Most patients with psoriasis who respond to ixekizumab then discontinue treatment can regain response within 12 weeks of retreatment, according to a long-term Japanese phase three study. It was published online October 16 in the Journal of the European Academy of Dermatology and Venereology.
"These results highlight the potential of ixekizumab as a treatment for Japanese patients with moderate-to-severe psoriasis under conditions that reflect the treatment interruptions that might occur in clinical practice," wrote authors led by Yoshinori Umezawa, M.D., of the Jikei University School of Medicine in Tokyo.
The study provides reassurance that if patients forget to take a few doses or have an interruption in insurance coverage, they most likely will regain their original response level, said Jashin Wu, M.D., of the Dermatology Research and Education Foundation, who was not involved with the study.
The UNCOVER-J study used different response criteria than a short-term pooled study of ixekizumab treatment interruption published in the June 2017 Journal of the European Academy of Dermatology and Venereology. However, said Umezawa et al., the current study's findings in Japanese patients confirm those in the global population while more closely reflecting what happens in actual clinical practice.
The prior study, which used static Physician Global Assessment (sPGA) scores of zero or one at week 12 to define response, showed a median time to relapse (sPGA ≥ three) of approximately 20 weeks. After 12 weeks of retreatment, 80 percent, 56 percent and 35 percent of patients recaptured Psoriasis Area and Severity Index (PASI) 75, 90 and 100, and response rates persisted through week 24 of retreatment.
In UNCOVER-J, median time to relapse (PASI ≤ 50) was 143 days, and response rates after 12 weeks' retreatment (80 mg every four weeks) persisted out to 120 weeks. "However," wrote Umezawa et al., "not all patients recaptured the same degree of efficacy when ixekizumab was reintroduced." After an initial 52-week treatment period, PASI 75, 90 and 100 rates were 100 percent, 87 percent and 53 percent, versus 83 percent, 68 percent and 39 percent at week 120 of retreatment. Dermatology Life Quality Index (DLQI) and Psoriasis Scalp Severity Index (PSSI) scores followed a similar pattern.
Some studies have shown that intermittent biologic therapy raises patients' risk for developing anti-drug antibodies (ADAs). In UNCOVER-J, the rate of treatment-emergent ADAs (TE-ADAs) rose from 12.8 percent during the initial 52-week treatment period to 19.4 percent at 192 weeks. "Taking into account the longer duration of the treatment period, the incidence of TE-ADAs during the retreatment period has not increased from that of the initial 52-week maintenance treatment period," authors wrote. Additionally, as in the previous shorter study of interrupted ixekizumab therapy, few patients developed neutralizing antibodies. On the whole, retreatment with ixekizumab was well-tolerated.
Study limitations include its lack of a control group, open-label design and small sample size (70 responders), and the fact that all subjects were Japanese. Because Umezawa et al. did not use approved loading (160 mg) and induction (80 mg every two weeks) doses upon initiating retreatment, they added, further study of treatment interruptions using different withdrawal times and doses is warranted.
While the study's findings are significant, added Dr. Wu, they come as no surprise. "The finding of less than total recapture has been seen in all other biologic studies looking at recapture." A pooled analysis of the ERASURE and FIXTURE trials of the interleukin (IL)-17 inhibitor secukinumab showed that 95 percent, 70 percent and 38 percent of patients who had relapsed regained PASI 75, 90 and 100, respectively, after 12 weeks' retreatment.
Umezawa et al. noted that differing study designs make between-study comparisons difficult. A pooled analysis of the AMAGINE-1, -2 and -3 brodalumab trials found a median time to relapse (defined as the request of patient to initiate retreatment after withdrawal) of six to seven weeks, and retreatment was not offered in these trials.
Regarding UNCOVER-J, Dr. Wu said it is helpful know that the median period of relapse is five months after stopping ixekizumab. "Sometimes patients miss a dose for various reasons, so I would not expect a relapse unless they missed three to six doses in the maintenance period."
But because the recapture rate is not 100 percent, he added, the study underscores the importance of avoiding treatment gaps wherever possible.
Eli Lilly Japan K.K. was involved in the study design, data collection, data analysis and preparation of the manuscript.
Yoshinori Umezawa MD, Hitoe Torisu-Itakura MD, Yoji Morisaki MS, et al. "Long-Term Efficacy and Safety Results from an Open-Label Phase III Study (UNCOVER-J) in Japanese Plaque Psoriasis Patients: Impact of Treatment Withdrawal and Retreatment of Ixekizumab," Journal of the European Academy of Dermatology and Venereology. October 2018.