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

MACE major adverse cardovascular events, VTE venous thromboembolism

Abrocitinib dosing considerations

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 [24,25,26]. 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) [25,26,27,28,29]. 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 programFig. 2

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.

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.

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, 25,26,27, 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].