Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .).

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Mechanism of action• Patisiran is a double-stranded small interfering RNA that targets a sequence within the transthyretin (TTR) messenger RNA that is conserved across wild-type and all TTR variants to decrease hepatic production of mutant and wild-type TTR. Pharmacology • Patisiran has been consistently shown to achieve rapid onset (peak effect within ∼2 weeks), robust (∼80-90%) and sustained (>36 months) reduction of serum TTR when dosed at 0.3 mg/kg body weight every 3 weeks. • Prior treatment with TTR stabilizers did not interfere with the pharmacological activity of patisiran. Clinical efficacy • In the Phase III APOLLO study, patisiran treatment led to statistically significant improvements in polyneuropathy (modified Neuropathy Impairment Score +7) and Norfolk Quality of Life-Diabetic Neuropathy questionnaire measures compared with placebo in patients with hereditary TTR-mediated amyloidosis. • The beneficial effects of patisiran treatment on polyneuropathy and quality of life were consistent across all major subgroups (age, gender, race, region, genotype, neuropathy impairment score at the start of treatment, familial amyloid polyneuropathy stage, previous TTR stabilizer use and cardiac involvement) in the APOLLO study. • Patisiran improved multiple clinical end points compared with placebo in the APOLLO study, including motor strength, disability, gait speed, nutritional status and autonomic symptoms. • Patisiran treatment was associated with improvement in cardiac structure and function in a predefined cardiac subpopulation in the APOLLO study, with significant reductions in left ventricular wall thickness, left ventricular longitudinal strain and N-terminal prohormone of brain-type natriuretic peptide levels at 18 months. Safety • Patisiran was generally well tolerated and showed a consistent safety profile in patients with hereditary TTR-mediated amyloidosis across all phases of clinical development, in which 218 patients were exposed for periods of up to 4 years.Hereditary transthyretin-mediated amyloidosis is a rapidly progressive, heterogeneous disease caused by the accumulation of misfolded transthyretin protein as amyloid fibrils at multiple sites, and is characterized by peripheral sensorimotor neuropathy, autonomic neuropathy and/or cardiomyopathy. Current treatment options have limited efficacy and often do not prevent disease progression. Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein. In Phase II, III and long-term extension studies in patients with hereditary transthyretin-mediated amyloidosis, patisiran has consistently slowed or improved progression of neuropathy. In addition, the Phase III trial demonstrated significant improvements in quality of life measures and indicators of cardiomyopathy. Here, we highlight efficacy and safety data from the patisiran clinical trial programme.

In Alzheimer's disease, the neuritic or senile amyloid plaques in hippocampus and association cortex, the diffuse plaques in brain areas such as the cerebellum and sensorimotor cortex, and the amyloid deposits in the walls of pial and parenchymal blood vessels are mainly composed of amyloid β‐peptides. In the present study, either soluble 40‐residue amyloid β‐peptide radiolabeled with 125I (I‐sAβ) or [14C]polyethylene glycol ([14C]‐PEG, a reference material) was briefly infused into one lateral ventricle of normal rats. By 3.5 min, 30% of the I‐sAβ was cleared from ventricular CSF into blood; another 30% was removed over the next 6.5 min. No [14C]PEG was lost from the CSF‐brain system during the first 5 min, and only 20% was cleared by 10 min. Much of the I‐sAβ that reached the subarachnoid space was retained by pial arteries and arterioles. Virtually no I‐sAβ was found in brain. The clearance of amyloid β‐peptides from the CSF‐brain system, reported herein for normal rats, may be reduced in Alzheimer's disease, thus contributing to amyloid deposition in cerebral tissue and blood vessels.

Severe gout is associated with poor HRQOL and disability, especially for patients who experience more gout flares and have a greater number of involved joints. Subject perceptions of gout-related functioning and pain severity appear to be highly sensitive indicators of HRQOL and disability.

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T h e n e w e ng l a n d j o u r na l o f m e dic i n e n engl j med 356;23 www.nejm.org june 7, 2007 * All models were adjusted for the stratification variable of nephrotic status. ACE denotes angiotensin-converting enzyme, ARB angiotensin II-receptor blocker, and SAA serum amyloid A protein. † Underlying disease was categorized as rheumatoid arthritis, familial Mediterranean fever, or other. ‡ Mean arterial blood pressure values were calculated from systolic and diastolic blood pressure measurements.