Atopic dermatitis: Rocatinlimab – novel patient-tailored monoclonal antibody therapy

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Atopic dermatitis (AD) is a chronically relapsing, inflammatory skin disease with a great impact on the patient’s quality of life, especially due to pruritus. With a prevalence of 2–5% in young adults and up to 20% in children, AD is one of the most common skin diseases [1,2].
The currently available treatment armamentarium includes topical therapy (topical corticosteroids, calcineurin inhibitors crisaborole and ruxolitinib), phototherapy, and systemic therapy (conventional immunosuppressants and advanced target therapies). Conventional systemic immunosuppressive therapies may have limited efficacy and harbor long-term toxicity, which makes them not appropriate for continuous use [3,4].

Fortunately, in recent years, several new therapeutic options targeting specific cytokines, cytokine receptors, or intracellular signaling pathways have been developed, showing significant clinical benefits in patients with AD and paving the way for more effective and safer therapies [3,4,5,6].

Dupilumab, a fully human IgG4 monoclonal antibody directed against the IL-4Rα subunit of IL-4 and IL-13 receptors, changed the AD treatment paradigm as it was in 2017 as the first biological drug approved for the treatment of AD [5,6].

Since then, other therapeutic options targeting the IL-13 and janus kinase (JAK) pathway have been approved, such as tralokinumab (IL-13 inhibitor), upadacitinib (JAK1 inhibitor), abrocitinib (JAK1 inhibitor), and baricitinib (JAK1/2 inhibitor) [3,4,7,8], while others, such as lebrikizumab (IL-13 inhibitor) and nemolizumab (IL-31 inhibitor), are in an advanced stage of clinical development.

Nonetheless, some patients are still a therapeutic challenge, whether because they do not respond/lose clinical response or are unable to receive treatment due to tolerability and safety issues. These unmet needs require that new mechanisms of action and new targeted drugs continue to be developed.

This review aims to discuss the OX40-OX40L pathway as a potential therapeutic target for the treatment of AD, focusing on two OX40-OX40L inhibitors: rocatinlimab and amlitelimab.

reference link :https://www.mdpi.com/1999-4923/14/12/2753

Patients with moderate to severe atopic dermatitis who participated in a clinical trial of rocatinlimab – a novel, patient-tailored monoclonal antibody therapy – showed promising results both while taking the drug and up to 20 weeks after the therapy was stopped, Mount Sinai researchers reported in The Lancet.

The researchers said the results indicate that rocatinlimab has the potential to change the genetic makeup of a person’s atopic dermatitis for the long term, and possibly help sustain lasting results without continued use.

Rocatinlimab inhibits OX40, which is an immune molecule involved in activating inflammatory cells that play a key role in the development of atopic dermatitis and other inflammatory diseases.

“Atopic dermatitis, the most common type of eczema, is a debilitating chronic inflammatory skin disease that affects 1 in 10 Americans and millions of people worldwide,” said Emma Guttman, MD, Ph.D., Waldman Professor and System Chair, The Kimberly and Eric J. Waldman Department of Dermatology; Director, Center of Excellence in Eczema; and Director, Laboratory of Inflammatory Skin Diseases, at the Icahn School of Medicine at Mount Sinai.

“It often develops at a very young age, causing the skin to become inflamed, red, extremely itchy, painful, and very dry – all symptoms that greatly affect a patient’s quality of life. We are very optimistic about the results of this trial and the potential for disease modification and long-lasting effects to improve patients’ quality of life.”

In this phase 2b multicenter, double-blind, placebo-controlled study, 274 patients were recruited and (rocatinlimab: n=217; placebo: n=57) randomly assigned 1:1:1:1:1 to rocatinlimab every four weeks (150 mg or 600 mg) or every two weeks (300 mg or 600 mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up. This trial was conducted at 65 sites within the United States, Canada, Japan, and Germany.

Percent change from baseline in the Eczema Area and Severity Index (EASI) score was assessed as the primary endpoint at week 16, and significance versus placebo was achieved with all active rocatinlimab doses (-48% to -61%) doses compared to placebo (-15%). All active dose cohorts also continued improving after week 16, and most patients maintained the response for at least 20 weeks off treatment.

