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.”

Michel Vounatsos, Biogen CEO (via YouTube)

UP­DAT­ED: Bio­gen spot­lights a pair of painful pipeline set­backs as ad­u­canum­ab show­down looms at the FDA

Biogen has flagged a pair of setbacks in the pipeline, spotlighting the final failure for a one-time top MS prospect while scrapping a gene therapy for SMA after the IND was put on hold due to toxicity.

Both failures will raise the stakes even higher on aducanumab, the Alzheimer’s drug that Biogen is betting the ranch on, determined to pursue an FDA OK despite significant skepticism they can make it with mixed results and a reliance on post hoc data mining. And the failures are being reported as Biogen was forced to cut its profit forecast for 2020 as a generic rival started to erode their big franchise drug.

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A new chap­ter in the de­cen­tral­ized clin­i­cal tri­al ap­proach

Despite the promised decentralized trial revolution, we haven’t yet moved the needle in a significant way, although we are seeing far bolder commitments to this as we continue to experience the pandemic restrictions for some time to come. The vision of grandeur is one thing, but operationalizing and execution are another and recognising that change, particularly mid-flight on studies, is worthy of thorough evaluation and consideration in order to achieve success. Here we will discuss one of the critical building blocks of a Decentralized and Remote Trial strategy: TeleConsent; more than paper under glass, it is a paradigm change and key digital enabler.

John Maraganore, Alnylam CEO (Scott Eisen/Bloomberg via Getty Images)

With lumasir­an on the FDA's doorstep, Al­ny­lam reads out new PhI­II da­ta in PH1

Just over a month away from its December PDUFA date, Alnylam flaunted new data from two Phase III studies to back lumasiran in primary hyperoxaluria type 1 (PH1), a rare liver condition.

The Cambridge, MA-based biotech snagged a priority review for the candidate back in June, and got positive feedback from the EMA’s Committee for Medicinal Products for Human Use just last week. Lumasiran uses RNA interference (RNAi) to silence the gene for glycolate oxidase, an enzyme used in the production of oxalate.

Stephen Hoge, Moderna president (Moderna)

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Weeks away from a potential EUA application, Moderna announced they have completed enrollment in their 30,000-person Phase III Covid-19 vaccine trial, with over a third of volunteers non-white and a quarter over the age of 65.

The announcement caps what has been the most closely-watched recruitment race in the history of drug development, as Pfizer and Moderna rushed to get enough volunteers to prove whether or not experimental vaccines could actually protect people from contracting Covid-19. Pfizer reached that mark on Sept. 15. Moderna said around the same time that they would slow down enrollment to ensure they enrolled enough participants from minority and at-risk groups.

Pfiz­er scoops up an an­tibi­ot­ic in rare M&A deal, bag­ging a vir­tu­al start­up op­er­at­ing on a shoe­string bud­get

Pfizer is stepping up with a rare antibiotics buyout deal today, grabbing Palo Alto, CA-based Arixa Pharmaceuticals in a bid to add a new oral version of avibactam, a beta lactamase inhibitor — or BLI — approved back in 2015 as part of the IV treatment Avycaz.

The Arixa acquisition follows some encouraging Phase I responses demonstrating that 60% to 80% of the oral drug is absorbed into the bloodstream. Only 7% of the IV version is absorbed orally, far below the 30% threshold Arixa has pointed to as a therapeutic threshold. The buyout gives Pfizer’s hospital group a line on a new oral combo with antibiotics like ceftibuten to go after drug-resistant cases of urinary tract infections and other ailments.

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News brief­ing: UK biotech 4D phar­ma heads for Nas­daq via SPAC; Dr. Red­dy's shuts down man­u­fac­tur­ing af­ter cy­ber­at­tack

Another pharma company is intending to use a SPAC to join the Nasdaq.

4D pharma, a UK-based biotech, is reverse-merging with a blank check company in a deal worth up to $37.6 million. The move will give 4D pharma a new Nasdaq ticker, which will be $LBPS, using the American Depositary Share program. 4D will continue to trade on the London stock exchange under its previous ticker.

As a result of the move, 4D pharma will gain $14.6 million in cash held by the blank check company, dubbed Longevity. The merger is expected to be completed in early 2021, after which shares will be immediately tradeable on Nasdaq.

Can B cells break the bound­aries of cell ther­a­py? Long­wood start­up has $52M to prove a new en­gi­neer­ing tech

Back in December 2017, as the cell therapy world was still basking in the virtually back-to-back approvals of two pioneering CAR-Ts, researchers at Seattle Children’s Research Institute reported a scientific first in a different corner of the field: engineer B cells to treat disease.

The team, led by David Rawlings and Richard James, eventually worked with Longwood Fund to start a biotech around those findings. And now Atlas Venture and RA Capital Management are coming on board to lead a $52 million launch round, joined by Alta Partners, for Be Biopharma.

Bo Cumbo, AavantiBio CEO (file photo)

Bo Cum­bo jumps from the top com­mer­cial post at Sarep­ta to the helm of a gene ther­a­py start­up with some in­flu­en­tial back­ers, big plans and $107M

After a 7-year stretch building the commercial team at Sarepta, longtime drug salesman Bo Cumbo is jumping to the entrepreneurial side of the business, taking the helm of a startup that’s got several deep-pocket investors. And he’s not just bringing his experience in selling drugs.

He tells me that when he told Sarepta CEO Doug Ingram about it, his boss got excited about the venture and opted to jump in with a $15 million investment from Sarepta to add to the launch money, alongside 3 of the busiest investors in biotech.

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HHS secretary Alex Azar (at the podium) and FDA commissioner Stephen Hahn (Pete Marovich/Getty Images)

Covid-19 roundup: Azar open­ly plan­ning Hahn ouster — re­port; Vul­ner­a­ble pop­u­la­tions like­ly to get vac­cines by Jan­u­ary

The relationship between HHS secretary Alex Azar and FDA commissioner Stephen Hahn has deteriorated to the point where Azar has suggested replacing Hahn, according to a Politico report.

Azar was angered by the FDA’s pushback of the Trump administration’s proposals for authorizing Covid-19 vaccines, so much so that he began openly floating potential replacements for Hahn. The report cited six unnamed sources that said Azar discussed bringing up Hahn’s removal to the White House.

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