EXPERT ANALYSIS FROM RWCS 2018
MAUI, HAWAII (FRONTLINE MEDICAL NEWS) – 2017 was a banner year in the field of psoriatic arthritis, marked by a huge bump in the number of publications on the topic along with the approval of three additional drugs, Arthur Kavanaugh, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“There is a tremendous amount of excitement now in the field of psoriatic arthritis,” observed Dr. Kavanaugh, professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego.
Indeed, a PubMed search turned up roughly 700 publications on psoriatic arthritis in 2017, roughly twice the number published each year during 2009-2011. This boom in research bodes well for better times ahead for psoriatic arthritis patients, who at present lag roughly a decade behind patients with rheumatoid arthritis in terms of treatment success.
Together with his colleague Eric M. Ruderman, MD, Dr. Kavanaugh highlighted the three new drug approvals for psoriatic arthritis in 2017 – abatacept(Orencia), tofacitinib(Xeljanz), and ixekizumab(Taltz) – and also discussed important recent studies of several drugs already available.
In the pivotal double-blind, phase 3 trial involving 424 psoriatic arthritis patients, roughly 60% with prior exposure to a tumor necrosis factor inhibitor and 60% on concomitant methotrexate, the proportion of patients with at least 20% improvement in the American College of Rheumatology criteria (ACR20) was 39.4% in patients on the selective T-cell costimulation modulator, compared with 22.3% among placebo-treated controls. The benefit on psoriasis lesions was modest, and there was no significant difference between the two study arms in terms of Health Assessment Questionnaire-Disability Index response rates ( Ann Rheum Dis. 2017 Sep;76:1550-8 ).
“It works reasonably well on joint disease. It’s not as good as some of the other options,” commented Dr. Ruderman , professor of medicine and associated chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.
“I think we could say the effect is modest,” Dr. Kavanaugh said. “The challenge to us still is to identify patients who are going to have a good response, likely the patients with more joint than skin symptoms.”
An attractive feature of the drug is that its safety profile is well known as a result of its extensive track record in treating RA, he added.
On the basis of the phase 3 OPAL Beyond ( N Engl J Med. 2017 Oct 19;377:1525-36 ) and OPAL Broaden ( N Engl J Med. 2017 Oct 19;377:1537-50 ) clinical trials, the dose approved by the Food and Drug Administration for psoriatic arthritis was 5 mg b.i.d.. There was a higher ACR20 response rate with 10 mg than 5 mg b.i.d. in OPAL Broaden, but not in OPAL Beyond. And since there was a suggestion of a higher adverse event rate with the 10-mg b.i.d. dosing without unequivocal evidence of superior efficacy, the Food and Drug Administration – which always puts safety first – went with 5 mg b.i.d., Dr. Ruderman explained.
In the phase 3, double-blind SPIRIT-P1 trial, featuring 417 biologic-naive psoriatic arthritis patients, the ACR20 response rate at week 24 was 62.1% with the interleukin-17A antagonist at 80 mg given subcutaneously every 2 weeks and 57.9% when dosed every 4 weeks, compared with 57.4% with adalimumab(Humira) at 40 mg every 2 weeks and 30.2% with placebo ( Ann Rheum Dis. 2017 Jan;76:79-87 ). The FDA-approved regimen was a 160-mg loading dose of ixekizumab, followed by 80 mg every 4 weeks.
Dr. Kavanaugh noted that an international team of investigators has identified beta-defensin 2 as an easily measurable biomarker of interleukin-17A–driven skin pathology after evaluating 170 proteins expressed in blood, psoriasis lesions, and nonlesional skin. It was a small study, with eight psoriasis patients and eight healthy controls studied before and after receiving secukinumab(Cosentyx), a monoclonal antibody directed against interleukin-17A (J Allergy Clin Immunol. 2017 Mar;139:923-932.e8 ). But it’s a study with big potential implications.
“This natural antibiotic compound we make that’s in the skin might be a marker of responsiveness to anti–interleukin-17 therapy. It could help in deciding which patients get which drugs. This needs further study, especially now that we’re using anti–interleukin-17 drugs more now,” the rheumatologist said.
