Rocatinlimab: A Novel T-Cell Rebalancing Therapy Targeting the OX40 Receptor in Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by eczematous skin lesions, intense pruritus, skin pain, sleep disruption, and mental health disturbances. There remains a need for a therapeutic option that delivers durable efficacy, safety, and convenient dosing across the AD patient population. This review provides an overview of AD pathogenesis driven by T-cell imbalance and describes a novel therapeutic option targeting the OX40 receptor, a costimulatory molecule expressed specifically on activated T cells. Expression of the OX40 receptor on skin-homing T cells is increased in AD. OX40-mediated activation of pathogenic T cells drives inflammation in AD and is critical for the formation of memory T cells, leading to persistent disease. Rocatinlimab (AMG 451/KHK4083) is a novel T-cell rebalancing therapy that inhibits and reduces pathogenic T cells by targeting the OX40 receptor. By reducing pathogenic T-cell number and activity, rocatinlimab has the potential to limit AD flares and modify the course of disease. Rocatinlimab showed promise for the treatment of moderate-to-severe AD in a phase 2b trial, significantly improving overall disease severity, skin involvement, pruritus, sleep disturbance, and quality of life compared with placebo at week 16. Improvements continued through week 36 during active treatment, and notably, were largely maintained in responders throughout a subsequent 20-week off-treatment period, providing evidence for durable on and off treatment responses. Rocatinlimab has also demonstrated a favorable safety and tolerability profile. A large, global phase 3 program (ROCKET) including eight studies is underway to further assess the efficacy, safety, maintenance of response, extended dosing, and off-treatment durability of rocatinlimab in adults and adolescents with moderate-to-severe AD.

Plain Language Summary

Atopic dermatitis (AD, also known as eczema) is a skin condition with symptoms of skin redness, itch, and pain that is caused by an overactive immune system. There is a need for medicines that provide safety along with long-term disease control for moderate-to-severe AD. Rocatinlimab, a new T-cell rebalancing medicine, can decrease the activity and reduce the number of T cells that cause AD by targeting the OX40 receptor. Rocatinlimab has been studied in clinical trials in patients with moderate-to-severe AD. Current evidence shows that rocatinlimab improved the total area and severity of affected skin significantly more than placebo. It also improved itch, sleep disturbance, and overall quality of life. These effects lasted for up to 36 weeks of treatment and were maintained up to 20 weeks after stopping rocatinlimab, which may reflect the unique way in which rocatinlimab works. Rocatinlimab was also generally well tolerated. Rocatinlimab is being investigated in ROCKET, a comprehensive phase 3 program of eight clinical studies, to better understand how well rocatinlimab works in adult and adolescent patients with moderate-to-severe AD.

Key Summary Points

There is an unmet need for novel treatments for moderate-to-severe atopic dermatitis that offer longer dosing intervals and provide durable responses off therapy.

T-cell imbalance is a root cause of atopic dermatitis.

Rocatinlimab (AMG 451/KHK4083) is a first-in-class T-cell rebalancing therapy that inhibits and reduces pathogenic T cells by targeting the OX40 receptor.

To date, rocatinlimab demonstrated strong efficacy, favorable safety, and durable response on and off therapy in treating moderate-to-severe atopic dermatitis.

Introduction

Atopic dermatitis (AD) is a chronic inflammatory disease characterized by eczematous skin lesions, intense pruritus, skin pain, sleep disruption, and mental health disturbances [1–3]. AD has the highest disease burden based on disability-adjusted life-years among skin disorders [4]. Due to chronic symptoms and unpredictable flares, patients with AD report diminished quality of life (QoL) as well as elevated rates of anxiety and depression [5–10]. Pruritus, the most burdensome symptom of AD [11], can greatly affect QoL, most notably as a result of causing sleep disturbance [12]. The impact of AD on QoL generally increases with increasing disease severity [5–7, 9–11]. Caregivers of patients with AD, and other household members, also experience a considerable burden [5, 8]. Additionally, comorbidities present in patients with AD (e.g., asthma, allergies, pain, obesity, cardiovascular disease) may add to the overall burden of this disease [8, 11, 13–15].

