Paul Tesar (Convelo Therapeutics)

Io­n­is, lead­ing MS re­searcher throw an­ti­sense at a new type of brain cells

No mat­ter how many mol­e­cules he threw at them, Paul Tesar couldn’t get the brain cells to sur­vive. Or he got them to sur­vive, but then — to every­one’s baf­fle­ment — they still couldn’t do what they were sup­posed to.

Tesar, a pro­fes­sor of in­no­v­a­tive ther­a­peu­tics at Case West­ern Uni­ver­si­ty, had spent years build­ing stem cell mod­els for mul­ti­ple scle­ro­sis, grow­ing brain organoids in dish­es and then see­ing what small mol­e­cules re­stored myelin pro­duc­tion. Now he was try­ing to do the same for oth­er myelin dis­eases, par­tic­u­lar­ly an ul­tra-rare ge­net­ic con­di­tion called Pelizaeus-Merzbach­er dis­ease, where a sin­gle mu­ta­tion leads to the death of the myelin-pro­duc­ing neu­rons, called oligo­den­dro­cytes, and can kill pa­tients in in­fan­cy.

“We’ve screened many thou­sands of small mol­e­cule com­pounds,” Tesar told End­points News. “But we could not get them to re­store func­tion.”

Then Tesar got an email from Io­n­is, the Cal­i­for­nia biotech that had just used an RNA-mod­i­fy­ing tech­nol­o­gy called an­ti­sense to build Spin­raza, the first FDA-ap­proved drug for the ge­net­ic neu­ro­log­i­cal dis­or­der spinal mus­cu­lar at­ro­phy.

Now, in a study pub­lished in Na­ture, Tesar and Io­n­is have shown they can use a sin­gle dose of drug built from that tech­nol­o­gy to keep those neu­rons both alive and well-func­tion­ing and treat the dis­ease — at least in mice. The pub­li­ca­tion isn’t ground­break­ing, an­ti­sense re­searchers say, but it shows for the first time that an­ti­sense can be used to ef­fec­tive­ly tar­get oligo­den­dro­cytes, an in­sight its au­thors hope will open up oth­er rare myelin dis­or­ders to ther­a­py.

“It’s not that it’s dif­fer­ent than every­thing that’s been done be­fore, but it goes fur­ther than every­thing that’s gone be­fore,” Jon Watts, a pro­fes­sor at the RNA Ther­a­peu­tics In­sti­tute at UMass Med­ical School who is not af­fil­i­at­ed with Io­n­is or the pa­per, told End­points, both in terms of “du­ra­tion of ef­fect af­ter a sin­gle dose, and the re­al fo­cus in get­ting the bi­ol­o­gy, the ther­a­peu­tic ef­fect in oligo­den­dro­cytes.”

The ap­plic­a­bil­i­ty to the most fa­mous and com­mon of myelin dis­or­ders, mul­ti­ple scle­ro­sis, is lim­it­ed, re­searchers say, both be­cause the ther­a­py re­lied on hav­ing a spe­cif­ic gene to tar­get and be­cause the pa­per doesn’t prove you can get an ef­fect on the pe­riph­er­al ner­vous sys­tem. Still, Berit Pow­ers, an as­sis­tant di­rec­tor at Io­n­is’s neu­rol­o­gy re­search de­part­ment and a co-au­thor, point­ed to sev­er­al oth­er ge­net­ic myelin dis­or­ders, known as leukody­s­tro­phies. That in­cludes an Io­n­is pro­gram on Alexan­der dis­ease, a rare child­hood con­di­tion with Parkin­son’s-like symp­toms.

“We’re cer­tain­ly ex­plor­ing the po­ten­tial of ASOs in non-mono­genic … con­di­tions like MS,” Pow­ers told End­points, us­ing a short­hand for an­ti­sense oligonu­cleotides. “But that work is very new.”

