OX40 Ligand Inhibitors for Moderate-to-Severe Atopic Dermatitis: A Review of Phase II Clinical Trial Data

Siddhartha Sood, MD¹; Alim R. Devani, MD, FRCPC^2-4; Tiago Torres, MD, PhD^5,6; Jensen Yeung, MD, FRCPC^1,2,7,8*; Vimal H. Prajapati, MD, FRCPC^2-4,9-11*

¹Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
²Probity Medical Research, Waterloo, ON, Canada
³Dermatology Research Institute, Calgary, AB, Canada
⁴Skin Health & Wellness Centre, Calgary, AB, Canada
⁵Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
⁶Department of Dermatology, Centro Hospitalar Universitário do Porto, Porto, Portugal
⁷Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁸Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁹Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
¹⁰Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹¹Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

*Jensen Yeung and Vimal H. Prajapati are co-senior authors

Abstract

Atopic dermatitis (AD) is a common, chronic immune-mediated inflammatory skin disease. The OX40-OX40 ligand (OX40L) pathway has emerged as a novel therapeutic target. On this basis, three phase II clinical trials have been conducted to evaluate the efficacy and safety of three different OX40-OX40L inhibitors (amlitelimab, rocatinlimab, and telazorlimab) in moderate-to-severe AD. Herein, we review the published data from these studies.

Keywords: OX40, OX40 ligand, amlitelimab, rocatinlimab, telazorlimab, immunomodulator, therapeutics, biologic, atopic dermatitis, eczema, clinical trial

Introduction

Atopic dermatitis (AD) is a common, chronic, immune-mediated inflammatory skin condition affecting between 5-10% of adults, with moderate-to-severe disease accounting for approximately 20-30% of cases.^1,2 AD is often associated with a significant negative impact on sleep, mental health, school/work productivity, and quality of life; furthermore, uncontrolled AD has a substantial financial burden on the healthcare system, accounting for $5 billion US dollars and $1.4 billion Canadian dollars in annual United States and Canadian healthcare expenditures, respectively.^3-5

While topical therapies are first-line treatment for moderate-to-severe AD management, these often fail and systemic therapies are required. This includes conventional systemic therapies (azathioprine; corticosteroids; cyclosporine; methotrexate; mycophenolate mofetil) and advanced systemic therapies, including biologics (dupilumab; lebrikizumab; tralokinumab) and Janus kinase (JAK) inhibitors (abrocitinib; baricitinib; upadacitinib).^6,7 More recently, investigational studies have explored the use of agents that selectively target OX40 (also known as CD134) and OX40 ligand (OX40L), both of which have been found to be highly expressed in skin affected by AD.^8-12 Herein, we review the phase II clinical trials of amlitelimab, rocatinlimab, and telazorlimab.

Background

While our understanding of the mechanisms behind AD continues to evolve, studies have demonstrated that the disease is predominated by a dysregulated immune system (especially type 2 inflammation) and impaired skin barrier function.⁸ Subsequent to skin barrier damage and following antigen presentation within the epidermis, it has been shown that OX40L is expressed on antigen presenting cells (such as Langerhans cells) and OX40 is expressed on activated T-cells.^8,9 Dysregulation of the OX40-OX40L pathway has been shown to not only promote the production of T helper type 2 (Th2) inflammatory cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-4, IL-13, IL-25, and IL-33, but also inflammatory cytokines involved in the Th1 (interferon-γ), Th22 (IL-22), and Th17 (IL-17A) immune pathways, which may have a role in AD-related chronic inflammation and epidermal hyperplasia.^8,9 Therefore, in contrast to currently approved systemic biologic therapies for AD that target IL-4Rα or IL-13, inhibition of the OX40-OX40L pathway simultaneously targets all of the aforementioned pathways that may be involved in AD.^8,9 To date, the three inhibitors of the OX40-OX40L pathway currently investigated in clinical trials include amlitelimab, rocatinlimab, and telazorlimab.^10-12

Amlitelimab (identifiers: KY1005; SAR445229) is a monoclonal antibody, investigated initially as an intravenous (IV) infusion and now subcutaneous (SC) injection, that selectively targets OX40L expressed on antigen-presenting cells (APCs) to prevent binding of OX40-expressing T-cells to APCs.¹⁰

Rocatinlimab (identifiers: KHK4083; AMG 451) is a monoclonal antibody, available as an SC injection, that targets OX40 by selectively binding to OX40-expressing T-cells.¹¹

Similar to rocatinlimab, telazorlimab (identifiers: GBR 830; ISB 830), available as an SC injection, targets OX40L by selectively binding to OX40-expressing T-cells.^11-13

Table 1 provides an overview of additional information regarding amlitelimab, rocatinlimab, and telazorlimab.^14,15

