Anthony Sun, Zentalis CEO (Zentalis)

AACR21: Zen­tal­is keeps the heat on As­traZeneca with ear­ly WEE1 da­ta show­ing a group of 'ex­cep­tion­al' re­spon­ders

Long a tar­get for drug­mak­ers, the DNA dam­age re­pair path­way has picked up some new steam in re­cent years with Big Phar­ma plac­ing its bets. One of the lead­ing can­di­dates there is a WEE1 en­zyme in­hibitor from As­traZeneca, and now a small biotech play­er is look­ing to play catch up.

Zen­tal­is’ WEE1 in­hibitor, ZN-c3, post­ed par­tial re­spons­es across a slate of tu­mor types with a tol­er­a­ble safe­ty pro­file as monother­a­py for sol­id tu­mor pa­tients who are ei­ther treat­ment-re­sis­tant or have no es­tab­lished stan­dard of care, ac­cord­ing to in­ter­im Phase I da­ta pre­sent­ed as a late break­er Sat­ur­day at the vir­tu­al AACR an­nu­al meet­ing.

In what the Zen­tal­is team hopes will be a mean­ing­ful com­peti­tor to As­traZeneca’s own WEE1 in­hibitor, ZN-c3 post­ed three “ex­cep­tion­al re­spons­es” among 55 pa­tients by the Feb. 12 da­ta cut­off, in­clud­ing in pa­tients with a long his­to­ry of pri­or ther­a­py and across tu­mor types. Ex­cep­tion­al re­spon­ders are pa­tients who post a com­plete or par­tial re­sponse where less than 10% of the pa­tient pop­u­la­tion is ex­pect­ed to show re­sults.

In one case, a Stage IV ovar­i­an can­cer pa­tient with 18 pri­or lines of ther­a­py — 11 of those in the metasta­t­ic set­ting — post­ed a 56% re­duc­tion in tar­get le­sions with a key bio­mark­er show­ing rapid on­set at the four-week mark of ther­a­py. Re­searchers al­so saw par­tial re­spons­es in pa­tients with col­orec­tal can­cer and non-small cell lung can­cer and two non-ex­cep­tion­al par­tial re­spons­es in uter­ine serous car­ci­no­ma.

It’s ear­ly days, but Zen­tal­is has enough to go on to move along in­to the Phase II por­tion of the monother­a­py study with an op­ti­mal dose — 300 mg — that the biotech says can min­i­mize side ef­fects while show­ing PD bio­mark­er ac­tiv­i­ty.

The monother­a­py study — which CEO An­tho­ny Sun said showed “re­mark­able safe­ty and tol­er­a­bil­i­ty” — is part of a broad clin­i­cal pro­gram for ZN-c3, one of a class of WEE1 in­hibitors that tar­gets tu­mor cells’ DNA dam­age re­pair path­way. Giv­en its aim to pre­vent cell re­pair caused by oth­er agents, WEE1s are a nat­ur­al tar­get for com­bi­na­tion ther­a­py, and Zen­tal­is is cur­rent­ly work­ing on a ZN-c3/chemo com­bo tri­al as well as planned stud­ies in com­bi­na­tion with PARP in­hibitors, which al­so tar­get the DDR path­way.

But Zen­tal­is is al­so keep­ing its eye on As­traZeneca’s WEE1, AZD1775, which has shown OS ben­e­fit in pan­cre­at­ic can­cer pa­tients and is be­ing en­vi­sioned as a suc­ces­sor drug to PARP in­hibitor Lyn­parza. Back in Au­gust 2019, the drug spurred an OS of 22 months with pro­gres­sion-free sur­vival of 9 months in a small-scale study of 32 pan­cre­at­ic can­cer pa­tients.

Zen­tal­is thinks ZN-c3 could even­tu­al­ly best AZD1775 with a bet­ter safe­ty pro­file, which Sun said was the re­sult of the mol­e­cule be­ing more se­lec­tive with bet­ter phar­ma­co­ki­net­ic qual­i­ties. The biotech is al­so in the process of de­vel­op­ing what it calls nov­el bio­mark­ers to help iden­ti­fy sol­id tu­mor pa­tients who could best ben­e­fit from ZN-c3’s use.

Ed­i­tor’s Note: This sto­ry has been up­dat­ed to cor­rect an er­ror. Zen­tal­is record­ed three ex­cep­tion­al tu­mor re­spons­es in the Phase I da­ta. 

The DCT-OS: A Tech­nol­o­gy-first Op­er­at­ing Sys­tem - En­abling Clin­i­cal Tri­als

As technology-enabled clinical research becomes the new normal, an integrated decentralized clinical trial operating system can ensure quality, deliver consistency and improve the patient experience.

The increasing availability of COVID-19 vaccines has many of us looking forward to a time when everyday things return to a state of normal. Schools and teachers are returning to classrooms, offices and small businesses are reopening, and there’s a palpable sense of optimism that the often-awkward adjustments we’ve all made personally and professionally in the last year are behind us, never to return. In the world of clinical research, however, some pandemic-necessitated adjustments are proving to be more than emergency stopgap measures to ensure trial continuity — and numerous decentralized clinical trial (DCT) tools and methodologies employed within the last year are likely here to stay as part of biopharma’s new normal.

