Investing in new enthusiasm - the era of small nucleic acid drugs from the two new drugs approved by the FDA

- Jul 17, 2018-

On September 19, 016, the FDA approved Sarepta Therapeutics' Exondys 51 (eteplirsen) for the treatment of exon 51 jumping Duchenne muscular dystrophy (DMA). Eteplirsen is an antisense RNA (an RNA molecule complementary to mRNA that inhibits the translation process of mRNA). It is administered intravenously to help DMD patients with exon 51 jump to synthesize some dystrophin (muscle nutrition). Protein), which delays disease progression, is the first DMD drug approved by the FDA.


On December 23, 2016, the FDA approved Biogen/Ionis Spinraza (nusinersen) for the treatment of spinal cord muscle atrophy (SAM) in adults and children. Nusinersen is an antisense oligonucleotide (a short nucleic acid fragment that binds complementary to SMN precursor RNA and blocks its incorrect splicing) and is administered by intrathecal injection to increase motor neuron survival in patients. The expression of SMN protein, which improves the motor function of patients, is the first SAM drug approved by the FDA.


The award-winning Eteplirsen and nusinersen not only provide new treatment options for patients with DMD and SAM, but also rekindle the enthusiasm of the pharmaceutical industry and investment institutions for small nucleic acid drugs.


Birth background of small nucleic acid drugs


As we all know, the gene fragment information on the DNA of the organism is mainly transmitted to the protein through messenger RNA (mRNA), and eukaryotic cells have a unique gene silencing mechanism to resist the invasion of foreign substances, protect the stability of genetic information, and regulate organisms. The various functions of the body, that is, the phenomenon of RNA interference (RNAi).


RNAi refers to a sequence-specific gene silencing phenomenon caused by the binding of an antisense RNA to a target gene mRNA in a base complementary pairing manner. The RNAi mechanism was first discovered in 1998 by Professor Andrew Z. Fire and Professor Craig C. Mello. In 2002, it was ranked as the top ten scientific achievements by Science magazine and won the Nobel Prize in Physiology and Medicine in 2006. Various technical applications based on RNAi are commonly referred to as small nucleic acid technologies. Eteplirsen and

Nusinersen promotes the correct expression of target genes through steric hindrance. The mechanism of action is not RNAi itself, but it belongs to the category of small nucleic acid drugs and belongs to the second generation of small nucleic acid drugs.

RNAi schematic


The traditional drug target is a protein, including kinases, receptors, antigens, etc., and the emergence of small nucleic acid technology has expanded the exploitable drug target to the upstream of the protein - RNA. It can be said that the discovery of RNAi has greatly broadened the source and development direction of human drugs. From natural medicines derived from plants, animals and ores, to chemical synthetic drugs, biopharmaceuticals, to genetic drugs and nucleic acid drugs, every major scientific discovery and technological innovation has brought more and better drug choices to human beings.


Research and development of small nucleic acid drugs


The discovery of RNAi has spawned many small biotechnology companies. In order to seize the technical commanding heights, major pharmaceutical companies have entered the field through mergers and acquisitions without fully assessing technical obstacles. In 2006, Merck spent $1.1 billion to acquire Sirna, which specializes in the development of RNAi drugs. From 2005 to 2009, the “promising prospects” of the RNAi sector attracted billions of dollars in capital investment.


Soon, everyone found that the effect of RNAi treatment is far less than expected. In March 2009, the first Miami-based pharmaceutical company OPKO to conduct human clinical trials of small interfering RNA (siRNA) drugs announced that bevasiranib for wet macular degeneration was discontinued in phase III due to poor performance. The administration of RNAi drugs and the serious side effects caused by off-target seem to be unresolved, and the drug companies have become pessimistic, and they have fled the field.


In November 2010, Roche announced his withdrawal from the RNAi field after three years of investment and $500 million in funding. Arrowhead took over Roche's RNAi platform; in February 2011, Pfizer and Abbott cut off RNAi drug development projects; In July, Merck shut down the RNAi Drug Development Center in San Francisco; in September 2011, Novartis terminated its five-year partnership with Alnylam, the largest independent RNAi drug development company. The development of RNAi drugs has encountered the cold winter of capital.


