Peptide for treating atopic dermatitis

Abstract

The present invention is directed to a pharmaceutical composition comprising a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) for use in a method of treating atopic dermatitis.

Description

TECHNICAL FIELD The present invention is directed to a pharmaceutical composition comprising a peptide for use in a method of treating atopic dermatitis. BACKGROUND OF THE INVENTION Atopic dermatitis (AD; also known as atopic eczema or neurodermatitis) is a multi-faceted, chronic relapsing, inflammatory skin condition commonly associated with other atopic manifestations such as food allergy, allergic rhinitis, and asthma (Bieber, 2008; Berke, 2012; Drucker, 2017). AD is the most common skin disease in children, affecting about 15% to 20% of children and 1% to 3% of adults worldwide (Nutten, 2015; Eichenfield, 2014). In Europe, AD prevalence follows the latitudinal pattern with higher prevalence values in northern Europe and decreases progressively toward southern Europe (Kowalska-Ol^dzka, 2019). The disease’s hallmark feature is severe pruritus (Furue, 2015; Tominag, 2014). In addition to pronounced itching and dry skin, eczema is found in different body surface areas depending on the affected person’s age: during childhood typically on the cheeks and the extensor sides of the extremities, and in adults typically on the flexor sides of the extremities. Other clinical features include oozing orcrusting, and lichenification, ie, skin that has become thickened and leathery. Common complications of AD are infections caused by Staphylococcus aureus, viral infections, or mycoses (Frazier, 2020). Management of AD aims to avoid triggers and manage exacerbating factors, improve skin hydration, and reduce inflammation through the use of topical and systemic immunosuppressants. Topical glucocorticosteroids and calcineurin inhibitors are used for flare management and proactive therapy for long-term control. Emollients (moisturizers) and topical corticosteroids are the mainstay of therapy, whereas calcineurin inhibitors such as tacrolimus and pimecrolimus may be preferred in sensitive skin areas and for long-term use (Wollenberg, 2018 May). Recently, phosphodiesterase-4 inhibitors are used in the treatment of AD, including crisaborole, which is approved as a topical treatment for mild to moderate AD in Europe and the United States (Guttman-Yassky, 2019). Systemic immunosuppressive treatment, for example with cyclosporine, methotrexate, azathioprine, or mycophenolic acid, is used for severe refractory cases (Wollenberg, 2018 June). Phototherapy and biologicals, such as dupilumab targeting the interleukin (IL)-4 / IL-13 receptor, are used for refractory or severe cases. Oral drugs such as Janus kinase inhibitors and histamine-4 receptor antagonists are in development or were recently approved for moderate to severe AD. Infection may cause disease exacerbation and can require additional antimicrobial treatment (Wollenberg, 2018 June). There exists a continuing need for an alternative treatment of atopic dermatitis. SUMMARY OF THE INVENTION The present invention is directed to a pharmaceutical composition comprising a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or its pharmaceutically acceptable salt for use in a method of treating atopic dermatitis (AD), wherein the pharmaceutical composition is administered at a peptide dose equivalent in moles to about 0.15 mg to about 1.5 mg of the acetate salt of said peptide, such as at a peptide dose equivalent in moles to about 0.45 mg and about 0.9 mg of the acetate salt of said peptide. In an embodiment, the pharmaceutical composition is administered three times a week, twice a week or once a week. In an embodiment, the pharmaceutical composition is administered twice a week. In an embodiment, the pharmaceutical composition is administered subcutaneously, intramuscularly or intravenously. In an embodiment, the pharmaceutical composition is administered subcutaneously. In an embodiment, the pharmaceutical composition is administered for 3 to 8 weeks. In an embodiment, the pharmaceutical composition is administered for 4 weeks. In an embodiment, the pharmaceutical composition is administered to a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of below 25. In an embodiment, the pharmaceutical composition is administered to a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of between 25 and 60. In an embodiment, the pharmaceutical composition is administered to a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of above 60. In an embodiment, administration of the pharmaceutical composition results in improving an AD-associated parameter, wherein the AD-associated parameter is the SCORing Atopic Dermatitis (SCORAD) score and administration of the pharmaceutical composition results in a decrease from baseline in Scoring Atopic Dermatitis (SCORAD) score of at least 20%, optionally of at least 50%. In an embodiment, administration of the pharmaceutical composition results in improving an AD-associated parameter, wherein the AD-associated parameter is affected body surface area (BSA) and administration of the pharmaceutical composition results in a decrease from baseline in affected body surface area (BSA) of at least 20%, optionally of at least 50%. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: SCORing Atopic Dermatitis (SCORAD) score reduction relative to baseline for an exemplary responder for 450 pg and 900 pg dose levels. Figure 2: Affected body surface area (BSA) reduction relative to baseline for an exemplary responder for 450 pg and 900 pg dose levels. DETAILED DESCRIPTION OF THE INVENTION The peptide si-544 (corresponding to “ctgx 544” described in WO 2015 / 169901 A1) is a blocker of the voltage-gated Kv1.3 potassium channel. 25 years of research have linked an increasing number of diseases including autoimmune disorders like AD to chronically activated, Kv1.3-dependent effector memory T cells (Tem) (Chandy, 2017; Hu, 2017). Normally, Tem restore ion homeostasis upon activation and subsequent calcium (Ca2+) influx by recruiting the only 2 potassium channels, Kv1.3 and KCa3.1, that are expressed in human T cells. In certain situations, Tem become chronically activated, eg, by autoantigens, and are driven into an exclusively Kv1.3-dependent state where KCa3.1 is no longer expressed at relevant levels. In contrast to normal, primary activated Tem, these Kv1,3-dependent, disease-associated Tem are sensitive to Kv1.3 blockade since KCa3.1 can no longer compensate for inhibited Kv1.3 channels (Chiang 2017). Thus, Kv1.3 is a target for new therapies in autoimmune diseases. Kv1.3 inhibition selectively targets chronically-activated, disease-associated Tem and does not result in a generalized immunosuppression, as seen in subjects under conventional therapies. The inventors of the present invention have found in a multi-center, phase 1b, double-blind, placebo-controlled, single and multiple ascending dose study in adults with atopic dermatitis that a dose of up to 900 pg of the acetate salt of a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) is safe and tolerable. In addition, a clear efficacy signal at 450 pg and 900 pg dose levels was observed. A phase 1 b trial studying another peptide inhibitor of the voltage-gated Kv1.3 potassium channel, namely dalazatide (a 37-amino acid peptide previously referred to as ShK-186 and SL5) in patients with plaque psoriasis, describes a maximum dose of 60 pg (Tarcha, 2017). From the published results (Tarcha, 2017), a plasma level ofdalazatide can be calculated; this plasma level is sufficient for appr. 15-20 % target (Kv1.3) engagement. The inventors of the present invention found that for si-544 significantly higher plasma levels can be safely achieved (> 20 ng / ml) resulting in at least >85% target engagement. As used in the specification and the claims, the singular forms of “a” and “an” also include the corresponding plurals unless the context clearly dictates otherwise. The term “about” in the context of the present invention denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%. It needs to be understood that the term “comprising” is not limiting. For the purposes of the pre-sent invention, the term “consisting of is considered to be a preferred embodiment of the term “comprising”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only. The term “si-544” as used herein means a peptide consisting of 38 natural amino acids without modification. The peptide consists of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1). The peptide may be prepared using techniques known in the art. For example the peptide may be synthesized using solid phase Fmoc chemistry. Such synthesis may e.g. be carried out on automated peptide synthesizers. Once synthesized, sequences may be verified using an automated peptide sequencer. It is noted that the peptide comprises eight cysteine residues forming four disulfide bridges and may thus require active folding into a native state for achieving optimal activity. Activity may be further enhanced by purifying completely folded peptides. Folding may be achieved by subjecting the synthesized peptides to oxidation to achieve disulfide bridges between cysteine residues. This may be done by incubating the peptides in e.g. phosphate buffer at pH of ~8.0 in the presence of atmospheric oxygen as is described in WO 2015 / 169901 A1 (“ctgx 544” corresponds to “si-544”). Folding may be followed by mass spectrometry as the folded peptide will show a slightly reduced mass corresponding to the loss of hydrogen atoms during disulfide bridge formation. Purification of completely folded peptides can be achieved by methods known in the art such as HPLC purification. A suitable approach is described in WO 2015 / 169901 A1 (“ctgx 544” corresponds to “si-544”). A pharmaceutical composition according to the invention can be administered orally, for example in the form of inhalable powder pills, 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 carried out intranasally, sublingually or buccally. Other suitable administration forms are, for example, percutaneous or topical administration, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or the inhalative administration in the form of nasal sprays or aerosol mixtures. Preferably, a pharmaceutical composition according to the invention can be administered subcutaneously, intramuscularly or intravenously, for example, with a standard needle and syringe or a pen delivery device. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded. According to certain embodiments, a pharmaceutical composition according to the invention is administered subcutaneously. In general, a pharmaceutical composition according to the present invention can comprise various pharmaceutically acceptable excipients which will be selected depending on which functionality is to be achieved for the composition. A “pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, release-modifying materials, carriers, diluents, binding agents and other adjuvants. Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents. The term “carrier” denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application. Suitable pharmaceutically acceptable carriers include, for instance, water, salt solutions, alcohols, oils, preferably vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone and the like. The pharmaceutical compositions can be sterilized and if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and / or aromatic substances and the like which do not deleteriously react with the active compound. The pharmaceutical composition according to the present invention can be administered at a peptide dose equivalent in moles to about 0.15 mg to about 1.5 mg of the acetate salt ofthe peptide. According to certain embodiments, the pharmaceutical composition according to the present invention is administered at a peptide dose equivalent in moles to about 0.15 mg to about 0.75 mg ofthe acetate salt ofthe peptide, such as 0.45 mg ofthe acetate salt ofthe peptide. According to certain embodiments, the pharmaceutical composition according to the present invention is administered at a peptide dose equivalent in moles to about 0.75 mg to about 1.5 mg ofthe acetate salt ofthe peptide, such as about 0.9 mg ofthe acetate salt ofthe peptide. In certain embodiments, it may be preferred that the pharmaceutical composition according to the present invention is administered at a dose of about 0.15 mg to about 1.5 mg ofthe peptide. According to certain embodiments, it may be preferred that the pharmaceutical composition according to the present invention is administered at a dose of about 0.15 mg to about 0.75 mg ofthe peptide, such as 0.45 mg ofthe peptide. According to certain embodiments, it may be preferred that the pharmaceutical composition according to the present invention is administered at a dose of about 0.75 mg to about 1.5 mg ofthe peptide, such as about 0.9 mg ofthe peptide. According to certain embodiments, the pharmaceutical composition according to the present invention is administered at a dosing 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 frequently so long as a therapeutic response is achieved. In some embodiments, the pharmaceutical composition according to the present invention is administered three times a week, twice a week or once a week, optionally twice a week. In certain embodiments, it may be preferred that the pharmaceutical composition according to the present invention is administered subcutaneously and twice a week. According to certain embodiments, the pharmaceutical composition according to the present 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 certain embodiments, it may be preferred that the pharmaceutical composition according to the present invention is administered for 4 weeks. SCORing Atopic Dermatitis (SCORAD) is a clinical assessment ofthe severity (eg., extent or intensity) of atopic dermatitis developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report ofthe European Task Force on Atopic Dermatitis. Dermatology. 1993; 186( 1 ):23-31; https: / / dermnetnz.org / topics / scorad). SCORAD is a composite score of 3 components: (A) the BSA involved in AD, (B)the severity of 6 clinical signs, and (C) a subject-reported component assessing pruritus and sleep loss. Individual component scores are calculated as follows: (A) Percentage of BSA affected by AD with each body part accounted for by: head and neck: 9%; upper limbs: 9% each; lower limbs: 18% each; anterior trunk: 18%; back: 18%; and genitals: 1%. The score for each affected area is added up with the total possible (ie, all areas affected) score for A being 100 (ie, 100% of BSA). (B) The severity of eczema is assessed on a 4-point scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe for each of the clinical signs: erythema, edema / papulation, oozing / crusting, excoriation, lichenification, and dryness. The maximum score for B is 18. (C) The subjective scoring of symptoms on a visual analog scale from 0 to 10 with 0 being no symptom and 10 being the worst possible severity of symptoms for each pruritus and sleep loss. The maximum possible score for C is 20. The total score is calculated by: A / 5 + 7 * b / 2 + C with a maximal total score of 103. A score <25 indicates mild, score 25-60 moderate, and score 61-103 severe AD. According to certain embodiments, the pharmaceutical composition according to the present invention is administered to a subject with mild AD, i.e. a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of below 25. According to certain embodiments, the pharmaceutical composition according to the present invention is administered to a subject with moderate AD, i.e. a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of between 25 and 60. According to certain embodiments, the pharmaceutical composition according to the present invention is administered to a subject with severe AD, i.e. a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of above 60. The SCORing Atopic Dermatitis (SCORAD) score is an examples of an “AD-associated parameter” according to the present disclosure. Affected body surface area (BSA) is another example of an “AD-associated parameter” according to the present disclosure. The assessment of the affected BSA follows the same rules as (A) of SCORAD described above (BSA involved in AD). An “improvement in an AD-associated parameter” means a decrease from baseline. As used herein, the term “baseline”, with regard to an AD-associated parameter, means the numerical value of the AD-associated parameter for a subject prior to or at the time of