Jerry Bagel

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.).

Consensus Guidelines for the Management of Plaque Psoriasis

The Canadian Guidelines for the Management of Plaque Psoriasis were reviewed by the entire National Psoriasis Foundation Medical Board and updated to include newly approved agents such as ustekinumab and to reflect practice patterns in the United States, where the excimer laser is approved for psoriasis treatment. Management of psoriasis in special populations is discussed. In the updated guidelines, we include sections on children, pregnant patients or pregnant partners of patients, nursing mothers, the elderly, patients with hepatitis B or C virus infections, human immunodeficiency virus-infected patients, and patients with malignant neoplasms, as well as sections on tumor necrosis factor blockers, elective surgery, and vaccinations.

A review of phototherapy protocols for psoriasis treatment

Phototherapy is a mainstay in the treatment of psoriasis and is available as psoralen plus UVA (PUVA), broadband UVB (BB-UVB), and narrowband UVB (NB-UVB). Phototherapy can be administered in the hospital, outpatient clinic, or in the patients home. The purpose of this review is to provide some practical guidance to general dermatologists and residents on the specifics of using phototherapy, which, despite its decreasing use, remains one of our most safe and effective treatment strategies for psoriasis care. We conducted a literature review of home phototherapy, BB-UVB, NB-UVB, and PUVA phototherapy using PubMed, MD Consult, and reference lists. A variety of protocols for BB-UVB, NB-UVB, and PUVA have been used in clinical trials. NB-UVB is more effective than BB-UVB and safer than PUVA. Typical regimens for NB-UVB involve dosing 3 times per week for at least 3 months. Treatment must be independently developed to suit each participants needs. Ultraviolet light is an effective, relatively safe modality that is a valuable tool in the treatment of psoriasis. NB-UVB phototherapy is considered the first-line treatment for extensive plaque type psoriasis.

Administration of DAB389IL-2 to patients with recalcitrant psoriasis: A double-blind, phase II multicenter trial

BACKGROUND Current therapies for recalcitrant psoriasis focus on immunoregulation and targeting of activated T-lymphocytes rather than keratinocytes. Previous studies with low doses of the lymphocyte-selective fusion protein DAB389IL-2 have shown benefit to patients with psoriasis. OBJECTIVE We examined the safety and efficacy of DAB389IL-2 in 41 volunteers receiving more frequent and higher doses than in a previous trial. METHODS Patients were randomized to receive either placebo or 5, 10, or 15 microg/kg daily of DAB389IL-2 intravenously for 3 consecutive days each week for 4 consecutive weeks with a subsequent 4-week observation period. RESULTS Of the placebo group, 17% (2 of 12) exhibited at least 50% improvement from baseline Psoriasis Area and Severity Index scores at the end of the study, whereas 24% of all treated patients (7 of 29) showed the same improvement. Overall, 3 of 12 (25%) patients given placebo as opposed to 12 of 29 (41%) patients treated with DAB389IL-2 improved to this same extent at some point during the study. The rate of improvement for treated patients was significantly greater than for placebo patients (p = 0.04; repeated measures ANOVA). Among treated patients, decreases in Psoriasis Area and Severity Index scores were paralleled by changes in the Physicians Global Assessment and the Dermatology Life Quality Index. Treatment in ten patients was discontinued because of adverse events. Flu-like symptoms were the most common with severity increasing at the two higher doses. Only one serious adverse event was reported. This occurred in a patient receiving 5 microg/kg daily who experienced vasospasm and a coagulopathy resulting in arterial thrombosis. CONCLUSION Our findings are consistent with the potential antipsoriatic activity of DAB389IL-2 demonstrated in an earlier study. However, DAB389IL-2 was less well tolerated at this dosing regimen, particularly at the highest dose, and it was too toxic at these doses and schedules to be considered in the routine treatment of psoriasis.

