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”

Pi­o­neer­ing Click Chem­istry in Hu­mans

Reimagining cancer treatments

Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, which is nearly one in six deaths. Recently, we have seen incredible advances in novel cancer therapies such as immune checkpoint inhibitors, cell therapies, and antibody-drug conjugates that have revamped cancer care and improved survival rates for patients.

Despite this significant progress in therapeutic targeting, why are we still seeing such a high mortality rate? The reason is that promising therapies are often limited by their therapeutic index, which is a measure of the effective dose of a drug, relative to its safety. If we could broaden the therapeutic indices of currently available medicines, it would revolutionize cancer treatments. We are still on the quest to find the ultimate cancer medicine – highly effective in several cancer types, safe, and precisely targeted to the tumor site.

Ivan Cheung, Eisai US chairman and CEO

Bio­gen, Ei­sai re­fresh amy­loid hy­poth­e­sis with PhI­II show­ing Alzheimer's med slows cog­ni­tive de­cline

In the first look at Phase III data for lecanemab, Eisai and Biogen’s follow-up Alzheimer’s drug to the embattled Aduhelm launch, results show the drug passed with flying colors on a test looking at memory, problem solving and other dementia metrics.

One of the most-watched Alzheimer’s therapies in the clinic, lecanemab met the study’s primary goal on the CDR-SB — Clinical Dementia Rating-Sum of Boxes — giving the biotech the confidence to ask for full approval in the US, EU and Japan by next March 31. The experimental drug reduced clinical decline on the scale by 27% compared to placebo at 18 months, the companies said Tuesday night Eastern time and Wednesday morning in Japan.

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Joshua Cohen (L) and Justin Klee, Amylyx co-CEOs

BREAK­ING: Af­ter long and wind­ing road, FDA ap­proves Amy­lyx's ALS drug in vic­to­ry for pa­tients and ad­vo­ca­cy groups

For just the third time in its 116-year history, the FDA has approved a new treatment for Lou Gehrig’s disease, or ALS.

US regulators gave the thumbs-up to the drug, known as Relyvrio, in a massive win for patients and their families. The approval, given to Boston-area biotech Amylyx Pharmaceuticals, comes after two years of long and contentious debates over the drug’s effectiveness between advocacy groups and FDA scientists, following the readout of a mid-stage clinical trial in September 2020.

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Vlad Coric, Biohaven CEO (Photo Credit: Andrew Venditti)

As Amy­lyx de­ci­sion waits in the wings, Bio­haven’s ALS drug sinks (again) in plat­form tri­al

The FDA’s decision on Amylyx’s ALS drug is set to come out sometime Thursday. In a space with few drugs, any approval would be a major landmark.

But elsewhere in the ALS field, things are a bit more tepid.

Thursday morning, Biohaven announced that its drug verdiperstat failed its arm of an ALS platform trial led by Massachusetts General Hospital. According to a press release, the drug did not meet its primary endpoint — improvement on an ALS functional status test — or any key secondary endpoints at 24 weeks. The trial had enrolled 167 patients, giving them either verdiperstat or placebo twice a day.

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Nooman Haque, head of life sciences and healthcare at Silicon Valley Bank, and John Carroll

I’m head­ed to Lon­don soon for #EU­BIO22. Care to join me?

It was great getting back to a live ESMO conference/webinar in Paris followed by a live pop-up event for the Endpoints 11 in Boston. We’re staying on the road in October with our return for a live/streaming EUBIO22 in London.

Silicon Valley Bank’s Nooman Haque and I are once again jumping back into the thick of it with a slate of virtual and live events on October 12. I’ll get the ball rolling with a virtual fireside chat with Novo Nordisk R&D chief Marcus Schindler, covering their pipeline plans and BD work.

Some­one old, some­one new: Mod­er­na pro­motes CTO, raids No­var­tis for re­place­ment amid pipeline push

Moderna CEO Stéphane Bancel made clear on the last quarterly call that “now is not the time to slow down.” On Thursday, he made a bit more room in the cockpit.

The company unveiled a new executive role on Thursday, promoting former chief technical operations and quality officer Juan Andres to president of strategic partnerships and enterprise expansion, and poaching a former Novartis exec to take his place.

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

Sanofi, Re­gen­eron’s Dupix­ent scores an­oth­er in­di­ca­tion with first-ever ap­proval for nodu­lar skin dis­or­der

Sanofi chief executive Paul Hudson told investors earlier this year that the Big Pharma was going to emphasize its sales kingpin Dupixent moving forward.

He wasn’t joking — the megablockbuster drug and sales king, recording just shy of $2 billion in sales this past quarter, has now officially secured its fifth indication from the FDA.

Sanofi and Regeneron, who jointly work on Dupixent development and commercialization, announced the new development on Thursday, saying that the FDA gave the all-clear to Dupixent to treat patients with prurigo nodularis, a rare autoimmune disorder characterized by a persistent, severe itch — and also visualized by hard, extremely itchy bumps known as nodules that form on the skin. The FDA noted in its announcement that it is the agency’s first approval for the disease.

Gilead names 'k­ing­pin­s' in coun­ter­feit HIV med law­suit

Gilead is mounting its counterfeit drug lawsuit, naming two “kingpins” and a complex network of conspirators who allegedly sold imitation bottles of its HIV meds, some of which ended up in US pharmacies.

The pharma giant on Wednesday provided an update on what it called a “large-scale, sophisticated counterfeiting conspiracy,” accusing two new defendants of “leading and orchestrating” a scheme to sell hundreds of millions of dollars in illegitimate drugs posing as meds such as Biktarvy and Descovy.

Tar­sus looks to raise aware­ness of eye­lid mite dis­ease in cam­paign aimed at eye­care spe­cial­ists

Eyelid mite disease may be “gross” but it’s also fairly common, affecting about 25 million people in the US.

Called demodex blepharitis, it’s a well-known condition among eyecare professionals, but they often don’t always realize how common it is. Tarsus Pharmaceuticals wants to change that with a new awareness campaign called “Look at the Lids.”

The campaign and website debut Thursday — just three weeks after Tarsus filed for FDA approval for a drug that treats the disease.

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