presented at the virtual annual meeting of the American Academy of Dermatology.
Tralokinumab is a fully human monoclonal antibody which binds specifically to interleukin-13 and thereby prevents downstream IL-13 signaling. In contrast,(Dupixent), at present the only approved biologic agent for AD, blocks both the IL-13 and IL-4 pathways.
Two of the pivotal phase 3 trials presented at AAD 2020 –and – were identically designed, randomized, double-blind, placebo-controlled, 52-week, multinational monotherapy studies including a collective 1,596 adults with moderate to severe AD. In contrast, was a 380-patient, double-blind, randomized, 32-week study of tralokinumab in combination with a topical corticosteroid versus placebo injections plus a topical corticosteroid.
“I would say the take-home point of these trials is they are proof of principle that blocking just IL-13 can be an effective approach. The studies help us understand that IL-13 is an important driver cytokine for the disease,” Eric Simpson, MD, lead clinical investigator for ECZTRA 2, said in an interview.
In all three phase 3 trials, the primary endpoint was achievement of a clinical response as defined by an Investigator Global Assessment score of clear or almost clear skin (IGA 0/1) plus at least a 75% improvement in the Eczema Area and Severity Index score (EASI-75) at week 16. In ECZTRA 1 and 2, this was accomplished in 16% and 22% of patients on 300 mg of tralokinumab administered subcutaneously every 2 weeks, compared with 7% and 11% of placebo-treated controls.
Patients with a clinical response at week 16 were then rerandomized to tralokinumab either every other week or every 4 weeks or to placebo for an additional 36 weeks. At 52 weeks, 51% and 59% of patients in ECZTRA 1 and 2, respectively, who had a clinical response at week 16 maintained an IGA 0/1 response while on tralokinumab every 2 weeks, as did 39% and 45% of those switched to treatment every 4 weeks. Similarly, 60% and 56% of clinical responders at week 16 maintained an EASI-75 response at week 52 with tralokinumab every 2 weeks, as did 49% and 51% of those rerandomized to treatment every 4 weeks.
The safety profile of tralokinumab in the two monotherapy trials was comparable with placebo.
In the ECZTRA studies, tralokinumab achieved significant improvement at week 16 in secondary endpoints including itch, health-related quality of life, and severity and extent of skin lesions.
How does tralokinumab, with its narrower focus targeting a single cytokine, stack up against dupilumab, the dual IL-13/IL-4 inhibitor that’s transformed the treatment of patients with moderate or severe AD?
Dr. Simpson, who was also principal investigator in a pivotal phase 3 trial for dupilumab, emphasized that no firm conclusions can be drawn because there have been no head-to-head comparative trials and the tralokinumab and dupilumab trials had different patient populations, geographic locations, and washout periods. With those caveats, however, he commented that, “just on the surface, numerically, for the monotherapy studies, dupilumab hit some higher targets than tralokinumab in terms of the percentage of patients clear or almost clear.”
In terms of safety, it appears that the risk of conjunctivitis may be lower with tralokinumab than dupilumab, with rates of 7% and 3% through 52 weeks in ECZTRA 1 and 2, respectively, versus 2% with placebo, although again this is “a caveated conclusion,” said, professor of dermatology at Oregon Health and Science University, Portland.
Tralokinumab combination therapy in ECZTRA 3
At 16 weeks, 39% of patients treated with tralokinumab plus topical corticosteroids had an IGA of 0/1 and 56% had an EASI-75 response, compared with 26% and 36% of patients on topical corticosteroids plus biweekly placebo injections. More than 90% of patients with a good clinical response at week 16 maintained that response at week 32 while on tralokinumab biweekly plus topical steroids. Among good responders at week 16 who were rerandomized to 300 mg of tralokinumab every 4 weeks plus topical steroids, 78% still had an IGA of 0/1 at week 32, and 91% had an EASI-75, reported , director of clinical research and contact dermatitis at George Washington University, Washington.
A randomized, placebo-controlled combination therapy study such as this provides information that’s especially useful in clinical practice, Dr. Simpson observed.
“When I’m talking to patients about any biologics or oral therapies, I usually quote the figures from the combination therapy studies because the vast majority of our patients are using topical therapy in addition to systemics,” he said in the interview.
Asked how he envisions tralokinumab’s role in clinical practice, should the drug receive regulatory approval, Dr. Simpson said that he welcomes the prospect of having an additional treatment option to discuss with patients. Tralokinumab could be considered either as first-line therapy in patients who are failing on topical therapy or for patients who don’t respond adequately to or experience limiting side effects on dupilumab.
“There isn’t any established, published treatment algorithm in atopic dermatitis, probably for good reason, since we don’t have data to tell us you should start here and then move there. Those are long, difficult studies to perform,” Dr. Simpson said.
LEO Pharma has announced that it has applied for marketing approval for tralokinumab to the European Medicines Agency and plans to do so with the Food and Drug Administration by year’s end.
Dr. Simpson reported receiving research grants from and serving as a consultant to LEO Pharma, sponsor of the ECZTRA trials. He has similar financial relationships with close to a dozen other pharmaceutical companies.