'Chang­ing the whole game of drug dis­cov­ery': Leg­endary R&D vet Roger Perl­mut­ter leaps back in­to work as a biotech CEO

Roger Perlmutter needs no introduction to anyone remotely involved in biopharma. As the R&D chief first at Amgen and then Merck, he’s built a stellar reputation and a prolific career steering new drugs toward the market for everything from cancer to infectious diseases.

But for years, he’s also held a less known title: science partner at The Column Group, where he’s regularly consulted about the various ideas the VCs had for new startups.

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UP­DAT­ED: Pfiz­er hits the brakes on their piv­otal tri­al for a BC­MA/CD3 bis­pe­cif­ic on safe­ty con­cerns while FDA road­block is hold­ing up Duchenne MD PhI­II

Pfizer’s ambitious plan to take a Phase II study of its BCMA CD3-targeted bispecific antibody elranatamab (PF-06863135) and run it through to an accelerated approval has derailed.

The pharma giant said in a release this morning that they have halted enrollment for their MagnetisMM-3 study after researchers tracked three cases of peripheral neuropathy in the ongoing Phase I. They are now sharing info with the FDA as they explore the red safety flag.

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Stéphane Bancel at the Endpoints #JPM20 breakfast panel in San Francisco, January 2020 (Photo: Jeff Rumans, Endpoints News)

Mod­er­na says Covid-19 vac­cine boost­er in­creased im­mune re­sponse against vari­ants of con­cern

About a month after announcing their variant-specific Covid-19 vaccine boosters showed promising results in mice, Moderna says it now has some human data to back it up.

Volunteers given a booster shot about six to eight months after receiving their second dose saw increased antibody levels against SARS-CoV-2 and two variants of concern: B.1.351, which was first identified in South Africa, and P.1, first identified in Brazil, the company said on Wednesday.

FDA ex­tends re­search agree­ment with MIT-li­censed or­gan-on-chip sys­tems

The FDA on Wednesday extended its four-year agreement with CN Bio, a developer of single- and multi-organ-on-chip systems used for drug discovery, for another three years.

CN Bio said the scope of the research performed by the FDA’s Center for Drug Evaluation and Research has expanded to include the exploration of the company’s lung-on-a-chip system to help with the agency’s evaluation of inhaled drugs, in addition to the agency’s work on its liver model.

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In quest to meet user fee goals, FDA’s per­for­mance con­tin­ues down­ward trend

A recent update to the FDA’s running tally of how it’s meeting its user fee-related performance goals during the pandemic shows an agency that is not out of the woods yet.

The latest numbers reveal that for a second straight quarter in 2021, the FDA has met its user fee goal dates for 93% of original new drug applications, which compares with 94% and 98% for the previous two quarters in 2020, respectively.

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Cynthia Butitta (L) and Joe Jimenez

Is that an­oth­er IPO in the mak­ing? Ex-No­var­tis CEO Joe Jimenez and a lead Kite play­er take up new posts at an off-the-shelf ri­val to 2 pi­o­neer­ing drugs

Right on the heels of taking on a $160 million crossover round in a likely leap to Nasdaq, Century Therapeutics CEO Lalo Flores is now pushing ahead with the high-profile ex-Novartis chief Joe Jimenez as chairman.

Jimenez’s greatest fame at Novartis was earned for one of its weakest products, as their pioneering personalized CAR-T Kymriah won the honors for the first such drug to make it to the market. Now a host of players, including Century, are barreling in behind the frontrunners with allogeneic rivals that can be created for off-the-shelf use.

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Joe Wiley, Amryt CEO

A biotech with a yen for pricey rare dis­ease drugs — and bar­gain base­ment shop­ping — adopts an­oth­er or­phan in lat­est M&A pact

After making it through a long, painful haul to get past a CRL and on to an FDA approval last summer, little Chiasma has found a buyer.

Amryt $AMYT, a company known for its appetite for acquiring expensive drugs for rare diseases at bargain prices, snagged Chiasma and its acromegaly drug Mycapssa (octreotide) capsules in an all-stock deal — with an exchange of 0.396 shares of Amryt for every share of Chiasma.

Ngozi Okonjo-Iweala, Director general of WTO (AP Photo/Keystone/Alessandro Della Bella)

Opin­ion: Waiv­ing Covid-19 vac­cine IP could save lives, but where is the man­u­fac­tur­ing ca­pac­i­ty?

Droves of House Democrats in Washington and members of the European Parliament have now glommed onto a major push by India and South Africa at the WTO to abolish all IP around Covid-19 vaccines.

At first blush, waiving this IP sounds like an easy win: More Covid-19 vaccines made locally for more people means more lives saved. Simple enough, especially as low-income countries have received just a tiny fraction of the world’s vaccine allotment so far.