KAUAI, HAWAII – Physicians have become much more cognizant of severe diarrhea and nausea as potential side effects of apremilast since the Food and Drug Administration–approved change in the warnings and precautions section of the drug’s labeling in June 2017. , director of the psoriasis clinic at Kaiser Permanente Los Angeles Medical Center, has a tip for avoiding these problems: Delay up-titrating.
“In my opinion, that may be too quick of an up-titration. I tell patients that, if they feel the GI issues are still a problem for them on day 6, they should take 30 mg just once a day for the first 1-2 months. After that we’ll see how they’re doing, and if they feel they can make the jump to twice a day, then they can go for it. Of course, I also tell them that maybe their psoriasis will not clear as well as if they’d been on apremilast twice a day right from day 6, but if they’re able to tolerate it and can continue to take it, they can improve while they’re on it,” the dermatologist said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.
Dr. Wu presented an update on recent developments regarding the newest oral drugs for psoriasis and one of the oldest: apremilast and methotrexate, respectively.
The revised warning label highlighting the risks of severe diarrhea and nausea associated with the oral phosphodiesterase-4 inhibitor says that most such events have occurred within the first few weeks of therapy. The guidance also notes that patients who reduced the dosage or discontinued treatment outright generally improved rapidly.
“I see this in a lot of my patients. They have to go to the bathroom pretty often. It’s actually unusual for me for a patient not to have any GI issues at all,” according to Dr. Wu.
He shared a number of other fresh insights into apremilast’s safety and efficacy derived from recent studies.
Efficacy appears to increase at least out to 1 year
A report from the phase 3b, randomized, placebo-controlled, 250-patient LIBERATE trial showed that the week 16 PASI 75 response rate was 39.8% with apremilast, 48.2% with etanercept (Enbrel), and 11.9% with placebo. After week 16, everyone switched to apremilast. The PASI 75 rate in patients on apremilast all along climbed from 39.8% at week 16 to 52.7% at week 52. That result was in the same ballpark as the 57% rate in those switched from etanercept to apremilast and the 53.4% PASI 75 rate at week 52 in patients switched from placebo to apremilast ().
“It was interesting to see that, as the study continued on for 1 year, the PASI 75 rate continued to improve. That’s worth noting: In general, I tell patients you have to be on a drug for about 3 months before we’re going to say if it worked or not, and that’s true even with drugs for other conditions, like doxycycline for acne. But this study seems to indicate that you have much better improvement at the 1-year point, and that’s not so much true for the biologics,” the dermatologist observed.
Safety to 3 years looks reassuringly good: 3-year follow-up of the 1,184-patient, phase 3, randomized, controlled ESTEEM 1 and 2 trials provided by far the longest look to date at apremilast’s safety. There were no surprises, no serious opportunistic infections, and no significant changes in laboratory values ().
Of note, 21.9% of patients on apremilast lost more than 5% of their baseline body weight. Most of the weight loss occurred during year 1 of treatment and mostly in patients with a higher baseline body mass index.“It seems like apremilast is definitely a good option if patients can tolerate the GI upset,” Dr. Wu said.
Apremilast can safely and effectively be combined with other psoriasis therapies: Dermatologists at the University of Toronto reported on a retrospective analysis of 81 biologic-naive psoriasis patients treated with apremilast in combination with methotrexate, acitretin (Soriatane), cyclosporine, narrowband UVB, etanercept, infliximab (Remicade), adalimumab (Humira), and/or ustekinumab (Stelara). Of these patients, 81% achieved a PASI 75 response at week 12 ().
“That’s pretty good. It’s certainly better than apremilast by itself. So if you can get the payer to cover a combination of apremilast and something else, it may help get to PASI 75,” Dr. Wu noted.
Session chair Craig L. Leonardi, MD, said he hasn’t had any luck in going that route.
“The insurance industry just won’t give me apremilast in combination with a biologic drug. Even though it makes complete sense to use it in place of methotrexate with a biologic, I just can’t get it,” according to Dr. Leonardi, a dermatologist at Saint Louis University.“I don’t have those limitations at Kaiser,” according to Dr. Wu. “I personally have only used apremilast and methotrexate and apremilast and acitretin in combination. I just want to be kind to Kaiser and not give two branded medications to a patient, but I certainly think it’s a feasible option.”
A simple response prediction rule:, professor and chair of dermatology at the Medical College of Wisconsin in Milwaukee, and his coinvestigators at AbbVie developed a methotrexate response/nonresponse prediction rule using data on 110 participants in the phase 3 CHAMPION trial. Then they validated the rule in the phase 3 M10-255 trial. They found that a PASI 25 response to methotrexate at week 4 was associated with an 8.9-fold increased likelihood of a week-16 PASI 75 response. Patients with a predicted response probability of less than 30% were asked to discontinue the drug; their week 16 PASI 75 rate was only 21.1%, compared with a 65.8% response rate in patients with a prediction rating ( ).
“Four weeks of methotrexate may be sufficient to determine the long-term response. It may not be necessary to put them on the drug for 3 months,” Dr. Wu commented.
Subcutaneous methotrexate: European investigators demonstrated that an intensified dosing schedule of subcutaneous methotrexate was safe and effective for treatment of moderate to severe plaque psoriasis in the 52-week, phase 3, randomized, 16-center, double-blind, 120-patient, placebo-controlled METOP study.The intensified subcutaneous regimen consisted of 17.5 mg/week initially, escalated to 22.5 mg/week after 8 weeks if a patient hadn’t achieved at least a PASI 50 response at that point. The primary outcome, the PASI 75 response at week 16, was 41% in the subcutaneous methotrexate group and 10% in controls, with a maximum PASI 75 rate of 51% seen beginning at week 24. The week 4 and 8 PASI 50 rates were 50% and 58%, respectively, with methotrexate versus 3% and 17% in placebo-treated controls. The subcutaneous regimen was generally well tolerated, with no serious infections or malignancies arising during 52 weeks ().
Dr. Wu reported receiving research funding from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and Regeneron.
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