FDA approved the Exondys 51 (eteplirsen) of Sarepta Therapeutics on September 19, 2016 for treating exon 51 skipping Duchenne muscular dystrophy (DMD). As a kind of antisense RNA (a kind of RNA molecule complementary to mRNA and able to inhibit mRNA translation process) drug, eteplirsen is given intravenously, and can help patients with exon 51 skipping DMD synthesize some dystrophin to slow the disease progression. It is the first DMD drug approved by FDA.
On December 23, 2016, FDA approved the Spinraza (nusinersen) of Biogen/Ionis for treating children and adults with spinal muscular atrophy (SMA). As a kind of antisense oligonucleotide (that can complement and bind to SMN pre-RNA, and block its incorrectly spliced short nucleic acid fragments), nusinersen is given intrathecally, and can increase expression of the SMN protection that promotes survival of motor neurons in bodies of patients, and improve the motor function of patients. It is the first SMA drug approved by FDA.
The approval of eteplirsen and nusinersen is a landmark. They do not only provide new treatment options for DMD and SMA patients, but also rekindle the enthusiasm of the pharmaceutical industry and investment institutions for RNAi drugs.
Background of Birth of RNAi Drugs
We all know that the gene fragment information on organism DNA is transferred to proteins mainly through messenger RNA (mRNA). Eukaryotic cells have a special gene silencing mechanism to resist invasion of foreign substances, protect stability of genetic information, and regulate various functions of organisms, which is the RNA interference (RNAi) phenomenon.
RNAi refers to a sequence-specific gene silencing phenomenon caused by the binding of antisense RNA and mRNA of target gene in the form of complementary base pairing. RNAi mechanism was first discovered by Professor Andrew Z. Fire and Professor Craig C. Mello in 1998 and selected to the top 10 scientific achievements by Science in 2002, and won the Nobel Prize in Physiology or Medicine for 2006. Various technical applications based on RNAi are known as RNAi technology. Eteplirsen and nusinersen promote the correct expression of target genes through steric hindrance, and their mechanisms of action are not RNAi, but they still belong to the category of RNAi drugs and are the second-generation RNAi drug.
Schematic drawing of RNAi
The conventional drug targets are proteins, including kinases, receptors and antigens, etc. The RNAi technology expands the drug targets that can be developed to the protein upstream—RNA. The discovery of RNAi can be said to greatly broaden source and development direction of human drugs. Each great scientific discovery and technological innovation, from natural drugs sourced from plants, animals and ore, to chemical synthetic drugs and biological drugs, to gene drugs and nucleic acid drugs, has brought more and better drug choices to human beings.
Ups and Downs of RNAi Drug R&D
The discovery of RNAi spawned many small biotech companies. To seize technical commanding point, big pharmaceutical enterprises competed to enter this field through M&A without full assessment of technical obstacles. MSD acquired Sirna, a company specialized in RNAi drug development, for USD 1.1 billion in 2006. The RNAi field with "attractive prospects" attracted billions of dollars of capital investment from 2005 to 2009.
Soon, people found that the therapeutic effect of RNAi was nowhere near the expectations. In March 2009, OPKO, a Miami pharmaceutical company first in conducting human clinical trials of small interfering RNA (siRNA) drugs, announced the end of trial of bevasiranib for wet macular degeneration in Phase III due to poor effect. The administration obstacle and the severe side effects caused by off-target of RNAi drugs seemed impossible to solve, therefore, big pharmaceutical enterprises became pessimistic and left the fiel...
(All Rights Reserved)