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.

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Kathy High (file photo)

Gene ther­a­py pi­o­neer Kathy High has left Spark af­ter com­plet­ing $4.3B union with Roche

Kathy High dedicated the past seven years of her life shepherding experimental gene therapies she’s developed at Children’s Hospital of Philadelphia toward the market as president and head of R&D at Spark Therapeutics. Now that the biotech startup is fully absorbed into Roche — with an FDA approval, a $4.3 billion buyout and a promising hemophilia program to boast — she’s ready to move on.

Roche confirmed her departure with Endpoints News and noted “she will take some well-deserved time off and then will begin a new chapter in a sabbatical at a university.”

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Deborah Dunsire

The fourth CGRP mi­graine drug is here. Time for Lund­beck to prove it's worth $2B

They may be late, but Lundbeck is now officially in the game for preventing migraine with CGRP drugs.

The FDA has OK’d eptinezumab, the prize in Lundbeck’s $2 billion acquisition of Alder. Like rival offerings from Amgen/Novartis, Eli Lilly and Teva, the antibody blocks the calcitonin gene-related peptide, which is believed to dilate blood vessels in the brain and cause pain.

It will now be sold as Vyepti. The company has yet to announce a price. Amgen and Novartis had set the wholesale acquisition cost of their pioneering Aimovig at $6,900 for a year’s supply before raising it slightly this year; Lilly and Teva had followed suit with Emgality and Ajovy.

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Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

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Tim Mayleben (file photo)

Es­pe­ri­on's goldilocks cho­les­terol fight­er wins FDA ap­proval — will its 'tra­di­tion­al' pric­ing ap­proach spur adop­tion?

It’s more effective than decades-old statins but not as good as the injectable PCSK9 — the goldilocks treatment for cholesterol-lowering, bempedoic acid, has secured FDA approval.

Its maker, Esperion Therapeutics, is betting that their pricing strategy — a planned list price of between $10 to $11 a day — will help it skirt the pushback the PCSK9 cholesterol fighters, Repatha and Praluent, got from payers for their high sticker prices.

The sky-high expectations for the pair of PCSK9 drugs that were first approved in 2015 quickly simmered — and despite a 60% price cut, coupled with data showing the therapies also significantly cut cardiovascular risk, sales have not really perked up.

Esperion is convinced that by virtue of being a cheaper oral therapy, bempedoic acid will hit that sweet spot in terms of adoption.

“We’re kind of like the old comfortable shoe,” Esperion’s chief commercial officer Mark Glickman remarked in an interview with Endpoints News ahead of the decision date. “It’s an oral product, once-daily and nontitratable — these are things that just resonate so true with patients and physicians and I think we’ve kind of forgotten about that.”

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James Collins, Broad Institute via Youtube

UP­DAT­ED: A space odyssey for new an­tibi­otics: MIT's ma­chine learn­ing ap­proach

Drug development is complex, expensive and comes with lousy odds of success — but in most cases, if you make it across the finish line brandishing a product with an edge (and play your cards right) it can be a lucrative endeavor.

As it stands, the antibiotic market is cursed — it harbors the stink of multiple bankruptcies, a dearth of innovation, and is consequently barely whetting the voracious appetites of big pharma or venture capitalists. Enter artificial intelligence — the biopharma industry’s cure-all for the pesky process of making a therapeutic, including data mining, drug discovery, optimal drug delivery, and addressable patient population.

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Gilead los­es two more patent chal­lenges on HIV pill, set­ting up court­room fight in Delaware

Gilead sustained two more losses in their efforts to rid themselves of an activist-backed patent lawsuit from the US government over a best-selling HIV pill.

Urged on by activists seeking to divert a portion of Gilead’s revenue to clinics and prevention programs, the Department of Health and Human Services made a claim to some of the patents for the best-selling HIV prevention drug, Truvada, also known as PrEP. Gilead responded by arguing in court that HHS’s patents were invalid.

Today, the US Patent and Trademark Office ruled that Gilead was likely to lose the last two of those challenges as well. The USPTO ruled against Gilead on the first two patents earlier this month.

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Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

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Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

“I’m ok, I don’t have Ebola,” Pascal told them. “I see that death toll rising and I can’t not do something about it.”

Last August, Regeneron learned they had succeeded: In a large trial across West Africa, their drug, REGN-EB3, was vastly more effective than the standard treatments. It was surprise news for the company, coming just 10 months into a trial they thought would take several years and a major victory in the global fight against a deadly virus that killed over 2,000 in 2019 and can carry a mortality rate of up to 90%.

For Kyratsous and Pascal, though, it brought only fleeting reprieve. Just four months after the NIH informed them REGN-EB3 worked, Kyratsous was back in his office reading the New York Times for updates on a new outbreak on another continent, and wondering alongside Pascal and senior management whether it was time to pull the trigger again.

In late January, as the death toll swelled and the first confirmed cases outside China broke double digits, they made a decision. Soon they were back on the phone with the multiple government agencies and their coronavirus partners at the University of Maryland’s Level 3 bio lab. The question was simple: Can Kyratsous and his team use a process honed over two previous outbreaks, and create a treatment before the newest epidemic ends? Or worse, if, as world health experts fear, it doesn’t vanish but becomes a recurrent virus like the flu?

“Christos likes things immediately,” Matt Frieman, Regeneron’s coronavirus collaborator at the University of Maryland, told Endpoints. “That’s what makes us good collaborators: We push each other to develop things faster and faster.”

Kristen Pascal (Regeneron)

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The first time Regeneron tried to respond to a global outbreak, it was something of a systems test, Kyratsous explains from his office at Regeneron’s Tarrytown headquarters. Kyratsous, newly promoted, has crammed it with photos of his family, sketches of viral vectors and a shark he drew for his 3-year-old son. He speaks rapidly – an idiosyncrasy his press person says has only been aggravated this afternoon by the contents of his “Regeneron Infectious Diseases”-minted espresso glass – and he gesticulates with similar fluidity, tumbling through antibodies, MERS, the novel coronavirus, Ebola-infected monkeys.

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Bank­rupt an­tibi­otics mak­er Ar­a­digm turns to old part­ner/in­vestor for fi­nal $3M fire sale

Grifols once paid Aradigm $26 million for a stake in its inhaled antibiotics. But with Aradigm now in bankruptcy, the Spanish drugmaker is dishing out a final $3.2 million to buy it all.

The fire sale — which comes one year after Aradigm filed for Chapter 11 following a regulatory trifecta for disaster — will see Grifols obtain assets and IP to Apulmiq (formerly Pulmaquin and Linhaliq in Europe), Lipoquin and free ciprofloxacin. In addition to waiving its claims in the bankruptcy case, Grifols also agreed to milestone payments up to $3 million more upon any regulatory approvals.