The results support rocatinlimab as a safe and effective treatment for moderate to severe atopic dermatitis, with potentially long-lasting efficacy and disease modification. Adverse events reported were generally similar between rocatinlimab groups. Common adverse events during the double-blind period included fever, chills, headache, aphthous ulcers (canker sores), and nausea.

“At week 36, all participants had been on the treatment for at least 18 weeks,” added Dr. Guttman, senior author of the study. “By this time, we saw that while the drug achieved the primary endpoints in all doses versus the placebo, it’s also a drug that improves over time, which is really unusual and unique among currently available treatment options.”

Researchers plan to continue this investigation in a phase 3 program in 2023. Future studies will also include a larger study population, longer follow-up, and exploration of combination therapy (such as rocatinlimab plus topical corticosteroids).


OX40-OX40L Inhibition

Figure 1. The co-stimulatory T-cell receptor OX40 is expressed predominantly on effector and regulatory T-cells. Its ligand, OX40L, is expressed on activated antigen-presenting cells and endothelial cells. Their interaction plays a central role in pro-inflammatory T-cell responses, including in atopic dermatitis. Rocatinlimab is a fully human anti-OX40 monoclonal antibody, which selectively depletes sOX40+ activated T-cells. On the other hand, amlitelimab, is a non-depleting IgG4 human anti-OX40L monoclonal antibody that binds OX40L and blocks interaction with OX40. Besides blocking antigens, the presenting T-cell activation, amlitelimab also blocks T-cell independent APC pro-inflammatory activity via the inhibition of OX40L back signaling.

GBR 830

GBR 830 was the first-in-class, humanized, a monoclonal antibody against OX40 to enter a phase 2a trial investigating the efficacy, safety, and tissue effects in AD patients (NCT02683928) [24,25]. Sixty-two moderate-to-severe AD patients were randomized to 3:1 to 10 mg/kg GBR830 or placebo on day 1 and day 29. On day 71, the proportion of patients achieving a 50% or greater improvement in the Eczema Area and Severity Index (EASI) score was greater with GBR 830 (76.9% [20/26]) versus the placebo (37.5% [3/8]). Biopsy specimens from lesioned skin were obtained before the first dose (baseline) at days 29 and day 71.

Significant decreases from the baseline in OX401 T-cell and OX40L1 DC staining in the lesioned skin were found with GBR 830 treatment at days 29 (p < 0.05) and 71 (p < 0.001). A significant reduction in mRNA cytokines such as IL-31, CCL11, CCL17, and S100 was also demonstrated. GBR 830 was well tolerated, with an equal treatment-emergent adverse events (TEAE) distribution (GBR 830, 63.0% [29/46] and placebo, 63.0% [10/16]). One serious event was reported in the GBR 830 group, but it was deemed unrelated to the study of the drug. The most reported TEAE was a headache, with no clinically meaningful differences between the groups. Myalgias were only reported in the GBR 830 group (6.5% [3/46]) [24,25].

No further studies have been developed with this drug.

3Rocatinlimab

Rocatinlimab, formerly known as AMG 451/KHK4083, is a fully human, non-fucosylated, immunoglobulin G1 (IgG1) anti-OX40 monoclonal antibody currently under investigation for the treatment of moderate-to-severe AD. It has been shown to selectively deplete OX40+ activated T-cells and suppress clonal T-cells and is expected to control Th2-driven conditions [26].

A phase 1, single-center, open-label trial evaluated 22 patients with moderate-to-severe AD through a 6-week treatment period with repeated intravenous infusions of 10 mg/kg KHK4083 every 2 weeks (a total of three infusions) and a 16-week follow-up period (NCT03096223) [27]. KHK4083-related infusion reactions of mild or moderate severity were the most reported and included pyrexia (11 patients, 50.0%) and chills (8 patients, 36.4%). Aphthous ulcers (4 patients, 18.2%), blood uric acid increase (3 patients, 13.6%), nasopharyngitis (3 patients, 13.6%), erythema (2 patients, 9.1%), and hordeolum (2 patients, 9.1%) were also described. From a baseline EASI (mean ± SD) of 33.98 ± 9.68, the percent change from the baseline at day 43 was −24.25 ± 27.55% and −74.12 ± 20.53% at day 155 [27].

