Moderate-to-Severe Plaque Psoriasis

To evaluate the efficacy of TAK-279 30 mg orally administered QD for 16 weeks, compared to placebo, in subjects with moderate-to-severe plaque psoriasis.

tablets

TAK-279
Apremilast

110
030

30mg

sPGA 0/1 response: Assessed as proportion of subjects achieving an sPGA of clear (0) or
almost clear (1) with a ≥2-point decrease from baseline at Week 16.
• PASI-75 response: Assessed as proportion of subjects achieving ≥75% improvement from
baseline in PASI score at Week 16

Participant eligibility was determined based on the following assessments during screening or the conditions described below:

1. The trial administrator determined that the participant was willing and able to understand and fully comply with the trial procedures and requirements (including digital tools and applications).

2. The participant provided written participant consent and any necessary privacy authorizations before commencing any trial procedure.

3. The participant was diagnosed with chronic plaque psoriasis for ≥6 months prior to the screening follow-up visit.

4. The participant had stable plaque psoriasis, defined as having had no major psoriasis flare-ups or morphological changes (assessed by the trial administrator) for ≥6 months prior to screening.

5. The participant had moderate to severe plaque psoriasis, defined as a PASI score ≥12 and an sPGA score ≥3 at screening and Day 1.

6. The participant had plaque psoriasis covering ≥10% of their total BSA at screening and Day 1.

7. The participant must be eligible for phototherapy or systemic treatment.

8. Participants must be at least 18 years old at the time of consent. In the European Union (EU)/European Economic Area (EEA) and the United Kingdom (UK), the trial administrator must document an appropriate benefit-risk assessment for participants aged 65 and over to justify their inclusion in the trial.

9. In the EU/EEA and UK, the trial administrator must document an appropriate benefit-risk assessment for participants who currently smoke or chew tobacco or have a history of long-term smoking (≥20 pack-years) or chewing tobacco to justify their inclusion in the trial.

10. Participants must meet the following contraceptive requirements: be of fertility but currently confirmed by laboratory testing as postmenopausal (i.e., follicle-stimulating hormone concentration >40 mIU/mL); or, if having sexual intercourse with an unsterilized and sperm-producing individual, consent to use a highly effective method of contraception from the date of signing the participant consent form, throughout the trial, and for 10 days after the last dose. Participants designated as male at birth do not need to use effective contraception during the trial. In the EU/EEA and UK, for subjects selected to use hormonal contraceptives as a highly effective method of contraception, the trial administrator must record an appropriate benefit-risk assessment at screening or every 3 months during the trial to justify the subject's inclusion.

Note: Oral hormonal contraceptives may easily interact with TAK-279, potentially reducing the effectiveness of the contraceptive method. Therefore, if a subject is taking any form of oral contraceptive, a second highly effective or effective method of contraception should be used during treatment. If a subject has sexual intercourse with a partner who could potentially result in pregnancy, a second highly effective or effective method of contraception should be used for at least 10 days after the last dose of trial treatment. Barrier methods are recommended, with male condoms being the preferred option.

11. For subjects in the EU/EEA or UK, due to the European Commission's decision from 2023/3/10 to take measures to minimize the risk of serious side effects of Janus kinase inhibitors (EMA/142279/2023) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) guidance on JAK inhibitors: new measures to reduce the risk of major cardiovascular events, malignancies, venous thromboembolism, serious infections and increased mortality as of 26 April 2023 (Drug Safety Update, Volume 16, Issue 9), the trial administrator must not have any reason to believe that the subject will be at risk by participating in the trial.

Subjects will be excluded from the trial if they meet any of the following exclusion criteria at screening or as described below:

1. The subject has evidence of non-plaque psoriasis (erythrodermic psoriasis, pustular psoriasis, significant guttate psoriasis, significant skinfold psoriasis, or drug-induced psoriasis). Limited reversal psoriasis is not excluded if the subject meets the inclusion criteria for typical plaque psoriasis presentation.

