expert roundtables

Use of Small-Molecule Drugs for Plaque Psoriasis

by Boni E. Elewski, MD; Steven R. Feldman, MD, PhD; and Bruce E. Strober, MD, PhD

Overview

In the treatment of plaque psoriasis, small-molecule drugs such as apremilast are not as effective as the injectable therapies that target the interleukin-23 (IL-23)/IL-17 axis. Efforts to improve the efficacy and tolerability of oral agents are ongoing, with some promising molecules under study.

Q:

What is the current state of small-molecule drugs in the management of plaque psoriasis? 

Bruce E. Strober, MD, PhD

Clinical Professor, Department of Dermatology
Yale University School of Medicine
New Haven, CT
Central Connecticut Dermatology
Cromwell, CT

We need better oral medications in the future, agents that fit the bill of higher efficacy, no monitoring requirements, and good tolerability.

Bruce E. Strober, MD, PhD

Small-molecule drugs for psoriasis include the older agents (ie, methotrexate, cyclosporine, and acitretin) and the more recently introduced oral agent apremilast. For the most part, the older small-molecule drugs are much less expensive than biologics, but they are not as effective. For example, only approximately 45% of patients on methotrexate achieve Psoriasis Area and Severity Index (PASI 75) at 12 or 16 weeks, whereas the PASI 75 rates are in the range of approximately 63% to 83% among those taking modern injectables.

The toxicities and challenges with older small molecules such as methotrexate are well known. Methotrexate has monitoring requirements that include liver enzyme testing and blood counts, and its use is contraindicated in some patient groups, including women of childbearing age and heavy alcohol drinkers. Cyclosporine is a very undesirable long-term drug for psoriasis. It is a good short-acting agent that provides quick clearing and it predictably works, but it causes renal toxicity and can raise blood pressure. I do not use it anymore, except in situations when I have to clear patients quickly. Acitretin is a retinoid that I think is slow acting, is minimally effective, and requires very high doses for efficacy. It also has tolerability issues that include mucocutaneous side effects and hair loss. Further, it is contraindicated in women of childbearing potential.

Apremilast was approved by the US Food and Drug Administration for moderate to severe psoriasis in 2014. It is easier to use than other older small-molecule drugs, but it does not improve on the relatively low efficacy of methotrexate. Apremilast does not require blood tests for monitoring and is prescribed often. It does have tolerability issues associated with its use, including diarrhea, nausea, and headache, and these can be a dealbreaker for some patients.

We need better oral medications in the future, agents that fit the bill of higher efficacy, no monitoring requirements, and good tolerability. Some patients just do not like the idea of a shot. Others likely value small-molecule oral therapeutics over injectables, even those with lower efficacy, because they believe that injectables are reserved for only rare situations, when an illness is more serious.

Steven R. Feldman, MD, PhD

Professor of Dermatology, Pathology, Social Sciences & Health Policy, and Molecular Medicine & Translational Science
Wake Forest School of Medicine
Winston-Salem, NC

“. . . if you could create a small-molecule drug targeting RORγt that has the efficacy and safety of an IL-17 or IL-23 inhibitor, that could be another quantum leap forward.”

Steven R. Feldman, MD, PhD

I agree that many patients who have never been on an injectable drug do not like the idea of having to get a shot. When I present biologics to my patients, I explain that the drug has to be given by injection, similar to insulin for patients with diabetes, and that individuals with diabetes have to take insulin several times a day, whereas biologics for psoriasis require injections only every 2 weeks, once per month, or every 3 months. By anchoring patients on the idea of taking the drug daily, the much less frequent dosing regimens of injectables for psoriasis seem much more palatable.

Patients often prefer a pill over an injection. The success of apremilast, which I believe is less effective than even the weakest of the biologics, proves that. Another small molecule, the Janus kinase inhibitor tofacitinib, is approved for psoriatic arthritis and could be used for psoriasis, but I do not prescribe it often. 

On the horizon, the intracellular signaling of IL-23 and IL-17 is a promising target, and agents that block TYK2 or retinoic acid receptor–related orphan receptor gamma t (RORγt) are in clinical development. So far, the TYK2 inhibitor deucravacitinib looks like it has a fairly clean side-effect profile, but I would need to see more and longer-term safety data from trials and real-life data to be convinced that there is a clean safety profile. Individuals who are born with TYK2 deficiency have an immunosuppressive disease, so there may be a concern that inhibiting TYK2 could inhibit more than just the psoriasis. 