The departure of large pharmaceutical companies has caused the rapid development of RNAi, but many companies are still determined to develop new RNA delivery technologies to solve the problem of poor drug-forming properties of siRNA drugs. In 2013, Sanofi's Genzyme's phosphorothioate oligonucleotide Mipomersen, targeting the ApoB-100 protein, was approved by the FDA for the treatment of familial hypercholesterolemia, the first FDA approval in 1998. The antisense RNA antiviral drug fomivirsen (ISIS2922) has been on the market for 15 years.


Perhaps it is too long to be silent, the confidence of the entire pharmaceutical industry for small nucleic acid drugs has not fully recovered. In 2014, Novartis sold most of its RNAi assets to Arrowhead for $35 million in cabbage prices. Since then, although the news that the RNAi drug ARC-520, which is expected to functionally cure hepatitis B, is good or bad, the listing process of the antisense RNA drug eteplirsen is also full of twists and turns, and it is still controversial after the listing in September 2016, but the pharmaceutical industry is still small. The understanding of drugs is constantly deepening.


By the end of 2016, Baijian/Ionis was approved by the FDA for the antisense oligonucleotide nusinersen, the second largest "common" rare disease SAM, only five years before its first clinical trial in 2011, and industry analysts are generally Both gave the ideal market expectation - sales peaked at nearly $2 billion. The entire pharmaceutical industry's view on RNAi drugs seems to have fundamentally changed, and it has regained its enthusiasm for "gene therapy" and set off a new wave of investment cooperation in the field of small nucleic acid drugs.

On January 6, 2017, Novartis and Ionis' Akcea signed a total of US$1.6 billion in strategic cooperation, including a $75 million down payment, a $100 million equity investment, a $50 million recent payment, and various milestones to jointly develop its lipid lowering. The RNA drugs AKEEA-APO (a) -LRx and AKEEA-APOCIII-LRx, announced the return of small nucleic acid drug sites.


In February 2017, Khorkova et al. of OPKO published a review in Nature Biotechnology to prospect the bright future of small nucleic acid drugs in central nervous system diseases.


In March 2017, Suzhou Ruibo Biotech, a leading domestic small nucleic acid drug company, successfully completed the B round of 270 million financing. In April 2017, Ruibo Biotech announced a cooperation agreement with nucleic acid pharmaceutical giant Ionis to obtain the full R&D and commercialization rights of Ionis' three RNA-targeted drugs for the treatment of metabolic diseases and cancer in China.


Small nucleic acid drugs - invest in new outlets


A new major scientific theory discovery or technology will inevitably go through the process of blind pursuit, questioning, re-cognition, and widespread application when transforming from laboratory to industry. The pharmaceutical industry has many examples, the hottest nowadays. PD-1 drugs also ushered in large-scale industrial applications 20 years after they were discovered, and were given a very high clinical status. Does the approval of Eteplirsen and nusinersen go public, means that small nucleic acid drugs will usher in a big era after a period of downturn?


RNAi drugs (antisense RNA) can be regarded as the first generation of small nucleic acid drugs, DNA-type oligonucleotides (ODNs) can be regarded as the second generation of small nucleic acid drugs. Nowadays, the third-generation small nucleic acid drugs targeting microRNAs have also emerged with their security and functional advantages, showing broad application prospects and becoming a new investment.


Some of the new findings on microRNAs have also changed the perception of some common chronic diseases. "Science" magazine published the latest research on pain (DOI: 10.1126/science.aam7671) published by Dr. Peng Changgeng, who returned to China as a first author, on June 1st, showing that the miR-183 family (microRNA) controls 80% of the genes involved in neuropathic pain, the expression level of the miR-183 family is negatively correlated with the sensitivity of pain, suggesting that the miR-183 family is a very potential target for the treatment of neuropathic pain, which is expected to be complex. Neuropathic pain, a medical treatment that is far from being met and a very common disease, offers new treatment options.


It is understood that the company founded by Dr. Peng Changgeng has a microRNA candidate drug (codename PJ150021) to be developed for the treatment of diabetic nephropathy and fatty liver. Gene therapy represented by small nucleic acid drugs has taken the wind, and it is believed that many domestic startups that have small nucleic acid drugs will soon win the favor of capital.

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