2. The subject requires systemic treatment (other than nonsteroidal anti-inflammatory drugs) during the trial due to an immune-related disease (e.g., inflammatory bowel disease).

3. The subject has a history of excessive sun exposure, has used a tanning machine within 4 weeks prior to Day 1, or is unwilling to minimize exposure to natural and artificial sunlight during the trial. When sun exposure cannot be avoided, the use of sunscreen and protective clothing is recommended.

4. The subject has a comorbid skin condition that, according to the trial administrator, would interfere with trial evaluation.

5. Tuberculosis (TB):

a. The subject has a history of active TB infection, regardless of treatment status.

b. Subjects are deemed by the trial administrator to have signs or symptoms of active TB (including but not limited to chronic fever, chronic sputum cough, night sweats, or weight loss).

c. Subjects have evidence of latent TB infection (LTBI), i.e., a positive QuantiFERON TB Gold [QFT] test result or two indeterminate QFT results, and the subject has no record of receiving appropriate LTBI prophylactic treatment, or is unable or unwilling to receive appropriate LTBI prophylactic treatment. Subjects are still eligible to participate if they do not have signs/symptoms of active TB and can provide a record of no active TB history, and (1) the subject can provide a record of previous and complete LTBI treatment (determined to be appropriate in duration and type according to current local national guidelines), or (2) the subject has a positive QFT result or two indeterminate QFT results but has started prophylactic treatment for at least 2 weeks prior to Day 1 (determined to be appropriate in duration and type according to current local guidelines). In the EU/EEA and UK, participants with evidence of latent TB infection (LTBI), regardless of their prophylactic treatment status, must be approved by an infectious disease or other TB specialist (e.g., a pulmonologist) to participate in the trial. Note: TB prophylactic treatment should be administered according to local guidelines; however, rifampin should not be used due to potential interactions with TAK-279 and apremilast. TB testing should be performed using QuantiFERON-TB Gold sent to a central laboratory unless local guidelines require alternative or additional testing.

d. Participants must have undergone any imaging studies during the screening period or within 6 months prior to screening, including X-rays, chest CT scans, MRI, or other chest imaging showing current or previous active TB. All participants must undergo X-ray examination regardless of the QuantiFERON TB test results, unless their chest imaging within 6 months prior to screening was normal.

6. Herpes Infection:

a. Subjects have an active herpes virus infection, including herpes zoster or herpes simplex type 1 and 2, at screening or on day 1 (proven by physical examination and/or medical history).

b. Subjects have a history of severe herpes infection, including any diffuse outbreak, multi-dermatometra herpes zoster, herpetic encephalitis, ocular herpes, or recurrent episodes of herpes zoster (defined as two episodes within 2 years).

7. Non-Herpes Viral Disease:

a. Subjects have hepatitis C virus (HCV) antibodies, and a confirmatory HCV RNA test (nucleic acid test or polymerase chain reaction) is positive. In the EU/EEA and UK, if a subject is positive for total anti-HCV Ab at screening but HCV RNA is not detected by PCR, HCV RNA PCR testing will be evaluated every 3 months until the end of the trial.

b. The subject's hepatitis B surface antigen (HBsAg+) is positive or untyped hepatitis B surface antigen is present, hepatitis B virus DNA is present (regardless of serological test results), or anti-hepatitis B core antibody is positive, but hepatitis B surface antibody is not positive (HBcAb+ and HBsAb-). In the EU/EEA and UK, if a subject is positive for total anti-HBc Ab at screening but HBV DNA is not detected by PCR testing, the subject will undergo repeated HBV DNA PCR testing every 3 months until the end of the trial; if a subject is positive for anti-HBs Ab at screening but HBV DNA is not detected by PCR testing, unless the subject's medical records prove that a series of HBV vaccinations have been completed, the subject will undergo repeated HBV DNA PCR testing every 3 months until the end of the trial.

c. The subject's HIV serological test result is positive, regardless of viral load.