A phase 2b multicenter, randomized, double-blind, parallel-group, placebo-controlled clinical trial (NCT03703102) was posteriorly developed to further evaluate the efficacy and safety of rocatinlimab in subjects with moderate-to-severe atopic dermatitis with an inadequate response to topical treatments [28]. The 274 subjects were randomly assigned (1:1:1:1:1) rocatinlimab with 150 mg subcutaneous (SC) every 4 weeks (Q4W), 600 mg SC Q4W, 300 mg SC every 2 weeks (Q2W), 600 mg SC Q2W, or a placebo. Rocatinlimab groups received treatment for 36 weeks, followed by an off-drug follow-up period of 20 weeks.

The placebo group received a placebo for 18 weeks, followed by an additional 18-week rocatinlimab treatment period (600 mg SC Q2W) and a 20-week off-drug follow-up period. According to the non-peer-reviewed data, at week 16, all rocatinlimab groups achieved a significant reduction in the percentage change from the baseline in EASI score at week 16 (−48.3% to −61.1%) compared to the placebo (−15.0%; all p < 0.001). Higher proportions of patients in the rocatinlimab groups achieved EASI75 (44.2%, 40.4%, 53.8%, and 38.9%, respectively, versus the placebo: 10.5%). Among the rocatinlimab patients, 36.5% to 55.8% achieved a 4-point improvement or greater from the baseline in the pruritus NRS score (placebo: 19.3%).

On each endpoint, greater improvements were observed at week 16 for rocatinlimab: 300 mg Q2W in comparison to other doses [28]. Efficacy measures continued to improve after week 16 for all rocatinlimab groups, with the highest responses observed for the 300 mg Q2W group (EASI75 = 65.4% and 63.5% at weeks 24 and 36, respectively) [28]. Through week 18, TEAE was reported in 81% of patients in the rocatinlimab group against 72% in the placebo group. The most frequent ones were pyrexia and chills after the first administration of rocatinlimab, nasopharyngitis, and atopic dermatitis (Table 1) [28].

Table 1. Main characteristics and results of clinical trials concerning rocatinlimab and amlitelimab.

TrialPhaseStudy DesignPrimary EndpointsMain Results
Rocatinlimab
NCT03096223
1Single-center, open-label
22 subjects with moderate-to-severe AD
Rocatinlimab 10 mg/kg intravenous Q2W
6 weeks of treatment + 16 weeks of follow-up
Incidence of treatment-emergent adverse events up to week 22Treatment-emergent adverse events: rocatinlimab-related infusion reactions (mild or moderate severity): pyrexia (11 patients, 50%) and chills (8 patients, 36.4%)
EASI change from baseline, % (mean ± SD):-24.25 ± 27.55% at day 43-74.12 ± 20.53% at day 155
Rocatinlimab NCT037031022bMulti-center, double-blind, placebo-controlled
274 subjects with moderate-to-severe AD
Randomized 1:1:1:1:1 to:rocatinlimab 150 mg SC Q4Wrocatinlimab 600 mg SC Q4Wrocatinlimab 300 mg SC Q2Wrocatinlimab 600 mg SC Q2Wplacebo18 weeks of treatment + 20 weeks of follow-up
% EASI change from baseline at week 16% EASI change from baseline at week 16 (-48.3% to -61.1%) vs. placebo (-15.0%; all p < 0.001).
≥4-point improvement from baseline in pruritus NRS score (36.5% to 55.8%) vs. placebo (19.3%)
post hoc analysis reported EASI score improvements up to 20 weeks after treatment has ceased
At week 18, most treatment-emergent adverse events were pyrexia and chills after the first administration of rocatinlimab, nasopharyngitis, and atopic dermatitis
Amlitelimab
NCT03161288
1Single-center, open-label, randomized, parallel group
64 healthy subjects
Subjects were enrolled into 8 cohorts and, in each cohort, they were randomized to amlitelimab or placebo (6:2).
All treatment-related adverse events; changes in vital signs, laboratory safety data, anti-viral antibody levels and viral DNA, acute cytokines and in electrocardiograms.All treatment emergent adverse events were of mild or moderate severity, without sequalae (++ headache).
There were no clinically significant changes in any safety laboratory parameters or other safety concerns.
Amlitelimab
NCT03754309
2aMulti-center, parallel group, double-blind, randomized, placebo controlled
89 moderate-to-severe AD patients
Randomized 1:1:1 to:-amlitelimab 200 mg loading dose + 100 mg Q4W-amlitelimab 500 mg loading dose + 250 mg Q4W-placebo12 weeks of treatment + 24 weeks of follow-up
% EASI change from baseline to day 113
Incidence of treatment-emergent adverse events
Mean percentage change from baseline in EASI ate week 16: amlitelimab low-dose (−80.1%) and high-dose (−69.9%) vs. placebo (−49.4%; p = 0.009 and p = 0.072, respectively).
% EASI-75: 59.3% in amlitelimab low-dose group, 51.9% in amlitelimab high-dose group and 25.0% in placebo group.
Pruritus NRS ≥ 4-point improvement at week 16: 57.9% in amlitelimab low-dose, 62.5% in amlitelimab high-dose, and 38.1% in placebo group.
No hypersensitivity or tolerability events were reported.

