Is OX40 Inhibition the Next Game Changer for Atopic Dermatitis?

Within the past 5 years, it has been exciting to see new treatments cater to targeting fundamental pathways in atopic dermatitis (AD). In 2017, dupilumab (Dupixent; Sanofi) significantly changed clinical practice as the first FDA-approved treatment for AD.¹ Following its release, several other systemic agents have been introduced to market.

As of this article, additional FDA-approved therapies for AD include IL-13 inhibitor tralokinumab (Adbry; LEO Pharma), Janus kinase (JAK) 1 inhibitor upadacitinib (Rinvoq; AbbVie), and JAK1 inhibitor abrocitinib (Cibinqo; Pfizer Inc).² Those currently in phase 3 studies include IL-13 inhibitor lebrikizumab (Ebglyss; Eli Lilly and Company) and IL-31 inhibitor nemolizumab (Galderma).2 Pharmaceutical companies have realized there is an unmet need for additional therapeutic options beyond our current landscape.

Ultimately, we ask ourselves: If one medication does not work or does not work fully, then what is next?

AD Pathophysiology

The pathophysiology of AD can be quite complex. We know there are various pathways that contribute to chronic pruritus and rash. Specifically, skin inflammation, skin barrier dysfunction, and dysbiosis are hallmark characteristics of development.² Cytokine release following type 2 inflammatory responses initiate many downstream events.² As seen with signaling molecules, IL-4 and IL-13 promote skin barrier dysfunction.² This release causes stimulatory effects on IgE, resulting in allergen immune responses.² There are also components where environmental allergens and overgrowth of Staphylococcus aureus play a role in altering the skin microbiome.²

The OX40-OX40L Pathway

Although we know much about AD, there are more areas to explore. Recent research has looked into the OX40-OX40L pathway. OX40-OX40L are known to be costimulatory immune checkpoint molecules. The costimulatory T-cell receptor OX40 is found on both effector and regulatory T cells.² Its ligand, OX40L, is expressed on activated antigen-presenting cells, dendritic cells, endothelial cells, macrophages, and activated B cells.² As a result, the binding of OX40-OX40L promotes the activation of T helper cells, leading to the expression of type 2 inflammatory signals, IL-4 and IL-13.2IL-33 is produced by keratinocytes that stimulate type 2 lymphoid and dendritic cells to express OX40L.

Additional studies suggest that, via this pathway, IL-22 (another cytokine associated with AD) may be expressed via the binding of OX40-OX40L.² Another interesting finding is that OX40 is expressed in higher concentrations in patients with AD compared with healthy adults. ²

Two drugs—rocatinlimab (Amgen) and amlitelimab (Sanofi)—are currently in steps toward FDA approval, with recent completion of phase 2 studies and entering phase 3 research (Figure 1^3-5).

Rocatinlimab

Rocatinlimab is a fully human, subcutaneous, IgG1 anti-OX40 receptor monoclonal antibody for moderate to severe AD. Rocatinlimab reduces the expression of the OX40 receptor, resulting in reduced T-cell inflammatory responses.³ Latest data from phase 2b studies demonstrated that patients experienced progressive clinical improvement. Rocatinlimab met its primary end point of percentage change from baseline in Eczema Area Severity Index (EASI) at 16 weeks, with 18-week active treatment extension and 20-week follow-up.³ Participants included adults with moderate to severe AD with documented history (within 1 year) of an inadequate response to topical medication or for whom topical treatments were not advisable.³ Highlighted secondary end points included EASI 50, EASI 75, EASI 90, Investigator Global Assessment (IGA) score of 0 (clear) or 1 (almost clear), and a percentage change from baseline in pruritus numeric rating scale (NRS) at 16 weeks.³