8. Other Infectious Diseases:

a. Subjects have a history of active infection or febrile illness within 7 days prior to Day 1, based on the investigator's assessment.

b. Subjects have a history of symptoms of systemic or invasive infection within 30 days prior to Day 1.

c. Subjects have a history of bacterial, viral, or fungal infection requiring hospitalization or intravenous antimicrobial therapy within 8 weeks prior to Day 1, or oral antimicrobial therapy within 30 days prior to Day 1.

d. Subjects have a history of chronic or recurrent bacterial illness, including but not limited to chronic pyelonephritis or cystitis, chronic bronchitis/pneumonia, osteomyelitis, or chronic skin ulcers/infections or fungal infections (excluding superficial onychomycosis).

e. Subjects have a history of artificial joint infection unless the artificial joint was removed or replaced at least 60 days prior to Day 1.

f. Subjects have a history of opportunistic infections (e.g., Pneumocystis pneumonia, histoplasmosis, coccidioidomycosis).

g. The subject had a bacterial infection within 60 days prior to Day 1 that was not treated.

9. The subject has any clinically significant medical condition, evidence of an unstable clinical condition (e.g., cardiovascular, renal, liver, blood, gastrointestinal, endocrine, pulmonary, or immune), or abnormal vital signs/physiological/laboratory test/ECG findings that the trial administrator determines would unduly risk the subject or interfere with the interpretation of trial results. These include, but are not limited to:

a. The subject has a known or suspected history of an immunocompromised condition/disease, including but not limited to any established congenital or acquired immunodeficiency; splenectomy.

b. The subject underwent major surgery within 60 days prior to Day 1, or plans to undergo major surgery during the trial.

c. The subject had unstable, poorly controlled, or severe hypertension at screening, confirmed by two repeated assessments.

d. The subject has a history of congestive heart failure, class III or IV, as defined by the New York Heart Association criteria.

e. Subjects must have a history of cancer or lymphoproliferative disorders, excluding successfully treated non-metastatic squamous or basal cell carcinoma of the skin and/or localized cervical carcinoma in situ. EU/EEA and UK trial administrators must document an appropriate benefit-risk assessment.

f. For subjects with asthma, chronic obstructive pulmonary disease (COPD), or other lung conditions, a history of hospitalization within the past 3 months, a history of intubation, current need for oral corticosteroids, or a history of needing more than one course of oral corticosteroids within the 6 months prior to Day 1.

g. Subjects must have a history of any of the following cardiovascular conditions:

• Newly diagnosed atrial fibrillation or episodes of atrial fibrillation with rapid ventricular response or other arrhythmias within the 6 months prior to screening; hospitalization for non-acute cardiac problems (e.g., pacemaker implantation); pulmonary embolism or deep vein thrombosis.

• Any cerebrovascular event, myocardial infarction, or previous coronary artery stenting or coronary shunt procedures. However, if the trial administrator determines that the subject has no suitable alternative treatment and more than 6 months have passed since any such event, the subject may participate in the trial provided that the EU/EEA and UK trial administrators document an appropriate benefit-risk assessment.

h. The subject has clinically significant ECG abnormalities, and the trial administrator determines that participation would pose an unacceptable risk to the subject.

i. The trial administrator determines that the subject has a significant/poorly controlled mental illness.

j. The subject has a history of suicidal ideation, suicidal behavior, or suicide attempts in their lifetime, as evidenced by 1) medical history; or 2) a record in the Columbia Suicide Severity Rating Scale (C-SSRS) document at the time of screening, or a "yes" answer to question 5 regarding suicidal ideation on the C-SSRS at the time of screening; or 3) the trial administrator believes there is a clinical risk of suicide.

k. The subject's Patient Health Questionnaire-8 (PHQ-8) score at the time of screening is 15 or higher.

