Ep­i­darex, Sofinno­va dou­ble down on a par­al­lel take on 3rd-gen CAR-T — aim­ing straight at ovar­i­an can­cer

When John Ma­her treat­ed the first head and neck can­cer pa­tient at Guy’s Hos­pi­tal in Lon­don with his pan-ErbB CAR-T back in 2015, he was among a small club of re­searchers con­vinced they had an an­swer to the chal­lenges that had kept those en­gi­neered T cells — wild­ly suc­cess­ful in hema­to­log­i­cal can­cers — ei­ther too dan­ger­ous or out of reach for pa­tients with sol­id tu­mors.

John Ma­her

The field has blos­somed since then, with a pro­lif­er­a­tion of tech­nolo­gies that promise to ad­dress any num­ber of chal­lenges iden­ti­fied as unique to sol­id tu­mors. And Ma­her him­self has rethought his ap­proach and come up with a new CAR-T plat­form to gen­er­ate the next slate of can­di­dates.

Now that the first can­di­date is near­ing the end of Phase I, his biotech spin­out, Leu­cid Bio, will have al­most $16 mil­lion (£11.5 mil­lion) to take those new pro­grams in­to the clin­ic.

T4, as the CAR-T Ma­her has ad­min­is­tered to 18 pa­tients with squa­mous cell can­cer of the head and neck is known, be­longs to the sec­ond gen­er­a­tion, ex­plained Leu­cid Bio CEO Artin Mous­savi. Those CARs con­sist of a bind­ing re­cep­tor on the sur­face mem­brane, a se­ries of sig­nal­ing do­mains, plus one of two cos­tim­u­la­to­ry do­mains: CD28 or 4-1BB.

It was a struc­ture Ma­her knew well af­ter work­ing as part of Michel Sade­lain’s Memo­r­i­al Sloan Ket­ter­ing team be­hind a cru­cial part of what be­came Bris­tol My­ers Squibb’s CD19 CAR-T, Breyanzi.

Artin Mous­savi

As sci­en­tists moved in­to the third gen­er­a­tion of CARs, they com­bined the two cos­tim­u­la­to­ry do­mains in hopes of get­ting more pow­er­ful T cell ac­ti­va­tion. But in his own re­search, Ma­her con­clud­ed that the way most of his peers did it — putting the CD28 and 4-1BB on top of each oth­er — didn’t quite en­hance the po­ten­cy as much as ex­pect­ed.

So he tried a dif­fer­ent con­fig­u­ra­tion, ar­rang­ing the two cos­tim­u­la­to­ry do­mains in a par­al­lel fash­ion, close to the cell sur­face, and get­ting rid of the ze­ta chain sig­nal­ing.

“What he dis­cov­ered there was he was get­ting far bet­ter po­ten­cy, far bet­ter sig­nal­ing but wasn’t in­duc­ing a senes­cence or an over­stim­u­la­tion and was able to stim­u­late those cells to kill tu­mor cell lines — many more cy­cles than the sec­ond gen­er­a­tion or third gen­er­a­tion CAR,” Mous­savi said.

Over the past few years, Ma­her — who jug­gles sev­er­al jobs teach­ing and see­ing pa­tients at King’s Col­lege Lon­don and East­bourne Hos­pi­tal while al­so serv­ing as Leu­cid’s CSO — has moved that tech­nol­o­gy from in vit­ro stud­ies to in vi­vo pre­clin­i­cal mod­els. They call it pCAR, short for par­al­lel CAR.

“It’s a plat­form,” Mous­savi said. “It gives us the abil­i­ty to add in aux­il­iary tech­nolo­gies that will en­hance its ef­fi­ca­cy against par­tic­u­lar chal­lenges in sol­id tu­mor space. So with ovar­i­an can­cer, we’re in­tro­duc­ing hom­ing en­hance­ments. We’re al­so in­tro­duc­ing our ex­pe­ri­ence in terms of route of ad­min­is­tra­tion.”

Al­though it tech­ni­cal­ly falls be­hind T4 (or LEU-001), LEU-011 — the au­tol­o­gous CAR-T be­ing po­si­tioned for plat­inum-re­sis­tant ovar­i­an can­cer — is now Leu­cid’s lead pro­gram. The biotech has de­vel­oped a pCAR ver­sion of T4 as well as ad­di­tion­al tech­nolo­gies to sup­port al­lo­gene­ic CAR-T in the fu­ture.

“I don’t be­lieve there is one tech­nol­o­gy on its own that will over­come all the bar­ri­ers for a par­tic­u­lar in­di­ca­tion,” he said. “So I see this as an evo­lu­tion in the CAR-T field.”

The Se­ries A fi­nanc­ing should fund a Phase I for ‘011 AND get the al­lo­gene­ic pro­grams ready for fur­ther test­ing, the CEO said.

Ep­i­darex and Sofinno­va, which had pro­vid­ed the seed fund­ing to sus­tain the com­pa­ny up to this point, were back for this round, joined by new in­vestors Vulpes In­vest­ment Man­age­ment, 2In­vest and Fu­ture Fund of the British Busi­ness Bank.

Thanks to a close re­la­tion­ship with Guy’s Hos­pi­tal (where the team of few­er than 20 is based), Leu­cid gets its clin­i­cal drug sup­ply from a GMP man­u­fac­tur­ing suite there. And don’t look for the splash mon­ey on pro­duc­tion any time soon.

