Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders

Definitions

• Ulcerative colitis is a chronic, idiopathic inflammatory disease that affects the colon. It has a bimodal pattern of incidence, with main onset in patients between 15 and 30 years of age and a second smaller peak between 50 and 70 years of age. It is characterized by relapsing and remitting inflammation characteristically restricted to the mucosal surface. Disease distribution is stratified by the extent of colonic involvement, from proctitis to leftsided colitis or extensive colitis (pancolitis). The incidence and prevalence of ulcerative colitis have been increasing over time worldwide.
• the method includes: administering to the subject a first dose of amiselimod, or a pharmaceutically acceptable salt or enantiomer thereof, during a first administration period; and administering to the subject a second dose of amiselimod, or a pharmaceutically acceptable salt or enantiomer thereof, during a second administration period, wherein the first dose is larger than the second dose.
• the method includes: administering to the subject a therapeutically effective first dose of amiselimod, or a pharmaceutically acceptable salt or enantiomer thereof, during a first administration period; and administering to the subject a therapeutically effective second dose of amiselimod, or a pharmaceutically acceptable salt or enantiomer thereof, during a second administration period, wherein the first dose is larger than the second dose.
• this disclosure includes a method of treating or ameliorating ulcerative colitis in subject in need thereof comprising the steps of administering to the subject a first dose of a composition comprising amiselimod during a first administration period; and administering to the subject a second dose of a composition comprising amiselimod during a second administration period, wherein the first dose is larger than the second dose.
• this disclosure includes a method of treating or ameliorating ulcerative colitis in subject in need thereof comprising the steps of administering to the subject a first dose of amiselimod or a pharmaceutically acceptable salt thereof during a first administration period; and administering to the subject a second dose of amiselimod or a pharmaceutically acceptable salt thereof during a second administration period, wherein the first dose is larger than the second dose.
• this disclosure includes a method of treating or ameliorating ulcerative colitis in subject in need thereof comprising the steps of administering to the subject a therapeutically effective first dose of amiselimod during a first administration period; and administering to the subject a therapeutically effective second dose of amiselimod during a second administration period, wherein the first dose is larger than the second dose.
• this disclosure includes a method of treating mild to moderate ulcerative colitis in subject in need thereof comprising the steps of administering to the subject a therapeutically effective first dose of amiselimod during a first administration period; and administering to the subject a therapeutically effective second dose of amiselimod during a second administration period, wherein the first dose is larger than the second dose.
• this disclosure includes a method of treating or ameliorating inflammation in the gastrointestinal tract in subject in need thereof comprising the steps of administering to the subject a first dose of a composition comprising amiselimod during a first administration period; and administering to the subject a second dose of a composition comprising amiselimod during a second administration period, wherein the first dose is larger than the second dose.
• the first dose is about 1.5 to about 2.5 times larger than the second dose.
• administration of the second dose comprises administration of about 0.05 mg to about 10 mg of amiselimod.
• administration of the first dose comprises administration of about 0.1 mg to about 1 mg of amiselimod.
• administration of the first dose comprises administration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod. In some embodiments of the foregoing methods, administration of the first dose comprises administration of less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod. In some embodiments of the foregoing methods, administration of the first dose comprises administration of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod.
• administration of the first dose comprises administration of about 0.8 mg of amiselimod. In some embodiments of the foregoing methods, administration of the first dose comprises administration of about 0.4 mg of amiselimod.
• administration of the first dose comprises administration of about 0.05 mg to about 10 mg of amiselimod per unit dose.
• administration of the second dose comprises administration of about 0.05 mg to about 10 mg of amiselimod per unit dose.
• administration of the second dose comprises administration of about 0.1 mg to about 1 mg of amiselimod per unit dose.
• administration of the first dose comprises administration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per unit dose. In some embodiments of the foregoing methods, administration of the first dose comprises administration of less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per unit dose. In some embodiments of the foregoing methods, administration of the first dose comprises administration of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per unit dose.
• administration of the first dose comprises administration of about 0.8 mg of amiselimod per unit dose. In some embodiments of the foregoing methods, administration of the first dose comprises administration of about 0.4 mg of amiselimod per unit dose.
• administration of the second dose comprises administration of about 0.4 mg of amiselimod per unit dose. In some embodiments of the foregoing methods, administration of the second dose comprises administration of about 0.2 mg of amiselimod per unit dose.
