Highlights

Zoryve (roflumilast) is a new drug indicated for the treatment of plaque psoriasis, including intertriginous areas (skin folds), in patients 12 years of age and older.

Zoryve, developed by Arcutis Biotherapeutics and made into a cream formulation, is approved by the U.S. Food and Drug Administration (FDA) in late July 2022.

Zoryve cream, which is applied once a day, is an optimal alternative to potent topical corticosteroids, being as effective as they are and superior in terms of safety. Zoryve can be used to treat plaque psoriasis of any severity and without any restrictions on the duration of the application.

Zoryve will be commercially available by mid-August 2022.

Zoryve (roflumilast)

 

Zoryve: Mechanism of Action of Roflumilast

Roflumilast is a selective phosphodiesterase 4 (PDE4) inhibitor, an enzyme that cleaves cyclic adenosine monophosphate (cAMP). The resulting increase in the intracellular concentration of cAMP leads to a decrease in the expression of several proinflammatory factors such as tumor necrosis factor (TNF), interleukin 17 (IL-17), interleukin 23 (IL-23), and others, as well as an increase in the expression of anti-inflammatory interleukin 10 (IL-10).

Suppression of the cAMP signaling pathway was first proposed for the treatment of psoriasis over two decades ago. [1] cAMP is a key secondary messenger that is expressed by all cells and is directly involved in a wide range of normal cellular responses.

Briefly, cAMP is activated by G-protein coupled receptor (GPCR) ligands, which mediate signal transduction upon cAMP activation, primarily through protein kinase A (PKA). [2] PKA then activates cAMP response element-binding protein that is possessed by numerous genes involved in the pathophysiology of psoriasis, including interleukin 2 (IL-2), interleukin 6 (IL-6), IL-10, and TNF. [3] The concentration of intracellular cAMP is mediated by adenylyl cyclase (AC) and phosphodiesterases (PDEs). PDEs are responsible for the degradation of the cAMP, with the PDE4 isoenzyme being the most active in immune cells such as lymphocytes, granulocytes, and monocytes/macrophages. [4] [5]

This is why PDE4 inhibitors suppress the production and secretion of inflammatory cytokines, including interferon gamma (IFN-γ), TNF, IL-2, interleukin 12 (IL-12), and IL-23, [6] and also reduce superoxide production and chemotaxis. [4] [6] In addition, PDE4 inhibitors increase levels of anti-inflammatory cytokines such as IL-10 by activating CREB.

Judging by half maximal inhibitory concentration (IC50) of roflumilast, it is about 25–300 times more potent than the commercialized PDE4 inhibitors apremilast and crisaborole. [7]

The originator of roflumilast is Altana Pharma. The oral version of roflumilast is represented by Daliresp/Daxas, promoted by AstraZeneca. Tableted Daliresp/Daxas is used to reduce the risk of exacerbations of severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and in its maintenance treatment in addition to bronchodilator therapy.

In July 2018, AstraZeneca licensed Arcutis the rights to the topical formulation of roflumilast. Arcutis has developed its topical variants in cream (ARQ-151) and foam (ARQ-154).

 

Zoryve: Efficacy and Safety of Roflumilast in Psoriasis Treatment

The efficacy and safety of roflumilast cream were validated in two design-identical clinical trials, DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389) phase 3 (randomized, double-blind, placebo-controlled, multicenter, in the U.S. and Canada), which enrolled patients (n=881) aged 2 years and older with plaque psoriasis.

Among the main inclusion criteria: severity of psoriasis from mild to severe, with disease covering 2% to 20% of body surface area (BSA).

Baseline characteristics of participants: median age 47 years (6-88); male 64%; median psoriatic lesions area of 5.5% BSA; according to the investigator’s global assessment (IGA), 16% of patients had mild (IGA 2), 76% had moderate (IGA 3), and 8% had severe (IGA 4) psoriasis.

Subjects received daily topical roflumilast or placebo.

