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). Patients 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. Patients 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 patient'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 patient requires current systemic corticosteroids

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