Tailoring Abrocitinib Treatment for Moderate-to-Severe Atopic Dermatitis to Patient Disease Course: A Narrative Review

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by intense itching, redness, and eczema. It significantly impacts the quality of life of affected individuals, often requiring long-term management strategies. Abrocitinib, an oral Janus kinase 1 (JAK1) inhibitor, is approved for the treatment of moderate-to-severe AD. Phase 2 and phase 3 abrocitinib randomized clinical trials in the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) clinical development program have demonstrated the efficacy and safety of abrocitinib in both adults and adolescents with moderate-to-severe AD. This review article explores the benefit–risk profile of a flexible abrocitinib dosing approach, tailoring dose based on individualized treatment of patients and highlighting the available supportive data from the JADE randomized clinical trials for healthcare professionals as part of joint provider–patient decision making. Dosing flexibility and maintenance with the lowest effective dose is necessary to treat patients according to their individual disease course while minimizing safety risks. Safety data indicate that incidence of treatment-emergent adverse events is reflective of the current dosage, with no carry-over risk from a previous higher dosage. Overall, abrocitinib represents a valuable AD therapy that can be administered according to individual patient needs.

Graphical abstract available for this article.

Graphical Abstract

Key Summary Points

Abrocitinib is an oral once-daily JAK1-selective inhibitor that has been approved for the treatment of adults and adolescents with moderate-to-severe atopic dermatitis (AD).

This review summarizes the benefit–risk profile of a flexible abrocitinib dosing approach for potential use in patients with moderate-to-severe AD, based on their individual disease characteristics.

Collective evidence from the efficacy, safety, and patient-reported outcomes data gathered from patients who participated in the phase 2 and phase 3 abrocitinib randomized clinical trials in the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) clinical development program encourages consideration of various dosing strategies in a patient’s treatment plan for long-term disease management, including dose down-titration, up-titration, and multiple dose changes.

Continuous therapy is often necessary to provide long-term disease control and to minimize occurrence of breakthrough flares experienced by patients with moderate-to-severe AD, and tailoring the dosing regimen of abrocitinib and maintaining treatment with the lowest effective dose is necessary when treating patients according to their individual disease courses while minimizing safety risks.

A flexible dosing approach allows for individualized treatment for patients, accounting for disease severity or burden, and other specific patient characteristics such as age and risk factors.

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Introduction

Approach to Treatment of Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intense itch and recurrent eczematous skin lesions [1, 2]. The clinical manifestations of AD are often heterogeneous and follow a longitudinal disease course, which may persist throughout a patient’s life or fluctuate with flares and periods of remission [3–5]. The exposome, which encompasses the biological response to all external factors a patient is exposed to during their lifetime, can significantly modify the disease course of AD, with factors such as season, temperature, and air pollution playing a role [6, 7]. Knowledge of patient itch triggers, such as changes in weather, can also aid in treatment planning [8]. Patient symptoms and disease severity are dynamic, impacting quality of life (QoL) significantly [9]. Patients with mild AD typically present with persistently mild disease, while those with moderate-to-severe AD are more likely to experience fluctuations [10]. Static assessment of AD severity during clinical visits may not accurately capture the long-term disease course and QoL burden; therefore, patient-reported outcomes (PROs) should always be considered alongside clinician-reported measures. Long-term disease management is often required to achieve stable control and to minimize exacerbations for patients with moderate-to-severe AD, often needing continuous therapy [11]. AD treatment guidelines recommend topical therapies (e.g., topical corticosteroids [TCS] and calcineurin inhibitors) and systemic therapies, including conventional systemics, biologics, and Janus kinase (JAK) inhibitors, for moderate or severe AD [11]. Patients whose AD signs and symptoms do not completely resolve with topical or, in some cases, conventional systemic therapies, those who experience drug intolerance, or those for whom these therapies are not advisable may consider treatment with systemic medications such as biologics (e.g., dupilumab) and JAK inhibitors, including abrocitinib, baricitinib, and upadacitinib, pursuant to country approval and/or availability, with consideration of the approved regional indication.

An important consideration for long-term therapy is use of the lowest possible drug dose to maintain efficacy while reducing the risk of dose-dependent adverse events, and most approaches to long-term AD control attempt to minimize drug exposure [12]. Tailoring treatment to individual patient needs, including dose adjustments and treatment interruptions, may be necessary to treat patients according to their individual disease course while managing the drug safety profile [1, 11, 13, 14]. The tapering down of treatment is associated with improved outcomes for patients compared with abrupt treatment withdrawal; the latter approach often leads to disease flare [15]. Furthermore, incorporating the patient’s perspective within the decision-making process is critical to create a patient-centric and optimized treatment approach that will minimize unnecessary medication exposure [16].

