Study of NDI-034858 in Participants With Moderate to Severe Plaque Psoriasis

A Phase 2b, Randomized, Multicenter, Double-blind, Placebo-controlled, Multiple-dose Study to Evaluate the Efficacy, Safety, and Tolerability of NDI-034858 in Subjects With Moderate to Severe Plaque Psoriasis

This is a Phase 2b, randomized, multicenter, double-blind, placebo-controlled, multiple-dose study designed to evaluate the efficacy, safety, and tolerability of NDI-034858 in participants with moderate to severe plaque psoriasis. This study will also evaluate the plasma concentrations of NDI-034858 and explore the immune response to NDI-034858 in participants with moderate to severe plaque psoriasis.

Approximately 259 male and female participants, aged 18 to 70 years (inclusive) were enrolled in this study. Participants were randomized to receive either one of the four doses of NDI-034858, or placebo on Day 1. The goal was to have approximately 50 participants randomized per treatment group (1:1:1:1:1 ratio) on Day 1. During the treatment period, NDI-034858 or placebo was orally administered QD for 12 weeks. The 12 week treatment period was followed by a 4-week safety follow-up period.

Participants received placebo matched to NDI-034858 oral capsules, once daily (QD) for up to 12 weeks.

Percentage of Participants Who Achieved at Least 75 Percent (%) Improvement From Baseline in Psoriasis Area and Severity Index (PASI-75) at Week 12

The PASI quantifies the severity of a participant's psoriasis based on both "lesion severity" and the "percent of body surface area (BSA)" affected. PASI is a composite scoring by the investigator of degree of erythema, induration, and scaling (each scored separately) for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin], and lower limbs [including buttocks]), with adjustment for the percent of BSA involved for each body region and for the proportion of the body region to the whole body. The PASI composite score varies in increments of 0.1 and range from 0 (no disease) to 72 (maximal disease), with higher scores representing greater severity of psoriasis. PASI 75 response is a binary measure defined as at least a 75% improvement in PASI score at Week 12, relative to baseline PASI score.

Percentage of Participants Who Achieved Physician's Global Assessment (PGA) Score of Clear (0) or Almost Clear (1) at Week 12

The PGA is a global assessment of the current state of the disease. It is a 5-point morphological assessment of overall disease severity with scores ranging from 0 to 4, where Score 0: Clear (No signs of psoriasis; post-inflammatory hyperpigmentation may be present); Score 1: Almost clear (No thickening; normal to pink coloration; no to minimal focal scaling); Score 2: Mild (Just detectable to mild thickening; pink to light red coloration; predominantly fine scaling); Score 3: Moderate (Clearly distinguishable to moderate thickening; dull to bright red; clearly distinguishable to moderate erythema; moderate scaling); Score 4: Severe (Severe thickening with hard edges; bright to deep dark red coloration; severe/coarse scaling covering almost all or all lesions). The percentage of participants who achieved a PGA score of clear (0) or almost clear (1) at Week 12 were reported.

Percentage of Participants Who Achieved at Least 90% Improvement From Baseline in Psoriasis Area and Severity Index (PASI-90) at Week 12

The PASI quantifies the severity of a participant's psoriasis based on both "lesion severity" and the "percent of BSA" affected. PASI is a composite scoring by the investigator of degree of erythema, induration, and scaling (each scored separately) for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin], and lower limbs [including buttocks]), with adjustment for the percent of BSA involved for each body region and for the proportion of the body region to the whole body. The PASI composite score varies in increments of 0.1 and range from 0 (no disease) to 72 (maximal disease), with higher scores representing greater severity of psoriasis. PASI 90 response is a binary measure defined as at least a 90% improvement in PASI score at Week 12, relative to baseline PASI score.

Percentage of Participants Who Achieved at Least 100% Improvement From Baseline in Psoriasis Area and Severity Index (PASI-100) at Week 12

The PASI quantifies the severity of a participant's psoriasis based on both "lesion severity" and the "percent of BSA" affected. PASI is a composite scoring by the investigator of degree of erythema, induration, and scaling (each scored separately) for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin], and lower limbs [including buttocks]), with adjustment for the percent of BSA involved for each body region and for the proportion of the body region to the whole body. The PASI composite score varies in increments of 0.1 and range from 0 (no disease) to 72 (maximal disease), with higher scores representing greater severity of psoriasis. PASI 100 response is a binary measure defined as at least a 100% improvement in PASI score at Week 12, relative to baseline PASI score.

The DLQI is a simple 10 question validated questionnaire that has been used in more than 40 different skin conditions. The DLQI is the most frequently used quality of life instrument in studies of randomized controlled trials in dermatology. Each question is scored on a four-point Likert scale: very much (3); a lot (2); a little (1); not at all (0). DLQI total score is defined as the sum of the 10 questions, ranging from 0 (not at all) to 30 (very much). Higher scores indicate more impact on quality of life of participants; and lower scores indicate less impact on the quality of life of participants.

