From the Journals

Efficacy and safety of lowering dupilumab frequency for AD

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Trials helps us to understand the options

The desire to decrease or stop a therapy such as dupilumab may be motivated by cost, current and potential adverse effects, and individual needs. Because atopic dermatitis is a waxing-and-waning disease with a predilection for cycles of escalation, there is some thought a priori that reduced treatment schedules or discontinued use of a drug may be possible in a state of low disease activity.

The investigators of the SOLO-CONTINUE trial found, however, that continuous treatment with the dosage used in the original SOLO trials (300 mg weekly or every 2 weeks) resulted in a better maintenance of response than a less-frequent dosage and was significantly better than placebo for all endpoints. The less-frequent dosage regimens (every 4 weeks and every 8 weeks), on the other hand, produced some dose-dependent reduction in efficacy.

The development of antidrug antibodies was found in approximately 11% of individuals who received placebo or dupilumab every 8 weeks, 6% of the monthly treatment group, and only 1% in the weekly group, suggesting that less-frequent administration results in higher immunogenicity. However, most of the antidrug antibody levels were low and did not seem to have any clinical effect, making this finding of uncertain relevance to patient care.

The study is valuable because, as more patients are exposed to the drug, more will want or need to reduce the dosage or stop use over time – and although it seems optimal to continue an every-2-weeks treatment regimen, this may not always be feasible. As we integrate new therapies and learn more about atopic dermatitis, it is important that we understand the options and implications around decreasing the dosage of dupilumab. This newly concluded trial is helpful in this regard.

Peter A. Lio, MD, is with the department of dermatology at Northwestern University, Chicago, and the Chicago Integrative Eczema Center. He reported receiving grants and personal fees from Regeneron, Sanofi Genzyme, and other companies, as well as other disclosures. His comments appear in JAMA Dermatology (2019 Dec 26. doi: 10.1001/jamadermatol.2019.3331).


 

FROM JAMA DERMATOLOGY

Patients with moderate to severe atopic dermatitis who responded well to the approved dupilumab regimen of 300 mg every 2 weeks in pivotal phase 3 monotherapy trials were more likely to have a continued response over the longer term if they maintained this regimen rather than switching to longer dosing intervals or discontinuing the medication.

This finding comes from a 36-week, randomized, double-blind, placebo-controlled trial that enrolled 422 patients who were previously successfully treated for 16 weeks with 300 mg of dupilumab weekly or every 2 weeks in two identically designed studies – SOLO 1 and SOLO 2.

The new international study – SOLO-CONTINUE – randomized these patients to continue the original regimen (weekly or every 2 weeks), to receive 300 mg of the biologic medication every 4 or 8 weeks, or to receive placebo.

Patients who continued the original regimen had the most consistent maintenance of treatment effect, while patients on longer dosage intervals or placebo had a dose-dependent reduction in response and no safety advantage. The incidence of treatment-emergent antidrug antibody was lowest with dupilumab weekly or every 2 weeks, and slightly higher with less-frequent dosing intervals, reported Margitta Worm, MD, of the Charité Universitätsmedizin Berlin, and coinvestigators.

“Because administration every 4 weeks or every 8 weeks did not provide an additional safety advantage and was numerically outperformed by administration weekly or every 2 weeks, we believe that it is prudent to adhere to the approved every 2 weeks regimen for adults and avoid less frequent treatment regimens (every 4 weeks or every 8 weeks) for long-term maintenance of efficacy,” they wrote in JAMA Dermatology.

Treatment success in the original SOLO trials was defined as having achieved an Investigator’s Global Assessment score of 0-1, or 75% improvement in Eczema Area and Severity Index Scores (EASI-75). As primary endpoints, SOLO-CONTINUE looked at the mean percentage change in EASI score over the course of the trial, and the percentage of patients who maintained EASI-75 at week 36.

Patients in the SOLO-CONTINUE trial who were randomized to receive dupilumab weekly or every 2 weeks had a mean percent change in EASI score of –0.06%. In contrast, patients assigned to the placebo group had a 21.7% decrease, and those taking the medication at 4- and 8-week intervals had mean changes of –3.84% and –6.84%, respectively. Post hoc analyses showed no apparent difference between dupilumab weekly and every 2 weeks in the maintenance of clinical response, the investigators reported.

Among patients with EASI-75 response at baseline, significantly more patients maintained this response at week 36 than patients receiving placebo, and there was again an apparent dose-dependent response. The percentage with EASI-75 at week 36 was 71.6% with the weekly or every-2-weeks regimen, 58.3% with the 4-week regimen, 54.9% with the 8-week regimen, and 30.4% in the placebo group.

Continuing treatment with 300 mg weekly or every 2 weeks resulted in greater maintenance of response across multiple other clinical endpoints and patient-reported outcomes as well (such as pruritus, atopic dermatitis symptoms, sleep, pain or discomfort, quality of life, and symptoms of anxiety and depression).

The more-frequent regimens also conferred no greater risk than less-frequent administration, and there were no new safety signals over the 36-week trial. Treatment-emergent adverse events (the most common were headache, nasopharyngitis, injection-site reactions, and herpes simplex virus infection) occurred in 70.7% of patients in the weekly or every-2-weeks group, 73.6% in the 4-week group, 75% in the 8-week group, and 81.7% in the placebo group.

Unlike earlier studies, the incidence of conjunctivitis was low (less than 6%) across all treatment groups, possibly because patients in the SOLO-CONTINUE trial were all high-level responders who tend to have conjunctivitis less frequently, the authors wrote.

Patients receiving less-frequent doses of dupilumab, particularly every 8 weeks, had greater rates of skin infections, flares, and rescue medication use than patients receiving doses weekly or every 2 weeks, the investigators reported. Treatment-emergent antidrug antibody incidence was slightly higher with less-frequent doses (11.7% and 6% in the 8-week and 4-week groups, respectively, compared with 4.3% and 1.2% in the every-2-weeks and weekly groups), which indicates a “higher incidence of immunogenicity with less-frequent dosage intervals” and is “consistent with other biologics,” they wrote.

Dupilumab is a human monoclonal antibody against the interleukin-4 receptor alpha that inhibits signaling of IL-4 and IL-13. The study was conducted at 185 sites in North America, Europe, Asia, and Japan. Patients had a mean age of 38.2 years; 53.8% were male.

While the trial suggests that the approved regimen of 300 mg every 2 weeks is best for long-term treatment, “therapeutic decisions are often influenced by cost-benefit considerations, in which case practitioners and other stakeholders involved in these decisions should carefully balance potential savings against suboptimal efficacy and long-term risks associated with discontinuous treatment regimens,” the investigators wrote.

The SOLO-CONTINUE trial was funded by Sanofi and Regeneron, the companies that market dupilumab. Dr. Worm reported receiving honoraria for consulting and lecture activity from Regeneron and Sanofi during and outside the conduct of the study, among other disclosures. The other authors had multiple disclosures related to these and multiple other pharmaceutical companies, or were employees of Sanofi or Regeneron.

SOURCE: Worm M et al. JAMA Dermatol. 2019 Dec 26. doi: 10.1001/jamadermatol.2019.3617.

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