EXPERT ANALYSIS FROM THE EADV CONGRESS
GENEVA (FRONTLINE MEDICAL NEWS) – The novel interleukin-4 and IL-13 signaling blocker dupilumab displayed consistently strong efficacy across all patient subgroups in a new analysis from the landmark 52-week CHRONOS trial, Andrew Blauvelt, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“Dupilumab with concomitant topical corticosteroids improved signs and symptoms of atopic dermatitis, compared with placebo injections regardless of age, sex, BMI, or prior history of asthma, allergic rhinitis, or food allergies,” he said. Indeed, he quipped that the biologic proved to be “boring” in its broad effectiveness.
“It’s a good thing for us. It means we don’t have to look for the type of AD [atopic dermatitis] patient that may respond to this drug. We can say pretty much all comers, at least in this trial, did well despite their baseline characteristics,” said Dr. Blauvelt , president of the Oregon Medical Research Center in Portland.
CHRONOS was a 14-country, 1-year, randomized, double-blind, placebo-controlled, phase 3 clinical trial in which 740 adults with moderate to very severe AD were assigned to mid-potency topical corticosteroids along with topical calcineurin inhibitors as needed in steroid-sensitive locations, then randomized 3:1:3 to either subcutaneous dupilumab (Dupixent) at 300 mg once weekly, placebo injections, or dupilumab at 300 mg every 2 weeks on top of the topical therapy.
Dupilumab , a fully human monoclonal antibody, was approved by the Food and Drug Administration in March 2017 at a loading dose of 600 mg, followed by 300 mg every 2 weeks for treatment of adults with moderate to severe AD. The biologic agent is soon expected to be approved across the European Union as well. CHRONOS was the first major trial designed to replicate how the biologic would likely be utilized in real-world clinical practice: that is, in conjunction with rather than as an alternative to topical therapy. Earlier pivotal phase 3 trials were required by regulatory agencies to pit dupilumab monotherapy against placebo.
CHRONOS participants were “a very tough crowd, so to speak,” the dermatologist recalled. Their median body surface area of involvement was a whopping 55%, 60% were men, the median baseline EASI (Eczema Area and Severity Index) score was 30, and fully half of patients had an IGA (Investigator’s Global Assessment) score of 4, indicative of severe disease. Plus, comorbid atopic/allergic diseases were common: half of subjects had a history of asthma, nearly half had a history of allergic rhinitis, and one-third had a history of food allergies.
Dr. Blauvelt previously presented the primary results of CHRONOS without the new subgroup analysis at the American Academy of Dermatology 2017 meeting. The primary results were subsequently published ( Lancet. 2017 Jun 10;389:2287-303 ). To recap, the bottom line: 39% of dupilumab-treated patients achieved an IGA score of 0/1 – that is, clear or almost clear – coupled with at least a 2-point improvement from baseline at week 16, versus 12% of controls on topical steroids plus placebo injections. That’s a strikingly impressive performance, according to the dermatologist.
“An IGA of 0/1 in AD is a very high bar. It tends to correlated with an EASI 90,” Dr. Blauvelt observed.
Rates of EASI 75 – meaning at least a 75% improvement from baseline EASI scores – were achieved in 64% of patients on weekly dupilumab plus topical steroids, 69% with dupilumab every 2 weeks plus topicals, and 23% on topical steroids plus placebo. These efficacy results were essentially mirrored at week 52, with no significant changes in response rates from week 16 to week 52.
In another new finding from CHRONOS presented by Dr. Blauvelt at the EADV congress, itch also improved sharply across the board in dupilumab-treated patients, regardless of their baseline demographic and other characteristics, meaning there’s no point for clinicians to reserve the biologic for selected subgroups of patients with moderate or severe AD. From a mean baseline score of 7.6 on the 10-point peak pruritus numerical rating scale, at least a 3-point improvement was achieved in 56% of patients on biweekly dupilumab plus topical steroids, 43% on weekly dupilumab and topical steroids, and in 16% on topical steroids plus placebo injections.
Of note, 84% of patients in the two dupilumab arms remained in the CHRONOS trial through the full 52 weeks. That’s a high retention rate for a 1-year study involving a disease with a major adverse quality of life impact. In contrast, only about two-thirds of controls on topical therapy plus placebo injections stuck with the study for the duration.
The high retention rate may have had much to do with dupilumab’s generally favorable safely profile, as seen not only in CHRONOS but in earlier trials. No new safety concerns arose during the 52-week study. The dupilumab and control groups had similar rates of most side effects, with just a few exceptions: nonherpetic skin infections and worsening AD occurred more frequently in controls on topical steroids alone, while mild injection site reactions were twice as common in patients who got dupilumab than in those who received placebo injections.
Also, conjunctivitis occurred in 14% of patients on weekly dupilumab and 19% with biweekly dupilumab, compared with 8% of controls. “To me, conjunctivitis is the only significant side effect for this drug that we’ve seen thus far,” Dr. Blauvelt commented. The mechanism of the conjunctivitis is unknown. It’s clear, however, that the rate goes up with duration on therapy.
