Darryl Toth

Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis

BACKGROUND Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physicians global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).

A prospective phase III, randomized, double‐blind, placebo‐controlled study of brodalumab in patients with moderate‐to‐severe plaque psoriasis

The interleukin‐17 cytokine family plays a central role in psoriasis pathogenesis.

Secukinumab retreatment-as-needed versus fixed-interval maintenance regimen for moderate to severe plaque psoriasis: A randomized, double-blind, noninferiority trial (SCULPTURE)

BACKGROUND Secukinumab has demonstrated high, sustained efficacy in psoriasis to 52 weeks on a fixed-interval regimen. OBJECTIVE We sought to compare a retreatment-as-needed versus a fixed-interval regimen. METHODS In this double-blind study, adults with moderate to severe plaque psoriasis were randomized 1:1 to subcutaneous secukinumab at 300 mg (n = 484) or 150 mg (n = 482) weekly from baseline until week 4, and at week 8. At week 12, patients achieving 75% or more improvement from baseline Psoriasis Area and Severity Index score (PASI 75) were rerandomized to 2 dose levels of secukinumab retreatment as needed (n = 217, 300 mg; n = 206, 150 mg) or fixed interval (n = 217; n = 203). Primary end point was noninferiority of retreatment as needed versus fixed interval for maintaining PASI 75 to week 52. RESULTS Secukinumab induced high responses by week 12 (84.4%-91.1% PASI 75 responders). From week 12 to week 52, more patients on fixed interval (78.2%, 300 mg; 62.1%, 150 mg) maintained PASI 75 versus retreatment as needed (67.7%; 52.4%); statistical noninferiority of retreatment as needed was not established. Overall safety, including very low incidences of treatment-emergent anti-drug antibodies (<0.5%), was similar between regimens. LIMITATIONS The primary end point was developed without any known precedent. CONCLUSION Secukinumab fixed interval showed clear benefit versus the study-specified retreatment-as-needed regimen for maintaining efficacy. Both regimens exhibited safety consistent with previous trials. The potential of retreatment as needed with secukinumab warrants further investigation.

Assessment of the long-term safety and effectiveness of etanercept for the treatment of psoriasis in an adult population

BACKGROUND Etanercept is well tolerated and effective in moderate to severe plaque psoriasis. However, effectiveness and safety data beyond 2.5 years have not been reported. OBJECTIVE We sought to assess the effectiveness and safety profile of up to 4 years of etanercept therapy in psoriasis. METHODS We analyzed prospective data from previous trials and open-label extensions, including 506 patients who initiated etanercept therapy in either of two phase III trials. Patients received etanercept, 25 mg twice weekly, 50 mg weekly, or 50 mg twice weekly, depending on which trial therapy was started. Dosage adjustments were allowed in open-label extensions, but no patients exceeded 50 mg twice weekly. Outcomes included change from baseline for the static Physician Global Assessment and Dermatology Life Quality Index scores. Exposure-adjusted adverse event (AE) rates were calculated. RESULTS In all, 75.9% (95% confidence interval 67.9-84.0) and 27.8% (95% confidence interval 19.3-36.2) maintained Dermatology Life Quality Index response (≥ 5-point improvement from baseline) and static Physician Global Assessment response (clear or almost clear) at 48 months, respectively. AE and serious AE rates were 243.5 and 7.8 events per 100 patient-years, respectively. No serious AE rates exceeded 1.0 event per 100 patient-years. Overall infection and serious infection rates were 96.9 and 0.9 events per 100 patient-years, respectively. No cases of tuberculosis or lymphoma were reported. LIMITATIONS Effectiveness data were limited to static Physician Global Assessment and Dermatology Life Quality Index scores. Analysis of AE rates was limited to available comparator databases. CONCLUSION Etanercept demonstrated sustained effectiveness and a favorable safety profile with no cumulative toxicity for up to 4 years, representing, to our knowledge, the longest published study on etanercept use in psoriasis to date.

