Small molecules, big impact
Phosphodiesterase (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.