Management of AD aims to optimize long-term outcomes and QoL by alleviating the signs and symptoms of AD, reducing the frequency and severity of flares, and minimizing secondary complications, comorbidities, and potential therapeutic risks [2, 6, 9, 16–20]. One of the primary treatment goals is to achieve and maintain durable, long-term disease control. While moisturizers and topical therapies have been the mainstay of AD treatment and continue to have a place in the treatment paradigm, especially for patients with mild disease [19–21], advances in understanding of the pathophysiology of AD have contributed to the development of systemic therapies for patients with moderate-to-severe disease, including biologics targeting interleukin (IL)-4 and/or IL-13 (e.g., dupilumab, tralokinumab, lebrikizumab) and IL-31 (nemolizumab) and Janus kinase (JAK) inhibitors (e.g., abrocitinib, upadacitinib, baricitinib) (Table 1) [19, 22–34]. Despite these expanded treatment options, many patients still fail to achieve an adequate and sustained response. In phase 3 trials, 40% or fewer of patients treated with dupilumab, lebrikizumab, tralokinumab, or nemolizumab achieved clear or almost clear skin after 16 weeks [22, 23, 33, 35]. In a retrospective cohort analysis, the cumulative probability of nonresponse in patients receiving dupilumab was 35% after 12 months [36]. Oral JAK inhibitors have achieved higher rates of clear or almost clear skin in randomized clinical trials (~50–60%) than biologics [37]. However, boxed warnings for JAK inhibitors related to serious infections and cardiovascular, thrombotic, and cancer risks limit the type of patient appropriate for this class, particularly for long-term use (Table 1) [31, 38, 39]. A large multinational survey of patients with moderate-to-severe AD receiving systemic therapies showed a substantial residual disease burden exists, with mean (standard deviation) worst pruritus Numeric Rating Scale (NRS) score of 4.6 (3.1), Dermatology Life Quality Index (DLQI) score of 9.1 (7.6), Eczema Area and Severity Index (EASI) of 12.6 (12.9), and SCORing Atopic Dermatitis (SCORAD) of 38.3 (23.3) [10]. A TARGET-DERM real-world registry longitudinal study identified that many patients with moderate-to-severe AD do not achieve adequate disease control after 12 months of systemic therapies [40, 41]. The current treatment landscape underscores the importance of adopting more proactive management strategies in AD, along with the need for treatment options that not only alleviate acute symptoms, but also provide long-term disease control by targeting the root cause of underlying inflammation.

Table 1.

