Peptide for treating psoriasis vulgaris or psoriatic arthritis

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 psoriasis vulgaris. In a second aspect, the present invention is directed to a pharmaceutical composition comprising a peptide for use in a method of treating psoriatic arthritis.

Description

[0001]Maiwald Ref.: S12905WO2 PEPTIDE FOR TREATING PSORIASIS VULGARIS OR PSORIATIC ARTHRITIS TECHNICAL FIELD In a first aspect, the present invention is directed to a pharmaceutical composition comprising a peptide for use in amethod of treating psoriasis vulgaris. In a second aspect, the present invention is directed to a pharmaceuticalcomposition comprising a peptide for use in a method of treating psoriatic arthritis. BACKGROUND OF THE INVENTION Psoriasis vulgaris (Ps) is a common autoimmune-mediated inflammatory disease of adults and children. Therelapsing course of psoriasis negatively affects a patient’s quality of life. The condition is associated with social isolation, anxiety, and depression, and can harm personal relationships and employment status. Skin involvement is the most prominent symptom of this disease; however, psoriasis is a chronic, multisystem inflammatory disease. Patients with mild-to-moderate psoriasis control their disease primarily with topical medications or phototherapy. For patients with moderate-to-severe disease,first-line therapy includes methotrexate, acitretin, apremilast, and biologics.All of these treatments must be closely monitored (Kessler, 2022). There exists a continuing need for an alternativetreatment of psoriasis vulgaris. Psoriatic arthritis (PsA) is a complex inflammatory musculoskeletal and skin disease. Up to 30% of patients with psoriasis may develop PsA over the course of their lifetime. Musculoskeletal manifestations of PsA include peripheral arthritis, spondylitis, dactylitis (inflammation of the whole digit) and enthesitis (inflammation where a tendon, ligament or joint capsule inserts onto the bone). Skin manifestations of PsA include psoriasis (which has numerous phenotypes but the most common type associated with PsA is psoriasis vulgaris or plaque psoriasis) and nail disease. Beyond the musculoskeletal and skin features, patients with PsA experience fatigue, physical function limitations, sleep disturbance, as well as diminished work capacity and social participation. Treatment for PsA includes traditional or conventional disease modifying antirheumatic drugs (DMARDs), biologic therapies such as TNF inhibitors (TNFi), IL-17 inhibitors (IL-17i), IL-12 / 23 inhibitor (IL-12 / 23i), and new targeted oral agents including a phosphodiesterase-4 inhibitor and a Janus kinase (JAK) / signal transducer and activator of transcription (STAT)inhibitor (Ogdie, 2020). There exists a continuing need for an alternative treatment of psoriatic arthritis.SUMMARY OF THE INVENTION Aspect A In aspect A, the present invention is directed to a pharmaceutical composition comprising a peptide consisting ofthe amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or itspharmaceutically acceptable salt for use in a method of treating psoriasis vulgaris (Ps), wherein the pharmaceuticalcomposition is administered at a peptide dose equivalent in moles to about 0.15 mg to about 1.5 mg of the acetatesalt of said peptide, such as at a peptide dose equivalent in moles to about 0.45 mg and about 0.9 mg of the acetatesalt of said peptide.In an embodiment of aspect A, the pharmaceutical composition is administered three times a week, twice a week oronce a week. In an embodiment of aspect A, the pharmaceutical composition is administered twice a week.In an embodiment of aspect A, the pharmaceutical composition is administered subcutaneously, intramuscularly orintravenously. In an embodiment of aspect A, the pharmaceutical composition is administered subcutaneously.DB:RRIn an embodiment of aspect A, the pharmaceutical composition is administered for 3 to 8 weeks.In an embodiment of aspect A, the pharmaceutical composition is administered for 4 weeks.In an embodiment of aspect A, the pharmaceutical composition is administered to a subject with Ps with a PsoriasisArea and Severity Index (PASI) score of < 10.In an embodiment of aspect A, the pharmaceutical composition is administered to a subject with Ps with a PsoriasisArea and Severity Index (PASI) score of ≥ 10.In an embodiment of aspect A, administration of the pharmaceutical composition results in improving a Ps-associated parameter, wherein the Ps-associated parameter is the the Psoriasis Area and Severity Index (PASI) score and administration of the pharmaceutical composition according to the present invention results in a decreasefrom baseline in the Psoriasis Area and Severity Index (PASI) score of at least 20%, optionally of at least 50%.Aspect B In aspect B, the present invention is directed to a pharmaceutical composition comprising a peptide consisting ofthe amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or itspharmaceutically acceptable salt for use in a method of treating psoriatic arthritis (PsA), wherein the pharmaceuticalcomposition is administered at a peptide dose equivalent in moles to about 0.15 mg to about 1.5 mg of the acetatesalt of said peptide, such as at a peptide dose equivalent in moles to about 0.45 mg and about 0.9 mg of the acetatesalt of said peptide.In an embodiment of aspect B, the pharmaceutical composition is administered three times a week, twice a week oronce a week. In an embodiment of aspect B, the pharmaceutical composition is administered twice a week.In an embodiment of aspect B, the pharmaceutical composition is administered subcutaneously, intramuscularly orintravenously. In an embodiment of aspect B, the pharmaceutical composition is administered subcutaneously.In an embodiment of aspect B, the pharmaceutical composition is administered for 3 to 8 weeks.In an embodiment of aspect B, the pharmaceutical composition is administered for 4 weeks.In an embodiment of aspect B, the pharmaceutical composition is administered to a subject with PsA with aPsoriasis Area and Severity Index (PASI) score of < 10.In an embodiment of aspect B, the pharmaceutical composition is administered to a subject with PsA with aPsoriasis Area and Severity Index (PASI) score of ≥ 10.In an embodiment of aspect B, administration of the pharmaceutical composition results in improving a PsA-associated parameter, wherein the PsA-associated parameter is the the Psoriasis Area and Severity Index (PASI) score and administration of the pharmaceutical composition according to the present invention results in a decreasefrom baseline in the Psoriasis Area and Severity Index (PASI) score 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 responderfor 450 µg and 900 µg dose levels. Figure 2: Affected body surface area (BSA) reduction relative to baseline for an exemplary responder for 450 µgand 900 µg dose levels. Figure 3: Analysis of the blinded data of 29 psoriasis patients revealed first signals of efficacy. Normalized PASIvalues for 29 subjects of the study are shown. 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-gatedKv1.3 potassium channel.25 years of research have linked an increasing number of diseases including autoimmunedisorders like AD to chronically activated, Kv1.3-dependent effector memory T cells (TEM) (Chandy, 2017; Hu, 2017).Normally, TEMrestore ion homeostasis upon activation and subsequent calcium (Ca2+) influx by recruiting the only2 potassium channels, Kv1.3 and KCa3.1, that are expressed in human T cells. In certain situations, TEM becomechronically 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 targetschronically-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 µg of the acetate salt of a peptide consisting of the amino acid sequence TIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) is safe and tolerable. In addition, at 450 µg and 900 µg dose levels, high plasma levels were achieved resulting in virtually full target engagement. In view of these results, it seems acceptable to assume that the pharmaceutical composition according to the present invention is safe, tolerable and efficacious in patients withpsoriasis vulgaris (Ps) and psoriatic arthritis (PsA). This is further supported by the analysis of the blinded data of 29psoriasis patients that revealed first signals of efficacy. A phase 1b 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 amaximum dose of 60 µg (Tarcha, 2017). From the published results (Tarcha, 2017), a plasma level of dalazatide canbe calculated; this plasma level is sufficient for appr.15 – 20 % target (Kv1.3) engagement. The inventors of thepresent 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 isdefined to comprise at least a certain number of embodiments, this is also meant to encompass a group whichpreferably consists of these embodiments only. The term “si-544” as used herein means a peptide consisting of 38 natural amino acids without modification. Thepeptide 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 synthesizedusing 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 peptidecomprises eight cysteine residues forming four disulfide bridges and may thus require active folding into a nativestate 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 bymethods known in the art such as HPLC purification. A suitable approach is described in WO 2015 / 169901 A1 (“ctgx544” 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 ofsuppositories. Administration can also be carried out intranasally, sublingually or buccally. Other suitableadministration 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 apen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceablecartridge 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 ofthe pharmaceutical composition, the entire device is discarded. According to certain embodiments, a pharmaceuticalcomposition 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, andlubricating 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 doseequivalent in moles to about 0.15 mg to about 1.5 mg of the acetate salt of the peptide. According to certainembodiments, the pharmaceutical composition according to the present invention is administered at a peptide doseequivalent in moles to about 0.15 mg to about 0.75 mg of the acetate salt of the peptide, such as 0.45 mg of theacetate salt of the peptide. According to certain embodiments, the pharmaceutical composition according to thepresent invention is administered at a peptide dose equivalent in moles to about 0.75 mg to about 1.5 mg of theacetate salt of the peptide, such as about 0.9 mg of the acetate salt of the peptide. In certain embodiments, it may bepreferred that the pharmaceutical composition according to the present invention is administered at a dose of about0.15 mg to about 1.5 mg of the peptide. According to certain embodiments, it may be preferred that thepharmaceutical composition according to the present invention is administered at a dose of about 0.15 mg to about0.75 mg of the peptide, such as 0.45 mg of the peptide. According to certain embodiments, it may be preferred thatthe pharmaceutical composition according to the present invention is administered at a dose of about 0.75 mg toabout 1.5 mg of the peptide, such as about 0.9 mg of the 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 threetimes a week, twice a week or once a week, optionally twice a week. In certain embodiments, it may be preferred thatthe 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 isadministered for 3 to 8 weeks, 3 to 6 weeks, or 3 to 4 weeks, optionally for 3, 4, 6, or 8 weeks. In certainembodiments, it may be preferred that the pharmaceutical composition according to the present invention isadministered for 4 weeks.The Psoriasis Area and Severity Index (PASI) score is a tool used to measure the severity and extent of psoriasis(Fredriksson 1978, https: / / dermnetnz.org / topics / pasi-score). A representative area of psoriasis is selected for eachbody region (head and neck; upper limbs; trunk; lower limbs). The intensity of redness (erythema), thickness(induration), and scaling (desquamation) of the psoriasis is assessed as none (0), mild (1), moderate (2), severe (3),or very severe (4). The three intensity scores are added up for each of the four body