Newly Approved Therapies for the Treatment of Plaque Psoriasis in Adults

Plaque psoriasis is the most common type of psoriasis among adults and older children, with a prevalence in adults ranging from 0.5 percent to as high as 11.4 percent worldwide.^1-4 It is a chronic, systemic, inflammatory disorder with a significant psychosocial burden and is associated with comorbidities, such as distress, depression, anxiety, self-consciousness, impaired social functioning, decreased work productivity or unemployment, higher BMI, smoking, and alcohol use.^1-3,5-7.8,9 The purpose of this review is to discuss the two most recently approved agents in depth.

Skyrizi (risankizumab-rzaa)

Mechanism of action. Risankizumab is a human monoclonal IgG1 antibody that specifically binds to the p19 subunit of IL-23. IL-23 is a heterodimeric complex that consists of two subunits: p19 and p40.⁹

Risankizumab in psoriasis clinical trials. In a randomized, double-blind, placebo-controlled Phase 1 clinical trial, risankizumab was associated with clinical improvement in patients with moderate to severe plaque psoriasis starting at week 2 and up to 66 weeks after treatment.^1,10 By week 12, risankizumab at multiple subcutaneous and intravenous doses was effective, compared to the control.^1,10-12 Specifically, 87 percent of all risankizumab-treated participants (27/31) achieved 75 percent reduction in Psoriasis Area and Severity Index (PASI 75) score compared to none of eight placebo-treated participants (P<.001).^1,10-12 Use of risankizumab was also found to be associated with decreased expression of genes and proteins seen in patients with active psoriatic disease (involved in the IL-23/IL-17 axis, keratinocyte and epithelial-cell differentiation, tissue inflammation).^12,13 All patients who received subcutaneous risankizumab obtained a static Physician’s Global Assessment (sPGA) score of 0 (“clear”) or 1 (“almost clear”) at weeks 12 and 24, compared to none of patients in the control group.^1,10-12,14 Common adverse events (AEs) occurred in 65 percent of risankizumab-treated patients (20/31) and included upper respiratory tract infections, nasopharyngitis, and infection. Serious adverse events (SAEs) occurred during the study but were not found to be treatment-related.^1,10-12,14

In a Phase 2 randomized trial comparing risankizumab and ustekinumab, subcutaneous risankizumab was associated with a superior clinical response compared to ustekinumab in the treatment of moderate to severe psoriasis.^12-14 At week 12, 77 percent of risankizumab-treated patients (90mg and 180mg, pooled) achieved a 90 percent reduction in Psoriasis Area and Severity Index (PASI 90) compared to 40 percent of patients treated with ustekinumab (P<0.001).^12-14 The onset of activity with risankizumab was also found to be faster and the duration of effect longer than with ustekinumab. Furthermore, patients in the risankizumab 180mg group achieved PASI 90 eight weeks earlier, and the duration of its effect lasted more than two months longer than for those treated with ustekinumab.^12-14 Clinical responses with risankizumab correlated well with quality measurements, such as increased quality of life, decreased joint pain in patients with psoriatic arthritis (PsA), and improvements in scalp, palmoplantar, and nail psoriasis.^12,14,15 It was also found that immunohistochemical biomarkers associated with the IL-17/IL-23 axis and gene expression linked to psoriatic pathogenesis were reduced by week 4 in the risankizumab-treated group, consistent with Phase 1 trial findings.^12,13 The most common AE among all treatment groups was nasopharyngitis.^12,16 However, the study was neither large enough nor long enough in duration to assess the safety profile of risankizumab.