Overview of systemic treatments approved for moderate-to-severe AD

Drug	Target	Study name	Study design	Primary endpoint	Primary endpoint results	Safety summary
Dupilumab (Dupixent®, Regeneron Pharmaceuticals, Inc.; Tarrytown, NY) [28]	IL-4Rα	SOLO1 (NCT02277743) and SOLO2 (NCT02277769) [22]	Phase 3, randomized, double-blind, placebo-controlled, parallel-group trials of identical design in 671 (SOLO1) and 708 (SOLO2) adults with moderate-to-severe AD	Percentage of patients with IGA 0 (clear) or 1 (almost clear) and ≥ 2-point reduction from baseline at week 16	SOLO1  Placebo: 10%  Dupilumab 300 mg Q2W: 38% (P < 0.001)  Dupilumab 300 mg QW: 37% (P < 0.001) SOLO2  Placebo: 8%  Dupilumab 300 mg Q2W: 36% (P < 0.001)  Dupilumab 300 mg QW: 36% (P < 0.001)	Most common AEs: injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye, eosinophilia
Lebrikizumab (Ebglyss®; Almirall, S.A.; Barcelona, Spain) [29]	IL-13	ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) [23]	Phase 3, randomized, double-blind, placebo-controlled, parallel-group trials of identical design in 424 (ADvocate1) and 427 (ADvocate2) adults and adolescents with moderate-to-severe AD	Percentage of patients with IGA 0 (clear) or 1 (almost clear) and ≥ 2-point reduction from baseline at week 16	ADvocate1  Placebo: 12.7%  Lebrikizumab 250 mg Q2W: 43.1% (P < 0.001) ADvocate2  Placebo: 10.8%  Lebrikizumab 250 mg Q2W: 33.2% (P < 0.001)	Most common AEs: conjunctivitis/conjunctivitis allergic, injection site reactions, and dry eye
Tralokinumab (Adbry®; Leo Pharma Inc.; Madison, NJ) [30]	IL-13	ECZTRA1 (NCT03131648) and ECZTRA2 (NCT03160885) [24]	Phase 3, randomized, double-blind, placebo-controlled trials of identical design in 802 (ECZTRA1) and 794 (ECZTRA2) adults with moderate-to-severe AD	Percentage of patients with IGA 0 (clear) or 1 (almost clear) at week 16 EASI-75 at week 16	ECZTRA1  IGA 0/1   Placebo: 7.1%   Tralokinumab 300 mg Q2W: 15.8% (P = 0.002)  EASI-75   Placebo: 12.7%   Tralokinumab 300 mg Q2W: 25.0% (P < 0.001) ECZTRA2  IGA 0/1   Placebo: 10.9%   Tralokinumab 300 mg Q2W: 22.2% (P < 0.001)  EASI-75   Placebo: 11.4%   Tralokinumab 300 mg Q2W: 33.2% (P < 0.001)	Most common AEs: URTI, conjunctivitis, injection site reactions, eosinophilia
Nemolizumab (Nemluvio®; Galderma Laboratories, L.P.; Dallas, TX)	IL-31	ARCADIA 1 (NCT03985943) and ARCADIA 2 (NCT03989349) [33]	Phase 3, randomized, double-blind, placebo-controlled trials in 620 (ARCADIA 1) and 522 (ARCADIA 2) adults and adolescents with moderate-to-severe AD	Percentage of patients with IGA 0 (clear) or 1 (almost clear) and ≥ 2-point reduction from baseline at week 16 EASI-75 at week 16	ARCADIA 1  IGA 0/1 and ≥ 2-point reduction from baseline   Placebo: 25%   Nemolizumab 30 mg Q4W: 36% (P = 0.0003)  EASI-75   Placebo: 29%   Nemolizumab 30 mg Q4W: 44% (P < 0.0001) ARCADIA 2  IGA 0/1 and ≥ 2-point reduction from baseline   Placebo: 26%   Nemolizumab 30 mg Q4W: 38% (P = 0.0006)  EASI-75   Placebo: 30%   Nemolizumab 30 mg Q4W: 42% (P = 0.0006)	Most common AEs: headache, arthralgia, urticaria, myalgia
Abrocitinib (Cibinqo®; Pfizer Inc.; New York, NY) [38]	JAK	JADE MONO-1 (NCT03349060) [27]	Phase 3, randomized, double-blind, placebo-controlled, parallel-group trial in 387 adults and adolescents with moderate-to-severe AD	Percentage of patients with IGA 0 (clear) or 1 (almost clear) and ≥ 2-point reduction from baseline at week 12 EASI-75 at week 12	IGA 0/1 and ≥ 2-point reduction from baseline   Placebo: 8%   Abrocitinib 100 mg QD: 24% (P = 0.0037)   Abrocitinib 200 mg QD: 44% (P < 0.0001) EASI-75  Placebo: 12%  Abrocitinib 200 mg QD: 40% (P < 0.0001)  Abrocitinib 100 mg QD: 63% (P < 0.0001)	Most common AEs: nasopharyngitis, nausea, headache, herpes simplex, increased blood creatine phosphokinase, dizziness, urinary tract infection, fatigue, acne, vomiting, impetigo, oropharyngeal pain, hypertension, influenza, gastroenteritis, dermatitis contact, upper abdominal pain, abdominal discomfort, herpes zoster, and thrombocytopenia Black box warninga: serious infections, mortality, malignancy, MACE, and thrombosis
Baricitinib (Olumiant®; Lilly USA, LLC; Indianapolis, IN) [31, 32]	JAK	BREEZE-AD1 and BREEZE-AD2 [25]	Phase 3, randomized, double-blind, placebo-controlled, parallel-group trials of identical design in 624 (BREEZE-AD1) and 615 (BREEZE-AD2) adults with moderate-to-severe AD	Percentage of patients with IGA 0 (clear) or 1 (almost clear) and ≥ 2-point reduction from baseline at week 16	BREEZE-AD1  Placebo: 4.8%  Baricitinib 2 mg QD: 11.4% (P < 0.05)  Baricitinib 4 mg QD: 16.8% (P < 0.001) BREEZE-AD2  Placebo: 4.5%  Baricitinib 2 mg QD: 10.6% (P < 0.05)  Baricitinib 4 mg QD: 13.8% (P ≤ 0.001)	Most common AEs: increased LDL cholesterol, URTI, headache, herpes simplex, and urinary tract infections Black box warninga: serious infections, mortality, malignancy, MACE, and thrombosis
Upadacitinib (Rinvoq®; AbbVie Inc.; North Chicago, IL) [39]	JAK	Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) [26]	Phase 3, randomized, double-blind, placebo-controlled, parallel-group trials of identical design in 847 (Measure Up 1) and 836 (Measure Up 2) adults and adolescents with moderate-to-severe AD	Percentage of patients with IGA 0 (clear) or 1 (almost clear) and ≥ 2-point reduction from baseline at week 16 EASI-75 at week 16	Measure Up 1  IGA 0/1 and ≥ 2-point reduction from baseline   Placebo: 8%   Upadacitinib 15 mg QD: 48% (P < 0.0001)   Upadacitinib 30 mg QD: 62% (P < 0.0001)  EASI-75   Placebo: 16%   Upadacitinib 15 mg QD: 70% (P < 0.0001)   Upadacitinib 30 mg QD: 80% (P < 0.0001) Measure Up 2  IGA 0/1 and ≥ 2-point reduction from baseline   Placebo: 5%   Upadacitinib 15 mg QD: 39% (P < 0.0001)   Upadacitinib 30 mg QD: 52% (P < 0.0001)  EASI-75   Placebo: 13%   Upadacitinib 15 mg QD: 60% (P < 0.0001)   Upadacitinib 30 mg QD: 73% (P < 0.0001)	Most common AEs: URTI, acne, herpes simplex, headache, blood creatine phosphokinase increased, cough, hypersensitivity, folliculitis, nausea, abdominal pain, pyrexia, increased weight, herpes zoster, influenza, fatigue, neutropenia, myalgia, and influenza-like illness Black box warninga: serious infections, mortality, malignancy, MACE, and thrombosis