This is hard­ly Tesar’s first for­ay in­to biotech. In 2015, he showed in Na­ture how cer­tain small mol­e­cules could re­gen­er­ate myelin — the holy grail for an MS ther­a­py — and found­ed Con­velo Ther­a­peu­tics around that work. Last year, they part­nered with Genen­tech for an undis­closed sum and an ex­clu­sive op­tion to ac­quire the com­pa­ny.

Myelin is a fat­ty sub­stance that coats neu­rons, in­su­lat­ing them and help­ing elec­tric cur­rents pass through. Tesar’s lab was broad­ly in­ter­est­ed in the ques­tion of “why myelin fails,” both in MS and rare dis­eases, and about 7 years ago he got a grant to work from the PMD Foun­da­tion.

First, Tesar built stem cell mod­els of the dis­ease, fig­ur­ing out how dif­fer­ent mu­ta­tions in a sin­gle gene, called PLP1, lead oligo­den­dro­cyte prog­en­i­tor cells (the stem cell-like cells that will be­come oligo­den­dro­cytes) to cre­ate a “tox­ic RNA” and a mu­tat­ed pro­tein that kills them soon af­ter they dif­fer­en­ti­ate. Then, he tried to sup­press that gene with dif­fer­ent chem­i­cals, even­tu­al­ly test­ing over 3,000 dif­fer­ent com­pounds.

He was able to even­tu­al­ly get the oligo­den­dro­cytes to sur­vive, but to his sur­prise, they didn’t pro­duce myelin as they should. The sur­viv­ing cells still couldn’t prop­er­ly func­tion, “re­veal­ing,” he wrote in a 2018 Cell pa­per “a sec­ond phase of pathol­o­gy.” A hy­po­thet­i­cal treat­ment, he ar­gued, would have to both keep prog­en­i­tor cells alive and then treat the sur­vivors in a way that in­duces myeli­na­tion.

With an­ti­sense, he and Pow­ers’ Io­n­is team were able to do both. An­ti­sense oligonucelotides con­sist of strands of RNA that are a mir­ror im­age of the RNA you want to tar­get. The mir­ror binds to and si­lences, or turns off, that gene. In the study, the re­searchers con­firmed that PLP1 was dis­ease-caus­ing by knock­ing out the gene in cell lines with CRISPR. Then they in­ject­ed mice with an­ti­sense strands through the spinal cord, the same way Spin­raza is de­liv­ered. (You can’t use CRISPR to treat the dis­ease in hu­mans, be­cause there’s no good way yet of de­liv­er­ing it.)

Pow­ers and Tesar were un­sure if they would be able to tar­get oligo­den­dro­cytes and prog­en­i­tor cells. What they found, though, was “com­plete restora­tion of oligo­den­dro­cytes” and a “pro­found res­cue of neu­ro­log­i­cal func­tion.” Myelin, too, was fi­nal­ly re­stored. Mice that died af­ter 3 weeks now lived for over 200 days.

Io­n­is hasn’t li­censed the drug and it’s un­clear yet the im­pli­ca­tions for oth­er dis­eases, but re­searchers say the re­sults could trans­late in­to hu­mans quick­ly, at least by drug de­vel­op­ment stan­dards.

“I do think it’s very rapid­ly trans­lat­able,” Watts said. “Based on the da­ta they’re show­ing here, and based on the un­met need, this ap­pears to be some­thing that could be trans­lat­ed pret­ty quick­ly in­to a Phase I tri­al.”

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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In his­toric Covid-19 ad­comm, vac­cine ex­perts de­bate a sea of ques­tions — but of­fer no clear an­swers

The most widely anticipated and perhaps most widely watched meeting in the FDA’s 113-year history ended late Thursday night with a score of questions and very few answers.

For nearly 9 hours, 18 different outside experts listened to public health agencies and foundations present how the United States’ Covid-19 vaccine program developed through October, and they debated where it should go from there: Were companies testing the right metrics in their massive trials? How long should they track patients before declaring a vaccine safe or effective? Should a vaccine, once authorized, be given to the volunteers in the placebo arm of a trial?