• administration of the first and second doses comprise, independently, administration of daily doses of amiselimod.
• administration of the first dose comprises administration of about 0.05 mg to about 10 mg of amiselimod per daily dose.
• administration of the second dose comprises administration of about 0.05 mg to about 10 mg of amiselimod per daily dose.
• administration of the first dose comprises administration of about 0.1 mg to about 1 mg of amiselimod per daily dose.
• administration of the second dose comprises administration of about 0.1 mg to about 1 mg of amiselimod per daily dose.
• administration of the first dose comprises administration of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per daily dose. In some embodiments of the foregoing methods, administration of the first dose comprises administration of less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per daily dose. In some embodiments of the foregoing methods, administration of the first dose comprises administration of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1.0 mg of amiselimod per daily dose.
• administration of the second dose comprises administration of about 0.4 mg of amiselimod per daily dose. In some embodiments of the foregoing methods, administration of the second dose comprises administration of about 0.2 mg of amiselimod per daily dose.
• FIG. 3 shows a timeline of the open-label extension (OLE) period for a proposed amiselimod study.
• the terms "effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
• Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
• inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
• Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic,
• Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
• Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
• materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
• pharmaceutically acceptable carrier also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
• the "pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein.
• Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
• patient refers to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
• the patient, subject or individual is a human.
• the term “potency” refers to the dose needed to produce half the maximal response (ED50).
• a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.
• treatment is defined as the application or administration of a therapeutic agent, /. ⁇ ., a compound or compounds as described herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, or the symptoms of a condition contemplated herein.
• Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
• modulate and modulation refer to a change in biological activity for a biological molecule (e.g., a protein, gene, peptide, antibody, and the like), where such change may relate to an increase in biological activity (e.g., increased activity, agonism, activation, expression, upregulation, and/or increased expression) or decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and/or decreased expression) for the biological molecule.
• increase in biological activity e.g., increased activity, agonism, activation, expression, upregulation, and/or increased expression
• decrease in biological activity e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and/or decreased expression
• amiselimod encompasses both the free base and pharmaceutically acceptable salts thereof (e.g., amiselimod hydrochloride).
• PBLs peripheral blood lymphocytes
• Oral administration of amiselimod reduced colitis in the adoptive transfer of CD4 CD45R.B lllgl1 T cells in SCID mice, and amiselimod's effect was comparable to that of a murine anti-tumor necrosis factorci (TNF-a) antibody in this model.
• TNF-a murine anti-tumor necrosis factorci
• compositions described herein refer to compositions that include amiselimod and a pharmaceutically acceptable excipient.
• compositions described herein include a pharmaceutically acceptable salt of amiselimod and a pharmaceutically acceptable excipient.
• compositions containing the compound(s) described herein include a pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable excipient.
• the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
• the compositions described herein are orally available compositions.
• compositions described herein may be in tablet or capsule dosage form. In some embodiments, compositions described herein are in tablet form. In some embodiments, compositions described herein are in capsule form.
• compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account.
• routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
• the compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g, trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
• compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
• excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
• the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
• the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
• binding agents e.g., polyvinylpyrrolidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose
• fillers e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate
• the treatment of inflammation in a subject's GI tract can be accomplished using any of the methods for treating UC described herein.
• the inflammation in a subject's GI tract is a result of or caused by an inflammatory bowel disease (IBD) other than UC, UC, Crohn's disease (CD), celiac disease, irritable bowel syndrome (IBS), and the like.
• IBD inflammatory bowel disease
• the methods described herein may be provided for the treatment of mild to moderate UC.
• the methods described herein may be provided for the treatment of mild UC.
• the methods described herein may be provided for the treatment of moderate UC.
• the first dose includes at most about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 mg of amiselimod. In various embodiments, the first dose includes about 0.8 mg or about 0.4 mg.
• the second administration period is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years. In some embodiments, the second administration period is at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 years. In some embodiments, the second administration period continues for the lifetime of the subject.
• the objective of this study was to evaluate the safety profile of amiselimod, a selective sphingosine 1 -phosphate receptor modulator which has been shown to regulate lymphocyte trafficking and is in development for the treatment of inflammatory bowel disease.