AD atopic dermatitis, AE adverse event, EASI Eczema Area and Severity Index, IGA Investigator’s Global Assessment, MACE major adverse cardiac events, QD once daily, QoL quality of life, QW every week, Q2W every 2 weeks, URTI upper respiratory tract infection

^aBlack-box warning from U.S. prescribing information

AD is a heterogeneous disease in terms of clinical features, severity, and lesion characteristics and distribution [3], which is driven by increased number and activity of pathogenic T cells that promote inflammation [42–44]. While T helper 2 (Th2) cells and their associated cytokines (e.g., IL-4, IL-13, IL-31) are key in AD pathogenesis and play a central role in skin inflammation and pruritus, other T-cell subtypes beyond Th2 (e.g., Th1, Th17, and Th22) also contribute to the overall inflammatory response [3, 45, 46]. The relative contribution of these T-cell subsets is variable and likely to evolve over the course of disease [47]. Increased activity and migration of pathogenic T cells result in a T-cell imbalance, which is a root cause of AD and other inflammatory diseases.

Given the diverse inflammatory pathways controlled by effector and memory T cells, targeting individual cytokines or cytokine-associated signaling pathways, as many current therapies do, may not be sufficient to control disease activity. In particular, memory T cells are increasingly recognized as central drivers of disease chronicity in AD, given their ability to persist long-term in peripheral tissues and rapidly reactivate inflammatory responses upon antigen re-encounter. These cells contribute to the relapsing nature of AD and may underlie flare cycles even after clinical improvement [48–50]. Despite their importance, memory T cells are not directly targeted by currently available therapies, which predominantly focus on cytokine blockade or receptor antagonism [19, 22–34]. Rocatinlimab (AMG 451/KHK4083) is a T-cell rebalancing therapy that inhibits and reduces pathogenic T cells by targeting the OX40 receptor on activated T cells [51–53]. Directly targeting pathogenic T cells may provide an option to reduce inflammation across multiple pathways, leaving fewer pathogenic effector and memory T cells to drive inflammation, and preventing the formation of memory T cells that may contribute to disease chronicity (Fig. 1) [50, 54, 55]. This mechanism could potentially allow rocatinlimab to rebalance T cells and achieve durable efficacy across heterogeneous patient types.

Fig. 1.

Rocatinlimab mechanism of action [51–53]

Role of the OX40 Receptor in Atopic Dermatitis

The pathogenesis of AD primarily involves a complex interaction between skin barrier dysfunction and dysregulation of T-cell-mediated inflammatory pathways [45, 56, 57]. An increased number and activity of pathogenic T cells promotes downstream T-cell-mediated inflammation, resulting in a T-cell imbalance, which contributes to disease severity, flares, and progression [43, 44]. Multiple pathogenic T-cell subtypes contribute to disease heterogeneity and chronicity, including effector T cells (e.g., Th1, Th2, Th17, and Th22), which initiate and maintain a broad range of inflammatory responses, and memory T cells, which contribute to the chronic inflammation [3, 43–46, 48–50].

T-cell activation is initiated by antigen-specific stimulation of the T-cell receptor along with early co-stimulatory molecules including CD28 to avoid anergy. Additional co-stimulatory signals determine the type and magnitude of the T-cell response by driving T-cell survival, maturation, and effector function. After the initial immune response, co-stimulatory signals also direct the development and reactivation of long-lived memory T cells [58, 59]. Due to their role as immune amplifiers, increased expression of co-stimulatory receptors has been reported in multiple inflammatory diseases, including AD, and may provide a mechanism for the amplification of pathogenic T cells and their associated proinflammatory signals [60, 61].

The OX40 receptor is a co-stimulatory molecule that is transiently upregulated on T cells upon antigen-driven activation and expressed on various effector T-cell subsets including Th1, Th2, Th17, and Th22 cells [54, 62, 63]. The binding partner for OX40 receptor is OX40 ligand, which is primarily expressed on the surface of activated antigen-presenting cells (e.g., dendritic cells), as well as on other cell types, such as mast cells, vascular endothelial cells, and type 2 innate lymphoid cells [54, 62, 64, 65]. The expression of OX40 receptor is elevated in skin-homing circulating CD4+ T cells in patients with AD, which may promote further migration of pathogenic T cells to the skin [61].