The objective of this review is to summarize the benefit–risk profile of a flexible abrocitinib dosing approach for potential use in patients with moderate-to-severe AD based on individual disease characteristics. Considerations for different patient populations and timing of abrocitinib dose changes based on patient disease characteristics and response to treatment are also discussed.

Abrocitinib Dosing and Administration Overview

Abrocitinib is an oral, once-daily, JAK1-selective inhibitor that has been approved for the treatment of adults and adolescents with moderate-to-severe AD [17–23]. Abrocitinib is available in two dosing strengths, 100 mg and 200 mg, and the phase 3 pivotal randomized clinical trials for abrocitinib evaluated both doses. The specific dose recommendations for abrocitinib vary across different regions (Table 1). Currently, the approved dosing recommendations for regions, including Australia, Canada, China, Japan, the European Union, and the United Kingdom, allow for starting dose flexibility, with either 200 mg or 100 mg once daily as a starting dose. In the United States, the recommended starting dose is 100 mg once daily, with the option to increase to 200 mg once daily for patients who do not respond adequately. The timeframe before considering a dosage increase, if needed, can vary, allowing for flexibility to tailor treatment to the individual disease course of each patient. Additionally, a 50-mg dose of abrocitinib is available for specific populations, such as those with certain renal impairments or certain drug interactions, depending on local product labels.

Table 1.

Selected approved abrocitinib dosing recommendations

Region	Dosing recommendations
Australia	Recommended starting dose is 100 mg or 200 mg based on individual patient characteristics In patients receiving strong CYP 2C19 inhibitors, the recommended dose is 50 mg QD In patients with moderate (eGFR 30 to < 60 mL/min) or severe (eGFR < 30 mL/min) renal impairment, the recommended starting dose is 50 mg QD Lowest effective dose for maintenance should be considered
Canada	Recommended starting dose is 100 mg or 200 mg QD based on individual goal of therapy and potential risk for adverse reactions In patients with moderate (eGFR 30 to < 60 mL/min) or severe (eGFR < 30 mL/min) renal impairment, the recommended dose should be reduced by half to 100 mg or 50 mg QD Lowest effective dose for maintenance should be considered
China	Recommended starting dose of 100 mg or 200 mg QD based on potential risk for adverse reactions If an adequate response is not achieved with 100 mg QD, consider increasing dose to 200 mg QD (could be short-term use, < 12 weeks) In patients receiving strong CYP 2C19 inhibitors, the recommended dose should be reduced by half to 100 mg or 50 mg QD In patients with moderate (eGFR 30 to < 60 mL/min) renal impairment, the recommended dose is 50 mg QD Lowest effective dosage should be used to maintain response
Europe	Recommended starting dose of 100 mg or 200 mg QD based on individual patient characteristics In patients receiving strong CYP 2C19 inhibitors and patients with moderate (eGFR 30 to < 60 mL/min) renal impairment, the recommended dose should be reduced by half to 100 mg or 50 mg QD In patients with severe (eGFR < 30 mL/min) renal impairment, the recommended starting dose is 50 mg QD, and maximum daily dose is 100 mg Lowest effective dose for maintenance should be considered
Japan	Recommended starting dose is 100 mg QD, and a dose of 200 mg QD may be given according to the patient’s condition In patients with moderate (eGFR 30 to < 60 mL/min) or severe (eGFR < 30 mL/min) renal impairment, the recommended dose should be reduced by half to 100 mg or 50 mg QD
UK	Recommended starting dose of 100 mg or 200 mg QD based on individual patient characteristics In patients receiving strong CYP 2C19 inhibitors and patients with moderate (eGFR 30 to < 60 mL/min) renal impairment, the recommended dose should be reduced by half to 100 mg or 50 mg QD In patients with severe (eGFR < 30 mL/min) renal impairment, the recommended starting dose is 50 mg QD, and maximum daily dose is 100 mg For most patients, particularly those with severe disease, 200 mg is the recommended starting dose Lowest effective dose for maintenance should be considered
USA	Recommended starting dose is 100 mg QD For patients with inadequate response to 100 mg QD, dose can be increased to 200 mg QD In patients known or suspected to be CYP 2C19 poor metabolizers and patients receiving strong CYP 2C19 inhibitors, the recommended dose is 50 mg QD (100 mg QD for those patients not responding to 50 mg QD) In patients with moderate (eGFR 30 to < 60 mL/min) renal impairment, the recommended dose is 50 mg QD (100 mg QD for those patients not responding to 50 mg QD) Lowest effective dose should be used to maintain response