regions to give subtotals A1(head and neck), A2 (upper limbs), A3 (trunk), and A4 (lower limbs). Each subtotal is multiplied by the body surfacearea represented by that region: A1 x 0.1 = B1; A2 x 0.2 = B2; A3 x 0.3 = B3; and A4 x 0.4 = B4. The percentage area affected by psoriasis is evaluated in the four regions of the body. In each region, the area is expressed as nil (0), 1-9% (score 1), 10-29% (score 2), 30-49% (score 3), 50-69% (score 4), 70-89% (score 5) or 90- 100% (score 6). Each of the body area scores is multiplied by the area affected: B1 x (0 to 6) = C1; B2 x (0 to 6) = C2; B3 x (0 to 6) = C3; and B4 x (0 to 6) = C4. The PASI score is C1 + C2 + C3 + C4. Maximum score is 72. A score< 10 indicates mild and a score of ≥ 10 indicates moderate to severe.According to certain embodiments of aspect A, the pharmaceutical composition according to the present inventionis administered to a subject with mild Ps, i.e. a subject with Ps with a Psoriasis Area and Severity Index (PASI) scoreof < 10. According to certain embodiments, the pharmaceutical composition according to the present invention isadministered to a subject with moderate to severe Ps, i.e. a subject with Ps with a Psoriasis Area and Severity Index(PASI) score of ≥ 10.The Psoriasis Area and Severity Index (PASI) score is an examples of a “Ps-associated parameter” according to thepresent disclosure. An “improvement in a Ps-associated parameter” means a decrease from baseline. As usedherein, the term “baseline”, with regard to a Ps-associated parameter, means the numerical value of the Ps- associated parameter for a subject prior to or at the time of administration of a pharmaceutical composition of the present invention. To determine whether a Ps-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 Ps-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 11 , 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, week 9, week 10, week 11 , week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, 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 Ps associated parameter. According to certain embodiments, the “Ps-associated parameter”is the Psoriasis Area and Severity Index (PASI) score and the pharmaceutical composition according to the presentinvention results in a decrease from baseline in Psoriasis Area and Severity Index (PASI) score of at least 10%, of atleast 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 of aspect B, the pharmaceutical composition according to the present inventionis administered to a subject with mild PsA, i.e. a subject with PsA with a Psoriasis Area and Severity Index (PASI)score of < 10. According to certain embodiments, the pharmaceutical composition according to the present inventionis administered to a subject with moderate to severe PsA, i.e. a subject with PsA with a Psoriasis Area and SeverityIndex (PASI) score of ≥ 10.The Psoriasis Area and Severity Index (PASI) score is an examples of a “PsA-associated parameter” according tothe present disclosure. An “improvement in a PsA-associated parameter” means a decrease from baseline. As usedherein, the term “baseline”, with regard to a PsA-associated parameter, means the numerical value of the PsA- associated parameter for a subject prior to or at the time of administration of a pharmaceutical composition of the present invention. To determine whether a PsA-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 PsA-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 11 , 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, week 9, week 10, week 11 , week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20,week 21 , week 22, week 23, week 24, or longer, after the initial treatment with a pharmaceutical composition of thepresent invention. The difference between the value of the parameter at a particular time point following initiation oftreatment and the value of the parameter at baseline is used to establish whether there has been an "improvement"(e.g., a decrease) in the PsA-associated parameter. According to certain embodiments, the “PsA-associatedparameter” is the Psoriasis Area and Severity Index (PASI) score and the pharmaceutical composition according tothe present invention results in a decrease from baseline in Psoriasis Area and Severity Index (PASI) score of atleast 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%. Preferred embodiments of aspect B1 of the present invention relate to:1. A pharmaceutical composition comprising a peptide consisting of the amino acid sequenceTIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or its pharmaceutically acceptable salt foruse in a method of treating psoriatic arthritis (PsA), wherein the pharmaceutical composition is administered at apeptide 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 item 1, wherein the pharmaceutical composition isadministered 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 item 1, wherein the pharmaceutical composition isadministered 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 items 1 to 3, wherein the pharmaceuticalcomposition is administered three times a week, twice a week or once a week.5. The pharmaceutical composition for use according to any one of items 1 to 3, wherein the pharmaceuticalcomposition is administered twice a week.6. The pharmaceutical composition for use according to any one of items 1 to 5, wherein the pharmaceuticalcomposition is administered subcutaneously, intramuscularly or intravenously.7. The pharmaceutical composition for use according to any one of items 1 to 5, wherein the pharmaceutical composition is administered subcutaneously.8. The pharmaceutical composition for use according to any one of items 1 to 7, wherein the pharmaceuticalcomposition is administered for 3 to 8 weeks.9. The pharmaceutical composition for use according to any one of items 1 to 7, wherein the pharmaceuticalcomposition is administered for 4 weeks.10. The pharmaceutical composition for use according to any one of items 1 to 9, wherein the pharmaceuticalcomposition is administered to a subject with PsA with a Psoriasis Area and Severity Index (PASI) score of < 10.11. The pharmaceutical composition for use according to any one of items 1 to 9, wherein the pharmaceuticalcomposition is administered to a subject with PsA with a Psoriasis Area and Severity Index (PASI) score of ≥ 10.12. The pharmaceutical composition for use according to any one of items 1 to 11, wherein administration of thepharmaceutical composition results in improving an PsA-associated parameter, wherein the PsA-associated parameter is the the Psoriasis Area and Severity Index (PASI) score and administration of the pharmaceutical composition according to the present invention results in a decrease from baseline in the Psoriasis Area and Severity Index (PASI) score of at least 20%, optionally of at least 50%. 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 areintended as illustrations of single aspects of the invention only, and methods which are functionally equivalent arewithin 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 electrocardiogrameCRF 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 dosestudy to evaluate the safety, tolerability, and efficacy of si-544 in adults with atopic dermatitis 1. Nonclinical data of si-544Toxicology 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 (2mg / kg) once-daily administration of si-544 over a period of 28 days (data not shown). The first study was prematurelyterminated 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 theNOAEL. This is the highest concentration or amount found by experiment or observation causing no detectableadverse alterations of morphology, functional capacity, growth, development, or life span of the target organism under defined conditions. The starting (15 µg per subject) and maximal (900 µg 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 µg / 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 of5 L, a dose of 15 µg / subject results in a maximal blood concentration of 3 ng / mL, which reflects a worst-casescenario 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 µg per subject still results in safety margins of more than 67-fold based on amg / kg dose calculation and more than 7- to 19-fold based on extrapolated human Cmax and AUC data.2. Summary of study in humansTitle 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 wasonly 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• Type, frequency, severity, and causalsi-544 treatment 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 atDay 1 •MAD part: PK parameter in blood plasma atDays 1 and 25 Secondary (MAD part) Objective Endpoint • To determine the pharmacodynamics (PD)• Change from Baseline in number of T cells inof si-544 peripheral blood at Day 29, and Weeks 8, 12, and 16 •Change from Baseline in immunophenotypingof T-cell subsets at Day 29, and Weeks 8, 12, and 16 •Change from Baseline in serum cytokinelevels at Day 29, and Weeks 8, 12, and 16 •Optionala: Change from Baseline ofexpression levels of Kv1.3 vs KCa3.1 of TEMcells at Day 29, and Weeks 8, 12, and 16 • To determine the immunogenicity of si-544^ Change from Baseline in anti-drug antibodies (ADAs)treatment against si-544 in serum at Day 29 • To determine the efficacy of si-544• Change from Baseline in inflamed areas usingtreatment the body surface area (BSA) index at Days 15 and 29, and Weeks 8, 12, and 16 •Change from Baseline in AD severity bySCOring 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 injection. a Depending on results of immunophenotyping of T-cell subsets. SCORing Atopic Dermatitis (SCORAD) is a clinical assessment of the severity (e.g., extent or intensity) of atopicdermatitis developed by the European Task Force on Atopic Dermatitis (Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology.1993;186(1):23- 31; https: / / dermnetnz.org / topics / scorad). SCORAD is a composite score of 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, anddryness. 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 10being 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. 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 wererandomized within each cohort to treatment with si-544 or placebo. Initially, 2 sentinel subjects were treated(randomized to placebo or si-544) in each cohort. Further subjects were only treated if no safety issues occurred asassessed by the investigator. In the SAD part, 20 eligible subjects were treated in 5 dose cohorts of 4 subjects each. The dose levels for Cohorts1 to 5 were 15 µg, 50 µg, 150 µg, 450 µg, and 900 µg si-544 or placebo. Subjects received a single dose on Day 1(starting with the lowest dose cohort) and the safety and tolerability was assessed at Days 4 and 8.