Table 1:

Supporting Evidence from Clinical Trials

Results from Phase II Monotherapy Studies

Amlitelimab

In a phase IIa multicentre double-blind randomized controlled trial (NCT03754309) of adult patients with moderate-to-severe AD (n=89),¹⁰ the efficacy and safety of low-dose (200 mg IV loading dose followed by 100 mg IV every 4 weeks [Q4W]; n=29) and high-dose (500 mg IV loading dose followed by 250 mg IV Q4W; n=30) amlitelimab versus placebo (n=29) were evaluated. The primary efficacy endpoint of a least squares mean percentage change in Eczema Area and Severity Index (EASI) was reported at week 16, with that being -69.97% and -80.12% for the low-dose and high-dose amlitelimab groups, respectively, versus -49.4% in the placebo group (Table 2, Figure 1). In addition, 75% and 90% improvements in EASI (EASI75 and EASI90, respectively) responses at week 16 were achieved by 59% (16/27) and 52% (14/27), respectively, and 33% (9/27) and 30% (8/27), respectively, of patients in the low-dose and high-dose amlitelimab groups versus 25% (6/24) and 13% (3/24), respectively, of patients in the placebo group (Figure 2A and Figure 2B). Furthermore, at week 16, 44% (12/27) and 37% (10/27) of patients achieved a validated Investigator Global Assessment score of clear or almost clear (vIGA 0/1) with ≥2-point improvement from baseline in the low-dose and high-dose amlitelimab groups, respectively, versus 8% (2/24) in the placebo group (Figure 3), while pruritus Numerical Rating Scale (NRS) ≥4 improvement was achieved by 47% (13/27) and 38% (10/27) of patients in the low-dose and high-dose amlitelimab groups, respectively, versus 19% (5/24) of patients in the placebo group (Figure 4). The mean change in Dermatology Life Quality Index (DLQI) from baseline at week 16 was -8 (low-dose amlitelimab) and -10.4 (high-dose amlitelimab) versus -7.1 (placebo) at week 16 (Figure 5). SCORing Atopic Dermatitis (SCORAD) scores were not reported in this study. Safety evaluation revealed similar adverse event (AE) profiles between amlitelimab and placebo groups, with the majority of treatment-emergent AEs (TEAEs) being mild and self-limiting in nature. The most common TEAEs were nasopharyngitis (6.9% [2/27] to 10% [3/27]), headache (10% [3/27]), eye disorders (10% [3/27]; of these: allergic conjunctivitis [n=1] and infective conjunctivitis [n=1]), upper respiratory tract infection (10% [3/27]), iron deficiency anemia (6.9% [2/27]), elevated liver enzymes (3.4% [1/27] to 6.7% [2/27]), and folliculitis (3.4% [1/27] to 6.7% [2/27]). There were four serious TEAEs reflecting an infected dermal cyst in a patient with a history of prior recurrent dermal cysts (n=1), worsening AD (n=2), insomnia (n=1), and neck pain (n=1). There were four treatment discontinuations, two due to worsening of AD (treatment group not specified), one due to lack of efficacy in the placebo group, and one due to nasopharyngitis in the amlitelimab group.

Table 2 (Click to enlarge):

Figure 1:

Figure 2:

Figure 3:

Figure 4:

Figure 5:

Figure 6:

