From mice to dogs, and some­day man: George Church's gene ther­a­py cock­tail for ag­ing-re­lat­ed dis­eases

George Chruch Re­ju­ve­nate

Emerg­ing gene-ther­a­py tech­nol­o­gy could help dogs live health­i­er, if not longer, lives as man’s best friend.

A start­up called Re­ju­ve­nate Bio — launched out of George Church’s lab at Har­vard Med­ical School (HMS) and the Wyss In­sti­tute for Bi­o­log­i­cal­ly In­spired En­gi­neer­ing at Har­vard Uni­ver­si­ty — on Thurs­day, with big plans to make work on gene ther­a­py tech­nol­o­gy en­gi­neered to pre­vent and treat a slew of age-re­lat­ed dis­eases in dogs and ex­tend their healthspan.

“Sci­ence hasn’t yet found a way to make com­plex an­i­mals like dogs live for­ev­er, so the next best thing we can do is find a way to main­tain health for as long as pos­si­ble dur­ing the ag­ing process,” said Church in a re­port by the Wyss In­sti­tute.

As we age, the propen­si­ty to be af­flict­ed with dis­ease(s) ris­es. But dis­eases are typ­i­cal­ly re­searched and treat­ed in­di­vid­u­al­ly, and the ex­ist­ing ar­ma­men­tar­i­um of treat­ments does not ac­com­mo­date the in­ter­con­nect­ed­ness of ill­ness­es that arise in lock­step with age. So, Har­vard re­searchers took a macro-lev­el ap­proach to the prob­lem of age-re­lat­ed dis­eases and de­vel­oped a gene ther­a­py fo­cused on a tri­fec­ta of longevi­ty as­so­ci­at­ed genes: FGF21, αK­lotho and sTGF𝝱R2 — which have pre­vi­ous­ly been shown to be as­so­ci­at­ed with in­creased health and lifes­pan ben­e­fits in mice that were ge­net­i­cal­ly en­gi­neered to over­ex­press them.

“We be­lieve that gene ther­a­py is a great tool for ac­tu­al­ly go­ing af­ter chron­ic age-re­lat­ed con­di­tions, par­tic­u­lar­ly if you have tar­get sets that have re­al­ly strong safe­ty pro­files,” Re­ju­ve­nate CEO Daniel Oliv­er said in an in­ter­view with End­points News.

“The genes we’re us­ing in­side of our gene ther­a­pies have been shown in trans­genic mouse mod­els to ex­tend their life. And so we have built-in safe­ty pro­files for the genes we’re us­ing — we have three-plus years of safe­ty da­ta in mice be­fore we even start.”

Noah David­sohn Re­ju­ve­nate

The re­searchers cre­at­ed sep­a­rate gene ther­a­py de­liv­ery ve­hi­cles for each gene us­ing a serotype of ade­no-as­so­ci­at­ed virus (AAV8) and then in­ject­ed the AAV con­structs in­to mouse mod­els of obe­si­ty, type II di­a­betes, heart fail­ure, and re­nal fail­ure to as­sess ef­fi­ca­cy.

The da­ta were strik­ing. FGF21 alone caused a com­plete re­ver­sal of weight gain and type II di­a­betes in obese, di­a­bet­ic mice fol­low­ing a sin­gle shot, and a com­bi­na­tion with sTGF𝝱R2 al­so di­min­ished kid­ney at­ro­phy by 75% in mice with re­nal fi­bro­sis. The gene sTGF𝝱R2 alone and in com­bi­na­tion with ei­ther of the oth­er two gene ther­a­pies im­proved heart func­tion in mice with heart fail­ure, sug­gest­ing that that co-ad­min­is­tra­tion of FGF21 and sTGF𝝱R2 could treat all four age-re­lat­ed con­di­tions.

To be sure, in this ini­tial study in mice the in­ject­ed genes did not stray in­to the an­i­mals’ genomes and did not mod­i­fy their nat­ur­al DNA — which is a con­cern giv­en the ex­ist­ing eu­genic prac­tices preva­lent in the pet in­dus­try.