administration of a pharmaceutical composition of the present invention. To determine whether an AD-associated parameter has “improved”, the parameter is quantified at baseline and at one or more time points after administration of the pharmaceutical composition of the present invention. For example, an AD-associated parameter may be measured at day 1 , day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 1 1 , day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71 , day 85; or at the end of week 1 , week 2, week 3, week 4, week 5, week 6, week 7, week 8, week9, week 10, week 1 1 , week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week20, week 21 , week 22, week 23, week 24, or longer, after the initial treatment with a pharmaceutical composition of the present invention. The difference between the value of the parameter at a particular time point following initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., a decrease) in the AD associated parameter. According to certain embodiments, the “AD-associated parameter” is the SCORing Atopic Dermatitis (SCORAD) score and the pharmaceutical composition according to the present invention results in a decrease from baseline in Scoring Atopic Dermatitis (SCORAD) score of at least 10%, of 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%. According to certain embodiments, the “AD-associated parameter” is the affected body surface area (BSA) and the pharmaceutical composition according to the present invention results in a decrease from baseline in affected body surface area (BSA) of at least 10%, of 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%. Examples In the following section, particular examples illustrating various embodiments and aspects of the invention are presented. The present invention, however, is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only, and methods which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those described herein will become readily apparent to those skilled in the art from the foregoing description. Abbreviations The following abbreviations may appear in the example section: AD atopic dermatitis ADA anti-drug antibodies ADR adverse drug reaction AE adverse events AUC area under the plasma concentration-time curve BSA body surface area CA competent authority Cmax maximum concentration CNS central nervous system DEC dose escalation committee DLT dose-limiting toxicities ECG electrocardiogram eCRF electronic case report form FIH first-in-human ICF informed consent form IEC independent ethics committees IL interleukin IMP investigational medicinal product ISF investigator site file MAD multiple ascending dose MTD maximum tolerated dose NCI-CTCAE National (US) Cancer Institute-Common Toxicity Criteria for Adverse Events NOAEL no observed adverse effect level PD pharmacodynamic(s) PK pharmacokinetic(s) PP per-protocol SAD single ascending dose SAE serious adverse events SAF safety analysis set SAP statistical analysis plan SCORAD scoring atopic dermatitis SUSAR suspected unexpected serious adverse reaction TCM central memory T cells TEM effector memory T cells WHO-DD World Health Organization Drug Dictionary Example 1 - A multi-center, Phase 1b, double-blind, placebo-controlled, single and multiple ascending dose study to evaluate the safety, tolerability, and efficacy of si-544 in adults with atopic dermatitis 1. Nonclinical data of si-544 Toxicology Repeat-dose toxicity studies were conducted in rodent (rats) and the highly relevant non-rodent species (Cynomolgus monkeys). Repeated once-daily intravenous or subcutaneous doses of si-544 were tested in a 28-day study in Wistar rats (data not shown). Clinical symptoms were only observed during the treatment and not during the recovery period. All clinical symptoms were considered to be test item related, except cyanosis of the tail and crusts on the neck, which were consequences of repeated injections. Overall, test item related clinical symptoms started shortly after intravenous application, lasting 30 minutes to up to several hours, and included in the high-dose subcutaneous group: slightly reduced spontaneous activity and piloerection in males, and ataxia, reduced spontaneous activity, prone position, slight swelling of the snout (edema), increased salivation, muscle twitches / tremor and piloerection in females. A histopathological no observed adverse effect level (NOAEL) was established at 4 mg / kg / day. Repeated-dose toxicity studies were performed to obtain information on the toxicity and the toxicokinetic profile of si-544 in Cynomolgus monkeys after repeated intravenous (0.5 mg / kg, 1 mg / kg, and 2 mg / kg) or subcutaneous (2 mg / kg) once-daily administration of si-544 over a period of 28 days (data not shown). The first study was prematurely terminated due to unexpected findings not related to si-544. In the second study, despite some clinical signs (mainly bizarre behavior, such as scratching, scratching the hands, scratching against the box wall, opening and closing the mouth, movements similar to ticks) and some changes in biochemistry parameters (decrease in sodium, albumin and total protein) and effects in spleen (lymphoid follicle development), alterations which are not considered adverse effects, the dose of 2 mg / kg / day administered intravenously or subcutaneously for 4 weeks can be considered the NOAEL. This is the highest concentration or amount found by experiment or observation causing no detectable adverse alterations of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions. The starting (15 pg per subject) and maximal (900 pg per subject) dose for the SAD part were selected based on results from 28-day repeated-dose toxicity studies in rats and monkeys. Even though the monkey is considered to be the most relevant species for humans, a conservative approach is undertaken, and the safe starting dose calculations are based on the rat (1 mg / kg dose in a central nervous system [CNS] function study) because it is the most sensitive species. For the targeted starting dose of 15 pg / subject, a safety margin of more than 4000-fold based on a mg / kg dose calculation and more than 400-fold based on extrapolated human maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) data using the respective exposure values derived from the most sensitive safety endpoint (CNS function study in rats) are calculated. Assuming a volume of distribution in humans of 5 L, a dose of 15 pg / subject results in a maximal blood concentration of 3 ng / mL, which reflects a worst-case scenario as due to the subcutaneous route of administration the blood si-544 curve is likely to be flatter than that of a bolus intravenous injection. In rats and monkeys, the Cmax values after i.v. and s.c. injections differed by about a factor of 3. The selected highest dose level of 900 pg per subject still results in safety margins of more than 67-fold based on a mg / kg dose calculation and more than 7- to 19-fold based on extrapolated human Cmax and AUC data. 2. Summary of study in humans Title of the study A multi-center, Phase 1b, double-blind, placebo-controlled, single and multiple ascending dose study to evaluate the safety, tolerability, and efficacy of si-544 in adults with atopic dermatitis Clinical phase: Phase 1b Study periods The study consisted of 2 parts, a single ascending dose (SAD) part, and a multiple ascending dose (MAD) part. SAD part: Screening (33 days), single treatment, 7 days safety follow-up MAD part: Screening (33 days), treatment period (4 weeks), follow-up (12 weeks) Study objectives and endpoints The study consisted of a single ascending dose (SAD) and a multiple ascending dose (MAD) part. Efficacy was only be assessed in the MAD part of the study. Table 1: Study objectives and endpoints Objective Endpoint Primary (SAD and MAD part) • To determine the safety and tolerability of si-544 treatment • Type, frequency, severity, and causal relationship of adverse events (AEs), serious adverse events, and dose-limiting toxicities (DLTs) during the study • Change from Baseline in clinical laboratory, electrocardiogram (ECG), vital signs, and peripheral oxygen saturation to all assessments during the study Secondary (SAD and MAD part) • To determine the PK of si-544 • SAD part: PK parameter in blood plasma at Day 1 • MAD part: PK parameter in blood plasma at Days 1 and 25 Secondary (MAD part) • To determine the pharmacodynamics (PD) of si-544 • Change from Baseline in number of T cells in peripheral blood at Day 29, and Weeks 8, 12, and 16 • Change from Baseline in immunophenotyping of T-cell subsets at Day 29, and Weeks 8, 12, and 16 • Change from Baseline in serum cytokine levels at Day 29, and Weeks 8, 12, and 16 • Optional3: Change from Baseline of expression levels of Kv1.3 vs KCa3.1 of Tem cells at Day 29, and Weeks 8, 12, and 16 • To determine the immunogenicity of si-544 treatment • Change from Baseline in anti-drug antibodies (ADAs) against si-544 in serum at Day 29 • To determine the efficacy of si-544 treatment • Change from Baseline in inflamed areas using the body surface area (BSA) index at Days 15 and 29, and Weeks 8, 12, and 16 • Change from Baseline in AD severity by SCOring AD (SCORAD) at Days 15 and 29, and Weeks 8, 12, and 16 For all endpoints, Baseline is defined as the last measurement before the first investigational medicinal product 5 injection. a Depending on results of immunophenotyping of T-cell subsets. Methodology This is a multi-center, Phase 1b, double-blind, placebo-controlled, SAD and MAD, first-in-human study in subjects with mild to severe AD receiving si-544. The study consisted of 2 parts, an SAD and an MAD part. In both parts, subjects were treated in cohorts and were randomized within each cohort to treatment with si-544 or placebo. Initially, 2 sentinel subjects were treated 5 (randomized to placebo or si-544) in each cohort. Further subjects were only treated if no safety issues occurred as assessed by the investigator. In the SAD part, 20 eligible subjects were treated in 5 dose cohorts of 4 subjects each. The dose levels for Cohorts 1 to 5 were 15 pg, 50 pg, 150 pg, 450 pg, and 900 pg si-544 or placebo. Subjects received a single dose on Day 1 (starting with the lowest dose cohort) and the safety and tolerability was assessed at Days 4 and 8. 10 Each cohort comprised 2 sentinel subjects (randomized 1:1 to placebo and si-544) and 2 subjects treated with si-544. In the MAD part, eligible subjects were treated twice a week for 4 weeks (treatment period). The safety and tolerability, and PK was assessed during the treatment period. Follow-up visits were performed for 12 weeks after MAD treatment to assess the safety, PD, immunogenicity, and efficacy. 15 Each cohort comprised the 2 sentinel subjects (randomized 1:1 to placebo and si-544) and another 6 subjects randomized 5:1 to si-544 and placebo. Assessments The schedule of assessments is provided in Table 2 (SAD part) and Table 3 (MAD part) below Table 2: Schedule of assessments - SAD part Screening Treatment SFU D-35 to D-2 D1 D2* (phone) D4 D8 / ET ±1 day ±1 day Informed consent X In- and exclusion criteria X Demographic data X Height, weight, BMI X Medical history X Serology® X Pregnancy test (blood) X Physical examination X xb X X Neurological examinationk X xb X X Vital signs0 and POS X xd X X Electrocardiogram X X® X Clinical laboratory’ X X® X X SARS-CoV-2 test1 X PK blood sampling9 xh Randomization xj IMP injection X Sentinel safety assessment X Previous and concomitant medication X--------------------------------------------------------------------------------x Adverse events X---------------------------------------------------------------------------------x * In sentinel subjects only: telephone call 24 hours after IMP injection to assess the safety. aFor HIV, HBV, HCV and Tbc-IGRA. bTo be performed before IMP injection. cAssessment of blood pressure, heart rate, respiration rate, and body temperature. dTo be performed before and 30 minutes to 1 hour after IMP injection. eTo be performed 30 minutes to 1 hour after IMP injection. f Hematology, biochemistry, coagulation, and urinalysis. g Only in subjects of Cohorts 4 and 5. hBlood collections upto 15 minutes before, and immediately, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after IMP injection. The sampling window will be ±1 minute for <1 hour, ±5 minutes for 2 hours, ±15 minutes for 4 hours, and ±30 minutes for 8 hours post injection. The time point for blood collection takes priority over any other scheduled study activity. The exact time of drawing blood must be documented. j To be performed as soon as eligibility is confirmed. kHamstring and pupillary reflex, motor function, sensibility tests, Romberg test, Unterbergertest, heel walk, toe (ball) walk, line walk, blind walk, and 1 -leg stand. In case of abnormal neurologic findings at Day 1, the subject may not be treated. 1 As per study center’s standard. BMI = body mass index, D = day, ET = early termination, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, IMP = investigational medicinal product, PK= pharmacokinetic, POS = peripheral oxygen saturation, SAD = single ascending dose, SFU = safety follow-up, Tbc-IGRA = tuberculosis interferon gamma release assay. Table 3: Schedule of assessments - MAD part Scr Treatment period FU W1 W2 W3 W4 W5 W8 W12 W16 D-35 to D-2 D1 D4 D8 D11 D15 D18 D22 D25 D29 D50 D78 D106 / ET ±1 d ±1 d ±1 d ±1 d ±1 d ±1 d ±1 d ±3 d ±7 d ±7 d ±7 d Informed consent X In- and exclusion criteria X Demographic data X Body weight, height, BMIa X X X X X X X X X Medical history X Serology13 X Pregnancy test (blood) X X X Physical examination X xc xc xc xc xc xc xc xc X X X X Neurological examination1 X xc xc xc xc xc xc xc xc X X X X Vital signs® and POS X xh xh xh xh xh xh xh xh X X X X Electrocardiogram X X1 X1 X1 X1 X1 X1 X1 X1 X Clinical laboratory’ X X1 X1 X1 X1 X1 X1 X1 X1 X X X X SARS-CoV-2 testm X PK blood sampling9 X X PD blood sampling for Flow cytometry of T cells (PB) xc X X X X Serum cytokines xc X X X X Kv1.3 / KCa3.1 expression Tem xc X X X X ADA xc X xd Affected BSA and body surface indexj X xc X X X X X SCORAD X xc X X X X X Randomization xk IMP injection X X X X X X X X Previous and concomitant medication X------- -X Adverse events X------- — -X a After Screening, only body weight. b For HIV, HBV, HCV, and Tbc-IGRA. c To be performed before IMP injection. If applicable: Blood sampling window: upto 15 minutes before IMP injection. d To be performed if ET before or on Day 29. e Blood pressure, heart rate, respiration rate, and body temperature. f Hematology, biochemistry, coagulation, and urinalysis. g Blood collections up to 15 minutes before, and immediately, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after IMP injection. The sampling window will be ±1 minute for <1 hour, ±5 minutes for 2 hours, ±15 minutes for 4 hours, and ±30 minutes for 8 hours post injection. The time point for blood collection takes priority over any other scheduled study activity. The exact time of drawing blood must be documented. h To be performed before and 30 minutes to 1 hour after IMP injection. ' To be performed 30 minutes to 1 hour after IMP injection. j As assessed for the SCORAD. k To be performed as soon as eligibility is confirmed. 