• a randomized, double-blind, multiple-dose, placebo-controlled, parallel study with a nested crossover design evaluated the safety and tolerability profile of amiselimod. Healthy adults were randomized in a 2: 1 : 1 ratio during a 28-day treatment period accordingly: a single dose of placebo followed by oral amiselimod (upwardly titrated in doses ranging from 0.4 to 1.6 mg to achieve steady-state concentrations ); a single dose of oral moxifloxacin 400 mg followed by placebo; or placebo followed by a single dose of moxifloxacin 400 mg (for the safety analysis, moxifloxacin arms were combined).
• the safety population included all subjects who received at least one dose of treatment. Adverse events (AE) and serious AEs were collected.
• Treatment-emergent AEs were defined as an AE that was starting or worsening at the time of or after study drug administration. Changes in clinical laboratory parameters (including lymphocyte counts), physical examinations, vital signs, and electrocardiogram parameters (including heart rate, PR, QRS, and QT intervals) were recorded. Subjects were permitted to withdraw if lymphocyte counts were ⁇ 0.2 x 10 9 /L.
• Table 2 Treatment-Emergent Adverse Events (>5%) by Treatment Group-Number of Subjects Reporting an Event (% of Subjects Dosed)
• the study includes a Screening Period (of up to 28 days) and a 12-week Double-Blind Treatment Period (Day 1 through Day 85) for all subjects. Subjects completing the study through Day 85 will be given the opportunity to continue in the OLE Period of the study, if eligible, to receive treatment through Week 48 (Day 337) with a safety follow-up at Week 60 (Day 421). Subjects who choose to not participate in the OLE Period or who are not eligible will be followed for 84 days following the Double-Blind Period in a Safety Follow-up Period through Week 24 (Day 169ZEOS).
• Group A (low dose): Amiselimod loading dose of 0.4 mg QD (Day 1-14) then maintenance dose of 0.2 mg QD (Day 15-85);
• Approximately 20 subjects per treatment group will participate in serial PK sampling at selected sites. The remaining subjects will have sparse PK samples collected. The randomization will be stratified by severity (mild UC [modified Mayo Score of 3 or 4] or moderate UC [modified Mayo Score of 5 to 8]) and concurrent corticosteroid use (Y/N). A maximum of 80% of subjects randomized will have moderate UC and a maximum of 30% of subjects randomized will have mild UC. Assessments performed during the Day 85 Visit will serve as baseline assessments for subjects enrolling in the OLE (Open-label extension) Period.
• OLE Open-label extension
• the final dose on Day 85 will be according to the randomization assignment for the Double-Blind Period (i.e., blinded placebo or active IMP).
• the Day 85 dose will be the first dose of open-label amiselimod for the OLE Period (i.e., 0.4 mg QD).
• a diagram of the study design for the Double-Blind Period is provided in FIG. 2.
• a diagram for the OLE Period is provided in FIG. 3. Selection of Study Population
• Diagnosis of active mild to moderate UC confirmed at least 12 weeks prior to randomization by clinical and endoscopic evidence (corroborated by a histopathology report).
• Mild UC is defined as a modified Mayo Score of 3 or 4.
• Moderate UC is defined as a modified Mayo Score of 5 to 8.
• Candidates will be excluded from study entry if any of the following exclusion criteria exist at Screening or Baseline Visits or at the timepoint specified in the individual criterion listed.
• Diagnosis of proctitis defined as a rectal inflammation within 15 cm from the anal verge.
• C. difficile colitis/diarrhea within 60 days of the Screening Visit. Rescreening may occur 7 days after successful treatment for C. difficile.
• diabetes mellitus type 1 OR diabetes mellitus 2 with use of insulin or with >8 years disease duration after its diagnosis or with significant comorbid conditions (e.g., retinopathy, nephropathy, or neuropathy). Subjects with hemoglobin Ale (HbAlc) >7.5% during the screening period will also be excluded.
• HbAlc hemoglobin Ale
• Any biologies or newly approved UC treatment agents e.g., infliximab, adalimumab, certolizumab, golimumab, etanercept, vedolizumab, ustekinumab, tofacitinib, or natalizumab
• adalimumab certolizumab
• golimumab golimumab
• etanercept vedolizumab
• ustekinumab tofacitinib
• natalizumab natalizumab
• immunosuppressants e.g., AZA, 6-mercaptopurine, or methotrexate 28 days prior to randomization.
• FMT fecal microbiota transplantation
• lymphocyte-depleting therapies e.g., anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow transplantation, alemtuzumab, daclizumab.
• SIP sphingosine 1-phosphate
• Any conduction abnormalities e.g., Wolff Parkinson White.
