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.

ZS Per­spec­tive: 3 Pre­dic­tions on the Fu­ture of Cell & Gene Ther­a­pies

The field of cell and gene therapies (C&GTs) has seen a renaissance, with first generation commercial therapies such as Kymriah, Yescarta, and Luxturna laying the groundwork for an incoming wave of potentially transformative C&GTs that aim to address diverse disease areas. With this renaissance comes several potential opportunities, of which we discuss three predictions below.

Allogenic Natural Killer (NK) Cells have the potential to displace current Cell Therapies in oncology if proven durable.

Despite being early in development, Allogenic NKs are proving to be an attractive new treatment paradigm in oncology. The question of durability of response with allogenic therapies is still an unknown. Fate Therapeutics’ recent phase 1 data for FT516 showed relatively quicker relapses vs already approved autologous CAR-Ts. However, other manufacturers, like Allogene for their allogenic CAR-T therapy ALLO-501A, are exploring novel lymphodepletion approaches to improve persistence of allogenic cells. Nevertheless, allogenic NKs demonstrate a strong value proposition relative to their T cell counterparts due to comparable response rates (so far) combined with the added advantage of a significantly safer AE profile. Specifically, little to no risk of graft versus host disease (GvHD), cytotoxic release syndrome (CRS), and neurotoxicity (NT) have been seen so far with allogenic NK cells (Fig. 1). In addition, being able to harness an allogenic cell source gives way to operational advantages as “off-the-shelf” products provide improved turnaround time (TAT), scalability, and potentially reduced cost. NKs are currently in development for a variety of overlapping hematological indications with chimeric antigen receptor T cells (CAR-Ts) today, and the question remains to what extent they will disrupt the current cell therapy landscape. Click for more details.

Susan Galbraith, AstraZeneca EVP, Oncology R&D

Can­cer pow­er­house As­traZeneca rolls the dice on a $75M cash bet on a buzzy up­start in the on­col­o­gy field

After establishing itself in the front ranks of cancer drug developers and marketers, AstraZeneca is putting its scientific shoulder — and a significant amount of cash — behind the wheel of a brash new upstart in the biotech world.

The pharma giant trumpeted news this morning that it is handing over $75 million upfront to ally itself with Scorpion Therapeutics, one of those biotechs that was newly birthed by some top scientific, venture and executive talent and bequeathed with a fortune by way of a bankroll to advance an only hazily explained drug platform. And they are still very much in the discovery and preclinical phase.

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Lat­est news on Pfiz­er's $3B+ JAK1 win; Pacts over M&A at #JPM22; 2021 by the num­bers; Bio­gen's Aduhelm reck­on­ing; The sto­ry of sotro­vimab; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

For those of you who attended #JPM22 in any shape or form, we hope you had a fruitful time. Regardless of how you spent the past hectic week, may your weekend be just what you need it to be.

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A $3B+ peak sales win? Pfiz­er thinks so, as FDA of­fers a tardy green light to its JAK1 drug abroc­i­tinib

Back in the fall of 2020, newly crowned Pfizer chief Albert Bourla confidently put their JAK1 inhibitor abrocitinib at the top of the list of blockbuster drugs in the late-stage pipeline with a $3 billion-plus peak sales estimate.

Since then it’s been subjected to serious criticism for the safety warnings associated with the class, held back by a cautious FDA and questioned when researchers rolled out a top-line boast that their heavyweight contender had beaten the champ in the field of atopic dermatitis — Dupixent — in a head-to-head study.

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Robert Califf, FDA commissioner nominee (Graeme Sloan/Sipa USA/Sipa via AP Images)

Rob Califf ad­vances as Biden's FDA nom­i­nee, with a close com­mit­tee vote

Rob Califf’s second confirmation process as FDA commissioner is already much more difficult than his near unanimous confirmation under the Obama administration.

The Senate Health Committee on Thursday voted 13-8 in favor of advancing Califf’s nomination to a full Senate vote. Several Democrats voted against Califf, including Sen. Bernie Sanders and Sen. Maggie Hassan. Several other Democrats who aren’t on the committee, like West Virginia’s Joe Manchin and Ed Markey of Massachusetts, also said Thursday that they would not vote for Califf. Markey, Hassan and Manchin all previously expressed reservations about the prospect of Janet Woodcock as an FDA commissioner nominee too.

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Michel Vounatsos, Biogen CEO (World Economic Forum/Ciaran McCrickard)

Bio­gen vows to fight CM­S' draft cov­er­age de­ci­sion for Aduhelm be­fore April fi­nal­iza­tion

Biogen executives made clear in an investor call Thursday they are not preparing to run a new CMS-approved clinical trial for their controversial Alzheimer’s drug anytime soon.

As requested in a draft national coverage decision from CMS earlier this week, Biogen and other anti-amyloid drugs will need to show “a meaningful improvement in health outcomes” for Alzheimer’s patients in a randomized, placebo-controlled trial to get paid for their drugs, rather than just the reduction in amyloid plaques that won Aduhelm its accelerated approval in June.

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CRO own­er pleads guilty to ob­struct­ing FDA in­ves­ti­ga­tion in­to fal­si­fied clin­i­cal tri­al da­ta

The co-owner of a Florida-based clinical research site pleaded guilty to lying to an FDA investigator during a 2017 inspection, revealing that she falsely portrayed part of a GlaxoSmithKline pediatric asthma study as legitimate, when in fact she knew that certain data had been falsified, the Department of Justice said Wednesday.

Three other employees — Yvelice Villaman Bencosme, Lisett Raventos and Maytee Lledo — previously pleaded guilty and were sentenced in connection with falsifying data associated with the trial at the CRO Unlimited Medical Research.

‘Skin­ny la­bels’ on gener­ics can save pa­tients mon­ey, re­search shows, but re­cent court de­ci­sions cloud fu­ture

New research shows how generic drug companies can successfully market a limited number of approved indications for a brand name drug, prior to coming to market for all of the indications. But several recent court decisions have created a layer of uncertainty around these so-called “skinny” labels.

While courts have generally allowed generic manufacturers to use their statutorily permitted skinny-label approvals, last summer, a federal circuit court found that Teva Pharmaceuticals was liable for inducing prescribers and patients to infringe GlaxoSmithKline’s patents through advertising and marketing practices that suggested Teva’s generic, with its skinny label, could be employed for the patented uses.

A patient in Alaska receiving an antibody infusion to prevent Covid hospitalizations in September. All but one of these treatments has been rendered useless by Omicron (Rick Bowmer/AP Images)

How a tiny Swiss lab and two old blood sam­ples cre­at­ed one of the on­ly ef­fec­tive drugs against Omi­cron (and why we have so lit­tle of it)

Exactly a decade before a novel coronavirus broke out in Wuhan, Davide Corti — a newly-minted immunologist with frameless glasses and a quick laugh — walked into a cramped lab on the top floor of an office building two hours outside Zurich. He had only enough money for two technicians and the ceiling was so low in parts that short stature was a job requirement, but Corti believed it’d be enough to test an idea he thought could change medicine.

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