An adverse event (AE) means any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. TEAEs were defined as any AEs with onset date on or after the first study treatment dosing. An SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital abnormality or birth defect, an important medical event. TEAEs included both serious and non-serious AEs.

The analysis of NDI-034858 levels in plasma was performed using a validated reversed-phase Ultra High-Performance Liquid Chromatography coupled with tandem mass-spectrometry (UHPLC-MS/MS) method. Here, plasma concentrations of NDI-034858 determined at given timepoints were reported.

Week 1: Day 1, Pre-dose and 1-hour post-dose; Week 4: Pre-dose, 1-hour and 4 hours post-dose; Week 8: Pre-dose; Week 12: Post-dose

Inclusion Criteria: In order to be eligible to participate in this study, a participant must meet all of the following criteria, either at the screening and Day 1 visits or only at one of the specified visits (screening or Day 1) as noted in the criterion: Male or female participant aged 18 to 70 years, inclusive, at the time of consent. Participant has a history of plaque psoriasis for at least 6 months prior to the screening visit. Participant had no significant flare in psoriasis for at least 3 months before screening (information obtained from medical chart or participant's physician, or directly from the participant). Participant has moderate to severe plaque psoriasis as defined by a PASI score ≥ 12 and a PGA score ≥ 3 at screening and Day 1. Participant has plaque psoriasis covering ≥ 10% of his or her total BSA at screening and Day 1. Participant must be a candidate for phototherapy or systemic therapy. For female participants of childbearing potential involved in any sexual intercourse that could lead to pregnancy: the participant must agree to use a highly effective contraceptive method from at least 4 weeks prior to Day 1 until at least 4 weeks after the last study product administration. Highly effective contraceptive methods include hormonal contraceptives (eg, combined oral contraceptive, patch, vaginal ring, injectable, or implant), intrauterine devices or intrauterine systems, vasectomized partner(s) (provided vasectomy was performed ≥ 4 months prior to screening), bilateral tubal ligation or occlusion, or double barrier methods of contraception (eg, male condom with cervical cap, male condom with diaphragm, and male condom with contraceptive sponge) in conjunction with spermicide. Female participants of childbearing potential have had a negative serum pregnancy test at screening and negative urine pregnancy test at Day 1. For male participants involved in any sexual intercourse that could lead to pregnancy, participant must agree to use one of the highly effective contraceptive methods listed in Inclusion Criterion 6, from Day 1 until at least 12 weeks after the last study product administration. If the female partner of a male participant uses any of the hormonal contraceptive methods listed above, this contraceptive method should be used by the female partner from at least 4 weeks before Day 1 until at least 12 weeks after the last study product administration. Participant has a BMI within the range of 18 to 42 kg/m2, inclusive (BMI = weight [kg]/[height (m)]2), and total body weight >50 kg (110 lb). Participant is willing to participate and is capable of giving informed consent. Note: Consent must be obtained prior to any study-related procedures. Participant must be willing to comply with all study procedures and must be available for the duration of the study. Exclusion Criteria: A participant who meets any of the following criteria at the screening and/or Day 1 visits, as applicable, will be excluded from participation in this study: Participant is a female who is breastfeeding, pregnant, or who is planning to become pregnant during the study. Participant has evidence of erythrodermic, pustular, predominantly guttate psoriasis, or drug induced psoriasis. Participant has a history of skin disease or presence of skin condition that, in the opinion of the investigator, would interfere with the study assessments. Participant has immune-mediated conditions commonly associated with psoriasis, such as psoriatic arthritis, uveitis, inflammatory bowel disease, that require systemic treatment (including corticosteroids, immunosuppressants, or biologics). Note: Participants with immune-mediated conditions that do not require systemic treatment may be included in the study. Certain therapies such as NSAIDs may be permitted, but should be discussed with the Medical Monitor prior to determination of participant eligibility. Participant has any clinically significant medical condition, evidence of an unstable clinical condition (eg, cardiovascular, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, or local active infection/infectious illness), psychiatric condition, or vital signs/physical/laboratory/ECG abnormality that would, in the opinion of the investigator, put the participant at undue risk or interfere with interpretation of study results. Participant had a major surgery within 8 weeks prior to Day 1 or has a major surgery planned during the study. Participant has a history of Class III or IV congestive heart failure as defined by New York Heart Association Criteria. Participant has been hospitalized in the past 3 months for asthma, has ever required intubation for treatment of asthma, currently require oral corticosteroids for the treatment of asthma, or has required more than one short-term (≤ 2 weeks) course of oral corticosteroids for asthma within 6 months prior to Day 1. Participant has a history of cancer or lymphoproliferative disease within 5 years prior to Day 1. Participant with successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix are not to be excluded. Participant has a history of fever, inflammation, or systemic signs of