Oral Therapies

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Article
Bridging the GapsNew Directions and Practice-Impacting Recommendations in Plaque Psoriasis

This publication was developed independently by MJH Life Sciences Global Medical Affairs. Support for the thought leaders meeting and the publication was provided by Arcutis Biotherapeutics, Inc; The Bristol Myers Squibb Company; Janssen Global Services, LLC; and UCB, Inc.

Although topical therapies tend to be the cornerstone for treatment of psoriasis (PsO), systemic therapy may need to be added to achieve complete disease control (particularly for difficult-to-treat areas).1 Additionally, some patients prefer oral systemic options because of their convenience, ease of administration, and ability to be started and stopped.

Before the year 2000, oral therapies for PsO included methotrexate, acitretin, and cyclosporine. These medications tend to be relatively accessible and lower in cost than newer oral therapies or biologics.1 Methotrexate, a competitive inhibitor of dihydrofolate reductase, may be useful as an add-on to biologic therapy for patients who develop immunogenicity or who have an incomplete response to the biologic therapy.1 Cyclosporine, which inhibits calcineurin and blocks proinflammatory signals by binding to cyclophilin, may be used for short periods of time to achieve a quick response as patients wait for access to a targeted therapy.1 Cyclosporine has also demonstrated safety when used by pregnant women, and it also may be a good option for pediatric patients. Acitretin, an oral retinoid, is used infrequently because of its relatively low efficacy and teratogenic potential, but it may be a good option for a patient with concurrent squamous cell carcinoma, palmoplantar PsO, or pustular PsO.1 Also, unlike methotrexate and cyclosporine, acitretin has the advantage of not suppressing the immune system.1

However, these nontargeted agents have several limitations, including the need for long-term laboratory monitoring, the potential for drug-drug interactions, broad immunosuppression with methotrexate and cyclosporine, and adverse effects (AEs) with prolonged use. Long-term use of methotrexate has been associated with hepatotoxicity and liver fibrosis, bone marrow suppression, and, occasionally, pulmonary fibrosis, whereas extended use of cyclosporine has been linked to renal toxicity, hypertension, and development of nonmelanoma skin cancers. Furthermore, acitretin use has been related to teratogenicity for up to 3 years after its discontinuation; therefore, its use is contraindicated in people of childbearing potential. Given these limitations, there is an unmet need for more targeted oral therapies that allow for effective long-term management of plaque PsO.

Targeted Oral Therapies

Apremilast

Apremilast is a phosphodiesterase-4 (PDE4) inhibitor that binds to the PDE4 enzyme within inflammatory cells and that stops the conversion of cyclic adenosine monophosphate (cAMP) to AMP; the resulting increase in cAMP increases levels of the anti-inflammatory interleukin-10 (IL-10) and decreases proinflammatory cytokines IL-17F, IL-17A, IL-22, and tumor necrosis factor-α levels.2 In the phase 3 ESTEEM-1 (NCT01194219) and ESTEEM-2 (NCT01232283) trials, a significantly greater proportion of patients achieved the primary end point of 75% or greater improvement in the Psoriasis Activity Severity Index (PASI 75) at 16 weeks of treatment compared with those who received placebo (ESTEEM-1: 33.1% vs 5.3%; difference, 27.8% [95% CI, 23.1% to 32.5%]; P < .0001; ESTEEM 2: 28.8% vs 5.8%; P < .001).3,4 Responses with apremilast were durable. Of the patients in both trials who achieved a PASI 75 response at week 32 and then were randomly assigned to continue apremilast, approximately two-thirds had a PASI 75 response at 52 weeks, and 5-year data show that efficacy and safety were sustained over time.3-5 During the placebo-controlled period (weeks 0-16), the most common AEs reported with use of apremilast were diarrhea, nausea, nasopharyngitis, and upper respiratory infection.3,4 Most AEs were mild or moderate in severity, and discontinuations because of an AE occurred in less than 8% of patients.3,4

Apremilast is often used as an add-on to other medications, although it may be an attractive option for patients who need systemic therapy and are hesitant to try a biologic. Apremilast is also the only systemic agent that is currently approved by the FDA for mild, moderate, and severe PsO; in addition, this drug has been approved for use in patients who have psoriatic arthritis and is a good option for these individuals.6

Apremilast does not require regular laboratory monitoring or tuberculosis tests prior to use or impose restrictions on receiving live vaccines. However, patients often need guidance on navigating the AEs, particularly gastrointestinal (GI) toxicities, that are associated with apremilast administration. Altering dosing in the induction phase and prescribing antinausea or antidiarrheal medications may help mitigate some of the GI effects; a switch to a different medication should be considered if no improvement in GI symptoms is observed after 4 weeks.

Deucravacitinib

Deucravacitinib is a selective allosteric tyrosine kinase 2 (TYK2) inhibitor that binds to the TYK2 enzyme’s regulatory domain, which is different from other members of the Janus kinase (JAK) family; in contrast, many JAK inhibitors bind to the active catalytic domain of the enzyme, which is shared and conserved among all members of the JAK family.7 This unique binding means that at clinically relevant doses, deucravacitinib has not been shown to affect the JAK1/2/3 pathways. Additionally, TYK2 plays a role in the signaling of immune pathways, meaning that a TYK2-targeted agent is unlikely to have metabolic, hematopoietic, or myelopoietic effects like those of the JAK inhibitors that affect signaling across a wider range of biologic functions.