The primary efficacy endpoint for plaque psoriasis treatment was the proportion of patients who demonstrated clear or nearly clear skin (IGA 0/1) after 8 weeks of therapy along with an IGA improvement of at least 2 points.

Use of Zoryve cream achieved the reported primary endpoint among 42% and 38% of patients in the DERMIS-1 and DERMIS-2 clinical trials — versus 6% and 7% among those receiving placebo (p<0.0001).

Topical roflumilast also managed to treat psoriasis in intertriginous areas — psoriasis in areas of skin-to-skin contact such as the armpits, under breast, abdominal folds, groin, and between the buttocks. Therapy success was recorded for 71% and 68% of patients — vs. 14% and 19% (p<0.0001).

42% and 39% of patients treated with Zoryve demonstrated at least 75% skin clearance, according to the Psoriasis Area and Severity Index (PASI 75) — vs. 8% and 5% (p<0.0001).

Among patients who had a score of at least 4 points on the Worst Itch Numeric Rating Scale (WI-NRS) score (WI-NRS) [0 no itch, 10 worst itch imaginable], use of Zoryve resulted in a reduction of the WI-NRS score of 4 or more points among 68% and 69% — vs. 27% and 36% in the placebo groups (p<0.0001). Statistically significant relief of pruritus began to be noted after 2–4 weeks of treatment.

When the results of the clinical trials were pooled, it turned out that the success of psoriasis treatment with topical roflumilast was fair for 40% of patients — vs. 7% in the control group (p<0.0001).

The PASI75 score was achieved in 40% of subjects, treatment success for intertriginous psoriasis was recorded for 70%, and itching was relieved in 69%.

The effectiveness of psoriasis treatment was independent of its severity. Thus, with an initial skin lesions > 10% BSA, therapy with topical roflumilast was successful for 47% of patients, with 5%–10% BSA for 37%, and with < 5% BSA for 40%.

In patients with psoriatic plaques on the knees and/or elbows, which are particularly difficult areas to treat, Zoryve provided an IGA 0/1 for 49% of patients — vs. 8% in the placebo group (p<0.0001).

Topical roflumilast improved quality of life according to the Dermatology Life Quality Index (DLQI) by 65% and 69% in DERMIS-1 and DERMIS-2 — vs. a 13% and 9% improvement with placebo (p<0.0001).

Administration of Zoryve cream was characterized by acceptable tolerability. The most common adverse events included diarrhea (in 3.1% of patients), headache (2.4%), insomnia (1.4%), nausea (1.2%), application site pain (1.0%), upper respiratory tract infections (1.0%), and urinary tract infections (1.0%).

The NCT03764475 phase 2b (nonrandomized, open-label, multicenter, in the U.S. and Canada) clinical trial tested the long-term administration of topical roflumilast in the treatment of patients (n=332) with plaque psoriasis. It included both participants who had completed the 12-week NCT03638258 phase 2b clinical trial and those who had not previously received Zoryve.

After a 52-week treatment of plaque psoriasis with Zoryve cream, therapeutic success was documented for 35% and 40% of patients, respectively. At the same time, IGA 0/1 with an IGA improvement of at least 2 points was maintained by 67% of patients who came out to it after 12 weeks of therapy. Successful treatment of intertriginous psoriasis was recorded for 67% of patients who had not previously received topical roflumilast.

According to the interim results of the DERMIS-OLE (NCT04286607) phase 3 clinical trial, administration of Zoryve for 32 weeks resulted in the following proportions of patients with successful treatment of plaque psoriasis: 41%, 50%, 57% and 48% after 8, 12, 20 and 32 weeks of therapy, respectively.

 

Roflumilast: What’s Next

Arcutis intends to expand the range of indications for topical roflumilast. Thus, this drug in the cream formulation is undergoing final clinical testing in the treatment of atopic dermatitis (eczema), and, in the foam formulation, seborrheic dermatitis and psoriasis, including scalp psoriasis.