Rocatinlimab

A phase IIb multicentre randomized controlled trial (NCT03703102) was conducted to evaluate the efficacy and safety of several dosing regimens of rocatinlimab for moderate-to-severe AD in adults (n=274).¹¹ This study included four different treatment arms for rocatinlimab, including 150 mg SC Q4W (n=52), 600 mg SC Q4W (n=52), 300 mg SC every 2 weeks (Q2W) (n=52), and 600 mg SC Q2W (n=54), as well as a placebo arm (n=57). The primary efficacy endpoint of least squares mean percent change in EASI from baseline was reported at week 16, with this being -48.3%, -49.7%, -46.1%, and -42.3% in the 150 mg Q4W, 600 mg Q4W, 300 mg Q2W, and 600 mg Q2W rocatinlimab groups, respectively, versus -15% in the placebo group (Table 2, Figure 1). EASI75 response at week 16 was achieved by 44% (23/52; 150 mg Q4W), 40% (21/52; 600 mg Q4W), 54% (28/52; 300 mg Q2W), and 39% (21/54; 600 mg Q2W) of rocatinlimab-treated patients versus 11% (6/57) of placebo-treated patients, with EASI90 response at week 16 being observed in 19% (10/52; 150 mg Q4W), 12% (6/52; 600 mg Q4W), 37% (19/52; 300 mg Q2W), and 19% (10/54; 600 mg Q2W) of rocatinlimab-treated patients versus 4% (2/57) of placebo-treated patients (Figure 2A and Figure 2B). In addition, achievement of vIGA 0/1 with ≥2-point improvement from baseline was noted for 19% (10/52; 150 mg Q4W), 15% (8/52; 600 mg Q4W), 31% (16/52; 300 mg Q2W), and 19% (19/52; 600 mg Q2W) of rocatinlimab-treated patients versus 2% (1/57) of placebo-treated patients at week 16 (Figure 3), while pruritus NRS ≥4 improvement was achieved by 37% (19/52; 150 mg Q4W), 46% (24/52; 600 mg Q4W), 56% (29/52; 300 mg Q2W), and 44% (24/54; 600 mg Q2W) of rocatinlimab-treated patients versus 19% (11/57) of placebo-treated patients at week 16 (Figure 4). The mean change in DLQI from baseline at week 16 was -2.6 (150 mg Q4W), -4.7 (600 mg Q4W), -6.5 (300 mg Q2W), and -5.1 (600 mg Q2W) for rocatinlimab-treated patients and -2.6 for placebo-treated patients (Figure 5), while the mean percent change in SCORAD from baseline at week 16 was -34.9% (150 mg Q4W), -35.1% (600 mg Q4W), -46.7% (300 mg Q2W), and -40.8% (600 mg Q2W) for rocatinlimab-treated patients versus -11.9% for placebo-treated patients (Figure 6). The majority of TEAEs were mild and self-limiting in nature. The most common TEAEs in the rocatinlimab group (n=216) were pyrexia (17%, 36/216), nasopharyngitis (14%, 30/216), chills (11%, 24/216), headache (9%, 19/216), aphthous ulcers (7%, 15/216), and nausea (6%, 13/216). Between the placebo and rocatinlimab groups, pyrexia, chills, headache, aphthous ulcers, and nausea were more commonly seen with the rocatinlimab versus placebo. There was one serious TEAE in the rocatinlimab group reflecting an anal abscess. While the specific details of the AEs leading to discontinuation were not reported, there were 9% (19/216) of patients that discontinued rocatinlimab due to TEAEs.

Telazorlimab

Three dosing regimens of telazorlimab (150 mg SC loading dose followed by 75 mg SC Q4W [low-dose; n=77]; 600 mg SC loading dose followed by 300 mg SC Q4W [mid-dose; n=80]; 600 mg SC loading dose followed by 300 mg SC Q2W [high-dose; n=76]) were assessed in part 1 of a phase IIb multicentre randomized controlled trial (NCT03568162) of adult patients with moderate-to-severe AD (n=313)¹², with an additional fourth dosing regimen of telazorlimab (1200 mg SC loading dose followed by 600 mg SC Q2W [very high-dose; n=75]) in part 2 only (n=143). In this study, the primary efficacy endpoint of a least squares mean percent change from baseline in EASI was reported at week 16, with this being -31%, -48.6%, -54.4%, and -59% for the low-dose, mid-dose, high-dose, and very-high-dose telazorlimab groups, respectively, versus -34.2% to -41.8% for the placebo group (Table 2, Figure 1). Notably, while numerically higher, the mean percent changes in EASI with the four telazorlimab dosing regimens were not found to be significantly higher than placebo. At week 16, EASI75 response was achieved by 11.7% (9/77; low-dose), 20.5% (16/78; mid-dose), 23.7% (16/76; high-dose), and 25.3% (19/75; very high-dose) of telazorlimab-treated patients versus 11.3% (9/80) to 18.9% (14/74) of placebo-treated patients (Figure 2A and Figure 2B). EASI90 responses at week 16 were not reported in this study. In addition, week 16 vIGA 0/1 response was noted for 6.5% (5/77; low-dose), 10.3% (8/78; mid-dose), 13.2% (10/76; high-dose), and 12% (9/75; very-high-dose) of telazorlimab-treated patients versus 5% (4/80) to 5.4% (4/74) of placebo-treated patients (Figure 3). Pruritus NRS ≥4-point improvement was achieved by 5.2% (4/77; low-dose), 11.5% (9/78; mid-dose), 7.9% (6/76; high-dose), and 13.3% (10/75; very-high-dose) of telazorlimab-treated patients versus 9.5% (7/74) to 10% (8/80) of placebo-treated patients (Figure 4). The mean change in DLQI from baseline at week 16 was -3.4 (low-dose), -5.5 (mid-dose), -6 (high-dose), and -6.7 (very-high-dose) (Figure 5) for telazorlimab-treated patients versus -3.7 for placebo-treated patients, while the mean percent change in SCORAD from baseline at week 16 was -14.3% (low-dose), -21.2% (mid-dose), -24.3% (high-dose), and -26.8% (very-high-dose) for telazorlimab-treated patients versus -13.8% to -17.2% for placebo-treated patients (Figure 6). An open-label extension study of telazorlimab 300 mg Q2W (n=135) and telazorlimab 600 mg Q2W (n=53) was conducted from 16 weeks up to 54 weeks with continued therapy. During this period, a continued improvement in EASI was observed. Safety evaluation revealed that common TEAEs with telazorlimab were worsening AD (17.3% [13/75] to 22.1% [17/77]), nasopharyngitis (3.9% [3/76] to 11.5% [9/78]), upper respiratory tract infection (5.1% [4/78] to 9.1% [7/77]), headache (2.6% [2/77] to 10% [8/80]), urinary tract infection (2.6% [2/77] to 5.2% [4/77]), pruritus (1.3% [1/78] to 5.2% [4/77]), and fatigue (1.3% [1/77] to 5.1% [4/78]). Serious TEAEs with telazorlimab occurred in nine patients, including worsening AD (n=4), atrial fibrillation (n=1), cataract lens release (n=1), severe hypertension (n=1), and viral infection (n=1). Discontinuation due to TEAEs occurred in three patients receiving telazorlimab, including paresthesia (n=1), pernicious anemia (n=1), and thrombocytosis (n=1). No new TEAEs emerged during the open-label extension period.

