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.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

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President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

Mer­ck flesh­es out Keytru­da win in first-line cer­vi­cal can­cer, adding more fire­pow­er to its ear­ly can­cer push

Merck has worked hard to bring its I/O blockbuster Keytruda into earlier and earlier lines of therapy, and now the wonder drug appears poised to make a quick entry into early advanced cervical cancer.

A combination of Keytruda and chemotherapy with or without Roche’s Avastin cut the risk of death by 33% over chemo with or without Avastin (p=<0.001) in first-line patients with persistent, recurrent or metastatic cervical cancer, according to full data from the Phase III KEYNOTE-826 study presented Saturday at #ESMO21.

EQRx chairman Alexis Borisy and CEO Melanie Nallichieri

EQRx, CStone un­furl full lung can­cer da­ta for PD-L1 drug in what the part­ners are call­ing a first

As a self-stylized drug pricing disruptor, EQRx has high hopes for its lead PD-(L)1 to offer proof of concept for the entire business model. After touting a win back in May, the biotech is back with full data in lung cancer that could back up an approval.

Patients dosed with EQRx and CStone Pharmaceuticals’ sugemalimab posted median progression-free survival of 9 months compared with 5.8 months for patients given placebo (p=0.0026), according to full data from the Phase III GEMSTONE-301 study in Stage III non-small cell lung cancer set to be presented at this weekend’s #ESMO21.

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As­traZeneca touts Imfinzi im­munother­a­py com­bos for lung can­cer in push to dri­ve PD-L1 drug up­take

Facing the big dogs in the PD-(L)1 space, AstraZeneca has taken its own contender Imfinzi into blockbuster territory in its four years on the market but sees even bigger things for the drug. Combinations could be the key, and early results from a mid-stage test are adding some fuel to that strategy.

Imfinzi combined with one of two investigational immunotherapies — a CD73 antibody dubbed oleclumab or an Innate’s anti-NGK2a named monalizumab — topped Imfinzi alone in terms of overall response and progression-free survival in patients with stage III non-small cell lung cancer whose tumors had not worsened during concurrent chemoradiation, according to interim data from the Phase II COAST trial set to be presented at #ESMO21.