1 Hamstring and pupillary reflex, motor function, sensibility tests, Romberg test, Unterbergertest, heel walk, toe (ball) walk, line walk, blind walk, and 1 -leg stand. In case of abnormal neurologic findings at treatment days, the subject may not be treated. m As per study center’s standard. ADA = anti-drug antibodies, BMI = body mass index, BSA = body surface area, D / d = day(s), ET = early termination, FU = follow-up, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, IMP = investigational medicinal product, MAD = multiple ascending dose, PB = peripheral blood, PD = pharmacodynamic, PK = pharmacokinetic, POS = peripheral oxygen saturation, Scr = Screening, SCORAD = scoring atopic dermatitis, Tbc-IGRA = tuberculosis interferon gamma release assay, Tem = effector memory T cells, W = week. Efficacy and immunogenicity assessments The analyses of efficacy and immunogenicity was done in the MAD part. SCORing Atopic Dermatitis The AD severity assessment was done by SCORing Atopic Dermatitis (SCORAD) as scheduled in Table 3. SCORAD is a composite score of 3 components: (A) the BSA involved in AD, (B) the severity of 6 clinical signs, and (C) a subject-reported component assessing pruritus and sleep loss. Individual component scores are calculated as follows: Percentage of BSA affected by AD with each body part accounted for by: o head and neck: 9% o   upper limbs: 9% each o   lower limbs: 18% each o anterior trunk: 18% o back: 18% o genitals: 1%. The score for each affected area is added up with the total possible (ie, all areas affected) score for A being 100 (ie, 100% of BSA). The severity of eczema is assessed on a 4-point scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe for each of the clinical signs: erythema, edema / papulation, oozing / crusting, excoriation, lichenification, and dryness. The maximum score for B is 18. The subjective scoring of symptoms on a visual analog scale from 0 to 10 with 0 being no symptom and 10 being the worst possible severity of symptoms for each pruritus and sleep loss. The maximum possible score for C is 20. The total score is calculated by: A / 5 + 7 * b / 2 + C with a maximal total score of 103. A score <25 indicates mild, score 25-60 moderate, and score 61-103 severe AD. Body surface index The body surface index is used to assess the inflamed skin areas as percentage of the total BSA as scheduled in Table 3. The assessment of the affected BSA follows the same rules as (A) of SCORAD described above (BSA involved in AD). Anti-drug antibodies Serum samples for ADAs for assessing the immunogenicity were obtained as scheduled in Table 3. Pharmacokinetics and pharmacodynamics assessments General information The analysis of PK was done in Cohorts 4 and 5 of the SAD part and analyses of PK and PD was done in the MAD part. Specimen collection Blood samples for PK and PD analysis were obtained at the visits as detailed in Table 2 for the SAD part and Table 3 for the MAD part. Blood samples for PK assessments were taken at: • predose: immediately (ie, up to 15 minutes) before IMP injection • postdose: immediately after, and 5, 15, 30 minutes, 1,2, 4, and 8 hours after IMP injection; sampling window: ±1 minute for <1 hour, ±5 minutes for 2 hours, ±15 minutes for 4 hours, and ±30 minutes for 8 hours postinjection. On dosing days, blood samples for PD analyses were taken up to 15 minutes before IMP injection. Bioanalytical methods Bioanalytic analyses of si-544 was performed using a validated high-performance liquid chromatography tandem mass spectrometer method. Pharmacokinetic assessments The following PK parameters were calculated from plasma concentrations for the SAD part on Day 1 and for the MAD part on Day 1 and Day 25: • Cmax • time to reach maximum concentration (Tmax) •   AUC from time 0 to 8 hours, AUCo-sh •   AUC from time 0 to the time of the last quantifiable concentration, AUCo-iast • AUC from time 0 to infinite time, AUCo-~ • terminal elimination rate constant, Az • apparent terminal elimination half-life time, T1 / 2 The PK parameters were calculated using Phoenix WinNonlin 6.4 or higher. Pharmacodynamic assessments The following PD assessment was done using fluorescent activated cell sorting: • number of T cells: Tcm, Tem and regulatory T cells • serum cytokine levels: interferon-y, IL-1 p, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17, and tumor necrosis factor-a • immunophenotyping of T cell subsets, including the AD-specific markers CD2, CLA, CD4, CD8, CD45RA, CCR7, CD45RO, Ki67, and optionally (depending on the results of immunophenotyping of T-cell subsets) Kv1.3 and KCa3.1 Safety assessments Adverse events Definitions An AE is any untoward medical occurrence in a subject administered a medicinal product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the IMP. Any worsening in severity or frequency of a concomitant disease or any new disease diagnosed in the study must be documented as an AE. Worsening of AD will not be considered an AE unless the worsening is clinically significantly exceeding the usual fluctuations of the disease. Clinically significant abnormal laboratory findings are considered AEs, but abnormal laboratory findings may not be considered AEs, if there is no change compared to baseline values. All AEs occurring between signing the informed consent form and the time of the first IMP injection are defined as "pretreatment-emergent" events. All AEs occurring after the first IMP injection are defined as treatment-emergent adverse events. A serious AE (SAE) is any AE occurring at any dose that: • results in death • is life-threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability or incapacity • is a congenital anomaly or birth defect • is an important medical event An adverse drug reaction (ADR) is any noxious and unintended response to a medicinal product related to any dose. As per the ICH guideline - E2A, the definition of an ADR implies a reasonable possibility of a causal relationship between the AE and the IMP. An unexpected ADR is an adverse reaction, the nature and severity of which is not consistent with the applicable reference document (reference safety information in the investigator’s brochure). Reports which add significant information on specificity or severity of a known, already documented AE constitute unexpected AEs. Specific examples are: acute renal failure as a labeled AE with a subsequent new report of interstitial nephritis or hepatitis with a subsequent report of fulminant hepatitis. A suspected unexpected serious adverse reaction (SUSAR) is a suspected adverse reaction related to the IMP that is both unexpected and serious. SUSARs will be subject to expedited regulatory reporting. Reports which add significant information on specificity or severity of a known, already documented AE constitute unexpected AEs. Specific examples would be acute renal failure as a labeled AE with a subsequent new report of interstitial nephritis or hepatitis with a subsequent report of a fulminant hepatitis. Classification of adverse events Causality The causal relationship of the AE and the IMP will be assessed as follows: Related:                       There is a reasonable possibility of a causal relationship between the event and the IMP. This means that there are facts (evidence) or arguments to suggest a causal relationship. Not related:                    There is no reasonable possibility of a causal relationship between the event and the IMP. This means that there are neither facts (evidence) nor arguments to suggest a causal relationship. Severity The severity of AEs will be graded according to the National (US) Cancer Institute-Common Toxicity Criteria for AEs (NCI-CTCAE, Version 5.0). If not specifically defined in the NCI-CTCAE, Table 4 applies. Table 4: Severity grading of adverse events Grade Severity Description 1 Mild Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated 2 Moderate Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL* 3 Severe Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL** 4 Life-threatening Life-threatening consequences; urgent intervention indicated. Emergency room visit or hospitalization. 5 Death Death related to the AE instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. ** Self-care ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and not bedridden. ADL = activity of daily living. Outcome categories Outcome of an AE at the time of the last observation will be classified according to the following scale: Resolved: The subject has fully recovered from the event or the condition has returned to the level observed at Baseline. Resolving: The subject has recovered from the event, but the condition has not returned to the level observed at Baseline. Not resolved: The event is ongoing at the time of reporting and the condition has not returned to the level observed at Baseline. Resolved As a result of the AE, the subject suffered persistent and significant with sequelae: disability / incapacity (eg, became blind, deaf or paralyzed) or the condition became chronic or stabilized and no worsening is expected. Fatal: The subject died due to the event. If the subject died due to other circumstances than the event, the outcome should be stated otherwise (eg, not resolved or resolving). Unknown: Outcome is not known or not reported. Action taken with IMP 5 Action taken with the IMP will be assigned to one of the following categories: None: No action taken Drug withdrawn: Discontinuation ofthe IMP Not applicable: This category should be used in circumstances such as when the subject has died, or the treatment had been completed before reaction(s) orevent(s), or the IMP had not been administered. Documentation of adverse events All AEs that occured after the subject has signed the informed consent form (ICF) until the subject’s study completion were recorded. AEs with verbatims matching with terms listed in NCI-CTCAE, Version 5.0 were graded 10 according to the specific definitions of severity provided in this listing. AEs not listed on the NCI-CTCAE grading system were graded on a 5-point scale provided in Table 4 above. Clinical safety laboratory investigations Biological samples for clinical safety laboratory tests and pregnancy testing in women of childbearing potential will be collected as indicated in Table 2 and Table 3. All safety laboratory assessments and parameters are specified in 15 Table 5. Table 5: Clinical safety laboratory parameters Laboratory assessment Parameters Hematology Platelets, erythrocytes, leukocytes, differential leukocyte count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration Biochemistry • Liver function: alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, total bilirubin, unconjugated (indirect) and conjugated (direct) bilirubin • Kidney function: blood urea nitrogen, creatinine, uric acid, estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) Coagulation Urinalysis Serology (Screening only) Blood pregnancy test • Other: Sodium, potassium, magnesium, chloride, inorganic phosphate, calcium, creatine phosphokinase, amylase, lipase, total protein, albumin, glucose (nonfasting), hemoglobin A1c*, triglycerides, cholesterol, ferritin, D-dimer, lactate dehydrogenase, and C-reactive protein * At Screening (SAD part and MAD part) and last visit (MAD part) only Partial thromboplastin time, prothrombin time, international normalized ratio (INR) pH, leukocytes, nitrites, blood, protein, glucose, ketones, urobilinogen, and bilirubin by dipstick Microscopic examination of the urine sediment only if tested positive for blood Hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency virus, tuberculosis interferon gamma release assay Human chorionic gonadotropin (only for women of childbearing potential) Vital signs, peripheral oxygen saturation, physical examinations, and electrocardiogram Vital sign measurements, peripheral oxygen saturation, physical examinations, and ECG were performed as specified in Table 2 and Table 3. Vital signs included body temperature, heart rate, respiration rate, and diastolic and systolic blood pressure Peripheral oxygen saturation was measured by pulse oximetry using a finger clip. A physical examination was performed evaluating any clinically significant abnormalities within the following body systems: general appearance; skin; head and neck, eyes, ears, nose, and throat; cardiovascular and pulmonary system; abdomen; musculoskeletal; extremities; neurological system (see also below section regarding neurological examination); and lymph nodes. A 12-lead ECG (PR-, QRS-, QT and QTc[F]-intervals) was recorded. At Screening, height and weight was assessed, and the body mass index was calculated. The weight was also be assessed during the MAD part. Neurological examination The following neurological assessments were performed as scheduled in Table 2 and Table 3: • Hamstring and pupillary reflex • Motor function • Sensibility tests • Romberg test (neurological function for balance): The subject is asked to stand upright with both feet together and arms next to the body or crossed in front of the body. First, the subjects keep their eyes open while the examiner assesses the body movement relative to balance. Second, the subject stands upright with eyes closed while the examiner notes any balance impairment within 1 minute. The Romberg test is positive when subjects have a loss of balance with their eyes closed. Loss of balance can be defined as the increased swaying of the body, foot movement in the direction of the fall, or falling. • Unterberger test (vestibular pathology): The subject is asked to walk stationary with high knees for 1 minute with eyes closed and arms outstretched. During the examination, no optical or acoustic stimuli (eg, bright light, ticking clock) may allow orientation in the room. The examiner pays attention to any rotation of the subject’s body. A reproducible rotation to the left or the right is a pathological finding leading toward an affection of the ipsilaterale inner ear or the cerebellum (ataxia). • heel walk • toe (ball) walk • line walk •   blind walk •   1-leg stand Dose-limiting toxicities Toxicity was assessed according to the National Cancer Institute-Common Terminology Criteria for AEs (NCI-CTCAE, Version 5.0). If not specifically defined in the NCI-CTCAE, grading follows the severity grading of AEs (mild, moderate, severe, life-threating, death, Table 4). The following AEs are defined as DLTs, if occurring under si-544 treatment: • Grade >3 paresthesia • Grade >3 hypoesthesia • Abnormal vital signs Grade >3 (if different from Baseline) • Abnormal ECG Grade >3 (if different from Baseline) • Any toxicity Grade >3 considered relevant by the DEC Dose selection MAD part The DEC recommended the dose levels to be used in the MAD part, based on the occurrence of DLTs under si-544 treatment, and the MTD during the SAD part (see Table 6 below). Table 6: Dose selection MAD part Results SAD part                         Dose levels to be used in MAD part Cohort 5 completed with <1 DLT           Cohorts 4 and 5 (ie, 450 pg and 900 pg si-544) Cohort 4 = MTD                          Cohorts 3 and 4 (ie, 150 pg and 450 pg si-544) Cohort 3 = MTD                          Cohort 3 only (ie, 150 pg si-544) DLT = dose limiting toxicity, SAD = single ascending dose, MAD = multiple ascending dose, MTD = maximum tolerated dose. Investigational medicinal products, dose cohorts, and number of subjects Test product si-544 acetate in 0.9% NaCI solution, subcutaneous injection in the abdomen: •SAD part: single dose • MAD part: multiple doses - twice a week for 4 weeks Reference product Placebo (0.9% NaCI solution), volume and administration as described for the test product Subject population Adults with mild to severe AD Inclusion criteria SAD and MAD part 1. Subject has the capacity for consenting, was informed about the nature, the scope, and the relevance of the clinical study, voluntarily agrees in participation and in the study provisions, and duly signed the informed consent form approved by the ethics committee before any study-related procedure. 2. Men and women aged >18 to 75 years 3. Willing and able to adhere to the protocol requirements 4. deleted 5. Women of childbearing potential must: a. have a negative pregnancy test (blood) at Screening. b. agree to use, and be able to comply with, highly effective measures of contraceptive control (failure rate less than 1 % per year when used consistently and correctly) without interruption, from Screening through 30 days after the last IMP treatment. Reliable methods for this study are: i. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) ii. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) Hi. intrauterine device iv. intrauterine hormone-releasing system v. bilateral tubal occlusion vi. vasectomized sexual partner (provided that the partner is the sole sexual partner of the woman of childbearing potential and has received medical assessment of the surgical success) vii. sexual abstinence (only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment) Abstinence is only accepted as true abstinence: when this is in line with the preferred and usual lifestyle of the subject (periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods and withdrawal] is not an acceptable method of contraception). c. agree to abstain from breast feeding during the study participation and for 90 days after the last IMP treatment. Postmenopausal (no menses for at least 1 year without alternative medical cause) or surgically sterile women (tubal ligation, hysterectomy, or bilateral oophorectomy) may be enrolled. 