RNA interference therapy: the climax is near
Decidedly innovative medicine against familial amyloid polyneuropathy
"Alnylam Pharmaceuticals" (Alnylam Pharmaceuticals) and "Genzyme" (Genzyme), owned by "Sanofi" (Sanofi), issued a statement on the encouraging results of the APOLLO phase III clinical trials of the experimental patisiran (patisiran), intended for the treatment of hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (hATTR-PN), also known as familial amyloid polyneuropathy (FAP). An application for registration of this candidate drug will be submitted this year.
Patisiran, like all other Alnailam candidate drugs, is based on RNA interference (RNAi) therapy approaches. We are talking about a natural mechanism for suppressing gene expression (silencing) at the stage of transcription, translation, deadenylation or degradation of matrix RNA (mRNA) using small interfering RNA molecules (miRNA). For the discovery of this process, Andrew Fire and Craig Mello received the 2006 Nobel Prize in Physiology or Medicine.
Alnalaym has developed the proprietary RNAi technology GalNAc-siRNA, when a miRNA molecule (siRNA) combines with the ligand of the asialoglycoprotein receptor (ASGPR) from the amino sugar N-acetylgalactosamine (GalNAc), eventually giving birth to a bioconjugate with the properties of simplified delivery, high efficiency and prolonged exposure.
In the wake of the announcement, the share price of Alnailam added almost 40%, thereby witnessing the culmination of almost 15 years of work in attempts to prove that RNA interference therapy has the right to become a new approach to the management of diseases.
Phase III APOLLO clinical trials involved 225 hATTR-PN patients (a total of 39 different genotypes of the disease) who were prescribed intravenous patisiran at a dose of 0.3 mg/kg every three weeks or placebo for 18 months.
The primary endpoint was a change relative to the initial indicator according to the modified scale of neuropathic disorders +7 (mNIS+7). This generalized indicator of neurological disorders evaluates sensorimotor capabilities, nerve conduction, reflexes, and functions of the autonomic nervous system. In the patisiran group, the desired changes were statistically smaller (that is, a clear improvement was witnessed) in comparison with the control group (p<0.00001).
Patisiran also managed to reach all secondary endpoints within the Norfolk questionnaire for assessing the quality of life in diabetic neuropathy (Norfolk QoL-DN), muscle strength assessment (NIS-W), the scale of general disability based on the Rasch model (R-ODS), the 10-minute walk test, modified body mass index (mBMI), a questionnaire for assessing the symptoms of the functionality of the autonomic nervous system (COMPASS-31).
The safety profile of patisiran was excellent, despite the fact that fewer patients decided to discontinue treatment compared to the placebo group: 7.4% vs. 37.7%.
Detailed results, provided with statistical data, will be available in early November.
If everything goes well, patisiran will appear on the market in mid-2018. A one–year course of innovative medicine will cost a six-figure sum - by analogy with the cost of other orphan diseases.
A decent assortment of candidate drugs has been assembled on the Alnalaym drug conveyor, divided into three therapeutic groups: genetic diseases, cardiometabolic disorders, infectious liver diseases. For example, fitusiran (fitusiran) is being developed for the treatment of hemophilia A and B, givosiran (givosiran) is needed to combat acute hepatic porphyria, and inclisiran (inclisiran) is designed to lower cholesterol.
Meanwhile, Ionis Pharmaceuticals is not losing hope for its inotersen, which is similarly focused on familial amyloid polyneuropathy. The drug, built on the basis of antisense therapy, has recently been studied by the company on its own, after GlaxoSmithKline, which launched a large-scale business reorganization, refused to deal with rare diseases.
Portal "Eternal youth" http://vechnayamolodost.ru
22.09.2017