ESK-001 for Psoriasis

(ONWARD2 Trial)

Not currently recruiting at 171 trial locations

Overseen By Alumis Information

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Alumis Inc

Must not be taking: Biologics, Immunosuppressants, JAK inhibitors, others

Disqualifiers: Nonplaque psoriasis, Immune-mediated conditions, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests ESK-001, a new oral treatment for individuals with moderate to severe plaque psoriasis, a condition that causes red, scaly skin patches. The main goals are to determine if ESK-001 can reduce psoriasis severity and to assess its safety. Participants will be compared to those taking a placebo (a harmless pill) and Apremilast, an existing psoriasis medication. Individuals with plaque psoriasis for at least six months that significantly affects daily life may be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering access to a potentially effective new treatment.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop certain medications before joining the trial. Specifically, you must stop topical treatments 2 weeks before, phototherapy or systemic treatments 4 weeks before, and certain biologic agents and immunosuppressants up to 6 months before the study starts.

Is there any evidence suggesting that ESK-001 is likely to be safe for humans?

Research has shown that ESK-001 is generally well-tolerated. In one study, after 28 weeks, patients taking the highest dose of ESK-001 experienced significant improvement in psoriasis, with most achieving a 75% reduction in severity. This improvement occurred without major safety issues. Another study found ESK-001 safe and effective after 12 weeks, with manageable side effects. These findings suggest that ESK-001 is safe for individuals with moderate to severe plaque psoriasis. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for psoriasis?

Researchers are excited about ESK-001 for psoriasis because it offers a unique approach compared to standard treatments like biologics or other oral medications such as methotrexate and cyclosporine. ESK-001 is administered as an oral tablet and is designed to target specific pathways involved in the inflammation process of psoriasis, potentially leading to fewer side effects and improved patient outcomes. Additionally, its oral administration provides a convenient alternative to injectable treatments, making it easier for patients to manage their condition.

What evidence suggests that ESK-001 might be an effective treatment for psoriasis?

Research has shown that ESK-001, which participants in this trial may receive, holds promise for treating moderate to severe plaque psoriasis. Studies have found that many patients taking ESK-001 experience significant improvement in their skin symptoms. Specifically, a large number of patients saw their psoriasis symptoms improve by 75% or more. Some patients even achieved complete clearance of psoriasis with longer use. These improvements depend on the dose, with higher doses generally proving more effective. Overall, ESK-001 has effectively reduced the severity of psoriasis over time. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

Adults aged 18+ with moderate to severe plaque psoriasis for at least 6 months can join this study. They'll take a daily drug for half a year, visit the clinic regularly, and report on their skin condition, itchiness, and life quality changes.

Inclusion Criteria

PASI ≥12

sPGA ≥3

I agree to use effective birth control methods if I can have children or am sexually active with someone who can.

Exclusion Criteria

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

My kidney, liver, or bone marrow is not functioning properly.

I do not have plaque psoriasis or other skin inflammation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants take the study drug or placebo daily for 24 weeks, with regular clinic visits for checkups, tests, and assessments.

24 weeks

Regular clinic visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of psoriasis severity and quality of life.

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• ESK-001

Trial Overview The trial is testing ESK-001's effectiveness against psoriasis compared to a placebo (dummy pill) and Apremilast (an approved treatment). Participants will be randomly assigned to one of these treatments for 24 weeks.

How Is the Trial Designed?

Group I: ESK-001 Experimental Treatment 1 Intervention

ESK-001 administered as an oral tablet

Group II: Apremilast Active Control 1 Intervention

Apremilast administered as an oral capsule

Group III: Placebo Placebo Group 1 Intervention

Matching oral placebo

Who Is Running the Clinical Trial?

Alumis Inc

Lead Sponsor

Trials

9

Recruited

4,200+

Published Research Related to This Trial

Three tyrosine kinase inhibitors from the tyrphostin family effectively halted the growth of psoriatic keratinocytes in laboratory studies without causing harmful cytotoxic effects.

