Left to right: Kingson Lin, Kevin Rakin, Seth Herzon and Ranjit Bindra

By ex­ploit­ing the DNA re­pair sys­tem, Yale sci­en­tists want to crack chemother­a­py re­sis­tant brain can­cer

In 2005, Roger Stupp pub­lished an ar­ti­cle in NE­JM, show­ing that adding temo­zolo­mide to ra­dio­ther­a­py ex­tend­ed brain can­cer pa­tients’ sur­vival time by 2 months. For a can­cer in which me­di­an sur­vival was usu­al­ly less than a year, that was prac­tice-chang­ing.

Temo­zolo­mide would be added to the first line of chemother­a­pies for glioma pa­tients, and its use along­side ra­di­a­tion would be termed “The Stupp Pro­to­col.”

How­ev­er, a large num­ber of pa­tients were un­re­spon­sive to TMZ, and many who were re­spon­sive would go on to de­vel­op re­sis­tance to TMZ.

In a new study pub­lished in Sci­ence, Yale sci­en­tists de­scribe an al­ter­na­tive drug to TMZ that may over­come that re­sis­tance prob­lem. Led by Seth Her­zon and Ran­jit Bindra, they looked specif­i­cal­ly at glioblas­toma cells that are MGMT-de­fi­cient — a bio­mark­er for cells that would re­spond bet­ter to TMZ ini­tial­ly, but de­vel­op re­sis­tance lat­er on.

MGMT is a DNA re­pair pro­tein. It works via a “sui­cide” mech­a­nism, in which it takes away a methyl group from the dam­aged DNA, there­by fix­ing it, but in­ac­ti­vates it­self as a re­sult. On the oth­er hand, once in the body, TMZ breaks down to be­come an alky­lat­ing agent, which means it adds alkyl groups (of which the sim­plest is a methyl group) to the DNA, there­by dam­ag­ing the DNA.

(Last year, sci­en­tists dis­cov­ered that TMZ, once thought to be ex­ceed­ing­ly sta­ble, is al­so high­ly ex­plo­sive, ap­par­ent­ly. It’s ten­ta­tive­ly clas­si­fied as a Class 1 ex­plo­sive, putting it in the same zone as dy­na­mite.)

In healthy cells where MGMT works as it should, af­ter TMZ is added, the cells’ DNA re­pair sys­tems read­i­ly cor­rect the DNA le­sions. But in MGMT-de­fi­cient tu­mors, those le­sions build up, which trig­gers the cell’s mis­match re­pair sys­tem. The MMR sys­tem rec­og­nizes the DNA is dam­aged, and caus­es the tu­mor cells to die.

How­ev­er, the prob­lem is that even­tu­al­ly mu­ta­tions pop up in the MMR path­way it­self, and the tu­mor re­curs.

So Her­zon and Bindra con­ceived an ap­proach that would, like TMZ, dam­age the DNA in glioma cells, but do away with the re­sis­tance once mu­ta­tions hap­pen in the MMR path­way. In their pa­per, they de­scribe one can­di­date, KL-50, which is what’s known as an in­ter­strand crosslink­ing (ICL) agent. Es­sen­tial­ly, it slow­ly cre­ates a link be­tween the two strands of DNA — slow enough that healthy cells can re­verse it. But in can­cer cells, the link proves to be tox­ic and caus­es the cell to die.

Her­zon not­ed that ICL agents “in and of it­self [are] not a nov­el find­ing — those types of mol­e­cules are well known in the lit­er­a­ture, and have been used un­suc­cess­ful­ly for decades in the clin­ic. What’s unique about our com­pound is that it is, in essence, a cell lines-spe­cif­ic crosslink­ing agent, so it on­ly forms these in­ter­strand crosslinks in an MGMT-de­fi­cient back­ground.”

But to healthy cells, “the mol­e­cule is es­sen­tial­ly in­vis­i­ble,” Her­zon said.

In ad­di­tion, by us­ing the ICL mech­a­nism, the drug isn’t de­pen­dent on the cell’s MMR sys­tem.

“We de­signed it in a way so that it would be im­per­vi­ous to re­sis­tance mu­ta­tions that are com­mon with glioma. One of those is mu­ta­tions in mis­match re­pair. With temo­zolo­mide, mis­match re­pair mu­ta­tions ren­der the drug com­plete­ly in­ac­tive,” Bindra said. “But we specif­i­cal­ly made these DNA mod­i­fiers in a way that they’re im­per­vi­ous to that mu­ta­tion. But they’re still de­pen­dent on the loss of MGMT, so they still have that ther­a­peu­tic in­dex.”

