Eli Lilly-backed biotech grabs $100M to dispatch antibody-oligonucleotide conjugates after muscular dystrophy
Hold up your hand. Make a fist. Now open it. And again.
If you can do it fully and with ease, then the proteins in your hand are likely working properly. If you can’t then they may not be. In people with myotonic muscular dystrophy, something more atomic is going on.
In those folks, the problem is RNA. Certain base pairs repeat far beyond normal, up to 11,000 superfluous letters in some cases. The extended strands form “clumps.” Proteins misform and can’t function properly. They often allow one movement but not the reverse, a condition called myotonia that gives the dystrophy its name.
The question for years has been how to fix the RNA. One small biotech says they have tech ready to enter the clinic and have raised the cash to do so. In an RTW-led funding round, Avidity Bio raised $100 million to advance an antibody and oligonucleotide-based treatment.
“Using the technology that we’re talking about you can reverse that and replace these misplaced proteins or mispliced RNA with properly spliced RNA,” Avidity CSO Art Levin told Endpoints News. “In the actual treatment of patients, we should actually be able to reverse some of the nature of this disease.”
At least 13 other groups joined for the Series C, including Alethea Capital, Alexandria Venture Investments, Boxer Capital of Tavistock Group, Cormorant Asset Management, LP, CureDuchenne, Logos Capital. Eli Lilly also chipped in $15 million from an existing collaboration.
Levin dates the first indication that oligonucleotides – synthetic strands of 15-30 base pairs built to be complementary to specific sections of RNA – could be used to modify human RNA to a 1978 National Academy of the Sciences paper. The problem, he said, is how to deliver these molecules to the right place. (There have also been concerns about safety, as Levin laid out in a NEJM article this year).
Largely with RTW’s backing, Avidity has been working on combining the oligonucleotides with monoclonal antibodies, into a single conjugate that can be more easily directed to precise tissues. Monoclonal antibodies have been applied as biological homing beacons in a wide range of new therapies.
“The key is we’ve had difficulty delivering them,” Levin said of oligonucleotides. “With this technology, we can do what was tried in the past but much better.”
Once the conjugate arrives at the site, the oligonucleotide would do one of two things. It could bind to an enzyme complex and delete the matching sequences from the RNA. Or it could change how the body processes the RNA, such as by inhibiting the RNA’s translation into proteins.
Levin compared their technique to one of two treatments for the more well-known Duchenne’s muscular dystrophy. Although an expensive gene therapy — by which an artificial gene is inserted into the DNA — has gotten press of late, another approach is to change how the existing RNA is processed and thus create a functional protein.
“The technology we’re using is more akin to the second,” Levin said.
Oligonucleotide therapy, though, has thus far had efficacy and safety issues, including renal and platelet problems, although Avidity is betting that it can minimize the risk by making delivery more precise. The NEJM review notes one trial where a 5 mg dose was associated with acute tubular necrosis. He wrote the effect was not observed elsewhere.
Avidity said they are planning to enter the clinic soon, but would not yet say when.
For patients, the need is substantial. You can find videos online of doctors performing a diagnostic test. It centers on things like the fist-test, the most minor but easily observable symptoms: Shake my hand. Release. Grip my thumb. Release.
“It doesn’t hurt,” says one person whose ring finger contorts as they let go. “It’s just stiff.”
That’s in addition to longevity-related issues, such as cardiac symptoms, which Avidity also hopes to tackle.
“Imagine trying to walk without relaxing your ankles,” Levin said, “imagine what that would do to your gait on a daily basis.”