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.”

Art Levin

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.”

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Sen. Patty Murray (D-WA) (Graeme Sloan/Sipa USA/Sipa via AP Images)

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Committee chair Patty Murray (D-WA) made clear in her opening remarks that the US cannot “let the few instances of bad actors” overshadow the hard work of the many immigrant researchers in the US, many of which have won Nobel prizes for their work. But she also said, “There is more the NIH can be doing here.”

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Novavax CEO Stanley Erck at the White House in 2020 (Andrew Harnik, AP Images)

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