The inhibitors' effectiveness in stopping keratinocyte proliferation correlates with their ability to block EGF receptor kinase activity, suggesting they could be promising new treatments for psoriasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tyrphostins suppress the growth of psoriatic keratinocytes. Ben-Bassat, H., Vardi, DV., Gazit, A., et al.[2019]

The PTK inhibitor AG-1571 (SU-5271) effectively inhibits the proliferation of psoriatic keratinocytes, showing a strong correlation with its ability to inhibit the epidermal growth factor receptor (EGFR), which is implicated in psoriasis.

Recent in vivo models of psoriasis provide promising platforms for evaluating PTK inhibitors, potentially leading to new targeted therapies for managing this skin condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biological activity of tyrosine kinase inhibitors: novel agents for psoriasis therapy. Ben-Bassat, H.[2009]

This study found increased activation of MSK2 and CREB in lesional psoriatic skin, suggesting that these proteins may contribute to the development of psoriasis, as evidenced by phospho blotting and immunofluorescence staining.

The research indicates that the p38-MAPK/MSK1/MSK2 and CREB signaling pathway is involved in psoriasis, as activation of this pathway in keratinocytes was inhibited by a p38 inhibitor, highlighting a potential target for therapeutic intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitogen- and stress-activated protein kinase 2 and cyclic AMP response element binding protein are activated in lesional psoriatic epidermis. Funding, AT., Johansen, C., Kragballe, K., et al.[2022]

In a phase IIIb study involving 119 patients with moderate-to-severe plaque psoriasis, guselkumab was significantly more effective than fumaric acid esters (FAE), achieving a PASI 90 response in 82% of patients compared to only 14% for FAE at week 24.

Guselkumab also had a better safety profile, with a lower incidence of adverse events (73% vs. 98% for FAE) and no patients discontinuing treatment due to side effects, highlighting its potential as a safer option for systemic treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS). Thaçi, D., Pinter, A., Sebastian, M., et al.[2021]

Inhibition of Lymphocyte-specific protein tyrosine kinase (Lck) using the inhibitor A-770041 significantly reduced clinical features of psoriasis in mice, such as skin thickness and inflammation, by modulating immune responses.

The study demonstrated that Lck plays a critical role in promoting inflammatory signaling in CD4+ T cells during psoriatic inflammation, suggesting that targeting Lck could be an effective therapeutic strategy for treating psoriasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lck signaling inhibition causes improvement in clinical features of psoriatic inflammation through reduction in inflammatory cytokines in CD4+ T cells in imiquimod mouse model. Al-Harbi, NO., Ahmad, SF., Almutairi, M., et al.[2022]

Biological therapies for psoriasis, including monoclonal antibodies and recombinant proteins, target specific pathways in the disease, making them potentially safer and more effective than traditional treatments.

Four biological agents—alefacept, efalizumab, etanercept, and infliximab—are already in clinical use, with many more under investigation, highlighting a significant advancement in psoriasis treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biologicals dramatic advances in the treatment of psoriasis. Wilsmann-Theis, D., Martin, S., Reber, M., et al.[2019]

Targeted biologic therapies that focus on interleukin (IL)-17 and IL-23 have proven to be highly effective in treating psoriasis, highlighting the significance of the IL-23/Th17 cell pathway in the disease's development.

While many patients with mild psoriasis could benefit from topical treatments, there is a strong preference for safe and effective oral medications; however, current JAK inhibitors may not fully meet this need due to concerns about their safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging systemic drugs in the treatment of plaque psoriasis. Balogh, EA., Bashyam, AM., Ghamrawi, RI., et al.[2021]

This study found that MSK1 is significantly activated in lesional psoriatic skin, indicating its potential role in the inflammatory processes associated with psoriasis.

In cultured human keratinocytes, reducing MSK1 expression led to a notable decrease in the production of key pro-inflammatory cytokines (IL-6, IL-8, and TNF-alpha), suggesting that MSK1 could be a target for therapeutic intervention in psoriasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitogen- and stress-activated protein kinase 1 is activated in lesional psoriatic epidermis and regulates the expression of pro-inflammatory cytokines. Funding, AT., Johansen, C., Kragballe, K., et al.[2022]

Tildrakizumab, a monoclonal antibody targeting the IL-23p19 subunit, showed significant clinical improvement in patients with moderate-to-severe psoriasis, with all subjects achieving a 75% reduction in PASI scores by day 196 in the 3 and 10 mg/kg groups.

