Can a lit­tle known drug in As­traZeneca's pipeline make a come­back as a PARP add-on? Yale sci­en­tists ex­plain how

As­traZeneca’s cedi­ranib may not have made the cut as a sin­gle agent to treat ovar­i­an can­cer, but Yale re­searchers think it could serve as a pow­er­ful add-on to am­pli­fy the ef­fects of PARP in­hibitors.

Pe­ter Glaz­er

The the­o­ry has been that cedi­ranib works by block­ing the for­ma­tion of new blood ves­sels, thus de­priv­ing tu­mors of the nu­tri­tion and oxy­gen nec­es­sary to live and grow. But in a mouse tri­al, a team out of Pe­ter Glaz­er’s lab found that the drug al­so di­rect­ly af­fects path­ways in­volved in DNA re­pair — a po­ten­tial­ly more use­ful func­tion.

The sci­en­tists set out to ex­plain some un­ex­pect­ed re­sults from a re­cent Phase II study, in which a com­bi­na­tion of cedi­ranib with Lyn­parza (ola­parib) im­proved pro­gres­sion-free sur­vival com­pared to Lyn­parza alone (16.5 ver­sus 8.2 months, haz­ard ra­tio 0.50; p = 0.007) in pa­tients with re­lapsed plat­inum-sen­si­tive ovar­i­an can­cer. More im­por­tant­ly, a sub­set of pa­tients in the tri­al with­out doc­u­ment­ed BR­CA1/2 mu­ta­tions demon­strat­ed su­pe­ri­or PFS as well as over­all sur­vival. That’s sur­pris­ing giv­en that a BR­CA mu­ta­tion is of­ten seen as a pre­req­ui­site for As­traZeneca and Mer­ck’s star PARP in­hibitor to work.

Alan­na Ka­plan

Af­ter ex­plor­ing the phe­nom­e­na in mice and cell cul­ture, Glaz­er and his team — in­clud­ing lead in­ves­ti­ga­tor Alan­na Ka­plan — con­clud­ed that cedi­ranib has a di­rect ef­fect on ho­mol­o­gy-di­rect­ed re­pair, a mech­a­nism that can­cer cells can ma­nip­u­late. The down-reg­u­la­tion, they write in Sci­ence Trans­la­tion­al Med­i­cine, hap­pens on­ly in tu­mors but not bone mar­row cells, which has tra­di­tion­al­ly been the dose-lim­it­ing fac­tor for PARP drugs.

“Un­like ola­parib, it doesn’t di­rect­ly block a DNA re­pair mol­e­cule, stop­ping DNA from stitch­ing it­self back to­geth­er. It af­fects the reg­u­la­tion by which DNA re­pair genes are ex­pressed,” Glaz­er added in a state­ment.

More specif­i­cal­ly, cedi­ranib does so through platelet-de­rived growth fac­tor re­cep­tor (PDGFR) in­hi­bi­tion, ac­ti­va­tion of pro­tein phos­phatase 2A (PP2A), and E2F tran­scrip­tion fac­tor 4 (E2F4)/RB tran­scrip­tion­al core­pres­sor like 2 (RB2/p130)–me­di­at­ed re­pres­sion of BR­CA1/2 and RAD51 gene ex­pres­sion.

The ef­fects are not lim­it­ed to Lyn­parza, ei­ther; cedi­ranib al­so sen­si­tized cells to an­oth­er PARP in­hibitor de­vel­oped by Pfiz­er, BMN673 (ta­la­zoparib).

Back in 2016 As­traZeneca pulled an EMA ap­pli­ca­tion for cedi­ranib and axed a monother­a­py pro­gram for the drug. Its web­site now lists a Lyn­parza/cedi­ranib com­bo as a project in a piv­otal phase, with a US fil­ing in ovar­i­an can­cer planned for 2020.

The Yale re­searchers will move on to in­ves­ti­gate whether this new­found syn­thet­ic lethal­i­ty — the idea of killing can­cer cells more ef­fec­tive­ly by tar­get­ing two genes at the same time — in oth­er can­cer types.


Im­age Source: Shut­ter­stock

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; 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.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

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Mi­rati's KRAS drug looks like the fa­vorite in colon can­cer with new da­ta, putting the pres­sure square on Am­gen

With Amgen already providing proof-of-concept for KRAS inhibitors with its sotorasib, Mirati Therapeutics is piecing together a follow-up effort in lung cancer with data it thinks are superior. But in colon cancer, where solo sotorasib has turned in a dud, Mirati may now have a strong case for superiority.

Mirati’s adagrasib, dosed solo or in combination with chemotherapy cetuximab, showed response rates grater than sotorasib solo  and as part of combination study in a similar patient population also revealed this week at #ESMO21. Mirati’s data were presented as part of a cohort update from the Phase II KRYSTAL-1 study testing adagrasib in a range of solid tumors harboring the KRAS-G12C mutation.

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President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

The best of the rest: High­lights from the be­low-the-fold pre­sen­ta­tions at #ES­MO21

This year’s ESMO Congress has had a major focus on Big Pharma drugs — most notably candidates from Merck and AstraZeneca — but there have also been updates from smaller biotechs with data looking to challenge the big-name drugmakers.

Today, we’re highlighting some of the data releases that flew under the radar at #ESMO21 — whether from early-stage drugs looking to make a mark or older stalwarts with interesting follow-up data.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

Multiple antibiotic resistant Pseudomonas aeruginosa bacterium

A new way to in­fil­trate (and de­stroy) some of the dead­liest drug-re­sis­tant bugs

About four years ago, Ruben Tommasi, the gregarious scientific chief of antibiotics startup Entasis, walked into a meeting with his top chemist and top biologist to chew over another batch of unchanging results.

“It felt like we were running the same experiment over and over,” Tommasi told Endpoints News. “We had all sort of come to that point in time where we felt like we were banging our heads against the wall.”

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