CYP cytochrome P450; eGFR estimated glomerular filtration rate; QD once daily

Efficacy, Safety, and Patient-Reported Outcomes Data by Dosing Strategy

Approaching Abrocitinib Treatment and Response-Based Dosing Strategy

In clinical practice, the decision by healthcare practitioners (HCPs) on which abrocitinib dose is appropriate for patients is guided by regional product labels. Multiple clinical factors as well as consideration of the patient’s perspective should also be taken into account. However, the overarching goal for both clinicians and patients is to achieve long-term control of AD symptoms with minimal disease exacerbations and safety risks [11]. From a clinical perspective, the first step involves assessing the benefit–risk profile for each individual patient, as appropriate dose selection for treatment initiation could enhance the abrocitinib benefit–risk profile (Fig. 1). Patients experience varying disease and symptom burdens and should receive treatment tailored to their specific characteristics.

Fig. 1.

Abrocitinib dosing considerations

MACE major adverse cardovascular events, VTE venous thromboembolism

For patients with more severe symptoms or disease burden, HCPs may consider the 200-mg dose of abrocitinib to achieve rapid symptom control. However, the 200-mg dose has been associated with a higher frequency of some adverse events and is not an approved starting dose in all regional product labels [24–26]. For patients with less severe symptoms or disease burden, tolerability issues, or risk factors such as age over 65 years or cardiovascular issues, a starting dose of 100 mg may provide efficacy while helping to minimize safety risks. Factors such as certain renal and hepatic conditions and specified concomitant medication use should also be considered prior to treatment initiation as well as dosing decisions. In patients who are initiated on the 100-mg dose of abrocitinib, increasing the dose may provide additional symptom control, if needed. A flexible, response-based dosing strategy may be considered to maximize the benefit to the patient, while balancing risk (Fig. 1). The lowest efficacious dosage should be used to maintain response.

Collective evidence from the efficacy, safety, and PRO data gathered from patients who participated in the phase 2 and phase 3 abrocitinib randomized clinical trials in the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) clinical development program supports various dosing strategies available for HCPs to consider in a patient’s treatment plan for long-term disease management.

Abrocitinib 200-mg Starting Dose with Down-Titration to 100 mg

Patients initiated on abrocitinib 200 mg in the JADE clinical development program had higher response rates than patients on a 100-mg starting dose, with 37–55% of patients receiving abrocitinib 200 mg achieving ≥ 90% improvement in Eczema Area and Severity Index (EASI-90) response by study end (week 12 or week 16; Table 2) [25–29]. Data from the phase 3 JADE REGIMEN (NCT03627767) study support a starting dose of abrocitinib 200 mg to gain rapid improvement in skin and itch symptoms in patients with AD, with down-titration to the 100-mg dose for maintenance [13]. JADE REGIMEN was a multicenter, responder-enriched, double-blind, placebo-controlled, randomized withdrawal study with rescue treatment in patients experiencing flare and included three treatment phases (Fig. 2a) [13]. Patients with moderate-to-severe AD received once-daily abrocitinib 200 mg monotherapy during a 12-week open-label induction period; those who met protocol-defined response criteria (defined as patients who achieved a score of 0 or 1 in Investigator’s Global Assessment [IGA 0/1 with ≥ 2-grade improvement from baseline] and ≥ 75% improvement from baseline in Eczema Area and Severity Index [EASI-75] response) were randomly allocated in a double-blind randomized maintenance period with continuous abrocitinib 200 mg dosing, dose down-titration to abrocitinib 100 mg, or treatment-withdrawal (placebo) for up to 40 weeks. Patients who experienced a flare, defined as ≥ 50% loss of initial EASI response with a new IGA score ≥ 2 at week 12, entered a 12-week open-label rescue period of abrocitinib 200 mg with medicated topical therapy.

Table 2.

