Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.

BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

Expression of antimicrobial peptides in the normal and involved skin of patients with infective cellulitis.

BACKGROUND: Endogenous antimicrobial peptides participate in the innate defense of skin against a variety of pathogens. The systemic expression of these peptides in normal-appearing skin of patients with infective cellulitis is unknown. METHODS: Study patients were adults with infective cellulitis and signs of systemic inflammation. Skin biopsy and serum specimens were obtained from patients and from control subjects with no active infection. Cathelicidin and human beta-defensin 2 mRNA expression were determined by real-time polymerase chain reaction. RESULTS: Skin biopsy specimens from 11 patients and 4 uninfected control subjects were analyzed. The relative expression level for cathelicidin mRNA was elevated in both the involved and the distal normal-appearing skin of patients with cellulitis, compared with expression in the skin of control subjects (mean ratios, 39.46 vs. 1.32, P=.0059; and 21.41 vs. 1.32, P=.0059). Similarly, the relative expression level of human beta -defensin 2 mRNA was elevated in both the involved skin (mean ratios, 20,844 vs. 11.65; P=.0015) and in distal normal-appearing skin of patients with cellulitis (mean ratios, 201.1 vs. 11.65; P=.0103). DISCUSSION: In response to cutaneous infection there is a local and distal increase in endogenous antimicrobial peptide mRNA in both involved and normal-appearing skin. These observations show, for the first time to our knowledge, that after infection the human body responds by increasing systemic innate immunity.