Lee Kraus, UT Southwestern

PARP in­hibitors some­times work be­yond BR­CA-mu­ta­tions, re­searchers may fi­nal­ly know why

A class of po­tent can­cer treat­ments could shine brighter than pre­vi­ous­ly thought in a broad­er ar­ray of pa­tients, new re­search sug­gests.

PARP in­hibitors, in­clud­ing As­traZeneca’s $AZN pi­o­neer­ing Lyn­parza, Clo­vis’ $CLVS Rubra­ca and GSK’s $GSK Ze­ju­la — work by thwart­ing PARP pro­teins that help re­pair dam­aged DNA in cell — there­by steer­ing can­cer cells on­to a path of an­ni­hi­la­tion. So far, their use has pri­mar­i­ly been in ovar­i­an can­cers con­tain­ing BR­CA mu­ta­tions, rare ge­net­ic mu­ta­tions that dis­able a DNA re­pair path­way in can­cer cells, as well as BR­CA-mu­tat­ed breast can­cer. (Al­though last month, Ze­ju­la was grant­ed pri­or­i­ty re­view to ex­pand its use in late-stage ovar­i­an can­cer pa­tients with or with­out BR­CA mu­ta­tions).

While the as­sault on DNA re­pair is be­ing waged, these drugs are al­so at­tack­ing ri­bo­somes — the ma­chin­ery that makes pro­teins, said Lee Kraus, di­rec­tor of the Green Cen­ter for Re­pro­duc­tive Bi­ol­o­gy Sci­ences at UT South­west­ern. “These find­ings could in­crease the pa­tient pop­u­la­tion ben­e­fit­ing from these drugs by two, three, or four-fold. Up to 70 per­cent of breast can­cer pa­tients could now be good can­di­dates.”

The da­ta, pub­lished in the jour­nal Mol­e­c­u­lar Cell on Wednes­day, could ex­plain why breast can­cer pa­tients can be re­spon­sive to PARP in­hibitors, de­spite not car­ry­ing BR­CA mu­ta­tions.

Kraus and his team iden­ti­fied a po­ten­tial bio­mark­er — a pro­tein called DDX21, which is re­quired for the pro­duc­tion of ri­bo­somes in small sub­cel­lu­lar com­part­ments called nu­cle­oli. But DDX21 in the nu­cle­o­lus re­quires PARP-1, which is tar­get­ed by ex­ist­ing PARP in­hibitors. The use of these drugs, there­fore, blocks DDX21, there­by in­hibit­ing ri­bo­some pro­duc­tion. This means en­hanced DDX21 lev­els in the nu­cle­o­lus could in­di­cate can­cers that might be the most re­spon­sive to PARP in­hibitors, the re­searchers posit­ed.

“Can­cer cells are ad­dict­ed to ri­bo­somes. Can­cer cells grow fast and must make pro­teins to sup­port cell di­vi­sion and oth­er es­sen­tial process­es go­ing on in the cell. If you can slow down or in­hib­it the pro­duc­tion of ri­bo­somes, then you can slow down the growth of the can­cer cell,” Kraus said in a state­ment.

Kraus et al are now work­ing on de­sign­ing clin­i­cal tri­als with UT South­west­ern on­col­o­gists to test their the­o­ry.

Kraus is a founder and con­sul­tant of Ri­bon Ther­a­peu­tics, which ear­li­er this year raised $65 mil­lion to tar­get oth­er PARPs in the broad fam­i­ly of 17 en­zymes. The Cam­bridge, Mass­a­chu­setts-based biotech’s lead pro­gram is first go­ing af­ter PARP7, a pro­tein al­so sim­i­lar­ly ac­ti­vat­ed by stress and cel­lu­lar re­sponse mech­a­nisms.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

Alaa Halawaa, executive director at Mubadala’s US venture group

The ven­ture crew at Mubadala are up­ping their biotech cre­ation game, tak­ing care­ful aim at a new fron­tier in drug de­vel­op­ment

It started with a cup of coffee and a slow burning desire to go early and long in the biotech creation business.

Wrapping up a 15-year discovery stint at Genentech back in the summer of 2021, Rami Hannoush was treated to a caffeine-fueled review of the latest work UCSF’s Jim Wells had been doing on protein degradation — one of the hottest fields in drug development.

“Jim and I have known each other for the past 15 years through Genentech collaborations. We met over coffee, and he was telling me about this concept of the company that he was thinking of,” says Hannoush. “And I got immediately intrigued by it because I knew that this could open up a big space in terms of adding a new modality in drug discovery that is desperately needed in pharma.”