EASI, PP-NRS, and IGA response with consistent and flexible abrocitinib dosing in the JADE clinical development program

	Consistent dose
	Phase 2b, JADE MONO-1, MONO-2 [24–26]		JADE TEENa, COMPAREb, DAREc,d [27–29]
	Abrocitinib 100 mg QD monotherapy	Abrocitinib 200 mg QD monotherapy	Abrocitinib 100 mg QD ± TCS	Abrocitinib 200 mg QD ± TCS
12-week response
EASI-75	39.7–44.5%	61.0–64.6%	58.7–68.5%	70.3–76.3%
EASI-90	18.6–25.9%	37.7–52.1%	36.6–41.6%	47.6–49.5%
PP-NRS4	37.4–50.0%	55.3–63.6%	47.5–52.6%	55.4–66.0%
IGA 0/1	23.7–29.6%	38.1–43.8%	36.6–41.6%	46.2–51.8%
16-week response
EASI-75	–	–	60.3%	71.0–77.3%
EASI-90	–	–	38.0%	46.1–54.3%
PP-NRS4	–	–	47.0%	62.8–67.2%
IGA 0/1	–	–	34.8%	47.5–55.3%
26-week response
EASI-75	–	–	–	73.0%
EASI-90	–	–	–	54.6%
PP-NRS4	–	–	–	68.1%
IGA 0/1	–	–	–	55.6%
	Flexible dose
	JADE REGIMEN [13]
12-week open-label period response		Abrocitinib 200 mg QD monotherapy
EASI-75	–	75.6%	–	–
PP-NRS4	–	68.3%	–	–
IGA 0/1	–	65.9%	–	–
40-week randomized maintenance period	Abrocitinib 100 mg QD monotherapy
EASI-75	46.5%	–	–	–
PP-NRS4	27.3%	–	–	–
IGA 0/1	36.8%	–	–	–
12-week rescue periode				Abrocitinib 200 mg QD ± TCS
EASI-75	–	–	–	82.2%
PP-NRS4	–	–	–	54.9%
IGA 0/1	–	–	–	64.0%

ClinicalTrials.gov identifiers: NCT02780167 (phase 2b), NCT03349060 (JADE MONO-1), NCT03575871 (JADE MONO-2), NCT03796676 (JADE TEEN), NCT03720470 (JADE COMPARE), NCT04345367 (JADE DARE), NCT03627767 (JADE REGIMEN)

^aData included up to 12 weeks of treatment

^bData included up to 16 weeks of treatment

^cData included up to 26 weeks of treatment

^dJADE DARE did not include an abrocitinib 100 mg treatment arm

^ePatients who met the protocol definition of a flare during the double-blind 40-week maintenance period entered the rescue period and received abrocitinib 200 mg ± TCS. Rescue baseline was defined as the last measurement collected between last dose of blinded treatment during the maintenance period and day 1 of rescue treatment

EASI-75 achieving ≥ 75% improvement from baseline in Eczema Area and Severity Index response, EASI-90 achieving ≥ 90% improvement from baseline in Eczema Area and Severity Index response, IGA 0/1 achieving a score of 0 (clear) or 1 (almost clear) in Investigator’s Global Assessment with a ≥ 2-point reduction from baseline, PP-NRS4 achieving ≥ 4-point improvement from baseline in Peak Pruritus Numerical Rating Scale response, QD once daily, TCS topical corticosteroid

Fig. 2.

Abrocitinib a 200 mg to 100 mg down-titration in the JADE REGIMEN study and b multiple dose titrations (200 mg, 100 mg, 200 mg, 100 mg) in JADE REGIMEN and JADE EXTEND.

Red boxes in a indicate patients who initiated abrocitinib 200 mg for 12 weeks, achieved a protocol-defined response, and then down-titrated to randomized abrocitinib 100 mg for maintenance. Green boxes in b indicate patients who initiated abrocitinib 200 mg for 12 weeks, achieved a protocol-defined response and then down-titrated to randomized abrocitinib 100 mg for maintenance, experienced a flare and up-titrated to abrocitinib 200 mg rescue therapy for 12 weeks, and entered the JADE EXTEND study where they down-titrated to abrocitinib 100 mg.

^aPatients who achieved an IGA score of 0 (clear) or 1 (almost clear) with a ≥ 2-point reduction from baseline and ≥ 75% improvement from baseline in EASI response.

^bDefined as a ≥ 50% loss of the initial EASI response at week 12 with a new IGA score ≥ 2.