In a phase I study involving multiple doses, a majority of subjects (10 out of 15 in the 3 mg/kg group and 13 out of 14 in the 10 mg/kg group) achieved PASI75 by day 112, confirming the efficacy of specific IL-23 inhibition in reducing psoriasis severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical improvement in psoriasis with specific targeting of interleukin-23. Kopp, T., Riedl, E., Bangert, C., et al.[2019]

In two phase III studies involving 1861 patients with moderate to severe plaque psoriasis, tofacitinib significantly improved health-related quality of life, with a higher percentage of patients achieving a Dermatology Life Quality Index score of 1 or less compared to placebo at week 16, and these improvements were maintained through week 52.

Tofacitinib also led to rapid relief from itch, with improvements noticeable just one day after starting treatment, and a greater proportion of patients reported satisfaction with the treatment compared to those on placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib improves pruritus and health-related quality of life up to 52 weeks: Results from 2 randomized phase III trials in patients with moderate to severe plaque psoriasis. Feldman, SR., Thaçi, D., Gooderham, M., et al.[2017]

Citations

1. investors.alumis.com investors.alumis.com/news-releases/news-release-details/late-breaking-esk-001-phase-2-ole-data-presented-2025-aad-annual?mobile=1&mobile=1

Late-Breaking ESK-001 Phase 2 OLE Data Presented at 2025 ... These data demonstrated that patients receiving 40 mg twice daily dosing of ESK-001 achieved long-term sustained or increasing clinical responses through Week ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40659116/

Highly selective, allosteric inhibition of TYK2 with oral ESK ... ESK-001 demonstrated significant dose-dependent improvement in signs and symptoms of psoriasis while achieving continuous target inhibition at the highest dose.

3. alumis.com alumis.com/file.cfm/18/docs/aad2025_pstr_pro_final.pdf

Patient-Reported Outcomes in the Phase 2 Studies of ESK- ... Longer ESK-001 treatment in OLE study resulted in substantially increased PASI and sPGA response rates, while maintaining the improved quality ...

4. conferences.medicom-publishers.com conferences.medicom-publishers.com/content/conference-reports/excellent-long-term-data-for-tyk2-inhibitor-esk-001-in-psoriasis/

Excellent long-term data for TYK2 inhibitor ESK-001 in psoriasis In terms of efficacy, PASI rates increased with longer-term use of ESK-001, with PASI75, PASI90, and PASI100 rates of 77.5%, 61.3%, and 38.8% at ...

5. hcplive.com hcplive.com/view/twice-daily-esk-001-treatment-for-psoriasis-leads-majority-achieving-pasi-75

Twice-Daily ESK-001 Treatment for Psoriasis Leads to ... The interim data suggest that the drug resulted in dose-dependent, sustained improvements in participants' Psoriasis Area and Severity Score ( ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11602527/

Safety, tolerability, pharmacokinetics, and pharmacodynamics ... Being well‐tolerated and exhibiting clear PK/PD characteristics, ESK‐001 offers further clinical development as treatment for TYK2‐mediated ...

7. investors.alumis.com investors.alumis.com/news-releases/news-release-details/late-breaking-data-eadv-esk-001-oral-tyk2-inhibitor-treatment?mobile=1&mobile=1

Late-Breaking Data at EADV of ESK-001, an Oral TYK2 ... 28-week data show ESK-001 was generally well tolerated and most patients treated with the top dose of 40 mg twice daily achieved PASI 75 ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT06846541

Long-term Safety and Efficacy of ESK-001 in Moderate to ... The objective of the ESK-001-018 long term extension is to evaluate the safety and efficacy of ESK-001 over time. The scientific questions it aims to answer ...

9. dermatologyadvisor.com dermatologyadvisor.com/news/esk-001-may-be-safe-effective-moderate-to-severe-plaque-psoriasis/

ESK-001 May Be Safe, Effective for Moderate to Severe ... ESK-001, a novel therapy for moderate to severe plaque psoriasis, had acceptable safety and efficacy outcomes at 12 weeks of treatment.