As tar­get­ed ther­a­pies get ever more pre­cise, Deer­field un­veils $50M bet on a Har­vard pro­fes­sor's chem­istry in­sights

Be­hind the seem­ing­ly sim­ple con­cept of tar­get­ed can­cer ther­a­pies is the drug de­vel­op­er’s headache that the tar­get is al­ways chang­ing. Each gen­er­a­tion of ki­nase in­hibitors may be os­ten­si­bly hit­ting the same onco­gene, but in ad­di­tion to block­ing the wild­type onco­gene, they must now al­so ad­dress the mu­ta­tions that have de­vel­oped along the way, spurring re­sis­tance to cur­rent drugs.

The more those tar­get ki­nas­es evolve, too, the more they could re­sem­ble off-tar­get ki­nas­es you don’t want to bind. So each it­er­a­tion re­quires more se­lec­tiv­i­ty — some­times down to dif­fer­ences of a few atoms.

Matthew Shair

Matthew Shair be­lieves chem­istry can evolve fast enough to pro­vide an an­swer.

By uti­liz­ing struc­ture-based drug de­sign — by now a fa­mil­iar tool in small mol­e­cule de­vel­op­ment — his biotech start­up, Nu­va­lent, has spent the past cou­ple of years on two com­pounds that tar­get the tu­mor dri­vers ROS1 and ALK for the clin­ic.

Now that the $50 mil­lion in Se­ries A cash has pro­pelled them to the cusp of the clin­ic, with the first hu­man stud­ies planned for the sec­ond half of 2021, the Har­vard pro­fes­sor is ready to tease the biotech world with a glimpse of his ef­forts.

“I see Nu­va­lent emerg­ing as one of the (if not the) pre­mier com­pa­nies de­vel­op­ing tar­get­ed can­cer ther­a­peu­tics,” Cameron Wheel­er, a part­ner at Deer­field who helped start the com­pa­ny and now chairs its board, wrote in an email.

Nu­va­lent’s ap­proach, Shair told End­points News, starts with go­ing to physi­cians and seek­ing their in­put on what prop­er­ties they want in a drug.

“What hasn’t been pos­si­ble for in­stance in the ROS1 space is to have a mol­e­cule that works against the known mu­tants — the known mu­ta­tions, in­clud­ing ones that are just re­cent­ly seen in pa­tients and even the ROS1 pro­tein be­fore it’s mu­tat­ed, so-called wild­type pro­tein,” he said, “and avoid­ing in­ter­act­ing with an off tar­get called TRK.”

Cameron Wheel­er

The next step re­quires a lot of crys­tal struc­tures and rel­e­vant in­for­ma­tion to un­der­stand the mu­ta­tions as well as the in­ter­ac­tion be­tween small mol­e­cule and lig­and, in or­der to lo­cate po­ten­tial drug can­di­dates that sit in the mid­dle of that con­vo­lut­ed Venn di­a­gram.

CEO James Porter has been lead­ing a team of 14 sci­en­tists to re­fine the twin lead pro­grams, en­sur­ing they are pre­cise­ly tai­lored to the prob­lem, while ap­ply­ing any in­sights to a pipeline of oth­er tar­get­ed drugs.

While mul­ti­ple drugs have been ap­proved for ROS1-pos­i­tive non-small cell lung can­cer, pa­tients who have pro­gressed cur­rent­ly have no op­tion be­yond first-gen­er­a­tion drugs. Sim­i­lar­ly, an emerg­ing ALK+ pa­tient pop­u­la­tion presents a “wide open space” for Nu­va­lent’s im­me­di­ate fo­cus.

“We rec­og­nize that if we are rig­or­ous with project se­lec­tion, ex­e­cu­tion of our pro­grams, we have dis­ci­plined de­ci­sion-mak­ing, we can use our skills in chem­istry to cre­ate some so­lu­tions for pa­tients,” he said, adding that Shair has been close­ly in­volved with each of the steps as the head sci­en­tif­ic ad­vi­sor.

James Porter

The two have known each oth­er since Porter be­came one of the first chemists at In­fin­i­ty Phar­ma­ceu­ti­cals, where Shair was a co-founder.

“Twen­ty years ago, every com­pa­ny like Ari­ad and Mil­len­ni­um and Enan­ta, they had their own mouse fa­cil­i­ty on site,” Shair re­flect­ed. “Be­cause you couldn’t out­source phar­ma­co­ki­net­ic stud­ies, you couldn’t out­source in vi­vo ef­fi­ca­cy. Now it’s all out­source­able. And every­thing — just about every­thing is out­source­able ex­cept for I think the de­sign of the mol­e­cules, the de­sign of your clin­i­cal tri­als, the de­sign of your pro­grams. So that’s a huge sea change which has — I like to think about it, it’s de­moc­ra­tized drug dis­cov­ery. It al­lows a team of 10, 20, 30 peo­ple, to put 2 com­pounds in the clin­ic. You could nev­er do that 20 years ago.”

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.

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

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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.

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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‘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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