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.”

Adap­tive De­sign Meth­ods Of­fer Rapid, Seam­less Tran­si­tion Be­tween Study Phas­es in Rare Can­cer Tri­als

Rare cancers account for 22 percent of cancer diagnoses worldwide, yet there is no universally accepted definition for a “rare” cancer. Moreover, with the evolution of genomics and associated changes in categorizing tumors, some common cancers are now characterized into groups of rare cancers, each with a unique implication for patient management and therapy.

Adaptive designs, which allow for prospectively planned modifications to study design based on accumulating data from subjects in the trial, can be used to optimize rare oncology trials (see Figure 1). Adaptive design studies may include multiple cohorts and multiple tumor types. In addition, numerous adaptation methods may be used in a single trial and may facilitate a more rapid, seamless transition between study phases.

Matt Gline (L) and Pete Salzmann

UP­DAT­ED: Roivant bumps stake in Im­muno­vant with a $200M deal. But with M&A off the ta­ble, shares crater

Roivant has worked out a deal to pick up a chunk of stock in its majority-owned sub Immunovant $IMVT, but the stock buy falls far short of its much-discussed thoughts about buying out all of the 43% of shares it doesn’t already own.

Roivant, which recently inked a SPAC move to the market at a $7 billion-plus valuation, has forged a deal to boost its ownership in Immunovant by 6.3 points, ending with 63.8% of the biotech’s stock following a $200 million injection. That cash will bolster Immunovant’s cash reserves, giving it a $600 million war chest to fund a slate of late-stage studies for its big drug: the anti-FcRn antibody IMVT-1401.

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Sanofi preps a multi­bil­lion-dol­lar buy­out of an mR­NA pi­o­neer af­ter falling be­hind in the race for a Covid-19 jab — re­port

It looks like Sanofi CEO Paul Hudson is dead serious about his intention to vault directly into contention for the future of mRNA vaccines.

A year after paying Translate Bio a whopping $425 million in an upfront and equity payment to help guide the pharma giant to the promised land of mRNA vaccines for Covid-19, Sanofi is reportedly ready to close the deal with a buyout.

Translate’s stock $TBIO soared 78% after the market closed Monday. A spokesperson for Sanofi declined to comment on the report, telling Endpoints News that the company doesn’t comment on market rumors.

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Anthony Sun, Zentalis and Zentera CEO (Zentalis)

With clin­i­cal tri­als lined up for Zen­tal­is drugs, Chi­na's Zen­tera sets its sights on more deal­mak­ing and an IPO

As Zentalis geared up for an AACR presentation of early data on its WEE1 inhibitor earlier this year, its Chinese joint venture Zentera wasn’t idle, either.

Zentera, which has headquarters in Shanghai, had already nabbed clearance to start clinical trials in China for three of the parent company’s drugs. In May — just a month after Zentalis touted three “exceptional responses” out of 55 patients for their shared lead drug, ZN-c3 — it got a fourth CTA approval.

Thomas Soloway, T-knife CEO

What hap­pens when you give a mouse a hu­man self-anti­gen? In­vestors bet $110M to find out

T-knife Therapeutics launched last August on a mission to isolate T cell receptors not from human donors, but from mice. Now, with a new CEO and a candidate bound for the clinic, the Versant-backed company is reloading with a fresh $110 million.

“What we are trying to do for the field of TCR therapy and solid tumor therapy is very analogous to what the murine platforms have done in antibody development,” CEO Thomas Soloway told Endpoints News. 

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UP­DAT­ED: Watch out Glax­o­SmithK­line: As­traZeneca's once-failed lu­pus drug is now ap­proved

Capping a roller coaster journey, AstraZeneca has steered its lupus drug anifrolumab across the finish line.

Saphnelo, as the antibody will be marketed, is the only treatment that’s been approved for systemic lupus erythematosus since GlaxoSmithKline’s Benlysta clinched an OK in 2011. The British drugmaker notes it’s also the first to target the type I interferon receptor.

Mirroring the population that the drug was tested on in late-stage trials, regulators sanctioned it for patients with moderate to severe cases who are already receiving standard therapy — setting up a launch planned for the end of August, according to Ruud Dobber, who’s in charge of AstraZeneca’s biopharmaceuticals business unit.

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Not all mR­NA vac­cines are cre­at­ed equal. Does it mat­ter?; Neu­ro is back; Pri­vate M&A af­fair; 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.

As part of our broader and deeper drive, Endpoints has been pairing webinars with our special reports to cover more angles on a given topic. In conjunction with Max Gelman’s neuroscience feature, Kyle Blankenship moderated an insightful panel to discuss where the field is headed. You can register to watch it on demand here.

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Bris­tol My­ers pulls lym­phoma in­di­ca­tion for Is­to­dax af­ter con­fir­ma­to­ry tri­al falls flat

Amid an industrywide review of cancer drugs with accelerated approval, Bristol Myers Squibb had to make the tough call last month to yank an approval for leading I/O drug Opdivo after flopping a confirmatory study. Now, a second Bristol Myers drug is on the chopping block.

Bristol Myers has pulled aging HDAC inhibitor Istodax’s indication in peripheral T cell lymphoma after a Phase III confirmatory study for the drug flopped on its progression-free survival endpoint, the drugmaker said Monday.

Rick Pazdur (via AACR)

FDA's on­col­o­gy head Rick Paz­dur de­fends the ac­cel­er­at­ed ap­proval path­way, claim­ing it is 'un­der at­tack'

The FDA is sounding the alarm over its accelerated approval pathway as backlash continues over the recent nod in favor of Biogen’s Alzheimer’s drug Aduhelm, and an ODAC meeting on six such approvals that could potentially be pulled from the market — two of which already have.

“Do you think accelerated approval is under attack? I do,” Rick Pazdur, head of FDA’s Oncology Center of Excellence, said at a Friends of Cancer Research webinar on Thursday.

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