A new class steps forward

April 6, 2017

Phosphodiesterase (PDE) inhibitors including apremilast and crisaborole ointment may provide safer alternatives than traditional steroid-sparing agents for psoriasis and atopic dermatitis. Side effects of apremilast may include GI symptoms, weight loss and depression, and taking apremilast with anti-seizure drugs or rifampin lowers apremilast blood levels, Apremilast is being studied in inflammatory bowel disease, Behcet's disease and pediatric psoriasis, and may have a place in the treatment of hidradenitis suppurativa (HS).

Dr. ChapmanPhosphodiesterase (PDE) inhibitors put dermatology on the cusp of a new class of medications that may replace traditional steroid-sparing agents such as methotrexate and azathioprine, says an expert at the American Academy of Dermatology 75th Annual Meeting.

Approved by the U.S. Food and Drug Administration (FDA) for psoriasis and psoriatic arthritis (PsA) in 2014, the PDE4 blocker apremilast likely will become a workhorse PDE inhibitor in dermatology that's valued at least as much for its safety as its efficacy, says M. Shane Chapman, M.D. He is section chief of dermatology at Dartmouth-Hitchcock Medical Center in Lebanon, N.H

An enzyme that breaks down cyclic adenosine monophosphate (cAMP) into AMP, PDE belongs to the 12-member family of phosphodiesterases, says Dr. Chapman. Inhibiting PDE4, PDE7 or PDE8 reduces the amount of AMP, reducing several downstream pro-inflammatory cytokines and transcription factors including tumor necrosis factor alpha (TNFa), interleukin (IL) 17, interferon alpha and interferon gamma, he says, although probably not as much as biologic drugs for psoriasis do. Because PDE resides in T- cells, dendritic cells, neutrophils, monocytes and some peripheral blood cells, he added, its effects impact virtually every organ.

Presently, "We have very good medications for psoriasis – but they are immunosuppressive. With apremilast, there seems to be little or no effect on T-cell function or antibody response. There's no inhibition of IgG or IgE. The corollary may be that adaptive immunity is unaffected. This might be truly immunomodulatory," not immunosuppressive like prednisone, cyclosporine and some of the psoriasis biologics.

Buzz about safety

"The buzz around this drug is happening not so much for its efficacy. It's really about safety." Although apremilast is approved for moderate to severe psoriasis, Dr. Chapman says that in his experience, "It's really not the drug for severe psoriasis. I would say it's for mild to moderate psoriasis," depending on how these are defined. "I don't believe it's going to replace adalimumab or ixekizumab anytime soon."

In the Phase 3 ESTEEM 1 study, the proportion of patients who achieved 75% reductions in psoriasis area and severity index (PASI 75) scores at week 16 was 33%.1 That's well below the proportion of PASI 75 responders in studies of previous biologic drugs, the newest of which are often discussed in terms of PASI 90 or PASI 100 responses, he says.

After 52 weeks, 29% of patients reached PASI 75.2 When one combines the two Phase 3 trials and a comparison trial against etanercept,3 he says, 30% to 40% of patients achieved between PASI 50 and PASI 75. Most patients on apremilast should probably expect PASI 50, Dr. Chapman says, with responses often lasting at least a year.

Subanalysis of ESTEEM data also showed that patients with psoriasis of the palms, soles, nails and scalp fare particularly well, he says. "I see the same thing in my practice. For some reason, palmoplantar psoriasis – but not pustular psoriasis – seems to do very well with this medication, similar to or better than with methotrexate. We use topical steroids and other treatments (such as 10 mg of an oral retinoid daily) in addition to apremilast."

A psoriasis study that pitted apremilast against methotrexate showed little difference in efficacy,4 says Dr. Chapman, "And apremilast costs a lot more than methotrexate. But it's the safety of apremilast that interests patients and physicians."

For PsA, Dr. Chapman says, "Apremilast would not be my go-to medication, but it has an effect." For patients with mild to moderate psoriasis and very mild PsA, "It's a very good choice that may help their psoriatic arthritis as well."

