Brodalumab significantly improved plaque psoriasis in this 12-week, phase 2 study. (Funded by Amgen; ClinicalTrials.gov number, NCT00975637.).

BACKGROUND Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. METHODS We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. RESULTS Three years after infusion, two participants (one who had received 6×10 12 vector genomes [vg] per kilogram of body weight and one who had received 2×10 13 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 13 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 13 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. CONCLUSIONS Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 13 vg per kilogram or 6×10 13 vg per kilogram of the gene therapy.

SummaryBackground The interleukin-17 cytokine family plays a central role in psoriasis pathogenesis. Objectives To evaluate the efficacy and safety of brodalumab, a human anti-interleukin-17 receptor antibody, in treating patients with moderate-to-severe plaque psoriasis. Methods In this phase III, double-blind, placebo-controlled study (NCT01708590; AMAGINE-1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12-week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA ≥ 3 were re-treated with the induction dose. After ≥ 12 weeks of retreatment, patients with sPGA 2 for ≥ 4 weeks or sPGA ≥ 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with ≥ 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12. Results There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable. Conclusions Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate-to-severe plaque psoriasis.

Psoriasis is a complex inflammatory process resulting from activation of the well-defined IL-23/T17 cytokine axis. We review the role of key cytokines interleukin (IL)-17 and IL-23 in psoriasis, as well as tumor necrosis factor alpha (TNα), focusing on therapeutic cytokine interventions and what they reveal about psoriatic inflammation. The potential role of recently described epidermal IL-36RN and CARD14 genetic mutations in psoriasis pathogenesis will also be explored, as they augment keratinocyte responses to pro-inflammatory cytokines. The discovery of these genetic mutations in familial and pustular psoriasis suggest new links between cytokine-induced gene products and IL-1 family members from keratinocytes, which may regulate features of the disease, including epidermal hyperplasia and neutrophil infiltrating responses.

Although the histologic changes seen in psoriasis have long been well characterized, the underlying cellular and molecular mechanisms have only begun to be elucidated over the past 20 years. Proinflammatory factors such as tumor necrosis factor (TNF)-α have a central role in psoriasis pathogenesis, and many T helper 1 (Th1) cytokines and messenger RNAs are elevated in psoriatic lesions. Interleukin-17A (IL-17A), IL-17F, and other Th17 cell–derived cytokines have been shown in murine models to induce features that mimic human psoriasis. This review focuses on the emerging biology of the IL-17 cytokine family in psoriasis, and on the molecular and genetic information gained from animal models and human clinical studies that confirm IL-17 as a crucial proinflammatory cytokine in psoriasis. Expression of IL-17A, IL-17C, and IL-17F is strikingly increased in psoriatic lesions, and successful therapy is associated with restoration of the expression of a wide range of genes (including effector molecules downstream of IL-17 such as cytokines, chemokines, and antimicrobial peptides) to near normal levels. Therapeutic agents in development that target IL-17 are discussed, and an emerging model of the key role of IL-17 in the pathogenesis of psoriasis is presented.