High threshold efficacy responses in moderate-to-severe atopic dermatitis are associated with additional quality of life benefits: pooled analyses of abrocitinib monotherapy studies in adults and adolescents.

BACKGROUND: Once-daily abrocitinib treatment provided meaningful improvements in signs and symptoms of moderate-to-severe atopic dermatitis (AD) in randomized controlled studies.
OBJECTIVE: To evaluate proportions of patients with responses meeting higher threshold efficacy responses than commonly used efficacy end points and to determine if these responses were associated with quality-of-life (QoL) benefits.
METHODS: Data from a phase 2b (NCT02780167) and two phase 3 studies (NCT03349060/JADE MONO-1; NCT03575871/JADE MONO-2) in adult and adolescent patients (N = 942) with moderate-to-severe AD receiving once-daily abrocitinib 200 mg, abrocitinib 100 mg or placebo were pooled. Commonly used (Eczema Area and Severity Index [EASI]-75 and ≥4-point improvement in Pruritus Numerical Rating Scale [PP-NRS4]) and higher threshold efficacy end points (EASI-90 to <EASI-100, EASI-100 or PP-NRS0/1 response) were evaluated. Proportions of patients across Children's Dermatology Life Quality Index/Dermatology Life Quality Index (CDLQI/DLQI) band descriptors who achieved various efficacy end points were analysed.
RESULTS: More abrocitinib-treated patients achieved commonly used or higher threshold efficacy end points at week 12 vs. placebo. More abrocitinib-treated patients who achieved higher threshold efficacy end points reported 'no effect' of AD on QoL (by CDLQI/DLQI) at week 12 vs. those who achieved commonly used but not higher threshold efficacy end points (PP-NRS0/1 vs. PP-NRS4 but not PP-NRS0/1 responders [200 mg: 66.3% vs. 17.5%; 100 mg: 62.1% vs. 20.0%]; EASI-100, EASI-90 to <EASI-100 vs. EASI-75 to <EASI-90 responders [200 mg: 67.6%, 48.9% vs. 28.8%; 100 mg: 63.2%, 48.1% vs. 36.7%]).
CONCLUSIONS: Substantial proportions of patients with moderate-to-severe AD receiving abrocitinib met higher threshold efficacy end points, and this was associated with meaningful additional QoL benefits compared with those who did not meet these higher efficacy thresholds. Not only do a substantial proportion of abrocitinib-treated patients achieve higher threshold efficacy end points but they also do so in a similar timeframe as the more commonly used thresholds for efficacy end points. CLINICAL TRIALS: NCT02780167, NCT03349060 and NCT03575871.

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin condition characterized by pruritus, eczematous lesions and dry skin that affects up to 25% of children and 5% to 10% of adults worldwide. , , , , , , The signs and symptoms of AD, especially pruritus, are severely burdensome and can lead to the development of depressive symptoms, , , psychological distress and sleep disturbance, , , , which impact patient quality of life (QoL). , , , Abrocitinib, an oral, once‐daily, Janus kinase 1 (JAK1) inhibitor, was recently approved for the treatment of moderate‐to‐severe AD in adults and adolescents in Great Britain and Japan and in adults in the European Union and the United States. Inhibition of JAK1 modulates various cytokines relevant to the pathophysiology of AD, including interleukin (IL)‐4, IL‐13, IL‐31 and thymic stromal lymphopoietin (TSLP). , , Additionally, inhibition of the JAK1 pathway ameliorates the sensation of pruritus through direct neuronal JAK1 inhibition. Hence, selective inhibition of JAK1 modulates multiple downstream signalling pathways critical to the pathogenesis and symptoms of AD.

