Avidity Biosciences Inc. CEO Sarah Boyce told BioWorld it's "a little too soon" to say when the company's lead program in myotonic dystrophy type I might reach the clinic, but the firm's $100 million series C financing will help with that effort and the portfolio in rare muscle diseases, as the antibody-oligonucleotide conjugate (AOC) platform undergoes further development.
AOCs are designed to add another level of precision to the tissue selectivity of monoclonal antibodies. The series C follows La Jolla, Calif.-based Avidity's deal with Eli Lilly and Co., of Indianapolis, focused on immunology and other indications. In the arrangement, Avidity collected $20 million up front and up to $405 million per target to support work with an unspecified number of new AOCs. Avidity's approach, which can leverage transferrin and other transporters to deliver oligonucleotides into varying tissue types, will allow Lilly to reach beyond hepatocytes to muscle, heart, tumor and immune cells. The pharma giant maintains a multimillion-dollar R&D center near Avidity headquarters. (See BioWorld, April 23, 2019.)
Avidity's chief scientific officer, Arthur Levin, said that, since the infusion of cash from the Lilly deal, the company has made considerable progress. "We've identified the monoclonal antibody that we'll be using to take the first program to the clinic, we've identified the siRNA sequence that will be conjugated to that monoclonal antibody, and we've actually begun the scale-up activities that are required in order to begin IND-enabling work," he said. "It's been a very exciting time for us. Lots of great data that ranges everywhere from human cells to animal models to nonhuman primate data."
Myotonic dystrophy type I is caused by the expansion of CTG repeats in the DMPK gene, from about 20 repeats in healthy people to as many as 4,000 in patients. The DMPK mRNA contains CUG repeats, which bind with high affinity to an important splicing factor called muscle blind-like protein (MBNL). Longer CUG repeat expansions in patients create a figurative "sponge" that binds MBNL and prevents it from performing its normal function. Myotonic dystrophy is the most common form of muscular dystrophy that begins in adulthood, and it is characterized by progressive muscle wasting and weakness. People with the affliction often have prolonged muscle contractions and are not able to relax certain muscles after use.
"The data that we have to date would support quarterly administration of a therapeutic," Levin noted. "This is very much in line with what Alnylam and The Medicines Co. are doing with their PCSK9 inhibitor, where they can deliver it twice a year." Quarterly dosing might not match the one-and-done delivery of gene therapy, he said, but "not a gene therapy might be a blessing," a reference to recent woes that beset players in the Duchenne muscular dystrophy (DMD) space.
Cambridge, Mass.-based Solid Biosciences Inc. this week disclosed a severe adverse event that led to the FDA placing a clinical hold on the phase I/II study with SGT-001 in DMD. Avidity is applying its technology to DMD as well, and said its approach has proved 100-fold more potent than existing oligonucleotide therapies for DMD in a mouse model of the disease. (See BioWorld, Nov. 13, 2019.)
Potential partnering in pipeline
"Our approach will have significant advantages," Levin said. "First of all, we're not trying to change or insert a gene. There are still unknowns with respect to the administration of an adenovirus containing a gene vector. We get around those by using monoclonals. In our case, we're targeting a protein on the cell surface," using AOC methodology "completely developed in-house about three and a half years ago. We've been a little bit in stealth mode" while refining the system.
CEO Boyce said Avidity has "a few [would-be competitors] who are trying to follow us," though the firm's researchers stand as "pioneers, way out in front." Levin added that the company is "running as fast as we can to stay ahead of the rest of the pack. We have a multiple-year head start, and lots of experience around the table. What we did differently is that we found we had to optimize each and every component [of the AOC]. People ask what is the secret sauce? The secret sauce is that everything matters." He added that the muscle-disease pipeline is promising "but the technology is so much broader than that. We've really just begun to scratch the surface. That's one of the reasons a lot of people are trying to copy us."
Asked the length of runway provided by the new money, Boyce said she would "not go into that level of detail," but said the funds are enough to get the lead program into the clinic and build a team around it. On the subject of further partnering, she said candidates in the rare muscle disease space represent "the kind of thing we get really excited about being able to take all the way through" to commercialization. Otherwise, "we do what every company does. We talk to people all the time," and other deals might get made in separate areas.
The financing was led by RTW Investments and included new investors Cormorant Asset Management LP, CureDuchenne, Logos Capital, Perceptive Advisors LLC and ST Pharm. Existing investors also participated and include Alethea Capital, Alexandria Venture Investments, Boxer Capital of Tavistock Group, Brace Pharma Capital, Ecor1 Capital, Partner Fund Management and Takeda Ventures. Lilly contributed $15 million to the financing in connection with the research collaboration. Roderick Wong, managing partner of RTW, will join Avidity's board.