OX40 signaling promotes the proliferation and survival of T cells, as well as differentiation of activated effector T cells into memory cells [54, 58, 66]. Upon reactivation, memory T cells express the OX40 receptor, which further induces their expansion. A subset of memory T cells, known as resident memory T cells, reside in the skin and are believed to play a role in the chronicity of AD, contributing to the recurrence and localization of AD lesions [49, 58]. In both effector and memory T cells, stimulation of the OX40 receptor enhances production of proinflammatory cytokines including IL-4, IL-13, IL-22, and IL-31 [54, 67, 68], which can further activate T cells and the expression of OX40 receptor [61]. The expression pattern of the OX40 receptor in AD and its function as an amplifier of effector and memory T-cell responses make it an attractive target for inflammatory diseases such as AD [69].

Mechanism of Action of Rocatinlimab

Rocatinlimab, an immunoglobulin (Ig)G1 non-fucosylated human monoclonal antibody, is a T-cell rebalancing therapy that inhibits and reduces pathogenic T cells by targeting the OX40 receptor [51–53]. This unique mechanism has the potential to provide benefit across the heterogeneous AD patient population by leaving fewer pathogenic T cells available to drive inflammation and disease severity (Fig. 1) [50, 54]. Additionally, the reduction in the generation and reactivation of pathogenic memory T cells provides potential for a deep and durable response [55]. Unlike treatments that solely inhibit downstream cytokines, rocatinlimab addresses the underlying cause of AD by targeting pathogenic effector T cells that contribute to disease severity and pathogenic memory T cells, which may play a direct role in the recurrence of disease.

Clinical Efficacy and Safety Data in AD

The safety, tolerability, immunogenicity, and preliminary efficacy of rocatinlimab was first assessed in AD in a phase 1, single-center, open-label trial (NCT03096223) [52]. Rocatinlimab 10 mg/kg was administered intravenously in 22 Japanese patients aged 20 years or older with moderate-to-severe AD every 2 weeks (Q2W) for 6 weeks (total of 3 infusions), after which patients were followed for an additional 16 weeks. This preliminary study suggested rocatinlimab was generally well tolerated. Treatment-emergent adverse events (TEAEs) occurred in 17/22 patients (77.3%), all of which were mild or moderate. No deaths, serious adverse events (AEs), or discontinuations due to TEAEs were reported. Fever and chills were the most frequently reported drug-related TEAEs (incidence rate 50.0% and 36.4%, respectively). This is a common reaction to biologics, particularly when the treatment is administered as an infusion, and usually only occurs after the first few infusions [70, 71]. Other common drug-related TEAEs (rates ≥ 5%) included aphthous ulcer (18.2%), blood uric acid increase (13.6%), nasopharyngitis (13.6%), erythema (9.1%), and hordeolum (9.1%). No clinically meaningful changes in vital signs, laboratory values, or electrocardiography recordings were observed. The overall assessment of immunogenicity showed low positive responses.

In this small population, rocatinlimab demonstrated promising efficacy. EASI scores decreased by 24.3% from baseline to week 6 (last dose) and decreased further over 22 weeks, reaching a decrease of 74.1% at week 22. At week 6, 10/20 (50%) patients experienced ≥ 1-point improvement in Investigator’s Global Assessment (IGA) scores. At week 22, 16/20 (80%) of patients achieved ≥ 1-point IGA improvement. Mean pruritus NRS score decreased by 28.4% at week 6 and 63.6% at week 22. Altogether, results from the phase 1 trial indicated rocatinlimab could potentially benefit patients with moderate-to-severe AD with an acceptable safety profile.

Following the positive results of the phase 1 trial, the efficacy and safety of rocatinlimab were evaluated in 274 adult patients (42% women, mean age 38 years, mean disease duration 16 years) with moderate-to-severe AD in a phase 2b, multicenter, double-blind, placebo-controlled study conducted in the USA, Germany, Canada, and Japan (NCT03703102) [55]. Eligible patients included those with a documented history of inadequate response to topical medications or where topical treatment was medically inadvisable.

Patients were randomly assigned to subcutaneous injections of rocatinlimab 150 mg Q4W (n = 54), rocatinlimab 600 mg Q4W (n = 54), rocatinlimab 300 mg Q2W (n = 55), rocatinlimab 600 mg Q2W (n = 54), or placebo (n = 57) for 18 weeks. During an 18-week active-treatment extension (weeks 18–36) period, patients initially assigned to rocatinlimab continued the same dose and frequency and patients assigned to placebo switched to rocatinlimab 600 mg Q2W. Subsequently, all patients were followed up for a 20-week off-treatment period (weeks 36–56).

