About ESK-001

ESK-001 is an investigational next-generation tyrosine kinase 2 (TYK2) inhibitor that is designed to correct immune dysregulation across a spectrum of diseases driven by proinflammatory mediators, including IL-23, IL-17, and type 1 interferon (IFN).^1,2

ESK-001's selective targeting is designed to deliver maximal inhibition while minimizing off-target binding and effects.¹

ESK-001 is currently being investigated for the oral treatment of plaque psoriasis and systemic lupus erythematosus (SLE). Potential future indications include psoriatic arthritis, inflammatory bowel disease, and other chronic inflammatory conditions.^1,3-4

ESK-001 for the Treatment of Psoriasis

Based on data we observed in the Phase 2 trial; we commenced our Phase 3 program to evaluate ESK-001’s potential to fill a crucial gap in psoriasis patient care as an oral therapy that is designed to target the persistent systemic inflammation occurring in and beneath the skin.

About Psoriasis

Psoriasis is an immune-mediated disease affecting more than 7.5 million adults in the United States. The most common form is plaque psoriasis, characterized by dry, itchy, raised skin patches (plaques) covered with scales that may crack, causing bleeding and pain. 

The National Psoriasis Foundation defines the severity of psoriasis based on how it impacts a person's quality of life, and the percentage of the body affected. Nearly one-quarter of people with psoriasis have cases that are considered moderate to severe.

Psoriasis is a chronic disease that currently has no cure. While treatments are available, there is a need for more solutions, especially for oral therapies.
 

About the ONWARD Phase 3 Clinical Program

The ONWARD Phase 3 clinical program consists of two parallel global, multi-center, randomized, double-blind, placebo- and active comparator-controlled 24-week clinical trials designed to evaluate the efficacy and safety of ESK-001 in adult patients with moderate to severe plaque psoriasis (NCT06586112 and NCT06588738). Each trial is expected to enroll approximately 840 patients randomized 2:1:1 to receive either ESK-001 40 mg twice-daily, placebo or apremilast. The co-primary efficacy endpoints will be the proportion of patients with moderate to severe plaque psoriasis achieving greater than or equal to 75% reduction in Psoriasis Area and Severity Index (PASI 75) and static Physician’s Global Assessment (sPGA) score 0/1 of ESK-001 compared to placebo at Week 16. Patients completing Week 24 will have the opportunity to participate in a long-term extension (LTE) trial, ONWARD3, that will evaluate long-term safety, as well as durability and maintenance of response. In parallel with the Phase 3 clinical program, Alumis is developing a once-daily modified release (MR) oral formulation of ESK-001 that can replace the current immediate release (IR) oral formulation that is dosed twice daily.

About the STRIDE Clinical Trial

STRIDE was a randomized, double-blind, placebo-controlled Phase 2 dose ranging clinical trial evaluating the efficacy, safety, pharmacokinetics and pharmacodynamics of ESK-001 in patients with moderate to severe plaque psoriasis. The trial enrolled more than 220 patients across multiple doses of ESK-001 for 12 weeks. The primary endpoint of the trial was the proportion of patients with moderate to severe plaque psoriasis achieving greater than or equal to 75% reduction in PASI score (PASI 75) across doses of ESK-001 and placebo. PASI, or Psoriasis Area and Severity Index, is an instrument used to score, assess and grade the severity of psoriatic lesions and the patient's response to treatment.

In the STRIDE trial, ESK-001 demonstrated higher clinical response rates over placebo for all primary and secondary endpoints. Treatment with ESK-001 was well tolerated with no treatment-related serious adverse events. The most common AEs were headache, upper respiratory tract infection and nasopharyngitis. These data were presented during a late-breaking session at the American Academy of Dermatology (AAD) Annual Meeting in 2024.

Upon completion of the STRIDE clinical trial, patients were eligible to be enrolled in an OLE trial evaluating two ESK-001 doses (40 mg once daily and 40 mg twice daily). In the interim 28-week OLE data presented at the 2024 European Academy of Dermatology & Venereology (EADV) Congress, a dose-dependent sustained increase in PASI endpoint responses was observed over time, with the majority of patients reaching PASI 75 at the 40 mg twice daily dose. ESK-001 continued to show a favorable safety profile in the OLE. Treatment emergent adverse event (TEAE) frequency and severity were similar across study arms, with the majority being mild-to-moderate and self-limited. Similar to the Phase 2 STRIDE clinical trial, the most common TEAEs were upper respiratory tract infections, nasopharyngitis, and headaches. The OLE trial is currently ongoing.

ESK-001 for the Treatment of Systemic Lupus Erythematosus (SLE)

ESK-001 is a TYK2 inhibitor that reduces signaling through several cytokine receptors including receptors for interleukin (IL)-23, and type 1 interferon. ESK-001 has the potential to reduce SLE disease activity by interfering with pro-inflammatory pathways known to be involved in the pathogenesis of SLE.

About SLE

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease and is the most common type of lupus. Lupus occurs when the immune system attacks its own tissues, causing inflammation, and in some cases permanent tissue damage, which can be widespread – affecting many parts of the body like the skin, joints, heart, lung, kidneys, circulating blood cells, and brain. Current treatments aim to alleviate symptoms of lupus or reduce inflammation to minimize organ damage; there is no cure for lupus.

About the LUMUS Clinical Trial

LUMUS is a global, multicenter, randomized, double-blind, placebo-controlled Phase 2 trial that is designed to evaluate the efficacy, safety and pharmacokinetics of multiple doses of ESK-001 in adult patients with moderately to severely active, autoantibody-positive SLE. The trial is expected to enroll 388 patients across multiple doses of ESK-001 or placebo for a treatment period of 48 weeks. Following the trial, eligible patients may enroll in an open-label extension trial or participate in a four-week safety follow up period. The primary endpoint of the trial will compare the proportion of patients with improvement in BICLA at Week 48 relative to baseline across doses of ESK-001 and placebo. British-Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA) is an accepted composite measure of overall SLE disease activity. Secondary endpoints include safety and tolerability, as well as various measures of effect on disease activity. 

REFERENCES:

1. Ucpinar S, et al. Clin Transl Sci. 2024;17(12):e70094. 2. Rusiñol L, Puig L. Int J Mol Sci. 2023;24(4):3391. 
3. ClinicalTrials.gov identifier: NCT05966480. Accessed December 17, 2024. https://clinicaltrials.gov/study/NCT05966480 
4. ClinicalTrials.gov identifier: NCT06588738. Accessed December 17, 2024. https://clinicaltrials.gov/study/NCT06588738