"CRISPR gives way, RNA editing therapies are going to speed up." This is the title of an article published in "Nauter" in February this year ("Move over, CRISPR: RNA-editing therapies pick up steam").

RNA editing technology, which is coming to the fore, is seen as having the potential to surpass CRISPR due to its safer and more flexible characteristics. The technology is in its infancy, and the bets of MNCs such as Eli Lilly and GSK have once pushed its popularity to a climax. However, Wave, an RNA editing pioneer founded in 2012, took more than 10 years to push its first RNA editing project WVE-006 into clinical trials. During this period, due to the clinical failure of other nucleic acid drugs, Wave's stock price fell from a high of US$56 per share to around US$1 per share, and market expectations were no longer there.

After years of silence, a counterattack driven by clinical data is taking place. On October 16, Wave released positive clinical phase 1b/2a data for WVE-006. The data showed that in two patients with PiZZ-type AATD (alpha-1 antitrypsin deficiency), a single subcutaneous injection of WVE-006 brought their average plasma total AAT level to approximately 11µM, and the circulating wild-type M-AAT protein in the patient's plasma reached an average of 6.9µM on day 15, accounting for more than 60% of the total AAT.

Compared with baseline, the increase in neutrophil elastase inhibition was consistent with the production of functional M-AAT. The average total AAT protein increased from an unquantifiable level at baseline to 10.8µM on day 15, reaching the baseline level for regulatory approval of AAT enhancement therapy. Since PiZZ-type AATD patients cannot naturally synthesize M-AAT protein, the appearance of M-AAT protein proves that the mutant Z-AAT mRNA was successfully edited.

In other words, Wave's RNA editing platform has finally achieved mechanism verification. Wave CEO excitedly called it, "the first therapeutic RNA editing data in humans." After the data was released, Wave's stock price soared 75%. Prior to this, on September 24, another antisense oligonucleotide (ASO) drug WVE-N531 of Wave showed the potential to become a BIC drug for Duchenne muscular dystrophy in mid-term clinical trials, and the company's stock price soared 53%. In less than a month, Wave's stock price rose by more than 162%. It seems that Wave is fulfilling its promise of Reimagine Possible.

The success of WVE-006 clinical phase 1b/2a means that Wave's RNA editing platform has achieved mechanism verification. As we all know, the birth of CRISPR technology has brought gene editing from straight-screen machines to the era of smart machines, and has also brought us closer to the goal of successfully repairing human gene defects. In December last year, the FDA approved the launch of CASGEVY, the world's first CRPISPR-Cas9 genome editing therapy. In contrast, the development of RNA editing therapy is much slower. However, RNA editing technology, which is coming to the fore, is seen as a potential to surpass CRISPR. These two mainstream gene editing methods play an important role in the field of gene therapy. Although their ultimate goal is to achieve precise modification of genetic information, there are still significant differences between the two.

CRISPR-Cas9 technology edits genes by directly cutting specific gene sequences on the DNA chain. Although this method is highly efficient, the modification is permanent, and once an error occurs, it may lead to irreversible genetic mutations. In fact, since its birth, a major problem with CRISPR technology is its potential off-target effect. If CRISPR gene editing technology cuts other DNA fragments other than the intended target, it may destroy the function or regulation of non-targeted genes and cause serious consequences.

In addition, CRISPR technology involves directly modifying the genome of an individual, which not only causes ethical controversy, but also limits its application to a certain extent. Compared with CRISPR technology, RNA editing technology provides a safer and more flexible treatment option. Because the latter is to modify messenger RNA (mRNA), such as knocking out, replacing or inhibiting mutant RNA fragments, to achieve regulation of gene expression and treat genetic diseases.