Abrocitinib monotherapy was effective and well tolerated in clinical studies in patients with moderate‐to‐severe AD. , , In JADE MONO‐1 and JADE MONO‐2, identical phase 3 studies in adult and adolescent patients with moderate‐to‐severe AD, significantly greater proportions of patients treated with abrocitinib (200 mg or 100 mg) achieved commonly used efficacy threshold responses defined as Investigator Global Assessment (IGA) 0/1 response (clear [0] or almost clear [1] with ≥2‐grade improvement), ≥75% improvement in Eczema Area and Severity Index score (EASI‐75) response and/or ≥4‐point improvement from baseline in Peak Pruritus Numerical rating scale (PP‐NRS4) response compared with patients treated with placebo, and with a manageable safety profile. , Among the responders fulfilling these commonly used efficacy thresholds, a subset met higher threshold efficacy responses; for example, among those reaching EASI‐75 response, some had attained EASI‐90 or EASI‐100, and among those reaching PP‐NRS4 response, some achieved PP‐NRS0/1 (the latter reflecting profound itch control). Attaining these higher threshold efficacy responses may be associated with additional, clinically meaningful improvement in QoL. The objectives of these post hoc analyses were to determine the proportion of patients in the phase 2b and phase 3 abrocitinib monotherapy trials, who achieved higher threshold efficacy end points (90% improvement in EASI to <100% improvement in EASI [EASI‐90 to

Methods

Study design

These analyses used data pooled from three similarly designed abrocitinib monotherapy trials, including a phase 2b trial (NCT02780167) and two phase 3 trials (NCT03349060, JADE MONO‐1; NCT03575871, JADE MONO‐2) in adult and adolescent patients with moderate‐to‐severe AD treated with once‐daily abrocitinib 200 mg, abrocitinib 100 mg or placebo. , , Patients were randomly assigned in a 1:1:1:1:1 ratio in the phase 2b study to receive abrocitinib (200 mg, 100 mg, 30 mg or 10 mg) or placebo and in a 2:2:1 ratio in the phase 3 studies to receive abrocitinib (200 mg or 100 mg) or placebo. Details of all three studies along with primary efficacy and safety results were previously reported. , , All study documents and procedures were approved by the appropriate institutional review board/ethics committee at each study site. The studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation Good Clinical Practice Guidelines. All local regulatory requirements were followed. An internal review committee monitored the safety of patients throughout the studies. All patients provided written informed consent.

Patients

Study participants were patients aged 18–75 years (phase 2b) or ≥ 12 years (phase 3) with a clinical diagnosis of moderate‐to‐severe AD (IGA ≥3, EASI ≥12 [phase 2b] or ≥ 16 [phase 3], percentage of body surface area involvement [%BSA] ≥10, PP‐NRS; [used with permission of Regeneron Pharmaceuticals, Inc., and Sanofi ] ≥4 [phase 3 only]), for ≥1 year (phase 2b) and recent (phase 3: within 6 months) history of inadequate response to topical medications (corticosteroids or calcineurin inhibitors) given for ≥4 weeks or an inability to receive topical treatment because it was medically inadvisable. Previous dupilumab use was permitted in the phase 3 studies if it had been >6 weeks before study initiation. , Patients who previously used JAK inhibitors within 12 weeks (phase 2b) or ever (phase 3) or oral immunosuppressant agents (i.e. cyclosporine, azathioprine, methotrexate, mycophenolate mofetil and systemic corticosteroids) within 4 weeks or five half‐lives (whichever was longer) were excluded from the studies. , , Rescue medication (including topical corticosteroids) was prohibited during the studies. Full inclusion and exclusion criteria are published elsewhere. , ,

Post hoc analysis end points

End points assessed in this post hoc analysis included: proportion of patients who achieved commonly used efficacy end points and the proportion of patients who achieved higher threshold efficacy end points (EASI‐90 to

Statistical analyses

Binary end points were analysed using the Cochran–Mantel–Haenszel test, adjusted by randomization strata. Patients who permanently discontinued the study were defined as non‐responders at all visits after the last observation. Continuous end points were analysed using a mixed‐effect model with repeated measures based on all observed data. The model included factors for treatment group, randomization strata, visit, treatment‐by‐visit interaction, and relevant baseline value. Median times to response were analysed with observed responses (not including patients with missing or censored response data) using empirical methods for confidence intervals (CIs) for quantiles. These analyses were not controlled for multiplicity and no statistical hypotheses were tested.