^cPatients who were ineligible for randomization to the maintenance period; discontinued treatment during the induction, maintenance, or rescue phases; or did not enter the long-term extension study were followed up in the 4-week untreated period. EASI Eczema Area and Severity Index, IGA Investigator’s Global Assessment, QD once daily, TCS topical corticosteroids

Of a total of 1233 patients who entered the open-label phase of JADE REGIMEN and received the abrocitinib 200-mg dose, 798 (64.7%) patients achieved response per protocol and, of these, 265 were randomly allocated (down-titrated) to 100 mg. Response rates with abrocitinib 200 mg to 100 mg down-titration were greater compared to treatment withdrawal (placebo), through the maintenance period from week 4 after randomization up to week 40. For example, EASI-75 response rate at the end of the 40-week maintenance period was 46.5% (Table 2), which was substantially higher than placebo (14.0%). Among patients who down-titrated from the 200-mg dose to 100 mg, 60.8% were also able to maintain response for the 40-week maintenance period without a flare or need for rescue treatment, compared with 23.6% of patients in the placebo (treatment withdrawal) arm. More patients who started on abrocitinib 200 mg and down-titrated to a 100-mg dose had improvements in PROs, including pruritus (Peak Pruritis Numerical Rating Scale [PP-NRS]), quality of life (Dermatology Life Quality Index [DLQI]/Children’s Dermatology Life Quality Index [CDLQI]), and sleep (SCORing Atopic Dermatitis [SCORAD] sleep subscale) versus placebo that were sustained throughout the maintenance period. Itch improvement is often considered by patients to be one the most important treatment outcomes. In JADE REGIMEN, 27.3% of patients who down-titrated from 200 mg to 100 mg achieved ≥ 4-point improvement from baseline in PP-NRS response (PP-NRS4) at the end of this period versus 8.3% of patients who had treatment withdrawal (placebo). Post hoc analyses of JADE REGIMEN looking at predictors of not flaring found that patients with lower baseline disease severity who showed strong response from week 8 through week 12 of abrocitinib 200-mg induction (IGA 0/1 or 100% improvement from baseline in EASI response [EASI-100]) were feasible candidates for maintenance therapy with abrocitinib 100 mg [12, 30].

Treatment-emergent adverse events (TEAEs) occurred in 41.5% of patients during the 200-mg induction period, and in 34.6% of patients who maintained continuous treatment with abrocitinib 200 mg versus 25.3% of patients who down-titrated to 100 mg during maintenance. The fewer TEAEs reported in the down-titration group versus the continuous abrocitinib 200-mg maintenance group suggest a dose response. This is supportive evidence to the evaluation of safety dose–response in the placebo-controlled randomized clinical trials programs. The safety profile with abrocitinib 200 mg to 100 mg down-titration is comparable to that observed with continuous abrocitinib 100-mg treatment and demonstrates a lack of carryover effects from the initial higher dose.

For appropriate patients, an induction-maintenance dose down-titration approach with abrocitinib 200 mg followed by 100 mg may be a viable strategy to achieve rapid symptom control and then maintain efficacy while minimizing risk of TEAEs.

Abrocitinib 100-mg Starting Dose with Up-Titration to 200 mg

A starting dose of abrocitinib 100 mg was evaluated in patients enrolled in the pivotal phase 3 JADE randomized clinical trials JADE MONO-1, JADE MONO-2, JADE COMPARE, and JADE TEEN [14, 25–27, 29]. Abrocitinib was assessed as monotherapy in adolescents and adults in the JADE MONO-1 and MONO-2 trials, which included 156 and 158 patients, respectively, in the abrocitinib 100-mg treatment arms [25, 26]. In the JADE COMPARE and JADE TEEN trials, abrocitinib was assessed in combination with topical medications in adults and adolescents, respectively, including 238 and 95 patients in the 100-mg treatment arms [27, 29]. All trials included a 200-mg abrocitinib treatment arm and a placebo control arm; in JADE COMPARE, an active comparator, dupilumab, was also included. Across all trials, significantly more patients who received abrocitinib 100 mg achieved the primary efficacy endpoints (IGA and EASI-75 response at week 12), as well as clinically meaningful reductions in pruritus intensity, than those who received placebo. EASI-75 response was achieved with abrocitinib 100-mg treatment at week 12 by 39.7%, 44.5%, 58.7%, and 68.5% of patients in JADE MONO-1, MONO-2, COMPARE, and TEEN versus 11.8%, 10.4%, 27.1%, and 41.5% with placebo, respectively [14].