The year 2017 also brought important new studies of several drugs already available for psoriatic arthritis.
Intravenous golimumab (Simponi Aria)
Dr. Kavanaugh was first author of the GO-VIBRANT study, a phase 3, double-blind clinical trial in which 480 biologic-naive psoriatic arthritis patients were randomized to a 30-minute infusion of IV golimumab at 2 mg/kg or placebo at weeks 0, 4, 12, and 20.
The primary endpoint, an ACR20 response at week 14, was achieved in 75.1% of patients on the tumor necrosis factor inhibitor versus 21.8% on placebo. An ACR50 response occurred in 43.6% of patients on IV golimumab, compared with 6.3% on placebo, and a Psoriasis and Area Severity Index 75 skin response was achieved in 59.2% on IV golimumab and 13.6% of controls. At week 24, the IV golimumab group demonstrated significantly less radiographic progression as measured by the total modified Sharp/van der Heijde score. The drug was well tolerated, with no opportunistic infections or tuberculosis, and the infusion reaction rate was below 2% ( Arthritis Rheumatol. 2017 Nov;69:2151-61 ).
In a recent update of the 606-patient FUTURE 1 trial, secukinumab resulted in clinically meaningful improvement in key patient-reported outcomes at week 24, including global assessment of disease activity, which decreased by a mean of 20.6 and 20 points in patients on 150 and 75 mg, respectively, every 4 weeks, compared with a 7.4-point drop in placebo-treated controls.
Psoriatic arthritis quality of life scores improved by 3.5 and 3.2 points in the two secukinumab arms, compared with 0.4 points in controls. Dermatology Life Quality Index scores improved by 8.8 and 7.9 points, versus 0.7 in controls. Patients on the interleukin-17A inhibitor also showed significantly greater improvement in self-assessments measuring pain and fatigue ( Ann Rheum Dis. 2017 Jan;76:203-7 ).
At the 2018 meeting of the American Academy of Dermatology, Dr. Kavanaugh presented 5-year outcomes of the open-label extension of the 504-patient, phase 3 PALACE-1 trial. In an as-observed analysis, patients on apremilast 30 mg b.i.d. up to week 260 had a 71.7% ACR20 response rate, a 48.6% ACR50 response rate, and a 28.4% ACR70 response. Eighty percent of patients on the oral phosphodiesterase-4 (PDE-4) inhibitor had a dactylitis count of 0, and 54.5% had a Maastricht Ankylosing Spondylitis Enthesitis Score of 0.
In a report from the 219-patient, phase 3B ACTIVE trial , investigators showed that biologic-naive patients randomized to apremilast at 30 mg b.i.d. had a significantly greater ACR20 response as early as week 2, which was the first assessment. At that point, the ACR20 rate was 16.4% with apremilast, compared with 6.4% in placebo-treated controls. The apremilast group also demonstrated significant early improvements in patient-reported outcomes, including the Health Assessment Questionnaire-Disability Index, morning stiffness, and enthesitis severity.
The primary outcome, the ACR20 rate at week 16, was 38.2% with active treatment versus 20.2% in controls ( Ann Rheum Dis. 2018 Jan 17. doi: 10.1136/annrheumdis-2017-211568 ).
“The main advantage of apremilast is safety – and that’s a big advantage,” Dr. Kavanaugh commented.
Military physicians tell him they are prescribing a lot of apremilast for armed forces deploying overseas because it’s not immunosuppressive and doesn’t entail laboratory testing.
The research agenda for PDE-4 inhibition in psoriatic disease is extensive, he noted. There is a need for formal studies of PDE-4 inhibition in combination with conventional disease-modifying antirheumatic drugs or biologics. Topical formulations, once-daily dosing, and the possibility that PDE-4 inhibition might be the preferred therapy in patients with certain comorbid conditions, such as chronic obstructive pulmonary disease or a history of recurrent infections, are all topics worthy of study. A biomarker to identify in advance which patients with psoriatic arthritis or psoriasis will attain maximum clinical benefit from apremilast, and in which domains, would be of enormous help to clinicians.
Dr. Kavanaugh and Dr. Ruderman reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.