Results

Demographics and baseline characteristics were similar among pooled monotherapy patients treated with abrocitinib or placebo (Table 1). Mean (standard deviation) baseline EASI, PP‐NRS, DLQI and CDLQI scores were 28.8 (12.7), 7.0 (1.9), 14.6 (6.9) and 12.7 (6.0) respectively. These baseline values indicate moderate‐to‐severe AD at baseline, and that the disease had a ‘very large effect’ on QoL.

Table 1

Demographic and baseline characteristics

Characteristic	Pooled treatment group
	Placebo (n = 210)	Abrocitinib		All (N = 942)
		100 mg (n = 369)	200 mg (n = 363)
Age (years), mean (SD)	35.0 (15.0)	35.9 (15.8)	34.1(16.4)	35.0 (15.9)
Age group, n (%)
12–17 years	25 (11.9)	51 (13.8)	48 (13.2)	124 (13.2)
18–64 years	178 (84.8)	297 (80.5)	289 (79.6)	764 (81.1)
≥65 years	7 (3.3)	21 (5.7)	26 (7.2)	54 (5.7)
Male, n (%)	117 (55.7)	215 (58.3)	197 (54.3)	529 (56.2)
Race, n (%)
White	141 (67.1)	253 (68.6)	231 (63.6)	625 (66.3)
Black or African American	22 (10.5)	31 (8.4)	30 (8.3)	83 (8.8)
Asian	39 (18.6)	80 (21.7)	85 (23.4)	204 (21.7)
Other	3 (1.4)	2 (0.5)	5 (1.4)	10 (1.1)
Multiracial	2 (1.0)	2 (0.5)	8 (2.2)	12 (1.3)
Not reported	3 (1.4)	1 (0.3)	4 (1.1)	8 (0.8)
Ethnicity, n (%)
Hispanic or Latino	11 (5.2)	14 (3.8)	12 (3.3)	37 (3.9)
Not Hispanic or Latino	196 (93.3)	352 (95.4)	349 (96.1)	897 (95.2)
Not reported	3 (1.4)	3 (0.8)	2 (0.6)	8 (0.8)
Disease duration (years), mean (SD)	23.5 (15.2)	23.7 (16.1)	22.0 (15.1)	23.0 (15.5)
EASI score (%), mean (SD)	27.6 (11.8)	29.4 (12.4)	29.0 (13.4)	28.8 (12.7)
BSA affected (%), mean (SD)	45.8 (22.1)	48.6 (22.5)	47.2 (23.6)	47.4 (22.8)
PP‐NRS
No. of patients	207	368	362	937
Mean (SD) score	7.0 (1.9)	7.1 (1.9)	7.0 (1.9)	7.0 (1.9)
DLQI †
No. of patients	184	315	311	810
Mean (SD) total score	14.3 (7.2)	15.1 (7.1)	14.4 (6.6)	14.6 (6.9)
CDLQI
No. of patients	24	48	47	119
Mean (SD) total score	12.5 (6.3)	12.4 (6.4)	13.1 (5.5)	12.7 (6.0)

For patients aged 18 years or more.

AD, atopic dermatitis; BSA, body surface area; CDLQI, Children's Dermatology Life Quality Index; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; PP‐NRS, Peak Pruritus Numerical Rating Scale; SD, standard deviation.