In a separate phase IIa study of telazorlimab (n=46), a 10 mg/kg IV dose was evaluated at day 0 and day 29. In this study, patients receiving telazorlimab were noted to have a statistically significant reduction in EASI of -56% as compared to -38% with placebo. Furthermore, 42.3% (11/26) achieved EASI75 with telazorlimab as compared to 25% (2/8) with placebo. There were 23.1% (6/26) of patients who achieved IGA 0/1 with telazorlimab versus 12.5% (1/8) with placebo. The mean reduction from baseline in SCORAD was found to be -45.4% with telazorlimab versus -31% with placebo.¹² Telazorlimab was well-tolerated with common TEAEs including headache (13%, 6/46), worsening AD (13%, 6/46), nasopharyngitis (8.7%, 4/46), postprocedural infection (8.7%, 4/46), and myalgia (6.5%, 3/46). There were two discontinuations due to tooth abscess. Interestingly, this study identified that administration of telazorlimab downregulated several Th2 (IL-31; CCL11; CCL17; TSLPR) and Th17/Th22 (IL-23; IL-8) inflammatory cytokines in lesional samples taken at day 71.¹³

Future Research

Currently, there are several phase III clinical trials underway to evaluate amlitelimab and rocatinlimab for moderate-to-severe AD in adults and adolescents. For amlitelimab, these include: ESTUARY (NCT06407934)¹⁶, RIVER-AD (NCT05492578)¹⁷, COAST-1 (NCT06130566)¹⁸, COAST-2 (NCT06181435)¹⁹, SHORE (NCT06224348)²⁰, AQUA (NCT06241118)²¹, and HYDRO (NCT06015308)²². For rocatinlimab, these include: ROCKET-IGNITE (NCT05398445)²³, ROCKET-HORIZON (NCT05651711)²⁴, ROCKET-ASCEND (NCT05882877)²⁵, ROCKET-SHUTTLE (NCT05724199)²⁶, ROCKET-ORBIT (NCT05633355)²⁷, ROCKET-ASTRO (NCT05704738)²⁸, ROCKET-Outpost (NCT06224192)²⁹, and ROCKET-VOYAGER (NCT05899816)³⁰. There are no future studies listed on ClinicalTrials.gov at this time to further evaluate telazorlimab. Additional clinical trials are currently being conducted to investigate the use of amlitelimab and rocatinlimab for other dermatologic conditions such as alopecia areata (amlitelimab), hidradenitis suppurativa (amlitelimab), and prurigo nodularis (rocatinlimab).^31-33 Based on preclinical evidence, it should be noted that the OX40 pathway may be involved in the replication of human herpesvirus-8 (HHV-8) associated Kaposi sarcoma; however, future safety data is needed to further elucidate this association.^34,35

Conclusions

OX40-OX40L inhibitors, including amlitelimab, rocatinlimab, and telazorlimab, have demonstrated promising short-term efficacy and safety follow-up to week 16 in phase II clinical trials. Currently, there are several phase III clinical trials being conducted for amlitelimab and rocatinlimab for moderate-to-severe AD in adolescents and adults. The results of these pivotal studies will be imperative to determine the place in therapy of these agents in our ever expanding therapeutic armamentarium for AD.

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