Patients whose symptoms do not adequately respond to abrocitinib 100-mg treatment may benefit from an up-titration to abrocitinib 200 mg. A predictive model developed using data from JADE MONO-1, MONO-2, COMPARE, and TEEN determined that, in patients who started on the abrocitinib 100-mg dose, attainment of ≥ 50% improvement from baseline in EASI response (EASI-50) at week 4 may be the best predictor of attaining an EASI-75 response at week 12 [31]. Patients who failed to reach this week 4 endpoint may be considered for a dose up-titration to 200 mg to optimize efficacy response. An IGA score of 2, PP-NRS4, or EASI score of 8 were also found to be suitable alternative predictors. In the JADE REGIMEN study, patients who had a disease flare during the maintenance period received abrocitinib 200 mg plus TCS as rescue therapy, which was effective for treating their flares [32, 33]. Of the 265 patients who down-titrated to the 100-mg dose during maintenance, 104 (39.2%) experienced a flare and received rescue therapy. Substantial proportions of these patients regained EASI-75 (32.0%), IGA 0/1 (50.5%), and PP-NRS4 (39.7%) response with rescue treatment, as evidenced by improvement in their scores to pre-flare levels. Among patients who experienced a flare, skin clearance response (EASI-75) with rescue therapy (dose up-titration) was not affected by the time to onset. Early onset of flare was defined as occurring less than 10 weeks after initiating maintenance treatment, and late onset was defined as occurring 10 weeks or more after initiating maintenance treatment. Efficacy response rates to rescue therapy were comparable between patients with early onset and late-onset flare (IGA 0/1: 66% versus 52%; EASI-75: 80% versus 69%), suggesting that abrocitinib rescue therapy as dose up-titration to 200 mg plus TCS had similar efficacy in patients with early and late flares that occurred after initial dose down-titration to abrocitinib 100 mg [12, 34]. Dose up-titration to abrocitinib 200 mg was effective treatment for flares in patients receiving abrocitinib 100 mg, regardless of the severity or timing of flare [34].

From a safety perspective, abrocitinib is known to be associated with a dose-dependent increase in thrombocytopenia risk. Platelet dynamics simulations suggest that abrocitinib dosage up-titration from 100 mg to 200 mg between week 4 and week 8 is unlikely to negatively affect platelet count recovery [31]. Patients who receive this dose up-titration, while likely to achieve treatment success at week 12 as described above, would be expected to have no significant impact on platelet count recovery outcomes. The platelet dynamics observed with an abrocitinib dose increase from 100 mg to 200 mg were similar to the dynamics observed with continuous dosing with abrocitinib 100 mg or abrocitinib 200 mg. In all simulations, the nadir in platelet count was observed at about 4 weeks, followed by a period of recovery. However, the impact of dose up-titration on other safety events commonly associated with abrocitinib was not assessed in these predictive models, limiting interpretation of overall safety.

The most common drug-related, dose-dependent adverse events observed in an assessment of pooled placebo-controlled studies of abrocitinib were nausea, vomiting, upper abdominal pain, herpes simplex, headache, dizziness, acne, and creatine phosphokinase increase [35]. One patient experienced a nonserious event of asymptomatic rhabdomyolysis that resulted in permanent discontinuation of the study drug [36]. Further studies are needed to elucidate other safety implications of dose up-titration; the safety profile of abrocitinib in this scenario is likely to be consistent with that seen with the continuous dose of abrocitinib 200 mg, despite the lower dose received during treatment initiation.

Multiple Dose Changes over the Long Term

Long-term management of AD as a chronic disease may necessitate patients to adjust their doses multiple times to balance the benefit–risk profile of treatment [11, 13]. For instance, a patient who has responded well to abrocitinib 200 mg may reduce the dose to 100 mg to maintain efficacy while lowering the risk of TEAEs and later need temporary up-titration to treat a flare. Tailoring the abrocitinib dose for each patient allows for dose adjustments in response to flares and periods of control while always considering maintenance with the lowest effective dose.

Patients from qualifying phase 3 parent studies could be enrolled into the ongoing long-term extension JADE EXTEND study [37]. A selected group of 90 patients from the JADE REGIMEN trial who enrolled into JADE EXTEND represent a long-term flexible dosing population (variable-dose efficacy cohort) with dose down-titration, followed by up-titration and another down-titration (Fig. 2b) [38]. These patients, who achieved protocol-defined response criteria during the 12-week abrocitinib 200 mg open-label induction phase, entered the randomized maintenance phase and received abrocitinib 100 mg for up to 40 weeks. Upon experiencing a flare, they received rescue treatment with abrocitinib 200 mg plus TCS for 12 weeks before entering JADE EXTEND, where they were allocated to receive abrocitinib 100 mg with or without TCS.