A review of malignancies observed during efalizumab (Raptiva®) clinical trials for plaque psoriasis

Background: Psoriasis is a chronic, incurable immune-mediated disease. Most therapies used for moderate to severe psoriasis are immunosuppressive. Agents that depress immune function, including traditional psoriasis therapies, have been associated with an increased incidence of malignancies. Efalizumab is a recombinant monoclonal immunoglobulin G1 (IgG1) antibody approved for use in psoriasis patients. Objectives: To evaluate the incidence of malignancy in patients receiving efalizumab during clinical trials compared with placebo-treated patients, psoriasis patients from external cohorts and the general US population. Methods: Patient data were pooled from multiple phase III placebo-controlled, open-label efalizumab clinical trials, and the incidence rate of reported malignancies was calculated as a function of patient years of observation. The results for the efalizumab-treated patients were compared with the data on psoriasis patients from insurance claims databases and a registry of events in the general population. Results: The efalizumab- and placebo-treated patients had similar incidence rates of malignancy, including lymphoproliferative disease, solid tumor, malignant melanoma and nonmelanoma skin cancer. The incidence of nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, in patients receiving efalizumab or placebo was elevated relative to the external databases. Conclusions: These results suggest that efalizumab treatment does not increase a patient’s risk for malignancy. The difference observed with nonmelanoma skin cancer may be due to biases introduced by the clinical trial methodology. Additional patient observation is necessary to ascertain whether a link exists between efalizumab therapy and nonmelanoma skin cancer above that normally observed in psoriasis patients.

Transitioning patients from efalizumab to alternative psoriasis therapies: findings from an open-label, multicenter, phase IIIb study

Background  Rebound in psoriasis is, by definition, a rapid worsening of disease following the discontinuation of therapy for psoriasis; it occurs following the abrupt discontinuation of many therapies. To prevent rebound on discontinuation of efalizumab, this study evaluated the effectiveness of transitioning patients to an alternative psoriasis therapy.

Safety profile of intravenous and subcutaneous siplizumab, an anti-CD2 monoclonal antibody, for the treatment of plaque psoriasis: results of two randomized, double-blind, placebo-controlled studies

Several biologics targeting different cytokines and receptors, including T‐cell receptors, have been approved for psoriasis treatment. Siplizumab, a humanized anti‐CD2 monoclonal antibody, may potentially provide an alternative therapy for psoriasis. Its safety profile and immunogenicity was examined in adults with plaque psoriasis. Two multicenter phase II randomized, double‐blind, placebo‐controlled studies: one tested two intravenous (I.V.) doses (0.012 and 0.04 mg/kg) of siplizumab every 2 weeks × 8 doses (124 patients); the second study tested three subcutaneous (S.C.) dose regimens of siplizumab (5 mg × 12 weeks, 5 mg × 6 weeks + placebo × 6 weeks, 7 mg × 4 weeks + placebo × 8 weeks), and placebo × 12 weeks (420 patients). Adverse events (AEs) and laboratory values were monitored. Immunogenicity was determined by anti‐siplizumab antibodies quantification. In both studies, siplizumab exhibited an acceptable safety profile; most common AEs judged to be siplizumab related were lymphopenia, chills, and headache, reported at a higher frequency in the siplizumab‐treated vs. placebo group. Siplizumab‐related reductions in absolute lymphocyte count did not result in clinical evidence of immune suppression. Anti‐siplizumab antibodies were detected after exposure to siplizumab; however, there was no evidence of an association between antibody development and AEs. Siplizumab exhibited an acceptable safety profile in adult patients with plaque psoriasis when administered as multiple I.V. or S.C. doses. Higher, clinically relevant doses of siplizumab would need to be tested to fully assess its safety.

Quality of life in plaque psoriasis patients treated with voclosporin: a Canadian phase III, randomized, multicenter, double-blind, placebo-controlled study

