CymaBay scraps key NASH, PSC pro­grams af­ter lead drug trig­gers safe­ty alarms — share price im­plodes

When CymaBay Ther­a­peu­tics re­cent­ly ac­knowl­edged de­feat in a 12-week read­out of its Phase II tri­al of se­ladel­par, the biotech grasped at “sig­nif­i­cant im­prove­ments in bio­chem­i­cal mark­ers of liv­er in­jury” as a rea­son to re­main hope­ful about the 52-week biop­sy re­sults. But that hope is now dashed.

Not on­ly did the drug fail to re­duce liv­er fat, it al­so ap­peared to cause cell in­jury.

These “atyp­i­cal his­to­log­i­cal find­ings” — in­clud­ing cas­es of sus­pect­ed in­ter­face he­pati­tis — ob­served in pa­tients who re­spond­ed to their drug forced CymaBay to slam the brakes to its se­ladel­par clin­i­cal pro­gram, ter­mi­nat­ing the Phase IIb study in NASH in ques­tion and a Phase IIa in pri­ma­ry scle­ros­ing cholan­gi­tis (PSC) as well as putting all stud­ies in pri­ma­ry bil­iary cholan­gi­tis on hold.

“We are very dis­ap­point­ed in hav­ing to halt the de­vel­op­ment of se­ladel­par at this time but pa­tient safe­ty and care is para­mount,” CEO Su­jal Shah said in a state­ment.

Shares of the biotech $CBAY, which dipped in the wake of dis­ap­point­ing da­ta in June, are down a fur­ther 76.22% to $1.32 Mon­day morn­ing.

SVB Leerink an­a­lysts called it “a worst case sce­nario el­e­vat­ing safe­ty is­sues that are un­like­ly to be re­solved in the near fu­ture, in our opin­ion.”

“The risk/re­ward clear­ly fa­vors sig­nif­i­cant risk, even as we await ad­di­tion­al in­for­ma­tion and clar­i­ty from CBAY,” they wrote in a note. “Our mod­el is cur­rent­ly un­der re­view.”

But CymaBay’s good day turned out to be a good one for In­ter­cept, which has just clinched pri­or­i­ty re­view and a March 26, 2020 PDU­FA for their NASH drug obeti­cholic acid (OCA).

From Baird’s Bri­an Sko­r­ney:

This fol­lows a long his­to­ry of PPAR ag­o­nists blow­ing up (muragli­tazar, trogli­ta­zone) and high­lights what we be­lieve is an un­der­ap­pre­ci­a­tion of the risks of clin­i­cal de­vel­op­ment in the NASH space. OCA re­mains the on­ly med­ica­tion, to date, that has shown a fi­brot­ic ben­e­fit in a prospec­tive­ly de­fined con­trolled study, and its done it twice. We con­tin­ue to be­lieve OCA is like­ly to be the on­ly game in town for NASH for the fore­see­able fu­ture.

Safe­ty is­sues have pre­vi­ous­ly ben raised in the PPAR ag­o­nist class. This fam­i­ly of drugs ac­ti­vate pro­teins called per­ox­i­some pro­lif­er­a­tor-ac­ti­vat­ed re­cep­tors, which reg­u­late gene ex­pres­sion and are be­lieved to play a role in bile acid syn­the­sis, in­flam­ma­tion, fi­bro­sis and lipid me­tab­o­lism.

Back in 2007 Glax­o­SmithK­line aban­doned its own ef­fort in the field — a col­lab­o­ra­tion with Lig­and Phar­ma­ceu­ti­cals — af­ter their agent led to the for­ma­tion of tu­mors in an­i­mal tests. (The com­pound, GW501516, sub­se­quent­ly took on a sec­ond life as an il­le­gal per­for­mance-en­hanc­ing drug for ath­letes).

France’s Gen­fit and In­ven­ti­va are al­so work­ing on their own PPAR ag­o­nists for NASH. Gen­fit $GN­FT took a small­er toll on CymaBay’s ter­mi­na­tion news than it did fol­low­ing CymaBay’s ini­tial read­out, slid­ing 3.35% to $14.72. Al­most a year ago the drug­mak­er tout­ed that their elafi­bra­nor in­duced a sta­tis­ti­cal­ly sig­nif­i­cant de­crease in serum al­ka­line phos­phatase (ALP) lev­els for PBC pa­tients, and ear­li­er this year it won or­phan sta­tus for that in­di­ca­tion.

While the mar­ket ea­ger­ly awaits Phase III re­sults from Gen­fit, it has al­so se­cured a deal with Terns Phar­ma­ceu­ti­cals to bring the ther­a­py to Chi­na.

On CymaBay’s part, ex­ecs said they are in­ves­ti­gat­ing the sur­prise find­ings, which in­volved pa­tients who “demon­strat­ed on-study im­prove­ment or sta­bi­liza­tion of their bio­chem­i­cal mea­sures of in­flam­ma­tion and liv­er in­jury and no liv­er-re­lat­ed ad­verse events af­ter 52 weeks of treat­ment.”

Tal Zaks, Moderna CMO (Moderna via YouTube)

UP­DAT­ED: NI­AID and Mod­er­na spell out a 'ro­bust' im­mune re­sponse in PhI coro­n­avirus vac­cine test — but big ques­tions re­main to be an­swered

The NIAID and Moderna have spelled out positive Phase I safety and efficacy data for their Covid-19 vaccine mRNA-1273 — highlighting the first full, clear sketch of evidence that back-to-back jabs at the dose selected for Phase III routinely produced a swarm of antibodies to the virus that exceeded levels seen in convalescent patients — typically in multiples indicating a protective response.