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 andtolerability, and PK was assessed during the treatment period. Follow-up visits were performed for 12 weeks afterMAD treatment to assess the safety, PD, immunogenicity, and efficacy. Each cohort comprised the 2 sentinel subjects (randomized 1:1 to placebo and si-544) and another 6 subjectsrandomized 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 partScreening Treatment SFUD-35 to D-2 D1 D2* (phone) D4 D8 / ET±1 day ±1 dayInformed consent xIn- and exclusion criteria xDemographic data x Height, weight, BMI x Medical history xSerologyax Pregnancy test (blood) xPhysical examination x xb x xNeurologicalx xb x xexaminationkVital signsc and POS x xd x xElectrocardiogram x xe xClinical laboratoryf x xe x xSARS-CoV-2 testlx PK blood samplinggxhRandomization xjIMP injection xSentinel safety x assessment Previous and x --------------------------------------------------------------------------------x concomitant medicationAdverse events x---------------------------------------------------------------------------------x* In sentinel subjects only: telephone call 24 hours after IMP injection to assess the safety.a For HIV, HBV, HCV and Tbc-IGRA. b To be performed before IMP injection. c Assessment of blood pressure, heart rate, respiration rate, and body temperature. dTo be performed before and 30 minutes to 1 hour after IMP injection.e To be performed 30 minutes to 1 hour after IMP injection.f Hematology, biochemistry, coagulation, and urinalysis.gOnly in subjects of Cohorts 4 and 5. hBlood 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 minutesfor 2 hours, ±15 minutes for 4 hours, and ±30 minutes for 8 hours post injection. The time point for blood collectiontakes 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. k Hamstring and pupillary reflex, motor function, sensibility tests, Romberg test, Unterberger test, heel walk,toe (ball) walk, line walk, blind walk, and 1-leg stand. In case of abnormal neurologic findings at Day 1, the subjectmay not be treated. l 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 partScr Treatment period FUW1 W2 W3 W4 W5 W8 W12 W16D-35D1 D4 D8 D11 D15 D18 D22 D25 D29 D50 D78 D106to D-2 / ET ±1 d ±1 d ±1 d ±1 d ±1 d ±1 d ±1 d ±3 d ±7 d ±7 d ±7 dInformed consent xIn- and exclusionx criteriaDemographic data xBody weight,x x x x x x x x xheight, BMIaMedical history xSerologybx Pregnancy testx x x(blood) Physicalx xc xc xc xc xc xc xc xc x x x xexamination Neurologicalx xc xc xc xc xc xc xc xc x x x xexaminationl Vital signseandx xh xh xh xh xh xh xh xh x x x xPOSElectrocardiogram x xi xi xi xi xi xi xi xi xClinical laboratoryf x xi xi xi xi xi xi xi xi x x x xSARS-CoV-2 x testmPK bloodx xsamplinggPD blood sampling for Flow cytometry ofxc x x x xT cells (PB)Serum cytokines xc x x x xKv1.3 / KCa3.1xc x x x xexpression TEMADA xc x xdAffected BSA andx xc x x x x xbody surface indexjSCORAD x xc x x x x xRandomization xkIMP injection x x x x x x x xPrevious and x ----------------------------------------------------------------------------------------------x concomitant medicationAdverse events x ----------------------------------------------------------------------------------------------xaAfter Screening, only body weight.bFor HIV, HBV, HCV, and Tbc-IGRA.c To be performed before IMP injection. If applicable: Blood sampling window: up to 15 minutes before IMPinjection.d To be performed if ET before or on Day 29. e Blood pressure, heart rate, respiration rate, and bodytemperature.fHematology, 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 minutesfor 2 hours, ±15 minutes for 4 hours, and ±30 minutes for 8 hours post injection. The time point for blood collectiontakes 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.i To be performed 30 minutes to 1 hour after IMP injection. j As assessed for the SCORAD.kTo be performed as soon as eligibility is confirmed.lHamstring and pupillary reflex, motor function, sensibility tests, Romberg test, Unterberger test, 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.mAs per study center’s standard.ADA = anti-drug antibodies, BMI = body mass index, BSA = body surface area, D / d = day(s), ET = earlytermination, FU = follow-up, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiencyvirus, 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 = effectormemory 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: ohead and neck: 9%o upper limbs: 9% eacho lower limbs: 18% eacho 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 foreach 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 inTable 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 MADpart. Specimen collection Blood samples for PK and PD analysis were obtained at the visits as detailed in Table 2 for the SAD part and Table3 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; samplingwindow: ±1 minute for ≤1 hour, ±5 minutes for 2 hours, ±15 minutes for 4 hours, and ±30 minutes for8 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 tandemmass spectrometer method. Pharmacokinetic assessments The following PK parameters were calculated from plasma concentrations for the SAD part on Day 1 and for theMAD part on Day 1 and Day 25:^ Cmax^ time to reach maximum concentration (Tmax)^ AUC from time 0 to 8 hours, AUC0-8h^ AUC from time 0 to the time of the last quantifiable concentration, AUC0-last^ AUC from time 0 to infinite time, AUC0-∞^ terminal elimination rate constant, λz^ apparent terminal elimination half-life time, T1 / 2The 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-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17, and tumornecrosis factor-α ^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 notnecessarily 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. Aserious 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 eventAn adverse drug reaction (ADR) is any noxious and unintended response to a medicinal product related to anydose. As per the ICH guideline - E2A, the definition of an ADR implies a reasonable possibility of a causalrelationship between the AE and the IMP. An unexpected ADR is an adverse reaction, the nature and severity of which is not consistent with the applicablereference 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. Asuspected unexpected serious adverse reaction (SUSAR) is a suspected adverse reaction related to the IMPthat is both unexpected and serious. SUSARs will be subject to expedited regulatory reporting. Reports which addsignificant 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 eventand 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 eventand 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 forAEs (NCI-CTCAE, Version 5.0). If not specifically defined in the NCI-CTCAE, Table 4 applies.Table 4: Severity grading of adverse eventsGrade Severity Description1 Mild Asymptomatic or mild symptoms; clinical or diagnostic observations only;intervention not indicated 2Moderate Minimal, local or noninvasive intervention indicated; limiting age-appropriateinstrumental ADL* 3Severe Severe or medically significant but not immediately life-threatening;hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL** 4Life-threatening Life-threatening consequences; urgent intervention indicated. Emergencyroom visit or hospitalization. 5Death 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, takingmedications, 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 tothe level observed at Baseline. Resolving: The subject has recovered from the event, but the condition has not returnedto the level observed at Baseline. Not resolved: The event is ongoing at the time of reporting and the condition has notreturned 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 othercircumstances 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 Action taken with the IMP will be assigned to one of the following categories: None: No action takenDrug withdrawn: Discontinuation of the IMPNot applicable: This category should be used in circumstances such as when thesubject has died, or the treatment had been completed before reaction(s) or event(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 studycompletion were recorded. AEs with verbatims matching with terms listed in NCI-CTCAE, Version 5.0 were gradedaccording to the specific definitions of severity provided in this listing. AEs not listed on the NCI-CTCAE gradingsystem 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 willbe collected as indicated in Table 2 and Table 3. All safety laboratory assessments and parameters are specified inTable 5.Table 5: Clinical safety laboratory parametersLaboratory assessment ParametersHematology Platelets, erythrocytes, leukocytes, differential leukocyte count (neutrophils,lymphocytes, monocytes, eosinophils, basophils), hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentrationBiochemistry ^ 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 glomerularfiltration rate (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) ^Other: Sodium, potassium, magnesium, chloride, inorganic phosphate, calcium,creatine phosphokinase, amylase, lipase, total protein, albumin, glucose (non- fasting), 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 Coagulation Partial thromboplastin time, prothrombin time, international normalized ratio (INR)Urinalysis pH, leukocytes, nitrites, blood, protein, glucose, ketones, urobilinogen, and bilirubinby dipstick Microscopic examination of the urine sediment only if tested positive for blood Serology (Screening Hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, human only) immunodeficiency virus, tuberculosis interferon gamma release assay Blood pregnancy test 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 asspecified in Table 2 and Table 3.Vital signs included body temperature, heart rate, respiration rate, and diastolic and systolic blood pressurePeripheral oxygen saturation was measured by pulse oximetry using a finger clip.A physical examination was performed evaluating any clinically significant abnormalities within the following bodysystems: 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. A12-lead ECG (PR-, QRS-, QT and QTc[F]-intervals) was recorded. At Screening, height and weight wasassessed, 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 balancewith 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 armsoutstretched. 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 standDose-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 DECDose selection MAD part The DEC recommended the dose levels to be used in the MAD part, based on the occurrence of DLTs under si-544treatment, 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 partCohort 5 completed with ≤1 DLT Cohorts 4 and 5 (ie, 450 µg and 900 µg si-544)Cohort 4 = MTD Cohorts 3 and 4 (ie, 150 µg and 450 µg si-544)Cohort 3 = MTD Cohort 3 only (ie, 150 µg 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% NaCl solution, subcutaneous injection in the abdomen: •SAD part: single dose• MAD part: multiple doses - twice a week for 4 weeksReference product Placebo (0.9% NaCl solution), volume and administration as described for the test product Subject population Adults with mild to severe AD Inclusion criteria SAD and MAD part1. Subject has the capacity for consenting, was informed about the nature, the scope, and therelevance 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 years3. Willing and able to adhere to the protocol requirements4. deleted5. 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 (failurerate 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 withinhibition of ovulation (oral, intravaginal, transdermal) ii. progestogen-only hormonal contraception associated with inhibition of ovulation (oral,injectable, implantable) iii. intrauterine deviceiv. intrauterine hormone-releasing systemv. bilateral tubal occlusionvi. vasectomized sexual partner (provided that the partner is the sole sexual partner of thewoman of childbearing potential and has received medical assessment of the surgical success) vii. sexual abstinence (only if defined as refraining from heterosexual intercourse during theentire 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 (periodicabstinence [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 lastIMP 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 pregnantwoman 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 ADMAD part only 8. Clinical diagnosis of mild to severe AD with a SCORAD ≥15Exclusion criteria SAD and MAD part 1. Change (ie, starting anew, change in frequency, or change in drug substance) in standard systemicand topical therapy, or in immunosuppressive drug therapy within 4 weeks before Screening (for biologics 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 ofthe IMP 3. Uncontrolled hypertension or uncontrolled diabetes4. History of seizures5. Presence or history of paresthesia or neuropathy6. Clinically significant ECG abnormalities, as judged by the investigator7. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, renal, or othermajor systemic disease, as judged by the investigator 8. Presence of acute infection within 7 days before Screening, as judged by the investigator9. Known or active infection with Mycobacterium tuberculosis10. Known or active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus11. Vaccination within 2 weeks before Screening and / or planned vaccination during the SAD part or thetreatment period of the MAD part 12. Pregnancy13. Any finding or medical condition prohibiting the inclusion in the study, as judged by the investigator14. Current or previous (within 4 weeks before Screening) participation in another clinical study with aninvestigational medicinal product or medical device 15. Known or suspected abuse of alcohol, drugs, or medicinal products16. Employee of the sponsor, or employee, or relative of the investigator17. 