Novel Interleukin 17 Antibody Quickly Reduces Psoriasis

Diana Swift

October 02, 2015

The experimental monoclonal antibody brodalumab, an interleukin 17 (IL-17) receptor antagonist, achieved a 100% reduction in plaque psoriasis symptoms in twice as many patients as the commonly used antibody ustekinumab (Stelara, Janssen Biotech Inc), according to findings from a phase 3 multicenter trial published in the October 1 issue of the New England Journal of Medicine.

"Brodalumab is the only IL-17 receptor antagonist in clinical development," said lead author Mark Lebwohl, MD, a professor of dermatology at Icahn School of Medicine, Mount Sinai Hospital, New York City, in a Mount Sinai news release.

By binding to receptors for IL-17A, brodalumab silences this immune-signaling protein and its ligands, thereby countering psoriatic inflammation, the investigators explained in the release. "When it comes to complete clearing, our results are better than any previously published and confirm that targeting the IL-17 receptor is highly effective in the treatment of moderate to severe plaque psoriasis," said Dr Lebwohl. He noted that many treated patients had no traces of psoriasis on their bodies.

In two phase 3 comparative studies (Study of Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Subjects [AMAGINE-2] and AMAGINE-3), a total of 3712 adult patients (mean age, 45 years; close to 70% male and about 90% white) with moderate to severe psoriasis were randomly assigned with well-matched characteristics across groups to one of the following three regimens: brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight of 100 kg or less and 90 mg for patients heavier than 100 kg), or placebo. At week 12, patients receiving brodalumab were again randomly assigned to receive a maintenance dose every 2, 4, or 8 weeks, whereas patients in the ustekinumab group continued to receive ustekinumab every 12 weeks, and placebo patients began to receive brodalumab every 2 weeks.

At week 12, the psoriasis area-and-severity index (PASI) 75 (a 75% reduction in symptoms from baseline) response rates were higher with brodalumab at both doses than with placebo (86% and 67%, respectively, vs 8%, in AMAGINE-2; and 85% and 69%, respectively, vs 6%, in AMAGINE-3; P < .001).

The rates of static physician's global assessment scores of 0 or 1 were also higher with brodalumab (P < .001), as were patient self-assessments.

Furthermore, the week 12 PASI 100 response rates were significantly higher with the 210-mg dose of brodalumab than with ustekinumab, which blocks inflammatory cytokines IL-12 and IL-23, at 44% vs 22% in AMAGINE-2 and 37% vs 19% in AMAGINE-3 (P < .001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P = .08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P = .007).

"These results suggest that [IL-17A] plays a central role in psoriasis by directly driving downstream signaling in keratinocytes and inducing expression of proinflammatory molecules," the authors write, adding that ustekinumab acts upstream by targeting IL-23.

As for speed, brodalumab also reduced the signs and symptoms of psoriasis more rapidly. The median time to a PASI 75 response with 210 mg of brodalumab every 2 weeks was 4 weeks, which is approximately twice as fast as the median time to a response with ustekinumab.

Commenting on the results, Jeffrey Weinberg, MD, a Mount Sinai associate clinical professor of dermatology who was not involved in these two AMAGINE studies but does do research for Amgen, told Medscape Medical News: "This drug has a high level of efficacy, but that does not mean we should switch from the effective drugs we are using now." He adds that brodalumab and the other two agents in its class, ustekinumab and ixekizumab, are all "useful additions to the therapeutic armamentarium for treating psoriasis," although subsets of patients may respond better to one or the other.

Stephen Stone, MD, a dermatologist and professor at South Illinois School of Medicine in Springfield, also found the results impressive. “Those of us who treat psoriasis are really excited,” he said. “This study suggests that IL-17 receptor blockers may actually be quite a step ahead in our systemic treatment of psoriasis.” He added that both the study drugs represent an advance in efficacy over previous drugs.

Adverse Event Profile Needs Study

In terms of serious adverse events per 100 patient-years through week 52, these were 8.3 with brodalumab and 13.0 with ustekinumab in AMAGINE-2, respectively, and 7.9 and 4.0, respectively, in AMAGINE-3.

There were three deaths in patients receiving brodalumab, including two suicides. "I can see no mechanism by which the drug would have contributed to these," Dr Lebwohl told Medscape Medical News, adding that underlying disease and depression were more likely to have been related to the deaths.

"But the suicidal ideation seen with this drug is a concern," Dr Weinberg said. "Although the number is small, we are not in a position to rule out an association or a potential association with the drug."

Rates of neutropenia during induction were higher with both brodalumab and ustekinumab than placebo. Most cases were mild, and the exposure-adjusted event rates of neutropenia per 100 patient-years of exposure to brodalumab through week 52 were 0.2 in AMAGINE-2 and 1.5 in AMAGINE-3; the corresponding rates with ustekinumab were 0.8 and 0.8.

In addition, mild or moderate candida infections occurred more frequently with brodalumab than with ustekinumab or placebo. "These yeast infections were expected," Dr Lebwohl said, and they are consistent with the immune role of IL-17A mucocutaneous microbial surveillance.

Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab.

The authors concede that disparities in patient-years of exposure among groups may have limited interpretations of potential dosage effects on exposure-adjusted adverse-event rates. "The sizes of the study populations, which were sufficient for the assessments of efficacy and common adverse events, may have been inadequate for the detection of rare adverse events, which would require longer follow-up of large numbers of patients to provide a full understanding of the safety profile of brodalumab," they write.

“The suicides coming out so early might make you hesitate a little in prescribing this drug, especially since other biologics like anti–tumor necrosis factor agents have long-term safety records in actual clinical practice,” added Dr Stone. “These deaths may sensitize us to the possibility of a signal that we need to keep our eyes open [for], and they could slow the shift over from current drugs we have longer experience with.”

The data need further evaluation and prospective follow-up, stressed Dr Weinberg. "The overall side effect profile does not raise the alarm at this point — there's nothing shocking — but as with any new drug, we need to do due diligence to see if the side effects seen increase or new ones occur that were not seen."

The studies in this article were funded by Amgen and AstraZeneca. Several authors reported receiving financial support from Amgen for this research, as well as grants and personal fees from Amgen and other companies for unrelated work. Dr Weinberg has received research support and speaker's fees from Amgen for work unrelated to this article. Dr Stone reports no conflicts of interest.

N Engl J Med. 2015;373:1318-1328. Abstract

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