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.

Scoop: Boehringer qui­et­ly shut­ters a PhII for one of its top drugs — now un­der re­view

Boehringer Ingelheim has quietly shut down a small Phase II study for one of its lead drugs.

The private pharma player confirmed to Endpoints News that it had shuttered a study testing spesolimab as a therapy for Crohn’s patients suffering from bowel obstructions.

A spokesperson for the company tells Endpoints:

Taking into consideration the current therapeutic landscape and ongoing clinical development programs, Boehringer Ingelheim decided to discontinue our program in Crohn’s disease. It is important to note that this decision is not based on any safety findings in the clinical trials.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Deborah Dunsire, Lundbeck CEO

Af­ter a 5-year re­peat PhI­II so­journ, Lund­beck and Ot­su­ka say they're fi­nal­ly ready to pur­sue OK to use Rex­ul­ti against Alzheimer's ag­i­ta­tion

Five years after Lundbeck and their longtime collaborators at Otsuka turned up a mixed set of Phase III data for Rexulti as a treatment for Alzheimer’s dementia-related agitation, they’ve come through with a new pivotal trial success they believe will finally put them on the road to an approval at the FDA. And if they’re right, some analysts believe they’re a short step away from adding more than $500 million in annual sales for the drug, already approved in depression and schizophrenia.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,400+ biopharma pros reading Endpoints daily — and it's free.

Chris Anzalone, Arrowhead CEO

Take­da, Ar­row­head spot­light da­ta from small tri­al show­ing RNAi works in a rare liv­er con­di­tion

Almost two years after Takeda wagered $300 million cash to partner with Arrowhead on an RNAi therapy for a rare disease, the companies are spelling out Phase II data that they believe put them one step closer to their big dreams.

In a small, open label study involving only 16 patients who had liver disease associated with alpha-1 antitrypsin deficiency (AATD), Arrowhead’s candidate — fazirsiran, previously ARO-AAT — spurred substantial reductions in accumulated mutant AAT protein in the liver, a hallmark of the condition. Investigators also tracked improvements in symptoms, with seven out of 12 who received the high, 200 mg dose seeing regression of liver fibrosis.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,400+ biopharma pros reading Endpoints daily — and it's free.

Alex­ion puts €65M for­ward to strength­en its po­si­tion on the Emer­ald Isle

Ireland has been on a roll in 2022, with several large pharma companies announcing multimillion-euro projects. Now AstraZeneca’s rare disease outfit Alexion is looking to get in on the action.

Alexion on Friday announced a €65 million ($68.8 million) investment in new and enhanced capabilities across two sites in the country, including at College Park in the Dublin suburb of Blanchardstown and the Monksland Industrial Park in the central Irish town of Athlone, according to the Industrial Development Agency of Ireland.

State bat­tles over mifepri­s­tone ac­cess could tie the FDA to any post-Roe cross­roads

As more than a dozen states are now readying so-called “trigger” laws to kick into effect immediate abortion bans following the overturning of Roe v. Wade on Friday, these laws, in the works for more than a decade in some states, will likely kick off even more legal battles as states seek to restrict the use of prescription drug-based abortions.

Since Friday’s SCOTUS opinion to overturn Americans’ constitutional right to an abortion after almost 50 years, reproductive rights lawyers at Planned Parenthood and other organizations have already challenged these trigger laws in Utah and Louisiana. According to the Guttmacher Institute, other states with trigger laws that could take effect include Arkansas, Idaho, Kentucky, Mississippi, Missouri, North Dakota, Oklahoma, South Dakota, Tennessee, Texas, and Wyoming.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 144,400+ biopharma pros reading Endpoints daily — and it's free.

A Mer­ck part­ner is sucked in­to the fi­nan­cial quag­mire as key lender calls in a note

Another biotech standing on shaky financial legs has fallen victim to the bears.

Merck partner 4D Pharma has reported that a key lender, Oxford Finance, shoved the UK company into administration after calling in a $14 million loan they couldn’t immediately make good on. Trading in their stock was halted with a market cap that had fallen to a mere £30 million.

“Despite the very difficult prevailing market conditions,” 4D reported on Friday, the biotech had been making progress on finding some new financing and turned to Oxford with an alternative late on Thursday and then again Friday morning.

Members of the G7 from left to right: Prime Minister of Italy Mario Draghi, European Commission President Ursula von der Leyen, President Joe Biden, German Chancellor Olaf Scholz, British Prime Minister Boris Johnson, Canadian Prime Minister Justin Trudeau, Prime Minister of Japan Fumio Kishida, French President Emmanuel Macron and European Council President Charles Michel (AP Photo/Susan Walsh)

Biden and G7 na­tions of­fer funds for vac­cine and med­ical prod­uct man­u­fac­tur­ing project in Sene­gal

Amidst recently broader vaccine manufacturing initiatives from the EU and European companies, the G7 summit in the mountains of Bavaria has brought about some positive news for closing vaccine and medical product manufacturing gaps around the globe.

According to a statement from the White House, the G7 leaders have formally launched the partnership for global infrastructure, PGII. The effort will aim to mobilize hundreds of billions of dollars to deliver infrastructure projects in several sectors including the medical and pharmaceutical manufacturing space.

Fed­er­al judge de­nies Bris­tol My­er­s' at­tempt to avoid Cel­gene share­hold­er law­suit

Some Celgene shareholders aren’t happy with how Bristol Myers Squibb’s takeover went down.

On Friday, a New York federal judge ruled that they have a case against the pharma giant, denying a request to dismiss allegations that it purposely slow-rolled Breyanzi’s approval to avoid paying out $6.4 billion in contingent value rights (CVR).

When Bristol Myers put down $74 billion to scoop up Celgene back in 2019, liso-cel — the CAR-T lymphoma treatment now marketed as Breyanzi — was supposedly one of the centerpieces of the deal. After going back and forth on negotiations for about six months, BMS put $6.4 billion into a CVR agreement that required an FDA approval for Zeposia, Breyanzi and Abecma, each by an established date.

David Hung, Nuvation Bio president and CEO (Nuvation Bio)

FDA places par­tial clin­i­cal hold on David Hung biotech af­ter cer­tain can­cer pa­tients ex­pe­ri­ence eye in­flam­ma­tion

Two and a half years after setting out on another foray into oncology R&D, a biotech headed by David Hung — of Medivation fame — has run into its first setback.

San Francisco-based Nuvation Bio announced early Monday the FDA placed a partial clinical hold on a Phase I dose-escalation study of NUV-422, its CDK inhibitor program for certain types of solid tumors. The trial began enrolling patients in December 2020, and, according to Nuvation, researchers were in the middle of exploring dose escalation and defining the maximum dose tolerable in patients.