James Martin (via Texas Heart Institute)

A gene ther­a­py to re­store dam­aged tis­sue af­ter a heart at­tack clears pigs

James Mar­tin had been try­ing to ma­nip­u­late a par­tic­u­lar gene to re­grow heart and bone cells for six years when, while brain­storm­ing for a grant one day in 2009, he stum­bled on an old fruit fly study out of Al­bert Ein­stein Med­ical Cen­ter in New York.

The study showed that mu­ta­tions in a path­way called Hip­po (so named be­cause it can lead to a hip­popota­mus-like growth) could cause fly tis­sues to grow at ab­nor­mal rates. Mar­tin, a pro­fes­sor at Bay­lor Col­lege of Med­i­cine, won­dered whether it may do the same in heart cells.

Soon enough, the re­sults were so dra­mat­ic that he shift­ed his fo­cus. He showed he could get mice to com­plete­ly re­cov­er af­ter a dev­as­tat­ing heart at­tack. “Our find­ings in­di­cate that the fail­ing heart has a pre­vi­ous­ly un­rec­og­nized repar­a­tive ca­pac­i­ty,” he wrote af­ter a 2017 study.

And on Thurs­day, Mar­tin un­veiled an ap­proach that could soon have im­pli­ca­tions in hu­mans. Mar­tin and his team de­vised a gene ther­a­py that suc­cess­ful­ly re­grew the heart cells of pigs who have been ma­nip­u­lat­ed to re­sem­ble pa­tients re­cov­er­ing from a heart at­tack. The re­sults were pub­lished in Sci­ence Trans­la­tion­al Med­i­cine.

“We were over the moon,” Mar­tin told End­points News. “We were tak­ing this from the be­gin­ning of a very ba­sic sci­ence ques­tion to some­thing that could be re­al­ly trans­for­ma­tive as a heart fail­ure ther­a­py.”

Mar­tin is now work­ing with the FDA and a start­up he found­ed, Yap Ther­a­peu­tics, to move the ther­a­py in­to the clin­ic. Out­side ex­perts praised the re­sults, while cau­tion­ing that sig­nif­i­cant ob­sta­cles re­main.

Ron Crys­tal

Ron Crys­tal, a pro­fes­sor of gene ther­a­py at Cor­nell, not­ed the pigs saw a 14.3% in­crease in heart func­tion, as mea­sured by ejec­tion frac­tion, i.e. the amount of blood that leaves the heart every time it con­tracts. That’s far from a cure, but it would rep­re­sent the on­ly ther­a­py that can ac­tu­al­ly re­store func­tion af­ter a heart at­tack. Cur­rent ther­a­pies sim­ply try to lim­it the dam­age.

“It’s a very nice ex­am­ple tak­ing ba­sic bi­ol­o­gy and trans­lat­ing that to a pos­si­ble ther­a­py for hu­mans,” Crys­tal told End­points. “If you can re­store 12% to 15%, that’s great.”

Af­ter a heart at­tack, mil­lions of cells in the heart die, gen­er­al­ly leav­ing the re­main­ing mus­cle un­able to shoul­der the bur­den of pump­ing blood to the whole body. About half of all heart fail­ure pa­tients die with­in five years.

Clin­i­cal tri­als for drugs to slow progress on that front have been a waste­land, with drugs from Mer­ck, Am­gen and No­var­tis all fail­ing to show sig­nif­i­cant im­prove­ments in sur­vival, even if they re­duce hos­pi­tal­iza­tions. A va­ri­ety of ap­proach­es have been put forth to re­gen­er­ate the heart, in­clud­ing cell and gene ther­a­py, but they have large­ly fiz­zled af­ter safe­ty is­sues arose in an­i­mals or ear­ly tri­als pro­duced few re­sults.

In Mar­tin’s study, his team used an old tech­nol­o­gy called short hair­pin RNA, de­signed to knock out the Hip­po path­way. They pack­aged those in­to an AAV vec­tor and de­liv­ered it via a catheter in­to the cells that sur­round­ed the site of the heart at­tack, a ground ze­ro of dead mus­cle cells.

The Hip­po path­way acts as a mas­ter reg­u­la­tor across the an­i­mal king­dom, al­low­ing growth in ear­ly de­vel­op­ment and stop­ping it as or­gan­isms ma­ture. The hair­pin would re­duce the path­way’s func­tion, al­low­ing the cells to di­vide again.

“You’re turn­ing back the clock,” said Crys­tal.

Mar­tin saw the heart cells pro­lif­er­ate for about three months. The fact that the cells stopped was im­por­tant: A pre­vi­ous ef­fort by an­oth­er lab to re­gen­er­ate heart cells worked too well. The cells just kept di­vid­ing, like a can­cer.

To trans­late in­to the clin­ic, Mar­tin will have to show longer term safe­ty da­ta, prov­ing on­ly right heart cells grow and then stop grow­ing at the right time. He al­so plans to tin­ker with oth­er genes in hopes of restor­ing heart func­tion by more than just 15%.

“It’s still pre­lim­i­nary,” Mar­tin said. But “we have over­come many of the ob­sta­cles”

Why it Works: Man­u­fac­tur­ing a Vac­cine in a Mul­ti-Prod­uct Fa­cil­i­ty.

