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 a 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 met.

After years of silence, a counterattack driven by clinical data is taking place. On October 16, Wave released positive data from the Phase 1b/2a clinical trial of WVE-006. Data showed that in two patients with PiZZ-type AATD (alpha-1 antitrypsin deficiency), a single subcutaneous injection of WVE-006 resulted in an average total plasma AAT level of approximately 11µM, and 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 total AAT. The increase in neutrophil elastase inhibition compared to baseline 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 its 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 modifies 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. It 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 shattering of hopes 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.

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 for discovery cooperation 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. According to the agreement, Wave will receive an advance payment of $170 million from GSK, as well as development and milestone initiation payments for the WVE-006 project, up to $3.3 billion.

A week after reaching a cooperation with GSK, Wave announced positive Phase 1b/2a data for WVE-N531 in the treatment of DMD boys. In Part A of Wave's WVE-N531 trial, WVE-N531 demonstrated an industry-leading exon skipping level of 53%. In addition, compared to approved ASO drugs, WVE-N531's pharmacokinetic parameters show that the drug has a half-life of 25 days. This may support its monthly dosing, which is higher than the once-a-week dosing of existing drugs. This is due to its new chemical modification technology, PN chemistry. Compared with more traditional phosphothioate or phosphodiester linkages, oligonucleotide linkages containing PN chemistry are more stable, and therefore have the potential to achieve longer drug half-lives and long-term effects.

After the above data were released and the cooperation with GSK was announced, Wave's stock price soared one after another. On September 24 this year, the latest clinical data showed that in addition to continuing to maintain the leading exon skipping level (57%), WVE-N531 also achieved 9% of the average muscle content-adjusted anti-dystrophin, with good safety and tolerability. This once again drove Wave's stock price soared 53%. At the same time, despite the heavy blow in the field of Huntington's disease, Wave still retains an ASO drug, WVE-003. It can be said that WVE-003 carries the hope of the two drugs WVE-120101 and WVE-120102, which have been discontinued. Its special feature is that it is highly targeted. WVE-003 can identify and target harmful huntingtin protein (mHTT) without affecting normal huntingtin protein (wtHTT). Since the function of wtHTT is essential to the health of the central nervous system and mHTT may interfere with the function of wtHTT,

In June this year, Wave announced the data of the Phase I/II SELECT-HD study of WVE-003. The results showed that the mHTT level of patients in the WVE-003 group was significantly lower than that in the placebo group (mHTT decreased by 46% at the 24th week of treatment; mHTT decreased by 44% at the 28th week of treatment). Wave believes that the peak sales of WVE-003 are expected to reach US$5 billion. However, Takeda decided on October 11 to give up exercising options for Huntington's disease therapies, including WVE-003. The cooperation between the two parties began in 2018, and Takeda has paid Wave about $260 million. WVE-003 is the last undeclared result of the previous cooperation agreement, but Takeda decided to give up introducing the drug. Compared with other nucleic acid therapies, Wave attaches great importance to the development of RNA-targeted drugs, and the first RNA editing project WVE-006 has also received a bet from GSK. WVE-006 is an RNA editing oligonucleotide therapy for AATD. AATD is a common hereditary genetic disease, usually caused by a point mutation from G to A in the SERPINA1 gene (Z allele), which can cause severe lung and liver diseases.

Currently, the only treatment option for AATD lung disease is to deliver AAT protein through weekly intravenous infusion, which is only for lung disease (global sales of more than $1.4 billion in 2023); there is currently no treatment for AATD liver disease, and many patients eventually need liver transplants. Therefore, new therapies including WVE-006 have attracted much attention in the market. The principle of WVE-006 is to design specific small molecule RNA to specifically guide the ADAR enzyme in the cell to precisely edit the mismatched bases on specific mRNA, thereby correcting the erroneous genetic information and restoring the normal expression of AAT protein. At the same time, as the world's first RNA editing compound to enter clinical trials, WVE-006 also affects the market's imagination and expectations of RNA editing therapy to a certain extent.

On October 16, Wave announced positive data from the Phase Ib/IIa RestorAATion-2 study. Although the data came from only two patients, Wave said that the data showed convincing evidence that its drugs successfully edited the messenger molecules used by cells to convert DNA into proteins, that is, its RNA editing platform 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%. After completing the RestorAATion-2 study, WAVE will transfer the development and commercialization rights of WVE-006 to GSK and will be eligible for milestone payments of up to $525 million, as well as tiered royalties.

If we count from September, its stock price has risen by 162%, which is a great turnaround. If there is any secret, it probably points to one point: despite hitting the bottom, Wave did not sink, but selectively persisted and improved pipeline research and development, and precipitated platform technology. At present, it is using positive clinical progress data to fulfill its promise of Reimagine Possible. Of course, for Wave, the RNA editing technology has just been verified, and Takeda has withdrawn the cooperation, which means that it still has many unknowns and challenges on the road of nucleic acid drugs.

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