Novartis has commercialized an RNA therapy that treats high cholesterol by hitting a target in the liver. By acquiring DTx Pharma, the Swiss pharmaceutical giant is betting the biotech can take its RNA research to more diseases in more parts of the body.

Per deal terms announced this week, Novartis will pay $500 million up front to buy DTx. Milestones could bring the biotech another $500 million. San Diego-based DTx comes with a lead drug candidate ready for Phase 1 testing in Charcot-Marie-Tooth (CMT) disease, a rare neuromuscular disorder with no FDA-approved therapies. But the deal is about more than this lead program, DTx-1252. Novartis is just as interested in the technology platform that developed it, according to Robert Baloh, global head of neuroscience for the Novartis Institutes for BioMedical Research.

“It was a lead that came in from the program itself, and the indication, and the ability to address that indication,” Baloh told MedCity News. “But the further data that came in really fits well with our ambitions to deliver outside of the liver.”

The drug research involves RNA interference, an approach that uses small interfering RNA (siRNA) to stop a gene from producing a disease-causing protein. The first such “gene-silencing” therapies were for diseases that can be treated by hitting targets in the liver. Alnylam Pharmaceutical’s Onpattro was the first FDA-approved siRNA drug. The therapy treats a rare disease by stopping the gene that produces misfolded liver proteins that drive the disorder. Novartis’s Leqvio works by silencing the gene that produces PCSK9, a liver protein that in high amounts makes it harder for the body to clear away the bad form of cholesterol.

Both Onpattro and Leqvio have components that facilitate uptake of the therapies by liver cells. But RNA drug developers are trying to bring siRNA therapies beyond the liver. DTx’s approach uses combinations of naturally occurring fatty acids to get an siRNA to target a particular cell type and improve its uptake by those cells, CEO Artie Suckow told MedCity News. For the variant of Charcot-Marie-Tooth called CMT1A, the targets are Schwann cells, which are found in the peripheral nervous system. CMT1A is driven when a gene called PMP22 produces too much protein. To have an effect, the DTx therapy doesn’t need to completely stop PMP22 production, just knock it down by about 30%, Suckow said.

In preclinical research, DTx demonstrated its CMT1A therapy was able to engage Schwann cells. Results also showed that this approach was able to knock down a variety of different targets, including PMP22. By the end of the study, mice that previously could not balance or walk were able to walk just like mice that did not have the disease, Suckow said. Key data came from tests of the CMT1A therapy in non-human primates, which showed a likely therapeutic index—the dose range that balances both safety and efficacy. Strong data in monkeys is an encouraging sign for how a therapy will work in humans.

“Folks in our space argue that non-human primate data is critical to predicting translation to humans,” Suckow said. “A big part of the traction we got from some of the highest profile investors, as well as pharma, is on the back of non-human primate data.”

As DTx prepared to advance into a Phase 1 study, Suckow and Chief Business Officer Pete Condon were raising a Series C round of financing. Since DTx formed in startup incubator JLABS @ San Diego in 2017, the startup has kept in touch with investors and pharma companies potentially interested in investing in or acquiring it, Suckow said. As the financing round came together, DTx negotiated several term sheets from investors. It also received a term sheet from Novartis.

As Novartis followed DTx’s progress in recent years, it became more interested in the lead program’s approach of addressing the root cause of CMT, Baloh said. The pharma giant also learned more about the startup’s technology platform. Baloh acknowledged that DTx’s research is early, but he said that beyond neuromuscular diseases and central nervous system disorders, neurodegeneration is another area where Novartis is interested in exploring potential applications of DTx’s technology.

Novartis isn’t the only company pursuing genetic medicines for muscle disorders. Sarepta Therapeutics has a preclinical CMT1A gene therapy acquired from Nationwide Children’s Hospital. Avidity Biosciences is developing oligonucleotide drugs capable of reaching tissues other than the liver. It has reached Phase 1/2 testing in myotonic dystrophy type 1 (DM1), Duchenne muscular dystrophy, and facioscapulohumeral muscular dystrophy. RNA medicines developer Dyne Therapeutics has reached Phase 1/2 testing with two DM1 therapeutic candidates, each addressing a different target.

In addition to its preclinical research in muscle-targeting siRNAs, DTx has discovery-stage research for undisclosed central nervous system targets as well as research in additional cell types, including skin and cardiac tissue. DTx’s first clinical test will be in CMT, and it’s a disease area Baloh knows well. Earlier in his career, as a professor of neurology at Washington University, CMT was one of his research areas, he said. Later, at Cedars-Sinai Medical Center, he built closer connections with the CMT community, eventually serving a stint on the scientific advisory board for the Charcot-Marie-Tooth Association.

“Even though many people haven’t heard of this disease, it’s one of the most common inherited diseases of the peripheral nervous system,” Baloh said. “While it’s not fatal alike ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy), it causes significant disability. It would be an absolute thrill to bring this program all the way to the clinic.”

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