From the Medical Board of the National Psoriasis Foundation: The risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies

BACKGROUND Many studies have identified cardiovascular risk factors in patients with psoriasis. Some psoriasis therapies may increase cardiovascular disease (CVD) and others may decrease CVD. OBJECTIVE We reviewed the literature to define the impact of common psoriasis therapies on cardiovascular measures and outcomes. RESULTS Phototherapy has no major cardiovascular impact and may reduce levels of proinflammatory cytokines. Acitretin increases serum lipids and triglycerides, but has not been shown to increase cardiovascular risk. Cyclosporine A increases blood pressure, serum triglycerides, and total cholesterol. Methotrexate is associated with a decreased risk of CVD morbidity and mortality. Among the biologics, data for tumor necrosis factor inhibitors suggest an overall reduction in cardiovascular events. Most data on short-term ustekinumab use suggest no effect on major adverse cardiovascular events, however some authorities remain concerned. Nevertheless, ustekinumab use over a 4-year period shows a decrease in major adverse cardiovascular events when compared both with the general US population and with psoriatics in Great Britain. LIMITATIONS Most studies lack the power and randomization of large clinical trials and long-term follow-up periods. In addition, the increased risk of CVD associated with psoriasis itself is a confounding factor. CONCLUSION Some therapies for moderate to severe psoriasis, including methotrexate and tumor necrosis factor inhibitors, may reduce cardiovascular events in psoriatic patients. Ustekinumab appears to be neutral but there may be a long-term benefit. Appropriate patient counseling and selection and clinical follow-up are necessary to maximize safety with these agents. Further long-term study is necessary to quantify the benefits and risks associated with biologic therapies.

Moderate to severe plaque psoriasis with scalp involvement: A randomized, double-blind, placebo-controlled study of etanercept

BACKGROUND Biologic therapies are used to treat moderate to severe psoriasis, but evidence from randomized, controlled studies is lacking regarding scalp-related effectiveness. OBJECTIVE To evaluate the efficacy and safety of etanercept for scalp symptoms (erythema, induration, scale, and percentage of scalp involvement) in patients with moderate to severe plaque psoriasis and scalp involvement. METHODS In this randomized, placebo-controlled study, adult patients with stable plaque psoriasis and significant scalp symptoms received etanercept 50 mg twice weekly (BIW) by subcutaneous injection (SC) for 12 weeks, followed by etanercept 50 mg once weekly (QW) and placebo QW (Group A, n = 62) or SC placebo BIW for 12 weeks, followed by etanercept 50 mg BIW for 12 weeks (Group B, n = 62). The primary end point was percentage change in Psoriasis Scalp Severity Index (PSSI) at week 12. RESULTS Demographics and disease characteristics were balanced: 56% men, 73% white, median age 41 years, median BMI 30.2 kg/m(2). At week 12, mean PSSI improvement was 86.8% (standard deviation [SD], 18.0%) in Group A and 20.4% (SD, 39.3%) in Group B (P < .0001). At week 24, mean PSSI improvements were as follows: Group A, 90.6% (SD 13.1%); Group B, 79.1% (SD 33.6%). At week 12, 51 of 59 (86%) Group A patients and 7 of 61 (11%) Group B patients achieved PSSI 75 (P <.0001). Three patients (2.7%) reported 5 serious adverse events: cholecystitis/cholelithiasis, fall/rib fracture, and metastatic malignant melanoma. LIMITATIONS The study was insufficiently powered to detect rare adverse events potentially associated with etanercept. CONCLUSIONS Etanercept is an effective, well-tolerated treatment for plaque psoriasis involving the scalp.

Treatment of intertriginous psoriasis: From the Medical Board of the National Psoriasis Foundation

BACKGROUND Involvement of areas of the skin fold is common in patients with psoriasis although the exact incidence is unknown. This report summarizes studies regarding the therapy of intertriginous psoriasis. OBJECTIVE A task force of the National Psoriasis Foundation Medical Board was convened to evaluate treatment options. Our aim was to arrive at a consensus on therapy for intertriginous or inverse psoriasis. METHODS Reports in the literature were reviewed regarding psoriasis affecting the skin-fold areas and its therapy. LIMITATIONS There are few evidence-based studies on the treatment of intertriginous psoriasis. RESULTS The recommended short-term (2-4 weeks) therapy for inverse psoriasis is low- to mid-potency topical steroids. For long-term therapy, topical calcipotriene (calcipotriol) or one of the immunomodulating agents, pimecrolimus or tacrolimus, is favored. CONCLUSIONS Low- to mid-potency topical steroids are recommended as first-line, short-term treatment. It is recommended that their use should either be of limited duration (less than 2-4 weeks) or that the lowest effective strength be used intermittently for long-term care to minimize the potential for risks. Calcipotriene (calcipotriol), pimecrolimus, and tacrolimus, while not as highly efficacious as topical steroids, are associated with fewer long-term risks and are therefore recommended for long-term therapy when feasible.