“We’re not try­ing to rein­vent the wheel in terms of elab­o­rate man­u­fac­tur­ing,” Mous­savi said. “What we’re try­ing to do is to make sure that we have a very cost-ef­fec­tive man­u­fac­tur­ing sys­tem that’s scal­able.”

At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While oncology researchers have long pursued the potential of cellular immunotherapies for the treatment of cancer, it was unclear whether these therapies would ever reach patients due to the complexity of manufacturing and costs of development. Fortunately, the recent successful development and regulatory approval of chimeric antigen receptor-engineered T (CAR-T) cells have demonstrated the significant benefit of these therapies to patients.

All about Omi­cron; We need more Covid an­tivi­rals; GSK snags Pfiz­er’s vac­cine ex­ec; Janet Wood­cock’s fu­ture at FDA; 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.

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Usama Malik

Ex-Im­munomedics CFO charged with in­sid­er trad­ing, faces up to 20 years in prison af­ter al­leged­ly tip­ping off girl­friend and rel­a­tives of a PhI­II suc­cess

The former CFO of Immunomedics, who helped steer the company to its $21 billion buyout by Gilead last year, has been charged with insider trading, the Department of Justice announced Thursday.

Usama Malik tipped off his then-girlfriend and four others that a Phase III study for Trodelvy would be stopped early four days before Immunomedics publicly announced the result in April 2020, DoJ alleged in its complaint. The individuals then purchased Immunomedics shares, selling them after the news broke and Immunomedics’ stock price doubled.

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Merck's new antiviral molnupiravir (Quality Stock Arts / Shutterstock)

As Omi­cron spread looms, oral an­tivi­rals ap­pear to be one of the best de­fens­es — now we just need more

After South African scientists reported a new Covid-19 variant — dubbed Omicron by the WHO — scientists became concerned about how effective vaccines and monoclonal antibodies might be against it, which has more than 30 mutations in the spike protein.

“I think it is super worrisome,” Dartmouth professor and Adagio co-founder and CEO Tillman Gerngross told Endpoints News this weekend. Moderna CEO Stéphane Bancel echoed similar concerns, telling the Financial Times that experts warned him, “This is not going to be good.”

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Biospec­i­men M&A: Dis­cov­ery ac­quires Al­bert Li's he­pa­to­cyte project; PhI­II tri­al on Bay­er's Nube­qa reached pri­ma­ry end­point

Discovery Life Sciences has acquired what claims to be the Maryland-based host of the world’s largest hepatocyte inventory, known as IVAL, to help researchers select more effective and safer drug candidates in the future.

The combined companies will now serve a wider range of drug research and development scientists, according to Albert Li, who founded IVAL in 2004 and is set to join the Discovery leadership team as the CSO of pharmacology and toxicology.

Radek Spisek, Sotio CEO (Cellestia)

A qui­et Czech biotech bags $315M to dri­ve its blos­som­ing can­cer pipeline through the clin­ic

In the rather insular world of biotech, most innovation inevitably comes from a cluster of R&D hubs — Cambridge, San Francisco, etc. But sometimes success stories sprout from rocky soil, which is most certainly the case with Prague-based Sotio Biotech and its suddenly jam-packed pipeline of cancer drugs.

After years in quiet development, Sotio now has $315 million in new funds to play with from parent company PPF Group, an investment group founded in the Czech Republic, as the biotech looks to advance its growing pipeline through early- and mid-stage trials.

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With on­ly burns to show in gene ther­a­py, Astel­las inks deal with AAV spe­cial­ist Dyno in push for a bet­ter cap­sid

On the hunt for a better AAV capsid for gene therapy, Eric Kelsic’s Dyno Therapeutics has set itself apart with its focus on machine learning to help speed discovery. Now, Japanese drugmaker Astellas — fresh off a slate of gene therapy burns — is taking a bet on Dyno as it looks to the future.

Astellas and Dyno will work together as part of an R&D pact to develop next-gen AAV vectors for gene therapy using Dyno’s CapsidMap platform directed at skeletal and cardiac muscle, the companies said Wednesday. Under the terms of the deal, Dyno will design AAV capsids for gene therapy, while Astellas will be responsible for conducting preclinical, clinical and commercialization activities for gene therapy product candidates using the capsids.

In­cor­po­rat­ing Ex­ter­nal Da­ta in­to Clin­i­cal Tri­als: Com­par­ing Dig­i­tal Twins to Ex­ter­nal Con­trol Arms

Most drug development professionals are familiar with the nerve-racking wait for the read-out of a large trial. If it’s negative, is the investigational therapy ineffective? Or could the failure result from an unforeseen flaw in the design or execution of the protocol, rather than a lack of efficacy? The team could spend weeks analyzing data, but a definitive answer may be elusive due to insufficient power for such analyses in the already completed trial. These problems are only made worse if the trial had lower enrollment, or higher dropout than expected due to an unanticipated event like COVID-19. And if a trial is negative, the next one is likely to be larger and more costly — if it happens at all.

Paul Hudson, Sanofi CEO (Cyril Marcilhacy/Bloomberg via Getty Images)

Sanofi snaps up new vac­cine can­di­date and de­vis­es mR­NA game plan around it — but not for what you think

Paul Hudson has spotlighted vaccines, immunology and dermatology as some of the top R&D focuses at Sanofi. His latest deal brings all of them together.

The French pharma giant isn’t sharing any financial details about the buyout of Origimm, a low-profile, private Austrian biotech whose technology promises to identify antigens causing skin disease and build vaccines against them. Their lead candidate targets acne vulgaris.

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