Jon Wigginton, Cullinan Oncology CMO

Cul­li­nan On­col­o­gy launch­es new sub­sidiary fo­cused on col­la­gen-bind­ing cy­tokine treat­ment

Cul­li­nan On­col­o­gy op­er­ates as both a biotech and an in­vest­ment fund, hous­ing each of its as­sets in sub­sidiaries un­der one large um­brel­la. A lit­tle over a month af­ter its last launch, Cul­li­nan has an­nounced an­oth­er such project.

The Cam­bridge-based com­pa­ny in­tro­duced Cul­li­nan Am­ber on Wednes­day morn­ing, the ninth drug de­vel­op­ment en­ter­prise in its port­fo­lio, and has ob­tained an ex­clu­sive li­cense from MIT to uti­lize col­la­gen bind­ing tech­nol­o­gy. Thanks to this tech, Cul­li­nan Am­ber’s lead pro­gram will com­bine two an­ti­tu­mor cy­tokines, IL-12 and IL-2, with a col­la­gen-bind­ing do­main to pro­duce what CMO Jon Wig­gin­ton hopes are more lo­cal­ized can­cer treat­ments.

“When you in­ject this mol­e­cule in­to the tu­mor,” Wig­gin­ton said, “it me­di­ates sig­nif­i­cant an­ti­tu­mor ac­tiv­i­ty, and by virtue of its col­la­gen-bind­ing do­main, it binds the col­la­gen in the tu­mor and is re­tained there bet­ter.”

In­ter­leukins play a role in en­hanc­ing the body’s im­mune sys­tem, stim­u­lat­ing T and NK cell pop­u­la­tions to at­tack tu­mor sites. But like many can­cer im­munother­a­pies, this can lead to high tox­i­c­i­ty in healthy cells.

Cul­li­nan Am­ber’s plan is to de­vel­op a sin­gle mol­e­cule that con­tains both IL-12 and IL-2, with the MIT tech pro­vid­ing a way to keep the im­mune re­sponse at the tu­mor site. Pre­clin­i­cal an­i­mal test­ing has shown that by in­ject­ing the com­pound di­rect­ly in­to the tu­mor and bind­ing to the tu­mor col­la­gen, the cy­tokines stayed with­in the tu­mor en­vi­ron­ment. This tech was pi­o­neered by MIT pro­fes­sor K. Dane Wit­trup, who will be ad­vis­ing the Cul­li­nan Am­ber team.

Owen Hugh­es

“What we’ve been able to show is not on­ly do the an­i­mals gain weight over time, sim­i­lar to the con­trol group, but we es­sen­tial­ly evis­cer­ate their tu­mors,” CEO Owen Hugh­es said. “It’s re­al­ly the ad­vent of the col­la­gen-bind­ing do­main that al­lows us to cap­i­tal­ize on what is very po­tent an­ti­tu­mor ac­tiv­i­ty with these cy­tokines.”

Of course, col­la­gen is present through­out the hu­man body, and though ear­ly an­i­mal test­ing has en­cour­aged Cul­li­nan, the next chal­lenge is to en­sure such re­sults trans­late to hu­mans. This is the stage at which sev­er­al com­pa­nies pre­vi­ous­ly aban­doned their IL-12 and IL-2 projects, Wig­gin­ton said, be­cause of the tox­i­c­i­ty as­so­ci­at­ed with the cy­tokines.

If some of the IL-12 and IL-2 were to spread out­side the tu­mor en­vi­ron­ment in hu­mans, side ef­fects would be ev­i­dent al­most right away, Wig­gin­ton said. But thus far, the col­la­gen-bind­ing do­main has proven quite ef­fec­tive and some test­ing has even shown signs of elim­i­nat­ing dis­tant tu­mors.

“Peo­ple his­tor­i­cal­ly have in­ject­ed oth­er agents like IL-12 in­to tu­mors, but those ap­proach­es have been lim­it­ed by, in some cas­es, they haven’t shown the abil­i­ty to gen­er­ate sys­temic im­mu­ni­ty,” Wig­gin­ton said. “We think that the agent will solve sev­er­al his­tor­i­cal chal­lenges in the phase de­vel­op­ment of cy­tokines, and cre­ate the op­por­tu­ni­ty then to bring com­bi­na­tions to­geth­er with much more fa­vor­able risk ben­e­fit.”

Tar­get­ing those off-site tu­mors will be the next step for Cul­li­nan Am­ber as it moves in­to clin­i­cal stages. IND-en­abling stud­ies are ex­pect­ed to be­gin some­time be­fore the end of 2020.

Though lots of tests re­main, Wig­gin­ton hopes the com­pound can ul­ti­mate­ly be safe­ly used across a va­ri­ety of sol­id tu­mor can­cers.

“This is not a mol­e­cule that should nec­es­sar­i­ly be re­strict­ed to a spe­cif­ic tu­mor type,” Wig­gin­ton said. “We would start out with a Phase I tri­al with a mix of dif­fer­ent tu­mor pa­tients, guid­ed by what we see from that and any trans­la­tion­al stud­ies, and prob­a­bly pick a small num­ber of co­hort ex­pan­sions to be­gin to char­ac­ter­ize the an­ti­tu­mor ac­tiv­i­ties and see how the mol­e­cule is safe and well-tol­er­at­ed.”

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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