Repeat courses of intravenous alefacept in patients with chronic plaque psoriasis provide consistent safety and efficacy

Background Psoriasis is a chronic, relapsing skin disease that may require multiple treatment courses. Alefacept targets the memory T cells implicated in psoriasis pathogenesis. This open‐label study evaluated the safety and tolerability, efficacy, and pharmacodynamics of repeat courses of alefacept in men and women with chronic plaque psoriasis. This article reports the interim results of this ongoing study.

Combining Biologic Therapies With Other Systemic Treatments in Psoriasis: Evidence-Based, Best-Practice Recommendations From the Medical Board of the National Psoriasis Foundation

IMPORTANCE While monotherapy with biologic agents is effective for many patients with psoriasis, some patients require combination therapy. Evidence-based recommendations on combination therapy provide guidance for treating appropriately selected patients with psoriasis. OBJECTIVE To make evidence-based, best-practice recommendations regarding combining biologics with other systemic treatments, including phototherapy, oral medications, or other biologics, for psoriasis treatment. EVIDENCE REVIEW We searched the MEDLINE database for studies from January 1, 1946, to June 18, 2013, that evaluated therapies combining biologics with phototherapy, oral medications, or other biologic agents. The Medical Board of the National Psoriasis Foundation arrived at best-practice recommendations through group discussion and voting. FINDINGS Few trials evaluated the efficacy and safety of combination therapies in moderate to severe psoriasis. Combining biologics, such as etanercept or adalimumab, with phototherapy likely results in greater reduction in disease severity than either alone. Etanercept and methotrexate combination is more effective than monotherapy with either medication. A combination of infliximab with methotrexate results in greater efficacy than infliximab alone. With concomitant use of acitretin, the dosing of etanercept can be reduced to maintain similar levels of efficacy. Short-term cyclosporine use has been combined with etanercept or adalimumab to control psoriasis flares. Based on the expert opinion of the Medical Board of the National Psoriasis Foundation, the preferred order for combining a second modality with biologics is biologic and methotrexate combination, biologic and acitretin combination, and then biologic and phototherapy combination. In the psoriasis literature, there are overall insufficient data on combining biologics with acitretin, cyclosporine, or a second biologic. CONCLUSIONS AND RELEVANCE Among appropriately selected patients with psoriasis, carefully chosen combinations may result in greater efficacy, while minimizing toxicity.

Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris – A randomized phase II study

Abstract Background: An aerosol foam formulation of fixed combination calcipotriene 0.005% (as hydrate; Cal) plus betamethasone dipropionate 0.064% (BD) was developed to improve psoriasis treatment. Objectives: To compare the efficacy and safety of Cal/BD aerosol foam with Cal/BD ointment after 4 weeks. Methods: In this Phase II, multicenter, investigator-blind, 4-week trial, adult patients with psoriasis vulgaris were randomized to Cal/BD aerosol foam, Cal/BD ointment, aerosol foam vehicle or ointment vehicle (3:3:1:1). The primary efficacy endpoint was the proportion of patients at week 4 who achieved treatment success (clear or almost clear with at least a two-step improvement) according to the physician’s global assessment of disease severity. Results: In total, 376 patients were randomized. At week 4, significantly more patients using Cal/BD aerosol foam achieved treatment success (54.6% versus 43.0% [ointment]; p = 0.025); mean modified (excluding the head, which was not treated) psoriasis area and severity index score was significantly different between Cal/BD aerosol foam and Cal/BD ointment (mean difference –0.6; p = 0.005). Rapid, continuous itch relief occurred with both active treatments. One adverse drug reaction was reported with Cal/BD aerosol foam (application site itch). Conclusions: Cal/BD aerosol foam demonstrates significantly greater efficacy and similar tolerability compared with Cal/BD ointment for psoriasis treatment.