The primary endpoint was met with statistically significant greater least-squares mean (LSM) percentage change from baseline to week 16 in EASI score in all rocatinlimab groups (−48.3% to −61.1% across doses) versus placebo (−15.0%; all P < 0.001; Fig. 2A) [55]. At week 16, numerically greater proportions of patients receiving rocatinlimab achieved EASI-75 and a validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-AD™) score of 0 or 1 versus placebo (EASI-75: 39–54% across doses versus 11% placebo; vIGA-AD™ score of 0/1 with a ≥ 2-points reduction from baseline: 15–31% across doses versus 2% placebo; Fig. 2B, C). A post hoc analysis showed progressive and durable improvements in EASI scores with rocatinlimab treatment across all anatomic regions, including the head and neck, as well as the trunk, upper extremities, and lower extremities [72].

Fig. 2.

Percentage change from baseline in A EASI, B EASI-75 response, C vIGA 0/1 and ≥ 2-point improvement response, and D ≥ 4-point pruritus NRS response^b [55]. ^aPatients in the placebo group received rocatinlimab 600 mg Q2W from week 18 to week 36. ^bOn the basis of nonresponder imputation analysis. Reprinted from Guttman-Yassky et al. [55], copyright (2023), with permission from Elsevier. EASI Eczema Area and Severity Index, vIGA validated Investigator’s Global Assessment for Atopic Dermatitis, NRS Numeric Rating Scale, Q2W every 2 weeks, Q4W every 4 weeks

Rocatinlimab also improved symptoms of AD commonly identified as meaningful from the patient’s perspective [55]. Compared with placebo, rocatinlimab demonstrated greater LSM percentage change from baseline in pruritus NRS score (−25.6% to −48.0% across doses versus −6.2% with placebo) at week 16. Improvement of at least 4 points on the pruritus NRS was achieved by 37% to 56% of patients across rocatinlimab groups versus 19% of placebo (Fig. 2D). Patients also reported less sleep disturbance with rocatinlimab treatment. Overall, improvements in disease severity and QoL as measured by SCORAD and DLQI were observed in patients receiving rocatinlimab [55, 73, 74].

A post hoc analysis of the phase 2b study evaluated the time to onset of efficacy during rocatinlimab treatment. Nominal significance in EASI score improvements versus placebo were observed by week 2 in the rocatinlimab 300 mg and 600 mg Q2W cohorts (−13.3% and −13.7%, respectively; P ≤ 0.028) and in all dose groups by week 6 (−20.5% to −32.1%, P ≤ 0.001). Relative to placebo, EASI scores were improved in the prominent body regions, including the head and neck and upper extremities, after 1 rocatinlimab dose [72]. Nominal significance in pruritus improvement was observed with rocatinlimab versus placebo by week 2 in all dose groups (−18.4% to −22.0%, P ≤ 0.018) except for the 600 mg Q4W group (−9.7%, P = 0.208), and across all dose groups by week 4 (−15.7% to 27.2%, P ≤ 0.045) [75].

In addition to onset of efficacy, the durability of treatment response is an important aspect of therapy. During the active-treatment extension phase of the phase 2b study, improvements in disease severity, pruritus, and QoL observed at week 16 continued up to week 36 in all rocatinlimab dose groups, and improvement was observed among patients who switched from placebo to rocatinlimab 600 mg Q2W (Fig. 2, Fig. 3) [55]. Durable improvements in EASI score were observed for all anatomic regions, and these sustained responses were numerically highest in the head and neck [72]. Notably, response was largely maintained for 20 weeks during the off-treatment follow-up period in a subset of patients (Fig. 3), suggesting sustained efficacy in responders when rocatinlimab levels are likely very low or out of the system, since most IgG₁ antibodies typically have a half-life of ~21 days [76, 77]. The continued improvement in clinician- and patient-reported outcomes beyond week 16 differs from other approved targeted systemic treatments for AD, which typically peaks around week 16 [35, 78–80]. This durability of response following discontinuation of rocatinlimab may reflect its unique mechanism of targeting pathogenic T cells directly, rebalancing T-cell number and activity, and reducing memory T cells. The relative contribution of topical therapy is not known during the off-treatment remission time and needs further study.

Fig. 3.

