Novel Subcutaneous Biologics Show Promise in Atopic Dermatitis

Two novel monoclonal antibody therapies delivered subcutaneously appear to have a significant impact on disease severity in patients with moderate to severe atopic dermatitis (AD), without raising safety concerns, suggest two early stage trials.

The research was presented at the annual meeting of the European Academy of Dermatology and Venereology.

In one of the studies, TREK-AD, a phase 2b study, 302 patients were randomly assigned to one of four doses and two dosing schedules of eblasakimab (ASLAN Pharmaceuticals), which targets interleukin (IL)-13, or placebo.

Eblasakimab showed significant improvements in Eczema Area and Severity Index (EASI) scores vs placebo across doses and schedules, said presenter Eric Simpson, MD, professor of dermatology, Oregon Health & Science University, Portland. The "speed of onset was rapid" with eblasakimab, "with clinical improvements seen as early as week 2," he said.

In the STREAM-AD trial, nearly 400 patients were randomly assigned to one of several doses and schedules of amlitelimab (Kymab Ltd), an anti-OX40 ligand antibody, or placebo. Treatment resulted in significantly larger reductions in EASI scores from baseline with the novel therapy compared with placebo.

These reductions were "clinically meaningful," said presenter Stephan Weidinger, MD, PhD, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany, who also noted amlitelimab was "well-tolerated."

Approached for comment, Tiago R. Matos, MD, PhD, MSc, from Amsterdam University Medical Centers in the Netherlands, welcomed the "ground-breaking research and treatments for skin diseases."

He told Medscape Medical News: "As we gain more detailed understanding of the mechanisms behind each disease, novel treatments evaluate if increased specificity can lead to higher improvement of symptoms with less side effects."

"An example is the monoclonal antibody binding precisely to IL-13, allowing other potentially beneficial pathways to remain active."

Simpson told the audience that IL-4 and IL-13 play a central role in triggering allergy and AD symptoms, and that eblasakimab "is the only monoclonal antibody that can bind to the IL-13 receptor and block IL-13 signaling."

Translational data has shown that IL-13 receptor blockade can efficiently reduce Th2 cytokine expression, without increasing Th1 cytokines, which may reduce rates of conjunctivitis vs other means of IL blockade.

TREK-AD involved patients who had moderate to severe AD for at least 1 year, with an EASI score of ≥16, a Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of ≥3 (scale 0-4), and ≥10% Body Surface Area involvement.

They were randomly assigned to one of four eblasakimab treatment groups or placebo. Patients initially received 2-3 loading doses of the active intervention or placebo, followed by one of four doses of subcutaneous eblasakimab once a month or once every 2 weeks, or placebo once every 2 weeks, for 16 weeks. This was followed by a 12-week safety follow-up period.

Of 484 patients screened, 289 were randomly assigned. Their average age was 38.7 years, and 55.7% were male. The average age of onset of AD was 17.9 years, and the mean duration was 21.7 years. The mean baseline EASI score was 27.9.

The study met its primary endpoint, in that three of the four eblasakimab doses were associated with a significantly greater EASI percentage change from baseline at week 16 vs placebo:

• 600 mg once a month: 73% (P = .001)

• 300 mg every 2 weeks: 69.8% (P = .005)

• 400 mg every two weeks: 65.8% (P = .029)

• Placebo: 51.1%

All four eblasakimab doses were also associated with a significantly greater EASI percentage change from baseline at week 16 compared with placebo among patients with a baseline EASI score of ≥21. Reductions in this subgroup of patients with severe AD ranged from 60.2% to 74.8% for eblasakimab vs 38% for placebo (P = .0068 to P < .0001).

For most doses, eblasakimab was also associated with significant increases in the proportion of patients achieving an improvement in EASI scores of ≥75% and ≥90% at week 16, and the proportion with a vIGA-AD score of 0/1.

Turning to safety, Simpson said "you can see a few more adverse events in the treatment groups compared to placebo, but serious adverse events are low all the way across the board," with few injection site reactions.

However, he noted they were "hoping" maybe there would be less conjunctivitis with the highest dose of eblasakimab, but "unfortunately…we still have almost 11% [affected] in the treatment group compared to 2% in the placebo arm."

Amlitelimab Results

At the meeting, Weidinger explained the OX40 axis is a secondary co-stimulatory pathway that regulates antigen-specific Th2 and Th1/Th17/Th22 cells, as well as the secretion of pro-inflammatory cytokines.

Amlitelimab targets the OX40 ligand to prevent interaction with OX40 on activated T cells without depleting OX40 concentrations. This, he said, represents "a novel opportunity for effective intervention at an early stage of the immune response."

STREAM-AD is a 52-week, two-part trial involving patients with moderate-to-severe AD randomly assigned to a range of amlitelimab doses and schedules or placebo, for 16 weeks, when the primary endpoint was assessed.

They were followed out to week 24 to assess secondary endpoints before entering the second part of the trial.

Presenting results on 390 patients from the first part of the trial, Weidinger said the mean age of the patients was 37.8 years, 56.2% were male, and the average duration of AD was 22.3 years. The average EASI score at baseline was 28.9.

The study met its primary endpoint: All doses and schedules of amlitelimab were associated with statistically significant improvements in the percentage change in EASI scores from baseline to Week 16, with a least-squares mean differences vs placebo ranging from 22.2% to 37.6%.

The 250 mg dose of amlitelimab given monthly following a 500 mg loading dose was also associated with significant increases vs placebo in the proportion of patients achieving an improvement in EASI scores of ≥75% and IGA scores of 0/1, and reductions in a Peak Pruritus Numerical Rating Scale score of ≥4.

Weidinger said the safety data so far revealed "nothing really remarkable," with no large differences between the amlitelimab and placebo groups in terms of the proportion of patients with treatment emergent adverse events, and "only a few serious adverse events."

"Overall," he continued, "the vast majority of the adverse events were mild or moderate," and the treatment discontinuation rate was "rather low," while the incidence of conjunctivitis was "very low."

TREK-AD was sponsored by ASLAN Pharmaceuticals. STREAM-AD was funded by Kymab, a Sanofi company.

Simpson disclosed relationships with AbbVie, Amgen, Arema Pharmaceuticals, Aslan Pharma, Boston Consulting Group, Collective Acumen, LLC (CA), Dermira, Eli Lilly, Evidera, ExcerptaMedica, Forte Bio RX, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin Pharmaceutical Development, Leo Pharm, Medscape, Merck, Pfizer, Physicians World, Regeneron, Roivant, Sanofi-Genzyme, Trevi Therapeutics, Valeant, and WebMD. Weidinger disclosed relationships with AbbVie, Almirall, AstraZeneca, Galderma, Janssen, Kymab Ltd (a Sanofi company), LEO Pharma, Lilly, Pfizer, Regeneron, Roche Posay, and Sanofi.