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 field at a loss.

Roche announced dropping out the research in RNAi field in November 2010 after spending 3 years and USD 500 million, with its RNAi platform taken by Arrowhead; in February 2011, Pfizer and Abbott cut away RNAi drug R&D project; in July 2011, MSD shut down the RNAi drug R&D center in San Francisco; in September 2011, Novartis terminated the 5-year cooperation with Alnylam, the largest independent RNAi drug R&D company. The RNAi drug R&D encountered the capital winter.

The departure of big pharmaceutical enterprises made the RNAi R&D rapidly cool, however, there were still many persistent companies hoping to develop new RNA drug delivery technology to solve the difficulty of poor druggability of siRNA drugs. The Mipomersen, a phosphorothioate oligonucleotide drug targeting ApoB-100 protein, of Genzyme under Sanofi, was approved the marketing by FDA for treating familial hypercholesterolemia in 2013--15 years after the marketing of fomivirsen (ISIS2922), the first antisense RNA antiviral drug approved by FDA in 1998.

The entire pharmaceutical industry did not fully restore confidence in RNAi drugs, perhaps because the field had been quiet for too long. After Novartis sold most of its RNAi assets for a low price of USD 35 million to Arrowhead in 2014, though there was good and bad news of the RNAi drug ARC-520 claimed to hopefully provide functional cure for hepatitis B, and the marketing process of the antisense RNA drug eteplirsen encountered twists and turns, plus the continuous controversy after its marketing in September 2016, the pharmaceutical industry’s understanding of the RNAi drugs has been continuously deepened.

The antisense oligonucleotide: nusinersen of Biogen/Ionis for the 2^nd largest rare disease SMA was approved the marketing at the end of 2016--only 5 years from its first clinical trial in 2011. The industry analysts generally offered ideal market expectations for it—the sales expected to peak at nearly USD 2 billion. Suddenly, the entire pharmaceutical industry has seemed to have a fundamental change of perspective on RNAi drugs, and restored the enthusiasm for "gene therapy", with the new round of investment and cooperation in the RNAi drug field gaining steam.

On January 6, 2017, Novartis entered into strategic cooperation with Akcea under Ionis, with total amount of USD 1.6 billion, including USD 75 million up-front payment, USD 100 million equity investment, and USD 50 million recent payment and various milestone fees, to together develop its lipid-lowering RNA drugs: AKCEA-APO (a) -LRx and AKCEA-APOCIII-LRx, marking Novartis’ return to the RNAi field.

Khorkova et al. of OPKO company published a review in Nature Biotechnology in February 2017, looking ahead to the bright prospects of RNAi drugs for central nervous system diseases.

Suzhou Ribo Life Science, the enterprise leading in RNAi drugs in China, successfully completed Series B financing of RMB 270 million in March 2017. Ribo Life Science announced that it entered into a cooperation agreement with Ionis, a nucleic acid pharmaceutical giant, in April 2017, to obtain all the right to develop and commercialize in China 3 RNA targeted drugs separately in metabolic disease and cancer.

RNAi Drugs—New Investment Forefront

The transition of one new great scientific theory discovery or technology from laboratory to industry is inevitable to undergo the process of blind pursuit, questioning, re-understanding and wide application, and such cases have been too numerous to enumerate in the pharmaceutical industry. The PD-1 drugs hottest at present are widely applied in industry 20 years after the discovery and are endowed with a very high clinical position. Will the marketing approval of eteplirsen and nusinersen mean that the RNAi drugs will also usher in a big era after undergoing a downturn?

RNAi drugs (antisense RNA) can be deemed as the first-generation RNAi drug, the oligodeoxynucleotides (ODNs) in DNA form can be deemed as the second-generation RNAi drug, and now, the third-generation RNAi drugs targeting microRNA also have emerged by virtue of the safety and functional advantages, showed broad application prospects, and become a new investment forefront.

Some new research findings on microRNA also have changed people’s cognition of some common chronic diseases. Science published the latest research results (DOI: 10.1126/science.aam7671) of Professor Peng Changgeng who has returned China for entrepreneurship on pain as the first author on June 1, showing that miR-183 cluster (microRNA) controls 80% known genes that participate in neuropathic pain, the expression quantity of miR-183 cluster shows negative correlation with the pain sensitivity, and miR-183 cluster is a very promising target for treating neuropathic pain and is expected to provide a new treatment option for complex neuropathic pain, a common disease of which the medical demand is far from being satisfied.

According to information, the company founded by Professor Peng Changgeng has a microRNA candidate drug (code: PJ150021) planned to be developed for treating diabetic nephropathy and fatty liver, which has accepted successively 2 investigations of the pharmaceutical giant Eli Lilly. With the gene therapy represented by RNAi drugs riding the wind, many Chinese startups conducting layout in the RNAi drugs are sure to win the favor of capital very soon.

  Source: Data of Pharmcube