical device.

[0625] General exclusion criteria

[0626] 17. The sponsor's employee, or the researcher's employee or relative.

[0627] 18. Detained in an institution by order of judicial or administrative authorities.

[0628] 19. Lacking legal capacity or having limited legal capacity

[0629] Previous medications and combined medications

[0630] Any medications taken during screening and planned for use during the study should be kept at a stable dose. From screening until the end of the study period (EoS), changes to the dose of concomitant medications or initiation of new medications are prohibited.

[0631] Research Evaluation

[0632] Demographic and baseline characteristics

[0633] • Demographic data (gender, age, race, ethnicity, fertility status)

[0634] • Weight, height, and body mass index

[0635] • Medical history

[0636] · Serology

[0637] Body surface area

[0638] Security

[0639] • Adverse events

[0640] Safety Laboratory

[0641] Physical and neurological examinations

[0642] ECG, vital signs, and peripheral blood oxygen saturation

[0643] • Pregnancy test (only for women of childbearing potential)

[0644] Pharmacokinetics

[0645] Blood was collected for analysis of Si-544 PK in plasma.

[0646] Pharmacodynamics

[0647] Blood collection for the following PD analyses:

[0648] • Fluorescently activated cell sorting: Immunophenotyping of the number of central memory T cells, effector memory T cells, and regulatory T cells in peripheral blood, as well as T cell subsets.

[0649] Serum cytokine levels

[0650] effect

[0651] • Disease activity (Visual Analog Scale [VAS])

[0652] • PASI (including photos of the affected body areas, if the subject consents)

[0653] · PGA

[0654] • For Ps only:

[0655] o DLQI

[0656] • Optional only for PsA:

[0657] o PsAQoL

[0658] o Pain (VAS)

[0659] o TJC-68 / SJC-66

[0660] Immunogenicity

[0661] Anti-drug antibodies

[0662] Statistical methods

[0663] Formal sample size calculations were not performed for the primary endpoint.

[0664] In each indication, subjects will be randomly assigned in a 3:1 ratio to receive either si-544 or placebo.

[0665] The planned analysis is exploratory in nature and does not involve any formal statistical hypothesis testing. Descriptive analyses of all endpoints will be performed using standard statistical methods. Statistical tests may be conducted to examine differences in PASI response rates between treatments. Subgroup analyses for different indications may be performed, if applicable.

[0666] Final data analysis will be conducted after all participants have completed the study. A blinded data review meeting will be held prior to hard-locking the database to assess any protocol deviations and to assign participants to the analysis set.

[0667] A blinded data analysis of 29 psoriasis patients revealed the first efficacy signal ( Figure 3 Subjects received either si-544 or placebo twice weekly for 4 weeks (treatment period), with the last day of treatment being day 25. PASI was evaluated on days 1, 15, and 29 (4 days after the last treatment). Figure 3The table shows the normalized PASI values ​​of the 29 participants in the study. These values ​​are normalized to D1, and subsequent changes (Dx vs. D1) are presented as percentages. A value >0% indicates deterioration, and a value <0% indicates improvement. Each line represents a single participant. Furthermore, Figure 3 The gray squares are shown, representing the range of efficacy of dalazatide during comparison (Tarcha, 2017, improvement in the range of -14% to -35%). Subjects in this clinical study achieved higher improvements (e.g., Figure 3 As shown, significantly lower than -35%), this indicates significantly better efficacy (as described in Tarcha, 2017).

[0668] References

[0669] Belpaire A, van Geel N, Speeckaert R. From IL-17 to IFN-γ ininflammatory skin disorders: Is transdifferentiation a potential treatment target? Frontiers in Immunology. 2022;13.

[0670] Berke R, Singh A, Guralnick M. Atopic dermatitis: an overview. Am FamPhysician. 2012;86(1):35-42.

[0671] Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483-94.

[0672] Chandy KG, Norton RS. Peptide blockers of Kv1.3 channels in T cells as therapeutics for autoimmune disease. Curr Opin Chem Biol. 2017;38:97-107

[0673] Chiang EY, Li T, Jeet S, Peng I, Zhang J, Lee WP, et al. Potassiumchannels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions. Nat Commun. 2017;8:14644.

[0674] Drucker AM, Wang AR, Li WQ, Sevetson E, Block JK, Qureshi AA. TheBurden of Atopic Dermatitis: Summary of a Report for the National EczemaAssociation. J Invest Dermatol. 2017;137(1):26-30.

[0675] Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, SimpsonEL, et al. Guidelines of care for the management of atopic dermatitis:section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol.2014;70(2):338-51.

[0676] Ferrucci SM, Tavecchio S, Marzano AV, Buffon S. Emerging SystemicTreatments for Atopic Dermatitis. Dermatol Ther (Heidelb). 2023;13(5):1071-81.