6. Men must practice true abstinence or agree to use a condom during sexual contact with a pregnant woman or a woman of childbearing potential for at least 90 days after the last IMP treatment, even after undergoing a successful vasectomy. SAD part only 7. Clinical diagnosis of mild to severe AD MAD part only 8. Clinical diagnosis of mild to severe AD with a SCORAD >15 Exclusion criteria SAD and MAD part 1. Change (ie, starting anew, change in frequency, or change in drug substance) in standard systemic and topical therapy, or in immunosuppressive drug therapy within 4 weeks before Screening (for biologies such as dupilumab, the therapy may not be changed within 12 weeks before Screening), as judged by the investigator 2. Known history of hypersensitivity to constituents or excipients in the pharmaceutical formulation of the IMP 3. Uncontrolled hypertension or uncontrolled diabetes 4. History of seizures 5. Presence or history of paresthesia or neuropathy 6. Clinically significant ECG abnormalities, as judged by the investigator 7. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, renal, or other major systemic disease, as judged by the investigator 8. Presence of acute infection within 7 days before Screening, as judged by the investigator 9. Known or active infection with Mycobacterium tuberculosis 10. Known or active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus 11. Vaccination within 2 weeks before Screening and / or planned vaccination during the SAD part or the treatment period of the MAD part 12. Pregnancy 13. Any finding or medical condition prohibiting the inclusion in the study, as judged by the investigator 14. Current or previous (within 4 weeks before Screening) participation in another clinical study with an investigational medicinal product or medical device 15. Known or suspected abuse of alcohol, drugs, or medicinal products 16. Employee of the sponsor, or employee, or relative of the investigator 17. Use of prohibited medication (see Previous and concomitant medication below) 18. Subjects committed to an institution by virtue of an order issued either by the judicial or the administrative authorities 19. Legal incapacity or limited legal capacity MAD part 20. Previous participation in the SAD part of this study with IMP dosing within 3 months before the planned first dosing of the MAD part. Previous and concomitant medication The following medications and therapies are prohibited during both parts of the study, as indicated: • From 12 weeks before Screening and during SAD part and treatment period of MAD part: change in therapy with certain biologies such as dupilumab • From 4 weeks before Screening and during SAD part and treatment period of MAD part: change in immunosuppressive drug therapy • From 4 weeks before Screening and during both study parts: use of other investigational medicinal products or medical devices • From 2 weeks before Screening and during both study parts: any vaccination Statistical methods No formal sample size calculation was done, but 4 subjects each in Cohorts 1 to 5 of the SAD part, and 8 subjects in each dose level participating in the MAD part are considered enough to determine safety and tolerability, and evaluate PK, response to the IMP, and efficacy of si-544. 3. Result of study in humans 3.1 Overview of Results The IMP (si-544) was well tolerated in the SAD cohorts (dose levels for cohorts 1 to 5 were 15 pg, 50 pg, 150 pg, 450 pg, and 900 pg si-544 or placebo administered subcutaneously). Thus, in the MAD part, the dose levels 450 pg and 900 pg si-544 were used (for dose selection of the MAD part see also Table 6 above): 8 subcutaneous (s.c.) injections over 4 weeks per patient (12 patients) and 4 additional patients received placebo. No patient discontinued the study. All patients were closely monitored (e.g. electrocardiogram, peripheral oxygen saturation and neurological safety) and no IMP-related changes were observed. Regarding PK, it is noted that high plasma levels in both cohorts (450 pg and 900 pg si-544) were achieved resulting in virtually full target engagement. No si-544 related serious AEs were observed and no dose reductions ortemporary / permanent discontinuations from dosing due to SAEs / AEs (i.e. no safety signal and no DLT) was observed. AEs observed were at placebo level (rare, mild and transient). Immunocompetence was fully maintained in all treated patients as revealed by blood diagnostics, e.g.no significant change in blood cell count, no significant changes in cytokine expression and no significant changes in blood chemistry were observed. The IMP (si-544) delivered a clear efficacy signal (SCORAD & BSA) at 450 |jg and 900 pg dose levels in the MAD cohorts (s.c.) after 4 weeks of treatment. A high response rate was observed: 9 out of 12 si-544 treated patients showed significant improvement relative to baseline for SCORAD and BSA. First signs of efficacy were observed already after 2 weeks of dosing. SCORAD and BSA improvement persists at end of study at day 106 (D106) showing 5 that duration of effect clearly extended beyond dosing period. Regarding SCORAD, it is noted that 3 out of 9 of patients showed improvements > 50% (and up to 98%). Figure 1 shows the SCORAD reduction relative to baseline for an exemplary responder for 450 pg and 900 pg dose levels. As shown in Figure 1 duration of effect clearly extended beyond dosing period. Regarding BSA, it is noted that 4 out of 9 patients showed improvements > 85% (virtually full skin clearance). 10 Figure 2 shows the BSA reduction relative to baseline for an exemplary responder for 450 pg and 900 pg dose levels. As shown in Figure 2 duration of effect clearly extended beyond dosing period. 3.2 Detailed results 15     3.2.1 Study subjects 3.2.1.1 Disposition of subjects and data set analyzed Of 50 screened subjects, 36 subjects were enrolled, ie, randomized, and treated with the assigned IMP (SAD part: 15 subjects with si-544, 5 with placebo; MAD part: 12 subjects with si-544, 4 with placebo). Subjects receiving 20 placebo were pooled for the data analysis. 1 subject participated in both study parts in compliance with the requirements (ie, the first IMP injection of the MAD part was 3 months after the single dose IMP injection received in the SAP part) and was treated with 450 pg si-544 in the SAD part and 900 pg si 544 in the MAD part. All (36) randomized subjects completed the assigned treatment and the study. 25 All 36 enrolled subjects (SAD part: 20 subjects, MAD part: 16 subjects) were part of the SAF and the PP set, as no protocol deviations were classified as major. 3.2.1.2 Demographics and other baseline characteristics A summary of demographics for the SAF is provided in Table 7 and Table 8. 30 In the SAD part (Table 7), more than twice as many women (70%) than men (30%) were included with only women in the 15 pg and 50 pg si-544 treatment groups. All subjects were White and not Hispanic or Latino. The median age was 31 years, ranging from 19 to 60 years. In the placebo and 15 pg si-544 treatment group, the median age was markedly higher than in the other treatment groups. The BMI slightly varied across the treatment groups. Table 7: Demographics - SAD part (SAF) 15 pg si-544 (N = 3) 50 pg si-544 (N = 3) 150 pg si-544 (N = 3) 450 pg si-544 (N = 3) 900 pg si-544 (N = 3) Placebo (N = 5) Total (N =20) Sex male N (%)a - - 1 (33.3) 2 (66.7) 1 (33.3) 2 (40.0) 6 (30.0) female N (%)a     3(100.0) 3 (100.0) 2 (66.7) 1 (33.3) 2 (66.7) 3 (60.0) 14 (70.0) Fertility status (women) surg sterile, N (%)b              1 (33.3) postmeno, N (%)b              1 (33.3) 1 (33.3) - 1 (100.0) - 2 (66.7) 2 (14.3) 4 (28.6) CBP, N (%)b 1 (33.3) 2 (66.7) 2 (100.0) - 2 (100.0) 1 (33.3) 8 (57.1) Race Table 7: Demographics - SAD part (SAF) 15 pg si-544 (N = 3) 50 pg si-544 (N = 3) 150 pg si-544 (N = 3) 450 pg si-544 (N = 3) 900 pg si-544 (N = 3) Placebo (N = 5) Total (N =20) White Ethnicity N (%)a 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 20 (100.0) not Hisp or Lat N (%)a 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 20 (100.0) Age [years] Mean (SD) 47.0(13.0) 30.3(10.4) 21.0(1.7) 43.0(14.2) 25.0(1.7) 44.0 (16.9) 36.0(14.6) Median 54.0 27.0 22.0 38.0 26.0 51.0 30.5 Min, max 32, 55 22, 42 19, 22 32, 59 23, 26 23, 60 19, 60 BMI [kg / m2] Mean (SD) 23.87 (1.79) 29.30 (10.78) 22.13 (1.93) 28.20 (3.60) 29.37 (5.86) 25.98 (5.75) 26.43 (5.66) Median 24.30 24.00 21.50 28.40 32.70 27.30 24.40 Min, max 21.9, 25.4 22.2, 41.7 20.6, 24 3 24.5, 31.7 22.6, 32.8 19.7, 32.3 19.7, 41.7 N = 0 is shown as a Percentage is based on the N in the treatment group. b Percentage is based on the number of women in the treatment group. BMI = body mass index, CBP = childbearing potential, Hisp = Hispanic, Lat = Latino, max = maximum, min = minimum, N = number of subjects, postmeno = postmenopausal, SAD = single ascending dose, SAF = safety analysis set, surg = surgically. In the MAD part (Table 8), the sex distribution was nearly balanced with 56.3% men and 43.8% women. All but 1 subject were White and not Hispanic or Latino. The median age was 29 years, ranging from 19 to 49 years. Age and BMI were similar across treatment groups. Based on the SCORAD at Screening, nearly all subjects (87.5%) had 5 moderate AD. Table 8: Demographics - MAD part (SAF) 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Total (N = 16) Sex male N (%)a 3 (50.0) 4 (66.7) 2 (50.0) 9 (56.3) female N (%)a 3 (50.0) 2 (33.3) 2 (50.0) 7 (43.8) Fertility status (women) CBP N (%)b 3 (100.0) 2 (100.0) 2 (100.0) 7 (100.0) Race White N (%)a 6 (100.0) 5 (83.3) 4 (100.0) 15 (93.8) Asian N (%)a - 1 (16.7) - 1 (6.3) Ethnicity Hispanic or Latino N (%)a - - 1 (25.0) 1 (6.3) not Hispanic or Latino N (%)a 6 (100.0) 6 (100.0) 3 (75.0) 15 (93.8) Age [years] Mean (SD) 30.5(10.4) 26.3(6.2) 29.3(5.1) 28.6(7.6) Median 29.5 27.0 29.0 28.5 Min, max 20, 49 19, 33 24, 35 19, 49 BMI [kg / m2] Mean (SD) 27.03 (3.72) 24.38 (3.85) 25.60 (2.55) 25.68 (3.50) Median 27.35 24.50 25.15 25.15 Min, max 20.5, 31.4 19.3, 30.9 23.0, 29.1 19.3, 31.4 SCORAD score Mean (SD) 42.83 (8.49) 33.35 (8.71) 46.15(15.16) 40.11 (11.24) Median 42.10 33.60 46.60 37.95 Table 8: Demographics - MAD part (SAF) 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Total (N = 16) Min, max 33.5, 56.7 20.1, 43.0 30.0, 61.4 20.1, 61.4 SCORAD category mild AD N (%)a - 1 (16.7) - 1 (6.3) moderate AD N (%)a 6 (100.0) 5 (83.3) 3 (75.0) 14 (87.5) severe AD N (%)a - - 1 (25.0) 1 (6.3) N = 0 is shown as a Percentage is based on the N in the treatment group. b Percentage is based on the number of women in the treatment group. AD = atopic dermatitis, BMI = body mass index, CBP = childbearing potential, MAD = multiple ascending doses, max = maximum, min = minimum, N = number of subjects, SAF = safety analysis set, SCORAD = scoring atopic dermatitis. 3.2.1.3 Medical history and concurrent illnesses Any medical history and concurrent illnesses are summarized in Table 9 and Table 10. As per eligibility criteria, all subjects in both study parts had AD. In addition, immune system disorders (various 5 allergies) were most frequently reported in both study parts. Beyond that, in the SAD part, 2 subjects reported migraine, and in the MAD part, 4 subjects each reported depression and asthma. All other conditions were reported by maximal 1 subject in any treatment group. Table 9: Medical history by system organ class - SAD part (SAF) System organ class Preferred term Number (%)a of subjects 15 si-(N pg 544 = 3) 50 pg si-544 (N = 3) 150 pg si-544 (N = 3) 450 pg si-544 900 pg si-544 (N = 3) Placebo Total (N =20) (N = 5) (N = 3) Any event 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 20 (100.0) Congenital, familial and genetic disorders 1 (33.3) - - - - - 1 (5.0) Endocrine disorders - 1 (33.3) - - 1 (33.3) - 2 (10.0) Eye disorders - 1 (33.3) - - - 1 (20.0) 2 (10.0) Immune system disorders 3 (100.0) 2 (66.7) 2 (66.7) 3 (100.0) 2 (66.7) 4 (80.0) 16 (80.0) Allergy to animal 2 (66.7) 1 (33.3) - - 1 (33.3) 2 (40.0) 6 (30.0) Mite allergy 1 (33.3) 1 (33.3) 1 (33.3) 1 (33.3) 1 (33.3) 3 (60.0) 8 (40.0) Seasonal allergy - 1 (33.3) 1 (33.3) 1 (33.3) 1 (33.3) 3 (60.0) 7 (35.0) Infections and infestations - - - - 2 (66.7) 2 (40.0) 4 (20.0) Injury, poisoning and procedural complications - - - - 2 (66.7) - 2 (10.0) Metabolism and nutrition - 1 (33.3) - 1 (33.3) 1 (33.3) - 3 (15.0) disorders Nervous system disorders - - - - 1 (33.3) 2 (40.0) 3 (15.0) Migraine - - - - - 2 (40.0) 2 (10.0) Psychiatric disorders - 1 (33.3) - - - 1 (20.0) 2 (10.0) Respiratory, thoracic and - 1 (33.3) - - - 1 (20.0) 2 (10.0) mediastinal disorders Table 9: Medical history by system organ class - SAD part (SAF) Number (%)a of subjects System organ class Preferred term 15 pg si-544 (N = 3) 50 pg si-544 (N = 3) 150 pg si-544 (N = 3) 450 pg si-544 (N = 3) 900 pg si-544 (N = 3) Placebo (N = 5) Total (N =20) Skin and subcutaneous 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 20 (100.0) tissue disorders Dermatitis atopic 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 20 (100.0) Social circumstances - - - - - 1 (20.0) 1 (5.0) Surgical and medical 1 (33.3) - - - - 1 (20.0) 2 (10.0) procedures Vascular disorders - 1 (33.3) - - - 1 (20.0) 2 (10.0) N = 0 is shown as Preferred terms are only shown for medical history reported in >2 subjects in any treatment group. a Percentage is based on the N in the treatment group. N = number of subjects, SAD = single ascending dose, SAF = safety analysis set. Table 10: Medical history and concurrent illnesses by system organ class - MAD part (SAF) System organ class Preferred term Number (%)a of subjects 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Total (N = 16) Any medical or surgical history 6 (100.0) 6 (100.0) 4 (100.0) 16 (100.0) Blood and lymphatic system disorders - 1 (16.7) - 1 (6.3) Cardiac disorders - 1 (16.7) - 1 (6.3) Endocrine disorders - 1 (16.7) - 1 (6.3) Eye disorders - 1 (16.7) - 1 (6.3) Immune system disorders 2 (33.3) 5 (83.3) 4 (100.0) 11 (68.8) Allergy to animal - 1 (16.7) 2 (50.0) 3 (18.8) Drug hypersensitivity - 3 (50.0) 1 (25.0) 4 (25.0) Food allergy - 2 (33.3) 1 (25.0) 3 (18.8) Mite allergy 1 (16.7)- 1 (16.7) 2 (50.0) 4 (25.0) Seasonal allergy 2 (33.3)- 2 (33.3) 3 (75.0) 7 (43.8) Infections and infestations 1 (16.7) 1 (16.7) 1 (25.0) 3 (18.8) Metabolism and nutrition disorders 2 (33.3) 1 (16.7) - 3 (18.8) Musculoskeletal and connective tissue disorders 1 (16.7) 1 (16.7) 1 (25.0) 3 (18.8) Nervous system disorders - 1 (16.7) - 1 (6.3) Psychiatric disorders 3 (50.0) 3 (50.0) - 6 (37.5) Depression 2 (33.3) 2 (33.3) - 4 (25.0) Reproductive system and breast disorders 2 (33.3) - - 2 (12.5) Respiratory, thoracic and mediastinal disorders 1 (16.7) 1 (16.7) 2 (50.0) 4 (25.0) Asthma 1 (16.7) 1 (16.7) 2 (50.0) 4 (25.0) Skin and subcutaneous tissue disorders 6 (100.0) 6 (100.0) 4 (100.0) 16 (100.0) Dermatitis atopic 6 (100.0) 6 (100.0) 4 (100.0) 16 (100.0) Surgical and medical procedures 1 (16.7) - - 1 (6.3) Vascular disorders - 1 (16.7) - 1 (6.3) Table 10: Medical history and concurrent illnesses by system organ class - MAD part (SAF) Number (%)a of subjects System organ class                           450 pg si-544   900 pg si-544   Placebo        Total Preferred term                               (N = 6)         (N = 6)         (N = 4)         (N = 16) N = 0 is shown as Preferred terms are only shown for medical history reported in >2 subjects in any treatment group. a Percentage is based on the N in the treatment group. MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set. 3.2.1.4 Previous and concomitant therapy Previous (ie, with starting date within 3 months before Screening) and concomitant medication taken by at least 2 subjects in any treatment group are summarized in Table 11 and Table 12. Typical for the underlying disease, the most commonly taken medications in the both study parts were dermatological corticosteroid preparations and other 5 preparations for the treatment of AD. Table 11: Previous and concomitant medication - SAD part (SAF) Number (%)a of subjects WHO-DD ATC level 2 Preferred name 15 pg si-544 (N = 3) 50 pg si-544 (N = 3) 150 pg si-544 (N = 3) 450 pg si-544 (N = 3) 900 pg si-544 (N = 3) Placebo (N = 5) Total (N =20) Any medication 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 20 (100.0) Analgesics - - - - - 2 (40.0) 2 (10.0) Corticosteroids, dermatological 3 (100.0) 2 (66.7) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 19 (95.0) preparations Betamethasone - - - - 2 (66.7) - 2 (10.0) Hydrocortisone - - - - - 3 (60.0) 3 (15.0) Methylprednisolone 3 (100.0) - 1 (33.3) 1 (33.3) 2 (66.7) - 7 (35.0) Mometasone - 1 (33.3) - 2 (66.7) 1 (33.3) 1 (20.0) 5 (25.0) Emollients and protectives - - - 1 (33.3) 3 (100.0) - 4 (20.0) Other dermatological - 3 (100.0) - - 1 (33.3) 3 (60.0) 7 (35.0) preparations Tacrolimus - 3 (100.0) - - - 1 (20.0) 4 (20.0) N = 0 is shown as ATC level 2 and preferred terms are only included for medications reported in >2 subjects in any treatment group. a Percentage is based on the N in the treatment group. ATC = anatomical therapeutic chemical, N = number of subjects, SAD = single ascending dose, SAF = safety analysis set, WHO-DD = World Health Organization Drug Dictionary. Table 12: Previous and concomitant medication - MAD part (SAF) WHO-DD ATC level 2 Preferred name Number (%)a of subjects 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Total (N = 16) Any medication 5 (83.3) 6 (100.0) 4 (100.0) 15 (93.8) Antianemic preparations - 2 (33.3) - 2 (12.5) Antifungals for dermatological use 2 (33.3) 2 (33.3) - 4 (25.0) Antihistamines for systemic use 1 (16.7) 3 (50.0) 3 (75.0) 7 (43.8) Table 12: Previous and concomitant medication - MAD part (SAF) WHO-DD ATC level 2 Preferred name Number (%)a of subjects 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Total (N = 16) Cetirizine 1 (16.7) 1 (16.7) 2 (50.0) 4 (25.0) Antiinflammatory and antirheumatic products 2 (33.3) 3 (50.0) - 5 (31.3) Ibuprofen 2 (33.3) 3 (50.0) - 5 (31.3) Corticosteroids, dermatological preparations 3 (50.0) 5 (83.3) 3 (75.0) 11 (68.8) Hydrocortisone 1 (16.7) 2 (33.3) - 3 (18.8) Methylprednisolone 2 (33.3) 1 (16.7) 1 (25.0) 4 (25.0) Mometasone - 2 (33.3) 1 (25.0) 3 (18.8) Drugs for obstructive airway diseases 1 (16.7) 1 (16.7) 2 (50.0) 4 (25.0) Salbutamol - 1 (16.7) 2 (50.0) 3 (18.8) Emollients and protectives 2 (33.3) 5 (83.3) 2 (50.0) 9 (56.3) Other emollients and protectives 1 (16.7) 3 (50.0) - 4 (25.0) Ophthalmologicals - 1 (16.7) 2 (50.0) 3 (18.8) Psychoanaleptics 1 (16.7) 2 (33.3) - 3 (18.8) Sex hormones and modulators of the genital 3 (50.0) 2 (33.3) 2 (50.0) 7 (43.8) system N = 0 is shown as ATC level 2 and preferred names are only included for medications reported in >2 subjects in any treatment group. a Percentage is based on the N in the treatment group. ATC = anatomic therapeutic chemical, MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set, WHO-DD = World Health Organization Drug Dictionary. 