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 theadministrative authorities 19. Legal incapacity or limited legal capacityMAD part 20. Previous participation in the SAD part of this study with IMP dosing within 3 months before theplanned 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 intherapy with certain biologics such as dupilumab •From 4 weeks before Screening and during SAD part and treatment period of MAD part: change inimmunosuppressive drug therapy •From 4 weeks before Screening and during both study parts: use of other investigational medicinalproducts or medical devices •From 2 weeks before Screening and during both study parts: any vaccinationStatistical 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 humans3.1 Overview of Results The IMP (si-544) was well tolerated in the SAD cohorts (dose levels for cohorts 1 to 5 were 15 µg, 50 µg, 150 µg, 450 µg, and 900 µg si-544 or placebo administered subcutaneously). Thus, in the MAD part, the dose levels 450 µg and 900 µg 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 µg and 900 µg si-544) were achieved resulting in virtually full target engagement. No si-544 related serious AEs were observed and no dose reductions or temporary / 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).5 Immunocompetence was fully maintained in all treated patients as revealed by blood diagnostics, e.g.no significantchange 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 µg and 900 µg dose levels in the MADcohorts (s.c.) after 4 weeks of treatment. A high response rate was observed: 9 out of 12 si-544 treated patients0 showed significant improvement relative to baseline for SCORAD and BSA. First signs of efficacy were observedalready after 2 weeks of dosing. SCORAD and BSA improvement persists at end of study at day 106 (D106) showingthat 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 µg and 900 µg dose levels. As5 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). Figure 2 shows the BSA reduction relative to baseline for an exemplary responder for 450 µg and 900 µg dose levels. As shown in Figure 2 duration of effect clearly extended beyond dosing period.0 3.2 Detailed results3.2.1 Study subjects3.2.1.1Disposition of subjects and data set analyzed 5 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 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 µg si-544 in0 the SAD part and 900 µg si 544 in the MAD part. All (36) randomized subjects completed the assigned treatment and the study. All 36 enrolled subjects (SAD part: 20 subjects, MAD part: 16 subjects) were part of the SAF and the PP set, as noprotocol deviations were classified as major. 5 3.2.1.2Demographics and other baseline characteristics A summary of demographics for the SAF is provided in Table 7 and Table 8. In the SAD part (Table 7), more than twice as many women (70%) than men (30%) were included with only women in the 15 µg and 50 µg si-544 treatment groups. All subjects were White and not Hispanic or Latino. The median agewas 31 years, ranging from 19 to 60 years. In the placebo and 15 µg si-544 treatment group, the median age was0 markedly higher than in the other treatment groups. The BMI slightly varied across the treatment groups.Table 7: Demographics - SAD part (SAF)15 µg 50 µg 150 µg 450 µg 900 µgPlacebo 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) SexTable 7: Demographics - SAD part (SAF)15 µg 50 µg 150 µg 450 µg 900 µgPlacebo 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) 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) 1 (33.3) - - - - 2 (14.3)postmeno, N (%)b 1 (33.3) - - 1 (100.0) - 2 (66.7) 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 White N (%)a 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 20 (100.0)Ethnicity not Hisp orN (%)a 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 3 (100.0) 5 (100.0) 20 (100.0)LatAge [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 30.5Min, max 32, 55 22, 42 19, 22 32, 59 23, 26 23, 60 19, 60BMI [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 24.40Min, 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, 41.7N = 0 is shown as ‘-’.aPercentage is based on the N in the treatment group.bPercentage 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 1subject were White and not Hispanic or Latino. The median age was 29 years, ranging from 19 to 49 years. Ageand BMI were similar across treatment groups. Based on the SCORAD at Screening, nearly all subjects (87.5%) had5 moderate AD. Table 8: Demographics - MAD part (SAF)450 µg si-544 900 µg si-544Placebo Total (N = 6) (N = 6) (N = 4) (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 LatinoN (%)a - - 1 (25.0) 1 (6.3)Table 8: Demographics - MAD part (SAF)450 µg si-544 900 µg si-544Placebo Total (N = 6) (N = 6) (N = 4) (N = 16) not Hispanic orN (%)a 6 (100.0) 6 (100.0) 3 (75.0) 15 (93.8)LatinoAge [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 28.5Min, max 20, 49 19, 33 24, 35 19, 49BMI [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 25.15Min, max 20.5, 31.4 19.3, 30.9 23.0, 29.1 19.3, 31.4SCORAD 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 37.95Min, max 33.5, 56.7 20.1, 43.0 30.0, 61.4 20.1, 61.4SCORAD 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 ‘-’.aPercentage is based on the N in the treatment group.bPercentage 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 atopicdermatitis. 3.2.1.3Medical 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 (variousallergies) were most frequently reported in both study parts. Beyond that, in the SAD part, 2 subjects reportedmigraine, and in the MAD part, 4 subjects each reported depression and asthma. All other conditions were reportedby maximal 1 subject in any treatment group.Table 9: Medical history by system organ class - SAD part (SAF)Number (%)aof subjects 15 µg 50 µg 150 µg 450 µg 900 µgPlacebo Total 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) (N = 20) 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 and1 (33.3) - - - - - 1 (5.0)genetic disorders 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)Table 9: Medical history by system organ class - SAD part (SAF)Number (%)aof subjects 15 µg 50 µg 150 µg 450 µg 900 µgPlacebo Total 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) (N = 20) Infections and infestations - - - - 2 (66.7) 2 (40.0) 4 (20.0)Injury, poisoning and- - - - 2 (66.7) - 2 (10.0)procedural complications 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 Skin and subcutaneous3 (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 medical1 (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 treatmentgroup. 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)Number (%)aof subjects System organ class450 µg si-544 900 µg si-544Placebo Total Preferred term (N = 6) (N = 6) (N = 4) (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)Table 10: Medical history and concurrent illnesses by system organ class - MAD part (SAF)Number (%)aof subjects System organ class450 µg si-544 900 µg si-544Placebo Total Preferred term (N = 6) (N = 6) (N = 4) (N = 16)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)N = 0 is shown as ‘-’. Preferred terms are only shown for medical history reported in ≥2 subjects in any treatmentgroup.aPercentage is based on the N in the treatment group.MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set.3.2.1.4Previous and concomitant therapy Previous (ie, with starting date within 3 months before Screening) and concomitant medication taken by at least2 subjects in any treatment group are summarized in Table 11 and Table 12. Typical for the underlying disease, themost commonly taken medications in the both study parts were dermatological corticosteroid preparations and other preparations for the treatment of AD.Table 11: Previous and concomitant medication - SAD part (SAF)Number (%)aof subjects WHO-DD15 µg 50 µg 150 µg 450 µg 900 µgPlacebo Total ATC level 2 si-544 si-544 si-544 si-544 si-544 Preferred name (N = 3) (N = 3) (N = 3) (N = 3) (N = 3) (N = 5) (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, dermatological3 (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)Table 11: Previous and concomitant medication - SAD part (SAF)Number (%)aof subjects WHO-DD15 µg 50 µg 150 µg 450 µg 900 µgPlacebo Total ATC level 2 si-544 si-544 si-544 si-544 si-544 Preferred name (N = 3) (N = 3) (N = 3) (N = 3) (N = 3) (N = 5) (N = 20)N = 0 is shown as ATC level 2 and preferred terms are only included for medications reported in ≥2 subjects inany treatment group.aPercentage is based on the N in the treatment group.ATC = anatomical therapeutic chemical, N = number of subjects, SAD = single ascending dose, SAF = safetyanalysis set, WHO-DD = World Health Organization Drug Dictionary.Table 12: Previous and concomitant medication - MAD part (SAF)WHO-DD Number (%)aof subjects ATC level 2450 µg si-544 900 µg si-544Placebo Total Preferred name (N = 6) (N = 6) (N = 4) (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)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 genital3 (50.0) 2 (33.3) 2 (50.0) 7 (43.8)systemN = 0 is shown as ‘-’. ATC level 2 and preferred names are only included for medications reported in ≥2 subjects inany treatment group.aPercentage is based on the N in the treatment group.ATC = anatomic therapeutic chemical, MAD = multiple ascending doses, N = number of subjects, SAF = safetyanalysis set, WHO-DD = World Health Organization Drug Dictionary.3.2.1.5Treatment 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 of16 subjects received all 8 IMP injections as scheduled.1 subject in the 450 µg si-544 treatment group missed theIMP dose on Day 4 due to elevated laboratory and 2 subjects in the 900 µg si-544 treatment group missed 1 doseeach 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 µg si-544 injection in the SAD part and 8 injectionswith 900 µg 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 evaluationsThe 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 events3.2.2.1.1. Brief summary of adverse eventsAn 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 withplacebo 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 µg 50 µg 150 µg 450 µg 900 µgPlacebo 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 (%)anAEs N (%)anAEs N (%)anAEs N (%)anAEs N (%)anAEs N (%)anAEs N (%)aAny 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)TEAEN / n = 0 is shown as Categories with no entries in any group are not included.aPercentage is based on the N in the treatment group.nAE = 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 inthe 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 µg si-544 treatment group (depression, not related to the IMP).Table 14: Overview of treatment-emergent adverse events – MAD part (SAF)450 µg si-544 900 µg si-544Placebo Total (N = 6) (N = 6) (N = 4) (N = 16) nAEsN (%)anAEsN (%)anAEsN (%)anAEsN (%)aAny 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)Table 14: Overview of treatment-emergent adverse events – MAD part (SAF)450 µg si-544 900 µg si-544Placebo Total (N = 6) (N = 6) (N = 4) (N = 16) nAEsN (%)anAEsN (%)anAEsN (%)anAEsN (%)aN / n = 0 is shown as Categories with no entries in any group are not included.aPercentage is based on the N in the treatment group.MAD = multiple ascending doses, nAE = number of adverse events, N = number of subjects, SAF = safety analysisset, TEAE = treatment-emergent adverse event.3.2.2.1.2. Display of adverse eventsAn overview of TEAEs by system organ class is provided in Table 15 and Table 16. In the SAD part, no TEAEs were reported for subjects receiving 15 µg si-544. In the other treatment groups, none ofthe TEAEs was reported in more than 1 subject (Table 15).Table 15: Treatment-emergent adverse events by system organ class - SAD part (SAF)Number (%)aof subjects 15 µg 50 µg 150 µg 450 µg 900 µgPlacebo 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- - 1 (33.3) 1 (33.3) - 1 (20.0)disordersGastrointestinal disorders - - 1 (33.3) - 1 (33.3) -General disorders and- - 1 (33.3) - 1 (33.3) -administration site conditionsInfections and infestations - 1 (33.3) - - 1 (33.3) 1 (20.0)Investigations - 1 (33.3) 1 (33.3) - - -Metabolism and nutrition- - 1 (33.3) - - -disordersNervous system disorders - - 1 (33.3) - 1 (33.3) -Skin