Durability of EASI-75 response after treatment discontinuation [55]. ^aPatients in the placebo group received rocatinlimab 600 mg every 2 weeks after week 18 throughout the treatment expansion period until week 36. Probability of not having relapse (defined as loss of EASI-75 response) during the off-drug follow-up period is shown for patients who achieved EASI-75 response at week 36 (last dose of rocatinlimab, week 34). Patients who received rescue treatment before the week 36 assessment discontinued study drug and underwent end-of-study assessment. A total of 37 patients who received rescue treatment during the follow-up period while maintaining EASI-75 response (32 received topical corticosteroids; 5 received systemic therapy) were not considered as having relapsed. However, they were censored at the visit date of that EASI evaluation because efficacy assessments were omitted after initiation of rescue therapy. For patients who completed the study or discontinued the study during the follow-up period, data were censored at the visit date of their last EASI evaluation. Reprinted from Guttman-Yassky et al. [55], copyright (2023), with permission from Elsevier. EASI Eczema Area and Severity Index, EASI-75 75% reduction from baseline in EASI score, Q2W every 2 weeks, Q4W every 4 weeks

Biomarkers that correlate with clinical severity in patients with moderate-to-severe AD include thymus and activation-regulated chemokine (TARC)/CC chemokine ligand (CCL)-17, IL-22, lactate dehydrogenase (LDH), and eosinophil counts [81]. Treatment with rocatinlimab resulted in sustained reductions in AD-related serum and skin biomarkers. Mean serum concentrations of TARC/CCL-17 (Th2 signature), IgE, and IL-22 (Th17/Th2 signature) decreased during the 18-week double-blind treatment with rocatinlimab relative to placebo and remained suppressed throughout the 18-week active-treatment extension and for 20 weeks off-drug during the follow-up period (to week 56) [53, 55, 82]. Reductions in serum total IgE concentrations were generally consistent with improvements in EASI scores [82]. Concentrations of LDH and mean eosinophil counts, which were elevated at baseline, declined gradually during rocatinlimab treatment and remained reduced through week 56 [55]. A reduction of OX40+ helper T cells in the blood and OX40+ skin cells was evident early during on-treatment period and persisted during the off-treatment period [53]. These biomarker findings were consistent with those observed during the phase 1 study [52].

Rocatinlimab was well tolerated in the phase 2b study [55]. During the double-blind treatment phase, the occurrence of any AE was reported by 81% of patients across rocatinlimab groups versus 72% of those receiving placebo. The most common AEs with rocatinlimab included pyrexia (17% with rocatinlimab versus 4% with placebo), nasopharyngitis (14% versus 16%), chills (11% versus 0%), headache (9% versus 2%), aphthous ulcer (7% versus 0%), and nausea (6% versus 2%). Injection-related reactions occurred at a lower rate in the phase 2b study than the phase 1 study, particularly pyrexia (17% in the phase 2b study versus 50% in the phase 1 study) and chills (11% versus 36%). In the phase 2b study, it was found that injection-related reactions occurred primarily after the first subcutaneous administration of rocatinlimab. Injection-related reactions were of mild-to-moderate severity, resolved within 72 h, and did not lead to treatment discontinuation. Rates of study discontinuation including due to AEs during the placebo-controlled period were lower in all rocatinlimab groups than the placebo group (15–24% versus 40%). There were no serious hypersensitivity reactions or deaths, as well as no clinically meaningful changes in vital signs, laboratory values, or ECGs. Safety findings were consistent across the 56-week study period. No signs of immunosuppression or immune dysregulation were observed.

Future Studies

The comprehensive phase 3 ROCKET program consists of eight multicenter clinical trials (ROCKET-Ignite [NCT05398445], ROCKET-Horizon [NCT05651711], ROCKET-Shuttle [NCT05724199], ROCKET-Astro [NCT05704738], ROCKET-Orbit [NCT05633355], ROCKET-Voyager [NCT05899816], ROCKET-Ascend [NCT05882877], and ROCKET-Outpost [NCT06224192]) that will evaluate the efficacy, safety, and durability of rocatinlimab monotherapy and in combination with topical therapy in adults and adolescents with moderate-to-severe AD, including patients with or without prior exposure to biologics or systemic JAK inhibitors [83]. Given rocatinlimab’s potential for a durable response, multiple dosing regimens and schedules will be evaluated to identify the most effective option(s). The long-term safety, tolerability, durability, and efficacy of rocatinlimab will be evaluated by ROCKET-Ascend, a long-term extension trial that includes multiple treatment groups on the basis of the parent trials (ROCKET-Ignite, ROCKET-Horizon, ROCKET-Shuttle, ROCKET-Astro, ROCKET-Orbit, or ROCKET-Voyager). Evaluation of the extended dosing schedule has the potential to raise the bar of efficacy in treatment of moderate-to-severe AD.

