For someone who thought he’d retire after giving up the reins at Intellia, Nessan Bermingham, Ph.D., is a busy guy. Just two months after launching Korro Bio, he’s unveiling a new biotech, Triplet Therapeutics, with $59 million and a mission to develop drugs for repeat expansion disorders such as Huntington disease and fragile X syndrome.
The company is taking aim at disorders caused by too many repeats of certain DNA sequences. These include triplet repeat disorders, so called because they result from repeats of three nucleotide bases, or letters. It’s able to think more holistically about this group of diseases, which number about 40, because of a new understanding of how they develop.
“Historically, people have viewed each of these diseases as standalone, that fundamentally, what was driving was actually separate,” Bermingham told FierceBiotech.
Thanks to new genetic data—most of which weren’t even available when Triplet was founded in 2018—the company identified one central pathway that drives repeat expansion disorders: the DNA damage response (DDR) pathway.
“We have historically thought each disease is different. We’ve now moved over to thinking that’s wrong, that there is a unifying pathway that is driving these diseases and that actually, disease is not caused by the repeat you’re born with,” Bermingham said. In some patients, that repeat grows over time, which plays a role in the onset and progression of disease.
“What we think is happening is as DNA is transcribed, the double-stranded DNA opens up and transcription machinery reads it to make RNA. The DNA then goes to close and it kinks. It doesn’t happen all the time, but when it does, the DDR pathway goes in and repairs it, which makes the repeat longer and causes greater instability in the DNA,” Bermingham said.
One kink can make the DNA more likely to develop more kinks, growing longer and longer, like a snowball rolling down a hill. Eventually, it reaches a point where it becomes toxic to the cell, he said.
Current treatments for Huntington disease and other repeat expansion disorders focus on improving symptoms and do not change the course of the disease. Development efforts by companies like Roche and Wave Life Sciences target RNA, which stops toxic proteins from being made, but they do not address the underlying mutation.
“What we are doing is going upstream and developing drugs against very specific members of the DDR pathway … to stop that expansion from taking place,” Bermingham said. The company will work on antisense oligonucleotides and small interfering RNA medicines.
Targeting the DDR pathway means Triplet will develop drugs not on a disease-by-disease basis, but on a tissue-by-tissue basis. That means it could potentially target several diseases with one drug.
“If we develop a drug that targets the brain, it opens up Huntington, DRPLA [Dentatorubral-pallidoluysian atrophy, a progressive disorder with multiple symptoms including involuntary movements and epilepsy], ataxias, myotonic dystrophy. [It would be] exactly the same drug, exactly the same formulation, exactly the same treatment paradigm,” Bermingham said.
The $59 million raise gives Triplet about two years of runway to get its lead programs into clinical trials. In the year since its founding, the company has gone from “a sheet of paper” to monkey studies with its lead programs. Ten million dollars came in seed funding from Atlas Venture—which also backed and built Intellia and Korro with Bermingham—with the remaining $49 million making up a series A round from MPM Capital, Pfizer Ventures, Invus Partners, Partners Innovation Fund and Alexandria Venture Investments.
“Our first indication will be Huntington disease, with follow-up in areas such as ataxias and myotonic dystrophy,” Bermingham said. “The other work we’re doing is looking at the extent of the applications of these therapies. We can imagine Friedreich’s ataxia, DRLPA and fragile X … Our intent is to evaluate the potential of not all 40 [repeat expansion disorders], but as many of those 40 as appropriate.”
The cash will also bankroll natural history studies of the different diseases to better understand the group as the company thinks about first-in-human trials. Triplet has just moved into new digs in Kendall Square in Cambridge, Massachusetts, as it looks to grow to about 45 to 50 people.