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Ul­tragenyx in­jects $40M to grab Solid's mi­crody­s­trophin trans­gene — while side­step­ping the AAV9 vec­tor that stirred up safe­ty fears

Since before Ilan Ganot started Solid Bio to develop a gene therapy for kids like his son, who has Duchenne muscular dystrophy, Ultragenyx CEO Emil Kakkis has been watching and advising the former investment banker as he navigated the deep waters of drug development.

Just as Solid is getting back up on its feet after a yearlong clinical hold, Kakkis has decided to jump in for a formal alliance.

With a $40 million upfront, Ultragenyx is grabbing 14.45% of Solid’s shares $SLDB and the rights to its microdystrophin construct for use in combination with AAV8 vectors. Solid’s lead program, which utilizes AAV9, remains unaffected. The company also retains rights to other applications of its transgene.

A top drug pro­gram at Bay­er clears a high bar for CKD — open­ing the door to an FDA pitch

Over the past 4 years, Bayer has been steering a major trial through a pivotal program to see if their drug finerenone could slow down the pace of chronic kidney disease in patients suffering from both CKD as well as Type 2 diabetes.

Today, their team jumped on a virtual meeting hosted by the American Society of Nephrology to offer a solid set of pivotal data to demonstrate that the drug can delay dialysis or a kidney replacement as well as cardio disease, while also adding some worrying signs of hyperkalemia among the patients taking the drug. And they’re hustling it straight to regulators in search of an approval for kidney disease and cardio patients — one of the toughest challenges in the book, as demonstrated by repeated past failures.

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Biond­Vax stock im­plodes af­ter a big PhI­II gam­ble for its uni­ver­sal flu vac­cine fails

After flying high on Wall Street for the last few months of a pandemic, BiondVax’s stock and dreams of getting approval for its universal flu vaccine hit the windshield.

The Jerusalem-based biotech announced on Friday that its only clinical candidate, M-001, failed both primary and secondary endpoints in a Phase III study. There was no statistically significant difference in reduction of flu illness and severity between the vaccine and placebo groups, according to the company. The vaccine did prove safe, if ineffective, BiondVax said.

Pascal Soriot, AstraZeneca CEO (Zach Gibson/Bloomberg via Getty Images)

UP­DAT­ED: FDA gives As­traZeneca the thumbs-up to restart PhI­II Covid-19 vac­cine tri­als, and J&J is prepar­ing to re­sume its study

Several countries had restarted their portions of AstraZeneca’s global Phase III Covid-19 vaccine trial after the study was paused worldwide in early September, but the US notably stayed on the sidelines — until now. Friday afternoon the pharma giant announced the all clear from US regulators. And on top of that, J&J announced Friday evening that it’s preparing to resume its own Phase III vaccine trial.

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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Adam Koppel and Jeffrey Schwartz, Bain

Bain ex­ecs Adam Kop­pel and Jef­frey Schwartz line up $125M for their first blank check deal as Wall Street con­tin­ues to em­brace biotech

Adam Koppel and Jeffrey Schwartz have jumped into the blank check game, raising $125 million for a stock listing in search of a company.

Their SPAC, BCLS Acquisition Corp, raised $125 million this week, with a line on $25 million more as it scouts for a biotech in search of money and a place on Wall Street.

The two principals at Bain Life Sciences have been on a romp since they set up the Bain operation 4 years ago. Their S-1 spells out a track record of 22 deals totaling $650 million for the life sciences group, which led to 9 IPOs.

Covid-19 roundup: An mR­NA play­er gets a boost out of the lat­est round of an­i­mal da­ta; Phase­Bio pulls the plug on treat­ment tri­al

The big tell for CureVac $CVAC is coming up with a looming early-stage readout on their mRNA Covid-19 vaccine in the clinic. But for now they’ll make do with an upbeat assessment on the preclinical animal data they used to get into the clinic.

Researchers for the German biotech say they got the high antibody titers and T cell activation they were looking for, lining up a hamster challenge to demonstrate — in a simple model — that the vaccine could protect the furry creatures. Like the other mRNA vaccines, the drug sends instructions to spur cells to decorate themselves with the distinctive spike on the virus to elicit an immune response.