In two randomized, double-blind, placebo-controlled, and ustekinumab-controlled Phase 3 trials (UltIMMa-1 and UltIMMa-2), risankizumab showed greater efficacy in the treatment of moderate to severe plaque psoriasis compared to ustekinumab and placebo.^12,14,15 At week 16 of UltIMMa-1, 75.3 percent of risankizumab-treated patients (150mg) achieved PASI 90 versus 42 percent of ustekinumab-treated patients (45mg or 90mg) and 4.9 percent of placebo-treated patients (p<0.0001 vs placebo and ustekinumab). At week 16 of UltIMMa-2, 74.8 percent of risankizumab-treated patients achieved PASI 90 versus 47.5 percent of ustekinumab-treated patients and two percent of placebo-treated patients (p<0.0001 vs placebo and ustekinumab).^12,14,15 In UltIMMa-1 and UltIMMa-2, sPGA 0 or 1 was achieved by 83.7 percent and 87.8 percent of risankizumab-treated patients, respectively, compared to 63 percent and 78.5 percent ustekinumab-treated patients, respectively, and 7.8 percent and 5.1 percent of placebo-treated patients, respectively (p<0.0001 vs placebo and ustekinumab).^12,14,15 By week 52, risankizumab maintained superiority in clinical response compared to ustekinumab and placebo. In UltIMMa-1 and UltIMMa-2, significantly more patients treated with risankizumab achieved PASI 90 (81.3 percent) and sPGA scores of 0 or 1 (84.8 percent) compared to 44.7 percent and 62.3 percent of ustekinumab-treated patients, respectively (p<0.001). A greater proportion of risankizumab-treated patients also achieved PASI 75 and PASI 100 than patients treated with ustekinumab (91.6 percent and 57.9 percent, respectively; p<0.001).¹⁶ In the studies, treatment adverse event profiles were similar among all treatment groups.^15,16

In another Phase 3 randomized and double-blind study (IMMvent), risankizumab was more effective than adalimumab at providing skin clearance in patients with moderate to severe psoriasis. At week 16, 72 percent of risankizumab-treated patients achieved PASI 90 compared to 47 percent of adalimumab-treated patients (p<0.0001).^12,14,17 In addition, 84 percent of risankizumab-treated patients achieved sPGA scores of 0 or 1 compared to 60 percent of adalimumab-treated patients (p<0.0001). In adalimumab-intermediate responders, PASI 90 was achieved by 66 percent of patients who switched to risankizumab at week 44 versus 21 percent of patients who remained on adalimumab (p<0.0001).^12,14,17 At week 44, mean PASI improvement from baseline was 92.9 percent in patients who switched to risankizumab versus 71.9 percent in patients who continued adalimumab therapy (P < .001).¹⁷ Switching to risankizumab also correlated with a greater improvement in quality of life (QoL) as measured by the proportion of risankizumab-treated versus adalimumab-treated patients who achieved Dermatology Life Quality Index (DLQI) scores of 0-1 (no effect on patient’s life) at week 44 (66.0 percent vs 28.6 percent, respectively; P < .001).¹⁷ There were no additional safety concerns among patients who switched from adalimumab to risankizumab, suggesting that risankizumab offers flexibility in the long-term management of psoriasis.¹⁴

A recent analysis of phase III studies—UltIMMa-1, UltIMMa-2, and IMMvent—revealed that risankizumab treatment was associated with superior efficacy compared to placebo regardless of psoriasis treatment history, including prior biologic failure.¹⁴ Further studies are currently underway and the results of these Phase 3 clinical trials are pending.

Duobrii (0.01% halobetasol and 0.045% tazarotene lotion)

Mechanism of action. Duobrii is a newly approved dual-agent medication in the form of a lotion, composed of two topical treatments for psoriasis—halobetasol propionate (HP) and tazarotene (TAZ)—which have established safety profiles.⁸ It combines the anti-inflammatory effects of HP (0.01%), a corticosteroid, with the immunomodulatory effects of TAZ (0.045%), a vitamin A derivative. HP, a class I topical corticosteroid, possesses anti-inflammatory, antimitotic, antiapoptotic, vasoconstrictive, and immunomodulatory functions, yet the exact mechanism of action in treating plaque psoriasis is unknown.¹⁸ TAZ is known to down-regulate markers of keratinocyte differentiation, proliferation, and inflammation, while upregulating markers associated with antiproliferative activity (tazarotene induced gene (TIG)-1, TIG-2, TIG-3).¹⁹ The combination of HP/TAZ is thought to reduce irritant effects from tazarotene and cutaneous halobetasol-related AEs without the limitation of two weeks’ consecutive use.^20-24 The combination drug is also known to have synergistic efficacy, thereby providing rapid symptomatic relief, increased duration of treatment benefit, and prolonged length of remission.^20,22-24

