Long-term safety results from a phase 3 open-label study of a fixed combination halobetasol propionate 0.01% and tazarotene 0.045% lotion in moderate-to-severe plaque psoriasis
Authors: Mark G. Lebwohl, Jeffrey L. Sugarman, Linda Stein Gold, David M. Pariser, Tina Lin, Radhakrishnan Pillai, Gina Martin, Susan Harris, Robert Israel
Journal: Journal of the American Academy of Dermatology (2018)

To the Editor: Psoriasis is a chronic immune-mediated disease with a variable natural history marked by remissions and exacerbations that is often refractory to treatment. Topical therapy, first-line for mild disease, is often in combination with systemic agents in more severe psoriasis.1Menter A. Korman N.J. Elmets C.A. et al.Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies.J Am Acad Dermatol. 2009; 60: 643-659Abstract Full Text Full Text PDF PubMed Scopus (409) Google Scholar Approval for potent steroids is limited to 2-4 weeks.1Menter A. Korman N.J. Elmets C.A. et al.Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies.J Am Acad Dermatol. 2009; 60: 643-659Abstract Full Text Full Text PDF PubMed Scopus (409) Google Scholar, 2Levin E. Gupta R. Butler D. et al.Topical steroid risk analysis: differentiating between physiologic and pathologic adrenal suppression.J Dermatolog Treat. 2014; 25: 501-506Crossref PubMed Scopus (43) Google Scholar, 3Lam L.H. Sugarman J.L. Adrenal suppression with chronic topical corticosteroid use in psoriasis patients.J Drugs Dermatol. 2016; 15: 945-948PubMed Google Scholar Recent data on a novel halobetasol propionate 0.01%/tazarotene 0.045% (HP/TAZ) lotion formulation were published.4Sugarman J.L. Stein L.S. Lebwohl M.G. et al.A phase 2, multicenter, double-blind, randomized, vehicle controlled clinical study to assess the safety and efficacy of a halobetasol/tazarotene fixed combination in the treatment of plaque psoriasis.J Drugs Dermatol. 2017; 16: 194-201Google Scholar, 5Gold L.S. Lebwohl M.G. Sugarman J.L. et al.Safety and efficacy of a halobetasol/tazarotene fixed combination in the treatment of moderate-to-severe plaque psoriasis: results of two phase 3 randomized controlled trials.J Am Acad Dermatol. 2018; 79: 287-293Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar This combination provided synergistic and sustained efficacy over individual active ingredients after daily use for 8 weeks and a 4-week posttreatment period with good tolerability. Treatment success (at least a 2-grade improvement from baseline Investigator's Global Assessment [IGA] score and an IGA score equating to clear or almost clear) deltas (active minus vehicle) at week 8 and week 12 were 42.8% and 31.2%, respectively, for HP/TAZ lotion compared with 32.5% and 20.0%, respectively, for the combined effect (HP+TAZ).4Sugarman J.L. Stein L.S. Lebwohl M.G. et al.A phase 2, multicenter, double-blind, randomized, vehicle controlled clinical study to assess the safety and efficacy of a halobetasol/tazarotene fixed combination in the treatment of plaque psoriasis.J Drugs Dermatol. 2017; 16: 194-201Google Scholar The most common treatment-related adverse events (AEs) in the subsequent phase 3 studies were contact dermatitis (6.3%), pruritus (2.2%), and application site pain (2.6%).5Gold L.S. Lebwohl M.G. Sugarman J.L. et al.Safety and efficacy of a halobetasol/tazarotene fixed combination in the treatment of moderate-to-severe plaque psoriasis: results of two phase 3 randomized controlled trials.J Am Acad Dermatol. 2018; 79: 287-293Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The incidence of these AEs was much lower than that reported with TAZ alone in the phase 2 study (where the most common treatment-related AEs were application site pain [8.6%], pruritis [6.9%], and erythema [3.4%]).4Sugarman J.L. Stein L.S. Lebwohl M.G. et al.A phase 2, multicenter, double-blind, randomized, vehicle controlled clinical study to assess the safety and efficacy of a halobetasol/tazarotene fixed combination in the treatment of plaque psoriasis.J Drugs Dermatol. 