New Oral Agent May Shift Psoriasis Treatment Landscape

In the last 11 years, there have been remarkable advances in the treatment of moderate to severe psoriasis. In particular, the approval of several subcutaneously delivered selective blocking antibodies, such as Humira (adalimumab, AbbVie), Stelara (ustekinumab, Jannsen), and Remicade (infliximab, Janssen), as well as the fusion protein binder Enbrel (etanercept, Amgen), has changed how psoriasis is managed. In clinical trials, roughly 70 percent of patients achieve 75 percent clearance of psoriasis on many of these agents.1 Moreover, the safety data for these agents has been relatively clean, excepting a small increase in infections and the added burden of performing appropriate screenings (tuberculosis, opportunistic infections, etc.).1

Yet only about 20 percent of dermatologists prescribe the vast amount of biologics prescribed, and less than 250,000 patients with moderate to severe psoriasis have been treated with biologic agents. Studies from the National Psoriasis Foundation (www.psoriasis.org) show that 60 percent of patients with moderate to severe psoriasis receive only topical therapy (which will, in these cases, rarely be effective long-term) and up to 40 percent receive no treatment at all. In addition, over half of the psoriatic patients questioned were unhappy with their treatment.

With ever compelling efficacy and safety data, it is right to wonder: Where is the disconnect? More pointedly, why aren’t more patients receiving biologic therapy?

It is highly likely that some patients are still fearful that a biologic agent will do long-term harm to them, i.e. cancer, when, in fact, available data indicate no increase in malignancy rates with patients on biologic agents compared to age matched control groups. But this is not just an issue of fearful patients. In fact, many dermatologists also may have fears or are not comfortable with monitoring protocols associated with the use of these agents.

Oral Psoriasis Therapy

Questions and concerns such as these are an important backdrop for what may eventually be seen as one of the most significant developments in the treatment of psoriasis, which occurred earlier this year. Following on the heels of its approval for the treatment of psoriatic arthritis earlier this year, in September the FDA approved Otezla (apremilast, Celgene), the first new oral medication for psoriasis in over 30 years. It was also recently approved in Canada. Otezla, prescribed orally 30mg BID, may provide a new therapeutic avenue for those patients with moderate to severe psoriasis who require more than topical therapy but are unwilling at this moment to go on biologic therapy.

Practical Pointer

Despite a growing pool of compelling safety and efficacy data, biologic agents are still arguably underused in the treatment of psoriasis. Many clinicians and patients are reluctant to embrace biologics, perhaps due to the high cost of care, safety concerns, and/or the complicated nature of testing and treatment, in some cases. Thus, the new oral agent apremilast—which has an excellent safety profile and requires significantly less testing—may play an important role in bridging the wide gap and helping treat those patients who are currently unhappy using topical therapies or are unwilling to use injectable biologic agents.

Apremilast is a small molecule that gets absorbed through the intestine, and following circulation inhibits phosphodiesterase 4 (PDE-4) in inflammatory cells (dendritic cells, macrophages, lymphocytes) as well as keratinocytes, vascular endothelium, and synovium.2 Phosphodiesterase 4 catalyzes the breakdown of cAMP to AMP, the latter which induces transcription factors to synthesize TNF alpha, interferon gamma,IL-23.3 On the other hand, cAMP induces the transcription of anti-inflammatory molecules (IL-10) and therefore the inhibition of PDE-4. Apremilast increases cAMP levels resulting in less synthesis of pro-inlammatory molecules.3

Apremilast has a half-life of six to nine hours, therefore it is completely eliminated within two days. The Phase III ESTEEM 1 and ESTEEM 2 trials compared PASI 75 apremilast 30 mg bid to plecebo for 16 weeks. In ESTEEM 1, apremilast resulted in 33.1 percent of patients achieving PASI 75, compared to 5.3 percent of those in the placebo group.4 Moreover, 59 percent of patients achieved PASI 50 compared to 17 percent in the placebo group. Over 800 patients were evaluated in the trial, and for those that continued for 52 weeks, 61 percent achieved a PASI 75. Those that obtained a PASI 75 and were switched to placebo and lost PASI 75, 70 percent recaptured PASI 75 after resuming therapy.4