and subcutaneous tissue- - - 1 (33.3) 1 (33.3) -disordersN = 0 is shown as ‘-’.aPercentage 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 siteconditions were reported by the highest proportion of subjects in the 450 µg si-544 treatment group (each in 3 of6 subjects), and infections and infestations and nervous system disorders in the 900 µg si-544 treatment group (eachin 5 of 6 subjects). In the placebo treatment group, gastrointestinal disorders and infections and infestations were theonly 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)Number (%)aof subjects System organ class450 µg si-544 900 µg si-544Placebo Preferred term (N = 6) (N = 6) (N = 4)Any event 5 (83.3) 6 (100.0) 3 (75.0)Table 16: Treatment-emergent adverse events by system organ class and preferred term - MAD part (SAF)Number (%)aof subjects System organ class450 µg si-544 900 µg si-544Placebo Preferred term (N = 6) (N = 6) (N = 4)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 site3 (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)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.aPercentage 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 eventsSeverity Most TEAEs in the SAD part of the study were Grade 1, with only few Grade 2 events (in the 150 µg and 450 µg si-544 treatment groups) and no Grade 3 events (Table 17).Table 17: Treatment-emergent adverse events by severity - SAD part (SAF)Number (%)aof events 15 µg 50 µg 150 µg 450 µg 900 µgPlacebo si-544 si-544 si-544 si-544 si-544 Grade (N = 3) (N = 3) (N = 3) (N = 3) (N = 3) (N = 5)Number of events - 2 6 3 10 2Grade 1 - 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 aPercentage 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 the450 µg si-544 treatment group, 1 subject had Grade 3 transaminases increased and Grade 4 blood creatinephosphokinase 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 µg si-544 treatment group, 1 subject had 2 events of Grade 3 depression, and another subject hadGrade 3 nasopharyngitis. None of these events were considered related to the IMP.Table 18: Treatment-emergent adverse events by severity - MAD part (SAF)Number (%)aof events 450 µg si-544 900 µg si-544Placebo Grade (N = 6) (N = 6) (N = 4)Number of events 59 91 10Grade 1 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 ‘-’.aPercentage 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)Number (%)aof events 15 µg 50 µg 150 µg 450 µg 900 µgPlacebo si-544 si-544 si-544 si-544 si-544 Relationship to IMP (N = 3) (N = 3) (N = 3) (N = 3) (N = 3) (N = 5)Number of events - 2 6 3 10 2Not 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 aPercentage 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 = safetyanalysis set. In the MAD part, most TEAEs in both si-544 treatment groups and 1 TEAE out of 10 in the placebo treatment groupwere 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)Number (%)aof events 450 µg si-544 900 µg si-544Placebo Relationship to IMP (N = 6) (N = 6) (N = 4)Number of events 59 91 10Not related 12 (20.3) 24 (26.4) 9 (90.0)Related 47 (79.7) 67 (73.6) 1 (10.0)Table 20: Treatment-emergent adverse events by relationship to IMP - MAD part (SAF)Number (%)aof events 450 µg si-544 900 µg si-544Placebo Relationship to IMP (N = 6) (N = 6) (N = 4)aPercentage 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 = safetyanalysis set. Related TEAEs TEAEs related to the IMP are summarized in Table 21 and Table 22. In the SAD part, related TEAEs were onlyreported 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 (%)aof subjects 15 µg 50 µg 150 µg 450 µg 900 µgPlacebo 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- - 1 (33.3) - - -increased 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 aPercentage is based on N in the treatment group.IMP = investigational medicinal product, N = number of subjects, SAD = single ascending dose, SAF = safetyanalysis set.In the MAD part, more TEAEs related to the IMP were reported in the si-544 treatment group (in 9 out of12 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). RelatedTEAEs 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 orfew hours after onset. Paresthesia was the most frequently reported event (44 events in 5 subjects in total). Allevents 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 (%)aof subjects System organ class450 µg si-544 900 µg si-544Placebo 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 site3 (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) -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 ‘-’.aPercentage is based on the N in the treatment group.IMP = investigational medicinal product, MAD = multiple ascending doses, N = number of subjects, SAF = safetyanalysis set. Outcome In the SAD part, 3 TEAEs in 2 subjects (450 µg si-544: anemia, not related; 900 µg si-544: hypoesthesia foot andcheek [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 µg si-544: pulpitis dental, depression and insomnia [both in the samesubject], 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 events3.2.2.2.1 DeathsNo deaths occurred. 3.2.2.2.2 Other serious adverse eventsThe only serious TEAE reported was a Grade 3 depression in 1 subject in the 900 µg si-544 treatment group of theMAD part. The event was assessed as not being related to si-544 treatment. 3.2.2.2.3 Other significant adverse eventsDose-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 evaluation3.2.2.3.1 Laboratory values over time3.2.2.3.1.1 HematologyNo 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 chemistryNo 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 urinalysisNo 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 changesAll 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 abnormalitiesClinically 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 hadclinically significantly abnormal laboratory values that were reported as TEAEs in all but 1 subject whose conditionwas already present at Screening. In 2 subjects in the 150 µg si-544 treatment group the TEAEs were assessed asrelated 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 adhoc meeting and results of Day 4 were awaited before the next subject was dosed. As these values were withinnormal 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 event50 µg si-544 CRP Day 1 10.0 mg / L 0 - 4.9 CRP increased150 µg si-544 Lymphocytes Day 4 11.9 % 20 - 44 LymphopeniaLymphocytes (abs.) Day 4 0.83 109 / L 1.1 - 4.5 LymphopeniaCRP Day 4 14.7 mg / L 0 - 4.9 CRP increased150 µg si-544 Potassium Day 1 5.7 mmol / L 3.5 - 5.1 Hyperkalemia450 µg si-544 Hemoglobin Day 8 13.1 g / dL 13.5 - 17.2 AnemiaMicroscopicDay 8 5 1 / hpf 0 - 3 Anemiaerythrocytes (urine)900 µg si-544 Erythrocytes Day 1 3.16 1012 / L 3.9 - 5.15 Hb decreasedHb Day 1 9.2 g / dL 12 - 15.4 Hb decreasedHematocrit Day 1 28.3 % 35.5 - 45 Hb decreasedPlacebo Eosinophils Day 1 14.7 % 0.5 - 5.5 EosinophiliaDay 4 13.3 % 0.5 - 5.5 EosinophiliaEosinophils (abs.) Day 1 0.93 109 / L 0.02 - 0.5 EosinophiliaDay 4 0.93 109 / L 0.02 - 0.5 EosinophiliaAEs 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 hadclinically 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)NormalTreatment group Parameter Visit Value Unit range Adverse event450 µg si-544 AST Day 1 182 U / L 0 - 50 Transaminasesincreased Day 4 311 U / L 0 - 50 Transaminasesincreased CPK Day 1 14797 U / L 0 - 308 Blood CPKincreased Day 4 13781 U / L 0 - 308 Blood CPKincreased USV 1 1563 U / L 0 - 308 Blood CPKincreased Day 8 826 U / L 0 - 308 Blood CPKincreased CRP Day 8 12.9 mg / L 0 - 4.9 NasopharyngitisTable 24: Individual clinically significantly abnormal laboratory values – MAD part (SAF)NormalTreatment group Parameter Visit Value Unit range Adverse event450 µg si-544 CRP Day 78 22.9 mg / L 0 - 4.9 Rhinorrhea900 µg si-544 CPK Day 29 1352 U / L 0 - 308 MyalgiaCRP Day 78 11.4 mg / L 0 - 4.9 Nasopharyngitis900 µg si-544 CRP Day 11 32.1 mg / L 0 - 4.9 NasopharyngitisPlacebo Ferritin Day 78 13.1 µg / L 31.3 - 408.5 Iron deficiencyDay 106 14.2 µg / L 31.3 - 408.5 Iron deficiencyAST = aspartate aminotransferase, CPK = creatine phosphokinase, CRP = C-reactive protein, MAD = multipleascending doses, SAF = safety analysis set, USV = unscheduled visit.3.2.2.4 Electrocardiogram, vital signs, and peripheral oxygen saturation3.2.2.4.1 ElectrocardiogramFor no subject the ECG was evaluated as clinically significantly abnormal in the SAD or the MAD part. 3.2.2.4.2 Vital signsNo subject had a clinically significantly abnormal vital sign assessment in the SAD or the MAD part. 3.2.2.4.3 Peripheral oxygen saturationAbsolute values are summarized for the SAD part in Table 25 and for the MAD part in Table 26. No substantialchanges in mean peripheral oxygen saturation were observed from before to after IMP injection at Day 1 in the SADpart 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 µg 50 µg 150 µg 450 µg 900 µgPlacebo 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)Mean (SD) peripheral oxygen saturation [%] 450 µg si-544 900 µg si-544Placebo Visit (N = 6) (N = 6) (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 parameters3.2.2.5.1 Physical examinationIn 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 alreadypresent at Screening.6 subjects in the MAD part had clinically significantly findings that were not present atScreening 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 examinationThe only abnormal finding (clinically significant hypoesthesia) in 1 subject in the 900 µg si-544 treatment group ofthe SAD part had already been present at Screening. 3.2.2.6 Safety summarySAD part ^23 TEAEs were reported in 9 subjects (45%), 2 TEAEs in 1 subject treated with placebo, and 21 TEAEs in8 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 µg and 1 each in the 450 µg and 900 µg treatment group) with no reports in theplacebo treatment group ^2 subjects in the 150 µg si-544 treatment groups had clinically significantly abnormal laboratory values thatwere 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 oxygensaturation did not substantially change from Baseline in any treatment group ^No clinically significant abnormal findings that were not already present at Screening were reported inphysical or neurological examination MAD part^ 160 TEAEs were reported in 14 subjects (88%), 10 TEAEs in 3 subjects treated with placebo and150 TEAEs in 11 subjects treated with si-544^ Most TEAEs were Grade 1 or Grade 2; 1 subject in the 450 µg si-544 treatment group had 1 Grade 3(transaminases increased) and 1 Grade 4 (blood creatine phosphokinase increased) event. In the 900 µg si-544 treatment group, 2 subjects had Grade 3 events (depression and nasopharyngitis). None of the Grade 3or Grade 4 events were related to the si-544 treatment^ The only serious TEAE was reported in 1 subject in the 900 µg si-544 treatment group (depression, notrelated to the IMP) ^Infections and infestations, and general disorders and administration site conditions were reported by thehighest proportion of subjects in the 450 µg si-544 treatment group (in 3 of 6 subjects), and infections andinfestations and nervous system disorders in the 900 µg si-544 treatment group (in 5 of 6 subjects). In theplacebo 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 asrelated 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 subjectstotal) ^No subject had clinically significantly abnormal laboratory values reported as TEAE assessed as related tothe IMP ^No clinically significantly abnormal findings were observed in ECG, or vital signs. The peripheral oxygensaturation did not substantially change from Baseline in any treatment group ^6 subjects had clinically significantly physical examination findings reported as TEAEs (5 subjects treatedwith 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 examination3.2.3 Pharmacokinetics, pharmacodynamics, efficacy, and other evaluations3.2.3.1 Pharmacokinetics and pharmacodynamics3.2.3.1.1 Drug dose, drug concentration, and relationship to response3.2.3.1.1.1 Plasma concentration of free si-544Plasma concentration measurements of free si-544 were performed at Day 1 of the 450 µg and 900 µg si-544treatment 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 beforeand after dosing. Few subjects (1 subject in the SAD part, and 2 subjects in the MAD part) had first detectableconcentrations at 5 minutes after dosing, with a generally short window with detectable concentrations for mostsubjects. 