Dosing begins in Phase 2b trial for SLE therapy ESK-001

ESK-001 is designed to block TYK2, an enzyme involved in immune responses

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by Steve Bryson PhD |

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A Phase 2b clinical trial of ESK-001, an oral treatment for systemic lupus erythematosus (SLE), has begun dosing patients, according to its developer Alumis.

The trial, called LUMUS, is expected to enroll about 388 adults with moderately to severely active SLE who test positive for self-reactive antibodies (autoantibodies).

“We are very excited to have started this rigorously designed Phase 2b program for ESK-001 and evaluate its potential benefit for people living with SLE,” Alumis’ CEO, Martin Babler, said in a company press release.

Tyrosine kinase 2 (TYK2) is an enzyme that plays a central role in the self-directed immune responses that drive autoimmune inflammatory diseases like SLE.

ESK-001 is as an allosteric TYK2 inhibitor, meaning it blocks the enzyme’s action by altering its shape. This reduces cell signaling events associated with immune proteins called cytokines. TYK2 inhibitors can also target inflammation without interfering with related JAK proteins, which can cause serious side effects.

By selectively disrupting TYK2-related signaling, ESK-001 should safely dampen the excessive inflammatory responses found in autoimmune diseases.

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Testing effectiveness, safety of ESK-001

“TYK2 mediated cytokines have been shown to be critical drivers of disease in lupus, and there is a large unmet need for oral treatments with improved efficacy and side effect profiles,” Babler said.

In a Phase 1 study of healthy volunteers, ESK-001 fully blocked TYK2 activity over one day of dosing. The candidate therapy was also well tolerated, with no serious side effects or JAK-related safety events reported.

“ESK-001 is a highly selective allosteric inhibitor of TYK2 that demonstrated full, sustained target inhibition and was well tolerated in Phase 1 studies of healthy volunteers,” Babler said.

LUMUS is a worldwide, placebo-controlled trial set up to evaluate ESK-001’s effectiveness, safety, and pharmacological properties in adults with active SLE.

Participants will be randomly assigned to receive multiple doses of ESK-001 or a placebo for 48 weeks, or about a year. When the trial is complete, they may enter an open-label extension study or participate in a four-week safety follow-up.

The study’s main goal will be to assess the proportion of patients with reduced overall disease activity after 48 weeks, as assessed by the British-Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA). Secondary outcomes include evaluating the treatment’s safety and tolerability, and its effects on other measures of disease activity.

Alumis has also started dosing in OPTYK-1, a proof-of-concept Phase 2 clinical trial of ESK-001 for treating active noninfectious uveitis, a form of inflammation affecting the uvea, the middle layer of the eye wall, commonly associated with several systemic autoimmune conditions.

ESK-001 is also being tested in a third Phase 2 clinical trial called STRIDE in patients with moderate to severe plaque psoriasis, an autoimmune disorder marked by itchy, raised skin patches.

“The promising data to date for ESK-001 enables us to explore optimal dosing to drive efficacy, with the ultimate goal of achieving a best-in-class profile tailored to each disease indication,” Babler said.