Depth of response to abrocitinib

In the pooled analysis, patients treated with abrocitinib had marked improvement in EASI scores compared with placebo. At week 12, the proportions of patients (95% CI) who achieved EASI‐75 response were 62.3% (57.2–67.3), 41.9% (36.9–47.0) and 12.2% (7.7–16.7) for the abrocitinib 200 mg, abrocitinib 100 mg and placebo groups respectively (Fig. 1). At week 12, greater proportions of patients treated with abrocitinib achieved EASI‐75 to

Figure 1

Proportion of patients with moderate‐to‐severe AD who achieved (a) EASI‐75 response, (b) EASI‐75 to

Greater proportions of patients treated with abrocitinib achieved PP‐NRS4 response at week 12 compared with placebo; PP‐NRS4 responder proportions at week 12 were 57.3% (51.8–62.7), 42.9% (37.4–48.3) and 16.5% (11.2–21.8) for the abrocitinib 200 mg, abrocitinib 100 mg and placebo groups respectively (Fig. 2). Among PP‐NRS4 responders at week 12, greater proportions of patients treated with abrocitinib achieved PP‐NRS4 but not PP‐NRS0/1 response (22.5% [17.8–27.2], 20.4% [15.9–24.9] and 12.6% [7.8–17.4]; Fig. 2) and the higher threshold efficacy end point of PP‐NRS0/1 response (36.6% [31.3–42.0], 23.4% [18.7–28.1] and 5.3% [2.1–8.5]; Fig. 2) compared with placebo for the abrocitinib 200 mg, 100 mg and placebo groups respectively.

Figure 2

Proportion of patients with moderate‐to‐severe AD who achieved (a) PP‐NRS4 response (≥4‐point improvement from baseline), (b) PP‐NRS4 but not PP‐NRS0/1 response and (c) PP‐NRS0/1 response (baseline score ≥ 2; achieving score < 2) at weeks 2, 4, 8 and 12. AD, atopic dermatitis; CI, confidence interval; PP‐NRS, Peak Pruritus Numerical Rating Scale.

The efficacy of abrocitinib (200 mg and 100 mg) was better than that of placebo for all response thresholds evaluated from week 2 through week 12 (Figs. 1 and 2).

Time to response to abrocitinib

To assess the onset of observed response at the various efficacy thresholds, without overlap with higher threshold efficacy responses, analyses were performed that ‘windowed’ the efficacy responses for EASI‐75 to

Table 2

Median time (days) to first response based on various efficacy end points

Days (95% CI)	Pooled treatment group
	Placebo (n = 211)	Abrocitinib
		100 mg (n = 370)	200 mg (n = 364)
EASI responses
EASI‐75	31.0 (29–57)	30.0 (29–56)	29.0 (29–29)
EASI‐75 to <EASI‐90	57.0 (29–85)	56.0 (30–57)	56.0 (30–57)
EASI‐90	79.5 (56–85)	57.0 (56–58)	47.0 (30–57)
EASI‐90 to <EASI‐100	79.5 (56–85)	58.0 (56–85)	56.0 (31–57)
EASI‐100	0	84.5 (57–86)	84.0 (56–85)
PP‐NRS responses
PP‐NRS4	29.0 (13–58)	15.0 (11–29)	10.0 (8–12)
PP‐NRS4 but not PP‐NRS0/1	29.0 (10–58)	29.0 (13–57)	13.5 (9–29)
PP‐NRS0/1	83.0 (11–85)	29.0 (28–56)	14.5 (12–29)

Median time to response was calculated only among subjects with an observed time of event.

In the pooled analysis for observed EASI‐75 to

In the pooled analysis for observed PP‐NRS4 but not PP‐NRS0/1 response, median time to onset was 13.5 and 29.0 days for the abrocitinib 200 mg and abrocitinib 100 mg groups respectively. For the higher threshold efficacy end point of those observed to reach PP‐NRS0/1 response, median time to onset was similar at 14.5 and 29 days for the abrocitinib 200 mg and abrocitinib 100 mg groups respectively.