• Forced expiratory volume in one second (FEV1) or forced expiratory vital capacity (FVC) ⁇ 70% of predicted values at screening.
• the value (mL/min/mmHg) is ⁇ 80% of the predicted normal value for age, height, and gender.
• Hb Hemoglobin
• WBC White blood cell
• Neutrophil count ⁇ 1.50 x 109/L ( ⁇ l,500/pL).
• Lymphocyte count ⁇ 0.80 x 109/L ( ⁇ 800/pL).
• AST Aspartate aminotransferase
• ALT alanine aminotransferase
• Bilirubin >1.5 x the ULN. Subjects with Gilbert's syndrome may be enrolled with total bilirubin up to 5.0 mg/dl.
• the subject has completed the study at the time of the last scheduled study procedures. This will be Day 169 (Week 24) for subjects that do not continue into the OLE Period and Day 421 (Week 60) for subjects that complete the OLE Period.
• a confirmed absolute lymphocyte count (ALC) ⁇ 0.2 x 10 9 /L.
• Baseline safety ECGs will be defined as pre-dose Day 1. Subjects with any clinically significant abnormal ECG should be excluded and referred to a cardiologist for necessary management and follow-up.
• the subject has an increase in ALT and/or AST of >3 x ULN with a concurrent increase in total bilirubin of >2 x ULN or with the appearance of relevant clinical symptoms and no evidence of alternative etiology (e.g., Gilbert's syndrome).
• the subject has an increase in ALT and/or AST >5 x ULN. - If a single ALT and/or AST value >5 x ULN was reported, a second value will be obtained within 48 hours. The subject will remain on IMP during this time unless otherwise indicated. - If the repeat value was ⁇ 5 x ULN, the subject will continue treatment without interruption. - If the repeat value was >5 x ULN, treatment with IMP will be discontinued.
• ALT and/or AST >8 x ULN a second value will be obtained as soon as possible (within 24 hours); IMP should be withheld until confirmation of the abnormal value is received. If confirmed, IMP should be permanently discontinued. • Any subject with elevated ALT/AST meeting the above criteria should be monitored until ALT/AST reaches Baseline levels.
• Subjects withdrawn or discontinued prior to Day 85 will undergo the end of treatment procedures per the scheduled assessments for the Day 85ZEOT Visit.
• Subjects withdrawn or discontinued during the OLE Period will undergo the end of treatment procedures per the scheduled assessments the Week 48 (Day 337ZEOT) Visit.
• All subjects will be encouraged to return 84 days ( ⁇ 10 days) after study drug discontinuation for the Safety Follow-up Visit.
• Subject withdrawals will be documented clearly on the source documents and applicable case report forms (eCRFs). Notification of subject withdrawals will be made to the Sponsor, or designee. A subject that withdraws from the study or is lost to follow-up will not be replaced.
• Subjects who do not return for scheduled visits, as defined by the visit schedule may be considered lost to follow-up.
• the site will attempt to contact the subject through a minimum of 2 telephone calls. If the subject still cannot be contacted the site will send a certified letter, or similar verified delivery, to the last known address of the subject. If no contact is made by the subject, the site will consider the subject lost to follow-up. All followup attempts will be documented and kept with the subject's source documentation, and the applicable eCRFs will be completed.
• Study Duration The planned enrollment period is approximately 24 months. Each subject will be screened for up to 4 weeks followed by a 12-week Double-Blind Period. Subjects enrolling in the OLE Period of the study will have up to an additional 36 weeks of study treatment (through Week 48) with a safety follow-up 12 weeks after completion of treatment (Week 60). Subjects not enrolling in the OLE period of the study, will be followed for 12 weeks following completion of treatment (Week 24). The total expected study duration for the both the Double-Blind and the OLE Period is approximately 40 months.
• Amiselimod for this study will be provided as either a 0.2 mg or 0.4 mg capsule.
• subjects will be randomized into one of 3 groups: Group A, Group B, or Group C.
• the 0.2 mg, 0.4 mg, and placebo capsules will look identical to maintain the blind.
• the Investigator, site staff, subject and Sponsor study personnel (or their designees) will be blinded to the study group to which the subject is randomized.
• Subjects should take the IMP at approximately the same time each day. Subjects will be dosed as follows.
• Loading dosage (Day 1 - 14): o Group A (low dose): two 0.2 mg amiselimod capsules, orally, QD, o Group B (high dose): two 0.4 mg amiselimod capsules, orally, QD, o Group C (placebo): two placebo capsules, orally QD.
