Dun Yang (Anticancer Bioscience)

A syn­thet­ic lethal­i­ty play­er emerges in Chi­na, armed with lessons on un­drug­gable onco­gene from No­bel lau­re­ate's lab

As a long­time post­doc in the UCSF lab of Michael Bish­op — the No­bel lau­re­ate known, among oth­er things, for cloning the onco­gene MYC — Dun Yang knew the can­cer tar­get like an archer knows the bulls­eye.

“I al­ways talk about if we need­ed to nom­i­nate the most im­por­tant onco­gene […] that should be MYC,” he told End­points News. “The sec­ond one would be RAS. Be­cause more than 50% of hu­man can­cer over­ex­press MYC onco­gene.”

All those years of re­search al­so gave him in­ti­mate knowl­edge about the pit­falls of try­ing to de­vel­op can­cer ther­a­pies around the MYC pro­tein. The con­sen­sus had been that MYC, a tran­scrip­tion fac­tor, is un­drug­gable; even if you some­how man­age to hit it, the po­ten­tial ben­e­fit would like­ly be off­set by the po­ten­tial side ef­fects that come with block­ing its es­sen­tial phys­i­o­log­i­cal func­tions.

So in 2010 — just as PARP in­hibitors were gain­ing trac­tion — he and sev­er­al oth­er sci­en­tists in the lab pro­posed some­thing new.

Thad­deus Allen

“A lot of peo­ple have of course heard of (Bish­op),” said Thad­deus Allen, whose tenure as a re­search sci­en­tist at UCSF over­lapped with Yang’s. “But I think what peo­ple don’t re­al­ize is the last 10 to 15 years of re­search that went on in Mike Bish­op’s lab was re­al­ly fo­cused on syn­thet­ic lethal­i­ty and re­al­ly Dun Yang was at the cen­ter of that re­search that was go­ing on.”

In­stead of tar­get­ing MYC di­rect­ly, they tried go­ing af­ter a ki­nase that tu­mors over­ex­press­ing MYC tend to re­ly on, and showed in mice that the com­pound they test­ed could kill can­cer cells while spar­ing nor­mal ones.

Yang would even­tu­al­ly leave San Fran­cis­co to re­turn to his home­town of Cheng­du, Chi­na, to start a can­cer re­search in­sti­tute epony­mous with Bish­op and see if he can go big­ger with that idea.

Now, more than a decade af­ter pub­lish­ing that pa­per, he’s se­cured a to­tal of $21 mil­lion from pri­vate Chi­nese in­vestors to build a com­pa­ny that doesn’t just stand shoul­der to shoul­der with US syn­thet­ic lethal­i­ty play­ers like Re­pare, Ar­tios, Cyteir and Ideaya, but some­day grow up to be the Genen­tech of Chi­na.

An­ti­cancer Bio­science is the de­vel­op­ment and com­mer­cial­iza­tion arm of the J. Michael Bish­op In­sti­tute of Can­cer Re­search, Yang said, and the 50 em­ploy­ees tech­ni­cal­ly work for both en­ti­ties. The team is spread across Chi­na, the US, the UK and In­dia — where the CEO re­cruit­ed his med­i­c­i­nal chemists.

With two drugs, one of them in MYC, poised to com­plete IND-en­abling stud­ies this year and en­ter the clin­ic in 2022, the biotech is busy jug­gling a to­tal of five pre­clin­i­cal pipeline pro­grams, which they say span the ar­eas of tu­mor sup­pres­sor syn­thet­ic lethal­i­ty, poly­ploid cell syn­thet­ic lethal­i­ty, cen­tro­some am­pli­fi­ca­tion/declus­ter­ing ther­a­py and restora­tion of con­tact in­hi­bi­tion.

Jing Zhang

Build­ing nov­el screen­ings — led by VP Jing Zhang in the UK — that ze­ro in on the right vul­ner­a­bil­i­ties that can be tar­get­ed are core to An­ti­cancer’s ex­per­tise, said Allen, the com­pa­ny’s VP of trans­la­tion­al bi­ol­o­gy. In ad­di­tion to screen­ing on syn­thet­ic li­braries, An­ti­cancer is al­so keen on find­ing com­pounds from na­ture li­braries — col­lec­tions of plant sam­ples from a province that Yang said ac­counts for 60% of the plant di­ver­si­ty in the coun­try.