[0677] Frazier W, Bhardwaj N. Atopic Dermatitis: Diagnosis and Treatment. AmFam Physician. 2020;101(10):590-598.

[0678] Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with anew retinoid. Dermatologica. 1978;157(4):238-44.

[0679] Furue M, Kadono T. New therapies for controlling atopic itch. JDermatol. 2015 Sep;42(9):847-50.

[0680] Guttman-Yassky E, Hanifin JM, Boguniewicz M, Wollenberg A,Bissonnette R, Purohit V, et al. The role of phosphodiesterase 4 in thepathophysiology of atopic dermatitis and the perspective for its inhibition.Exp Dermatol. 2019 Jan;28(1):3-10.

[0681] Holm EA, Esmann S, Jemec GB. Does visible atopic dermatitis affectquality of life more in women than in men? Gend Med. 2004;1(2):125-30.

[0682] Hu T, Buus TB, Krejsgaard T, Nansen A, Lundholt BK, Spee P, et al.Expression and function of Kv1.3 channel in malignant T cells in Sézarysyndrome. Oncotarget.

[0683] 2019;10(47):4894-4906.

[0684] Kessler TR. Treating patients with moderate-to-severe psoriasisvulgaris. JAAPA. 2022 Mar 1;35(3):28-35.

[0685] Kopitar-Jerala N. The Role of Interferons in Inflammation andInflammasome Activation. Frontiers in Immunology. 2017;8.

[0686] Kowalska-Olędzka E, Czarnecka M, Baran A. Epidemiology of atopicdermatitis in Europe. J Drug Assess. 2019 Jun 12;8(1):126-128.

[0687] Nutten S. Atopic dermatitis: global epidemiology and risk factors.Ann Nutr Metab. 2015;66 Suppl 1:8-16.

[0688] Ogdie A, Coates LC, Gladman DD. Treatment guidelines in psoriaticarthritis. Rheumatology (Oxford). 2020 Mar 1;59(Suppl 1):i37-i46.

[0689] Plant A, Ardern-Jones MR. Advances in atopic dermatitis. Clin Med(Lond). 2021;21(3):177-81.

[0690] Tarcha EJ, Olsen CM, Probst P, Peckham D, Muñoz-Elías EJ, Kruger JG,Iadonato SP. Safety and pharmacodynamics of dalazatide, a Kv1.3 channelinhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial.PLoS One. 2017 Jul 19;12(7):e0180762.

[0691] Tominaga M, Takamori K. Itch and nerve fibers with special referenceto atopic dermatitis: therapeutic implications. J Dermatol. 2014 Mar;41(3):205-12.

[0692] Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M,Fink-Wagner A, et al. Consensus-based European guidelines for treatment ofatopic eczema (atopic dermatitis) in adults and children: part I. J Eur AcadDermatol Venereol. 2018 May;32(5):657-682. doi: 10.1111 / jdv.14891. Erratumin: J Eur Acad Dermatol Venereol. 2019 Jul;33(7):1436.

[0693] Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. J Eur AcadDermatol Venereol. 2018 Jun;32(6):850-878.

[0694] Zhang J. Yin and yang interplay of IFN-gamma in inflammation and autoimmune disease. J Clin Invest. 2007;117(4):871-3.

[0695] Severity scoring of atopic dermatitis: the SCORAD index. ConsensusReport of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.

[0696] List of implementation plans:

[0697] 1. A pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1), the composition being used in a method of treating psoriasis vulgaris (Ps) and / or improving Ps-related parameters, wherein the pharmaceutical composition is administered in a dose equivalent to about 0.15 mg to about 1.5 mg of an acetate of the peptide.

[0698] 2. The pharmaceutical composition for use according to embodiment 1, wherein the pharmaceutical composition is administered at a dose equivalent to about 0.45 mg of the acetate of the peptide.

[0699] 3. The pharmaceutical composition for use according to embodiment 1, wherein the pharmaceutical composition is administered at a dose equivalent to about 0.9 mg of the acetate of the peptide.

[0700] 4. The pharmaceutical composition for use according to any one of embodiments 1 to 3, wherein the pharmaceutical composition is applied three times a week, twice a week, or once a week.

[0701] 5. The pharmaceutical composition for use according to any one of embodiments 1 to 3, wherein the pharmaceutical composition is applied twice a week.

[0702] 6. The pharmaceutical composition for use according to any one of embodiments 1 to 5, wherein the pharmaceutical composition is administered subcutaneously, intramuscularly or intravenously.

[0703] 7. The pharmaceutical composition for use according to any one of embodiments 1 to 5, wherein the pharmaceutical composition is administered subcutaneously.

[0704] 8. The pharmaceutical composition for use according to any one of embodiments 1 to 7, wherein the pharmaceutical composition is administered for 3 to 6 weeks.

[0705] 9. The pharmaceutical composition for use according to any one of embodiments 1 to 7, wherein the pharmaceutical composition is administered for 4 weeks.

