New Topical Agents Take Encouraging Baby Steps in Skin Disease


CME NUGGETS

Ed Susman

Mr. Susman is a freelance medical writer based in Florida, USA. He travels worldwide to report from medical conferences, writing regularly for wire services, internet websites, and medical journals such as the Journal of the National Cancer Institute and AIDS.

For comments, edwardsusman@cs.com


VIENNA – Three investigational topic agents for treatment of atopic dermatitis in early phase studies show benefit to patients, researchers reported here at the 3rd biennial Inflammatory Skin Disease Summit.

A topical nitric oxide releasing cream, now known as SB414, showed trends towards benefit in reducing pruritis and other disease aspects of mild-to-moderate atopic dermatitis in a 2-week, randomized, vehicle controlled study, reported Tomoko Maeda- Chubachi, MD, vice president of medical dermatology for Novan, Inc., Morrisville, North Carolina.

In the 8-week, randomized Phase 2b trial, Moayed Hamza, MD, associate medical director of DS Biopharma, Dublin, said his candidate drug – the synthetic bioactive lipid immunomodulator DS107, in its 5 percent formulation, outperformed placebo in the Investigator’s global Assessment by continuing to show positive benefits to patients with mild-to-moderate atopic dermatitis even after the treatments had ended.

In a 2-week Phase 1b study of cerdulatinib, a dual Janus kinase/ spleen tyrosine kinase inhibitor, appeared to reduce parameters of atopic dermatitis in 8 patients diagnosed with mild to severe forms of the disease – and despite the small numbers of patients, those treated with cerdulatinib achieved statistically significant reductions in the EASI (Eczema Area and Severity Index), reported Anna Tallman, PhardD, vice president of medical affairs at Dermavent Sciences, Phoenix.

“What I like about these presentations,” session co-chair Robert Bissonnette, MD, president of Innovaderm Research, a clinical research organization in Montreal, said, “is that it shows the interest of pharmaceutical industry in developing new topical drugs for atopic dermatitis. Right now we have nothing in Phase III development in the form of a cream or an ointment – and this is what most patients need, what most physicians prescribe and what general practitioners prescribe.

“These were all early phase studies but they all suggested efficacy, so that is good,” he said. “Which one is better and which will get approved, I don’t know.”

Eyes may suffer with dupilumab

In another study, systemic treatment for atopic dermatitis may make eyes vulnerable to conjunctivitis, researchers suggested. By diminishing so-called goblet cells, dupilumab helps control atopic dermatitis – but that same mechanism of action may make a patient’s eyes vulnerable to conjunctival inflammation, said Daphne Bakker, MD, a PhD candidate at the University of Utrecht, the Netherlands.

She and colleagues performed conjunctival biopsies in 6 patients who developed the eye inflammation after taking dupilumab for atopic dermatitis.

“Our findings indicate that dupilumab related conjunctivitis is marked by goblet cell scarcity in the conjunctival epithelium accompanied by a T-cell and eosinophilic infiltrate,” Dr. Bakker said.

“More insight in the functional T cell profile and activation status of eosinophils is necessary to further clarify the underlying pathomechanism of conjunctivitis during dupilumab treatment in atopic dermatitis patients,” she said.

“Dupilumab is a very effective drug for treatment of atopic dermatitis,” she said. “It is the most effective drug we have against this disease.” But she suggested that the very thing that makes it effective against atopic dermatitis may cause a problem with a patient’s eyes.

“About 37 percent of out 105 patients have had conjunctival inflammation,” she said. “Dupilumab, generally, has quite a good safety profile, but we do see a lot of conjunctivitis.”

Dr. Bakker suggested that the inflammation occurs because of the lack of epithelium goblet cells which are responsible for creating mucous which creates tear film stability. We know from previous studies that goblet cells are normally stimulated by IL-13, and IL-13 is blocked by dupilumab.