At week 48 of abrocitinib treatment in JADE EXTEND, 69% of patients in this variable-dose efficacy cohort achieved an EASI-75 response, compared with 82% of patients treated with continuous abrocitinib 200 mg. Similarly, 44% of patients in the variable-dose efficacy cohort achieved a PP-NRS4 response, compared with 67% of those treated with continuous abrocitinib 200 mg. Both continuous and flexible abrocitinib dosing resulted in sustained clinically meaningful and high-threshold skin clearance, itch relief, and quality of life improvements over the long term, up to 48 weeks of treatment. Although continuous abrocitinib 200-mg treatment remained the most effective dosing strategy, a substantial proportion of patients treated with flexible dosing were also able to achieve long-term clinically meaningful responses. Over the long term, safety events were related to the current dose, and dose changes were found to not result in a carry-over risk.

A long-term safety analysis of patients from JADE REGIMEN and JADE EXTEND found that the incidence rates of all TEAEs, serious TEAEs, severe TEAEs, and TEAEs that led to treatment discontinuation were numerically lower in the variable-dose cohort than in the abrocitinib 200-mg consistent-dose cohort over 96 weeks, which may indicate a more favorable safety profile [39]. Additionally, incidence rates of TEAEs of special interest, namely serious infections, all herpes zoster infections, and adjudicated opportunistic herpes zoster infections were numerically lower in the flexible-dosing cohort than in the consistent 200-mg dosing cohort. Substantial proportions of patients in both cohorts achieved EASI-75, EASI-90, and PP-NRS response at week 12 and maintained response through week 96 of abrocitinib treatment [39].

Dosing Considerations for Different Age Populations and Patients with Risk Factors

Patient age is an important consideration for abrocitinib dosing, with older age being a risk factor for several TEAEs of special interest associated with JAK inhibitors [15]. Some TEAEs of special interest, including serious infections, malignancies, and cardiovascular events, trended higher in patients aged 65 years and older, those with cardiovascular and/or malignancy risk factors (i.e., current or former smoker), and in patients with intermediate and high atherosclerotic cardiovascular risk scores who were treated with abrocitinib [15, 36, 40]. As such, the abrocitinib 100-mg dose may be appropriate for patients at higher risk of TEAEs of special interest, including older patients. The 50-mg dose, where available, may also be considered per regional labeling recommendations.

The frequencies of TEAEs were similar between adults and adolescents during induction and maintenance in the JADE REGIMEN study, although adult patients tended to have higher proportions of serious TEAEs, while nausea rates were higher in adolescent patients compared with adults [41]. Treatment with abrocitinib, either through induction with 200 mg followed by maintenance with a reduced dose of 100 mg, or continuous dosing with 200 mg, has proven efficacious in both adults and adolescents with moderate-to-severe AD up to 112 weeks, with an acceptable long-term safety profile and no new safety signals observed [36, 41, 42].

Implications for Clinical Practice

Abrocitinib is approved for the treatment of moderate-to-severe AD at 200-mg and 100-mg doses, with a 50-mg once-daily dose for certain dose modifications. Dosing recommendations vary, and in addition to varying starting doses, up- or down-titration can occur on the basis of patient disease presentation, effectiveness, and tolerance. These data are informative for patients who initiate either abrocitinib 200 mg or abrocitinib 100 mg as a starting dose (per local guidelines). Specifically, these data may inform dose up-titration for patients who initiate abrocitinib 100 mg as a starting dose. For patients initiated on abrocitinib 100 mg, the data support a likely benefit in increasing the abrocitinib dose from 100 mg to 200 mg to improve efficacy with no significant impact on platelet count recovery, therefore providing additional safety insights to HCPs’ decision-making. Additionally, these data support assessment of response at week 4 of abrocitinib 100-mg treatment as a key timepoint to assess any dose change needs. In alignment with utilization of the lowest effective dosage, patients receiving abrocitinib 200 mg either as a starting dose or through up-titration may reduce their dose to 100 mg while likely maintaining response.

Assessment of a patient’s longitudinal disease course prior to abrocitinib initiation may be of value to understand any seasonal or temporal patterns, as some patients require stronger treatment in winter and little to no treatment in spring or summer. These baseline patterns can help with setting patient expectations for discussions about drug holiday and executing dose flexibility throughout the treatment plan.