The STRATUM (NCT04973228) phase 3 clinical trial found that 8 weeks of daily use of roflumilast foam provided clear or nearly clear skin (IGA 0/1) with an IGA increase of at least 2 points among 80% of adults and adolescents with moderate-to-severe seborrheic dermatitis — versus 59% in the placebo group (p<0.0001). Meanwhile, over 50% of patients receiving roflumilast achieved clear skin (IGA 0). Regulatory filing is scheduled for the first half of 2023.

Results from the 8-week ARRECTOR (NCT05028582) phase 3 clinical trial testing roflumilast foam in the treatment of scalp psoriasis in adults and adolescents will be available soon.

 

Expert Comments

High-potency topical glucocorticoids and vitamin D derivatives are the main drugs for psoriasis treatment. Topical glucocorticoids are effective in treating psoriasis, but their use is limited to 2 to 8 weeks, also due to adverse events that are slow to resolve (e.g., skin atrophy) or even irreversible with long-term use (e.g., striae). [1] [2] Vitamin D derivatives are less effective and may cause local irritation. [3] Topical calcineurin inhibitors have been used off-label to treat facial psoriasis and intertriginous psoriasis (otherwise ineffective), [4] but the frequency of their use declined dramatically when the risks of cancer became known. Topical retinoids (vitamin A derivatives) are used similarly, their use is accompanied by local irritation. [5] Treatment of sensitive areas affected by psoriasis, such as the face and intertriginous areas, with topical agents requires special attention, not only because of skin sensitivity, but also the need to consider factors that potentially enhance systemic absorption.

The therapeutic validity of phosphodiesterase 4 (PDE4) inhibition in the treatment of psoriasis was confirmed by Celgene’s oral Otezla (apremilast), which was bought by Bristol-Myers Squibb, which later sold the drug to Amgen for antitrust purposes. Tableted apremilast for the treatment of moderate-to-severe plaque psoriasis made its debut in September 2014. In December 2021, Otezla received approval for the treatment of plaque psoriasis regardless of severity.

PDE4 inhibition for dermatological diseases has also found its way into Pfizer’s topical Eucrisa (crisaborole). Crisaborole ointment, which appeared in December 2016, is indicated for the treatment of mild-to-moderate atopic dermatitis (eczema) in patients aged 3 months and older.

During the development of topical roflumilast, Arcutis aimed to create the ideal topical treatment for psoriasis, which should have therapeutic efficacy on the level of potent corticosteroids with the possibility of application on a continuous basis and on all skin areas. It seems to have succeeded.

If we compare the effectiveness of plaque psoriasis treatment with Zoryve cream, which eliminated psoriatic plaques in 8 weeks in 40% of patients, with the effectiveness of topical combination drugs containing potent corticosteroid and vitamin D/vitamin A, the effectiveness of roflumilast is not inferior. In other words, Zoryve is the optimal choice for patients who are prescribed topical corticosteroids to treat plaque psoriasis, which is the majority of patients.

Thus, an 8-week treatment with Wynzora (betamethasone + calcipotriene) cream by Denmark’s MC2 Therapeutics resulted in clear or nearly clear skin in 37% of patients with mild-to-moderate plague psoriasis. An 8-week regimen of Duobrii (halobetasol + tazarotene) lotion by Ortho Dermatologics, owned by Canada’s Bausch Health Companies, was successful in 36% and 45% of patients with moderate-to-severe plaque psoriasis. An 8-week treatment of mild-to-moderate plaque psoriasis with Taclonex (betamethasone + calcipotriene) suspension of Denmark’s Leo Pharma resulted in clear or nearly clear skin in 29% of patients, whereas a 4-week application of Taclonex ointment cured 48% of patients.

Approved in May 2022, Vtama (topinarof) cream, an aryl hydrocarbon receptor (AhR) agonist by Dermavant Sciences as part of Roivant Sciences, cleared psoriatic plaques from the skin in 36% and 40% of patients in 12 weeks of therapy.

