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.”

Jan Hatzius (Photographer: Christopher Goodney/Bloomberg via Getty Images)

When will it end? Gold­man econ­o­mist gives late-stage vac­cines a good shot at tar­get­ing 'large shares' of the US by mid-2021 — but the down­side is daunt­ing

It took decades for hepatitis B research to deliver a slate of late-stage candidates capable of reining the disease in.

With Covid-19, the same timeline has devoured all of 5 months. And the outcome will influence the lives of billions of people and a multitrillion-dollar world economy.

Count the economists at Goldman Sachs as optimistic that at least one of these leading vaccines will stay on this furiously accelerated pace and get over the regulatory goal line before the end of this year, with a shot at several more near-term OKs. That in turn should lead to the production of billions of doses of vaccines that can create herd immunity in the US by the middle of next year, with Europe following a few months later.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 86,500+ biopharma pros reading Endpoints daily — and it's free.

UP­DAT­ED: No­vavax her­alds the lat­est pos­i­tive snap­shot of ear­ly-stage Covid-19 vac­cine — so why did its stock briefly crater?

High-flying Novavax $NVAX became the latest of the Covid-19 vaccine players to stake out a positive set of biomarker data from its early-stage look at its vaccine in humans.

Their adjuvanted Covid-19 vaccine was “well-tolerated and elicited robust antibody responses numerically superior to that seen in human convalescent sera,” the company noted. According to the biotech:

All subjects developed anti-spike IgG antibodies after a single dose of vaccine, many of them also developing wild-type virus neutralizing antibody responses, and after Dose 2, 100% of participants developed wild-type virus neutralizing antibody responses. Both anti-spike IgG and viral neutralization responses compared favorably to responses from patients with clinically significant COVID‑19 disease. Importantly, the IgG antibody response was highly correlated with neutralization titers, demonstrating that a significant proportion of antibodies were functional.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 86,500+ biopharma pros reading Endpoints daily — and it's free.

J&J gets a fresh OK for es­ke­t­a­mine, but is it re­al­ly the game-chang­er for de­pres­sion Trump keeps tweet­ing about?

Backed by an enthusiastic set of tweets from President Trump and a landmark OK for depression, J&J scooped up a new approval from the FDA for Spravato today. But this latest advance will likely bring fresh scrutiny to a drug that’s spurred some serious questions about the data, as well as the price.

First, the approval.

Regulators stamped their OK on the use of Spravato — developed as esketamine, a nasal spray version of the party drug Special K or ketamine — for patients suffering from major depressive disorder with acute suicidal ideation or behavior.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 86,500+ biopharma pros reading Endpoints daily — and it's free.

Sean Nolan and RA Session II

Less than 3 months af­ter launch, the AveX­is crew’s Taysha rais­es $95M Se­ries B. Is an IPO next?

The old AveXis team is moving quickly in Dallas.

Three months ago, they launched Taysha with $30 million in Series A funding and a pipeline of gene therapies out of UT Southwestern. Now, they’ve announced an oversubscribed $95 million Series B. And the biotech is declining all interview requests on the news, the kind of broad silence that can indicate an IPO is in the pipeline.

Biotechs, including those relatively fresh off launch, have been going public at a frenzy since the pandemic began. Investors have showed a willingness to put upwards of $200 million to companies that have yet to bring a drug into the clinic. Still, if Taysha were to go public in the near future, it would be perhaps the shortest path from launch to IPO in recent biotech memory.

Stéphane Bancel, Moderna CEO (Steven Ferdman/Getty Images)

Mod­er­na CEO Stéphane Ban­cel out­lines a prospec­tive moth­er­lode of Covid-19 vac­cine rev­enue — will a back­lash fol­low?

Moderna shows no sign of slowing down, or turning charitable when it comes to pricing supplies of its Covid-19 vaccine.

One of the leaders in the Phase III race to get a Covid-19 vaccine across the finish line in record time, Moderna says it’s on track to complete enrollment in one of the most avidly watched studies in the world next month. And the biotech has already banked some $400 million in deposits for vaccine supply as it works through negotiations with countries around the world — as CEO Stéphane Bancel sets out to hire a commercial team.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 86,500+ biopharma pros reading Endpoints daily — and it's free.

Covid-19 roundup: J&J and BAR­DA agree to $1 bil­lion for 100 mil­lion dos­es; Plas­ma re­duces mor­tal­i­ty by 50% — re­ports

J&J has become the latest vaccine developer to agree to supply BARDA with doses of their Covid-19 vaccine, signing an agreement that will give the government 100 million doses in exchange for $1 billion in funding.

The agreement, similar to those signed by Novavax, Sanofi and AstraZeneca-Oxford, provides funding not only for individual doses but to help J&J ramp up manufacturing. Pfizer, by contrast, received $1.95 billion for the doses alone. Still, if one looked at each agreement as purchase amounts, J&J’s deal would be $10 per dose, slotting in between Novavax’s $16 per dose and AstraZeneca’s $4 per dose.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 86,500+ biopharma pros reading Endpoints daily — and it's free.

CF Foun­da­tion, Long­wood team on new in­cu­ba­tor for com­pa­nies with cut­ting-edge CF treat­ments

Nine months after launching a $500 million hunt for a cure for cystic fibrosis, the Cystic Fibrosis Foundation said it will use a portion of those funds to do something it has never done before: help launch new companies.

The CF Foundation, whose venture philanthropy efforts helped fund Vertex’s line of powerful CF drugs, is teaming with Longwood Fund to create a CF incubator. The incubator will identify new companies with platforms or technologies that can be applied in the rare genetic condition. The partners can then finance early development in exchange for a commitment from the companies to focus on applications in cystic fibrosis.

RA, No­var­tis back Gen­tiBio's seed round, plans to launch de­vel­op­ment of En­gTreg ther­a­pies

Boston, MA-based startup GentiBio landed a $20 million seed fund from three investors to dive into engineered regulatory T cell (EngTreg) development.

Marquee investors OrbiMed, Novartis Venture Fund and RA Capital Management have backed GentiBio’s mission to develop EngTregs for the treatment of autoimmune, alloimmune, autoinflammatory, and allergic diseases. Unlike other companies studying treatments using a patient’s own Tregs, GentiBio plans to make use of CD4+ immune cells, found in the blood.

Paul Laikind, ViaCyte CEO

Stem cell play­er Vi­a­Cyte ex­pands col­lab­o­ra­tion with Gore to de­vel­op sub­cu­ta­neous di­a­betes treat­ment

Longtime stem cell player ViaCyte has teamed up with a materials science company in an effort to solve immunosuppression challenges and advance its type 1 diabetes treatments.

Expanding on an existing collaboration, ViaCyte and W.L. Gore have agreed to combine the biotech’s PEC-Encap candidate with a Gore-produced membrane in what they hope will eliminate the need for immunosuppressive drugs. Such treatments have created foreign body responses in the past, and stamping these reactions out is the main goal, ViaCyte CEO Paul Laikind said.