Results in EASI scores were seen at 16 weeks across all study doses. Of note, the greatest improvement was observed with rocatinlimab 300 mg every 2 weeks following an initial 600-mg loading dose.³ Improvements were noted across all key primary and secondary end points through week 36. Study methods included an active treatment extension where participants were followed 20 weeks off treatment.³ Those with a documented EASI 75 response maintained such response following discontinuation. Adverse effect (AE) profiles were similar across groups and were well tolerated. Most common AEs were pyrexia, nasopharyngitis, chills, aphthous ulcers, and nausea.³

Amlitelimab

Amlitelimab, also subcutaneous, is an IgG4 human anti-OX40L monoclonal antibody for moderate to severe AD. By binding to the OX40 ligand, amlitelimab inhibits antigen-presenting T-cell activation and T-independent antigen signaling via type 2 and Th1/17/22 inflammation.⁴ With phase 2b studies recently completed, Sanofi announced that amlitelimab met its primary end point of percentage change in EASI baseline at 16 weeks.⁵ Study enrollees included adults with moderate to severe AD with documented history (within 6 months) of inadequate response or inadvisability of topical treatments. Key secondary outcomes included change in EASI from baseline at 24 weeks, EASI 75 at 16 and 24 weeks, IGA score of 0 or 1, and a proportion of patients with reduction of a weekly average of pruritus NRS greater than or equal to 4 with a baseline pruritus of greater than or equal to 4 from baseline at 16 and 24 weeks.⁵

Results in EASI scores were seen at 16 weeks across all study doses.⁵ Following 24 weeks of treatment, patients were again randomly assigned to review maintenance of clinical response over an additional 28-week period.⁵ Study results noted that responder rates continued following discontinuation of amlitelimab 250 mg every 4 weeks (loading dose 500 mg).⁵ Phase 2a AEs included headache, hyperhidrosis, upper respiratory tract infection, pyrexia, increased aspartate aminotransferase, and iron deficiency anemia.⁴ However, the phase 2b press release announced treatment-emergent AEs more commonly observed included headache and upper respiratory tract infection.⁵

Practical Considerations for the Clinician

The addition of OX40 inhibitors will expand an already growing tool kit for clinicians. However, questions remain regarding how to best implement these agents in practice. Although many questions will be answered once FDA approved, certain standards apply when prescribing (Figure 2).

Screening parameters include baseline biologic and infectious disease lab panels and counseling patients on treatment expectations and use. Given new to market classifications, we should identify payer step therapy criteria and ways to reduce patient cost burdens, then determine any need for ongoing lab monitoring and vaccine management strategies.

Study results for both rocatinlimab and amlitelimab highlight possibilities for extended dosing, given high responder rates off treatment. This may be an opportunity for improving adherence rates and reduced occurrences of flares in the setting of missed doses. Ultimately, we expect fewer questions regarding whether we have treatments available for AD but more so how we can best optimize therapy.

Aderonke Adeboye, PharmD, BCPS

Aderonke Adeboye, PharmD, BCPS, is a clinical pharmacy specialist with Emory University Hospital Midtown practicing within the Emory Dermatology Clinic in Atlanta, Georgia. Her practice setting affords her the opportunity to provide direct medication management services to patients diagnosed with autoimmune and inflammatory skin conditions.

References

1. Dupixent. Prescribing information. Regeneron; 2024. Accessed July 8, 2024. https://www.regeneron.com/downloads/dupixent_fpi.pdf

2. Lé AM, Torres T. OX40-OX40L inhibition for the treatment of atopic dermatitis—focus on rocatinlimab and amlitelimab. Pharmaceutics. 2022;14(12):2753. doi:10.3390/pharmaceutics14122753

3. Guttman-Yassky E, Simpson EL, Reich K, et al. An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study. Lancet. 2023;401(10372):204-214. doi:10.1016/s0140-6736(22)02037-2

4. Weidinger S, Bieber T, Cork MJ, et al. Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial. Br J Dermatol. 2023;189(5):531-539. doi:10.1093/bjd/ljad240

5. New phase 2b results for amlitelimab support potential for best-in-class maintenance of response in atopic dermatitis. News release. Sanofi; March 11, 2024. Accessed July 8, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-03-11-06-00-00-2843456