Re­ju­ve­nate Bio on Thurs­day un­veiled plans to kick off a pi­lot study test­ing the ef­fi­ca­cy of this gene ther­a­py tech­nol­o­gy in ar­rest­ing mi­tral valve dis­ease, which af­fects most Cav­a­lier King Charles spaniels by age eight and caus­es heart fail­ure.

The plan is to en­roll 10 dogs with mi­tral valve dis­ease, in­ject them with the gene ther­a­py, and as­sess whether they progress to the next stage of the dis­ease over a giv­en pe­ri­od, Oliv­er said. This pi­lot study — which will take at least a year to read­out — will serve as a lit­mus test for an an­i­mal drug tri­al with the FDA, which tends to take about three years to com­plete. If all goes well, the com­pa­ny hopes to ex­pand the treat­ment to all ca­nine breeds, as more than 7 mil­lion dogs in the Unit­ed States suf­fer from mi­tral valve dis­ease.

“We want to get rid of the mor­bidi­ties as­so­ci­at­ed with ag­ing, so dogs can be as hap­py and healthy as pos­si­ble through­out their lives,” said Re­ju­ve­nate Bio’s chief tech­nol­o­gy of­fi­cer Noah David­sohn, who is a for­mer Re­search Sci­en­tist at the Wyss In­sti­tute and HMS. David­sohn’s dog, named Bear, serves as Re­ju­ve­nate’s “chief in­spi­ra­tion of­fi­cer.”

Bear David­sohn Re­ju­ve­nate

The first crop of FDA-ap­proved gene ther­a­pies for hu­mans — such as Spark Ther­a­peu­tics’ Lux­tur­na and No­var­tis’ Zol­gens­ma — treat rare dis­eases. If Re­ju­ve­nate’s ther­a­py is found to be safe and ef­fec­tive in dogs, it could open the door to sim­i­lar ther­a­pies for age-re­lat­ed ill­ness­es and in­deed ag­ing in hu­mans, a field that has at­tract­ed an ex­plo­sion of in­ter­est and fund­ing.

Al­though ear­ly, the study in mice showed that these so-called longevi­ty gene ther­a­pies can be com­bined in­to a sin­gle ther­a­peu­tic mix­ture — com­pared to the tra­di­tion­al par­a­digm that dic­tates dif­fer­ent dis­eases ne­ces­si­tate mul­ti­ple in­ter­ven­tions (and ar­guably ac­cu­mu­la­tive ex­po­sure to side-ef­fects), the re­searchers con­clud­ed.

In tan­dem with the ex­cite­ment that came in re­ac­tion to the FDA ap­proval of pi­o­neer­ing hu­man gene-ther­a­pies was the push­back on what some crit­ics call as­tro­nom­i­cal prices.  Zol­gens­ma, for in­stance, is the world’s most ex­pen­sive ther­a­py at $2.1 mil­lion a pop, al­though its mak­er No­var­tis in­sists its cu­ra­tive po­ten­tial and in­stall­ment-based pric­ing makes it worth it. The com­pa­ny has al­so ini­ti­at­ed a con­tro­ver­sial lot­tery scheme to give away 100 dos­es of Zol­gens­ma in coun­tries out­side the Unit­ed States where it is not yet ap­proved.

“I think go­ing for­ward as gene ther­a­py is ap­plied to dis­eases with much high­er preva­lence — you will see the price come down,” Oliv­er said.

Mean­while, the in­ter­est in treat­ing dis­eases in pets — if their hu­man own­ers may be so in­clined — is on the rise, giv­en that 67% of US house­holds, or about 85 mil­lion fam­i­lies, own a pet, ac­cord­ing to the 2019-2020 sur­vey con­duct­ed by the Amer­i­can Pet Prod­ucts As­so­ci­a­tion.

For in­stance, to treat dis­eases like can­cer in dogs — surgery, chemother­a­py, or ra­di­a­tion are ex­ist­ing al­ter­na­tives. But tar­get­ed ther­a­pies are the next fron­tier. A Sil­i­con Val­ley start­up — called the One Health Com­pa­ny — raised $5 mil­lion last month to help fig­ure out which hu­man treat­ments can be re­pur­posed for their ca­nine coun­ter­parts. The com­pa­ny, which likened its tech­nol­o­gy to Foun­da­tion Med­i­cine’s next-gen­er­a­tion se­quenc­ing pan­el in an in­ter­view with STAT, helps se­quence the dog’s tu­mor and gen­er­ates rec­om­men­da­tions for treat­ment.

Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

OWS shifts spot­light to drugs to fight Covid-19, hand­ing Re­gen­eron $450M to be­gin large scale man­u­fac­tur­ing in the US

The US government is on a spending spree. And after committing billions to vaccines defense operations are now doling out more of the big bucks through Operation Warp Speed to back a rapid flip of a drug into the market to stop Covid-19 from ravaging patients — possibly inside of 2 months.

The beneficiary this morning is Regeneron, the big biotech engaged in a frenzied race to develop an antibody cocktail called REGN-COV2 that just started a late-stage program to prove its worth in fighting the virus. BARDA and the Department of Defense are awarding Regeneron a $450 million contract to cover bulk delivery of the cocktail starting as early as late summer, with money added for fill/finish and storage activities.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Noubar Afeyan, Flagship CEO and Tessera chairman (Victor Boyko/Getty Images)

Flag­ship ex­ecs take a les­son from na­ture to mas­ter ‘gene writ­ing,’ launch­ing a star-stud­ded biotech with big am­bi­tions to cure dis­ease

Flagship Pioneering has opened up its deep pockets to fund a biotech upstart out to revolutionize the whole gene therapy/gene editing field — before gene editing has even made it to the market. And they’ve surrounded themselves with some marquee scientists and execs who have crowded around to help shepherd the technology ahead.

The lead player here is Flagship general partner Geoff von Maltzahn, an MIT-trained synthetic biologist who set out in 2018 to do CRISPR — a widely used gene editing tool — and other rival technologies one or two better. Von Maltzahn has been working with Sana co-founder Jake Rubens, another synthetic biology player out of MIT who he describes as his “superstar,” who’s taken the CSO role.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Bill Haney, Dragonfly CEO (Dave Pedley/Getty Images for SXSW)

A boom­ing Drag­on­fly is tak­ing its TriN­KETs to Copen­hagen as the lat­est Bris­tol My­ers pact spurs ex­pan­sion plans — out­side the US

Bristol Myers Squibb is making a habit out of collaborating with the crew at Dragonfly, adding their 3rd deal in a series that now will take them into newly charted R&D territory. And the fast-growing team at the Cambridge-based biotech is adding a facility in Copenhagen for its next growth spurt, where the government is making it easy to recruit scientists internationally as the U.S. throttles back.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

David Hallal

AlloVir tests how much an an­tivi­ral biotech can reap in a pan­dem­ic stock mar­ket

The pandemic stock market has proven fruitful for virtually any type of biotech. Now a 7-year-old cell therapy startup will see how much it can yield for a company that specializes in fighting viruses.

AlloVir, a company that until 2019 largely lived off grant money, has filed for a $100 million IPO to back its line of off-the-shelf, virus-fighting T cells. Although in normal circumstances, $100 million could be a solid return for a biotech that got its first major round of funding only last year, we’ll have to wait to see how much the company ultimately earns. As Covid-19 has sent investor money scurrying to almost anyone in drug development, every single biotech to go public this year has prized above their midpoint or upsized their offering, according to Renaissance Capital, sometimes dramatically so.

RA Cap­i­tal dou­bles down on Sid­dhartha Mukher­jee's vi­sion for a new cell en­gi­neer­ing ap­proach, lead­ing Vor's $110M Se­ries B

Vor Biopharma is muscling up.

CEO Robert Ang, who was reluctant to divulge the headcount when discussing his move from Neon Therapeutics to Vor last August, readily offered that the team has grown from 6 to 50 in less than a year. The biotech is moving to a larger office on Cambridge Parkway Drive in weeks, giving it more space to complete the IND-enabling work and manufacturing scale-up — conducted by a CDMO partner — in preparation for clinical trials planned for the first half of 2021.