Inadequate symptom control with conventional AD therapies is frequently reported in moderate-to-severe AD. Substantial proportions of patients whose symptoms did not respond or who were intolerant to previous treatments with oral systemic or biologic therapies, including dupilumab, achieved clinically meaningful dose-dependent responses with abrocitinib treatment [43, 44]. Prior treatment exposure had no impact on short-term efficacy and only modest impact on long-term efficacy up to 112 weeks. Efficacy with up to 48 and 112 weeks of abrocitinib treatment suggests that abrocitinib can be a treatment option for appropriate patients, including for a subset of patients with a high burden of AD (i.e., inadequate disease control despite having previously received various systemic therapies) [43]. The long-term flexible dosing approach may be a viable strategy for maintenance of long-term disease control while minimizing safety risks, consistent with label recommendations for maintenance with the lowest effective dosage. TEAE frequency was related to the current dose, with no carry-over risk [17–23]. A flexible dosing approach allows for individualized treatment for all patients, accounting for disease severity and burden, and other specific patient characteristics such as age and risk factors. This approach may be optimized through clinicians’ monitoring of a patient’s quality of life, and by ensuring inclusion of the patient’s perspectives when designing and adjusting each individualized treatment plan.

Conclusions

Tailoring the dosing regimen of abrocitinib and maintaining treatment with the lowest effective dosage is necessary to treat patients according to their individual longitudinal disease course. Continuous therapy is often necessary for long-term disease control and to minimize the incidence of breakthrough flares experienced by patients with moderate-to-severe AD. This article highlights the scope of available flexible dosing strategies that can be considered to tailor abrocitinib treatment to the needs of each individual patient.

Author Contributions

Justine Alderfer contributed to the conceptualization of the manuscript. Jonathan I. Silverberg, Eric Simpson, Melinda Gooderham, Stephan Weidinger, Melissa Watkins, and Justine Alderfer contributed to the preparation of the manuscript, reviewed and edited the manuscript, and approved the final manuscript.

Funding

This manuscript, including the journal’s Rapid Service Fee, was sponsored by Pfizer Inc., New York, NY, USA.

Data Availability

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

Declarations

Conflicts of Interest

Jonathan I. Silverberg has served as an investigator for Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Menlo Therapeutics, Realm Therapeutics, Regeneron Pharmaceuticals, and Sanofi Genzyme; as a consultant for Pfizer Inc., AbbVie, Anacor, AnaptysBio, Arena Pharmaceuticals, Dermavant, Dermira, Eli Lilly and Company, Galderma, GlaxoSmithKline, Glenmark, Incyte, Kiniksa Pharmaceuticals, LEO Pharma, Menlo Therapeutics, Novartis, Realm Therapeutics, Regeneron Pharmaceuticals, and Sanofi Genzyme; and as a speaker for Regeneron Pharmaceuticals and Sanofi Genzyme. Eric Simpson has received grants from Pfizer Inc., Eli Lilly and Company, Kyowa Kirin, LEO Pharma, Merck, and Regeneron and personal fees from Pfizer Inc., Bausch Health (Valeant), Dermira, Eli Lilly and Company, Galderma, LEO Pharma, Menlo Therapeutics, Novartis, Regeneron, and Sanofi Genzyme. Melinda Gooderham has received grants, personal fees, honoraria, and/or nonfinancial support from Pfizer Inc., AbbVie, Amgen, AkrosPharma, Arcutis, AnaptysBio, Aristea, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly and Company, Galderma, JAMP Pharma, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Moonlake, Meiji, Nektar, Novartis, Roche, Sanofi Genzyme, Regeneron Pharmaceuticals, Sun Pharma, UCB, Ventyx, and Bausch Health. Stephan Weidinger has received institutional research grants from La Roche-Posay, LEO Pharma, and Sanofi Deutschland GmbH; has performed consultancies for Pfizer Inc., AbbVie, Eli Lilly and Company, Kymab, LEO Pharma, Novartis, Regeneron Pharmaceuticals, and Sanofi Genzyme; has lectured at educational events sponsored by AbbVie, Galderma, LEO Pharma, Novartis, Regeneron Pharmaceuticals, and Sanofi Genzyme; and is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of psoriasis and atopic dermatitis. Melissa Watkins and Justine Alderfer are employees and shareholders of Pfizer Inc.

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.