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Rohan Palekar, 89bio CEO

89bio’s PhII da­ta add to quick suc­ces­sion of NASH read­outs as field seeks turn­around

89bio said its drug was better than placebo at lessening fibrosis without worsening nonalcoholic steatohepatitis, or NASH, in two of three dose groups.

The San Francisco biotech said it thinks the Phase IIb data pave the way for a potential Phase III, following in the footsteps of another biotech in its drug class, Akero Therapeutics. To fund a late-stage study, CEO Rohan Palekar told Endpoints News 89bio “would need to raise additional capital,” with the company having about $188 million at the end of last year.

FDA in­di­cates will­ing­ness to ap­prove Bio­gen ALS drug de­spite failed PhI­II study

Ahead of Wednesday’s advisory committee hearing to discuss Biogen’s ALS drug tofersen, the FDA appeared open to approving the drug, newly released briefing documents show.

Citing the need for flexibility in a devastating disease like ALS, regulators signaled a willingness to consider greenlighting tofersen based on its effect on a certain protein associated with ALS despite a failed pivotal trial. The documents come after regulatory flexibility was part of the same rationale the agency expressed when approving an ALS drug last September from Amylyx Pharmaceuticals, indicating the FDA’s openness to approving new treatments for the disease.

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Roche and Lil­ly team up to de­vel­op blood test to de­tect ear­ly signs of Alzheimer's

Eli Lilly is teaming up with Roche to help develop a blood test to detect early signs of Alzheimer’s disease and determine whether a patient should go for further confirmatory testing.

Roche’s Elecsys Amyloid Plasma Panel (EAPP) measures pTau 181 protein assay and APOE E4 assay in human blood plasma – elevations in pTau 181 are present in the early stages of Alzheimer’s, while the presence of APO E4 is the most common genetic risk factor for the disease.

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Flare Therapeutics biochemists Yong Li (L) and Valerie Vivat

A $123M Flare will get Third Rock on­col­o­gy biotech in­to the clin­ic this year

Flare Therapeutics will start its first human trial this year with an investigational urothelial cancer drug after pulling together a $123 million Series B from Big Pharmas, VCs and its incubator, Third Rock Ventures.

Launched in 2021 on the idea that a biotech could finally succeed at drugging the much-sought-after but stubborn transcription factor, Flare Therapeutics said Wednesday it is now primed for the clinic after closing its large financing haul earlier this year. The raise is a relatively stark figure in a tough startup financing environment but further buoys the upbeat signals coming out of other Third Rock biotechs in recent weeks, including the $200 million CARGO Therapeutics and $100 million Rapport Therapeutics rounds.

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Francesco Marincola, newly-appointed Sonata Therapeutics CSO

Kite's head of re­search leaves for Flag­ship start­up Sonata

Another leader is departing Kite Pharma, and will to spend the “last part” of his career exploring how cancer evades the immune system.

Kite’s senior VP and global head of cell therapy research Francesco Marincola left the Gilead CAR-T unit last week for Sonata Therapeutics. Flagship last May unveiled the startup, which was pieced together from two fledgling biotechs Inzen and Cygnal Therapeutics. As CSO, Marincola will lead Sonata’s push to reprogram cancer cells to make them more immunogenic.

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Vipin Garg, Altimmune CEO

Al­tim­mune’s shares halved af­ter in­ter­im look at PhII weight loss drug da­ta

Altimmune’s attempt to catch up to Novo Nordisk and Eli Lilly’s GLP-1 drugs hit an investor snag Tuesday after the biotech shared interim Phase II weight loss data.

The Maryland biotech’s pemvidutide is a GLP-1/glucagon dual receptor agonist meant to activate GLP-1 receptors to squash appetite and glucagon to ramp up energy use. The 2.4 mg dose showed a placebo-adjusted weight loss of 9.7% at week 24 of 48, which Jefferies analysts said would be comparable to Novo Nordisk’s semaglutide (Wegovy) and Eli Lilly’s tirzepatide (Mounjaro).

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Josep Bassaganya-Riera, NImmune Biopharma

Ex­clu­sive: Af­ter get­ting his drug back, Lan­dos founder as­sem­bles new start­up for the big PhI­II test

By the time Josep Bassaganya-Riera stepped down as founding CEO of Landos Biopharma in 2021, the company had racked up Phase II data for its top autoimmune program, completed what he called a positive end-of-Phase-II meeting with the FDA and plans to launch pivotal Phase III trials.

Since then, though, the new leaders at Landos have reshuffled their plans for the drug, omilancor, first announcing they will run a Phase IIb ahead of a Phase III and eventually shelving it altogether.

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