BACKGROUND Quality of life assessments are important in the evaluation of new therapies for psoriasis. OBJECTIVE To determine the effect of voclosporin (VCS) treatment on quality of life in patients with psoriasis. PATIENTS AND METHODS 451 plaque psoriasis patients with ≥  10% body surface area involvement were randomly assigned in a double-blind fashion to 1 of 4 treatment groups (placebo, VCS 0.2 mg kg(-1) BID, VCS 0.3 mg kg(-1) BID, and VCS 0.4 mg kg(-1) BID) for up to 12 weeks of treatment. Quality of life was assessed using the Dermatology Life Quality Index (DLQI) and the Psoriasis Disability Index (PDI). RESULTS At 12 weeks, patients treated with VCS 0.4 mg kg(-1) BID had statistically significantly more favourable assessments than placebo-treated patients in all domains of the DLQI and the PDI. Patients treated with VCS 0.3 mg kg(-1) BID had statistically significant improvements in 5 of 10 domains of the DLQI and all domains of the PDI. Patients treated with VCS 0.2 mg kg(-1) BID had statistically significant improvements in 4 of 10 domains of the DLQI and 2 of 4 domains of the PDI. CONCLUSION Treatment with VCS 0.4 mg kg(-1) BID significantly improves the quality of life of patients with psoriasis.

Long-term efficacy of up to 15 months’ efalizumab therapy in patients with moderate-to-severe chronic plaque psoriasis

ABSTRACT:  The efficacy and safety of efalizumab in the treatment of moderate‐to‐severe chronic psoriasis has been established in studies of up to 3 years’ duration. This study aims to describe the efficacy of up to 15 months’ treatment with efalizumab and the convenience of therapy in patients with moderate‐to‐severe chronic plaque psoriasis. Patients who had completed a 3‐month, double‐blind, randomized, placebo‐controlled, Phase IIIb trial entered a 12‐month extension study and received efalizumab, 1 mg/kg/week administered subcutaneously, for up to 12 months. Of 450 patients originally randomly assigned to receive efalizumab, 40.9% achieved a reduction of ≥ 75% in the Psoriasis Area and Severity Index score after 15 months of treatment. Improvements were also observed on the frequency and severity subscales of the Psoriasis Symptom Assessment. The majority of patients reported that efalizumab treatment was more or much more convenient than other psoriasis treatments. Efalizumab, 1 mg/kg/week, provides long‐term efficacy and good convenience with up to 15 months of continuous treatment.

An Open Letter to Health Canada

Regulators are mandated to provide structured guidance on drug development. They approve drugs based upon their scientific and medical merits. They negotiate a disclosure of a drug’s profile—the label. And they provide ongoing monitoring of manufacturing, use, and safety once the drug is marketed. Posting of guidance documents notwithstanding, the foregoing are conducted behind closed doors and subject to coveted decision processes. The warnings and directions provided in the drug label are for the most part warranted. On occasion, the warnings and requirements are restrictive and unwarranted. The recent US Food and Drug Administration (FDA) approval and release of the brodalumab label bears witness. Brodalumab (Siliq), an IL-17R antagonist, was evaluated for the treatment of Crohn disease, psoriasis, and psoriatic arthritis (NCT02024646, NCT02029495). Six completed suicides occurred across all development programs, 4 within the psoriasis studies. One of the suicides reported in the psoriasis program was adjudicated as an accidental overdose of illicit drugs. With more than 4000 patients and nearly 10 000 patient years of exposure, the approximate suicide event rate of 30 per 100 000 patient years is marginally greater than the range of rates reported in the adult US population: 12 to 24 per 100,000. Depression is a known comorbidity of psoriasis. We know that depression is the major risk factor for suicide ideation, suicide attempts, and completion. Interestingly, depression scores improve in psoriasis populations receiving effective therapy, as do patients treated with brodalumab. The US Siliq label contains a boxed warning that advises physicians to be aware of the potential for depression and take action should a patient be at risk of suicide. Warnings of this sort deserve attention for all populations at risk. The label clearly states that no causal association with suicide ideation or completed suicide and brodalumab was found. Absence of implied and mechanistic causality, the cornerstones of Hill’s hypothesis, argues for statistical fluctuation within the sample population. Still, the monograph imposes an onerous burden on prescribers. The boxed warning and registration requirements appear orthogonal to a balanced and scientifically derived statement of facts. Motivation for inclusion of the boxed warning is obscure and unjustified. The Canadian health care system is undermanned and our patients underserviced. Imposing burdensome risk mitigation programs will do little more than impair access and limit therapeutic options available to our patients. As concerned clinicians, we respectfully request Health Canada provide scientifically and clinically sound guidance for brodalumab and not mime the United States.