• Subjects who continue into the OLE Period of the study will receive open-label amiselimod at 0.4 mg QD through Week 48 (Day 337).
• the modified Mayo Score will be used for the primary efficacy evaluation.
• the Mayo Score for ulcerative colitis disease activity provides an assessment of disease severity and can be used to monitor subjects during therapy. Scoring is accomplished by summation of subscores for endoscopic findings, stool frequency, rectal bleeding, and/or the Physician Global Assessment (PGA) with higher scores indicating worse severity. Each subscore ranges from 0 to 3.
• the primary efficacy analysis for this study will use the modified Mayo Score defined as the sum of the endoscopy findings sub score + stool frequency sub score + rectal bleeding subscore, with a range from 0 to 9. Endoscopy will be conducted to determine Mayo endoscopic subscore. Both local and central reading of the results will occur.
• the endoscopic subscore for endpoint analysis will be based on the centrally read endoscopic results.
• the rectal bleeding subscore and stool frequency subscore are evaluated based on patient-reported symptoms. Subjects will complete a daily diary to record their worst daily rectal bleeding and stool frequency.
• Mayo scoring In addition to the modified Mayo Score for the primary efficacy analysis, various iterations of Mayo scoring using endoscopic findings, stool frequency, rectal bleeding and/or the Physician Global Assessment (PGA) will be assessed for secondary and exploratory analyses. These include the complete Mayo Score (endoscopic + stool frequency + rectal bleeding + PGA subscores), the 2-component Mayo Score (rectal bleeding + endoscopic subscores) and clinical and remission outcomes based on Mayo scoring.
• the original Geboes index core (OGS) from the endoscopy will be provided to the Sponsor by the central reviewer. UC-related biomarkers will be examined. Blood samples obtained for safety laboratory evaluations will also be used to determine serum CRP levels. Stool samples will be collected to determine the presence/absence of fecal calprotectin and fecal lactoferrin. Subject assessment of improvement and quality of life will be assessed with the PGI-C and the EQ-5D-3L, respectively.
• AEs Adverse Events
• SAEs Serious Adverse Events
• AEs and SAEs will be collected throughout the study and graded for severity and relationship to IMP.
• Body temperature, respiratory rate, blood pressure, and HR will be measured.
• Blood pressure and HR measurements will be performed with subjects in a supine position for at least 5 minutes, except when they are seated or semi-reclined because of study procedures and/or AEs (e.g. nausea, dizziness) or if deemed necessary by the Investigator or designee.
• AEs e.g. nausea, dizziness
• Twenty-four (24) hour monitors will be used to collect continuous ECG data at the Screening Visit to exclude subjects with heart conditions. Data collected from the 24-hours after the Screening Visit will be reviewed by a central reviewer prior to or at the Baseline Visit for determination of eligibility.
• OCT optical coherence tomography
• PML Checklist Subjects will be monitored at each visit for the presence of signs or symptoms of PML using the PML Checklist.
• the PML subjective checklist will be administered at each visit by the Investigator, or appropriate designee, and whenever the subject or his/her family member reports the symptom.
• the IMP dose will be interrupted and an objective checklist will be performed by the Investigator. Only the portion of the objective checklist that corresponds to the portion of the positive subjective checklist will be performed. IMP dose may be re-started based on the Investigator's assessment of the severity of the symptoms.
• stool samples will be collected for microbiology testing and for fecal UC-related biomarker testing (calprotectin and lactoferrin). Details on collection, preparation and shipping of stool samples are provided in the Laboratory Manual.
• urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
• a concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between the time the subject is enrolled in the study and the EOS or EOT Visit.
• therapeutic intervention e.g., surgery/biopsy, physical therapy
• diagnostic assessment e.g., blood gas measurement, bacterial cultures
• Subjects who complete the Day 85 Visit will be given the opportunity to continue into the OLE Period, if eligible, to receive active amiselimod for up to one year. Subjects that cannot tolerate the IMP, are not eligible, or choose to not continue into the OLE Period will not continue to receive IMP and will return to the clinic for a Safety Follow-up Visit on Day 169, 84 days [12 weeks] after completion of IMP treatment.
• Subjects that do continue into the OLE Period will receive treatment with IMP for up to one year (48 weeks) after which treatment with amiselimod will cease.

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