2017; 16: 194-201Google Scholar We report results of a phase 3, long-term multicenter, open-label study in 555 participants (aged 19-87 [mean 51.9] years of age) with moderate-to-severe plaque psoriasis treated with HP/TAZ lotion followed for up to 1 year, with a focus on safety and tolerability. Baseline IGA was 3 (moderate) in 86.5% of participants and 4 (severe) in the remainder. Study participants were treated with HP/TAZ lotion once daily for 8 weeks and then as needed. Only investigator-approved nonmedicated cleansers, moisturizers, and sunscreens were allowed in the treatment areas; no other skin care product use was permitted in the study. Evaluations were carried out at baseline, weeks 2 and 4, and every 4 weeks thereafter. Treatment success was defined as an IGA score of 0 or 1 (clear or almost clear). Participants without treatment success at week 8 were to be treated for a further 4 weeks; otherwise, they received no further HP/TAZ lotion treatment. All participants were evaluated at week 12; those who demonstrated ≥1-grade improvement in IGA from baseline continued in the study. Only 26 (4.7%) discontinued at week 12 due to lack of efficacy. Treatment continued in 4-week cycles. Participants were treated with HP/TAZ lotion once daily for 4 weeks if they had not achieved treatment success or received no treatment until the next evaluation if they had achieved treatment success, with a maximum continuous exposure of 24 weeks. Participants who did not achieve treatment success after 24 weeks of continuous treatment were discontinued. Consistent with findings in other long-term psoriasis trials of patients with moderate-to-severe disease treated with biologics,6Noiles K. Vender R. Biologic survival.J Drugs Dermatol. 2009; 8: 329-333Google Scholar one fifth (20.9%) of participants stopped treatment at 24 weeks because of lack of efficacy. Data on adherence to topical treatment suggest these data are better than what would be expected.7Zaghloul S.S. Goodfield M.J.D. Objective assessment of compliance with psoriasis treatment.Arch Dermatol. 2004; 140: 408-414Crossref PubMed Scopus (245) Google Scholar, 8Duffin K.C. Yeung H. Takeshita J. et al.Patient satisfaction with treatments for moderate-to-severe plaque psoriasis in clinical practice.Br J Dermatol. 2014; 170: 672-680Google Scholar AE incidence was similar to that reported in the pivotal studies and peaked around day 60, remaining stable from day 90 until study end (Fig 1). Treatment-related AEs reported by ≥2% of participants within any designated treatment period included application site reactions of dermatitis, pruritus, and pain (Table I). Overall, 7.5% of participants discontinued due to treatment-emergent AEs: dermatitis and pruritus (7 persons each) and pain (6 persons) were the most frequent. Treatment-emergent serious AEs (SAEs) were noted in 3.3% of participants; none were considered treatment-related. Three participants discontinued due to SAEs (cellulitis gangrenous, pericardial effusion, small intestine adenocarcinoma). No deaths were reported, and no clinically noticeable trends identified with regard to other local skin AEs (eg, skin atrophy, folliculitis, telangiectasia, and striae). AEs were not correlated with the timing or duration of treatment applications, frequency, and duration of use. Marked improvements in baseline severity of itching, dryness, and burning/stinging occurred within 2 weeks and were sustained over the course of the study.Table ISummary of treatment emergent adverse events related to study drug reported by ≥2% of participants, by treatment period (safety population)Application site reactions0-12 weeks, N = 527>12-24 weeks, N = 392>24-36 weeks, N = 239>36 weeks, EOS, N = 219Dermatitis38 (7.2)20 (5.1)6 (2.5)2 (0.9)Pruritus22 (4.2)6 (1.5)4 (1.7)2 (0.9)Pain24 (4.6)2 (0.5)1 (0.4)1 (0.5)Values given are the number of percentage of reported adverse events.EOS, End of study. Open table in a new tab Values given are the number of percentage of reported adverse events. EOS, End of study. In summary, we report the long-term safety profile of HP/TAZ lotion in participants with moderate-to-severe psoriasis when used as monotherapy over a period of 1 year. Though infrequent, AEs reported were consistent with a product containing TCS and retinoid.9Weinstein G.D. Koo J.Y. Krueger G.G. et al.Tazarotene cream in the treatment of psoriasis: two multicenter, double-blind, randomized, vehicle-controlled studies of the safety and efficacy of tazarotene creams 0.05% and 0.1% applied once daily for 12 weeks.J Am Acad Dermatol. 2003; 48: 760-767Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 10Gupta S.K. Singh K.K. Lalit M. Comparative therapeutic evaluation of different topicals and narrow band ultraviolet B therapy combined with systemic methotrexate in the treatment of palmoplantar psoriasis.Indian J Dermatol. 2011 Mar; 56: 165-170Google Scholar Study limitations include the open-label design and lack of follow-up beyond 1 year. The authors acknowledge Brian Bulley, MSc, of Konic Limited for medical writing support. Ortho Dermatologics, a division of Valeant Pharmaceuticals North America LLC funded Konic's activities pertaining to this manuscript.