“It’s re­al­ly a new way to ap­proach tu­mor cell re­sis­tance, and al­so again, to ex­ploit the DNA re­pair de­fects,” Bindra said.

Roger Red­del

How­ev­er, for gliomas, which have his­tor­i­cal­ly been dif­fi­cult to treat, the ju­ry re­mains out on whether such a drug will work. “The new treat­ment looks very good in pre­clin­i­cal stud­ies, es­pe­cial­ly with re­gard to over­com­ing the most com­mon mech­a­nism of re­sis­tance to TMZ, but clin­i­cal tri­als will be re­quired to de­ter­mine whether it is bet­ter,” Roger Red­del of the Uni­ver­si­ty of Syd­ney told End­points News in an email.

“GBM is a dif­fi­cult tu­mor for many rea­sons in­clud­ing the way it in­fil­trates sur­round­ing brain tis­sue which means it is dif­fi­cult to re­move com­plete­ly by surgery, and the ex­ten­sive het­ero­gene­ity with­in in­di­vid­ual tu­mors and be­tween tu­mors of the same type. The new ap­proach does not specif­i­cal­ly ad­dress any of these is­sues, but has the po­ten­tial ad­van­tage that it seeks to im­prove one of the few treat­ments that has proven ef­fec­tive,” Red­del, who wrote an ac­com­pa­ny­ing ed­i­to­r­i­al on the study in Sci­ence, not­ed.

Bindra and Her­zon, along with co-au­thor King­son Lin, have spun their dis­cov­ery in­to Mod­i­fi Bio, which they launched from stealth to­day.

“As a physi­cian sci­en­tist [who has] ded­i­cat­ed my clin­i­cal ca­reer and the last 10 years treat­ing adult and pe­di­atric brain tu­mors, I think there’s a lot of room to move on bio­mark­er-di­rect­ed ther­a­pies, that have re­al­ly been rig­or­ous­ly val­i­dat­ed in vit­ro and in vi­vo to set them up for the great­est chance of suc­cess in the clin­ic,” Bindra, who di­rects Yale’s brain tu­mor cen­ter, said.

“We’ve seen so many fail­ures — they say GBM is a grave­yard for ther­a­peu­tics, but I say, if you bring dead drugs to the grave­yard, they’re not go­ing to sud­den­ly live,” Bindra said.

Their biotech, Mod­i­fi Bio, starts with $6.4 mil­lion in seed fund­ing, which it says will sup­port IND-en­abling stud­ies and en­able it to build out the plat­form that dis­cov­ered KL-50, which Bindra terms a ‘DNA mod­i­fi­er.’

No­tably, Roger Stupp al­so sits on Mod­i­fi’s ad­vi­so­ry board. Mod­i­fi, de­rived from the Span­ish word ‘mod­i­fi­ca­do’, hopes to be in Phase I tri­als by 2024, it said.

“The new ap­proach is al­so note­wor­thy be­cause the drug de­sign prin­ci­ple it us­es could be ex­tend­ed to oth­er tu­mor types with dif­fer­ent DNA re­pair de­fi­cien­cies,” Red­del al­so not­ed.

Durham-based Chimerix is an­oth­er biotech tak­ing the bio­mark­er-based ap­proach to gliomas. It bought On­co­ceu­tics last year, and is test­ing its can­di­date in re­cur­rent gliomas with an H3 K27M mu­ta­tion.

MedTech clinical trials require a unique regulatory and study design approach and so engaging a highly experienced CRO to ensure compliance and accurate data across all stages is critical to development milestones.

In­no­v­a­tive MedTech De­mands Spe­cial­ist Clin­i­cal Tri­al Reg­u­la­to­ry Af­fairs and De­sign

Avance Clinical is the Australian CRO for international biotechs providing world-class clinical research services with FDA-accepted data across all phases. With Avance Clinical, biotech companies can leverage Australia’s supportive clinical trials environment which includes no IND requirement plus a 43.5% Government incentive rebate on clinical spend. The CRO has been delivering clinical drug development services for international biotechs for FDA and EMA regulatory approval for the past 24 years. The company has been recognized for the past two consecutive years with the prestigious Frost & Sullivan CRO Best Practices Award and a finalist in Informa Pharma’s Best CRO award for 2022.

Ted Love, Global Blood Therapeutics CEO

Up­dat­ed: Pfiz­er scoops up Glob­al Blood Ther­a­peu­tics and its sick­le cell ther­a­pies for $5.4B

Pfizer is dropping $5.4 billion to acquire Global Blood Therapeutics.

Just ahead of the weekend, word got out that Pfizer was close to clinching a $5 billion buyout — albeit with other potential buyers still at the table. The pharma giant, flush with cash from Covid-19 vaccine sales, apparently got out on top.