In pivotal PsA trials, the proportion of patients who achieved 20% reductions in their American College of Rheumatology scores (ACR 20) was "good, not great," says Dr. Chapman. At week 16, around 30% of patients taking the 20 mg dose, and 40% of patients taking 30 mg (both doses twice daily), reached ACR20, versus less than 20% on placebo.5,6 But Apremilast probably won't prevent or reverse joint inflammation and destruction as TNF inhibitors and IL17 inhibitors do, he added.

Nevertheless, he says, "Apremilast is effective – in some patients, very effective. About 60% to 65% of my patients with mild or moderate psoriasis who go on it like it and stay on it." However, Dr. Chapman says he would probably refer patients whose main complaint is PsA to rheumatologists rather than prescribing apremilast.

Next: Counsel thoroughly

 

Counsel thoroughly

In all trials, says Dr. Chapman, patients tend to tolerate apremilast well. Nevertheless, "The gastrointestinal side effects are real. Patients may get diarrhea or an upset stomach. And if you don't counsel them about this, they're going to stop treatment." After two to four weeks, he added, the gastrointestinal upset resolves in more than 75% of patients. "Occasionally I may decrease the dose from two 30 mg tablets to one per day to get them through the first month."

Apremilast's packaging also warns of an increased risk of depression. However, says Dr. Chapman, "I have an issue with the whole idea because our patients with psoriasis are already depressed." Physicians must consider baseline depression levels in these patients when assessing whether apremilast raises this risk, he says. "I have not had any cases in which apremilast exacerbated depression. I tend to ask a few more questions these days," after receiving a manufacturer's letter cautioning that many patients who go on apremilast are already taking selective serotonin reuptake inhibitors.

Additionally, he says, 20% of patients lose at least 5% of their body weight while on apremilast. Although packaging presents weight-loss as a negative side effect, "Most people don't mind it." One of his patients experienced a 15% weight loss, prompting a malignancy workup, which was negative, and a reduction in her dose. "She has maintained response, and the 15% weight loss, and it's been a year." Physicians also should know that taking apremilast with anti-seizure drugs or rifampin lowers apremilast blood levels, Dr. Chapman says.

Another PDE4 inhibitor, crisaborole 2% ointment, is approved for topical use in patients with atopic dermatitis (AD) as young as two years old. As a nonsteroidal treatment, Dr. Chapman says, "It's not going to be the medication for your most severe cases, but it certainly has a role in atopic dermatitis." In pivotal trials, around 1/3 of patients achieved investigator global assessments of clear or almost clear.7 Going forward, "We may need to increase the dosing a bit for atopic dermatitis. Those clinical trials will happen."

As dermatologists grow comfortable with PDE inhibitors, he added, "We'll take these new medications and do what we do best, which is to use them (off-label) for other indications, change the dosing, grind them up into an ointment – we'll figure out the best ways to use them."

Presently, he says, apremilast is being studied in inflammatory bowel disease, Behcet's disease and pediatric psoriasis. "I also believe it might be a great drug for hidradenitis suppurativa (HS)." Case reports suggest that apremilast can soothe allergic contact dermatitis enough that patients can undergo patch testing,8 and that apremilast modestly improves erythrodermic psoriasis (although in this case apremilast-induced atrial fibrillation limited its utility).9 "You can see how dermatologists are starting to experiment with the medication."

Disclosures: Dr. Chapman is a consultant for Celgene, maker of apremilast.

References

1. Papp KReich KLeonardi 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.

2. 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):1387-99.

3. Reich KGooderham MGreen L, et al. The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol. 2017;31(3):507-517.

4. Armstrong AWBetts KASundaram MThomason DSignorovitch 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):740-6.

5. Edwards CJBlanco FJCrowley J, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis. 2016;75(6):1065-73.

6. Kavanaugh AMease PJGomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73(6):1020-6.

7. Paller ASTom WLLebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-503.

8. West CE, Fowler JF. Clearance of erythroderma in a patient on apremilast and positive patch test reactions while on treatment. Dermatitis. 2016;27(6):392.

9. Arcilla J, Joe D, Kim J, Kim Y, Truong VN, Jaipaul N. Erythrodermic psoriasis treated with apremilast. Dermatol Reports. 2016;8(1):6599.