“What’s new about our plat­form is we col­lect­ed from nov­el places,” added Allen, who’s al­so one of on­ly two staffers based in Cal­i­for­nia. “The com­pa­ny is in Cheng­du for a rea­son.”

“We have an un­matched nat­ur­al prod­ucts li­brary,” Yang wrote, “com­posed of over 17,500 crude ex­tracts, over 1,200 par­tial­ly pu­ri­fied frac­tions and around 2,500 pure nat­ur­al com­pounds. These sam­ples are made from over 2,600 plants, rep­re­sent­ing more than 1,500 plant species used in tra­di­tion­al Chi­nese med­i­cine.”

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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Kenneth Galbraith, incoming Zymeworks CEO

Zymeworks re­places half its C-suite, aims to lay off 25% of to­tal work­force as new CEO takes over

New Zymeworks CEO Kenneth Galbraith is aiming to hit the ground running when his tenure officially begins next month, but he’ll be doing so with a much different looking team.

In a lengthy press release outlining the biotech’s 2022 goals, Galbraith said Zymeworks will be laying off at least 25% of its staff over the course of the year. Half of its C-suite will also be replaced immediately as Galbraith looks to remake the company in his image after Ali Tehrani, Zymeworks’ founder and CEO since 2003, stepped down two weeks ago.

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Crit­ics push back on Alzheimer’s As­so­ci­a­tion ad blitz to get Medicare to change its Aduhelm rul­ing: 'Dead wrong'

The latest Alzheimer’s Association advertising campaign encourages people to fight.

Not against the disease or for more research or treatments, but against the Centers for Medicare and Medicaid Services. More specifically, CMS’ recent reimbursement decision to only pay for Biogen and Eisai’s controversial Alzheimer’s drug Aduhelm for patients in clinical trials.

With CMS’ preliminary decision now in a 30-day comment period, patient advocates’ goal is to convince CMS to reverse its decision with a marketing blitz and public pressure.

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Dan O'Day, Gilead CEO (Jim Watson/AFP via Getty Images)

Fail­ing to con­firm clin­i­cal ben­e­fit, Gilead pulls 2 ac­cel­er­at­ed ap­proval in­di­ca­tions for can­cer drug

Gilead recently decided to pull two indications for its cancer drug Zydelig — in relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic leukemia (SLL) — after failing to complete the confirmatory trials required as part of the accelerated approvals from 2014.

“As the treatment landscape for FL and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” Gilead said in a statement, noting it formally notified the FDA of its decision to voluntarily withdraw these indications.

Richard Pazdur (via AACR)

Time lim­its on ac­cel­er­at­ed ap­provals? FDA's on­col­o­gy chief Rick Paz­dur eyes po­ten­tial re­forms via in­ter­na­tion­al ap­proach­es

The spotlight on the accelerated approval pathway continues to shine bright, with the FDA’s top oncology official writing in an opinion that the pathway may be strengthened with bits and pieces of what other regulators in Europe and elsewhere have done with their expedited approval pathways, such as adding expiration dates for these faster approvals to ensure they confirm clinical benefit in a timely manner.

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Covid-19 roundup: HHS may strug­gle to ab­sorb Op­er­a­tion Warp Speed; Eu­rope has no plans for a fourth vac­cine dose

Operation Warp Speed, perhaps the greatest achievement of the former Trump administration, promptly delivered Covid-19 vaccine supplies nationwide when they became available, thanks to collaborations between HHS and the Department of Defense, while helping to fund and aid the manufacture of billions of doses.

But since the Biden administration took over a year ago, acting FDA commissioner Janet Woodcock transitioned out of her role as the therapeutics lead in Warp Speed, which has been converted into a new operation without the fancy name (now known as the “HHS-DOD COVID-19 Countermeasures Acceleration Group”), and as of the start of 2022, the Department of Defense is no longer helping HHS on the program.

Flori­da man con­vict­ed of fal­si­fy­ing clin­i­cal tri­al re­sults sen­tenced to over 2 years in prison

A Florida man who falsified medical records in connection to clinical trials was sentenced to 30 months in prison in federal court Thursday.

Daniel Tejeda, 35, of Clewiston, was also ordered to pay $2.1 million in restitution. Tejeda was a project manager and study manager for the CRO Tellus Clinical Research, and made it appear that subjects were participating in trials when they weren’t. Two other research workers from Florida were sentenced in the same case in August for 46 and 30 months, respectively.