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Sep 28, 2017
 |  BC Innovations  |  Product R&D

Wave’s purity progress

Wave reveals how it makes its stereopure oligos

Wave Life Sciences Ltd.’s latest data releases provide the fullest view to date into how the company synthesizes its stereopure oligos and the benefits that can be derived from the chemistry. But whether the technology represents a revolution or an evolution in the space remains to be seen.

Small molecule companies have long understood the value of stereopure compounds and devised methods to make or isolate them. However, Wave founder and original CEO Gregory Verdine told BioCentury that oligo companies had simply ignored stereochemistry before Wave launched in 2012.

None had developed a synthesis platform that could make “truly stereopure” drug-length oligos, nor had any rigorously searched for activities specific to stereoisoforms, he said.

“People were completely blithe to the fact that these molecules were horrendous mixtures of stereoisomers,” said Verdine. “Every chemist will tell you stereochemistry matters for every property of a molecule, and in fact that is now the classical test that medicinal chemists use for specificity.”

Verdine is a professor of chemistry at Harvard University and CEO of Fog Pharmaceuticals Inc., a staple peptide company he founded in 2015. Verdine has started 10 biotechs; his most recent newco, LifeMine Therapeutics Inc., announced a $55 million series A on Sept. 18.

Last month, Wave published its first peer-reviewed study on its stereopure oligo technology in Nature Biotechnology, and followed it with more data disclosures in a corporate presentation posted online Sept. 17.

Verdine told BioCentury the Nature Biotechnology paper showcased two advances: “We figured out how to make stereochemically pure oligos in a programmable way, and we cut to the chase in terms of which ones you should actually make to get improved properties.”

The company described stereopure oligos with heightened stability and defined a stereochemical code for boosting RNAse H-mediated degradation of target sequences. It also showed that a stereopure version of antisense oligo (ASO) Kynamro mipomersen from Ionis Pharmaceuticals Inc. and partner Kastle Therapeutics LLC led to longer-lasting knockdown of the drug’s target APOB-100 than the marketed version.

In its corporate presentation, Wave showed benefits of stereochemistry on target specificity, biodistribution and toxicity across a variety of targets.

“People were completely blithe to the fact that these molecules were horrendous mixtures of stereoisomers.”

Greg Verdine, Harvard University

Pharmas are starting to join the search for stereopurity.

In 2016, Wave partnered with Pfizer Inc. to generate stereopure oligos against APOCIII and up to four additional targets in metabolic disease. Pfizer paid Wave $40 million up-front and took a $30 million equity stake.

And Roche, which acquired oligo therapeutics company Santaris Pharma A/S in 2014, reported on the benefits of stereopure oligos at last year’s TIDES meeting. The company does not yet have programs using the technology in the clinic and declined to disclose its development plans.

But while the data are starting to bring skeptics around, the field is still divided.

Arthur Levin, former SVP of drug development at Ionis and now EVP of R&D at siRNA company Avidity Biosciences LLC, told BioCentury: “I’m a former skeptic but the door is opening on the basis of Wave’s published data and the data I have seen from Roche in the past year.”

But he and several other stakeholders who spoke with BioCentury said the magnitude of the improvements Wave reported in vivo were modest, and Wave’s claims about its technology are at odds with other publications on oligo stereochemistry.

Ionis SVP of Research Frank Bennett told BioCentury his company doesn’t...

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