Factors that may determine super-response to guselkumab
Today's report also covers long-term efficacy and safety of risankizumab in PsA patients, secukinumab dosing in PsO patients, and more (1,500 words, 8 minutes 20 seconds)
The Vender on Psoriasis e-newsletter is supported by an unrestricted grant from Sun Pharma Canada
Good morning and welcome to the fourth issue of Special Reports: Skin Spectrum Weekly presents “Vender on Psoriasis.” This series is based on Dr. Vender’s popular column appearing in each edition of The Chronicle of Skin & Allergy, which offers expert commentary and opinions on current clinical developments in PsO. We’d love to get your feedback and suggestions and invite you to be in touch. Please write to us at email@example.com
Factors that may determine super-response to guselkumab
This study was designed to determine the baseline characteristics of patients with moderate-to-severe psoriasis who achieved super-response (Psoriasis Area and Severity Index [PASI] 100 response at Weeks 20 and 28) following initiation of guselkumab treatment as published in the Journal of the European Academy of Dermatology and Venereology (Aug. 3, 2022).
Pooled data from the VOYAGE-1 and VOYAGE-2 studies identified super-responders. Baseline demographics, disease, and pharmacokinetic characteristics were compared to non-super-responders to identify which factors were potentially predictive of super-response status. A subset of patients randomized to guselkumab were analyzed (n=664); 271 patients achieved super-response vs. 393 who had non-super-response. Patient age at study entry and baseline body weight (≤90 kg vs. >90 kg), PASI, and Investigator’s Global Assessment (IGA) score were significant predictors of super-response status, with odds ratios (95% confidence intervals) of 0.98 (0.967-0.993; p=0.003), 1.42 (1.026-1.977; p=0.034), 0.97 (0.955-0.993; p=0.007), and 0.66 (0.433-0.997; p=0.048), respectively. More patients with super-response also achieved an early response: Week 2 PASI 75 (5.5% vs. 1.8%) and Week 8 PASI 100 (22.5% vs 3.3%) vs. non-super-response. Median serum guselkumab concentrations through Week 28 were slightly greater in patients with super-response vs. non-super-response. Patients who were younger, less obese, and who had less severe psoriasis were more likely to achieve early clinical responses (complete skin clearance) with guselkumab, the researchers reported.
Comment: The concept of super responder is a new finding that is very interesting and can predict how well a certain individual will respond to a particular biologic. In this guselkumab study, certain subtypes of individuals that tend to be super responders are identified. This gives great confidence to the patient and to the prescribing physician that the biologic is working well. One may also decide to choose a patient for this biologic based on the factors described in the study. An interesting thing to know would be if the super responders have longer drug survival and require less dose optimization. Although this biologic works well in the majority of individuals, choosing the specific identifying features can act as a biomarker for an excellent and predictable response to this biologic. Other biologics in this class or from other classes may show a similar response if these identifying features are examined statistically. This type of response may not be unique to guselkumab.
Long-term efficacy and safety of risankizumab in patients with active psoriatic arthritis
In this double-blind, dose-ranging phase 2 study, adults with active PsA were randomized 2:2:2:1:2 to risankizumab 150 mg at weeks 0, 4, 8, 12, and 16 (arm 1), 150 mg at weeks 0, 4, and 16 (arm 2), 150 mg at weeks 0 and 12 (arm 3), 75 mg at week 0 (arm 4), or placebo (arm 5). Patients who completed week 24 could receive risankizumab 150 mg in a 52-week open-label extension study, for a total treatment time of 76 weeks. The study was published in Rheumatology and Therapy (Aug. 5, 2022).
Assessments included American College of Rheumatology (ACR) responses, Psoriasis Area Severity Index (PASI) responses, minimal disease activity (MDA), and 28-joint Disease Activity Score based on C-reactive protein (DAS28[CRP]), the researchers reported.
In total, 185 patients were randomized; 173 (93.5%) completed week 16 and 145 (78.4%) entered the open-label extension. Significantly more patients in each risankizumab arm achieved ACR20 at week 16 versus placebo (primary endpoint: pooled arms 1 + 2 [59.5%] vs. placebo [35.7%]; treatment difference [90% CI] 24.0 [9.3, 38.7]; p=0.007). Similarly, significantly more patients in most risankizumab arms achieved ACR20/50/70, PASI75/90/100, MDA, and greater improvements in DAS28(CRP) versus placebo at week 16. Risankizumab 150 mg was well tolerated over 76 weeks, and the benefits of risankizumab were maintained long term. Treatment-emergent adverse events were comparable across treatment arms with no new safety findings, the researchers reported.