The deal immediately swells Pfizer’s previously tiny sickle cell disease portfolio from just a Phase I program to one with an approved drug, Oxbryta, plus a whole pipeline that, if all approved, the company believes could make for a $3 billion franchise at peak.

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BREAK­ING: Math­ai Mam­men makes an abrupt ex­it as head of the big R&D group at J&J

In an after-the-bell shocker, J&J announced Monday evening that Mathai Mammen has abruptly exited J&J as head of its top-10 R&D group.

Recruited from Merck 5 years ago, where the soft spoken Mammen was being groomed as the successor to Roger Perlmutter, he had been one of the top-paid R&D chiefs in biopharma. His group spent $12 billion last year on drug development, putting it in the top 5 in the industry.

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Steve Paul, Karuna Therapeutics CEO (Third Rock)

Karuna's schiz­o­phre­nia drug pass­es a close­ly-watched PhI­II test, will head to FDA in mid-2023

An investigational pill that combines a former Eli Lilly CNS compound with an overactive bladder drug was better than placebo at reducing a scale of symptoms experienced by patients with schizophrenia in a Phase III trial.

Karuna Therapeutics’ drug passed the primary goal in EMERGENT-2, the Boston biotech said early Monday morning, alongside quarterly earnings. The study is the first of Karuna’s four Phase III clinical trials to read out in schizophrenia and will provide the backbone to the biotech’s first drug approval application, slated for mid-2023.

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No­vavax shares shred­ded as Covid vac­cine sales fall more than 90% in Q2

Months after Novavax celebrated its first profitable quarter as a commercial company, the Gaithersburg, MD-based company is back in the red.

Sales for Novavax’s Covid-19 vaccine slipped to $55 million last quarter, down from $586 million in Q1, CEO Stanley Erck revealed on Monday after market close. The company’s stock $NVAX plummeted more than 32% in after-hours trading.

Upon kicking off the call with analysts and investors, Erck addressed the elephant in the room:

Uğur Şahin, BioNTech CEO (Kay Nietfeld/picture-alliance/dpa/AP Images)

De­spite falling Covid-19 sales, BioN­Tech main­tains '22 sales guid­ance

While Pfizer raked in almost $28 billion last quarter, its Covid-19 vaccine partner BioNTech reported a rise in total dose orders but a drop in sales.

The German biotech reported over $3.2 billion in revenue in Q2 on Monday, down from more than $6.7 billion in Q1, in part due to falling Covid sales. While management said last quarter that they anticipated a Covid sales drop — CEO Uğur Şahin said at the time that “the pandemic situation is still very much uncertain” — Q2 sales still missed consensus by 14%.

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FDA commissioner Rob Califf (Tom Williams/CQ Roll Call via AP Images)

With drug pric­ing al­most done, Con­gress looks to wrap up FDA user fee leg­is­la­tion

The Senate won’t return from its summer recess until Sept. 6, but when it does, it officially has 18 business days to finalize the reauthorization of the FDA user fee programs for the next 5 years, or else thousands of drug and biologics reviewers will be laid off and PDUFA dates will vanish in the interim.

FDA commissioner Rob Califf recently sent agency staff a memo explaining how, “Our latest estimates are that we have carryover for PDUFA [Prescription Drug User Fee Act], the user fee funding program that will run out of funding first, to cover only about 5 weeks into the next fiscal year.”

Pascal Soriot, AstraZeneca CEO (David Zorrakino/Europa Press via AP Images)

As­traZeneca and Dai­ichi Sankyo sprint to mar­ket af­ter FDA clears En­her­tu in just two weeks

Regulators didn’t keep AstraZeneca and Daiichi Sankyo waiting long at all for their latest Enhertu approval.

The partners pulled a win on Friday in HER2-low breast cancer patients who’ve already failed on chemotherapy, less than two weeks after its supplemental BLA was accepted. While this isn’t the FDA’s fastest approval — Bristol Myers Squibb won an OK for its blockbuster checkpoint inhibitor Opdivo in just five days back in March — it comes well ahead of Enhertu’s original Q4 PDUFA date.

David Reese, Amgen R&D chief

UP­DAT­ED: In a fresh dis­ap­point­ment, Am­gen spot­lights a ma­jor safe­ty is­sue with KRAS com­bo

Amgen had hoped that its latest study matching its landmark KRAS G12C drug Lumakras with checkpoint inhibitors would open up its treatment horizons and expand its commercial potential. Instead, the combo spurred safety issues that blunted efficacy and forced the pharma giant to alter course on its treatment strategy, once again disappointing analysts who have been tracking the drug’s faltering sales and limited therapeutic reach.

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