Covid-19 roundup: Squab­bles with gov­ern­ment de­lay Mod­er­na’s PhI­II — re­ports; No­vavax se­cures largest Warp Speed deal yet: $1.6B

A much-anticipated Phase III trial for Moderna’s Covid-19 vaccine is being held up as the company delayed submitting trial protocols and sparred with government scientists on how to run the study and even what the benchmark for success should be, Reuters reported.

Moderna, the first US company to put their vaccine into human testing, was supposed to enter a 30,000-person study this month in partnership with the NIH to determine whether it can prevent infection. STAT reported last week that the trial was facing delays over the protocol, but that a July start was still possible. Neither the NIH nor Moderna ever disclosed a specific date the trial should start, but Reuters reported that the agency had hoped to begin on July 10.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

Which drug de­vel­op­ers of­fer Trump a quick, game-chang­ing ‘so­lu­tion’ as the pan­dem­ic roars back? Eli Lil­ly and Ab­Cellera look to break out of the pack

We are unleashing our nation’s scientific brilliance and will likely have a therapeutic and/or vaccine solution long before the end of the year.

— Donald Trump, July 4

Next week administration officials plan to promote a new study they say shows promising results on therapeutics, the officials said. They wouldn’t describe the study in any further detail because, they said, its disclosure would be “market-moving.”

— NBC News, July 3

Something’s cooking. And it’s not just July 4 leftovers involving stale buns and uneaten hot dogs.

Over the long weekend observers picked up signs that the focus in the Trump administration may swiftly shift from the bright spotlight on vaccines being promised this fall, around the time of the election, to include drugs that could possibly keep patients out of the hospital and take the political sting out of the soaring Covid-19 numbers causing embarrassment in states that swiftly reopened — as Trump cheered along.

So far, Gilead has been the chief beneficiary of the drive on drugs, swiftly offering enough early data to get remdesivir an emergency authorization and into the hands of the US government. But their drug, while helpful in cutting stays, is known for a limited, modest effect. And that won’t tamp down on the hurricane of criticism that’s been tearing at the White House, and buffeting the president’s most stalwart core defenders as the economy suffers.

We’ve had positive early-stage vaccine data, most recently from Pfizer and BioNTech, playing catchup on an mRNA race led by Moderna — where every little sign of potential trouble is magnified into a lethal threat, just as every advance excites a frenzy of support. But that race still has months to play out, with more Phase I data due ahead of the mid-stage numbers looming ahead. A vaccine may not be available in large enough quantities until well into 2021, which is still wildly ambitious.

So what about a drug solution?

Trump’s initial support for a panacea focused on hydroxychloroquine. But that fizzled in the face of data underscoring its ineffectiveness — killing trials that aren’t likely to be restarted because of a recent population-based study offering some support. And there are a number of existing drugs being repurposed to see how they help hospitalized patients.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Cel­lec­tis slammed af­ter pa­tient dies and FDA slaps a hold on their tri­al for an off-the-shelf CAR-T for mul­ti­ple myelo­ma

Cellectis was slammed after the market close on Monday as the biotech reported that the FDA demanded it hit the brakes on their MELANI-01 trial for their off-the-shelf cell therapy UCARTCS1A after one of the patients in the study died of treatment-related cardiac arrest.

The multiple myeloma patient had previously been treated unsuccessfully with various therapies, noted the biotech, and had been given dose level two (DL2) of their allogeneic CAR-T.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 84,800+ biopharma pros reading Endpoints daily — and it's free.

Jean-Paul Clozel, Idorsia CEO (Patrick Straub/Keystone via AP Images)

Sec­ond PhI­II study for Idor­si­a's sleep drug re­turns pos­i­tive re­sults, but al­so rais­es new ques­tions

Following a successful Phase III study in April showcasing the safety and potential of its new sleep drug, Idorsia posted some mixed news in the second Phase III study, but that won’t stop a planned filing aimed at regulatory approval.

The drug, a dual orexin receptor antagonist (DORA) called daridorexant, was found to significantly improve sleep maintenance and subjective total sleep time in 25 mg doses, replicating results from the first Phase III study. However, improvements in sleep onset and daytime functioning narrowly missed statistical significance, despite numerical consistency with the April study.