10. The subject has a clinically significant history of drug or alcohol abuse within the 12 months prior to Day 1. The subject has received any of the following biologics or biosimilars within the specified timeframe or 5 half-lives (whichever is longer):

a. Received an antibody against IL-12/-23, IL-17, or IL-23 (e.g., ustekinumab, secukinumab, tildrakizumab, ixekizumab, or guselkumab) within the 6 months prior to Day 1.

b. Received a tumor necrosis factor inhibitor (e.g., etanercept, adalimumab, infliximab, certolizumab) within the 2 months prior to Day 1.

c. Within 3 months prior to Day 1, the subject received medications that modulate the integrin pathway to affect lymphocyte transport (e.g., natalizumab), or medications that modulate B cells or T cells (e.g., alemtuzumab, abatacept, or visilizumab).

d. Within 6 months prior to Day 1, the subject received rituximab or other immune cell elimination therapy.

11. Within 2 weeks prior to Day 1, the subject used medicated shampoos and/or body washes containing, but not limited to, salicylic acid, corticosteroids, coal tar, vitamin D3 analogs, or other compounds used to control psoriasis.

12. Subjects must have used any topical medications that may affect psoriasis presentation within the two weeks prior to Day 1 (including, but not limited to, corticosteroids, salicylic acid, urea, alpha or beta hydroxy acids, phenolic preparations [anthralin], retinol, vitamin D analogs [e.g., calcipotriol], methoxsalen, trimethylpsoralen, calcineurin inhibitors [e.g., tacrolimus], tapinarof, roflumilast, JAK inhibitors, or tar).

13. Subjects received any systemic nonbial treatment that could affect the psoriasis presentation within 4 weeks or 5 half-lives prior to Day 1 (whichever is longer), including oral, intravenous, intramuscular, intra-articular, intrathecal, or intralesional administration of corticosteroids; oral retinol; immunosuppressive/immunomodulatory drugs; methotrexate; azathioprine; 6-thioguanidine; mecaptopurine; mycophenolate mofetil; hydroxyurea; cyclosporine; 1,25-dihydroxyvitamin D3 analogs; psoralen; sulfasalazine; fumaric acid derivatives; JAK inhibitors.

14. Subjects used leflunomide within 6 months prior to Day 1.

15. The subject received phototherapy (including UV-B, psoralen and UV-A (PUVA), tanning beds, therapeutic tanning) or excimer laser therapy within 4 weeks prior to Day 1.

16. The subject used herbal preparations (e.g., herbal supplements, or traditional remedies derived from plants, minerals, or animals containing Chinese herbs) to treat psoriasis or other immune disorders within 4 weeks prior to Day 1.

17. The subject had prior exposure to any TAK-279 (also known as NDI-034858), other TYK2 inhibitors (including deucravacitinib), or participated in any trial containing a TYK2 inhibitor (e.g., deucravacitinib, VTX958, GLPG3667, etc.) unless the subject submitted a post-trial unblinding document confirming that the subject did not receive a TYK2 inhibitor or had prior exposure to apremilast.

18. Subjects received lithium, antimalarial drugs, or intramuscular gold therapy within 4 weeks prior to Day 1.

19. Subjects are currently receiving a potent or intermediate-potency cytochrome P450 3A4 enzyme (CYP3A4) inhibitor (such as itraconazole) or a potent or intermediate-potency cytochrome P450 3A4 enzyme (CYP3A4) inducer (such as rifampin, carbamazepine, or phenytoin), or have received a potent or intermediate-potency CYP3A4 inhibitor or inducer within 4 weeks prior to Day 1 or within 5 half-lives of the inducer or inhibitor (whichever is longer), or are expected to require treatment with a potent or intermediate-potency CYP3A4 inducer or inhibitor during the trial.

20. The subject received any live attenuated vaccine within 60 days prior to Day 1, or is scheduled to receive a live attenuated vaccine during the trial and within a maximum of 4 weeks after the last administration of the investigational drug.

21. The subject received an investigational antibody or biologic therapy within 6 months prior to Day 1.

22. The subject is currently receiving or has received a non-biologic investigational drug or device within 4 weeks prior to Day 1.

23. The subject is currently participating in a clinical trial or is expected to participate in a clinical trial during this trial.

2