[0706] 10. The pharmaceutical composition for use according to any one of embodiments 1 to 9, wherein the pharmaceutical composition is administered to a subject suffering from Ps with a Psoriasis Area and Severity Index (PASI) score of <10.

[0707] 11. The pharmaceutical composition for use according to any one of embodiments 1 to 9, wherein the pharmaceutical composition is administered to a subject suffering from Ps with a Psoriasis Area and Severity Index (PASI) score of ≥10.

[0708] 12. The pharmaceutical composition for use according to any one of embodiments 1 to 11, wherein the Ps-related parameter is the Psoriasis Area and Severity Index (PASI) score, and administration of the pharmaceutical composition according to the invention results in a reduction of the Psoriasis Area and Severity Index (PASI) score from baseline by at least 20%, optionally at least 50%.

[0709] 13. A pharmaceutical composition comprising a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or a pharmaceutically acceptable salt thereof, the composition being used in a method of treating psoriatic arthritis (PsA) and / or improving PsA-related parameters, wherein the pharmaceutical composition is administered in a dose equivalent to about 0.15 mg to about 1.5 mg of an acetate of the peptide.

[0710] 14. The pharmaceutical composition for use according to embodiment 13, wherein the pharmaceutical composition is administered at a dose equivalent to about 0.45 mg of the acetate of the peptide.

[0711] 15. The pharmaceutical composition for use according to embodiment 13, wherein the pharmaceutical composition is administered at a dose equivalent to about 0.9 mg of the acetate of the peptide.

[0712] 16. The pharmaceutical composition for use according to any one of embodiments 13 to 15, wherein the pharmaceutical composition is applied three times a week, twice a week, or once a week.

[0713] 17. The pharmaceutical composition for use according to any one of embodiments 13 to 15, wherein the pharmaceutical composition is administered twice weekly.

[0714] 18. The pharmaceutical composition for use according to any one of embodiments 13 to 17, wherein the pharmaceutical composition is administered subcutaneously, intramuscularly, or intravenously.

[0715] 19. The pharmaceutical composition for use according to any one of embodiments 13 to 17, wherein the pharmaceutical composition is administered subcutaneously.

[0716] 20. The pharmaceutical composition for use according to any one of embodiments 13 to 19, wherein the pharmaceutical composition is administered for 3 to 6 weeks.

[0717] 21. The pharmaceutical composition for use according to any one of embodiments 13 to 19, wherein the pharmaceutical composition is administered for 4 weeks.

[0718] 22. The pharmaceutical composition for use according to any one of embodiments 13 to 21, wherein the pharmaceutical composition is administered to a subject suffering from PsA with a Psoriasis Area and Severity Index (PASI) score of <10.

[0719] 23. The pharmaceutical composition for use according to any one of embodiments 13 to 21, wherein the pharmaceutical composition is administered to a subject suffering from PsA with a Psoriatic Area and Severity Index (PASI) score of ≥10.

[0720] 24. The pharmaceutical composition for use according to any one of embodiments 13 to 24, wherein the PsA-related parameter is the Psoriasis Area and Severity Index (PASI) score, and administration of the pharmaceutical composition according to the invention results in a reduction of the Psoriasis Area and Severity Index (PASI) score from baseline by at least 20%, optionally at least 50%.

Claims

1. A pharmaceutical composition comprising a peptide or a pharmaceutically acceptable salt thereof consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1), the composition being used in a method of treating psoriasis vulgaris (Ps), wherein the pharmaceutical composition is administered in a peptide dose equivalent to about 0.15 mg to about 1.5 mg of the acetate of the peptide on a molar basis.

2. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is administered in a peptide dose equivalent to about 0.45 mg of the acetate of the peptide on a molar basis.

3. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is administered in a peptide dose equivalent to about 0.9 mg of the acetate of the peptide on a molar basis.

4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the pharmaceutical composition is applied three times a week, twice a week, or once a week.

5. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the pharmaceutical composition is administered twice weekly.

6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the pharmaceutical composition is administered subcutaneously, intramuscularly, or intravenously.

7. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the pharmaceutical composition is administered subcutaneously.

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the pharmaceutical composition is administered for 3 to 8 weeks.

9. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the pharmaceutical composition is administered for 4 weeks.

10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein the pharmaceutical composition is administered to a subject suffering from Ps with a Psoriasis Area and Severity Index (PASI) score of <10.

11. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein the pharmaceutical composition is administered to a subject suffering from Ps with a Psoriasis Area and Severity Index (PASI) score of ≥10.

12. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein administration of the pharmaceutical composition results in an improvement in the Ps-related parameter, wherein the Ps-related parameter is the Psoriasis Area and Severity Index (PASI) score, and administration of the pharmaceutical composition according to the invention results in a reduction of the Psoriasis Area and Severity Index (PASI) score from baseline by at least 20%, optionally at least 50%.

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