HP/TAZ lotion in psoriasis clinical trials. In a Phase 2 randomized, double-blind, and vehicle-controlled study, HP/TAZ was more effective than its monads and the vehicle in achieving treatment success—defined as at least a 2-grade improvement from baseline in the Investigator’s Global Assessment (IGA) score and a score of 0 (‘clear’) or 1 (‘almost clear’).^20,22,23 HP/TAZ also improved signs of psoriasis (erythema, plaque elevation, and scaling at the target lesion) as early as two weeks. At week 8, 52.5 percent of HP/TAZ-treated patients had treatment success compared to 33.3 percent of HP-treated patients (P=0.033), 18.6 percent of TAZ-treated patients (P<0.001), and 9.7 percent in the vehicle control (P<0.001).^20,22,23 Patients treated with HP/TAZ-lotion also achieved a 2-grade improvement in IGA in erythema (54.2 percent), plaque elevation (67.8 percent), and scaling (64.4 percent). Treatment emergent adverse events (TEAEs) included application site reactions, and were attributed to the tazarotene component.^20,22,23 Safety data was consistent with the individual safety profiles of HP and TAZ and no new safety concerns were found with the combination drug.^20,22,23

In two Phase 3 randomized, double-blind, vehicle-controlled studies, HP/TAZ lotion once per day demonstrated statistically significant superiority in treatment efficacy compared to the vehicle-control. By week 8, 35.8 percent (study 1) and 45.3 percent (study 2) of HP/TAZ-treated patients achieved treatment success (at least a 2-grade improvement from baseline in IGA score and a score of 0 or 1) compared to the vehicle-control(7.0 percent and 12.5 percent , respectively; both P < .001). Patients stopped HP/TAZ lotion at week 8, and at week 12, the majority of subjects maintained sustained therapeutic success: 33.3 percent (study 1) and 33.4 percent (study 2) of HP/TAZ-treated patients compared to 8.5 percent and 8.8 percent of patients in the vehicle control group, respectively (both P < .001).²⁴ In addition, HP/TAZ lotion provided rapid and substantial reductions in affected body surface area (BSA) and improvements in patient-reported QoL. HP/TAZ lotion also improved signs and symptoms of psoriasis, including baseline itching (54 percent reduction by week 2), skin dryness (44 percent reduction by week 8) and burning/stinging (46 percent reduction by week 8). These improvements were sustained and efficacy was maintained after eight weeks of treatment. The most commonly reported AE was irritant contact dermatitis, a consequence of the tazarotene component as seen in Phase 2 studies. No new safety concerns were found with the combination drug, as seen with previous studies.²¹

In a long-term Phase 3 study focusing on the safety and tolerability of HP/TAZ, the incidence of adverse events (AEs) was similar to those in pivotal studies and peaked around day 60 before stabilizing at day 90 through the end of the study.²⁵ Treatment-related AEs were reported by ≥2 percent of participants and included application site reactions (dermatitis, pruritus, and pain). Treatment-emergent SAEs were observed in 3.3 percent of patients, yet none were considered treatment-related.²⁵ Interestingly, AEs did not correlate with the timing of medication application, frequency, or duration of treatment. During the course of the study, patients experienced marked improvements in severity of itching, dryness, and burning/stinging within two weeks of treatment administration, which was sustained over the course of the study.²⁵

Conclusion

Psoriasis is a chronic, relapsing, immune-mediated disease driven by a number of genetic, immunologic, and environmental factors. It carries a significant psychosocial burden to society as a whole, especially in patients with moderate to severe disease presenting with debilitating symptoms and treatment challenges. Continued research into the pathogenesis of psoriasis is necessary for the development of novel treatment modalities. The latest available treatment options approved by the FDA for psoriasis—Skyrizi (risankizumab-rzaa) and Duobrii (0.01% halobetasol and 0.045% tazarotene lotion)—are effective and safe treatments for plaque psoriasis in adults.

To learn more about new therapies for psoriasis, consider attending the inaugural 2020 San Diego Dermatology Symposium from September 11-13, 2020 at the InterContinental San Diego where Dr. Wu will discuss this more in depth. sddermsymposium.org

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