Can a next-gen take on a dead­ly weight loss pill con­quer car­diometa­bol­ic dis­eases? A Medicxi-backed start­up thinks so

Most drug de­vel­op­ers might re­mem­ber DNP, the yel­low­ish com­pound that’s been used over the years as a her­bi­cide and chem­i­cal in­ter­me­di­ate, as a dead­ly di­et pill. But Sha­har­yar Khan and Allen Cun­ning­ham won­dered about the ef­fect that it has shown, first in a 1930s study, in burn­ing ex­cess calo­ries.

Sha­har­yar Khan

The duo, who have worked to­geth­er for close to 20 years at a biotech fo­cused on mi­to­chon­dria-based ther­a­pies, found the bi­ol­o­gy fa­mil­iar. In cells — whether you’re a yeast or a hu­man be­ing — a mi­to­chon­dria takes sub­strates, fats and sug­ars and gen­er­ates en­er­gy. Slow that down, the the­o­ry goes, and the body burns more calo­ries to get its en­er­gy then re­turns to a state of en­er­gy bal­ance.

At Rivus Phar­ma­ceu­ti­cals, the new com­pa­ny Khan and Cun­ning­ham have launched, the goal is to di­rect that mech­a­nism, known as mi­to­chon­dr­i­al un­cou­pling, at a broad range of car­diometa­bol­ic dis­eases from heart fail­ure and NASH to Type 2 di­a­betes and hy­per­ten­sion.

More im­por­tant­ly, they would do it safe­ly, the part­ners said.

“So what we’ve done is we’ve tak­en that re­al­ly po­tent phar­ma­col­o­gy, and we’re try­ing to make it a mod­ern-day, cut­ting edge drug,” CSO Khan told End­points News. “And we think that it’s about time some­one does that, be­cause there’s this pro­found epi­dem­ic of dys­me­tab­o­lism, of en­er­getic ex­cess, that we know this par­tic­u­lar mech­a­nism can es­sen­tial­ly fix.”

Lon­gi­tude Cap­i­tal and Medicxi are lead­ing the $35 mil­lion Se­ries A, which al­so fea­tures Rx­Cap­i­tal and comes af­ter Phase I da­ta that “ex­ceed­ed our ex­pec­ta­tions,” ac­cord­ing to Medicxi chief sci­en­tif­ic ad­vi­sor David Grainger. Not on­ly was Rivus’ lead can­di­date, HU6, well-tol­er­at­ed, it al­so hit the marks on key meta­bol­ic pa­ra­me­ters.

Allen Cun­ning­ham

The trick for cre­at­ing these con­trolled meta­bol­ic ac­cel­er­a­tors — or CMAs, as Rivus has named them — lies in avoid­ing the pit­falls Khan reck­ons caused DNP’s tox­i­c­i­ties. First, you “flat­ten the PK curve,” lead­ing to sus­tained low ac­tiv­i­ty of un­cou­pling rather than too much at the same time. Sec­ond­ly, you pre­clude the dan­gers of over­dose by se­lect­ing com­pounds whose ab­sorp­tion is capped at a cer­tain lev­el.

De­spite its small size (the head­count stands at sev­en at the mo­ment, in­clud­ing the two co-founders), Rivus is un­abashed about its dis­pro­por­tion­ate am­bi­tions.

At a time when the con­cept of pre­ci­sion med­i­cine is seep­ing be­yond can­cer, star­tups tak­ing on car­diometa­bol­ic in­di­ca­tions are much more like­ly to ze­ro in on ge­net­i­cal­ly de­fined sub­groups of pa­tients. And it works: MyoKar­dia served as the poster child with Bris­tol My­ers Squibb’s $13 bil­lion takeover of its drug for a sub­set of ob­struc­tive hy­per­trophic car­diomy­opa­thy.

Cun­ning­ham, the CEO, not­ed that with­in the bas­ket of dis­eases Rivus will be go­ing af­ter, there are still dif­fer­ences in mar­ket sizes. Af­ter us­ing the Se­ries A cash to com­plete an on­go­ing Phase IIa meta­bol­ic study, all “strate­gic al­ter­na­tives” will be on the ta­ble to set up ide­al­ly con­cur­rent Phase IIb stud­ies in type 2 di­a­betes, NASH and se­vere hy­per­triglyc­eridemia. A sec­ond Phase IIa for HF­pEF (heart fail­ure with pre­served ejec­tion frac­tion) is slat­ed to be­gin ear­ly next year.

Hur­dles and ques­tions abound. Any one of those in­di­ca­tions, on their own, bring enor­mous chal­lenges that have tripped up play­ers big and small — al­though Khan be­lieves that’s the wrong way of look­ing at it.

“When you con­duct a tri­al in NASH, half of your pa­tients have di­a­betes; so you’re con­duct­ing a tri­al in di­a­betes as well. If you con­duct a tri­al in heart fail­ure, 80% of your pa­tients have obe­si­ty and hy­per­ten­sion; you’re con­duct­ing a tri­al in obe­si­ty and hy­per­ten­sion,” he said. “And so if you at­tend your­self to the fact that these dis­eases are not siloed, but that you’re try­ing to treat the pa­tient, I think that gives you an op­por­tu­ni­ty that oth­er ap­proach­es just don’t pro­vide you.”

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.

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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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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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.

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.

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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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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Marcelo Bigal, Ventus Therapeutics CEO

No­vo Nordisk joins No­var­tis, Roche in NL­RP3 are­na, bet­ting $70M cash on NASH, car­diometa­bol­ic us­es

As a drug target, the NLRP3 inflammasome has drawn serious interest from Big Pharma, inspiring a series of M&A deals from Novartis and Roche on top of venture investments by others. Now Novo Nordisk is jumping on the bandwagon — and the Danish pharma giant is taking the target where it knows best.

Novo Nordisk is getting its NLRP3 inhibitors from Ventus Therapeutics, a Versant-backed startup that set out to make some of the best NLRP3 drugs out there by incorporating new insights into the structure of the target complex.

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