Brodalumab, the new interleukin 17 receptor A (IL-17RA) inhibitor, doubled the number of patients with psoriatic arthritis (PsA) who had 20% improvement in American College of Rheumatology response criteria (ACR20) at 12 weeks in a phase 2 trial, as reported by Philip J. Mease, MD, and colleagues in an article published in the June 12 issue of the New England Journal of Medicine.
ACR20 rates at 12 weeks were 37% and 39%, respectively, for the low-dose and high-dose brodalumab groups vs 18% for the control group. At 24 weeks (after an open-label extension), the ACR 20 rates were 51% and 64% for the low-dose and high-dose brodalumab groups, respectively, vs 44% for patients who switched from placebo to brodalumab after week 12. Serious adverse event rates by week 12 were 3% in the brodalumab groups and 2% in the placebo group.
PsA Brodalumab Responses Continued to Develop After Week 12
"We observed a significantly greater ACR20 response with brodalumab than with placebo at week 12. Additionally, during open-label extension beyond 12 weeks, all responses further improved. Although open-label data are not as fully reliable as placebo-controlled data, the consistency and magnitude of the improvement across measures, generally maintained out to 52 weeks, raises the possibility that the drug takes longer to achieve fully optimal responses. The week 12 primary endpoint time point for arthritis/enthesitis/dactylitis responses was chosen a priori partly based on the rapidity and magnitude of the skin responses in the psoriasis trials with this agent. In phase 3, a later primary endpoint of 16 weeks has been chosen to see if optimal response can be observed during placebo-controlled phase," Dr. Mease, who is a rheumatologist at Swedish Medical Center and the University of Washington, Seattle, Washington, told Medscape Medical News.
Researchers in the phase 2, double-blind, placebo-controlled study randomly assigned 168 patients with active PsA to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. Patients in both groups who remained in the study at week 12 were offered open-label brodalumab (280 mg) every 2 weeks. The primary study endpoint was ACR20 at week 12.
For at least 4 weeks before the initiation of a study drug, the researchers required patients to receive stable doses of methotrexate (≤25 mg per week), leflunomide (≤20 mg per day), glucocorticoids (≤10 mg per day of prednisone equivalent), or nonsteroidal antiinflammatory drugs (NSAIDs). The researchers required washout periods of 2 and 3 months for anti-TNF and anti-interleukin-12/23 treatments, respectively
A total of 159 patients completed the 12-week double-blind phase, and 134 completed 40 weeks of open-label extension. The investigators reported data for 12-week and 24-week outcomes.
Dr. Mease said, "Although the [tumor necrosis factor] inhibitors have significantly changed our ability to meaningfully improve the care and outcomes (improvement of signs, symptoms, function, quality of life, and inhibit[ion of] progressive structural damage) of patients with [PsA], there remain a significant number of patients who either do not respond adequately to these medicines, have adverse effects to them, or lose effect over time, so there is a significant need for medicines with a different mechanism of action which can effectively treat these patients in a manner that is reasonably safe and tolerable. The IL-17 drugs have a striking effect on psoriasis, and now there is evidence that they can improve arthritis outcomes, [and] so will broaden our ability to provide disease control for PsA patients."
Alan Menter, MD, chair of dermatology at Baylor University Medical Center, Dallas, Texas, who was not involved in the study, told Medscape Medical News that the ACR20 response was slower to develop with brodalumab than he is accustomed to seeing clinically with responses to other agents in patients with psoriasis, and that this highlights both differences in study design and the emerging awareness among dermatology and rheumatology researchers that psoriasis and PsA differ in many key areas.
Brodalumab Data Add to Evidence of Psoriasis vs PsA Difference
Dr. Menter said, "Brodalumab is 1 of 3 anti-IL-17 agents currently under development. Early results with all 3 have shown dramatic responses in skin in psoriasis, but not such dramatic responses in joints. This shows that even though psoriasis and [PsA] tend to be considered together, the 2 conditions are not as closely linked as had been assumed. Therapeutically there are differences. Genetically, there are major differences. Even immunologically, within the joints, the inflammation is not identical to that in the skin. Anti-TNF agents give ACR20 responses in the 65% range but have quite varied Psoriasis Area and Severity Index skin scores."
Dr. Menter predicted that the future for PsA and for psoriasis treatments will be determined by the development of clinically usable pharmacogenomics.
"We need to use biomarkers in blood specimens from individual patients to target treatment with specific drugs. We are maybe 5 years away from that, but I expect that we will be able to maximize the benefits and minimize the costs by identifying patients most likely to benefit from a drug, and not prescribing it for the patient unlikely to respond to it or for the patient who is especially at risk for certain adverse events. That is the future of medicine," Dr. Menter said.
The PsA brodalumab study design differed from trials done in psoriasis in allowing patients to continue maintenance treatment with drugs such as methotrexate, leflunomide, or prednisone. In psoriasis trials, biologicals are typically tested as monotherapy. Dr. Menter suggested that this difference might have contributed to the high "placebo" ACR20 response rate reported in the control group (18% at week 12).
The study was supported by Amgen. Brodalumab is being codeveloped by Amgen and AstraZeneca/MedImmune. Dr. Mease and 5 coauthors report receiving grants from Amgen during the conduct of the study. Four coauthors are employed by and have an equity interest in Amgen. Dr. Menter has disclosed no relevant financial relationships.
N Engl J Med. 2014;370:2295-2306. Extract
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Cite this: Brodalumab Doubled Psoriatic Arthritis Responses - Medscape - Jul 23, 2014.
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