Targeting the OX40 Pathway

Targeting the OX40–OX40 ligand pathway is an exciting new approach to treating atopic dermatitis (AD) because it is a truly novel avenue. Having led clinical trials and presented about this approach at both the American Academy of Dermatology (AAD) Annual Meeting and the European Academy of Dermatology and Venereology (EADV) Congress this year, I want to simplify the concept so that every clinician can understand the unique promise of this pathway.

WHY OX40?

The beauty of targeting the OX40–OX40 ligand pathway is that we are going after the memory T cells. The simplest way to think about it is this: Lesions always come back to the same areas because memory T cells, which “remember” the disease, repopulate those sites.

Even when we treat patients very well with current agents—whether topical or systemic—we typically need to keep giving therapy continuously. If we stop the treatment, the memory T cells remain, and the disease comes back exactly in the prior areas.

EARLY AND ONGOING RESULTS

Within this class of drugs, we recently presented 24-week data on rocatinlimab. The phase 3 trials showed statistically significant improvement compared to placebo, with rocatinlimab as a monotherapy in the ROCKET-Ignite Trial and in a study combining rocatinlimab treatment with topical corticosteroids (ROCKET-SHUTTLE).

A particularly interesting finding is that placebo responses plateau, especially at the higher endpoints such as Eczema Area and Severity Index (EASI)-90 or EASI-100, while active treatment shows continuous improvement. This was observed both in the monotherapy trials and in combination with topical steroids—which is, of course, closer to real-world practice. As expected, outcomes were better when topical corticosteroids were included.

It is important to note that OX40 drugs may be slightly slower to act than some other biologics. However, at 24 weeks, the slope of response was still rising, and we thus expect the maximal efficacy to appear between 24 and 48 weeks.

THE POTENTIAL FOR DISEASE MODIFICATION

Despite the promising phase 3 results, what excites me most is what we learned from the phase 2 trial. Treatment was stopped and patients were followed for an extended period, and the majority of patients maintained their disease resolution for a period of 20 weeks.

Most biologics require ongoing dosing, and if you stop, the disease eventually comes back. With the OX40 blockade, we may be witnessing the first real steps toward disease modification in AD.

Patients ask us about what happens if they stop taking the drug every day. Until now, our answer has been that the disease will recur. With OX40-targeted therapy, we may finally be able to give a different answer.

LOOKING AHEAD

Rocatinlimab and other OX40 pathway inhibitors represent an exciting new direction in AD management. While the 24-week results for rocatinlimab are already encouraging, the 48-week and withdrawal data will be even more meaningful.

The possibility that patients could remain clear for months after discontinuing therapy would represent a profound shift for our field. This is an exciting time, and I am hopeful that these drugs will bring new options to our patients in need. 

Emma Guttman, MD, PhD

• Health-system Chair, Department of Dermatology, Icahn School of Medicine at Mount Sinai
• New York, NY