FDA lifts hold on CymaBay’s NASH drug, but the com­pa­ny may still leave the ail­ing field

Eight months af­ter a sin­gle tri­al read­out blew up their NASH pro­gram, their stock price and put de­vel­op­ment around their lead com­pound on in­def­i­nite hold, CymaBay has been cleared to get back to work.

The FDA has lift­ed the clin­i­cal hold it placed on the com­pa­ny and their ex­per­i­men­tal se­ladel­par last year af­ter planned biop­sies for their NASH tri­al re­vealed “atyp­i­cal his­to­log­i­cal find­ings” — a phrase that here means the drug, rather than re­duc­ing pa­tients’ liv­er fat, ap­peared to lead to liv­er dam­age. The Phase IIb tri­al was ter­mi­nat­ed, along with a Phase IIa for pri­ma­ry scle­ros­ing cholan­gi­tis (PSC). Stud­ies on pri­ma­ry bil­iary cholan­gi­tis were put on hold. SVB Leerink called it “a worst case sce­nario” and the stock fell from $5.55 to $1.89.

CymaBay said that an ex­pert pan­el they con­vened af­ter the tri­al read­out found “no clin­i­cal, bio­chem­i­cal, or his­to­log­i­cal ev­i­dence” that se­ladel­par was in­jur­ing pa­tients and “unan­i­mous­ly sup­port­ed” re-ini­ti­at­ing the tri­als. The FDA lift­ing the hold al­lows the com­pa­ny to pro­ceed with 3 tri­als test­ing the drug in NASH, pri­ma­ry bil­iary cholan­gi­tis and pri­ma­ry scle­ros­ing cholan­gi­tis.

Su­jal Shah

It doesn’t ap­pear that they will pro­ceed with all of them, though. Even if the drug wasn’t harm­ing NASH pa­tients in that tri­al, the com­pa­ny is still left with the fact that the drug didn’t ap­pear to be help­ing ei­ther. CymaBay didn’t say they were aban­don­ing NASH, but the in­di­ca­tion — a po­ten­tial block­buster mar­ket that once float­ed CymaBay’s stock – was con­spic­u­ous­ly ab­sent from CEO Su­jal Shah’s re­marks.

“This is a piv­otal event for se­ladel­par, which had gar­nered a high de­gree of pa­tient in­ter­est based on its promis­ing po­ten­tial for an­ti-cholesta­t­ic, an­ti-in­flam­ma­to­ry and re­duced symp­tom bur­den in pa­tients with PBC,” he said. “We are grat­i­fied and en­er­gized to be able to once again ad­vance se­ladel­par in­to a reg­is­tra­tional pro­gram to con­firm its ben­e­fit. It is our un­wa­ver­ing goal to one day make it avail­able to pa­tients with PBC, and po­ten­tial­ly for oth­er chron­ic, in­flam­ma­to­ry liv­er dis­eases.”

CymaBay’s stock rose 32% on the news, from $3.51 to $4.66.

SVB Leerink’s Thomas Smith said the de­ci­sion to start with PBC was no sur­prise, giv­en they’ve al­ready gen­er­at­ed blind­ed Phase III da­ta and the fact that the re­main­ing clin­i­cal work for PBC like­ly re­quires fol­low­ing sev­er­al hun­dred pa­tients for a year, as op­posed to thou­sands of pa­tients over mul­ti­ple years for NASH.

“Im­por­tant­ly, this reg­u­la­to­ry up­date re­moves a key reg­u­la­to­ry over­hang, and should al­le­vi­ate some in­vestor con­cerns re­gard­ing both the tim­ing and na­ture of the FDA’s re­sponse to the in­de­pen­dent pan­el find­ings,” he wrote in a note to in­vestors. “This is a crit­i­cal step for­ward in re­sum­ing se­ladel­par clin­i­cal de­vel­op­ment, and we ex­pect strength in CBAY shares this morn­ing.”

Pri­or to the hold, CymaBay had been run­ning a Phase III tri­al in PBC, a chron­ic dis­ease that slow­ly de­stroys bile ducts in the liv­er. That tri­al will now pro­ceed. A Phase II tri­al read­out last year showed 5 mg and 10 mg dos­es of the drug led to a 36% and 43% re­duc­tion in al­ka­line phos­phatase, a chem­i­cal bio­mark­er for the dis­ease.

In an email, Shah said that al­though they’re be­gin­ning with PBC, the com­pa­ny con­tin­ues to see po­ten­tial in NASH. “NASH is a com­plex, het­ero­ge­neous dis­ease and while we are en­cour­aged by the ef­fects of se­ladel­par in NASH, par­tic­u­lar­ly on fi­bro­sis, there is more work to be done around the right de­vel­op­ment strat­e­gy (e.g. com­bi­na­tions) that should be ex­plored,” he said.

As re­cent­ly as the win­ter of 2019, the field was con­sid­ered to be one of the next block­buster mar­kets for phar­ma, but a se­ries of big tri­al fail­ures, in­clud­ing CymaBay’s, have crip­pled ex­pec­ta­tions. Gen­fit, once one of the lead­ing NASH biotechs, an­nounced yes­ter­day they were ter­mi­nat­ing the pro­gram af­ter a Phase III fail­ure.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

So — that pig-to-hu­man trans­plant; Po­ten­tial di­a­betes cure reach­es pa­tient; Ac­cused MIT sci­en­tist lash­es back; 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.

