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.

2019 Trin­i­ty Drug In­dex Eval­u­ates Ac­tu­al Com­mer­cial Per­for­mance of Nov­el Drugs Ap­proved in 2016

Fewer Approvals, but Neurology Rivals Oncology and Sees Major Innovations

This report, the fourth in our Trinity Drug Index series, outlines key themes and emerging trends in the industry as we progress towards a new world of targeted and innovative products. It provides a comprehensive evaluation of the performance of novel drugs approved by the FDA in 2016, scoring each on its commercial performance, therapeutic value, and R&D investment (Table 1: Drug ranking – Ratings on a 1-5 scale).

UP­DAT­ED: FDA’s golodirsen CRL: Sarep­ta’s Duchenne drugs are dan­ger­ous to pa­tients, of­fer­ing on­ly a small ben­e­fit. And where's that con­fir­ma­to­ry tri­al?

Back last summer, Sarepta CEO Doug Ingram told Duchenne MD families and investors that the FDA’s shock rejection of their second Duchenne MD drug golodirsen was due to some concerns regulators raised about the risk of infection and the possibility of kidney toxicity. But when pressed to release the letter for all to see, he declined, according to a report from BioPharmaDive, saying that kind of move “might not look like we’re being as respectful as we’d like to be.”

He went on to assure everyone that he hadn’t misrepresented the CRL.

But Ingram’s public remarks didn’t include everything in the letter, which — following the FDA’s surprise about-face and unexplained approval — has now been posted on the FDA’s website and broadly circulated on Twitter early Wednesday.

The CRL raises plenty of fresh questions about why the FDA abruptly decided to reverse itself and hand out an OK for a drug a senior regulator at the FDA believed — 5 months ago, when he wrote the letter — is dangerous to patients. It also puts the spotlight back on Sarepta $SRPT, which failed to launch a confirmatory study of eteplirsen, which was only approved after a heated internal controversy at the FDA. Ellis Unger, director of CDER’s Office of Drug Evaluation I, notes that study could have clarified quite a lot about the benefit and risks associated with their drugs — which can cost as much as a million dollars per patient per year, depending on weight.

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How to cap­i­talise on a lean launch

For start-up biotechnology companies and resource stretched pharmaceutical organisations, launching a novel product can be challenging. Lean teams can make setting a launch strategy and achieving your commercial goals seem like a colossal undertaking, but can these barriers be transformed into opportunities that work to your brand’s advantage?
We spoke to Managing Consultant Frances Hendry to find out how Blue Latitude Health partnered with a fledgling subsidiary of a pharmaceutical organisation to launch an innovative product in a
complex market.
What does the launch environment look like for this product?
FH: We started working on the product at Phase II and now we’re going into Phase III trials. There is a significant unmet need in this disease area, and everyone is excited about the launch. However, the organisation is still evolving and the team is quite small – naturally this causes a little turbulence.

Wuhan virus out­break trig­gers in­evitable small-biotech ral­ly

Every few years, a public health crisis (think Ebola, Zika) spurred by a rogue pathogen triggers a small-biotech rally, as drugmakers emerge from the woodwork with ambitious plans to treat the mounting outbreak. In most cases, that enthusiasm never quite delivers.

Things are no different, as the coronavirus outbreak in Wuhan, China takes hold. There have been close to 300 confirmed human infections in China, and at least four deaths. Coronaviruses are a large family of viruses, which include MERS and SARS. On Tuesday, the CDC reported the virus was detected in a US traveler returning from Wuhan.

Hal Barron and Emma Walmsley, GSK

GSK’s ‘break­through’ BC­MA can­cer drug gets a pri­or­i­ty re­view — and a big win for the on­col­o­gy R&D team

After largely whiffing the past 2 years on the pharma R&D front, GlaxoSmithKline research chief Hal Barron has seized boasting rights to a key win that puts them back in the cancer drug development game.

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Who are the young bio­phar­ma lead­ers shap­ing the in­dus­try? Nom­i­nate them for End­points' spe­cial re­port

Update: Nominations open through end of day, Monday, January 27

Two years ago, when we did our first Endpoints 20-under-40, we profiled a set of up-and-comers who promised to help reshape the industry as we know it. Now we’re back and once again looking for the top 20 biopharma professionals under the age of 40. We’ll be profiling folks who have accomplished a lot at a young age but seem on the verge of accomplishing so much more.

John Oyler, Endpoints

BeiGene lines up its first shot at crack­ing the megablock­buster PD-1 mar­ket for lung can­cer. But can they over­come un­der­dog sta­tus?

BeiGene took another big step towards challenging Merck, Bristol-Myers Squibb, AstraZeneca and some other Big Pharma heavyweights for a share of the lucrative lung cancer market for the PD-(L)1s racking up billions in annual revenue.

The China-based biotech $BGNE run by CEO John Oyler posted positive top-line progression-free survival results for their pivotal Chinese study on their PD-1 antibody tislelizumab combined with chemo for squamous non-small cell lung cancer in frontline cases. Squamous NSCLC accounts for about 30% of the overall lung cancer market.

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Brex­it fears, Wood­ford woes over­shad­owed UK biotech and cut 2019 fi­nanc­ing by al­most half

The venture tide might have subsided, the IPO window may be closing and certain listed biotechs may be having a tough time amid Neil Woodford’s well-publicized demised, but there’s still plenty to celebrate in the UK BioIndustry Association’s eyes.

Overall investment in UK biotech last year fell from the record-breaking £2.2 billion levels of 2018 to £1.3 billion — including £679 million in venture capital, a meager £64 million in IPOs plus £596 million when you add up all public financings, according to a new report from the BIA.

Blue­print Med­i­cines po­ten­tial­ly de­lays Ay­vak­it de­ci­sion; Con­trol beats treat­ment in mesothe­lioma tri­al

→ Blueprint Medicines filed an amendment to its application to get the gastrointestinal stromal tumor (GIST) drug Ayvakit approved in fourth-line GIST, the company disclosed in the prospectus for a new $325 million public offering.  Blueprint got a big accelerated OK on the drug this month in a particular mutation, but because the FDA decided to split their review in two, they didn’t hear on fourth-line GIST. They were supposed to hear before February 14, but this amendment could push that date back by 3 months. Blueprint wrote that the amendment is designed to allow the company to comply with the FDA’s request for data from the Phase III VOYAGER before they give a judgment.