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Novel Agent Active in Dermatologic Conditions

WASHINGTON — A monoclonal antibody targeting interleukin-1 alpha (IL-1α) led to a 51% overall clinical improvement in patients with moderate or severe atopic dermatitis, a preliminary clinical trial showed.

All components of the composite score improved significantly with the higher dose of bermekimab versus the lower dose, which improved disease status by 17% from baseline. The magnitude of clinical improvement correlated with the mean serum level of bermekimab.

The drug was well tolerated, as only two grade III adverse events occurred in 38 patients, both treated with the lower dose of bermekimab, Eric Simpson, MD, of Oregon Health & Science University in Portland, reported here at the American Academy of Dermatology meeting.

“Targeting interleukin-1 alpha with this drug in adults with moderate to severe atopic dermatitis really showed a nice early signal for improved signs and symptoms,” Simpson said. “We observed rapid reduction in itch and pain. Maybe this has something to do with the sensory nerve potentiation. Based on these results, the bermekimab clinical program in atopic dermatitis will advance to later-stage studies.”

Results of a second small clinical trial of bermekimab showed significant improvement in moderate-severe hidradenitis suppurativa after 12 weeks of treatment. The drug proved active in patients with and without prior exposure to a tumor necrosis factor (TNF) inhibitor, as reported by Alice Gottlieb, MD, PhD, of Tufts University in Boston.

Both studies showed significant improvement in pain.

Atopic Dermatitis

IL-1 occurs in abundance in keratinocytes and the IL-1 receptor is found on virtually all cells, said Simpson. Activated leukocytes produce IL-1α, which induces matrix metalloproteinase, potentiates pain perception, drives neoangiogenesis, and induces inflammatory cell infiltrates in skin.

Bermekimab was derived from a natural human humoral response to IL-1α. The monoclonal antibody binds and neutralizes IL-1α, does not bind IL-1β, and binds all forms of IL-1α (full, processed, membrane-bound, and soluble).

Bermekimab has been evaluated clinically in a total of 130 patients representing five types of dermatologic diseases: atopic dermatitis, hidradenitis, acne, psoriasis, and pyoderma gangrenosum. The agent demonstrated good activity in all the conditions, said Simpson, and a new subcutaneous formulation achieves >90% bioavailability.

Investigators in a pilot trial of bermekimab enrolled patients with moderate-severe atopic dermatitis: body surface area (BSA) ≥10%, investigator global assessment (IGA) ≥3, and eczema area and severity index (EASI) ≥16. All the patients had an inadequate response or intolerance to topical corticosteroids.

Ten patients received four weekly injections of 200 mg of bermekimab, and the remaining 28 patients in the trial received seven weekly injections of 400 mg. The primary endpoint was safety and tolerability. Secondary endpoints included change from baseline in EASI, IGA, the Scoring Atopic Dermatitis (SCORAD) calculator, the Patient-Oriented Eczema Measure (POEM), IGA, pruritus, and pain.

One patient in the 200-mg group and eight in the 400-mg group discontinued before the end of the study, one because of lack of response, four for adverse events, and the rest for miscellaneous reasons. The patient data were included in the analysis as last observation carried forward (LOCF), said Simpson.

The 200-mg dose led to a mean serum trough level of 13 μg/mL versus 44 μg/mL for the 400-mg dose, a threefold difference. That tracked closely with the 3.4-fold difference in clinical improvement (defined by EASI, SCORAD, IGA, and global individual signs score or GISS), and bioavailability was 94% with the 400-mg dose and 62% with the 200-mg dose.

Patients in the 400-mg group had almost an 80% improvement from baseline in EASI score versus 20% with the lower dose (P<0.001), and the proportion of patients achieving 75% improvement in EASI were 70% versus 40%. The change in SCORAD averaged 20% with the lower dose of bermekimab and almost 70% with the higher dose (P<0.0001). The reduction in GISS averaged 10% with 200 mg and almost 60% with 400 mg (P<0.0001).

IGA improvement, limited to the 400-mg group, showed 30% improvement at 4 weeks and more than 40% at 7 weeks (P<0.001 for both). A fourth of patients achieved an IGA of 0 or 1 plus at least a 2-point improvement from baseline to week 7.

Itch and worst itch declined by 40-50% with 200 mg of bermekimab versus about 70% with 400 mg (P<0.0001). The mean reduction in pain score in the 400-mg group exceeded 80% by week 7.

Hidradenitis Suppurativa

Gottlieb reported findings of 42 patients with moderate to severe hidradenitis suppurativa enrolled in a phase II evaluation of the 400-mg dose of bermekimab. The study group consisted of 24 patients who had not responded to a TNF inhibitor and 18 who had no prior anti-TNF therapy. Baseline hidradenitis suppurativa clinical response (HiSCR) scores averaged 14.1 in the anti-TNF failure group and 6.3 in the non-TNF inhibitor group.

Eight patients, all in the anti-TNF failure subgroup, discontinued treatment before 12 weeks — two because of adverse events (injection-site redness, worsening hypertension). Their data were analyzed by LOCF imputation.

By week 12, 60% of patients in both subgroups met criteria for HiSCR positivity. Improvement in Physicians Global Assessment increased from 10% at week 2 to more than 20% at week 12 in the anti-TNF failure group (P=0.002), and from about 15% to more than 50% in the patients with no prior anti-TNF therapy (P<0.0001). Patients' self-rating of disease status improved by 40% and 50% at week 12 in the patients with and without prior anti-TNF treatment (P<0.0001). Quality-of-life scores improved by 40% and 60%, respectively (P<0.0001).

All but one adverse event were grade 1-2. Two serious adverse events occurred during the study, both considered unrelated to treatment medication (one fall and one case of grade 3 hidradenitis suppurativa-related pain).

“Weekly subcutaneous bermekimab improved all disease measures with excellent safety,” said Gottlieb. “These findings support progress to phase III. Targeting interleukin-1 alpha may represent a novel effective treatment for moderate to severe hidradenitis suppurativa.”

Both studies were supported by XBiotech.

Simpson disclosed relationships with AbbVie, Dermira, Eli Lilly, LEO Pharma, Pfizer, Pierre Fabre, Regeneron, and XBiotech.

Gottlieb disclosed relationships with AbbVie, Avotres, Celgene, Dermira, Incyte, Janssen, LEO Pharma, Lilly, Novartis, Sun Pharmaceutical, and XBiotech.


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