I think that the RORγt inhibitors are one of the more interesting classes of early pipeline small-molecule drugs that are being developed for psoriasis. RORγt is a key transcription factor in the pathway through which IL-23 and IL-17 communicate their signaling. So, if you could create a small-molecule drug targeting RORγt that has the efficacy and safety of an IL-17 or IL-23 inhibitor, that could be another quantum leap forward.


Boni E. Elewski, MD

James Elder Endowed Professor and Chair of Graduate Medical Education
Department of Dermatology
University of Alabama
Birmingham, AL

“Apremilast does have some unique uses, including in patients who are reluctant to take an injectable drug.”

Boni E. Elewski, MD

Apremilast does have some unique uses, including in patients who are reluctant to take an injectable drug. It is reasonably effective for psoriatic arthritis, and often such patients present with mild psoriasis with perhaps some joint pain and/or nail disease. Some of the biologic drugs may not be appropriate for such limited skin manifestations. Apremilast works reasonably well in the nails, scalp, and genital area, and you might consider it for a patient who presents with bad nail psoriasis, joint pain, and stiffness, for instance.

The investigational TYK2 inhibitor deucravacitinib works in the Janus kinase pathway, and it is far along in its clinical development. That is very exciting to me because it seems to have the efficacy of the injectable drugs, but it is given orally. The results of the studies of deucravacitinib are quite good, especially compared with placebo or apremilast. The PASI 75 values at weeks 16 and 24 (approximately 60% to 70%) were significantly higher than that of apremilast (approximately 38%) in the comparative head-to-head trial. Data to date suggest that deucravacitinib is well tolerated, but more information is needed, including whether monitoring will be required.

References

Armstrong A, Gooderham M, Warren RB, et al. POS1042: efficacy and safety of deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor, compared with placebo and apremilast in moderate to severe plaque psoriasis: results from the phase 3 POETYK PSO-1 study. Ann Rheum Dis. 2021;80(suppl 1):795-796.

Armstrong AW, Betts KA, Sundaram M, Thomason D, Signorovitch JE. Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-naïve patients with psoriasis. J Am Acad Dermatol. 2016;75(4):740-746. doi:10.1016/j.jaad.2016.05.040

Armstrong AW, Puig L, Joshi A, et al. Comparison of biologics and oral treatments for plaque psoriasis: a meta-analysis. JAMA Dermatol. 2020;156(3):258-269. doi:10.1001/jamadermatol.2019.4029

Bellinato F, Gisondi P, Girolomoni G. Latest advances for the treatment of chronic plaque psoriasis with biologics and oral small molecules. Biologics2021;15:247-253. doi:10.2147/btt.S290309

Claudia C-D, María-Elena V-H, Josué V-E, et al. Small molecules under development for psoriasis: on the road to the individualized therapies. Arch Dermatol Res. 2020;312(9):611-627. doi:10.1007/s00403-020-02056-3

Ghoreschi K, Balato A, Enerbäck C, Sabat R. Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis. Lancet. 2021;397(10275):754-766. doi:10.1016/S0140-6736(21)00184-7

Papp K, Gordon K, Thaçi D, et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med. 2018;379(14):1313-1321. doi:10.1056/NEJMoa1806382

Pastor-Fernández G, Mariblanca IR, Navarro MN. Decoding IL-23 signaling cascade for new therapeutic opportunities. Cells. 2020;9(9):2044. doi:10.3390/cells9092044

West J, Ogston S, Foerster J. Safety and efficacy of methotrexate in psoriasis: a meta-analysis of published trials [published correction appears in PLoS One. 2016;11(7):e0158928]. PLoS One. 2016;11(5):e0153740. doi:10.1371/journal.pone.0153740

Wu P, Chen S, Wu B, Chen J, Lv G. A TYK2 gene mutation c.2395G>A leads to TYK2 deficiency: a case report and literature review. Front Pediatr. 2020;8:253. doi:10.3389/fped.2020.00253

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