3.2.1.5 Treatment compliance and extent of exposure Extent of exposure All subjects in the SAD part (20) received the single IMP injection as scheduled. In the MAD part of the study, 13 of 16 subjects received all 8 IMP injections as scheduled. 1 subject in the 450 pg si-544 treatment group missed the IMP dose on Day 4 due to elevated laboratory and 2 subjects in the 900 pg si-544 treatment group missed 1 dose each due to missed visits (Day 8 and Day 22). All 3 subjects received the other 7 doses as scheduled. 1 subject took part in both study parts and received a single 450 pg si-544 injection in the SAD part and 8 injections with 900 pg si-544 in the MAD part.. Dose modifications No dose modifications were necessary. Measurement of compliance No compliance calculations were performed. In both study parts, the IMP was administered by the investigator at the study center. 3 subjects in total were not dosed as scheduled, all other subjects received all planned IMP doses. 3.2.2 Safety evaluations The first primary endpoint was the type, frequency, severity, and causal relationship of AEs, serious AEs, and DLTs in the study. The second primary endpoint was the change from Baseline in clinical laboratory, ECG, vital signs, and peripheral oxygen saturation to all assessments during the study. 3.2.2.1 Adverse events 3.2.2.1.1. Brief summary of adverse events An overview of TEAEs is given in Table 13 and Table 14. The proportion of subjects reporting events increased with increasing si-544 dose in both study parts. No related serious TEAEs nor any DLTs were reported in both study parts. In the SAD part, 23 TEAEs were reported in 9 subjects (45%). 4 subjects treated with si-544 and none treated with 5 placebo had TEAEs assessed as related to the IMP (Table 13). No serious TEAEs were reported. Table 13: Overview of treatment-emergent adverse events - SAD part (SAF) 15 pg 50 pg 150 pg 450 pg 900 pg Placebo Total si-544 si-544 si-544 si-544 si-544 (N = 3) (N = 3) (N = 3) (N = 3) (N = 3) (N = 5) (N =20) nAEs N (%)a nAEs N (%)a nAEs N (%)a nAEs N (%)a nAEs N (%)a nAEs N (%)a nAEs N (%)a Any TEAE - - 2 1 (33.3) 6 2 (66.7) 3 2(66.7) 10 3 (100.0) 2 1 (20.0) 23 9 (45.0) Any related - - - - 6 2 (66.7) 2 1 (33.3) 6 1 (33.3) - - 14 4(20.0) TEAE N / n = 0 is shown as Categories with no entries in any group are not included. a Percentage is based on the N in the treatment group. oae = number of adverse events, N = number of subjects, SAD = single ascending dose, SAF = safety analysis set, TEAE = treatment-emergent adverse event. In the MAD part, 160 TEAEs were reported in 14 subjects (88%), of which 10 TEAEs in 3 subjects were reported in the placebo treatment group. 10 subjects, of which 9 subjects were treated with si-544 and 1 subject with placebo, had TEAEs that were assessed as related to the IMP (Table 14). The only serious TEAE was reported in 1 subject in the 900 pg si-544 treatment group (depression, not related to the IMP). Table 14: Overview of treatment-emergent adverse events - MAD part (SAF) 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Total (N = 16) nAEs N (%)a nAEs N (%)a nAEs N (%)a nAEs N (%)a Any TEAE 59 5 (83.3) 91 6 (100.0) 10 3 (75.0) 160 14 (87.5) Any related TEAE 47 4 (66.7) 67 5 (83.3) 1 1 (25.0) 115 10 (62.5) Any serious TEAE - - 1 1 (16.7) - - 1 1 (6.3) N / n = 0 is shown as Categories with no entries in any group are not included. a Percentage is based on the N in the treatment group. MAD = multiple ascending doses, oae = number of adverse events, N = number of subjects, SAF = safety analysis set, TEAE = treatment-emergent adverse event. 10     3.2.2.1.2. Display of adverse events An overview of TEAEs by system organ class is provided in Table 15andTable 16. In the SAD part, no TEAEs were reported for subjects receiving 15 pg si-544. In the other treatment groups, none of the TEAEs was reported in more than 1 subject (Table 15). Table 15: Treatment-emergent adverse events by system organ class - SAD part (SAF) Number (%)a of subjects 15 pg 50 pg 150 pg 450 pg 900 pg Placebo si-544 si-544 si-544 si-544 si-544 System organ class (N = 3) (N = 3) (N = 3) (N = 3) (N = 3) (N = 5) Any event - 1 (33.3) 2 (66.7) 2 (66.7) 3 (100.0) 1 (20.0) Blood and lymphatic system   - disorders Gastrointestinal disorders       - 1 1 (33.3) (33.3) 1 (33.3) 1 (33.3) 1 (20.0) General disorders and         - - 1 (33.3) - 1 (33.3) - administration site conditions Infections and infestations      - 1 (33.3) - - 1 (33.3) 1 (20.0) Investigations                   - 1 (33.3) 1 (33.3) - - - Metabolism and nutrition       - - 1 (33.3) - - - disorders Nervous system disorders     - - 1 (33.3) - 1 (33.3) - Skin and subcutaneous tissue - - - 1 (33.3) 1 (33.3) - disorders N = 0 is shown as a Percentage is based on the N in the treatment group. N = number of subjects, SAD = single ascending dose, SAF = safety analysis set. In the MAD part, the system organ classes infections and infestations, and general disorders and administration site conditions were reported by the highest proportion of subjects in the 450 pg si-544 treatment group (each in 3 of 6 subjects), and infections and infestations and nervous system disorders in the 900 pg si-544 treatment group (each 5 in 5 of 6 subjects). In the placebo treatment group, gastrointestinal disorders and infections and infestations were the only system organ classes affected in more than 1 subject (2 of 4 subjects; Table 16). Table 16: Treatment-emergent adverse events by system organ class and preferred term - MAD part (SAF) System organ class Preferred term Number (%)a of subjects 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Any event 5 (83.3) 6 (100.0) 3 (75.0) Gastrointestinal disorders 2 (33.3) 4 (66.7) 2 (50.0) Hypoaesthesia oral - 2 (33.3) - Paraesthesia oral 1 (16.7) 3 (50.0) - General disorders and administration site 3 (50.0) 4 (66.7) 1 (25.0) conditions Injection site erythema 2 (33.3) 1 (16.7) - Injection site pruritus 3 (50.0) 1 (16.7) - Injection site reaction - 2 (33.3) - Infections and infestations 3 (50.0) 5 (83.3) 2 (50.0) Nasopharyngitis 3 (50.0) 4 (66.7) - Injury, poisoning and procedural complications - 1 (16.7) - Investigations 1 (16.7) - - Metabolism and nutrition disorders - - 1 (25.0) Musculoskeletal and connective tissue disorders 2 (33.3) 2 (33.3) - Nervous system disorders 1 (16.7) 5 (83.3) - Dizziness - 2 (33.3) - Paraesthesia 1 (16.7) 4 (66.7) - Psychiatric disorders - 1 (16.7) - Respiratory, thoracic and mediastinal disorders 1 (16.7) 1 (16.7) 1 (25.0) WO 2025 / 133134                                   PCT / EP2024 / 087928 Table 16: Treatment-emergent adverse events by system organ class and preferred term - MAD part (SAF) 5 Number (%)a of subjects System organ class                           450 pg si-544        900 pg si-544        Placebo Preferred term                               (N = 6)               (N = 6)               (N = 4) Skin and subcutaneous tissue disorders         -                     -                     1 (25.0) N = 0 is shown as Preferred terms are only included for events reported in >2 subjects in any treatment group. a Percentage is based on the N in the treatment group. MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set. 3.2.2.1.3.Analysis of adverse events Severity Most TEAEs in the SAD part of the study were Grade 1, with only few Grade 2 events (in the 150 pg and 450 pg si-544 treatment groups) and no Grade 3 events (Table 17). Table 17: Treatment-emergent adverse events by severity - SAD part (SAF) Number (%)a of events 15 pg       50 pg       150 pg      450 pg      900 pg      Placebo si-544       si-544       si-544       si-544       si-544 Grade                         (N = 3)      (N = 3)      (N = 3)      (N = 3)      (N = 3)      (N = 5) 10 Number of events             -            2           6           3           10          2 Gradel                        -            2 (100.0)    3 (50.0)      1 (33.3)      10 (100.0)   2 (100.0) Grade 2                         -             -             3 (50.0)      2 (66.7)      -             - Zero is shown as a Percentage is based on the number of events in each treatment group (calculated by hand). N = number of subjects, SAD = single ascending dose, SAF = safety analysis set. In the MAD part, most TEAEs were Grade 1 with few Grade 2 events in all treatment groups (Table 18). In the 450 pg si-544 treatment group, 1 subject had Grade 3 transaminases increased and Grade 4 blood creatine phosphokinase increased at the same time. Both events were assessed as not related to the IMP as the subject had started extensive exercise after a longer break in the previous days and had sore muscles. In the 900 pg si-544 treatment group, 1 subject had 2 events of Grade 3 depression, and another subject had Grade 3 nasopharyngitis. None of these events were considered related to the IMP. Table 18: Treatment-emergent adverse events by severity - MAD part (SAF) Number (%)a of events 450 pg si-544        900 pg si-544        Placebo Grade                                       (N = 6)              (N = 6)              (N = 4) Number of events                           59                 91                  10 Gradel                                        54 (91.5)             85 (93.4)             5 (50.0) Grade 2                                        3 (5.1)              3 (3.3)              5 (50.0) Grade 3                                          1  (1.7)               3  (3.3)               - Grade 4                                          1  (1.7)               -                      - Zero is shown as a Percentage is based on the number of events in each treatment group (calculated by hand). MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set. Causality assessment The causality assessment of TEAEs in the SAD part are summarized in Table 19. Details on related TEAEs are provided in Table 21. Table 19: Treatment-emergent adverse events by relationship to IMP - SAD part (SAF) Relationship to IMP Number (%)a of events 15 pg si-544 (N = 3) 50 pg si-544 (N = 3) 150 pg si-544 (N = 3) 450 pg si-544 (N = 3) 900 pg si-544 (N = 3) Placebo (N = 5) Number of events - 2 6 3 10 2 Not related - 2 (100.0) - 1 (33.3) 4 (40.0) 2 (100.0) Related - - 6 (100.0) 2 (66.7) 6 (60.0) - Zero is shown as a Percentage is based on the total number of events per treatment group (calculated by hand). IMP = investigational medicinal product, N = number of subjects, SAD = single ascending dose, SAF = safety analysis set. In the MAD part, most TEAEs in both si-544 treatment groups and 1 TEAE out of 10 in the placebo treatment group 5 were assessed as being related to the IMP (Table 20). Details on related TEAEs are provided in Table 22. Table 20: Treatment-emergent adverse events by relationship to IMP - MAD part (SAF) Relationship to IMP Number (%)a of events 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Number of events 59 91 10 Not related 12 (20.3) 24 (26.4) 9 (90.0) Related 47 (79.7) 67 (73.6) 1 (10.0) a Percentage is based on the total number of events per treatment group (calculated by hand). IMP = investigational medicinal product, MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set. Related TEAEs TEAEs related to the IMP are summarized in Table 21 and Table 22. In the SAD part, related TEAEs were only reported in the 3 higher dose si-544 treatment groups in a total of 4 subjects (Table 21). Table 21: Treatment-emergent adverse events related to the IMP by system organ class - SAD part (SAF) Number (%)a of subjects 15 pg 50 pg 150 pg 450 pg 900 pg Placebo System organ class si-544 si-544 si-544 si-544 si-544 Preferred term (N = 3) (N = 3) (N = 3) (N = 3) (N = 3) (N = 5) Any event - - 2 (66.7) 1 (33.3) 1 (33.3) - Blood and lymphatic system - - 1 (33.3) - - - disorders Lymphopenia - - 1 (33.3) - - - Gastrointestinal disorders - - 1 (33.3) - 1 (33.3) - Abdominal pain - - 1 (33.3) - - - Diarrhoea - - - - 1 (33.3) - General disorders and         - -               1 (33.3)     -               -               - administration site conditions Fatigue                     - -                 1 (33.3)      -                -                 - Investigations                   - -               1 (33.3)     -               -               - C-reactive protein increased - -               1 (33.3)     -               -               - Metabolism and nutrition       - -               1 (33.3)     -               -               - disorders Hyperkalaemia             - -               1 (33.3)     -               -               - Nervous system disorders     - -               1 (33.3)     -               1 (33.3)     - Dizziness                   - -               -               -               1 (33.3)     - Hypoaesthesia             - -               -               -               1 (33.3)     - Paraesthesia                - -               1 (33.3)     -               1 (33.3)     - Skin and subcutaneous tissue - -               -               1 (33.3)     -               - disorders Pruritus                        - -               -               1 (33.3)     -               - N = 0 is shown as a Percentage is based on N in the treatment group. IMP = investigational medicinal product, N = number of subjects, SAD = single ascending dose, SAF = safety analysis set. In the MAD part, more TEAEs related to the IMP were reported in the si-544 treatment group (in 9 out of 12 subjects total) than in the placebo treatment group (in 1 out of 4 subjects). The only related TEAE in the placebo treatment group was feeling hot (1 event, resolved 1 day after onset). Related 5 TEAEs in the si-544 groups included the system organ class gastrointestinal disorders, general disorders and administration site reactions (primarily injection site reactions), and nervous system disorders (Table 22). Most injection site reactions (except for 2 events of hematoma and 1 event of erythema) resolved within minutes or few hours after onset. Paresthesia was the most frequently reported event (44 events in 5 subjects in total). All events of paresthesia resolved within minutes to few hours after onset. Table 22: Treatment-emergent adverse events related to the IMP by system organ class - MAD part (SAF) Number (%)a of subjects System organ class 450 pg si-544 900 pg si-544 Placebo Preferred term (N = 6) (N = 6) (N = 4) Any event 4 (66.7) 5 (83.3) 1 (25.0) Gastrointestinal disorders 2 (33.3) 4 (66.7) - Hypoaesthesia oral - 2 (33.3) - Lip dry 1 (16.7) - - Paraesthesia oral 1 (16.7) 3 (50.0) - General disorders and administration site 3 (50.0) 3 (50.0) 1 (25.0) conditions Feeling cold - 1 (16.7) - Feeling hot - - 1 (25.0) Injection site erythema 2 (33.3) 1 (16.7) - Injection site haematoma 1 (16.7) - - Injection site pruritus 3 (50.0) 1 (16.7) - Injection site reaction - 2 (33.3) - Table 22: Treatment-emergent adverse events related to the IMP by system organ class - MAD part (SAF) System organ class Preferred term Number (%)a of subjects 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Injection site swelling 1 (16.7) - - Injection site urticaria 1 (16.7) - - Nervous system disorders 1 (16.7) 5 (83.3) - Dizziness - 2 (33.3) - Hypoaesthesia - 1 (16.7) - Paraesthesia 1 (16.7) 4 (66.7) - N = 0 is shown as a Percentage is based on the N in the treatment group. IMP = investigational medicinal product, MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set. Outcome In the SAD part, 3 TEAEs in 2 subjects (450 pg si-544: anemia, not related; 900 pg si-544: hypoesthesia foot and cheek [both in the same subject], related) had not resolved by the end of the study. The subject with anemia was advised to see a general practitioner and urologist, if necessary. Follow-up information on the subject with hypoesthesia revealed that both events had resolved after the end of the study (communication with investigator). In the MAD part, 5 TEAEs in 4 subjects (900 pg si-544: pulpitis dental, depression and insomnia [both in the same subject], spinal pain; placebo: leukoplakia oral; all not related) had not resolved by the end of the study. Follow-up information on the subject with depression and insomnia revealed that the subject was being treated and slowly recovering after the end of the study (communication with investigator). Action taken with IMP None of the TEAEs in any study part led to withdrawal of the subject from continued IMP treatment (if applicable) or from the study. 