Regarding safety, the most common adverse events were diarrhea, nausea, and vomiting; only one patient had to discontinue from the clinical trials due to these adverse events.4 By utilizing a titration pack during the first week of treatment whereby the dose is increased from 10mg on day one to 30mg BID at day seven, these adverse events seem to be diminished. There were no increases in infections, severe infections, tuberculosis, opportunistic infections, cancer, or MACE events. There were no significant laboratory abnormalities. There was a 1.3 percent incidence of depression compared to 0.6 percent of patients receiving placebo, so it is necessary to evaluate individuals with a history of depression and have them monitored.4 Of note, the package insert states that females are twice as likely to get nausea and diarrhea. Therefore, in female patients I extend the titration period to 10 days.

In the ESTEEM 2 trial, at week 16 apremilast-treated patients obtained a PASI 75 of 28.8 percent compared to 5.8 percent for placebo.5 At week 16, PASI 50 response was 44.8 percent in the apremilast-treated patients, compared to 18.7 in the placebo group. Additionally, there was a 41 percent (clear or minimal) scalp response, compared to 17 percent for placebo. Also, 65 percent of patients with palmoplantar psoriasis were clear or almost clear, compared to 31 percent in placebo. Also at 16 weeks, apremilast-treated patients experienced 31.5 percent improvement in pruritis and skin discomfort, compared to 7.3 percent of placebo-treated patients, a difference which was noted as soon as two weeks. DLQI scores also improved by 6.7 percent after 16 weeks in the apremilast group, compared to 2.8 percent of those in the placebo group.5 Also of note, 55 percent of patients treated with apremilast achieved PASI 50 by week 16. Moreover, if a patient obtained a PASI 50 by week 16-32, there was a good likelihood that they would obtain a PASI 75 at week 52.5

In terms of safety, 13.6 percent of patients were being treated for depression at baseline. During 16 weeks of treatment, those numbers increased by 0.5 percent in the placebo group and 1.2 percent in the apremilast group.5 In addition, there was one suicide in the placebo group, compared to zero in the apremilast group. In addition, one patient in the placebo group apremilast did not complete the study due to depression.

An Important Role

In essence, apremilast is an oral medication with an extremely good safety profile that does not require any laboratory monitoring. If its initial efficacy may not be favorable (33 percent achieving PASI 75 by week 16), it’s important to note that 61 percent of those who have a response achieve PASI 75 by the end of one year of therapy. Thus, apremilast may play an important role in bridging the wide gap and helping treat those patients who are currently unhappy using topical therapies or are unwilling to use injectable biologics. n

Dr. Bagel has served as consultant, researcher, or speaker for Amgen, AbbVie, Janssen, Eli-Lilly, Novartis, Celgene, and Pfizer.

Jerry Bagel, MD, FAAD, is director of the Psoriasis Treatment Center of Central New Jersey.

1. Carretero G, Ferrandiz C, Dauden E, et al. the BIOBADADERM Study Group. Risk of adverse events in psoriasis patients receiving classic systemic drugs and biologics in a five-year observational study of clinical practice: 2008-2013 results of the Biobadaderm registry. J Eur Acad Dermatol Venereol. March 31, 2014.

2. Schafer P, Parton A, Gandhi A, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrats anti-inflammatory activity in vitro and in model of psoriasis. British Journal of Pharmacology. 2010; 159: 842-55.

3. Conti M, Richter W, Mehats C, et al. Cyclic AMP-specific PDE4 phosphodesterases as critical components of cyclic AMP signaling. J. Biol. Chem. 2003; 278: 5493-5496.

4. Reich K, Papp K, Leonardi C, et al. Long-term safety and tolerability of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: Results from a phase III, randomized, controlled trial (ESTEEM 1). Poster presented at 72nd Annual Meeting of the American Academy of Dermatology. 2014; March 21-25; Denver, CO.

5. Paul C, Cather J, Gooderham M, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 2). Poster presented at 72nd Annual Meeting of the American Academy of Dermatology. 2014; March 21025; Denver, CO.