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 µggroup and 1 hour postinjection in the 900 µg group, while at Day 25 (ie, after multiple si-544 injections), mean si-544plasma concentrations were highest 1 hour postinjection in the 450 µg and 30 minutes postinjection in the 900 µgtreatment 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 µg 900 µg 450 µg 900 µg 450 µg 900 µg 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 5Meanna 6.22 na 11.86 na 12.58(SD) (0.577) (3.303) (6.032) 00:30 n 1 3 5 6 5 5Meanna 13.619.29 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 6Mean 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 6Mean 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 - 4Meanna 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 ofsubjects in the analysis, na = not applicable, SAD = single ascending dose, SAF = safety analysis set.3.2.3.1.1.2 Pharmacokinetic parametersPK parameters are summarized in Table 28. In both study parts, the geometric mean Cmax in the 450 µg si-544treatment group was about half the Cmax of the 900 µg si-544 treatment group, with a median Tmax of about 1 hour inall treatment groups and at all assessed time points. The total exposure to si-544 (AUC0-last) was 3 to 4 times higherin the 900 µg than in the 450 µg treatment group.Table 28: Pharmacokinetic parameters – SAD and MAD part (SAF)SAD Day 1 MAD Day 1 MAD Day 25450 µg 900 µg 450 µg 900 µg 450 µg 900 µg si-544 si-544 si-544 si-544 si-544 si-544 Parameter(N = 3) (N = 3) (N = 6) (N = 6) (N = 6) (N = 6)AUC0-8h n 1 - - 2 - 2[h*ng / mL] gMeanna na na 74.11 na 78.31(gCV [%]) (5.970) (9.713) AUC0-last n 2 3 5 6 5 6[h*ng / mL] gMean 12.27 47.05 13.82 42.60 12.38 40.07 (gCV [%]) (60.252) (58.501) (39.135) (60.797) (26.283) (79.424) AUC0-∞ n - - - 2 - 2[h*ng / mL] gMeanna na na 78.22 na 81.40(gCV [%]) (0.821) (9.433) n2 3 5 6 5 6 Cmax gMean 9.94 18.11 9.77 17.89 8.35 19.80 [ng / mL] (gCV [%]) (39.092) (10.832) (47.090) (36.743) (22.419) (44.185) t½ [h] n - - - 2 - 2Medianna na na 1.80 na 1.64(min, max) (1.33, 2.27) (1.60, 1.67) Tmax [h] n 2 3 5 6 5 6Median 0.76 1.00 1.00 1.00 1.00 0.99 (min, max) (0.52, 1.00) (1.00, 1.02) (0.50, 1.00) (0.50, 2.00) (0.98, 1.00) (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, AUC0-8h = AUC from time zero to 8 hours, AUC0-last = AUCfrom time zero until the time of the last quantifiable concentration, AUC0-∞ = 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, t½ = apparent terminal elimination half-life, Tmax = time to reach Cmax.3.2.3.1.1.3 Dose proportionalityDose proportionality was calculable with slopes close to 1 in the SAD part for AUC0-lastand Cmax(Table 29). Table 29: Dose proportionality - SAD part (SAF)Parameter Slope (95% CI)N 3AUC0-last [h*ng / mL] 1.94 (-0.35, 4.23)Cmax [ng / mL] 0.87 (-0.12, 1.85)AUC0-last = 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 Pharmacodynamics3.2.3.1.2.1 T cell subsetsA summary of CD2+ lymphocytes and T cell subsets is shown in Table 30. No substantial change from Baselinewas 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 placebotreatment 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 29o CD2+ CD4- CD8+ CCR7- CD45RA- (450 µg si-544 only; 900 µg si-544: no change from Baseline)o CD2+ CD4- CD8+ Ki-67+ (placebo no change from Baseline)^ Day 106o 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 treatmentgroup. Table 30: T cell subsets – MAD part (SAF)450 µg si-544 900 µg si-544 Placebo Parameter(N = 6)a (N = 6) (N = 4)a,bVisitMedian 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 0.020 -0.054 (0.319) -0.040 0.017 (0.225) -0.160 -0.160 (0.297)D29 CFB -0.060 -0.048 (0.167) -0.085 -0.053 (0.261) -0.120 -0.120 (0.156)D106 CD2+ CD4- CD8+ [%]cD1 (BL) 29.200 31.060 (5.893) 35.550 34.767 (4.189) 32.150 32.150 (5.020)CFB -2.400 -1.740 (1.412) -1.300 -1.600 (2.231) -1.000 -1.000 (3.111)D29 CFB -1.400 -1.460 (1.019) -1.700 -1.733 (1.179) 0.400 0.400 (1.556)D106 CD2+ CD4- CD8+ CCR7+ CD45RA- [%]cD1 (BL) 0.100 0.180 (0.192) 0.300 0.280 (0.084) 0.200 0.200 (0.000)CFB 0.000 -0.040 (0.089) -0.100 -0.120 (0.084) -0.100 -0.100 (0.000)D29 CFB 0.000 -0.040 (0.055) -0.100 -0.080 (0.130) -0.100 -0.100 (0.000)D106 CD2+ CD4- CD8+ CCR7+ CD45RA+ [%]cD1 (BL) 13.100 11.940 (5.410) 14.400 14.240 (3.053) 9.950 9.950 (1.485)CFB 0.400 0.880 (1.842) 0.600 0.840 (1.064) -0.500 -0.500 (1.414)D29 CFB -- - - D1 (BL) 1.800 2.000 (1.655) 3.100 3.440 (0.921) 4.200 4.200 (0.707)CFB -0.100 -0.160 (0.207) 0.000 0.000 (0.464) 0.450 0.450 (0.636)D29 CFB 0.200 0.320 (0.444) 0.400 0.260 (0.378) 0.550 0.550 (0.071)D106 CD2+ CD4- CD8+ CCR7- CD45RA+ [%]cD1 (BL) 15.000 16.920 (8.917) 18.400 15.940 (5.100) 17.900 17.900 (2.828)CFB -2.300 -2.360 (2.590) -0.800 -1.760 (3.058) -0.900 -0.900 (3.960)D29 CFB -1.500 -2.640 (3.663) -1.300 -1.720 (1.446) 1.250 1.250 (2.051)D106CD2+ CD4- CD8+ Ki-67+ [%]cD1 (BL) 1.300 1.180 (0.482) 1.300 1.433 (0.565) 0.750 0.750 (0.071)CFB -0.100 -0.200 (0.400) -0.400 -0.483 (0.467) 0.000 0.000 (0.566)D29 CFB -0.300 -0.220 (0.259) -0.550 -0.650 (0.501) 0.400 0.400 (0.000)D106CD2+ CD4+ CD8- [%]cD1 (BL) 60.000 58.580 (8.574) 55.650 53.217 (8.541) 56.550 56.550 (7.142)CFB 4.300 3.820 (3.406) 2.550 3.450 (3.701) 2.300 2.300 (5.091)D29 CFB 2.200 3.380 (2.784) 3.900 3.650 (1.600) -0.600 -0.600 (2.404)D106CD2+ CD4+ CD8- CCR7+ CD45RA- [%]cD1 (BL) 4.600 6.280 (6.784) 5.900 6.720 (1.805) 7.000 7.000 (0.707)CFB -0.200-1.500 -1.000 (1.122)-1.450 (1.061) -0.500 (0.663) -1.450 D29 CFB -1.800 (0.141) -0.200 -0.340 (0.488) -0.300 -1.000 (1.259) -1.800D106CD2+ CD4+ CD8- CCR7+ CD45RA+ [%]cD1 (BL) 31.800 34.820 (9.146) 32.000 31.300 (9.247) 31.800 31.800 (1.838)CFB 2.480 (2.641) 0.650 (5.303) 4.300 3.320 (3.097) 1.7000.650 D29 CFB -2.150 (4.172) 4.600 3.580 (3.840) 1.600 1.760 (1.001) -2.150D106CD2+ CD4+ CD8- CCR7- CD45RA- [%]cD1 (BL) 8.900 9.940 (6.982) 10.500 11.320 (1.497) 14.200 14.200 (3.253)CFB 2.300 (1.131) -0.100 0.420 (0.934) 0.100 0.200 (1.247) 2.300D29 CFB 1.000 (0.849) -0.100 -0.280 (1.180) -0.300 0.140 (1.014) 1.000D106CD2+ CD4+ CD8- CCR7- CD45RA+ [%]cD1 (BL) 5.400 7.560 (6.930) 3.900 3.520 (1.377) 3.550 3.550 (1.344)CFB 0.750 (0.212) 0.600 0.560 (1.640) 0.900 1.100 (0.880) 0.750D29 CFB 2.900 2.300 (1.131) 0.500 0.380 (1.361) 2.600 (1.409) 2.300D106CD2+ CD4+ CD8- Ki-67+ [%]cD1 (BL) 1.700 2.020 (1.013) 2.100 1.983 (0.500) 1.900 1.900 (0.283)CFB -0.140 (0.541) -0.400 (0.283) 0.100-0.300 -0.433 (0.383) -0.400D29 CFB -0.100 (0.000) -0.200 -0.340 (0.564) -0.650 -0.767 (0.505) -0.100D106 CD2+ CD45RO+ CLA+ [%]cD1 (BL) 10.700 10.960 (2.190) 6.150 7.933 (4.869) 15.000 15.000 (5.091)CFB -1.050 (4.172) -0.200 -1.160 (2.505) -0.050 -0.583 (1.806) -1.050D29 CFB -0.440 (2.273) -0.617 (1.551) 0.600 (4.525) -0.100 -0.350 0.600 D106 CD2+ CD45RO- CLA+ [%]cD1 (BL) 20.800 16.120 (9.358) 1.950 4.717 (6.000) 15.000 15.000 (5.798)CFB -4.940 (5.488) -0.400 (0.944) -0.700 (0.707) -2.000 -0.250 -0.700 D29 CFB -2.820 (3.706)-1.100 (1.208) -0.250 -0.250 (2.616)-1.100 -0.650 D106 aFor 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 = multipleascending doses, N = number of subjects, SAF = safety analysis set.3.2.3.1.2.2 Serum cytokinesBiomarkers were only assessed during the MAD part of the study. Descriptive statistics for serum cytokine levels atBaseline and changes from Baseline are summarized for parameters that were measurable in >1 subject in Table 31.IL-8 and TNF-α were the only parameters for which all subjects had values above the LLOQ at all visits. IL-1β, IL-2, IL-4, IL-12, IL-13, and IL-17A were not detectable (ie, below the LLOQ) in most (IL-1β) or all subjects (IL-2, IL-4, IL-12, IL-13, and IL-17A). Median IFN-γ levels were decreased at Day 29 compared to Baseline in both the 450 µg and 900 µg si-544treatment groups, while a slight increase is observed in the placebo treatment group. During follow up, decreasedmedian (and mean) IFN-γ levels were maintained in the 450 µg si-544 treatment group.By contrast, TNF-α and IL-8 levels increased at all postbaseline visits in the 450 µg group and at Day 29 in the900 µg si-544 treatment group but decreased at all postbaseline visits in the placebo treatment group. However, forall 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)450 µg si-544 900 µg si-544 Placebo Parameter(N = 6) (N = 6) (N = 4)VisitMedian Mean (SD) Median Mean (SD) Median Mean (SD)IFN-γ[pg / mL]D1 (BL) 9.815a 10.787 (7.808)a 7.355 6.537 (2.883) 3.165f 2.970 (0.799)fCFB -0.955a -4.722 (8.190)a -0.810 0.262 (2.717) 0.405 1.598 (2.737)D29 CFB -1.605b -4.530 (8.837)b -0.725 -0.540 (1.258) -0.245 0.943 (2.812)D50 CFB -1.195a -2.668 (10.706)a 0.530 0.412 (2.354) 2.005 6.773 (10.810)CFB -2.220 -3.323 (8.799) 0.260 3.978 (8.135) 2.745 4.070 (4.077)D106 IL-8 [pg / mL]D1 (BL) 9.565 9.190 (1.940) 8.970 9.105 (1.624) 9.990f 10.863 (4.551)fCFB -0.010 -0.473 (2.569) -0.515 -0.477 (0.603) -1.535 -2.413 (4.477)D29 CFB 1.905 1.410 (3.570) 0.210 0.203 (1.479) -0.230 -0.493 (1.193)D50 CFB 1.080 1.455 (4.404) -0.170 -0.862 (1.878) -0.585 -1.380 (4.984)D78 CFB -- - - D1 (BL) 1.210 1.198 (0.231) 1.100 1.138 (0.206) 1.235 1.563 (0.820)CFB 0.040 0.088 (0.156) 0.045 0.025 (0.126) -0.025 -0.393 (0.827)D29 CFB 0.100 0.070 (0.170) -0.085 -0.060 (0.201) -0.115 -0.433 (0.912)D50 CFB 0.045 0.188 (0.499) -0.090 -0.073 (0.164) -0.010 -0.353 (0.890)D78 CFB -- - - D1 (BL) 0.645c 0.920 (0.458)c 0.630 0.630 (0.000) 0.630d,f 0.630 (0.000)d,fCFB 0.010a-0.137 (0.282)a0.000e0.012 (0.029)e0.000d0.000 (0.000)dD29 CFB 0.220b 0.193 (0.553)b 0.000 0.000 (0.000) 0.000c 0.010 (0.020)cD50 CFB 0.000c-0.150 (0.579)c0.050c0.138 (0.208)c0.005b0.008 (0.010)bD78 CFB -0.010b0.063 (0.930)b0.000d0.032 (0.050)d0.000d0.000 (0.000)dD106 IL-10 [pg / mL] D1 (BL) 0.300d 0.360 (0.095)d 0.300d 0.317 (0.041)d 0.300d,f 0.300 (0.000)d,fCFB 0.000d-0.020 (0.033)d0.000e-0.013 (0.033)e0.000d0.000 (0.000)dD29 CFB 0.000d0.027 (0.052)d0.000d0.003 (0.059)d0.000d0.000 (0.000)dD50 CFB 0.000d0.053 (0.146)d0.000e-0.017 (0.041)e0.000d0.000 (0.000)dD78 CFB 0.000d0.143 (0.346)d0.000d0.037 (0.144)d0.000c0.010 (0.020)cD106 Only parameters for which >1 subject within a treatment group had values >LLOQ are included. Values <LLOQ werereplaced 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 b N = 2 c N = 3 d N = 4 e N = 5.f For N = 1, the sample was hemolytic.BL = Baseline, CFB = change from Baseline, D = Day, IL = interleukin, IFN = interferon, LLOQ = lower limit ofquantification, MAD = multiple ascending doses, N = number of subjects, SAF = safety analysis set, TNF = tumornecrosis factor. 3.2.3.2Immunogenicity Immunogenicity was assessed by anti-drug antibody titration.1 subject in the 900 µg si-544 treatment group had atitration result of 80 ng / mL at Day 29. Titration was negative for all other assessed subjects at Day 1 and Day 29.3.2.3.3 Efficacy resultsSecondary efficacy was only assessed during the MAD part of the study. 