The 82nd Annual Meeting of the American Academy of Dermatology (AAD) was held from March 8 to 12, 2024 in San Diego, USA. This is one of the largest and most influential international events in the field of dermatology in the world. on the afternoon of March 10, Professor Zhang Jianzhong, a well-known dermatologist and professor of Peking University People's Hospital, delivered an oral report in the Late-Breaking Research session of the conference, introducing Hengrui Pharmaceuticals' innovative drug, Emaxitinib ( SHR0302) in the treatment of moderate-to-severe atopic dermatitis (AD).

"Emaxitinib is a highly selective JAK1 inhibitor originally developed in China, which is a major breakthrough for us in the field of innovative drug development." Prof. Zhang Jianzhong explained that the Phase III clinical study showed that patients with moderate-to-severe AD treated with emaxitinib for 16 weeks showed significant improvement in skin lesions and itching symptoms, and the 52-week long-term follow-up also confirmed that the drug efficacy was sustained in the long term and the overall safety profile was favorable.

Study Background
AD is a common chronic, recurrent, inflammatory skin disease, and 2019 data show that there are 171 million AD patients worldwide. In China, the prevalence of AD has also been increasing, and according to statistics, the number of AD patients in China increased by 25.65% between 1990 and 2019.

AD patients often have intense itching, which seriously affects the quality of life. For moderate-to-severe AD, topical medications often do not control the condition well, and systemic therapy needs to be initiated. Traditional systemic therapeutic drugs mainly include antihistamines, immunosuppressants, and systemic application of glucocorticoids, etc. There are problems of insufficient efficacy and poor safety, which lead to poor patient compliance and low overall control rate. The introduction of innovative drugs such as biologics and Janus kinase (JAK) inhibitors has opened up new horizons for the treatment of moderate-to-severe AD.

The pathogenesis of AD mainly includes skin barrier dysfunction and immune dysregulation. Upstream Th2-type inflammatory factors, mainly IL4/IL13, are key and central to the pathogenesis of AD, and the downstream JAK-STAT signaling pathway plays an important role in the dysregulation of immune responses in AD [5]. Therefore, in recent years, the JAK-STAT pathway has been recognized as a highly promising therapeutic target in AD.

Emaxitinib (SHR0302) is a Class 1 new drug independently developed by Hengrui Pharmaceuticals, a new generation of highly selective JAK1 inhibitor, which is 16 times more selective for JAK1 than for JAK2. The drug can regulate the signaling of IL-4, IL-5, IL-13, IFN-γ and other cytokines involved in the pathogenesis of AD through highly selective inhibition of JAK1. Because of its minimal inhibition of JAK2, it also minimizes the risk of developing neutropenia with anemia. Phase II clinical studies have shown that emaxitinib is effective and well-tolerated in the treatment of moderate-to-severe AD, and is expected to provide a new therapeutic option for the majority of AD patients in China in the future.

Study Design
At the AAD, Prof. Jianzhong Zhang presented the long-term results of a Phase III study of emaxitinib in the treatment of moderate-to-severe AD. This multicenter, randomized, double-blind, placebo-controlled Phase III clinical study included 336 patients with moderate-to-severe AD from 53 medical centers in China and Canada. Patient enrollment criteria included:

(i) Age range of 12-75 years;

(ii) Confirmed diagnosis of moderate-to-severe AD;

(iii) Previous ineffective or intolerable use of topical glucocorticoids (TCS), calcineurin phosphatase inhibitors (TCIs), or the need for systemic therapies within 6 months prior to screening.

Enrolled patients are randomized 1:1:1 into three groups to receive emaxitinib 4 mg QD (administered once daily), emaxitinib 8 mg QD versus placebo for a total of 16 weeks, followed by a double-blind extension phase in which patients in the placebo group will be re-randomized 1:1 into the two emaxitinib treatment groups.

The co-primary endpoint of the study is the proportion of patients achieving an Investigator's Overall Assessment (IGA) response with a 75% improvement in the Eczema Area and Severity Index (EASI-75) at 16 weeks, and the long-term endpoints include the proportion of patients achieving an IGA response with an EASI-75 response over the 52-week treatment period, the proportion of patients achieving a response to the Worst Itch Intensity Numerical Rating Scale (WI-NRS) (WI-NRS improvement of ≥4 points) and drug safety and tolerability throughout the treatment period.

Study Results
In published preliminary results, the Phase III clinical study of emaxitinib for moderate-to-severe AD met its co-primary endpoints. The results showed that emaxitinib treatment of adolescent and adult patients with moderate-to-severe AD resulted in significantly better improvements in disease activity and pruritus than placebo, and was safe and well tolerated.

At 16 weeks, IGA response rates were 36.3%, 42.0%, and 9.0% in the emaxitinib 4mg, 8mg, and placebo groups, respectively, indicating that the drug was effective in improving disease activity in moderate-to-severe AD.

Emaxitinib also demonstrated significant efficacy in improving skin lesions, with EASI-75 response rates of 54.0%, 66.1%, and 21.6% in the emaxitinib 4mg, 8mg, and placebo groups, respectively, at 16 weeks.

Emaxitinib also significantly improved subjects' pruritus, with WI-NRS response rates of 37.2%, 40.2%, and 12.6% in the emaxitinib 4mg, 8mg, and placebo groups, respectively, at 16 weeks.

After completing the 16-week treatment phase, a total of 300 patients entered the extension phase. Ultimately, 258 patients completed 52 weeks of treatment.

Sustained Improvement in Skin Lesions
Results showed that among patients who continued treatment with emaxitinib from baseline, IGA and EASI-75 response rates were maintained over the treatment period from week 16 to week 52, with IGA response rates of 42.3% and 40.2% in the emaxitinib 4mg group versus the 8mg group at week 52, and EASI-75 response rates of 60.6% and 55.9% at week 52, respectively.

Significant relief of pruritus
In terms of pruritus, WI-NRS response rates also remained stable over the treatment period from week 16 to week 52 in patients who continued treatment with emaxitinib from baseline, with WI-NRS response rates of 59.6% in the emaxitinib 4 mg group versus 45.1% in the emaxitinib 8 mg group at week 52.

Improved Quality of Life
Significant improvements in multiple patient-reported outcomes (PROs) were observed as early as the 1st assessment in patients who continued treatment with emaxitinib from baseline, and efficacy was sustained over the treatment period from Week 16 to Week 52.At Week 52, the Childhood Dermatologic Quality of Life Index/Dermatologic Quality of Life Index (CDLQI/DLQI) decreased by as much as -8% in the emaxitinib 4 mg group vs. the 8 mg group compared to the baseline. The reduction in the CDLQI/DLQI (CDLQI/DLQI) from baseline was as high as -8.3 versus -8.5 points, and the reduction in the Atopic Dermatitis/Eczema Self-Examination Rating Scale (POEM) scores was -11.7 versus -11.9 points, respectively.

Overall Safety Tolerance
During the 52-week treatment period, the incidence of adverse events in the emaxitinib 4-mg and 8-mg groups was essentially comparable and mostly mild, with fewer discontinuations due to adverse reactions, no malignancies, major cardiovascular events (MACE), or thromboembolic events reported, and no new safety signals.

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