COVID-19 launched the pharmaceutical industry to the frontline in the battle against the fast-spreading global pandemic. The goal: distribute a safe, effective vaccine as quickly as possible. Major players in the vaccine market needed to partner with contract development and manufacturing organizations (CDMOs) to achieve the goal of mass vaccine quantities under expedited timelines. With CDMOs stepping up to play a critical role in the vaccine manufacturing process, multi-product CDMO facilities took the spotlight. Partnerships quickly formed as the race to save lives and fight a pandemic was on.

Habib Dable, Acceleron CEO

Days of heat­ed ru­mors cul­mi­nate in a re­port that Ac­celeron is in ad­vanced buy­out talks

Days of frothy rumors about possible M&A discussions at Acceleron were capped late Friday with a Bloomberg report asserting that the biotech company is in advanced talks for an $11 billion buyout deal.

Bloomberg was unable to identify any bidders in the deal, but speculation has been running rampant that the surging value of Acceleron stock had to be the result of leaks around the auction of the company. As of early Monday morning, we’re still awaiting the final word.

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Safe­ty fears force Pfiz­er to change piv­otal DMD gene ther­a­py tri­al pro­to­col

As one of the biggest players in an increasingly packed gene therapy space, Pfizer has taken an early lead over specialists like Sarepta in taking a Duchenne muscular dystrophy (DMD) candidate into late-stage testing. But new safety fears have led Pfizer to scale back that trial, cutting out patients with certain genetic mutations.

Pfizer has amended its enrollment protocol for a Phase III test for gene therapy fordadistrogene movaparvovec in DMD after investigators flagged severe side effects tied to specific mutations, according to a letter the drugmaker sent to Parent Project Muscular Dystrophy, a patient advocacy group.

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Merck CEO Rob Davis

Mer­ck emerges as lead bid­der in po­ten­tial Ac­celeron buy­out with deal pos­si­ble this week — re­port

With rumors swirling about a potential buyout of biotech Acceleron and its lead PAH drug sotatercept, market watchers have been keeping close tabs on industry movers and shakers due up for an expensive bolt-on. According to a new report, it appears Merck may be the one.

Merck is in “advanced talks” on a deal to acquire Cambridge, MA-based Acceleron in what previous reports pegged as a potential $11 billion buyout, the Wall Street Journal reported Monday. A deal could come as early as this week, according to the Journal.

Alexander Lefterov/Endpoints News

The coro­n­avirus vac­cine that the world for­got could still help save it

Back at the beginning of the pandemic — back when we still called the virus “novel” and a single case in Washington state could make headlines — there emerged the story of the coronavirus vaccine that the world forgot.

It was an allegory for our pandemic ill-preparedness. At a time when the world had been caught so flat-footed, there were a pair of scientists who had seen the crisis coming, lab-coated Cassandras with an antidote if only the world had listened sooner.

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Paul Hudson, Sanofi CEO (Cyril Marcilhacy/Bloomberg via Getty Images)

Sanofi calls it quits on mR­NA Covid-19 shots, scrap­ping vac­cine from $3.2B Trans­late Bio buy­out

Sanofi is throwing in the towel on mRNA-based Covid-19 vaccines.

The French drugmaker will halt development on its unmodified mRNA Covid-19 shot despite what it said were positive Phase I/II results, a spokesperson told Endpoints News on Tuesday morning. Sanofi said the reason it’s stopping the Covid-19 mRNA program, developed in partnership with its new $3.2 billion acquisition Translate Bio, is because the market is too crowded.

Brian Hubbard, Anji Pharmacetuticals CEO

Look­ing to rewrite the rules of drug li­cens­ing, start­up An­ji is on the hunt for 'dy­nam­ic eq­ui­ty' joint ven­tures

Licensing is one of the most common ways big drugmakers leverage biotech innovation to drive gains across their pipelines — and the structure of those deals is pretty well established. But one biotech with home bases in China and the US thinks it may have a better way.

On Tuesday, Cambridge-based biotech Anji Pharma closed a $70 million Series B with two late-stage molecules in the fold and a mission to rewrite the rules of drug licensing through what it calls “dynamic equity” deals and a joint venture-heavy game plan. The round was funded in whole by Chinese hedge fund CR Capital.

Con­tract re­search is hav­ing a mo­ment right now. Will M&A splash­es dri­ve the in­dus­try to even greater heights?

Contract research organizations are a fairly mysterious bunch. They’re typically considered the skilled laborers behind big drug development — the stage crews who run the trials behind some of the most (and least) successful data reveals in biopharma history.

But all that is changing.

This year, a couple of huge, out-of-the-blue M&A deals sounded the alarm on just how much money is flying around in this corner of the industry.

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Biohaven CEO Vlad Coric

Bio­haven turns out a dud in fa­tal neu­rode­gen­er­a­tive dis­ease, cast­ing doubt on drug's chances in ALS

With one migraine drug on the market, Biohaven has gone big with its next phase of growth, targeting major neurodegenerative diseases in Alzheimer’s and ALS. The former effort has already gone up in smoke, and a new failure elsewhere in the pipeline could now bode poorly for the latter.

Biohaven’s verdiperstat failed to outperform placebo in reducing the symptoms of patients with multiple system atrophy (MSA), a rare and fatal neurodegenerative disorder, according to a “focused analysis” of the drug’s Phase III trial in that disease toplined Monday.

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