Moderna execs say plainly that this first stage of research produced exactly the kind of efficacy they hoped to see in humans, with a manageable safety profile.

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Tillman Gerngross, Adagio Therapeutics CEO

An­ti­body leg­end Till­man Gern­gross is el­bow­ing his way in­to the Covid-19 R&D cru­sade: 'I don’t see this end­ing any­time soon'

One of the most influential — and outspoken — scientists at work in the field of antibody discovery is jumping into the frenzied race to create new therapeutics to treat and prevent Covid-19. And he’s operating with the conviction that the current outbreak now once again spreading like wildfire will create plenty of demand for what he has in mind.

Dartmouth professor and Adimab CEO Tillman Gerngross tells me he’s raised $50 million from a group of close VCs to spin out a new company — Adagio Therapeutics — with a full C-suite team assembled to hire up a staff and keep rolling toward the clinic.

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Trans­port Sim­u­la­tion Test­ing for Your Ther­a­py is the Best Way to As­sure FDA Ex­pe­dit­ed Pro­gram Ap­proval

Modality Solutions is an ISO:9001-registered biopharmaceutical cold chain engineering firm with unique transport simulation capabilities that support accelerated regulatory approval for biologics and advanced therapeutic medicinal products (ATMP). Our expertise combines traditional validation engineering approaches with regulatory knowledge into a methodology tailored for the life sciences industry. We provide insight and execution for the challenges faced in your cold chain logistics network.

Norbert Bischofberger, Kronos CEO

Gilead­'s ex-R&D chief Bischof­berg­er heads back to the biotech gi­ant to pick up a pair of late-stage drugs that had been put aside

Norbert Bischofberger knows entospletinib well.

Back during his long, blockbuster run as head of R&D at Gilead, researchers had once held some high hopes for this drug. But to make it work, he and the team felt it would need a new companion diagnostic to identify patients. There was talk of a combo approach to give it more punch. But the market was small, making them wonder if it would be worth going through a lengthy development cycle to get it through a pivotal.

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The $1B Mer­ck-Bay­er drug that di­vid­ed car­di­ol­o­gists in March gets pri­or­i­ty re­view

Three months after Merck published in the New England Journal of Medicine data that left doctors and investors divided over just how well its experimental heart drug worked, the FDA has handed that drug priority review. A decision is now due by January 20, 2021.

Merck first announced the drug, known as vericiguat, as a Phase III success last November. In 2016, Merck had paid $1 billion upfront for US rights to the Bayer-developed drug. Early projections foresaw a few hundred million a year in sales, but the unspecified late-stage success raised the possibility for far more. After all, Novartis’s flagship heart drug, Entresto, was earning $1.7 billion per year and was expected to reach up to $4 billion in annual sales.

GSK’s Shin­grix leader Guil­laume Pfe­fer has jumped on board Flag­ship to helm a biotech hy­brid as Afeyan’s lat­est CEO-part­ner

After spending 4 years in a senior post with GlaxoSmithKline’s star team positioning Shingrix for a blockbuster approval, Guillaume Pfefer is headed back to the biotech world — in style.

Pfefer has signed on to join Noubar Afeyan’s busy group of partners at Flagship, and he’s taking the helm of an upstart — which today is being merged with another Flagship startup — with some grand plans of its own. The announcement this morning notes that Pfefer will run Kintai Therapeutics, one of the grads of the Flagship labs.

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Who are the women blaz­ing trails in bio­phar­ma R&D and lead­ing the fight against Covid-19? Nom­i­nate them for End­points' spe­cial re­port

One of the many inequalities the pandemic has laid bare is the gender imbalance in biomedical research. A paper examining Covid-19 research authorship wondered out loud: Where are the women?

It’s a question that echoes beyond our current times. In the biopharma world, not only are women under-represented in R&D roles (particularly at higher levels), their achievements and talents could also be undermined by stereotypes and norms of leadership styles. The problem is even more dire for women of color.

Donald Trump and Anthony Fauci (AP Images)

Covid-19 roundup: Fau­ci fires back at White House cam­paign to un­der­mine him

Anthony Fauci has called the White House campaign to discredit him “a bit bizarre” and said he stands by his previous statements, even if he has since changed his views.

The NIAID chief — who has received an outpouring of support following reports that the Trump administration has sent a document akin to opposition research to multiple news outlets — spoke with his usual candor in interviews with The Atlantic.

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John Furey, Imvax CEO

A neu­ro­sur­geon spent the past 30 years de­vel­op­ing a neoanti­gen tu­mor vac­cine. Now he has $112M for a piv­otal test

As a neurosurgeon, David Andrews knew there wasn’t much he could do for his glioma patients after resecting — rarely fully — their tumor. Even with the best treatment and care available, median overall survival is just somewhere between 14 and 16 months.

Then in the 1990s, his mentor at Thomas Jefferson University introduced him to Renato Baserga, a pathologist who had been studying the effect of using antisense oligonucleotide to knock out the insulin-like growth factor type 1 receptor in cancers. As IGF-R1 drives tumor growth and metastasis, the preclinical reasoning went, implanting a molecule targeting the receptor together with the tumor material near lymph nodes can slow down the spread of the cancer.

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