Chas­ing a 'mas­ter mod­u­la­tor' in the en­do­cannabi­noid sys­tem, biotech up­start promis­es to shake up neu­ropsy­chi­atric treat­ments

For two years in the ear­ly 2000s, new dis­cov­er­ies and bud­ding en­thu­si­asm around the en­doge­nous cannabi­noid sys­tem — so named be­cause it’s re­spon­si­ble for the ef­fects of cannabis in the hu­man body — cul­mi­nat­ed in a mar­ket­ed drug: Sanofi’s Acom­plia.

An­drea Chic­ca

The first drug to specif­i­cal­ly tar­get the cannabi­noid re­cep­tor CB1, it was ul­ti­mate­ly with­drawn from the EU and Brazil due to find­ings that it may cause sui­ci­dal thoughts de­spite be­ing ef­fec­tive in treat­ing obe­si­ty. The FDA nev­er ap­proved it.

“For some years the com­pa­nies be­came a bit re­luc­tant to touch the re­cep­tor be­cause of this po­ten­tial ef­fect,” said An­drea Chic­ca, then a post­doc study­ing can­cer bi­ol­o­gy.

But the pen­du­lum has swung back again, ac­cord­ing to Chic­ca — whose biotech start­up, Synen­dos, has just gath­ered $21.85 mil­lion (CHF$20 mil­lion) to prove its suite of se­lec­tive en­do­cannabi­noid re­up­take in­hibitors can of­fer a brand new way to treat neu­ropsy­chi­atric dis­or­ders.

Chic­ca, a long­time re­searcher at the Uni­ver­si­ty of Bern, is CEO, CSO and, for now, the on­ly full-time em­ploy­ee of the biotech start­up.

Jürg Gertsch

The idea draws from a decade of ba­sic sci­ence work by him­self and Jürg Gertsch, chas­ing pro­teins known as en­do­cannabi­noid trans­porters. Even­tu­al­ly, they re­al­ized that the com­pounds they were gen­er­at­ing to block cannabi­noid re­up­take for ex­per­i­men­tal use could have po­ten­tial as hu­man med­i­cines, and de­vised a sec­ond gen­er­a­tion of what they called SERIs.

With­out giv­ing away the pre­cise tar­get, Chic­ca not­ed that what they’re go­ing af­ter sits up­stream to the clas­sic neu­ro­trans­mit­ters: sero­tonin, glu­ta­mate, GA­BA and oth­ers.

In oth­er words, it’s a “mas­ter mod­u­la­tor” that be­comes dys­reg­u­lat­ed in CNS dis­or­ders and trig­gers a cas­cade to the down­stream sig­nal­ing.

While Chic­ca ac­knowl­edges the op­ti­mism around psy­che­del­ic drugs, their in­trin­sic risks mean pa­tients must be treat­ed in very spe­cif­ic hos­pi­tal set­tings un­der tight con­trol of doc­tors.

“So they can­not re­al­ly be­come pills to be giv­en to a pa­tient that they can take at home for months,” he said.

Si­mon Rus­sell

Even cannabis, which is much less risky, is as­so­ci­at­ed with side ef­fects like cog­ni­tive, learn­ing and mem­o­ry is­sues. Synen­dos’ small mol­e­cules are de­signed to side­step those ex­act prob­lems while re­tain­ing the an­ti-stress func­tion. They can al­so pen­e­trate the brain, at least in an­i­mal mod­els — a nice plus for a com­pound Synen­dos is po­si­tion­ing for large in­di­ca­tions like post-trau­mat­ic stress dis­or­der, anx­i­ety, com­pul­sive be­hav­ior and even de­pres­sion.

“We aim not to ac­ti­vate the sys­tem from out­side, but re­store the en­doge­nous cannabi­noid sys­tem,” Chic­ca said. “So by in­creas­ing the lev­el of the en­doge­nous mol­e­cules that are al­ready present in our body, we don’t need to add any­thing.”

If suc­cess­ful — and this is no guar­an­tee in an area akin to a mine­field for drug de­vel­op­ers — Chic­ca sees Synen­dos ex­pand­ing to oth­er ar­eas such as neu­roin­flam­ma­tion.

The Se­ries A should grow the team and take the com­pa­ny through ini­tial, healthy vol­un­teers test­ing fol­lowed by a proof-of-con­cept in a yet-to-be-an­nounced in­di­ca­tion that links anx­i­ety, stress and mood re­lat­ed dis­or­ders. It’s al­so the first fi­nanc­ing Synen­dos has raised since spin­ning out of the Uni­ver­si­ty of Bern and the re­search con­sor­tium NC­CR Tran­sCure, as Chic­ca and Gertsch had been re­ly­ing on non-di­lu­tive fund­ing while work­ing with Base­Launch.

Si­mon Rus­sell, an en­tre­pre­neur-in-res­i­dence at the Basel-based ac­cel­er­a­tor and in­cu­ba­tor who has a full time job as CBO of Ome­icos Ther­a­peu­tics, joined the duo as a co-founder and board mem­ber.

Kur­ma Part­ners and Sun­stone Life Sci­ence Ven­tures led the round, with par­tic­i­pa­tion from BERN­I­NA BioIn­vest, Schroder Ad­veq, High-Tech Grün­der­fonds, Licht­stein­er Foun­da­tion, Es­sen­tial In­vest­ments, Zürcher Kan­ton­al­bank and pri­vate in­vestors.

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

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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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