3.2.3.3.1 Secondary efficacy endpoints3.2.3.3.1.1 Body surface indexThe inflamed skin areas were assessed as percentage of the total BSA using the body surface index. A summary ofthe body surface index is shown in Table 32. At Baseline, the mean affected BSA in the 900 µg si-544 with a bodysurface index of about 9% was substantially lower than in the 450 µg si-544 and placebo treatment group (19% and24%). After 4 weeks of treatment (Day 29), the body surface index had improved in all treatment groups.Improvement was lower in the 450 µg and 900 µg si-544 treatment groups with a decrease in the body surface indexof 9% and 12%, respectively, than in the placebo treatment group (decrease of 29%). During follow-up, the body 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 µg si-544 900 µg 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) naD15 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)aD29 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%. aFor 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 = multipleascending doses, N = number of subjects, na = not applicable, rel = relative, SAF = safety analysis set.3.2.3.3.1.2 Atopic dermatitis severityThe severity of AD was assessed using the SCORAD comprising 3 domains: extent of disease assessed using thebody surface index, intensity of the disease using the eczema severity score and the subjective symptom score. The eczema severity score is summarized in Table 33. At Baseline, the eczema severity was slightly higher in the450 µg than in the 900 µg si-544 treatment group, with the highest severity in the placebo treatment group. Theeczema severity had decreased in both si-544 treatment groups after 4 weeks of treatment (Day 29), and thisimprovement 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 µg si-544 900 µg si-544 Placebo (N = 6) (N = 6) (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) naD15 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 scorewas 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 scorewas slightly lower in the 900 µg si-544 treatment group than in the 450 µg si-544 and placebo treatment group.During the treatment period, subjective symptoms improved and this improvement was maintained during the follow- up 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. Table 34: Subjective symptom score – MAD part (SAF)Mean (SD) of subjective symptom score 450 µg si-544 900 µg si-544 Placebo (N = 6) (N = 6) (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) na7.28 (5.16) 6.47 (3.96)a-25.53 D15-33.13 (29.68) 5.53 (3.44) -35.17 (31.06)(33.45)aD29 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 = nosymptom 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 SCORADshowed an improvement in the AD severity in all treatment groups. Treatment with 450 µg si-544 showed higherimprovement of up to 36% from Baseline than treatment with 900 µg si-544 (relative improvement from Baseline up 21%), but with no marked difference to treatment with placebo (relative improvement up to 41%; Table 35). In alltreatment groups the proportion of subjects with mild AD increased over time (Table 36).Table 35: Total SCORAD absolute scores – MAD part (SAF)Mean (SD) of total SCORAD score 450 µg si-544 900 µg si-544 Placebo (N = 6) (N = 6) (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) na39.75 (20.57) -5.25 (35.72) 28.92 (9.89)36.20 (17.43)a-14.13 D15 -0.12 (33.59) (21.27)aD29 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 (%)aof subjects 450 µg si-544 900 µg si-544 Placebo (N = 6) (N = 6) (N = 4)mild moderate severe mild moderate severe mild moderate severe- 6 (100.0) - 2 4 (66.7) - - 3 (75.0) 1 (25.0)D1 (BL) (33.3)D15 2 (33.3) 3 (50.0) 1 (16.7) 2 (33.3) 4 (66.7) - - 3 (100.0)a -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.aPercentage 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 analysesNo subgroup analyses were performed. 3.2.3.4Statistical issues encountered during the analysis No statistical issues were identified in the study. 3.2.3.5Summary of pharmacokinetics, pharmacodynamics, efficacy, and other evaluations ^Free si-544 plasma concentrations were measurable from 5 minutes postdose onwards, with a medianTmax of about 1 hour in both study parts^ Dose proportionality was shown for Cmax and AUC0-last in the SAD part^ Analyses of T cell subsets in the MAD part showed no substantial change from Baseline with no apparentdifference between treatment groups for CD2+ lymphocyte counts ^IFN-γ levels decreased in both si-544 treatment groups at Day 29, which was maintained during follow upin the 450 µg si-544 treatment group, while IFN-γ levels in the placebo treatment group increased fromBaseline ^TNF-α and IL-8 levels increased at postbaseline visits compared to Baseline in the 450 µg si-544treatment group at all postbaseline visits and at Day 29 in the 900 µg si-544 treatment group, while theydecreased at all postbaseline visits in the placebo treatment group ^Cytokine levels were highly variable between subjects and some cytokines were not detectable (ie, belowthe LLOQ) in most (IL-1β) or all subjects (IL-2, IL-4, IL-12, IL-13, and IL-17A) ^All subjects (but 1 subject in the 900 µg si-544 treatment group at Day 29) had a negative anti-drugantibody 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 treatmentgroups compared to Baseline with no marked difference between si-544 and placebo treatment. 3.2.4. Discussion and overall conclusionSummary and discussion This study was a multi-center, Phase 1b, double-blind, placebo-controlled, SAD and MAD, FIH study in subjectswith 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 andphosphodiesterase-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 SADpart, 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 asplanned. After treatment of the 2 highest doses of the SAD part, 450 µg and 900 µg si-544, during the MAD part alsonone of the reported TEAEs fulfilled the definition of DLTs. All reported TEAEs considered related to treatment withsi-544 were of Grade 1 or Grade 2 including no serious TEAEs. TEAEs assessed as being related to treatment withsi-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 MADpart (44 events in 5 subjects), which was also reported as the most common treatment-related AE in a Phase 1b trialwith 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 µgsi-544. All events had resolved 2-3 days after onset and had no influence on dose escalation. No further clinicallysignificant 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 fromBaseline in CD2+- lymphocyte counts in any treatment group.The assessment of IFN-γ 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-γ (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 1b 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 AUC0-last in the SAD part^ si-544 showed first signals of efficacy in subjects with ADExample 2 - A multicenter, Phase 1b, double-blind, placebo-controlled study to evaluate the safety andtolerability, and the efficacy of si-544 in adults with psoriasis vulgaris or psoriatic arthritis Summary of study Study periods Screening (33 days), treatment period (4 weeks), follow-up (12 weeks)Table 3: Study objectives and endpoints Objectives EndpointsPrimary ^To determine the safety and ^ Type, frequency, severity, and causal relationship oftolerability of treatment with si- adverse events (AEs) and serious AEs 544^ Change in clinical laboratory, electrocardiogram (ECG), vitalsigns, and peripheral oxygen saturation from Baseline to all assessed timepoints Secondary ^To determine the ^ PK parameter in plasma at Day 1 and Day 25pharmacokinetics (PK) of si-544Objectives Endpoints^ To determine the ^ Change in the number of T cells in peripheral blood frompharmacodynamics (PD) of si-544Baseline to Day 29 (Week 5), Week 8, Week 12, andWeek 16^ Change in immunophenotypes of T-cell subsets fromBaseline to Day 29 (Week 5), Week 8, Week 12, andWeek 16^ Change in serum cytokine levels from Baseline to Day 29(Week 5), Week 8, Week 12, and Week 16^ To determine the immunogenicity ^ Change in anti-drug antibodies against si-544 in serumof si-544 treatmentfrom Baseline to Day 29 and Week 16^ To determine the efficacy of ^ Change in the psoriasis area and severity index (PASI)si-544 treatmentfrom Baseline* to Day 15, Day 29 (Week 5)*, Week 8,Week 12, and Week 16* supported by photographic pictures of the affected area, ifsubject consented ^Difference in PASI response rate (defined as subjectswith ≥1 score improvement from Baseline) at Day 15,Day 29 (Week 5)*, Week 8, Week 12, and Week 16^ Change in the physician’s global assessment (PGA) ofdisease activity from Baseline to Day 15, to Day 29(Week 5), Week 8, Week 12, and Week 16Secondary –psoriasis vulgaris only ^To determine the efficacy of ^ Change in the dermatological life quality index (DLQI)si-544 treatment on symptoms offrom Baseline to Day 29 (Week 5), Week 8, Week 12, andpsoriasis vulgaris (Ps)Week 16Optional secondary – psoriatic arthritis only^ To determine the efficacy of ^ Change in the psoriatic arthritis quality of life (PsAQoL)si-544 treatment on symptoms offrom Baseline to Day 29 (Week 5), Week 8, Week 12,psoriatic arthritis (PsA)Week 16^ Change in the subject’s assessment of pain using a VASfrom Baseline to Day 15, to Day 29 (Week 5), Week 8,Week 12, Week 16Optional secondary – psoriatic arthritis only (continued)^ To determine the efficacy of ^ Change in the tender joint count (TJC) 68 from Baselinesi-544 treatment on symptoms ofto Day 15, to Day 29 (Week 5), Week 8, Week 12,psoriatic arthritis (PsA)Week 16(continued)^ Change in the swollen joint count (SJC) 66 from Baselineto Day 15, to Day 29 (Week 5), Week 8, Week 12,Week 16For all assessments, Baseline is defined as the last measurement before the first injection of investigational medicinal product (IMP). MethodologyThis is an ongoingmulticenter, Phase 1b, double-blind, placebo-controlled study to evaluate the safety, tolerability,and efficacy of si-544 in adults with mild to severe Ps or PsA. Eligible subjects are randomized within each indication 3:1 to treatment with 900 µg si-544 or placebo and receiveinvestigational medicinal product (IMP) injections twice a week for 4 weeks (treatment period). During the treatmentperiod, the safety and tolerability, PK, PD, immunogenicity, and efficacy are assessed. Follow-up (FU) visits areperformed at Day 29 (Week 5; end of treatment, EoT), Week 8, Week 12, Week 16 (end of study, EoS), 12 weeksafter the treatment period to assess the safety, PD, immunogenicity, and efficacy. Subjects are considered enrolled once they are randomized. Subjects who prematurely terminate their studyparticipation before receiving 75% of the planned IMP injections (ie, before Day 18) are replaced. Subjectsprematurely terminating their study participation after receiving at least 75% of the planned IMP injections (ie, afterDay 18), are not replaced.Investigational products Test product 900 µg si-544 acetate in 0.9% NaCl solution, subcutaneous injection in the abdomenReference product Placebo (0.9% NaCl solution), subcutaneous injection in the abdomen Subject population Adults with mild to severe Ps and / or PsA Inclusion criteria General inclusion criteria 1. Subject has the capacity for consenting, was informed about the nature, the scope, and the relevance of theclinical 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 is performed 2. Men and women aged ≥18 to 75 years3. Willing and able to adhere to the protocol requirements4. Women of childbearing potential must:a. have a negative pregnancy test (blood) at Screeningb. agree to use, and be able to comply with, highly effective measures of contraceptive control (failurerate 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 withinhibition of ovulation (oral, intravaginal, transdermal) ii. progestogen-only hormonal contraception associated with inhibition of ovulation (oral,injectable, implantable) iii. intrauterine deviceiv. intrauterine hormone-releasing systemv. bilateral tubal occlusionvi. vasectomized sexual partner (provided that the partner is the sole sexual partner of thewoman of childbearing potential and has received medical assessment of the surgical success) vii. sexual abstinence (only if defined as refraining from heterosexual intercourse during theentire 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 lastIMP treatment. Postmenopausal (no menses for at least 1 year without alternative medical cause) or surgically sterile women (tuballigation, hysterectomy, or bilateral oophorectomy) may be enrolled. 5. Men must agree to practice true abstinence or to use a condom during sexual contact with a pregnantwoman or a woman of childbearing potential for at least 90 days after the last IMP treatment, even after undergoing a successful vasectomy. Disease-specific inclusion criteria 6. Inadequate response or intolerance to previous or current treatment with conventional disease-modifyinganti-rheumatic drugs (cDMARDs) Ps-specific inclusion criteria 7. Diagnosis of Ps at least 3 months before Screening8. Active Ps with ≥3% body surface area (BSA) involved and with at least 1 psoriatic plaque (other than nailchange) PsA-specific inclusion criteria 7. Diagnosis of PsA at least 3 months before Screening8. Diagnosis of active Ps with at least 1 psoriatic plaque (other than nail change)9. Active PsA defined asa. ≥1 tender joint out of 68 assessed joints, andb. ≥1 swollen joint out of 66 assessed joints (dactylitis of a digit counts as one joint each), andc. negative results for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodiesExclusion criteria Ps-specific exclusion criteria 1. Drug-induced psoriasisPsA-specific exclusion criteria 1. Late stage PsA with deformed jointsMedical history and concomitant disease exclusion criteria 2. Known history of hypersensitivity to constituents or excipients in the pharmaceutical formulation of the IMP3. Uncontrolled hypertension or uncontrolled diabetes4. History of seizures5. Presence or history of paresthesia or neuropathy6. Clinically significant ECG abnormalities, as judged by the investigator7. