The goal of this clinical trial is to learn if ESK-001 works to treat moderate to severe plaque psoriasis. The main questions it aims to answer are:

• Does ESK-001 reduce the severity of people's psoriasis?
• How safe is ESK-001 in people with moderate to severe plaque psoriasis?

The study includes 2 comparators: a placebo control (a 'dummy' tablet that does not contain the medicine ESK-001 but looks just like it) and an active control (apremilast, which is a medicine approved to treat psoriasis).

People taking part in this study must be men or women aged at least 18 years and have had plaque psoriasis for at least 6 months, currently moderate to severe.

Participants will:

• take drug every day for 24 weeks.
• visit the clinic for checkups and tests.
• fill out questionnaires about their psoriasis, itch severity, and change in quality of life.
• be assessed for health issues and side effects, physical examinations, vital signs, heart electrical activity measurements, and psychological health.
• provide blood and urine samples.

Inclusion Criteria:

1. Males or females, age ≥18 years
2. Diagnosis of plaque psoriasis for ≥6 months
3. Plaques covering ≥10% of BSA
4. PASI ≥12
5. sPGA ≥3
6. Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must agree to adhere to highly effective methods of contraception

Exclusion Criteria:

1. Nonplaque psoriasis or other inflammatory skin conditions

2. immune-mediated conditions commonly associated with psoriasis (eg inflammatory bowel disease). Participants with psoriatic arthritis may participate

3. Pregnant, lactating, or planning to get pregnant during the study

4. Use of drugs prior to Study Day 1 that treat or may affect psoriasis:

   • Topical within 2 weeks
   • Phototherapy or any systemic treatments within 4 weeks
   • Any biologic agent targeted to IL-12 or IL-23 within 6 months, oral IL-12 or IL-23 or TNFα inhibitor within 2 months, or IL-17 within 4 months
   • Systemic immunosuppressants or immunomodulatory drugs within 4 weeks
   • Modulators of B cells within 6 months, or T cells within 3 months
   • JAK inhibitors or TYK2 inhibitors within 4 weeks
   • PDE4 inhibitor within 2 months
   • Any investigational agent, within 30 days or 5 half-lives or is currently enrolled in an investigational study

5. Lack of clinical response to a TYK2, IL-12, or IL-23 targeted psoriasis treatment

6. Participants with QTcF >450 msec (males) or >470 msec (females) at Screening

7. Unstable cardiovascular disease, defined as a recent clinical deterioration or a cardiac hospitalization within the last 3 months

8. Evidence of recent or recurrent herpes zoster or herpes simplex viral infection

9. Evidence of active infection or positive test result for hepatitis B, hepatitis C, HIV or TB

10. History of serious bacterial, fungal, or viral infections that led to hospitalization, or any recent serious infection requiring antibiotic treatment

11. Any history of known or suspected congenital or acquired immunodeficiency state or condition that would compromise the participant's immune status

12. Lab abnormalities indicating significant renal, hepatic or bone marrow dysfunction

13. History of any immune-mediated or inflammatory medical condition for which participants requires current systemic corticosteroids

    * Stable doses of inhaled corticosteroids for treatment of asthma are allowed

14. Known current malignancy or current evaluation for a potential malignancy or history of malignancy within the past 5 years prior to screening, except for adequately treated basal cell or squamous cell skin carcinoma or carcinoma in situ of the cervix

15. Live vaccines within 4 weeks prior to Study Day 1

16. Participant has planned surgery during the study period

17. Any acute or chronic illness/condition or evidence of an unstable clinical condition that, in the opinion of the Investigator, will substantially increase the risk to the participant if he or she participates in the study

18. History of mental illness within the last 5 years, unless receiving a fixed regimen of psychiatric medications for at least 6 months before screening or has not required or been prescribed any psychiatric medication within 12 months before screening

19. Evidence of severe depressive symptoms or active suicidal ideation or behavior

The Sponsor Alumis Inc. is a clinical-stage biopharmaceutical company that has not yet adopted an Individual Participant Data (IPD) sharing plan.