Newer biologics that target interleukin (IL)-17 and IL-23 are changing the paradigm for psoriasis treatment, physicians reported at the American 2018 Academy of Dermatology Summer Meeting in July.
IL-17 inhibitors and IL-23 inhibitors offer efficacy improvements over previous-generation biologics, with at least equivalent safety, said J. Mark Jackson, M.D., of the University of Louisville. The newer-generation biologics also provide benefits for patients with psoriatic arthritis (PsA).
Regarding efficacy, secukinumab, ixekizumab and brodalumab all offer clearance rates of 30-40 percent and above for primary endpoints at 12 weeks, and 50 percent or more in longer-term follow-up.
In one pivotal trial, 81.6 percent, 59.2 percent and 28.6 percent of patients treated with secukinumab 300 mg reached Psoriasis Area and Severity Index (PASI) 75, 90 and 100, respectively, at 12 weeks. Placebo response rates for these endpoints were less than 5 percent (p<0.001 in all analyses). PASI 75, 90 and 100 response rates at week 52 in a separate trial published in the July 2015 Journal of the American Academy of Dermatology were approximately 80 percent, 60 percent and 35 percent, respectively, for a 300 mg fixed-interval dose, and 65 percent, 48 percent and 20 percent for a 150 mg fixed-interval dose, demonstrating that fixed-interval dosing created the best results.
Ixekizumab posted week 12 PASI 75 and PASI 100 rates of 90 percent and 41 percent, respectively, in two phase three trials published simultaneously in The Lancet in August 2015.
Brodalumab's week 12 PASI 75, 90 and 100 rates were 83.3 percent, 70.3 percent and 41.9 percent, respectively, as published in the August 2016 British Journal of Dermatology. In the AMAGINE-2 phase three trial, the drug maintained 52-week response rates of approximately 79 percent, 77 percent and 53 percent through week 120.
Both secukinumab and ixekizumab have bested the IL-12/23 inhibitor ustekinumab in head-to-head trials. In the CLEAR trial, secukinumab outperformed ustekinumab at week 16 in terms of PASI 90 and PASI 100 by margins of 21.4 and 15.9 percentage points, respectively (p<0.0001 in both analyses). This research appeared in the September 2015 Journal of the American Academy of Dermatology.
In the IXORA-S phase three trial, reported in the May 2017 British Journal of Dermatology, week 24 PASI 75, 90 and 100 rates for Ixekizumab were 91.2 percent, 83.1 percent and 49.3 percent, respectively, versus 81.9 percent, 59.0 percent and 23.5 percent for ustekinumab.
Secukinumab and ixekizumab have posted favorable American College of Rheumatology (ACR) 20 data in PsA after 24 weeks of treatment. In separate studies, said Dr. Jackson, 50 percent of secukinumab-treated patients achieved ACR 20, versus 52-59 percent for various TNF inhibitors. In the SPIRIT-P1 trial, 62 percent and 58 percent of ixekizumab-treated patients reached ACR 20 at week 24, versus 57 percent for adalimumab. ACR 50 and ACR 75 results showed similar patterns. Both secukinumab and ixekizumab include in their approved labels that they inhibit progression of structural damage.
Altogether, Dr. Jackson said that for psoriasis, IL-17 blockers work very quickly and show sustained efficacy, not just over primary end points, but also over one to three years and beyond, with no significant increases in adverse events. "They probably should not be utilized first-line in patients with inflammatory bowel disease." Studies have shown rare instances — in 0.1-0.3 percent of patients — of incidence and worsening of Crohn's disease and colitis. There are other biologic drugs that offer benefit for patients with psoriasis as well as these conditions.
Brodalumab trials have shown a slight signal for suicidal ideation and behavior, with six suicides occurring during its clinical development, according to a review published in Drug Design, Development and Therapy in July 2017. However, Dr. Jackson said, carefully designed follow-up studies have not demonstrated causation. "The FDA approved the medicine unanimously, based on the information from the trials, demonstrating their belief that there probably was no causation. But nonetheless, the warning is there."
Unanimous approval is not rare and does not mean that brodalumab is better than the other IL-17 blockers, he added. "All three agents are great."
IL-23 inhibitors also appear to work well and quickly for psoriasis, Dr. Jackson said, with long-term clearance rates of around 50%, sustained efficacy and favorable safety profiles. In the VOYAGE 1 phase three trial, 47.4 percent of guselkumab-treated patients achieved clearance at week 48. Regarding tildrakizumab, 65 percent and 39 percent of actively treated patients achieved PASI 75 and PASI 90, respectively, at week 12 in a pivotal trial. Risankizumab, now under FDA review for psoriasis, posted PASI 90 rates of 75.3 percent and 81.9 percent at week 16 and 52, respectively, in phase three. Additionally, all three IL-23 inhibitors may have benefit in PsA, and trials for this indication are ongoing.
IL-23 inhibitors allow for less frequent dosing than TNF inhibitors. After loading doses, labeled dosing for tildrakizumab and risankizumab is every 12 weeks, and every eight weeks for guselkumab, versus every two weeks for adalimumab and weekly for etanercept.
"The paradigm or treatment algorithm of having to start with methotrexate or TNF-alpha inhibitors is changing because these newer agents have demonstrated higher levels of efficacy," said Dr. Jackson.
Securing insurance coverage for approved IL-17 and IL-23 inhibitors remains somewhat of a battle, he said. But all their manufacturers offer discount programs, in an attempt to create first-line access for their drugs. "The winner among all these new agents will be the one that demonstrates the best access, with the best sustained efficacy and tolerability. To this point, it's a very competitive race."
Dr. Jackson has received research funding, honoraria, consulting fees and/or other support from AbbVie, Amgen, Janssen, Novartis and Pfizer.
J Mark Jackson MD. "Biologic Treatments for Psoriasis: IL-17 and -23 Inhibitors," American Academy of Dermatology 2018 Summer Meeting. July 29, 2018.