We’re incredibly excited to welcome Beth Bulik, seasoned pharma marketing reporter, to the team. You can find much of her work in our new Marketing channel — and in her weekly newsletter, Endpoints PharmaRx, which will launch in early November. Add it to your subscriptions here.

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NYU surgeon transplants an engineered pig kidney into the outside of a brain-dead patient (Joe Carrotta/NYU Langone Health)

No, sci­en­tists are not any clos­er to pig-to-hu­man trans­plants than they were last week

Steve Holtzman was awoken by a 1 a.m. call from a doctor at Duke University asking if he could put some pigs on a plane and fly them from Ohio to North Carolina that day. A motorcyclist had gotten into a horrific crash, the doctor explained. He believed the pigs’ livers, sutured onto the patient’s skin like an external filter, might be able to tide the young man over until a donor liver became available.

UP­DAT­ED: Agenus calls out FDA for play­ing fa­vorites with Mer­ck, pulls cer­vi­cal can­cer BLA at agen­cy's re­quest

While criticizing the FDA for what may be some favoritism towards Merck, Agenus on Friday officially pulled its accelerated BLA for its anti-PD-1 inhibitor balstilimab as a potential second-line treatment for cervical cancer because of the recent full approval for Merck’s Keytruda in the same indication.

The company said the BLA, which was due for an FDA decision by Dec. 16, was withdrawn “when the window for accelerated approval of balstilimab closed,” thanks to the conversion of Keytruda’s accelerated approval to a full approval four months prior to its PDUFA date.

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How to col­lect and sub­mit RWD to win ap­proval for a new drug in­di­ca­tion: FDA spells it out in a long-await­ed guid­ance

Real-world data are messy. There can be differences in the standards used to collect different types of data, differences in terminologies and curation strategies, and even in the way data are exchanged.

While acknowledging this somewhat controlled chaos, the FDA is now explaining how biopharma companies can submit study data derived from real-world data (RWD) sources in applicable regulatory submissions, including new drug indications.

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No­vo CEO Lars Fruer­gaard Jør­gensen on R&D risk, the deal strat­e­gy and tar­gets for gen­der di­ver­si­ty


I kicked off our European R&D summit last week with a conversation involving Novo Nordisk CEO Lars Fruergaard Jørgensen. Novo is aiming to launch a new era of obesity management with a new approval for semaglutide. And Jørgensen had a lot to say about what comes next in R&D, how they manage risk and gender diversity targets at the trendsetting European pharma giant.

John Carroll: I’m here with Lars Jørgensen, the CEO of Novo Nordisk. Lars, it’s been a really interesting year so far with Novo Nordisk, right? You’ve projected a new era of growing sales. You’ve been able to expand on the GLP-1 franchise that was already well established in diabetes now going into obesity. And I think a tremendous number of people are really interested in how that’s working out. You have forecast a growing amount of sales. We don’t know specifically how that might play out. I know a lot of the analysts have different ideas, how those numbers might play out, but that we are in fact embarking on a new era for Novo Nordisk in terms of what the company’s capable of doing and what it’s able to do and what it wants to do. And I wanted to start off by asking you about obesity in particular. Semaglutide has been approved in the United States for obesity. It’s an area of R&D that’s been very troubled for decades. There have been weight loss drugs that have come along. They’ve attracted a lot of attention, but they haven’t actually ever gained traction in the market. My first question is what’s different this time about obesity? What is different about this drug and why do you expect it to work now whereas previous drugs haven’t?

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David Livingston (Credit: Michael Sazel for CeMM)

Renowned Dana-Far­ber sci­en­tist, men­tor and bio­phar­ma ad­vi­sor David Liv­ingston has died

David Livingston, the Dana-Farber/Harvard Med scientist who helped shine a light on some of the key molecular drivers of breast and ovarian cancer, died unexpectedly last Sunday.

One of the senior leaders at Dana-Farber during his nearly half century of work there, Livingston was credited with shedding light on the genes that regulate cell growth, with insights into inherited BRCA1 and BRCA2 mutations that helped lay the scientific foundation for targeted therapies and earlier detection that have transformed the field.

Marty Duvall, Oncopeptides CEO

On­copep­tides stock craters as it pulls can­cer drug Pepax­to from the mar­ket

Shares of Oncopeptides crashed more than 70% in early Friday trading after the company said it’s pulling its multiple myeloma drug Pepaxto (melphalan flufenamide) from the US market after failing a confirmatory trial. The move will force the company to close its US and EU business units and enact significant layoffs.

The FDA had scheduled an adcomm meeting next Thursday to discuss Pepaxto, which first won accelerated approval in February and costs about $19,000 per course of treatment. The committee was to weigh in on whether the confirmatory trial demonstrated a worse overall survival in the treatment arm compared to the control arm.

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Pfiz­er pitch­es its Covid-19 vac­cine for younger chil­dren ahead of ad­comm next week

Pfizer will present its case to the FDA’s vaccine adcomm next week, seeking authorization for a lower-dose version of its Covid-19 vaccine for kids ages 5 through 12, which the Biden administration said will likely begin rolling out early next month.

Two primary doses of the 10 µg vaccine (the dose for those ages 12 and up is 30 μg) given 3 weeks apart in this group of children “have shown a favorable safety and tolerability profile, robust immune responses against all variants of concern including Delta, and vaccine efficacy of 90.7% against laboratory-confirmed symptomatic COVID-19,” the company said in briefing documents ahead of next Tuesday’s meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.