Roflumilast Side Effect Benefits Patients With Psoriasis and Overweight/Obesity

BERLIN — Further findings from the PSORRO study suggest that oral roflumilast may be an option for treating patients with moderate to severe plaque psoriasis, particularly if they have a high body mass index (BMI).

Reporting secondary outcomes from the investigator-led trial at the annual meeting of the European Academy of Dermatology and Venereology (EADV), Alexander Egeberg, MD, PhD, DMSc, noted that "clinically significant weight loss" was seen among patients who were treated with oral roflumilast, 500 µg once daily, vs those receiving placebo.

Indeed, after 12 weeks of therapy, 1 in 3 patients treated with oral roflumilast experienced at least a 5% drop in their baseline body weight vs no patients who received placebo (35% vs 0%; P < .05).

Additionally, a respective 17% vs 0% of patients lost 10% or more of their body weight, and 4% vs 0% lost 15% or more of their baseline body weight at 12 weeks.

After 24 weeks' treatment, a substantial percentage of patients still had ≥ 5%, ≥ 10%, or ≥ 15% weight loss, at 30%, 17%, and 13% for oral roflumilast compared with 9%, 0%, and 0% for placebo, respectively.

"We saw that the higher baseline weight correlated with the proportion of weight loss, so that the more heavy patients at baseline also were the ones who experienced the greatest weight loss," said Egeberg, who is professor of dermatology at the University of Copenhagen and a senior consultant at the Department of Dermatology at Bispebjerg Hospital, Copenhagen, Denmark.

A Beneficial Side Effect in Psoriasis?

"You may have heard in psoriasis about topical roflumilast, but oral roflumilast is actually also shown to be effective in treating psoriasis," said Egeberg.

Topical roflumilast is approved in the United States and Canada for treating plaque psoriasis.

Efficacy results from the PSORRO study were published earlier this year and showed a significantly greater improvement in Psoriasis Area and Severity Index (PASI) 75 with oral roflumilast vs placebo at 12 weeks (35% vs 0%), with a sustained effect seen at 24 weeks (44% vs 40%).

Weight loss was among the most common side effects seen, leading Egeberg and fellow PSORRO investigators to wonder whether this may actually be a beneficial effect in patients with psoriasis.

"Oral roflumilast is actually a drug that has been on the market for quite a number of years," Egeberg said.

Although only currently licensed for chronic obstructive pulmonary disease (COPD) in the United States, oral roflumilast, a phosphodiesterase (PDE) 4 inhibitor, is available as a generic, "which also means that it is extremely affordable," suggested Edeberg.

Weight loss may be a problem in patients with COPD, he acknowledged; these patients tend to be underweight as a result of their poor state of health caused by the lung condition. Weight loss could be an advantage in patients with psoriasis who are overweight or living with obesity and have poor cardiometabolic parameters.

The Psoriasis Treatment With Oral Roflumilast Study

The PSORRO study was a phase 2, multicenter, placebo-controlled, randomized trial performed between 2021 and 2022. A total of 46 adults with plaque psoriasis participated; half were initially treated with oral roflumilast and half with placebo.

Treatment was double-blind for the first 12 weeks, with all patients then receiving open-label treatment with roflumilast for 12 weeks.

The primary endpoint was the proportion of patients achieving at least 75% reduction from baseline PASI (PASI75). A host of secondary endpoints were studied, including weight and cardiometabolic parameters, which Egeberg reported at the EADV meeting.

Looking at the baseline characteristics of the oral roflumilast and placebo groups, the mean age was a respective 38 and 39 years, 65% and 83% were men, and the mean starting body weight was 102 kg and 105.1 kg.

After 12 weeks of treatment, body weight fell by a mean of 5.4 kg in the oral roflumilast group, with a further decrease of 1.4 kg by 24 weeks, bringing the total average weight loss to 6.8 kg. By comparison, weight loss among those in the placebo group was 0 kg at 12 weeks and around 2 kg at 24 weeks.

The majority of participants in both groups had high baseline BMIs; 70% of those who received oral roflumilast and 61% of those who received placebo had a BMI of 30 or higher.

"We wanted to investigate the impact of body weight, [so] we didn't allow patients to be underweight when they were included," Egeberg explained. Thus, for inclusion, patients had to have a BMI of 20 or higher.

An "extraordinary" finding was how some patients' weight status based on their BMI changed throughout the study.

"We could see people that went from obese class 3, all the way to obese class 1. And we could see people going from being overweight to normal weight, which is really extraordinary for patients with psoriasis," Egeberg said.

"But most importantly," he added, "we didn't have any patients who became underweight, suggesting that it actually is safe to use also in normal-weight patients."

Reduced Appetite Behind Benefit?

Trying to see why the weight loss occurred, Egeberg noted that it looked like it could be a result of a reduced appetite.

In common with other PDE-4 inhibitors, oral roflumilast treatment was associated with gastrointestinal symptoms — nausea, diarrhea, and abdominal pain — but all of these "decrease to placebo levels again, quite quickly," he said.

"This really suggests that it's not because of diarrhea, it's not because of nausea and abdominal pain; it is because of a reduced appetite that patients actually lose weight when treated with roflumilast," Egeberg said. It's a potential bonus for the drug's effects on the skin and could afford clinicians an opportunity to help motivate patients to eat well when they do eat, he observed.

Other cardiometabolic parameters assessed included blood pressure, glycated hemoglobin, total cholesterol and other key lipids, creatinine, alanine aminotransferase, and high-sensitivity C-reactive protein, but there were no noteworthy differences between the groups.

Roflumilast an inexpensive drug because it is generic, Egeberg observed, but that also means that its use is likely to be off-label.

"It will be up to the treating physician to decide if this is an optimal therapy for their patients," he suggested.

Cardiometabolic Comorbidities Important to Target

Obesity is a cardiometabolic comorbidity that is important to consider when treating your patients with psoriasis, Paolo Gisondi, MD, of the University of Verona in Italy, said at a separate presentation at the EADV meeting.

While not directly commenting on the roflumilast study, he noted that moderate to severe psoriasis was "frequently associated" with metabolic disorders that put people at additional risk for cardiovascular and fatty liver diseases.

The PSORRO study was an investigator-initiated and investigator-led study and received no commercial funding. Research funding came from the Danish Psoriasis Foundation, Herlev and Gentofte Hospital, and several charitable and humanitarian organizations. Egeberg acknowledged acting as the principal investigator, speaker, and/or consultant to multiple pharma companies, all of which were unrelated to the study he presented. Gisondi's comments were from a separate presentation, and he was not involved in the study.

European Academy of Dermatology and Venereology (EADV) 2023 Annual Meeting. Abstract 6626. Presented October 12, 2023 and Presentation D1T04.2C on October 11, 2023.

Sara Freeman is a medical journalist based in London, England.

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