In the phase 3 POETYK-PSO 1 trial (NCT03611751), investigators compared deucravacitinib with placebo as well as apremilast in patients with moderate to severe PsO. Response rates were significantly higher with deucravacitinib than apremilast for the coprimary end points of PASI 75 (194 [58.4%] vs 59 [35.1%]; P < .0001) and static Physician’s Global Assessment (sPGA) 0/1 (178 [53.6%] vs 54 [32.1%]; P < .0001). Apremilast is often considered a good therapeutic option for scalp PsO; in this study, however, a greater proportion of patients with moderate to severe scalp PsO achieved scalp sPGA of 0 or 1 with deucravacitinib than with apremilast (70.3% vs 39.1%; P < .0001).7 The proportion of patients who achieved the primary end point on deucravacitinib continued to increase from 16 to 24 weeks, suggesting that clinical improvement may take longer for some patients; if a patient is improving but not at treatment goal at week 16, it is advisable to continue deucravacitinib, as there is potential for even more improvement over time.7 Additionally, counseling patients on how deucravacitinib works and the expected time to response can help to set their expectations.

To assess the durability of response after discontinuation of deucravacitinib, the phase 3 POETYK-PSO 2 trial (NCT03611751) included a randomized withdrawal and maintenance period.8 The investigators found that the median time to loss of PASI 75 was 85 days in patients who initially received deucravacitinib and then were randomly assigned to receive placebo at 24 weeks. This durability and maintenance of response is in line with what is observed with biologic medications. This prolonged maintenance of response is reassuring for patients who need to temporarily discontinue the drug for surgery or access issues or those who may forget to take their medication. In these instances, there is a good chance that a temporary pause will not impact the overall skin efficacy that they have achieved. Because efficacy often declines rapidly after discontinuation of JAK inhibitors, deucravacitinib therapy may be valuable for patients who need to discontinue the drug for surgery or who forget to take their medication for a few weeks.

Conclusions

Although biologic therapy has been a mainstay for systemic treatment of PsO, novel oral therapies may provide a convenient option for patients who prefer oral therapy or are not ready for an injectable.1 Between novel oral options and traditional injectable biologics, the clinical armamentarium for psoriatic disease offers clinicians and patients many possibilities to achieve optimal outcomes.

In the POETYK-PSO 1 trial, the most common AEs noted among the deucravacitinib group were nasopharyngitis and upper respiratory infection, and the apremilast group had higher rates of diarrhea, nausea, and headache than did the placebo- or deucravacitinib-treated groups.7 Additionally, during the first 16 weeks, a very small proportion (1.8%) of the deucravacitinib-treated group discontinued therapy due to AEs as compared with 6.0% and 4.2% of the apremilast and placebo groups, respectively.7 Although 5 cases of herpes zoster were reported with use of deucravacitinib, none of the cases were serious or led to discontinuation of therapy.7

Additionally, patients on deucravacitinib do not have to worry about drug-drug interactions, which is particularly useful in individuals taking multiple medications. Patients with PsO—regardless of the medications that they are taking—are also at higher risk for metabolic syndrome and cardiovascular disease. As such, they should be counseled on the importance of having an annual physical examination by a primary care physician and regular laboratory testing that includes liver function tests and cholesterol levels.

Faculty presenters: Mona Shahriari, MD; and TJ. Chao, MPAS, PA-C. This article was reviewed, edited, and approved by Dr Shahriari, Mr Chao, and Dr Stein Gold.

References

  1. Menter A, Gelfand JM, Connor C, et al. Joint American Academy of Dermatology-National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020;82(6):1445-1486. doi:10.1016/j.jaad.2020.02.044
  2. Otezla mechanism of action (MOA). Otezalpro.com. Accessed December 19, 2023. https://www.otezlapro.com/otezla-mechanism-of-action/
  3. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37-49. doi:10.1016/j.jaad.2015.03.049
  4. Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol. 2015;173(6):1387-1399. doi:10.1111/bjd.14164
  5. Mease PJ, Hatemi G, Paris M, et al. Apremilast long-term safety up to 5 years from 15 pooled randomized, placebo-controlled studies of psoriasis, psoriatic arthritis, and Behçet's syndrome. Am J Clin Dermatol. 2023;24(5):809-820. doi:10.1007/s40257-023-00783-7
  6. Otezla. Prescribing information. December 2021. Accessed December 19, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/205437s011lbl.pdf
  7. Armstrong AW, Gooderham M, Warren RB, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial. J Am Acad Dermatol. 2023;88(1):29-39. doi:10.1016/j.jaad.2022.07.002
  8. Strober B, Thaçi D, Sofen H, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded,phase 3 Program for Evaluation of TYK2 inhibitor psoriasis second trial. J Am Acad Dermatol. 2023;88(1):40-51. doi:10.1016/j.jaad.2022.08.061

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