“Most of the cases have been mild to moderate and have not interfered with therapy. I’ve treated probably 80 patients with dupilumab, and I’ve had only 1 who had to stop due to her eyes,” the dermatologist recalled. The condition often responds to wetting eye drops, although topical corticosteroid eye drops are required sometimes, he added.
Elsewhere at the EADV congress, Marjolein De Bruin-Weller, MD , presented the 16-week outcomes of the CAFE trial, which demonstrated that dupilumab significantly improved AD symptoms and quality of life in patients who were intolerant to or inadequately managed using cyclosporine, or for whom the broad-spectrum immunosuppressant was deemed medically inadvisable. The clinical relevance of this finding lies in the fact that cyclosporine is indicated for treatment of AD in Europe and widely utilized off label for this purpose in the United States.
CAFE was a double-blind, randomized, placebo-controlled trial including 325 European patients with moderate or severe AD, all of whom were on a mid-potency topical corticosteroid with or without a topical calcineurin inhibitor. Two-thirds had previously been on cyclosporine with poor results; the drug was contraindicated in the others. Participants were randomized to subcutaneous injections of dupilumab at 300 mg weekly or biweekly or to placebo injections.
The primary outcome – an EASI-75 response at 16 weeks – was achieved in 59% of patients on weekly dupilumab, 63% of those on biweekly dupilumab, and 30% of controls on topical steroids plus placebo injections, according to Dr. De Bruin-Weller of the University Medical Center at Utrecht, the Netherlands.
A clinically meaningful 4-point or greater improvement from baseline in the Dermatology Life Quality Index occurred at 16 weeks in 79% and 88% of patients on dupilumab weekly or biweekly, respectively, compared with 44% of controls.
And among the three-quarters of CAFE participants reporting baseline moderate or severe pain or discomfort from AD, 55% of those on weekly dupilumab had none at all as assessed by the EQ-5D Pain/Discomfort Questionnaire at week 16, as did 64% on dupilumab every 2 weeks and 28% of controls on topical steroids.
At the prestigious joint EADV/AAD session of the European congress, Lawrence F. Eichenfield, MD, hailed dupilumab as evidence that “the systemic therapy revolution in atopic dermatitis is certainly happening,” with a plethora of additional agents targeting various key disease pathways now working their way through the developmental pipeline.
A key remaining question about dupilumab is, what about the safety and efficacy of the drug in the pediatric population, for whom the drug is not currently approved? Separate phase 3 randomized trials addressing this issue are now enrolling 6- to 11-year-olds and 12- to 17-year-olds.
Dr. Eichenfield is optimistic about the outcomes of these ongoing pediatric trials on the basis of an open-label, phase 2a, proof of concept study in 6- to 17-year-olds presented in a late-breaking research session at the 2017 annual meeting of the AAD. The pharmacokinetics were very similar to those seen in adults. Moreover, EASI scores improved by 32%-51% after just a single, weight-based injection of dupilumab and by up to 70% following four consecutive weekly injections.
“This is very, very exciting information. Whether the drug could actually be disease modifying is obviously a big question for us in pediatric dermatology,” observed Dr. Eichenfield, who is chief of pediatric and adolescent dermatology at Rady Children’s Hospital–San Diego and professor of dermatology and pediatrics at the University of California, San Diego.
He highlighted two important safety considerations regarding dupilumab: patients on the biologic should not be given any live vaccines, and the same IL-4 and IL-13 cytokine pathways targeted by dupilumab in patients with AD also are key in other atopic and allergic diseases. Indeed, the biologic showed positive outcomes in a recent pivotal phase 3 clinical trial for patients with uncontrolled persistent asthma, and an application for an expanded indication for dupilumab in such patients is expected to be filed with the FDA later in 2017. Dupilumab is also in phase 3 for patients with nasal polyps and in phase 2 studies for eosinophilic esophagitis.
“One of the interesting things about dupilumab is that we in dermatology are going to be in a situation where we’re able to impact diseases other than the single disease that the medication has been approved for,” Dr. Eichenfield said.
However, until such time as dupilumab actually receives an expanded indication for asthma and the details of how best to use the biologic in AD patients with that comorbidity have been worked out, it’s important for dermatologists prescribing dupilumab in those dual-diagnosis patients to discuss with them the necessity of staying on their asthma medications even though their skin is much improved, they’re feeling good, and their asthma seems to be doing better. During the dupilumab clinical trials program for AD, a fatal asthma exacerbation occurred in a patient with comorbid asthma who stopped taking asthma medications, he noted.
The CHRONOS and CAFE trials were funded by Sanofi and Regeneron Pharmaceuticals. Dr. Blauvelt, Dr. De Bruin-Weller, and Dr. Eichenfield reported serving as consultants to and researchers for those pharmaceutical companies and numerous others.