AD—atopic dermatitis; EASI—Eczema Area and Severity Index; NRS—numerical rating scale; Q2W—every 2 weeks; Q4W—every 4 weeks; SC—subcutaneous administration.

A clinical biomarker sub-study aimed at analyzing transcriptomic and proteomic profiles in skin biopsy specimens and serum samples of the participating AD patients. Skin biopsy specimens were collected from 20/150 Japanese patients at the baseline, week 8, week 16, week 36, and week 52, and the genomic profile showed significant and robust changes from the baseline throughout treatment, approaching that of the non-lesional skin. Quantitative polymerase chain reaction analysis revealed a reduced OX40 mRNA expression and the downregulation of Th2, Th1/Th17, and Th22-related genes after rocatinlimab treatment. The effects of rocatinlimab on gene expression persisted after the discontinuation of treatment at week 36, through week 52. A reduction in Th2/Th22 and pruritus-related molecules were also observed in proteomic analysis using serum samples at week 16 [29].

A post hoc analysis evaluated rocatinlimab’s efficacy concerning head and neck disease. The head and neck EASI score was calculated with the adjustment of 0.1, equating to 10% of the weighting of the head and neck region in the total EASI score. Reported results were consistent with the main analysis as all rocatinlimab doses resulted in greater head and neck EASI score improvements versus the placebo until week 56, 20 weeks after treatment had ceased [30].

A phase 3, 52-week, multicenter, randomized, double-blind, placebo-controlled trial is currently in progress (active, not recruiting) to further evaluate two different doses in four different treatment schemes (NCT05398445-ROCKET-IGNITE) (Table 2).

Table 2. Ongoing clinical trials of OX40-OX40L inhibitors for atopic dermatitis.

Clinical TrialDrugPhaseStatus
NCT05398445-ROCKET-IGNITERocatinlimabPhase 3Active, not recruiting
NCT05131477-STREAM-ADAmlitelimabPhase 2bRecruiting
NCT05492578–Long-term extensionAmlitelimabPhase 2Recruiting

Amlitelimab
Amlitelimab, also known as KY1005/SAR445229, is another OX40-OX40L pathway inhibitor but with a different mechanism of action. It is a non-depleting IgG4 human anti-OX40L monoclonal antibody that binds OX40L and blocks interactions with OX40. By targeting OX40L, amlitelimab aims to restore immune homeostasis between pro-inflammatory and anti-inflammatory T-cells.

In addition to blocking antigen-presenting T-cell activation, amlitelimab also blocks T-cell independent antigens that present the cells’ pro-inflammatory activity via the inhibition of OX40L back signaling, thus blocking both type 2 and Th1/17/22 inflammation [31,32].
A phase 1 trial (NCT03161288) was first conducted with 64 healthy subjects to evaluate its safety, tolerability, and immunogenicity profile.