Oral Otezla is able to clear the skin in 16 weeks in 20%–44% of patients.

Long-term use of Zoryve is generally safe, with cases of diarrhea kept to a minimum due to the topical formulation of this PDE4 inhibitor. Up to 40% of patients experience diarrhea when prescribed Otezla, an oral PDE4 inhibitor.

Understanding the saturation of the psoriasis treatment market, Arcutis did not get greedy, putting the U.S. price tag on Zoryve at $825 per tube. By comparison, the price of a package of Wynzora in the U.S. is $1275, Duobrii is $985, Taclonex is $1120, Vtama is $1400, and a month’s course of Otezla costs $4580.

Zoryve, of course, does not plan to compete with highly effective antipsoriatic biological drugs, such as Skyrizi (risankizumab), Bimzelx (bimekizumab), Tremfya (guselkumab), or Taltz (ixekizumab), which can treat up to 90% of patients with moderate-to-severe plaque psoriasis in 16 weeks.

Arcutis itself predicts that by 2030, topical roflumilast for psoriasis treatment could reach $0.7 billion to $1.2 billion in sales per year in the United States alone. If it adds treatments for atopic dermatitis and seborrheic dermatitis, demand would rise to an annual $1.8–$3.8 billion.

 

Extras

Zoryve (roflumilast). Prescribing information. U.S. [PDF]

Arcutis Biotherapeutics. Zoryve (roflumilast). FDA approval call. August 1, 2020. [PDF]

Arcutis Biotherapeutics. Investor day. March 28, 2022. [PDF]

DERMIS-1/DERMIS-2 phase 3 plaque psoriasis topline data review. Arcutis Biotherapeutics, February 2021. [PDF]

Pooled efficacy and safety results from the DERMIS-1 and DERMIS-2 phase 3 trials of once-daily roflumilast cream 0.3% by baseline body surface area. American Academy of Dermatology (AAD), March 2022. [PDF]

Pooled efficacy and safety results from the DERMIS-1 and DERMIS-2 phase 3 trials of once-daily roflumilast cream 0.3% for treatment of chronic plaque psoriasis. AAD, March 2022. [PDF]

Efficacy and safety of once-daily roflumilast cream 0.3% in patients with knee/elbow involvement: Pooled results from phase 3 trials (DERMIS-1 and DERMIS-2). AAD, March 2022. [PDF]

Long-term safety and efficacy of roflumilast cream 0.3% in patients with chronic plaque psoriasis: Interim results from a 24-week, phase 3 open-label study. AAD, March 2022. [PDF]

Phase 2b study of roflumilast foam in adolescents and adults with scalp and body psoriasis. Arcutis Biotherapeutics, November 2020. [PDF]

Roflumilast cream, a once-daily, potent phosphodiesterase-4 inhibitor, in chronic plaque psoriasis patients: Efficacy and safety from DERMIS-1 and DERMIS-2 phase 3 trials. European Academy of Dermatology and Venereology (EADV), May 2021. [source] [PDF]

Long-term safety and efficacy of roflumilast cream 0.3% in adult patients with chronic plaque psoriasis: Results from a 52-week, phase 2b open-label study. Innovations in Dermatology, March 2021. [PDF]

Trial of roflumilast cream for chronic plaque psoriasis. N Engl J Med. 2020 Jul 16;383(3):229-239. [source]

Roflumilast cream improves signs and symptoms of plaque psoriasis: Results from a phase 1/2a randomized, controlled study. J Drugs Dermatol. 2020 Aug 1;19(8):734-740. [source]

The proposed PASI-HD provides more precise assessment of plaque psoriasis severity in anatomical regions with a low area score. Dermatol Ther (Heidelb). 2021 Aug;11(4):1079-1083. [source]

The PASI-HD improved precision in measuring disease severity in subjects with mild to moderate plaque psoriasis treated with roflumilast cream, a phosphodiesterase-4 inhibitor. AAD, April 2021. [PDF]

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