3.2.2.2 Deaths, other serious adverse events, and other significant adverse events 3.2.2.2.1 Deaths No deaths occurred. 3.2.2.2.2 Other serious adverse events The only serious TEAE reported was a Grade 3 depression in 1 subject in the 900 pg si-544 treatment group of the MAD part. The event was assessed as not being related to si-544 treatment. 3.2.2.2.3 Other significant adverse events Dose-limiting toxicities No TEAEs defined as DLTs occurred during both study parts. TEAEs leading to withdrawal from IMP and / or study No permanent discontinuation from IMP treatment or withdrawals from the study due to TEAEs were reported 3.2.2.3 Clinical laboratory evaluation 3.2.2.3.1 Laboratory values overtime 3.2.2.3.1.1 Hematology No apparent differences in the change from Baseline between the si-544 and placebo treatment groups was obvious in any of the assessed parameters in both study parts. 3.2.2.3.1.2 Clinical chemistry No apparent differences in the change from Baseline between the si-544 and placebo treatment groups was obvious in any of the assessed parameters in both study parts. 3.2.2.3.1.2 Coagulation and urinalysis No apparent differences in the change from Baseline between the si-544 and placebo treatment groups was obvious in any of the assessed parameters in both study parts. 3.2.2.3.2 Individual subject changes All subjects with clinically significantly abnormal laboratory values at postbaseline visits had normal or not clinically significant values at Baseline. 3.2.2.3.3 Individual clinically significant abnormalities Clinically significantly abnormal laboratory values reported in the SAD and MAD part are shown in Table 23 and Table 24, respectively. No clinically significant abnormalities were reported for coagulation parameters. In the SAD part, 5 subjects in the si-544 treatment groups and 1 subject in the placebo treatment group had clinically significantly abnormal laboratory values that were reported as TEAEs in all but 1 subject whose condition was already present at Screening. In 2 subjects in the 150 pg si-544 treatment group the TEAEs were assessed as related to the treatment with si-544 (Table 23). These events had resolved 2 days (hyperkalemia) or 3 days (lymphopenia, C-reactive protein increased) after onset. The clinically significant abnormal hematology values of 1 subject at Day 1 were discussed by the DEC in an ad hoc meeting and results of Day 4 were awaited before the next subject was dosed. As these values were within normal range, dosing commenced (refer to the DEC recommendation form). Table 23: Individual clinically significantly abnormal laboratory values - SAD part (SAF) Treatment group Parameter Visit Value Unit Normal range Adverse event 50 pg si-544 CRP Day 1 10.0 mg / L 0-4.9 CRP increased 150 pg si-544 Lymphocytes Day 4 11.9 % 20-44 Lymphopenia Lymphocytes (abs.) Day 4 0.83 109 / L 1.1 -4.5 Lymphopenia CRP Day 4 14.7 mg / L 0-4.9 CRP increased 150 pg si-544 Potassium Day 1 5.7 mmol / L 3.5-5.1 Hyperkalemia 450 pg si-544 Hemoglobin Day 8 13.1 g / dL 13.5 -17.2 Anemia Microscopic Day 8 5 1 / hpf 0-3 Anemia erythrocytes (urine) 900 pg si-544 Erythrocytes Day 1 3.16 1012 / L 3.9-5.15 Hb decreased Hb Day 1 9.2 g / dL 12 -15.4 Hb decreased Hematocrit Day 1 28.3 % 35.5-45 Hb decreased Placebo Eosinophils Day 1 14.7 % 0.5-5.5 Eosinophilia Day 4 13.3 % 0.5-5.5 Eosinophilia Table 23: Individual clinically significantly abnormal laboratory values - SAD part (SAF) Treatment group Parameter Visit Value Unit Normal range Adverse event 50 pg si-544 CRP Day 1 10.0 mg / L 0-4.9 CRP increased Eosinophils (abs.) Day 1 0.93 109 / L 0.02-0.5 Eosinophilia Day 4 0.93 109 / L 0.02-0.5 Eosinophilia AEs shown in bold were assessed as IMP-related, AEs shown in italics were pretreatment adverse events. Abs. = absolute, AE = adverse event, CRP = C-reactive protein, Hb = hemoglobin, hpf = high-power field, IMP = investigational medicinal product, SAD = single ascending dose, SAF = safety analysis set. In the MAD part, 4 subjects in the si-544 treatment groups and 1 subject in the placebo treatment group had clinically significantly abnormal laboratory values reported as TEAEs. None of these were assessed as related to the IMP treatment (Table 24). Table 24: Individual clinically significantly abnormal laboratory values - MAD part (SAF) Treatment group Parameter Visit Value Unit Normal range Adverse event 450 pg si-544 AST Day 1 182 U / L 0-50 Transaminases increased Day 4 311 U / L 0-50 Transaminases increased CPK Day 1 14797 U / L 0-308 Blood CPK increased Day 4 13781 U / L 0-308 Blood CPK increased USV 1 1563 U / L 0-308 Blood CPK increased Day 8 826 U / L 0-308 Blood CPK increased CRP Day 8 12.9 mg / L 0-4.9 Nasopharyngitis 450 pg si-544 CRP Day 78 22.9 mg / L 0-4.9 Rhinorrhea 900 pg si-544 CPK Day 29 1352 U / L 0-308 Myalgia CRP Day 78 11.4 mg / L 0-4.9 Nasopharyngitis 900 pg si-544 CRP Day 11 32.1 mg / L 0-4.9 Nasopharyngitis Placebo Ferritin Day 78 13.1 pg / L 31.3 -408.5 Iron deficiency Day 106 14.2 pg / L 31.3 -408.5 Iron deficiency AST = aspartate aminotransferase, CPK = creatine phosphokinase, CRP = C-reactive protein, MAD = multiple ascending doses, SAF = safety analysis set, USV = unscheduled visit. 3.2.2.4 Electrocardiogram, vital signs, and peripheral oxygen saturation 5     3.2.2.4.1 Electrocardiogram For no subject the ECG was evaluated as clinically significantly abnormal in the SAD or the MAD part. 3.2.2.4.2 Vital signs No subject had a clinically significantly abnormal vital sign assessment in the SAD or the MAD part. 3.2.2.4.3 Peripheral oxygen saturation 10 Absolute values are summarized for the SAD part in Table 25 and for the MAD part in Table 26. No substantial changes in mean peripheral oxygen saturation were observed from before to after IMP injection at Day 1 in the SAD part nor during follow up, or from before to after IMP injection at treatment days in the MAD part nor during the follow up. Table 25: Peripheral oxygen saturation - SAD part (SAF) Mean (SD) peripheral oxygen saturation [%] 15 pg 50 pg 150 pg 450 pg 900 pg Placebo si-544 si-544 si-544 si-544 si-544 Visit (N = 3) (N = 3) (N = 3) (N = 3) (N = 3) (N = 5) D1 before IMP 97.0 (1.0) 98.7 (0.6) 98.7 (0.6) 97.7 (0.6) 99.0 (0.0) 98.4 (1.1) D1 after IMP 98.7 (0.6) 98.7 (0.6) 99.0 (0.0) 99.0 (0.0) 99.0 (0.0) 98.0 (0.7) D4 97.3 (0.6) 98.0 (1.7) 98.7 (0.6) 98.3 (1.2) 99.0 (0.0) 97.8 (0.8) D8 97.7 (0.6) 96.3 (3.8) 97.7 (1.2) 98.7 (0.6) 98.7 (0.6) 97.6 (1.5) D = Day, IMP = investigational medicinal product, N = number of subjects, SAD = single ascending dose, SAF = safety analysis set. Table 26: Peripheral oxygen saturation - MAD part (SAF) Visit Mean (SD) peripheral oxygen saturation [%] 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) D1 before IMP 98.3 (0.8) 97.8 (1.3) 97.8 (1.3) D1 after IMP 96.7 (3.0) 98.2 (1.0) 98.0 (0.8) D4 before IMP 98.0 (0.9) 98.3 (0.8) 98.5 (0.6) D4 after IMP 98.2 (0.8) 98.7 (0.5) 98.3 (1.0) D8 before IMP 98.2 (0.8) 98.6 (0.5) 98.8 (0.5) D8 after IMP 98.0 (0.9) 98.6 (0.9) 98.5 (1.0) D11 before IMP 97.7 (0.8) 98.5 (0.5) 96.8 (2.6) D11 after IMP 97.8 (1.0) 98.0 (1.5) 98.8 (0.5) D15 before IMP 98.3 (1.0) 98.3 (0.8) 97.3 (2.4) D15 after IMP 98.0 (1.3) 98.2 (1.3) 98.3 (1.0) D18 before IMP 97.0 (2.0) 98.7 (0.5) 98.0 (0.8) D18 after IMP 97.5 (1.2) 98.7 (0.5) 98.3 (0.5) D22 before IMP 98.0 (1.1) 98.6 (0.5) 97.8 (1.3) D22 after IMP 98.0 (1.1) 98.8 (0.4) 98.0 (0.0) D25 before IMP 97.7 (1.2) 98.5 (0.5) 98.0 (1.4) D25 after IMP 98.3 (0.8) 98.7 (0.5) 97.5 (1.3) D29 98.0 (0.9) 98.8 (0.4) 97.8 (1.5) D50 97.8 (1.0) 98.5 (0.8) 97.5 (1.7) D78 98.0 (1.1) 98.3 (0.8) 96.0 (3.4) D106 97.7 (0.8) 98.7 (0.5) 98.0 (1.2) D = Day, IMP = investigational medicinal product, MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set. 3.2.2.5 Other safety parameters 3.2.2.5.1 Physical examination In both study parts, most body systems were assessed as being normal. All subjects had clinically significantly abnormal skin findings due to the AD at Screening. Most other clinically significantly abnormal findings were already present at Screening. 6 subjects in the MAD part had clinically significantly findings that were not present at Screening and reported as the following TEAEs: 5 subject treated with si-544 had sore muscles (2 subjects), nasopharyngitis, joint swelling, and ligament sprain, and 1 subject treated with placebo had oral leukoplakia, rhinitis, and bronchitis. None of these events were related to the IMP. 3.2.2.5.1 Neurological examination The only abnormal finding (clinically significant hypoesthesia) in 1 subject in the 900 pg si-544 treatment group of the SAD part had already been present at Screening. 3.2.2.6 Safety summary SAD part •   23 TEAEs were reported in 9 subjects (45%), 2 TEAEs in 1 subject treated with placebo, and 21 TEAEs in 8 subjects treated with si-544 • All TEAEs were Grade 1 or Grade 2 • No DLTs and no serious TEAEs were reported • TEAEs related to the IMP were reported in a total of 4 subjects of the higher dose si-544 treatment groups (2 subjects in the 150 pg and 1 each in the 450 pg and 900 pg treatment group) with no reports in the placebo treatment group •   2 subjects in the 150 pg si-544 treatment groups had clinically significantly abnormal laboratory values that were reported as TEAEs assessed as related to the si-544 treatment (hyperkalemia; lymphopenia, C-reactive protein increased) • No clinically significantly abnormal findings were observed in ECG, or vital signs. The peripheral oxygen saturation did not substantially change from Baseline in any treatment group • No clinically significant abnormal findings that were not already present at Screening were reported in physical or neurological examination MAD part •   160 TEAEs were reported in 14 subjects (88%), 10 TEAEs in 3 subjects treated with placebo and 150 TEAEs in 11 subjects treated with si-544 • Most TEAEs were Grade 1 or Grade 2; 1 subject in the 450 pg si-544 treatment group had 1 Grade 3 (transaminases increased) and 1 Grade 4 (blood creatine phosphokinase increased) event. In the 900 pg si-544 treatment group, 2 subjects had Grade 3 events (depression and nasopharyngitis). None of the Grade 3 or Grade 4 events were related to the si-544 treatment • The only serious TEAE was reported in 1 subject in the 900 pg si-544 treatment group (depression, not related to the IMP) • Infections and infestations, and general disorders and administration site conditions were reported by the highest proportion of subjects in the 450 pg si-544 treatment group (in 3 of 6 subjects), and infections and infestations and nervous system disorders in the 900 pg si-544 treatment group (in 5 of 6 subjects). In the placebo treatment group, gastrointestinal disorders and infections and infestations were the only system organ classes affected in more than 1 subject (in 2 of 4 subjects) •   9 out of 12 subjects treated with si-544 and 1 out of 4 subjects treated with placebo had TEAEs assessed as related to the IMP; related TEAEs in the si-544 groups included gastrointestinal disorders, general disorders and administration site reactions (primarily injection site reactions), and nervous system disorders • Paresthesia was the most frequently reported related TEAE after si-544 treatment (44 events in 5 subjects total) • No subject had clinically significantly abnormal laboratory values reported as TEAE assessed as related to the IMP • No clinically significantly abnormal findings were observed in ECG, or vital signs. The peripheral oxygen saturation did not substantially change from Baseline in any treatment group •   6 subjects had clinically significantly physical examination findings reported as TEAEs (5 subjects treated with si-544 and 1 subject with placebo), none of which were related to the IMP • No clinically significant abnormal findings were reported in the neurological examination 3.2.3 Pharmacokinetics, pharmacodynamics, efficacy, and other evaluations 3.2.3.1 Pharmacokinetics and pharmacodynamics 3.2.3.1.1 Drug dose, drug concentration, and relationship to response 3.2.3.1.1.1 Plasma concentration of free si-544 Plasma concentration measurements of free si-544 were performed at Day 1 of the 450 pg and 900 pg si-544 treatment group in the SAD part and at Day 1 and Day 25 of both si-544 treatment groups in the MAD part. In both study parts, free si-544 concentrations were below the limit of quantification (5 ng / mL) immediately before and after dosing. Few subjects (1 subject in the SAD part, and 2 subjects in the MAD part) had first detectable concentrations at 5 minutes after dosing, with a generally short window with detectable concentrations for most subjects. Free si-544 plasma concentrations from 15 minutes postdose are summarized in Table 27. In the SAD part, mean si-544 plasma concentrations in both treatment groups were highest 1 hour postinjection. In the MAD part at Day 1, mean si-544 plasma concentrations were highest 30 minutes postinjection in the 450 pg group and 1 hour postinjection in the 900 pg group, while at Day 25 (ie, after multiple si-544 injections), mean si-544 plasma concentrations were highest 1 hour postinjection in the 450 pg and 30 minutes postinjection in the 900 pg treatment group. Table 27: Free si-544 plasma concentrations (ng / mL) - SAD and MAD part (SAF) SAD Day 1 MAD Day 1 MAD Day 25 Time 450 pg 900 pg 450 pg 900 pg 450 pg 900 pg point si-544 si-544 si-544 si-544 si-544 si-544 [hh:mm] (N = 3) (N = 3) (N = 6) (N = 6) (N = 6) (N = 6) 00:15 n - 3 1 5 1 5 Mean na 6.22 na 11.86 na 12.58 (SD) (0.577) (3.303) (6.032) 00:30 n 1 3 5 6 5 5 Mean na 13.61 9.29 16.48 6.78 20.95 (SD) (3.405) (6.383) (6.874) (2.065) (6.414) 01:00 n 2 3 5 5 5 6 Mean 7.92 18.18 9.08 20.49 8.52 20.49 (SD) (0.439) (1.960) (2.349) (4.496) (1.926) (6.459) 02:00 n 2 3 5 6 5 6 Mean 6.89 13.35 7.11 14.16 7.13 14.03 (SD) (2.472) (1.411) (1.165) (2.778) (1.796) (3.282) 04:00 n - 1 - 5 - 4 Mean na na na 6.37 na 7.42 (SD) (0.745) (0.427) n = 0 is shown as Descriptive statistics were only computed if at least half of the individual concentrations at the respective time point were >LLOQ (5 ng / mL); otherwise shown as ‘na’. LLOQ = lower limit of quantification, MAD = multiple ascending doses, N = number of subjects, n = number of subjects in the analysis, na = not applicable, SAD = single ascending dose, SAF = safety analysis set. 3.2.3.1.1.2 Pharmacokinetic parameters PK parameters are summarized in Table 28. In both study parts, the geometric mean Cmax in the 450 pg si-544 treatment group was about half the Cmax of the 900 pg si-544 treatment group, with a median Tmax of about 1 hour in all treatment groups and at all assessed time points. The total exposure to si-544 (AUCo-iast) was 3 to 4 times higher 5 in the 900 pg than in the 450 pg treatment group. Table 28: Pharmacokinetic parameters - SAD and MAD part (SAF) SAD Day 1 MAD Day 1 MAD Day 25 Parameter 450 pg si-544 (N = 3) 900 pg si-544 (N = 3) 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) AUCo-sh [h*ng / mL] n gMean (gcv [%]) 1 na na na 2 74.11 (5.970) na 2 78.31 (9.713) AUCo-iast [h*ng / mL] n gMean (gcv [%]) 2 12.27 (60.252) 3 47.05 (58.501) 5 13.82 (39.135) 6 42.60 (60.797) 5 12.38 (26.283) 6 40.07 (79.424) AUCo-~ [h*ng / mL] n gMean (gcv [%]) na na