Patisiran, an RNAi Therapeutic for the Treatment of Hereditary Transthyretin-Mediated Amyloidosis

Abstract

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.

Harnessing host–virus evolution in antiviral therapy and immunotherapy

“…Since viruses typically infect and replicate best in only a limited set of host tissues, delivering therapies to specific tissues may mitigate adverse effects. Synthetic lipid nanoparticles (LNPs) protect and deliver small RNAs for RNAi‐based therapy as well as synthetic vaccines and bioactive compounds, while modified viruses or virus‐like particles deliver RNA interference (RNAi)‐based therapies as well as nucleases and DNA for gene therapy . Despite additional challenges as outlined below, these technologies are currently applied to deliver specific treatments for viral infection, cardiovascular disease, inherited genetic disorders and cancer immunotherapy in animal models and humans …”

RNA-Based Therapeutics: From Antisense Oligonucleotides to miRNAs

“…In an exciting breakthrough for RNA-based therapeutics, the first short interfering RNA drug, Onpattro (patisiran) (Alnylam Pharmaceuticals), was granted approval for clinical use by the US FDA and within the EU in 2018 [100,101]. Onpattro is a new treatment option for patients with hereditary transthyretin-mediated (hATTR) amyloidosis [102,103], a rare, progressive, neurodegenerative and life threatening disease, with a median survival time of 4.7 years following diagnosis [104]. hATTR amyloidosis is caused by mutations in the transthyrethin (TTR) gene, which causes the TTR protein to misfold.…”

Inotersen for the treatment of adults with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis

“…Tafamidis is an oral, small-molecule TTR stabilizer that is approved in Europe and selected countries in Asia and Latin America for the treatment of ATTRv in adults with stage 1 symptomatic polyneuropathy to delay peripheral impairment [24][25][26]; tafamidis was not approved for neuropathy by the FDA because of inadequate evidence of efficacy [8,26]. In the randomized, placebo-controlled phase 2/3 Fx-005 study, tafamidis therapy demonstrated TTR stabilization in 98% of patients, reduced neurologic deterioration, preserved nerve function, and maintained QoL in patients with early-stage Val30Met ATTRv [27].…”