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.

Big Phar­ma's Twit­ter ex­o­dus; Mer­ck wa­gers $1.35B on buy­out; $3.5M gene ther­a­py; and more

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Paul Perreault, CSL Behring CEO

CSL lands FDA ap­proval for he­mo­phil­ia B gene ther­a­py, sets $3.5M list price

The FDA has approved the world’s first gene therapy for hemophilia B, ushering into the market a treatment that’s historic in both what it promises to do and how much it will cost.

CSL will be marketing the drug, Hemgenix, at a list price of $3.5 million — which sets a new record for the most expensive single-use gene therapy in the US.

In a statement provided to Endpoints News, the Australian company noted that the current costs of treating people with moderate to severe hemophilia B can be significant over a lifetime. By some estimates, healthcare systems could spend more than $20 million per person.

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Image: Shutterstock

MIT re­searchers re­veal DNA "Paste" tech be­hind lat­est gene edit­ing start­up

MIT scientists have developed a tool that they say can insert large gene sequences where they want in the genome.

In a paper published Thursday in Nature Biotechnology, MIT fellows Omar Abudayyeh, Jonathan Gootenberg and colleagues detail a technology they call PASTE, which they say can potentially be used to insert long strands of DNA and treat genetic diseases caused by many different mutations, such as cystic fibrosis and Leber congenital amaurosis, a rare eye disorder that causes blindness.

Elon Musk (GDA via AP Images)

Biggest drug com­pa­nies halt­ed Twit­ter ad buys af­ter Lil­ly in­sulin spoof

Almost all of the drug industry’s biggest advertisers cut their spending on Twitter to zero or near-zero over the last two weeks amid worries about impersonation of their brands by pranksters and the future of the social media company.

Among 18 of the biggest pharmaceutical advertisers in the US market, 12 cut their Twitter ad spending to nothing for the week beginning Nov. 14, according to Pathmatics, which tracks data on prescription drug ad spending as well as general corporate advertising. The list of drugmakers cutting spending to zero includes Merck, AstraZeneca, Eli Lilly, Novartis, Pfizer and others.

Rob Davis, Merck CEO

Up­dat­ed: No Seagen here: 'Do more' means a small $1.35B pur­chase of Ima­go for Mer­ck

Merck is making an acquisition, the Big Pharma announced before Monday’s opening bell. No, Seagen is not entering the fold, as had been speculated for quarters.

Folding under Merck’s wings will be Pfizer-backed Imago BioSciences. For nearly a year, Merck CEO Rob Davis has been saying the pharma giant needs to “do more” on the business development front after its 2021 $11.5 billion acquisition of Acceleron.

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J&J's Spra­va­to pulls a PhI­II win against Sero­quel XR in treat­ment-re­sis­tant de­pres­sion

A day before Thanksgiving, J&J’s Janssen has a new cut of Phase III Spravato data to be grateful for.

The pharma giant announced on Wednesday that its nasal spray, also known as esketamine, beat extended-release quetiapine, previously sold by AstraZeneca as Seroquel XR, in treatment-resistant depression (TRD). Of 676 adults, a significantly higher number of patients on Spravato were able to achieve remission and avoid relapse after 32 weeks, according to J&J.

Isao Teshirogi, Shionogi president and CEO (Kyodo via AP Images)

Sh­ionogi's Covid an­tivi­ral lands first ap­proval in Japan's new emer­gency ap­proval path­way

Japanese regulators on Tuesday signed off on Shionogi’s homegrown antiviral for Covid-19, known as Xocova (ensitrelvir), making it the first approval under Japan’s emergency regulatory approval system.

The emergency approval, following a back-and-forth with regulators since last February, is based on a safety profile with more than 2,000 patients who have accessed the pill, and clinical symptomatic efficacy for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in patients with mild to moderate SARS-CoV-2 infection, regardless of risk factors or vaccination status, and during the Omicron-dominant phase of the pandemic.

Karen Aiach, Lysogene CEO (RE(ACT) Discovery Institute)

Gene ther­a­py flunks PhII/III study, but for­mer Sarep­ta part­ner sees a path for­ward — if it can find the cash

The development path for Lysogene’s gene therapy for MPS IIIA has been a rocky one. After the FDA slapped a partial clinical hold on a Phase II/III study, a patient already dosed in the trial died, although it was deemed unrelated to treatment. Then earlier this year, Sarepta pulled out of their three-year partnership due to disagreements on who will handle commercial supply.

And now, Lysogene reported the trial has failed its primary endpoint.

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Dermavant Sciences' first consumer TV ad for its Vtama psoriasis med shows people ready for a new topical treatment.

Roivant’s Der­ma­vant de­buts first-ever TV com­mer­cial for pso­ri­a­sis cream Vta­ma

Dermavant Sciences has been marketing its first product, psoriasis med Vtama, to dermatologists for months, but on Tuesday it rolled out its first consumer campaign. The debut DTC effort including a streaming TV commercial encourages patients to a “Topical Uprising” in a nod to Vtama being a topical cream.

In the new commercial, a swell of people discards scarves and jacket coverings, gathering in the street to converge on a pharmacy to demand a steroid-free prescription. A moment of levity follows when a pharmacist says, “You know you can just talk to your doctor, right?” The gathered crowds collectively says, “Oh.”

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