na 2 78.22 (0.821) na 2 81.40 (9.433) Cmax [ng / mL] n gMean (gcv [%]) 2 9.94 (39.092) 3 18.11 (10.832) 5 9.77 (47.090) 6 17.89 (36.743) 5 8.35 (22.419) 6 19.80 (44.185) t% [h] n Median (min, max) na na na 2 1.80 (1.33, 2.27) na 2 1.64 (1.60, 1.67) Tmax [h] n Median (min, max) 2 0.76 (0.52, 1.00) 3 1.00 (1.00, 1.02) 5 1.00 (0.50, 1.00) 6 1.00 (0.50, 2.00) 5 1.00 (0.98, 1.00) 6 0.99 (0.50, 1.00) n = 0 is shown as Parameters were only calculated if at least 3 concentration values of 1 subject were >LLOQ (5 ng / mL) after Cmax; otherwise shown as ‘na’. Concentrations <LLOQ were set to zero or ignored. AUC = area under the plasma concentration time curve, AUCo-sh = AUC from time zero to 8 hours, AUCo-iast = AUC from time zero until the time of the last quantifiable concentration, AUCo-~ = AUC from time zero infinite time, Cmax = maximum plasma concentration, gCV = geometric coefficient of variation, gMean = geometric mean, LLOQ = lower limit of quantification, MAD = multiple ascending doses, max = maximum, min = minimum, N = number of subjects, n = number of subjects in the analysis, na = not applicable, SAD = single ascending dose, SAF = safety analysis set, t% = apparent terminal elimination half-life, Tmax = time to reach Cmax- 3.2.3.1.1.3 Dose proportionality Dose proportionality was calculable with slopes close to 1 in the SAD part for AUCo-iast and Cmax (Table 29). Table 29: Dose proportionality - SAD part (SAF) Parameter Slope (95% Cl) N 3 AUCo-iast [h*ng / mL] Cmax [ng / mL] 1.94 (-0.35, 4.23) 0.87 (-0.12, 1.85) AUCo-iast = area under the plasma concentration time curve from time zero until the time of the last quantifiable concentration, Cmax = maximum plasma concentration, N = number of subjects, SAD = single ascending dose, SAF = safety analysis set. 3.2.3.1.2 Pharmacodynamics 3.2.3.1.2.1 T cell subsets A summary of CD2+ lymphocytes and T cell subsets is shown in Table 30. No substantial change from Baseline was observed for CD2+ lymphocyte counts with no apparent difference between the treatment groups. For the following T cell subsets and timepoints, a difference in means and medians between si-544 and placebo treatment was observed: Increase from Baseline in the si-544 treatment groups vs decrease in the placebo treatment group: • Day 29: CD2+ CD4- CD8+ CCR7+ CD45RA+ • Day 106: o  CD2+ CD4+ CD8- o  CD2+ CD4+ CD8- CCR7+ CD45RA+ Decrease from Baseline in the si-544 treatment groups vs increase or no change from Baseline in the placebo treatment group: • Day 29 o  CD2+ CD4- CD8+ CCR7- CD45RA- (450 pg si-544 only; 900 pg si-544: no change from Baseline) o  CD2+ CD4- CD8+ Ki-67+ (placebo no change from Baseline) • Day 106 o  CD2+ CD4- CD8+ o  CD2+ CD4- CD8+ CCR7- CD45RA+ o  CD2+ CD4- CD8+ Ki-67+ o  CD2+ CD45RO+ CLA+ However, only 2 subjects had available Day 1 data to calculate the changes from Baseline in the placebo treatment group. Table 30: T cell subsets - MAD part (SAF) 450 pg sr -544 900 pg si-544 (N = 6) Placebo (N = 4)ab Parameter     (N = 6)a Visit         Median Mean (SD) Median Mean (SD) Median Mean (SD) CD2+ lymphocytes [ / nL] D1 (BL)        1.510 1.718 (0.506) 1.435 1.400 (0.260) 1.735 1.735 (0.375) CFB D29   0.020 -0.054 (0.319) -0.040 0.017 (0.225) -0.160 -0.160 (0.297) CFBD106 -0.060 -0.048 (0.167) -0.085 -0.053 (0.261) -0.120 -0.120 (0.156) CD2+ CD4- CD8+ [%]c D1 (BL)        29.200 31.060 (5.893) 35.550 34.767 (4.189) 32.150 32.150 (5.020) CFB D29   -2.400 -1.740 (1.412) -1.300 -1.600 (2.231) -1.000 -1.000 (3.111) CFBD106 -1.400 -1.460 (1.019) -1.700 -1.733 (1.179) 0.400 0.400 (1.556) CD2+ CD4- CD8+ CCR7+ CD45RA- [%]c D1 (BL)        0.100 0.180 (0.192) 0.300 0.280 (0.084) 0.200 0.200 (0.000) CFB D29   0.000 -0.040 (0.089) -0.100 -0.120 (0.084) -0.100 -0.100 (0.000) CFBD106 0.000 -0.040 (0.055) -0.100 -0.080 (0.130) -0.100 -0.100 (0.000) CD2+ CD4- CD8+ CCR7+ CD45RA+ [%]c D1 (BL)        13.100 11.940 (5.410) 14.400 14.240 (3.053) 9.950 9.950 (1.485) CFB D29   0.400 0.880 (1.842) 0.600 0.840 (1.064) -0.500 -0.500 (1.414) CFBD106 0.300 0.940 (2.725) -0.200 -0.100 (0.935) -1.450 -1.450 (0.495) CD2+ CD4- CD8+ CCR7- CD45RA- [%]c D1 (BL)        1.800 2.000 (1.655) 3.100 3.440 (0.921) 4.200 4.200 (0.707) CFBD29 -0.100 -0.160 (0.207) 0.000 0.000 (0.464) 0.450 0.450 (0.636) CFBD106 0.200 0.320 (0.444) 0.400 0.260 (0.378) 0.550 0.550 (0.071) CD2+ CD4- CD8+ CCR7- CD45RA+ [%]c D1 (BL)        15.000 16.920 (8.917) 18.400 15.940 (5.100) 17.900 17.900 (2.828) CFB D29   -2.300 -2.360 (2.590) -0.800 -1.760 (3.058) -0.900 -0.900 (3.960) CFBD106 -1.500 -2.640 (3.663) -1.300 -1.720 (1.446) 1.250 1.250 (2.051) CD2+ CD4- CD8+ Ki-67+ [%]c D1 (BL)        1.300 1.180 (0.482) 1.300 1.433 (0.565) 0.750 0.750 (0.071) CFBD29 -0.100 -0.200 (0.400) -0.400 -0.483 (0.467) 0.000 0.000 (0.566) CFBD106 -0.300 -0.220 (0.259) -0.550 -0.650 (0.501) 0.400 0.400 (0.000) CD2+ CD4+ CD8- [%]c D1 (BL)        60.000 58.580 (8.574) 55.650 53.217 (8.541) 56.550 56.550 (7.142) CFB D29   4.300 3.820 (3.406) 2.550 3.450 (3.701) 2.300 2.300 (5.091) CFBD106 2.200 3.380 (2.784) 3.900 3.650 (1.600) -0.600 -0.600 (2.404) CD2+ CD4+ CD8- CCR7+ CD45RA- [%]c D1 (BL)        4.600 6.280 (6.784) 5.900 6.720 (1.805) 7.000 7.000 (0.707) CFB D29   -0.200 -0.500 (0.663) -1.500 -1.000 (1.122) -1.450 -1.450 (1.061) CFBD106 -0.200 -0.340 (0.488) -0.300 -1.000 (1.259) -1.800 -1.800 (0.141) CD2+ CD4+ CD8- CCR7+ CD45RA+ [%]c D1 (BL)        31.800 34.820 (9.146) 32.000 31.300 (9.247) 31.800 31.800 (1.838) CFB D29   4.300 3.320 (3.097) 1.700 2.480 (2.641) 0.650 0.650 (5.303) CFBD106 4.600 3.580 (3.840) 1.600 1.760 (1.001) -2.150 -2.150 (4.172) CD2+ CD4+ CD8- CCR7- CD45RA- [%]c D1 (BL)        8.900 9.940 (6.982) 10.500 11.320 (1.497) 14.200 14.200 (3.253) CFBD29 -0.100 0.420 (0.934) 0.100 0.200 (1.247) 2.300 2.300 (1.131) CFBD106 -0.100 -0.280 (1.180) -0.300 0.140 (1.014) 1.000 1.000 (0.849) CD2+ CD4+ CD8- CCR7- CD45RA+ [%]c D1 (BL)        5.400 7.560 (6.930) 3.900 3.520 (1.377) 3.550 3.550 (1.344) CFB D29   0.600 0.560 (1.640) 0.900 1.100 (0.880) 0.750 0.750 (0.212) CFBD106 0.500 0.380 (1.361) 2.900 2.600 (1.409) 2.300 2.300 (1.131) CD2+ CD4+ CD8- Ki-67+ [%]c D1 (BL)        1.700 2.020 (1.013) 2.100 1.983 (0.500) 1.900 1.900 (0.283) CFBD29 0.100 -0.140 (0.541) -0.300 -0.433 (0.383) -0.400 -0.400 (0.283) CFBD106 -0.200 -0.340 (0.564) -0.650 -0.767 (0.505) -0.100 -0.100 (0.000) CD2+ CD45RO+ CLA+ [%]c D1 (BL) 10.700 10.960 (2.190) 6.150 7.933 (4.869) 15.000 15.000 (5.091) CFB D29 -0.200 -1.160 (2.505) -0.050 -0.583 (1.806) -1.050 -1.050 (4.172) CFB D106 -0.100 -0.440 (2.273) -0.350 -0.617 (1.551) 0.600 0.600 (4.525) CD2+ CD45RO- - CLA+ [%]c D1 (BL) 20.800 16.120 (9.358) 1.950 4.717 (6.000) 15.000 15.000 (5.798) CFB D29 -2.000 -4.940 (5.488) -0.250 -0.400 (0.944) -0.700 -0.700 (0.707) CFB D106 -1.100 -2.820 (3.706) -0.650 -1.100 (1.208) -0.250 -0.250 (2.616) a For N = 1, values were excluded as the Day 1 sample was erroneously taken after IMP injection. b For N = 1, the sample was hemolytic and could not be analyzed. c Percentage is based on CD2+ lymphocyte counts. BL = Baseline, CFB = change from Baseline, D = Day, IMP = investigational medicinal product, MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set. 3.2.3.1.2.2 Serum cytokines Biomarkers were only assessed during the MAD part of the study. Descriptive statistics for serum cytokine levels at Baseline and changes from Baseline are summarized for parameters that were measurable in >1 subject in Table 31. 5 IL-8 and TNF-a were the only parameters for which all subjects had values above the LLOQ at all visits. IL-1p, IL-2, IL-4, IL-12, IL-13, and IL-17Awere not detectable (ie, below the LLOQ) in most (IL-1 p) or all subjects (IL-2, IL-4, IL-12, IL-13, and IL-17A). Median IFN-y levels were decreased at Day 29 compared to Baseline in both the 450 pg and 900 pg si-544 treatment groups, while a slight increase is observed in the placebo treatment group. During follow up, decreased 10 median (and mean) IFN-y levels were maintained in the 450 pg si-544 treatment group. By contrast, TNF-a and IL-8 levels increased at all postbaseline visits in the 450 pg group and at Day 29 in the 900 pg si-544 treatment group but decreased at all postbaseline visits in the placebo treatment group. However, for all parameters, inter-subject variability was high. No apparent trend or difference between the treatment groups was seen for IL-6 and IL-10. Table 31: Serum cytokine levels - MAD part (SAF) Parameter Visit 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Median Mean (SD) Median Mean (SD) Median Mean (SD) IFN-y[pg / mL] D1 (BL) 9.815a 10.787 (7.808)a 7.355 6.537 (2.883) 3.165f 2.970 (0.799 / CFB D29 -0.955a -4.722 (8.190)a -0.810 0.262 (2.717) 0.405 1.598 (2.737) CFB D50 -1.605b -4.530 (8.837 / -0.725 -0.540 (1.258) -0.245 0.943 (2.812) CFB D78 -1.195a -2.668 (10.706 / 0.530 0.412 (2.354) 2.005 6.773 (10.810) CFB D106 -2.220 -3.323 (8.799) 0.260 3.978 (8.135) 2.745 4.070 (4.077) IL-8 [pg / mL] D1 (BL) 9.565 9.190 (1.940) 8.970 9.105 (1.624) 9.990f 10.863 (4.551 )f CFB D29 -0.010 -0.473 (2.569) -0.515 -0.477 (0.603) -1.535 -2.413 (4.477) CFB D50 1.905 1.410 (3.570) 0.210 0.203 (1.479) -0.230 -0.493 (1.193) CFB D78 1.080 1.455 (4.404) -0.170 -0.862 (1.878) -0.585 -1.380 (4.984) CFB D106 0.490 0.748 (2.940) -1.760 -1.655 (1.835) -0.490 -0.908 (2.543) TNF-a [pg / mL] D1 (BL) 1.210 1.198 (0.231) 1.100 1.138 (0.206) 1.235 1.563 (0.820) CFB D29 0.040 0.088 (0.156) 0.045 0.025 (0.126) -0.025 -0.393 (0.827) CFB D50 0.100 0.070 (0.170) -0.085 -0.060 (0.201) -0.115 -0.433 (0.912) CFB D78 0.045 0.188 (0.499) -0.090 -0.073 (0.164) -0.010 -0.353 (0.890) CFB D106 0.005 0.058 (0.206) -0.080 -0.060 (0.124) -0.145 -0.508 (0.908) IL-6 [pg / mL] D1 (BL) 0.645° 0.920 (0.458)° 0.630 0.630 (0.000) 0.630^ 0.630 (0.000)df CFB D29 0.010a -0.137 (0.282)a 0.000s 0.012 (0.029)6 0.000d 0.000 (0.000)d CFB D50 0.220b 0.193 (0.553)b 0.000 0.000 (0.000) 0.00CP 0.010 (0.020)° CFB D78 0.000° -0.150 (0.579)° 0.050° 0.138 (0.208)° 0.005b 0.008 (0.010)b CFB D106 -0.010b 0.063 (0.930)b 0.000d 0.032 (0.050)d 0.000d 0.000 (0.000)d IL-10 [pg / mL] D1 (BL) 0.300d 0.360 (0.095)d 0.300d 0.317 (0.041 )d 0.300^ 0.300 (0.000)d f CFB D29 0.000d -0.020 (0.033)d 0.000s -0.013 (0.033)6 0.000d 0.000 (0.000)d CFB D50 0.000d 0.027 (0.052)d 0.000d 0.003 (0.059)d 0.000d 0.000 (0.000)d CFB D78 0.000d 0.053 (0.146)d 0.000s -0.017(0.041)6 0.000d 0.000 (0.000)d CFB D106 o.oood 0.143 (0.346)d 0.000d 0.037 (0.144)d 0.00CP 0.010 (0.020)° Only parameters for which >1 subject within a treatment group had values >LLOQ are included. Values <LLOQ were replaced by the corresponding LLOQ. Means or medians corresponding to the LLOQ are shown in italics. CFB shown in italics indicate that the absolute mean or median at that visit equals the LLOQ. Values were below the LLOQ for:a N = 1 bN = 2 CN = 3 dN = 4 eN = 5. f For N = 1, the sample was hemolytic. BL = Baseline, CFB = change from Baseline, D = Day, IL = interleukin, IFN = interferon, LLOQ = lower limit of quantification, MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set, TNF = tumor necrosis factor. 3.2.3.2 Immunogenicity Immunogenicity was assessed by anti-drug antibody titration. 1 subject in the 900 pg si-544 treatment group had a titration result of 80 ng / mL at Day 29. Titration was negative for all other assessed subjects at Day 1 and Day 29. 5      3.2.3.3 Efficacy results Secondary efficacy was only assessed during the MAD part of the study. 3.2.3.3.1 Secondary efficacy endpoints 3.2.3.3.1.1 Body surface index The inflamed skin areas were assessed as percentage of the total BSA using the body surface index. A summary of 10 the body surface index is shown in Table 32. At Baseline, the mean affected BSA in the 900 pg si-544 with a body surface index of about 9% was substantially lower than in the 450 pg si-544 and placebo treatment group (19% and 24%). After 4 weeks of treatment (Day 29), the body surface index had improved in all treatment groups. Improvement was lower in the 450 pg and 900 pg si-544 treatment groups with a decrease in the body surface index of 9% and 12%, respectively, than in the placebo treatment group (decrease of 29%). During follow-up, the body 15 surface index further decreased to a similar level in both si-544 treatment groups. The highest improvement was observed in the placebo treatment group, which was most likely due to the differences already present at Baseline (eg, acute flare). Table 32: Body surface index - MAD part (SAF) Mean (SD) body surface index [% involvement] 450 pg si-544                   900 pg si-544                   Placebo (N = 6)                           (N = 6)                           (N = 4) Abs value Rel CFB [%] Abs value Rel CFB [%] Abs value Rel CFB [%] D1 (BL) 18.98 (20.34) na 8.68 (7.41) na 24.28 (13.19) na D15 19.50 (22.99) -12.55 (20.67) 9.03 (10.60) 9.40 (42.50) 20.30 (16.71 )a -8.27 (43.79)a D29 18.88 (20.66) -8.73 (35.77) 8.33 (11.22) -11.75 (61.18) 15.58 (14.63) -28.85 (50.16) D50 18.08 (20.38) -23.55 (35.35) 7.70 (11.69) -21.63 (56.68) 16.08 (16.85) -31.10 (59.16) D78 17.98 (21.85) -34.67 (42.67) 8.40 (12.47) -18.78 (66.63) 8.28 (7.75) -63.10 (38.87) D106 14.82 (16.19) -40.25 (40.72) 7.37 (13.04) -40.90 (58.52) 8.60 (8.10) -62.53 (39.97) The body surface index is calculated of a percentage of the BSA. The maximal possible body surface index was 100%. a For N = 1 data were missing due to an incomplete BSA assessment. Abs = absolute, BL = Baseline, BSA = body surface area, CFB = change from Baseline, D = Day, MAD = multiple ascending doses, N = number of subjects, na = not applicable, rel = relative, SAF = safety analysis set. 3.2.3.3.1.2 Atopic dermatitis severity The severity of AD was assessed using the SCORAD comprising 3 domains: extent of disease assessed using the body surface index, intensity of the disease using the eczema severity score and the subjective symptom score. 5 The eczema severity score is summarized in Table 33. At Baseline, the eczema severity was slightly higher in the 450 pg than in the 900 pg si-544 treatment group, with the highest severity in the placebo treatment group. The eczema severity had decreased in both si-544 treatment groups after 4 weeks of treatment (Day 29), and this improvement was maintained throughout the follow-up. A similar trend was observed in the placebo treatment group. Table 33: Eczema severity score - MAD part (SAF) Mean (SD) of eczema severity 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Abs value Rel CFB [%] Abs value Rel CFB [%] Abs value Rel CFB [%] D1 (BL) 7.67 (1.37) na 5.67 (1.51) na 9.25 (4.86) na D15 8.17 (3.19) 12.27 (61.26) 6.17 (1.72) 13.88 (44.00) 7.33 (5.13) -10.70 (12.88) D29 5.67 (1.37) -25.22 (16.85) 4.83 (2.71) -8.35 (61.25) 6.75 (3.77) -22.33 (21.10) D50 5.17 (1.47) -32.40 (14.66) 4.83 (1.72) -12.50 (26.74) 7.25 (4.35) -16.35 (28.17) D78 6.33 (2.94) -13.88 (46.86) 4.83 (2.56) -8.33 (59.40) 5.50 (2.38) -27.68 (41.71) D106 5.50 (1.76) -26.83 (25.95) 5.17 (3.31) -4.17 (63.62) 7.25 (3.59) -12.95 (32.44) The 6 clinical signs of eczema severity (erythema, edema / papulation, oozing / crusting, excoriation, lichenification, dryness) were assessed on a 4-point scale each from 0 = none to 3 = severe. The maximal possible total score was 18. Abs = absolute, BL = Baseline, CFB = change from Baseline, D = Day, MAD = multiple ascending doses, N = number of subjects, na = not applicable, rel = relative, SAF = safety analysis set. The total subjective symptom score is summarized in Table 34. At Baseline, the mean subjective symptom score 10 was slightly lower in the 900 pg si-544 treatment group than in the 450 pg si-544 and placebo treatment group. During the treatment period, subjective symptoms improved and this improvement was maintained during the followup period in all treatment groups. For the individual symptoms, no obvious trend was observed for sleep loss, but pruritus seemed to improve over time in all treatment groups. 