IL-1 receptor inhibitor fails on ocular itching endpoint

Take-home: Isunakinra, an interleukin-1 signaling inhibitor designed for topical ophthalmic administration, did not meet the primary endpoint in a phase III clinical trial for the treatment of moderate-to-severe allergic conjunctivitis.

Reviewed by Michael Goldstein, MD

Boston-Despite promising results in earlier studies, isunakinra (EBI-005, Eleven Biotherapeutics) did not display statistically significant efficacy for the treatment of moderate-to-severe allergic conjunctivitis compared to the vehicle control in a phase III study.

Isunakinra, a novel topical interleukin-1 (IL-1) receptor inhibitor, was safe and well tolerated in the multicenter, randomized, double-masked study, but the drug failed to meet the primary endpoint, said Michael Goldstein, MD, chief medical officer, Eleven Biotherapeutics and assistant professor of ophthalmology, Tufts University School of Medicine, Boston.

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“At this point we are not pursuing additional studies,” Dr. Goldstein said. “We’re thinking about different avenues for this drug, but we don’t have any studies planned.”

In the study, 258 patients were randomized 1:1 to isunakinra or vehicle control and treated 3 times a day for 4 weeks in an environmental setting. The primary endpoint was reduction in ocular itching.

IL-1 has been shown to play a role in inflammation throughout the body and is involved in the pathophysiology of allergic conjunctivitis. It is also an anti-inflammatory and could be used to treat dry eye, Dr. Goldstein said. Since IL-1 receptors also are found on the peripheral nerves, the protein theoretically could also affect people’s perception of pain or discomfort.

“From a mechanistic perspective, it is an excellent target,” Dr. Goldstein added.

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Recombinant protein        

Isunakinra is a recombinant protein, a chimera of the IL-1 and IL-1Ra molecules, combining the best binding sites of each to produce a purely antagonistic molecule that is more potent than either of its parents and more thermally stable, Dr. Goldstein said.

After the developers found a way to stabilize the protein and deliver it in a preservative-free formulation to avoid further irritating the ocular surface, isunakinra was tested in a phase 1 study in healthy volunteers in which it was well tolerated. In a proof-of-concept phase II trial in 159 patients with allergic conjunctivitis, comparing the drug to vehicle, it was again well tolerated. Patients showed improvement in ocular itching, tearing, and associated nasal symptoms.

The phase III study was begun, in which 94% of patients completed the trial and no adverse events were reported. However, isunakinra failed to meet the primary endpoint. Results were reported in January 2016.

Improving after one day

“We found that the patients for the most part improved both their signs and symptoms of allergic conjunctivitis starting one day after starting therapy and continuing over the 1-month study period,” Dr. Goldstein explained. “Prior to treatment with the study drug, all patients in this trial were initially challenged with olopatadine (Patanol, Alcon Laboratories).

“Interestingly, the improvement seen for isunakinra-treated subjects was greater than what was seen with olopatadine alone. The problem was that the vehicle group also improved, and the drug didn’t separate statistically from the vehicle,” he added.

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Post-hoc analysis to assess clinical relevance of high IL-1 producers identified by genotyping demonstrated a group of subjects with greater response to isunakinra therapy relative to vehicle than was seen for the overall study population.

“We had good safety, but we couldn’t show additional activity over what we could see with the vehicle across the entire study population,” Dr. Goldstein said.

Michael Goldstein, MD

Dr. Goldstein is chief medical officer of Eleven Biotherapeutics

E. Michael.Goldstein@elevenbio.com

This article was based on a poster presented at the 2016 annual meeting of the Association for Research in Vision and Ophthalmology.

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