illness suggestive of systemic or invasive infection within 4 weeks prior to Day 1. Participant has an active bacterial, viral, fungal, mycobacterial infection, or other infection (including TB or atypical mycobacterial disease), or any major episode of infection that required hospitalization or treatment with intravenous antibiotics within 12 weeks prior to Day 1, or oral antibiotics within 4 weeks prior to Day 1. Participant has a history of chronic or recurrent infectious disease, including but not limited to chronic renal infection, chronic chest infection, recurrent urinary tract infection, fungal infection (with the exception of superficial fungal infection of the nailbed), or infected skin wounds or ulcers. Participant has a history of an infected joint prosthesis or has received antibiotics for a suspected infection of a joint prosthesis, if that prosthesis has not been removed or replaced. Participant has active herpes infection, including herpes simplex 1 and 2 and herpes zoster (demonstrated on physical examination and/or medical history) within 8 weeks prior to Day 1. Participant has a history of known or suspected congenital or acquired immunodeficiency state or condition that would compromise the participant's immune status in the opinion of the investigator (eg, history of splenectomy, primary immunodeficiency). Participant has positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B core antigens (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). Participant has clinical or laboratory evidence of active or latent TB infection at screening. Participant with any of the following laboratory values at the screening visit: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values ≥ 3 times the upper limit of normal (ULN); Hemoglobin < 11.0 g/dL (< 110.0 g/L); White blood cell count < 3.5 x 109/L (< 3500/mm3); Absolute neutrophil count of < 1.8 x 109/L (< 1800/mm3); Absolute lymphocyte count of < 1.0 x 109/L (< 1000/mm3); Platelet count < 100 x 109/L (< 100,000/mm3); Total bilirubin ˃ 2 times the ULN. Participant who have given > 50 ml of blood or plasma within 30 days of screening or > 500 mL of blood or plasma within 56 days of screening (during a clinical study or at a blood bank donation). Participant has used any topical medication that could affect psoriasis (including corticosteroids, retinoids, vitamin D analogues [such as calcipotriol], JAK inhibitors, or tar) within 2 weeks prior to Day 1. Participant has used any systemic treatment that could affect psoriasis (including oral, intravenous, intraarticular, intrathecal, intramuscular, or intralesional corticosteroids, oral retinoids, immunosuppressive/immunomodulating medication, methotrexate, cyclosporine, oral JAK inhibitors, or apremilast) within 4 weeks prior to Day 1. Participant has received any UV-B phototherapy (including tanning beds) or excimer laser within 4 weeks prior to Day 1. Participant has had PUVA treatment within 4 weeks prior to Day 1. Participant has received any live-attenuated vaccine within 4 weeks prior to Day 1 or plans to receive a live-attenuated vaccine during the study and up to 4 weeks or 5 half lives of the study product, whichever is longer, after the last study product administration. Note: Nonlive-attenuated vaccines or boosters for Coronavirus Disease 2019 (COVID-19) (eg, RNA-based vaccines, inactivated adenovirus-based vaccines, protein-based vaccines) are allowed during the study. The study site should follow local guidelines related to COVID-19. Participant is currently receiving a nonbiological investigational product or device or has received one within 4 weeks prior to Day 1. Participant has received any marketed or investigational biological agent within 12 weeks or 5 half-lives (whichever is longer) prior to Day 1 (except those listed in Exclusion Criterion 27 and 28 that are to be excluded for 6 months). Participant was previously enrolled in any study with NDI-034858. Participant has a history of lack of response to any therapeutic agent targeting IL-12, IL-17, and/or IL 23 (eg, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, risankizumab) at approved doses after at least 12 weeks of therapy, and/or received one of these therapies within 6 months prior to Day 1. Participant has received rituximab or other immune-cell depleting therapy within 6 months. Participant is currently being treated with strong or moderate cytochrome P450 3A (CYP3A4) inhibitors (such as itraconazole), or has received moderate or strong CYP3A4 inhibitors within 4 weeks prior to Day 1. Participant is currently being treated with terbinafine, or has received terbinafine within 4 weeks prior to Day 1. Participant has consumed grapefruit within 1 week prior to Day 1. Participant has used tanning booths within 4 weeks prior to Day 1, has had excessive sun exposure, or is not willing to minimize natural and artificial sunlight exposure during the study. Participant has a known or suspected allergy to NDI-034858 or any component of the investigational product, or any other significant drug allergy (such as anaphylaxis or hepatotoxicity). Participant has a known history of clinically significant drug or alcohol abuse in the last year prior to Day 1. For participant consenting to biopsy collection only: Participant has a history of an allergic reaction or significant sensitivity to lidocaine or other local anesthetics. Participant has a history of hypertrophic scarring or keloid formation in scars or suture sites. Participant has taken anticoagulant medication, such as heparin, low molecular weight (LMW)-heparin, warfarin, or antiplatelet agents (except low-dose aspirin ≤ 81 mg which will be allowed), within 2 weeks prior to Day 1, or has a contraindication to skin biopsies. Nonsteroidal anti-inflammatory drugs will not be considered antiplatelet agents and will be allowed.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.