“So out hypothesis is that by blocking the IL-13 pathway, there is a decrease of goblet cells which leads to tear film instability and then to inflammation such as conjunctivitis,” she explained. “The inflammation does seem to go away when we stop the treatment.”

She suggested that clinicians be aware of this possible adverse reaction with dupilumab, but she acknowledged that at present there are few alternatives to dupilumab for individuals with atopic dermatitis.

Hair loss reversed

Patients with alopecia areata that involved more than half of their scalp were able to observe hair restoration with new oral drugs more effectively than with placebo – and some of the individuals achieved a complete recovery of hair loss, researcher said.

After 24 weeks of treatment with Pfizer’s investigational drug PF-06700841, about 60 percent of patients achieved a 30 percent mean change in the Severity of Alopecia Tool (SALT) score (P<0.001) as did about 48 percent of patients taking the company’s PF- 06651600 candidate drug (P<0.001) compared with no improvement among patients on placebo, reported Emma Guttman-Yassky, MD, PhD, professor and vice-chair of dermatology at the Icahn Mount Sinai, New York.

Remarkably, she reported more than 12 percent of the patients taking either drug achieved a SALT 100 – essentially restoration of hair on their scalp.

“Both PF-06700841 and PF-06651600 achieved the study’s primary and secondary endpoint,” Guttman-Yassky said in her oral presentation. “The clinical effects of both drugs were accompanied by significant increases in hair-keratin-associated genes in the biopsy sub-study samples.”

The success in hair restoration did not appear to be costly in the terms of adverse events, she said. “The number of patients with adverse events was comparable across all groups,” she said. She noted that 2 patients taking PF-06700841 were diagnosed with rhabdomyolysis, but she said those were two individuals who were engaged in heavy exercise. They did not have to be removed from the study, she said. There were no serious adverse events observed among the patients on PF-O6651600 or on placebo.

The patients in the study were in their mid 30s and most of them were women, Guttman-Yassky reported. The researchers enrolled 48 patients to receive PF-06651600, an oral JAK3 inhibitor; 47 patients were assigned to receive PF-06700841, an oral tyrosine kinase 2/JAK1 inhibitor and 47 patients were assigned to the placebo arm of the trial. PF-06651600 was dosed at 200 mg once daily for 4 weeks, followed by 50 mg once daily for 20 weeks; PF-06700841 was dosed at 60 mg once daily for 4 weeks, followed by 30 mg once daily for 20 weeks. She said that the 2 drugs were compared with placebo, but were not formally compared with each other.

Guttman-Yassky said that patients began to observe measurable difference in their hair loss restoration within 4 weeks with PF-06700841 and within 6 weeks with PF-O6651600, with both achieving statistical significance compared to placebo (P<0.01) at those time points. They maintained significance at the P<0.001 level throughout the rest of the 24 week trial.

She said that in addition to improvement of hair growth on the scalp, patients also reported improvements in eyelash and eyebrow regrowth. For PF-06700841, about 61 percent saw at least one grade improvement in eyelashes and 52 percent saw at least a one grade improvement in Eyebrow hair regrowth. For patients on PF-O6651600 there was a 45 percent improvement in eyelashes and a 36 percent improvement in eyebrows. All were significantly better than placebo (P<0.05).

Guttman-Yassky suggested that the agent might fulfill the ‘unmet need for a reliably effective therapy with a benefit-risk ratio that is appropriate for long-term use in patients with alopecia areata,”

In commenting on the study, session co-chair Erwin Tschachler, MD, professor of dermatology at the Medical University of Vienna, said. “This is an important study that needs to be pursued to find out what happens after you discontinue treatment and how long can you give treatment to these patients.”

He noted that a high percentage of the patients in the study did regrow their hair and in a short period of time. “But what we need to know about the patients taking these drugs is what will happen to them in 2 years,” he said. “So we will probably have to wait to hear that in 2 years from now.”

January 2019 Health and Lifestyle

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