The basic principle is to modify the bases on mRNA through specific enzymes or editing factors, thereby affecting protein synthesis. This process can be divided into two main types: single base editing and RNA exon editing. Taking single base editing as an example, by precisely editing a specific single base, incorrect genetic information can be corrected and normal protein expression can be restored. For example, adenine (A) on mRNA is edited to inosine (I). This is also the drug mechanism of WVE-006. It can be seen that since this is done at the mRNA level and does not directly change the DNA sequence, off-target effects and ethical issues can be effectively avoided. In addition, the short lifespan of mRNA molecules means that the effect of intervention through RNA editing is reversible.

An article in Nature commented that the development of RNA editing technology marks that our understanding of life sciences has entered a new level. Wave, a pioneer in RNA editing founded in 2012, is also highly expected. However, most of the time, the development of cutting-edge technologies is always full of twists and turns and challenges. In clinical trials, how to ensure the accuracy and efficiency of editing, and how to evaluate and optimize long-term safety and stability remain to be verified. It took Wave more than 10 years to bring WVE-006 to the clinic and obtain preliminary verification.

Although Wave has been deeply involved in the nucleic acid track for many years, its nucleic acid technology platform PRISM is also unique and is the only oligonucleotide platform that provides three RNA targeting methods (editing, splicing and silencing, including siRNA and antisense RNA).

However, Wave has had a rough fate. Since its listing, many projects have failed, causing market expectations to fall to the bottom. For example, in March 2019, Wave stopped two antisense oligonucleotide (ASO) drugs in Phase I/II clinical trials, WVE-120101 and WVE-120102. These are two therapies for Huntington's disease. Huntington's is a rare hereditary neurodegenerative disease. The disease has been proposed by medicine for more than 150 years, and it has been 30 years since the cause was determined, but there is still no cure. Researchers once hoped that ASO therapy could change the rules of the game for Huntington's disease.

However, the reality is that many ASO drugs for Huntington's disease have failed one after another. Data showed that none of the two drugs, WVE-120102 and WVE-120101, showed statistically significant clinical efficacy evidence at all evaluated doses. Prior to this, the ASO drug Tominersen, developed by Roche and Ionis, stopped Phase III clinical trials, which was seen by the outside world as a shattered hope for Huntington's gene therapy. Two pieces of bad news caused Wave's stock price to plummet 46%. However, unexpectedly, this was just the beginning of Wave's misfortune. At the end of 2019, Wave decided to terminate the development of suvodirsen, a drug for Duchenne muscular dystrophy (DMD) with exon 51 skipping mutations, after an interim analysis of the results of the Phase I OLE study. The results showed that dystrophin expression did not change compared with baseline after the use of the drug.

After the news was announced, Wave's stock price plummeted by more than 50%. Half a month ago, the market still hoped that it could surpass Sarepta, but with the failure of Huntington's disease and DMD, hopes were dashed, and its stock price also fell from a high of $56 per share to less than $8 per share. In the face of successive failures, Wave decided to lay off a quarter of its employees, reduce operating costs, and cut other DMD research and development work. For nearly three years, Wave had almost no news to boost the market, and its stock price even fell all the way to around $1 per share.

Of course, Wave did not give up research and development. After all, it has a technology platform and a number of drugs under development. WVE-N531 (splicing), an exon 53 molecule for the treatment of DMD; WVE-006 (editing), a SERPINA1 molecule for the treatment of AATD (alpha-1 antitrypsin deficiency); WVE-003 (silencing), an mHTT SNP3 molecule for the treatment of Huntington's disease; WVE-004 (silencing), a C9orf72 molecule for the treatment of related ALS and FTD (amyotrophic lateral sclerosis and frontotemporal dementia); and the INHBE project for the treatment of metabolic diseases.

Wave's technology platform and related drugs have also been favored by GSK. On December 13, 2022, the two parties reached a cooperation. The first is to use Wave's PRISM platform and GSK's expertise in genetics and genomics to conduct discovery collaboration to advance up to 8 GSK and up to 3 Wave projects.

In addition to these projects, GSK will also obtain exclusive global rights to Wave's preclinical project WVE-006. Under the agreement, Wave will receive an upfront payment of $170 million from GSK, as well as development and milestone initiation payments for the WVE-006 project, up to $3.3 billion.

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