Comment: These results are no surprise and add to the further efficacy that risankizumab has on the skin. Although this is a phase 2 study, one expects that phase 3 will have equal and comparable results. From the general rules and expectations for ACR 20, one would expect that it would be at 60% as shown in this study. However, minimal disease activity is extremely important to look at as well as reduction of progression of joint destruction. The reduction in dactylitis and enthesitis is also important to examine. It’s always interesting to me that the lower dose of this biologic tends to work better than the dosing for most biologics. Clinicians must also be aware that the response of axial symptoms may be different using this anti-IL 23A than when using biologics in the anti-IL 17 class.
Secukinumab dosing in psoriasis patients weighing 90 kg or more
Since obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment, investigators looked at the efficacy, safety and tolerability of secukinumab 300 mg every two weeks (Q2W) vs. secukinumab 300 mg every four weeks (Q4W) in patients with a higher body weight, according to a study published in the British Journal of Dermatology (Jan. 4, 2022).
A total of 331 patients with moderate-to-severe chronic plaque psoriasis weighing ≥90 kg were randomized to receive secukinumab 300 mg Q2W or secukinumab 300 mg Q4W. Patients who did not achieve PASI 90 at Week 16 on the Q4W regimen were reallocated to remain on the Q4W regimen or up-titrate to Q2W.
Results showed that at Week 16, Q2W dosing (n=165) led to significantly higher PASI 90 responses vs. Q4W [n=166; 73.2% vs. 55.5%, one-sided p-value=0.0003, odds ratio estimate (95% confidence intervals): 2.3 (1.4, 3.8). At Week 52, higher efficacy responses were maintained in the Q2W arm (n=165) vs. Q4W (n=83); PASI 75: 88.9% vs. 74.8%; PASI 90: 76.4% vs. 52.4%, PASI 100: 46.7% vs. 27.3%; IGA 0/1: 75.9% vs. 55.6% and DLQI 0/1: 66.1% vs. 48.8%. According to the investigators, PASI 90 non-responders at Week 16 who up-titrated to Q2W (n=31) showed higher efficacy responses at Week 32 (16 weeks post-up-titration, PASI 90: 38.7% vs. 16.5%) vs. those who remained on Q4W (n=40). Safety results were comparable across treatment arms and consistent with the established secukinumab safety profile.
The researchers concluded that secukinumab 300 mg Q2W demonstrated superior and sustained efficacy compared to Q4W in moderate-to-severe plaque psoriasis patients weighing ≥90 kg. Also, PASI 90 non-responders benefited from up-titration to a Q2W regimen.
Comment: This study has confirmed a long-standing concern with dermatologists who prescribe secukinumab. This first-to-class anti-IL 17 biologic has certainly had excellent success in treating patients with moderate to severe psoriasis, psoriatic arthritis and special site involvement such as nails, scalp and palmar-plantar psoriasis. However, it does have low biologic survival. Part of this decrease in efficacy seems to be in heavier patients. This study sponsored by the manufacturer showed that patients with a higher weight would benefit from more frequent dosing of secukinumab. Other IL-17 inhibitors such as brodalumab have found better success in patients with Q2 week dosing. This study confirms that heavier patients would benefit from Q2 week dosing of secukinumab. Although patients who are using standard every four-week dosing still benefit greatly with respect to PASI 75-90 and 100, the increased frequency of secukinumab every two weeks in heavier patients captures 15% (on average) more patients for PASI 75-90 and 100. One common misconception is that secukinumab does not work well in heavier patients. This study allows more frequent dosing. No safety concerns were found with this higher dosing either. This study confirms that heavier patients can be more effectively treated with more frequent dosing of secukinumab.
If you find the contents of this newsletter interesting, please check out the Vender on Psoriasis podcast. It’s available at Apple iTunes, Stitcher, Spotify, or wherever you get your podcasts.
Dr. Ron Vender is a Hamilton-based certified dermatologist with 31 years of clinical practice experience and over 100 clinical trials in psoriasis. He is founder and director of Venderm Innovations in Psoriasis, a centre of excellence for Psoriasis offering a comprehensive management solution for individuals with psoriasis.
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