Conclusions

Many patients with moderate-to-severe AD fail to achieve and maintain treatment success despite the current availability of conventional and advanced systemic therapies [40, 41]. Recent Aiming High in Eczema/Atopic Dermatitis (AHEAD) recommendations set new, higher treatment targets for AD, emphasizing a patient-centered approach [84]. The direct targeting of OX40 receptor with rocatinlimab offers a novel approach to achieve durable disease control in moderate-to-severe AD by rebalancing the number and activity of pathogenic T cells that drive inflammatory pathways and contribute to the severity and chronicity of disease. This approach targets multiple facets of AD pathophysiology in contrast with available therapies, which target a single cytokine pathway. In a phase 2b trial in patients with moderate-to-severe AD, rocatinlimab demonstrated efficacy across a range of clinical outcomes and patient-reported outcomes, including those commonly identified as important to patients [55]. According to the recent AHEAD recommendations, patients and caregivers should aim for long-term control of disease [84]. Benefits of rocatinlimab treatment were sustained in responders during a 20-week off-treatment period, suggesting a potential disease-modifying effect. Rocatinlimab also demonstrated a favorable safety profile, with injection-related reactions being the most common AEs occurring more frequently than with placebo, and no signs of immunosuppression or immune dysfunction. The ongoing phase 3 ROCKET program will further assess rocatinlimab in adults and adolescents with moderate-to-severe AD.

Author Contributions

Emma Guttman-Yassky, Eric Simpson, Ehsanollah Esfandiari, Hirotaka Mano, Jillian Bauer, Prista Charuworn, and Kenji Kabashima have made substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work; drafted the work or reviewed it critically for important intellectual content; approved the final version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

This study was sponsored by Amgen Inc. and Kyowa Kirin Co., Ltd. The journal’s Rapid Service Fee was funded by Amgen Inc.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Emma Guttman-Yassky: is an employee of Mount Sinai. She has received research grants (paid to the institution) from Amgen, Anaptysbio, Aslan, Bristol Myers Squibb, Boehringer Ingelheim, Cara Therapeutics, Concert, GlaxoSmithKline, Incyte, Kyowa Kirin, Janssen, LEO Pharma, Pfizer, RAPT, Regeneron, Sanofi, and UCB; and is a consultant for AbbVie, Almirall, Amgen, AnaptysBio, Apogee Therapeutics, Apollo Therapeutics Limited, Artax Biopharma, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Cara Therapeutics, Centrexion Therapeutics, Connect Biopharm, Eli Lilly, Enveda Biosciences, Escient Pharmaceuticals, Fairmount Funds Management, FL2022-001, Galderma, Gate Bio, Google Ventures, GlaxoSmithKline, Horizon Therapeutics, Incyte, Inmagene, Janssen Biotech, Japan Tobacco, Jasper Therapeutics, Kyowa Kirin, LEO Pharma, Merck, Nektar Therapeutics, Novartis Pharmaceuticals, Numab Therapeutics, OrbiMed Advisors, OTSUKA Pfizer, Pharmaxis, Pioneering Medicine VII, Proteologix US, RAPT, Regeneron, Ribon Therapeutics, Sanofi, SATO, Schrödinger, Sun Pharma Advanced Research Company, Teva Branded Pharmaceutical Products R&D, and UCB. Eric Simpson: reports personal fees from AbbVie, Amgen, Arcutis, Areteia Therapeutics, Bristol Myers Squibb, CorEvitas, Corvus, Dermira, Eli Lilly, Evelo Biosciences, FIDE, Forte Bio RX, Galderma, Gilead Sciences, GlaxoSmithKline, Impetus Healthcare, Incyte, Innovaderm Research, Janssen, Johnson & Johnson, Kyowa Kirin, LEO Pharma, Merck, MJH holding (4/29/2021), Numab Therapeutics AG, Pfizer, Physicians World, PRImE, Recludix Pharma, Regeneron, Roivant, Sanofi-Genzyme, Sitryx Therapeutics, Trevi Therapeutics, Valeant; grants (or serves as Principal investigator role) for AbbVie, Acrotech, Amgen, Arcutis, ASLAN, Castle, CorEvitas, Dermavant, Dermira, Incyte, Lilly, Kymab, Kyowa Kirin, National Jewish Health, LEO Pharma, Pfizer, Regeneron, Sanofi, Target, and VeriSkin. Ehsanollah Esfandiari, Hirotaka Mano: employees of Kyowa Kirin International. Jillian Bauer, Prista Charuworn: current or former employees and stockholders in Amgen Inc. Kenji Kabashima: has received consulting fees, honoraria, grant support, and/or lecturing fees from Amgen, Kyowa Kirin, Japan Tobacco, LEO Pharma, Maruho, Mitsubishi Tanabe, Ono Pharmaceutical, Procter & Gamble, Sanofi, Taiho, and Torii Pharmaceutical.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.