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, renal, or other majorsystemic disease, as judged by the investigator 8. Presence of acute infection within 7 days before Screening and Day 1, as judged by the investigator9. Known or active infection with Mycobacterium tuberculosis and / or positive Tbc-IGRA result at Screening10. Known or active infection with HIV, hepatitis B virus, or hepatitis C virus11. Any finding or medical condition prohibiting the inclusion in the study, as judged by the investigator12. Known or suspected abuse of alcohol, drugs, or medicinal productsTherapy exclusion criteria 13. Change (ie, initiating, change in frequency, or change in drug substance) in standard systemic and topicaltherapy for Ps or PsA, or in immunosuppressive drug therapy within 4 weeks before Screening (for biologicssuch as Cosentyx, Humira, and alike, the therapy may not be changed within 12 weeks before Screening),as judged by the investigator 14. Change (ie, initiating, change in frequency, or change in drug substance) in standard systemic therapy forany other indications (such as, eg, cardiovascular disease)15. Vaccination within 2 weeks before Screening and / or planned vaccination during the treatment period16. Current or previous (within 4 weeks before Screening) participation in another clinical study with an IMP or amedical device General exclusion criteria 17. Employee of the sponsor, or employee, or relative of the investigator18. Committed to an institution by virtue of an order issued either by the judicial or the administrative authorities19. Legal incapacity or limited legal capacityPrevious and concomitant medication Any medication taken at Screening and planned to be taken during the study should be kept on a stable dose. Changing doses of concomitant medications or initiation of new medications is prohibited from Screening until the EoS. Study assessments Demography and baseline characteristics ^Demographic data (sex, age, race, ethnicity, fertility status)^ Body weight, height, and body mass index^ Medical history^ Serology^ Body surface areaSafety ^Adverse events^ Safety laboratory^ Physical and neurological examination^ ECG, vital signs, and peripheral oxygen saturation^ Pregnancy testing (for women of childbearing potential only)Pharmacokinetics Blood collections for the analysis of si-544 PK in plasma Pharmacodynamics Blood collections for the following PD analyses: ^Fluorescence-activated cell sorting: number of central memory T cells, effector memory T cells, andregulatory T cells in peripheral blood and immunophenotyping of T-cell subsets^ Serum cytokine levelsEfficacy ^Disease activity (visual analogue scale [VAS])^ PASI (including photography of the affected body area, if subject consented)^ PGA^ For Ps only:o DLQI^ Optional for PsA only:o PsAQoLo Pain (VAS)o TJC-68 / SJC-66Immunogenicity Anti-drug antibodies Statistical methods No formal sample size calculation was done for the primary endpoint. Within each indication subjects will be randomized 3:1 to treatment with si-544 or placebo. The planned analyses are of exploratory nature without any formal statistical hypothesis testing. All endpoints will be analyzed descriptively using standard statistical methods. Statistical testing for the difference in PASI response rate between treatments may be done. Subgroup analyses for the different indications may be performed, if applicable. The final data analysis will be performed after all subjects have completed the study. A blind data review meeting will be held before hard locking the database to assess any protocol deviations and to allocate subjects to analysis sets. Analysis of the blinded data of 29 psoriasis patients revealed first signals of efficacy (Figure 3): Subjects receivedthe si-544 or placebo injections twice a week for 4 weeks (treatment period), last day of treatment is D25. PASI wasevaluated at D1, D15 and D29 (4 days after the last treatment). In Figure 3, normalized PASI values for 29 subjectsof the study are shown, i.e. PASI values of subjects were normalized for D1 and subsequent changes (Dx vs. D1) arepresented in %. Values >0% mean deterioration, values <0% mean improvement of symptoms. Each line representsone individual subject. In addition, Figure 3 shows a gray square indicating the efficacy range of dalazatide (Tarcha,2017, improvement in the range of -14 to -35 %). Subjects of the present clinical study reached higher improvement(significantly below -35% as shown in Figure 3) suggesting clearly better efficacy as described in Tarcha, 2017.REFERENCES Belpaire A, van Geel N, Speeckaert R. From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation apotential 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.Curr Opin Chem 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 themanagement 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. Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a new retinoid. Dermatologica.1978;157(4):238- 44. 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 Sézary syndrome. Oncotarget. 2019;10(47):4894-4906. Kessler TR. Treating patients with moderate-to-severe psoriasis vulgaris. JAAPA.2022 Mar 1;35(3):28-35. Kopitar-Jerala N. The Role of Interferons in Inflammation and Inflammasome Activation. Frontiers in Immunology. 2017;8. Kowalska-Olędzka 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. Ogdie A, Coates LC, Gladman DD. Treatment guidelines in psoriatic arthritis. Rheumatology (Oxford).2020 Mar1;59(Suppl 1):i37-i46. 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, Muñoz-Elías EJ, Kruger JG, Iadonato 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 sequenceTIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or its pharmaceutically acceptable salt foruse in a method of treating psoriasis vulgaris (Ps) and / or improving an Ps-associated parameter, wherein thepharmaceutical composition is administered at a dose equivalent to about 0.15 mg to about 1.5 mg of the acetate saltof said peptide.2. The pharmaceutical composition for use according to embodiment 1, wherein the pharmaceutical composition isadministered 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 isadministered 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 thepharmaceutical 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 thepharmaceutical 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 thepharmaceutical composition is administered subcutaneously.8. The pharmaceutical composition for use according to any one of embodiments 1 to 7, wherein thepharmaceutical composition is administered for 3 to 6 weeks.9. The pharmaceutical composition for use according to any one of embodiments 1 to 7, wherein thepharmaceutical composition is administered for 4 weeks.10. The pharmaceutical composition for use according to any one of embodiments 1 to 9, wherein thepharmaceutical composition is administered to a subject with Ps with a Psoriasis Area and Severity Index (PASI)score of < 10.11. The pharmaceutical composition for use according to any one of embodiments 1 to 9, wherein thepharmaceutical composition is administered to a subject with Ps with a Psoriasis Area and Severity Index (PASI)score of ≥ 10.12. The pharmaceutical composition for use according to any one of embodiments 1 to 11, wherein the Ps-associated parameter is the the Psoriasis Area and Severity Index (PASI) score and administration of thepharmaceutical composition according to the present invention results in a decrease from baseline in the PsoriasisArea and Severity Index (PASI) score of at least 20%, optionally of at least 50%.13. A pharmaceutical composition comprising a peptide consisting of the amino acid sequenceTIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or its pharmaceutically acceptable salt foruse in a method of treating psoriatic arthritis (PsA) and / or improving an PsA-associated parameter, wherein thepharmaceutical composition is administered at a dose equivalent to about 0.15 mg to about 1.5 mg of the acetate saltof said peptide.14. The pharmaceutical composition for use according to embodiment 13, wherein the pharmaceutical compositionis administered at a dose equivalent to about 0.45 mg of the acetate salt of the said peptide.15. The pharmaceutical composition for use according to embodiment 13, wherein the pharmaceutical compositionis administered at a dose equivalent to about 0.9 mg of the acetate salt of the said peptide.16. The pharmaceutical composition for use according to any one of embodiments 13 to 15, wherein thepharmaceutical composition is administered three times a week, twice a week or once a week.17. The pharmaceutical composition for use according to any one of embodiments 13 to 15, wherein thepharmaceutical composition is administered twice a week.18. The pharmaceutical composition for use according to any one of embodiments 13 to 17, wherein thepharmaceutical composition is administered subcutaneously, intramuscularly or intravenously.19. The pharmaceutical composition for use according to any one of embodiments 13 to 17, wherein thepharmaceutical composition is administered subcutaneously.20. The pharmaceutical composition for use according to any one of embodiments 13 to 19, wherein thepharmaceutical composition is administered for 3 to 6 weeks.21. The pharmaceutical composition for use according to any one of embodiments 13 to 19, wherein thepharmaceutical composition is administered for 4 weeks.22. The pharmaceutical composition for use according to any one of embodiments 13 to 21, wherein thepharmaceutical composition is administered to a subject with PsA with a Psoriasis Area and Severity Index (PASI)score of < 10.23. The pharmaceutical composition for use according to any one of embodiments 13 to 21, wherein thepharmaceutical composition is administered to a subject with PsA with a Psoriasis Area and Severity Index (PASI)score of ≥ 10.24. The pharmaceutical composition for use according to any one of embodiments 13 to 24, wherein the PsA-associated parameter is the the Psoriasis Area and Severity Index (PASI) score and administration of the pharmaceutical composition according to the present invention results in a decrease from baseline in the Psoriasis Area and Severity Index (PASI) score of at least 20%, optionally of at least 50%.

Claims

CLAIMS1. A pharmaceutical composition comprising a peptide consisting of the amino acid sequenceTIINVKCTSPKQCLPPCKAQTGCPYGKCMNRKCKCNRC (SEQ ID NO.: 1) or its pharmaceutically acceptable salt for use in a method of treating psoriasis vulgaris (Ps), wherein the pharmaceuticalcomposition is administered at a peptide dose equivalent in moles to about 0.15 mg to about 1.5 mg of theacetate salt of said peptide.

2. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition isadministered 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 isadministered 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 pharmaceuticalcomposition 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 pharmaceuticalcomposition is administered twice a week.

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

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

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

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

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

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

12. The pharmaceutical composition for use according to any one of claims 1 to 11, wherein administration ofthe pharmaceutical composition results in improving a Ps-associated parameter, wherein the Ps-associatedparameter is the the Psoriasis Area and Severity Index (PASI) score and administration of thepharmaceutical composition according to the present invention results in a decrease from baseline in the Psoriasis Area and Severity Index (PASI) score of at least 20%, optionally of at least 50%.

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