Subjects were enrolled into eight cohorts, and in each of them, they were randomized to the intravenous administration of KY1005 (different doses) or a placebo. Two subjects per cohort started as a sentinel group, and if no safety issues arose within 48 h after dosing, the remaining six subjects received treatment. At 4 and 8 weeks after the initial administration, the subjects received two maintenance doses (50% of the loading dose).

One subject in the 12 mg/kg cohort did not receive the second and third KY1005 doses due to a possible mild and self-limited hypersensitivity reaction. All treatment-emergent adverse events were of mild (n = 190) or moderate severity (n = 16) and were self-resolving without sequalae, a headache being the most reported one. There were no clinically significant changes in any safety laboratory parameters [31].

A phase 2a (NCT03754309) double-blind, randomized, controlled trial was conducted for 16 weeks with 89 moderate-to-severe AD patients who were intolerant or had an inadequate response to topical treatments. They were randomized 1:1:1 to an intravenous amlitelimab low dose (LD, 200 mg loading/100 mg maintenance Q4W, n = 29), high dose (HD, 500 mg loading/250 mg maintenance Q4W, n = 30), or a placebo (n = 29) until week 12. At the end of week 16, there were 59 evaluable patients, and at the end of week 36, there were 50. The main reason for the study discontinuation was a withdrawal of consent (15/29) [32,33].

According to non-peer-reviewed data, at week 16, the mean percentage change from the baseline in EASI was significantly greater in patients receiving amlitelimab LD (−80.1%) and HD (−69.9%) vs. the placebo (−49.4%; p = 0.009 and p = 0.072, respectively). EASI−75 was reached by 59.3% of patients in the amlitelimab LD group, 51.9% in the amlitelimab HD group, and 25.0% in the placebo group. The onset of response was as early as week 2 for both amlitelimab groups.

Additionally, 44% of patients treated with amlitelimab-LD and 37% of patients treated with amlitelimab-HD achieved a score of 0 (clear) or 1 (almost clear) on the validated Investigator’s Global Assessment (vIGA) scale compared with 8% with placebo (p < 0.001 both LD and HD). At week 36, 68% of patients who achieved a vIGA score of 0 or 1 at week 16 maintained their response 24 weeks after their last dose. Pruritus NRS ≥ 4-point improvement at week 16 was reached by 57.9% in amlitelimab LD, 62.5% in amlitelimab HD, and 38.1% in the placebo group [33].

Safety follow-up was conducted until week 36, and amlitelimab was globally well tolerated. The overall rate of TEAEs was 35% for amlitelimab-LD, 17% for amlitelimab-HD, and 31% for the placebo. No hypersensitivity or tolerability events were reported, and, despite the incidence of related TEAEs, no clinically relevant pattern of events was observed. (Table 1) [33]

Considering the importance of IL-22 in AD pathogenesis and its hypothesized association with the OX40-OX40L pathway, a specific analysis was performed to evaluate its behavior during treatment. The IL-22 baseline serum levels correlated significantly with the severity of the disease (EASI r = 0.53, p < 0.0001; and SCORAD r = 0.36, p = 0.001), and no significant differences were observed between the groups. At week 16, a significant decrease in IL-22 serum levels was observed in patients treated with amlitelimab but not in the placebo (p = 0.381). An amlitelimab-induced decrease in IL-22 levels was maintained until week 36 in those defined as vIGA 0/1 responders at week 16, 24 weeks after their last dose. On the other hand, there were no significant disparities in the baseline IL-22 between responders and non-responders [32].

A Phase 2b study is now recruiting (STREAM-AD; NCT05131477) to further evaluate the impact of amlitelimab, when given subcutaneously, in patients with moderate-to-severe atopic dermatitis. It is an interventional, randomized, parallel-group, phase 2b, double-blind, 5-arm trial, which aims to assess the effect of amlitelimab in adult patients with moderate-to-severe atopic dermatitis. Additionally, a single group, phase 2, long-term extension study (NCT05492578) will characterize the safety and efficacy of amlitelimab in treated adult participants with moderate-to-severe AD who have previously been enrolled in the study (NCT05131477) (Table 1).
Amlitelimab is also under research for the treatment of moderate-to-severe asthma (TIDE-asthma; NCT05421598).


More information: The Lancet (2022). DOI: 10.1016/S0140-6736(22)02037-2

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