Mandated step therapy for dupilumab delays the inevitable

Introduction

Up to one-third of pediatric patients and 50% of adults with atopic dermatitis (AD) have moderate-to-severe disease refractory to topical treatment [1, 2]. Systemic therapy, such as dupilumab, is often required, but dupilumab use is often limited by insurance requirements for mandated step therapy (MST) even when Food and Drug Administration-approved indications are met [3, 4]. Prior studies have indicated that the average number of treatments for dupilumab MST is 2.9 [5]; however, to date, no study has examined negative effects of dupilumab MST beyond a general discussion of ethics [6]. Our aim is to quantify treatment delay associated with dupilumab MST.

Methods

Patients with moderate-to-severe AD refractory to topical treatments (defined as lack of improvement >6 months after treatment initiation) who were prescribed dupilumab between January 1, 2018 and January 1, 2023 were identified. Subjects were grouped according to their need to fulfill step therapy requirements before demographic information and treatment response data were gathered. Primary endpoints were time delay and increased appointment number caused by step mandates (Table 1). This study was exempted from approval by the University of Virginia Institutional Review Board. Chi-square and t test analysis was performed using SAS-9.4 software. Two-sided p < .05 was defined as statistically significant.

Table 1. Demographic characteristics and treatment timeline comparison between patients with and without step therapy mandates to obtain dupilumab coverage.

	Step therapy mandates	WITHOUT step therapy mandates	P-value
Age, Mean ± SD (n)	31.9 ± 21.7 (114)	39.1 ± 26.3 (332)	.008
0–5 years	8	19
6–11 years	15	43
12–17 years	14	43
18–64 years	69	145
65–100 years	8	82
Sex, n (%)			.94
Male	52 (45.6)	167 (50.3)
Female	62 (54.3)	165 (49.6)
Race, n (%)			.46
White/Caucasian	63 (55.3)	232 (69.8)
Black/African American	36 (31.5)	67 (20.2)
Asian	4 (3.5)	12 (3.6)
Native American	0 (0)	1 (0.3)
Other	11 (9.6)	20 (6.0)
Ethnicity, n (%)			.99
Non-Hispanic	5 (4.4)	17 (5.1)
Hispanic	109 (95.6)	315 (94.9)
Insurance provider % (n)			.0000003
Medicaid	54.0% (61/113)	20.4% (66/323)
Private	34.5% (39/113)	46.7% (151/323)
Medicare	10.6% (12/113)	29.1% (94/323)
Other	0.9% (1/113)	3.7% (12/323)
Mandate- related therapy delays ± SD (n)
Step Therapy delay, months	4.6 ± 4.99 (74)	0 ± 0 (281)	<.001
Step Therapy delay, appointments	1.4 ± 1.96 (74)	0 ± 0 (281)	<.001
Time between initial presentation and symptomatic improvement, days	693 ± 544 (92)	581 ± 448 (295)	.048
Appointments before symptomatic improvement once dupilumab initiated	6.0 ± 3.25 (92)	5.6 ± 3.76 (295)	.403

Results

Of 446 patients meeting inclusion criteria, 114 were subject to MST. While there was no statistical difference between the two cohorts regarding sex, race, or ethnicity, the MST group was younger by 7.2 years (31.9 ± 21.7, (1–72) vs 39.1 ± 26.3, (1–92); p < .008) compared to their counterparts (Table 1). Patients with MST were more likely to have Medicaid-based insurance (54% vs. 20%, p < .0001).

Of patients with MST, nearly 65% eventually received dupilumab (Table 2). Most common therapies mandated were topical calcineurin inhibitors (64.9%) or systemic immunosuppressants (33.3%) with most insurance claims necessitating additional step therapy (67.5%). The other 35% did not receive dupilumab for a variety of reasons, namely patient preference, high copays, and insurance denial even after completing step therapy requirements (Table 2).

Table 2. General characteristics of cohort step therapy mandates.

Among patients with mandated step therapy	(N)	%
Therapy mandated
Topical calcineurin inhibitor	74	64.9
Systemic immunosuppressant	38	33.3
Topical phosphodiesterase-4 inhibitor*	17	14.9
Topical corticosteroid	12	10.5
Phototherapy	10	8.77
Oral corticosteroid	2	1.75
Number of steps mandated
1	77	67.5
2	34	29.8
3	3	2.6
Patients that eventually started dupilumab	74	64.9
Reasons for not starting dupilumab despite completing step requirements
Insurance denial	30	75
Patient did not desire	5	12.5
Copay cost	3	7.5
Age restriction	2	5

*Crisaborole was the topical phosphodiesterase-4 inhibitor used as this was the only approved molecule for AD within this category at the time that the study was conducted.

MST caused an average therapeutic delay of 4.6 ± 4.99 months and 1.4 ± 1.96 appointments (p < .001) before treatment could be initiated. When examining the total time elapsed between initial presentation and any symptomatic improvement, patients with MST required an additional 112 days (693 ± 544 vs. 581 ± 448, p = .048) compared to their peers without MST. Any symptomatic improvement was defined as documented reduction in BSA involvement, reduction in patient-reported symptoms (i.e. pruritis, erythema), or decrease in the duration or frequency of AD flares as reported by the patient.

Discussion

MST appears to disproportionately affect younger individuals and those on Medicaid. This delay in care prolongs symptoms and increases healthcare costs (increased appointments for similar outcomes). Most patients ended up receiving dupilumab regardless of MST, so MST simply delays definitive therapy. Study limitations include its retrospective nature, small sample size, lack of long-term follow-up, and single-center data source. Further studies are needed to validate these findings in a larger cohort sample as well as in different states, given differing insurance MST criteria in different areas.

Disclosure statement

Dr. Flowers serves as a principal investigator for Abbvie, Acelyrin, Regeneron/Sanofi and Sun Pharmaceuticals. He has served on advisory boards for Argenx, Bristol-Myers Squibb and Janssen.