Relationship of quality of life with depth of response

To assess association with QoL outcomes at the various efficacy thresholds, without overlap with higher threshold efficacy responses, analyses were performed that ‘windowed’ the efficacy responses: EASI‐75 to

Figure 3

Distribution of CDLQI/DLQI severity bands at (a) baseline and (b) week 12 of patients with moderate‐to‐severe AD who achieved EASI‐75 to

Figure 4

Distribution of CDLQI/DLQI severity bands at (a) baseline and (b) week 12 of patients with moderate‐to‐severe AD who achieved PP‐NRS4 response but not PP‐NRS0/1 response and PP‐NRS0/1 response at week 12 in the placebo, abrocitinib 100 mg and abrocitinib 200 mg treatment groups. AD, atopic dermatitis; CDLQI, Children's Dermatology Life Quality Index; DLQI, Dermatology Life Quality Index; PP‐NRS, Peak Pruritus Numerical Scale.

At baseline, limited numbers of patients reported small or no effect of AD on QoL (Fig. 3a and Fig. 4a). By week 12, greater proportions of patients reported fewer effects of AD on their QoL, with the greatest benefit on QoL observed among patients experiencing higher threshold EASI and PP‐NRS efficacy responses (Fig. 3b and Fig. 4b). For example, at 12 weeks, 28.8%, 36.7% and 46.2% of patients with EASI‐75 to

The difference regarding QoL outcomes was even more marked between patients reaching different PP‐NRS efficacy response thresholds. Approximately four times the proportion of PP‐NRS0/1 responders treated with abrocitinib 200 mg (3.79 times the proportion of responders) reported that their AD had ‘no effect’ on their QoL at week 12, compared with PP‐NRS4 responders who did not achieve PP‐NRS0/1 treated with the same dose (66.3% vs. 17.5%; (Fig. 4b). Similarly, approximately three times the proportion of PP‐NRS0/1 responders treated with abrocitinib 100 mg (3.11 times the proportion of responders) reported that their AD had ‘no effect’ on their QoL at week 12, compared with PP‐NRS4 responders who did not achieve PP‐NRS0/1 treated with the same dose (62.1% vs. 20.0%; Fig. 4b).

Representative patient cases

Changes in skin involvement in abrocitinib‐treated patients from baseline to week 12 are shown in Fig. 5. One patient who received abrocitinib 100 mg had an EASI score of 19.8 and 3.8 at baseline and week 12, respectively, that qualified as an EASI‐75 to

Figure 5

Photographs of patients who received abrocitinib 100 mg at baseline, week 2 and week 12. EASI, Eczema Area and Severity Index.

Discussion

The results of these post hoc pooled analyses indicate that substantial proportions of patients with moderate‐to‐severe AD achieve higher threshold efficacy end points (EASI‐90 to

Importantly, patients who met higher threshold efficacy end points reported clinically meaningful benefits to QoL compared with patients who achieved EASI‐75 to

The reported improvement in QoL among patients achieving higher threshold efficacy responses may, in part, be explained by patient expectations or goals of treatment for AD. For example, patients with AD desire to achieve complete or almost complete skin clearance and report greater overall self‐perceived importance of complete or almost complete skin clearance, as well as control of itch, when compared with patients with psoriasis. In addition to skin clearance, itch control is also an important treatment aim for patients with AD. Alignment on meeting patient goals that enhance the impact of therapy on QoL, especially in the context of attaining higher threshold efficacy responses in terms of skin clearance and itch, should be important considerations in guiding treatment decisions. There remains a need for better insight into the treatment targets that are important to patients, as this should affect management.

Limitations of these analyses include their post hoc nature, the relatively short duration of the studies (12 weeks) and that formal hypothesis testing was not possible. Nonetheless, these data provide robust evidence for treatment with abrocitinib leading to the attainment of higher threshold efficacy responses, and that these outcomes are associated with clinically meaningful improvements in QoL outcomes when compared with EASI‐75 to