15 Table 34: Subjective symptom score - MAD part (SAF) Mean (SD) of subjective symptom score 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Abs value Rel CFB [%] Abs value Rel CFB [%] Abs value Rel CFB [%] D1 (BL) 10.22 (3.87) na 8.18 (2.24) na 10.40 (4.60) na 7.28 (5.16) 6.47 (3.96)a -25.53 D15 -33.13 (29.68) 5.53 (3.44) -35.17 (31.06) (33.45)a D29 5.85 (2.93) -38.48 (35.18) 6.27 (5.96) -25.93 (56.57) 7.40 (5.22) -21.85 (43.51) D50 5.13 (4.20) -52.82 (25.57) 5.53 (6.31) -41.48 (52.04) 10.30 (4.69) 9.93 (44.31) D78 7.37 (4.96) -31.02 (30.17) 5.58 (6.69) -35.52 (64.14) 4.38 (3.30) -61.30 (27.00) D106 5.78 (4.52) -44.00 (33.82) 4.63 (6.23) -51.18 (51.58) 4.55 (2.66) -52.33 (21.15) The subjective symptoms sleep loss and pruritus were each scored on an visual analog scale from 0 = no symptom to 10 = worst possible severity. The maximal possible score was 20. a N = 3. Abs = absolute, BL = Baseline, CFB = change from Baseline, D = Day, MAD = multiple ascending doses, N = number of subjects, na = not applicable, rel = relative, SAF = safety analysis set. The total SCORAD is summarized by absolute scores in Table 35 and by category in Table 36. The SCORAD showed an improvement in the AD severity in all treatment groups. Treatment with 450 pg si-544 showed higher improvement of up to 36% from Baseline than treatment with 900 pg si-544 (relative improvement from Baseline up to 21%), but with no marked difference to treatment with placebo (relative improvement up to 41%; Table 35). In all 5    3 treatment groups the proportion of subjects with mild AD increased overtime (Table 36). Table 35: Total SCORAD absolute scores - MAD part (SAF) Mean (SD) of total SCORAD score 450 pg si-544 (N = 6) 900 pg si-544 (N = 6) Placebo (N = 4) Abs value Rel CFB [%] Abs value Rel CFB [%] Abs value Rel CFB [%] D1 (BL) 40.87 (8.46) na 29.75 (8.58) na 47.63 (16.90) na D15 39.75 (20.57) -5.25 (35.72) 28.92 (9.89) -0.12 (33.59) 36.20 (17.43)a -14.13 (21.27)a D29 29.47 (8.69) -28.17 (11.04) 24.87 (16.71) -13.20 (56.66) 34.13 (15.03) -26.73 (21.39) D50 26.83 (10.09) -35.57 (14.99) 24.00 (13.86) -20.87 (26.57) 38.90 (15.61) -12.05 (33.05) D78 33.13 (19.17) -21.57 (34.36) 24.18 (17.29) -16.43 (57.05) 25.28 (7.05) -40.90 (28.80) D106 28.00 (12.01) -32.73 (20.69) 24.18 (19.32) -19.32 (53.61) 31.63 (12.09) -30.58 (22.72) The total SCORAD score is calculated based on the affected BSA, the severity of eczema, and the subjective scoring of symptoms with a maximal possible score of 103. A score of <25 indicates mild, 25-60 moderate, and >60 severe AD. a N = 3. Abs = absolute, AD = atopic dermatitis, BL = Baseline, BSA = body surface area, CFB = change from Baseline, D = Day, MAD = multiple ascending doses, N = number of subjects, na = not applicable, rel = relative, SAF = safety analysis set, SCORAD = scoring atopic dermatitis. Table 36: Total SCORAD categories - MAD part (SAF) Number (%)a of subjects 450 pg si-544                   900 pg si-544                   Placebo (N = 6) (N = 6) (N = 4) mild moderate severe mild moderate severe mild moderate severe D1 (BL) - 6 (100.0) - 2 (33.3) 4 (66.7) - - 3 (75.0) 1 (25.0) D15 2 (33.3) 3 (50.0) 1 (16.7) 2 (33.3) 4 (66.7) - - 3 (100.0)3 - D29 2 33.3) 4 (66.7) - 3 (50.0) 3 (50.0) - 1 (25.0) 3 (75.0) - D50 3 (50.0) 3 (50.0) - 5 (83.3) 1 (16.7) - 1 (25.0) 3 (75.0) - D78 3 (50.0) 2 (33.3) 1 (16.7) 4 (66.7) 2 (33.3) - 2 (50.0) 2 (50.0) - D106 3 (50.0) 3 (50.0) - 4 (66.7) 2 (33.3) - 2 (50.0) 2 (50.0) - N = 0 is shown as Mild AD corresponds to a total SCORAD of <25, moderate to 25-60, and severe to >60. a Percentage is based on the N in the treatment group. b For N = 1 data were missing due to an incomplete BSA assessment. AD = atopic dermatitis, BL = Baseline, BSA = body surface area, D = Day, MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set, SCORAD = scoring atopic dermatitis. 3.2.3.3.2 Subgroup analyses No subgroup analyses were performed. 3.2.3.4 Statistical issues encountered during the analysis No statistical issues were identified in the study. 3.2.3.5 Summary of pharmacokinetics, pharmacodynamics, efficacy, and other evaluations • Free si-544 plasma concentrations were measurable from 5 minutes postdose onwards, with a median Tmax of about 1 hour in both study parts •   Dose proportionality was shown for Cmax and AUCo-iast in the SAD part •   Analyses of T cell subsets in the MAD part showed no substantial change from Baseline with no apparent difference between treatment groups for CD2+ lymphocyte counts •   IFN-y levels decreased in both si-544 treatment groups at Day 29, which was maintained during follow up in the 450 pg si-544 treatment group, while IFN-y levels in the placebo treatment group increased from Baseline • TNF-a and IL-8 levels increased at postbaseline visits compared to Baseline in the 450 pg si-544 treatment group at all postbaseline visits and at Day 29 in the 900 pg si-544 treatment group, while they decreased at all postbaseline visits in the placebo treatment group • Cytokine levels were highly variable between subjects and some cytokines were not detectable (ie, below the LLOQ) in most (IL-10) or all subjects (IL-2, IL-4, IL-12, IL-13, and IL-17A) • All subjects (but 1 subject in the 900 pg si-544 treatment group at Day 29) had a negative anti-drug antibody titer at Day 1 and Day 29 • AD severity as assessed by the affected BSA and the SCORAD in the MAD part improved in all treatment groups compared to Baseline with no marked difference between si-544 and placebo treatment. 3.2.4. Discussion and overall conclusion Summary and discussion This study was a multi-center, Phase 1b, double-blind, placebo-controlled, SAD and MAD, FIH study in subjects with mild to severe AD receiving si-544. The target indication, AD, is a is a multi-faceted, 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). The disease’s hallmark feature is severe pruritus (Furue, 2015; Tominag, 2014). In addition to pronounced itching and dry skin, eczema is found in different body surface areas with other clinical features such as oozing or crusting, and lichenification, ie, skin that has become thickened and leathery (Frazier, 2020). Current treatment options for AD include topical glucocorticosteroids and inhibitors of calcineurin and phosphodiesterase-4, systemic immunosuppressive treatment, or phototherapy and biologicals (Wollenberg, 2018 May; Ferrucci, 2023; Plant 2021). The aim of this study was to assess the safety and tolerability, and the PK, PD, immunogenicity, and efficacy of si-544 in adults with AD. All 36 subjects who were randomized to treatment with si-544 or placebo completed the trial, 20 subject in the SAD part, and 16 subjects in the MAD part. In the SAD part, more women (70%) than men (30%) were treated while in the MAD part, the sex ratio was more balanced (women: 44%, men: 56%). However, as generally more women than men may be affected by AD, the sex distribution followed the reported sex distribution of AD (Holm, 2004). The primary endpoints of the study focused on the safety and tolerability of the treatment, si-544 was shown to be safe and well-tolerated. No DLTs were reported during the SAD part, and thus, all dose cohorts were treated as planned. After treatment of the 2 highest doses of the SAD part, 450 pg and 900 pg si-544, during the MAD part also none of the reported TEAEs fulfilled the definition of DLTs. All reported TEAEs considered related to treatment with si-544 were of Grade 1 or Grade 2 including no serious TEAEs. TEAEs assessed as being related to treatment with si-544 were mainly injection site reactions that mostly resolved within a minutes or few hours of onset. Paresthesia was the most commonly reported TEAE assessed as being related to treatment with si-544 in the MAD part (44 events in 5 subjects), which was also reported as the most common treatment-related AE in a Phase 1b trial with dalazatide, another Kv1.3 channel inhibitor, and thus supporting the mode of action of si-544 (Tarcha, 2017). In the SAD part, 2 subjects had clinically significantly abnormal laboratory values 3 days after treatment with 150 pg si-544. All events had resolved 2-3 days after onset and had no influence on dose escalation. No further clinically significant abnormal findings in laboratory values, ECG, vital signs, or physical or neurological examination were reported posttreatment in the SAD or MAD part. The analysis of secondary endpoints assessing the T cell subsets did not show any substantial changes from Baseline in CD2+- lymphocyte counts in any treatment group. The assessment of IFN-y showed a decrease from Baseline after treatment with si-544 while an increase was observed in the placebo treatment group, suggesting that si-544 may reduce the inflammatory reaction involved in the severity of AD by inhibition of IFN-y (Belpaire, 2022; Kopitar-Jerala, 2017; Zhang, 2007). AD severity as assessed by affected BSA and SCORAD showed an improvement in all treatment groups. As the study was not statistically powered for efficacy, a statistically significant difference between si-544 and placebo treatment was not reached. The aim of this Phase 1 b study was primarily to demonstrate the safety and tolerability of si-544, which was achieved. Furthermore, it showed an initial efficacy signal. Conclusions •   si-544 was safe and well-tolerated • PK data showed the expected dose proportionality for Cmax and AUCo-iast in the SAD part •   si-544 showed first signals of efficacy in subjects with AD REFERENCES Belpaire A, van Geel N, Speeckaert R. From IL-17 to IFN-y in inflammatory skin disorders: Is transdifferentiation a potential treatment target? Frontiers in Immunology. 2022;13. Berke R, Singh A, Guralnick M. Atopic dermatitis: an overview. Am Fam Physician. 2012;86(1):35-42. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483-94. Chandy KG, Norton RS. Peptide blockers of Kv1.3 channels in T cells as therapeutics for autoimmune disease. CurrOpin Chern Biol. 2017;38:97-107 Chiang EY, Li T, Jeet S, Peng I, Zhang J, Lee WP, et al. Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions. Nat Commun. 2017;8:14644. Drucker AM, Wang AR, Li WQ, Sevetson E, Block JK, Qureshi AA. The Burden of Atopic Dermatitis: Summary of a Report for the National Eczema Association. J Invest Dermatol. 2017; 137(1 ):26-30. Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, 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. Ferrucci SM, Tavecchio S, Marzano AV, Buffon S. Emerging Systemic Treatments for Atopic Dermatitis. Dermatol Ther(Heidelb). 2023; 13(5): 1071-81. Frazier W, Bhardwaj N. Atopic Dermatitis: Diagnosis and Treatment. Am Fam Physician. 2020;101(10):590-598. Furue M, Kadono T. New therapies for controlling atopic itch. J Dermatol. 2015 Sep;42(9):847-50. Guttman-Yassky E, Hanifin JM, Boguniewicz M, Wollenberg A, Bissonnette R, Purohit V, et al. The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition. Exp Dermatol. 2019 Jan;28(1):3-10. Holm EA, Esmann S, Jemec GB. Does visible atopic dermatitis affect quality of life more in women than in men? Gend Med. 2004; 1(2): 125-30. 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 Sezary syndrome. Oncotarget. 2019; 10(47):4894-4906. Kopitar-Jerala N. The Role of Interferons in Inflammation and Inflammasome Activation. Frontiers in Immunology. 2017;8. Kowalska-Ol^dzka E, Czarnecka M, Baran A. Epidemiology of atopic dermatitis in Europe. J Drug Assess. 2019 Jun 12;8(1 ):126-128. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66 Suppl 1:8-16. Plant A, Ardern-Jones MR. Advances in atopic dermatitis. Clin Med (Lond). 2021;21(3):177-81. Tarcha EJ, Olsen CM, Probst P, Peckham D, Munoz-Elias EJ, Kruger JG, ladonato SP. Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: A randomized phase 1b trial. PLoS One. 2017 Jul 19;12(7):e0180762. Tominaga M, Takamori K. Itch and nerve fibers with special reference to atopic dermatitis: therapeutic implications. J Dermatol. 2014 Mar;41(3):205-12. 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 I. J Eur Acad Dermatol Venereol. 2018 May;32(5):657-682. doi: 10.1111 / jdv. 14891. Erratum in: J Eur Acad Dermatol Venereol. 2019 Jul;33(7):1436. 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 Acad Dermatol Venereol. 2018 Jun;32(6):850-878. Zhang J. Yin and yang interplay of IFN-gamma in inflammation and autoimmune disease. J Clin Invest. 2007;117(4):871-3. Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993; 186(1 ):23-31. EMBODIMENT LIST: 1. A pharmaceutical composition comprising a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or its pharmaceutically acceptable salt for use in a method of treating atopic dermatitis (AD) and / or improving an AD-associated parameter, wherein the pharmaceutical composition is administered at a dose equivalent to about 0.15 mg to about 1.5 mg of the acetate salt of said peptide. 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 salt of the said peptide. 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 salt of the said peptide. 4. The pharmaceutical composition for use according to any one of embodiments 1 to 3, wherein the pharmaceutical composition is administered three times a week, twice a week or once a week. 5. The pharmaceutical composition for use according to any one of embodiments 1 to 3, wherein the pharmaceutical composition is administered twice a week. 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. 7. The pharmaceutical composition for use according to any one of embodiments 1 to 5, wherein the pharmaceutical composition is administered subcutaneously. 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. 9. The pharmaceutical composition for use according to any one of embodiments 1 to 7, wherein the pharmaceutical composition is administered for 4 weeks. 10. The pharmaceutical composition for use according to any one of embodiments 1 to 9, wherein the pharmaceutical composition is administered to a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of below 25. 11. The pharmaceutical composition for use according to any one of embodiments 1 to 9, wherein the pharmaceutical composition is administered to a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of between 25 and 60. 12. The pharmaceutical composition for use according to any one of embodiments 1 to 9, wherein the pharmaceutical composition is administered to a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of above 60. 13. The pharmaceutical composition for use according to any one of embodiments 1 to 12, wherein the AD-associated parameter is the SCORing Atopic Dermatitis (SCORAD) score, and wherein administration of the pharmaceutical composition according to the present invention results in a decrease from baseline in 5             Scoring Atopic Dermatitis (SCORAD) score of at least 20%, optionally of at least 50%. 14. The pharmaceutical composition for use according to any one of embodiments 1 to 12, wherein the AD-associated parameter is affected body surface area (BSA), and wherein administration of the pharmaceutical composition according to the present invention results in a decrease from baseline in affected body surface area (BSA) of at least 20%, optionally of at least 50%. 10

Claims

1. A pharmaceutical composition comprising a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or its pharmaceutically acceptable salt for use in a method of treating atopic dermatitis (AD), wherein the pharmaceutical composition is administered at a peptide dose equivalent in moles to about 0.15 mg to about 1.5 mg of the acetate salt of said peptide.

2. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is administered at a peptide dose equivalent in moles to about 0.45 mg of the acetate salt of the said peptide.

3. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is administered at a peptide dose equivalent in moles to about 0.9 mg of the acetate salt of the said peptide.

4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the pharmaceutical composition is administered 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 a week.

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 with AD with a SCORing Atopic Dermatitis (SCORAD) score of below 25.

11. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein the pharmaceutical composition is administered to a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of between 25 and 60.

12. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein the pharmaceutical composition is administered to a subject with AD with a SCORing Atopic Dermatitis (SCORAD) score of above 60.

13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein administration ofthe pharmaceutical composition results in improving an AD-associated parameter, wherein the AD-associated parameter is the SCORing Atopic Dermatitis (SCORAD) score, and wherein administration of the pharmaceutical composition according to the present invention results in a decrease from baseline in Scoring Atopic Dermatitis (SCORAD) score of at least 20%, optionally of at least 50%.5         14. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein administration ofthe pharmaceutical composition results in improving an AD-associated parameter, wherein the AD-associated parameter is affected body surface area (BSA), and wherein administration of the pharmaceutical composition according to the present invention results in a decrease from baseline in affected body surface area (BSA) of at least 20%, optionally of at least 50%.10

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