Eli Lil­ly, No­var­tis back a biotech start­up boast­ing 'best of both world­s' pro­tein de­graders

Since head­ing up Glax­o­SmithK­line’s pro­tein degra­da­tion unit in 2012, Ian Churcher has wit­nessed a rapid ex­plo­sion of in­ter­est in the idea of lever­ag­ing the body’s garbage dis­pos­al sys­tem to elim­i­nate prob­lem­at­ic pro­teins. Huge amounts of mon­ey are flow­ing in from biotech VCs and Big Phar­ma play­ers, bankrolling a huge vol­ume of projects — some of which have now made it to the clin­ic.

Ian Churcher

“What I would say hasn’t changed is the fo­cus is still very much on a small num­ber of mech­a­nisms, around say VHL and cere­blon, and we knew about these mech­a­nisms very ear­ly,” he told End­points News. “So I think what that sug­gests is it’s re­al­ly quite dif­fi­cult to iden­ti­fy nov­el mech­a­nisms.”

He has since moved on to oth­er dis­cov­ery fields, but that feel­ing was what got him ex­cit­ed about fo­cus­ing on tar­get­ed pro­tein degra­da­tion again and tak­ing up the CSO post at Am­phista last May, just af­ter the UK-based biotech de­buted with a $7.5 mil­lion Se­ries A.

The hy­poth­e­sis at Am­phista, in­cu­bat­ed at aca­d­e­m­ic founder Alessio Ciul­li’s lab in Scot­land, has been that you can tar­get pro­teins for degra­da­tion by en­gag­ing oth­er parts of the ubiq­ui­tin-pro­tea­some sys­tem, said CEO Nic­ki Thomp­son.

Less than a year lat­er, they’ve scored $53 mil­lion in fresh fi­nanc­ing to prove it fur­ther.

No­var­tis and Eli Lil­ly hopped on­to the syn­di­cate along­side Gilde Health­care and For­bion, co-lead­ers of the round, and Am­phista’s ex­ist­ing back­ers at Bio­Mo­tiv and Ad­vent Life Sci­ences.

Nic­ki Thomp­son

Am­phista, Churcher not­ed, isn’t the on­ly com­pa­ny re­al­iz­ing the lim­i­ta­tions of PRO­TACs as pi­o­neered by Craig Crews (with whom Ciul­li had worked as a fel­low) and oth­ers like Jay Brad­ner be­fore he be­came the chief of No­var­tis In­sti­tutes for Bio­Med­ical Re­search. Their re­spec­tive spin­outs, Arv­inas and C4 Ther­a­peu­tics, are some of the first to start Phase I stud­ies — in prostate can­cer and hema­to­log­ic ma­lig­nan­cies, re­spec­tive­ly.

There’s Ly­cia, the start­up pur­su­ing Car­olyn Bertozzi’s ideas for tar­get­ing ex­tra­cel­lu­lar pro­teins; a string of oth­ers, like Monte Rosa, are mov­ing in­to “mol­e­c­u­lar glues” — small­er com­pounds that they hope would have bet­ter drug-like prop­er­ties.

But glues would ul­ti­mate­ly on­ly work for a small num­ber of tar­gets, he added. So they chose to keep the tra­di­tion­al two-part con­struct of bi­func­tion­al de­graders, with one half bind­ing to the drug tar­get and the oth­er half be­ing a “war­head” that would re­cruit a pro­tein to ini­ti­ate the degra­da­tion. By en­gi­neer­ing the war­heads to en­list things oth­er than those E3 lig­as­es — they still can’t re­veal what ex­act­ly makes it “gen­uine­ly dif­fer­ent” — they be­lieve they will open up whole new ar­eas for ex­plo­ration.

“We think we’ve over­come a lot of those prob­lems,” Churcher said. “So our bi­func­tion­al ap­proach gives us the best of both worlds — great drug-like prop­er­ties and a broad tar­get scope.”

With a goal to bring the lead pro­gram in­to the clin­ic in 2023, Thomp­son not­ed the Se­ries B will drill down on those ini­tial on­col­o­gy in­di­ca­tions and po­ten­tial­ly ex­pand to oth­ers that are cur­rent­ly out of bounds for pro­tein degra­da­tion.

De­spite the num­ber of com­pa­nies in the space, af­ter all, Kymera is pret­ty much the on­ly one that’s pub­licly gone af­ter some­thing out­side of can­cer by ex­plor­ing in­flam­ma­tion with Sanofi.

Thomp­son and Churcher en­vi­sion go­ing even fur­ther, pro­duc­ing next-gen mol­e­cules that might even ad­dress dis­eases of the cen­tral ner­vous sys­tem.

With 15 full-time em­ploy­ees at the mo­ment, they ex­pect to at least dou­ble over the com­ing 12 to 18 months while pur­su­ing a “lim­it­ed num­ber of” strate­gic part­ner­ships.

“The field will con­tin­ue to grow — there’s a huge amount of ef­fort, very smart minds go­ing in­to the area,” Churcher said. “But we re­al­ly do need to break out of the lim­i­ta­tions that the cur­rent mech­a­nisms do bring up­on the field. I think they will be suc­cess­ful, but I think there’s so much more scope to be even more suc­cess­ful.”

Image courtesy of The Janssen Pharmaceutical Companies of Johnson & Johnson.

Pro­tect­ing the glob­al phar­ma­ceu­ti­cal in­no­va­tion ecosys­tem – what’s at stake?

We are living in a new era of healthcare that is rapidly advancing progress impacting patient outcomes and experiences. We’ve seen a remarkable pace of transformational innovation, applied research, and advanced clinical development over the last decade.

Despite this tremendous progress, there is much more work to be done, and patients are counting on us – now more than ever – to continue that momentum. At the heart of our industry is a focus on developing and delivering medicines for some of the world’s most challenging diseases, including those that have few or no effective treatments today.

End­points 20(+2) un­der 40, 2023; Bio­phar­ma's high­est-paid CEOs; N-of-1 CRISPR sto­ry goes on af­ter tragedy; 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.

We will be off Monday in observance of Memorial Day — and when we get back, it will be a straight march to ASCO, BIO and more. Enjoy the (long) weekend!

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Rich Horgan (R) with his late brother, Terry

Rich Hor­gan spear­head­ed a gene ther­a­py for his broth­er. The tri­al end­ed in tragedy, but the work con­tin­ues for more pa­tients

Rich Horgan’s quest to create a custom gene therapy for his brother, Terry, ended in tragedy. But Horgan doesn’t believe it’s the end of the story.

Terry, a 27-year-old patient with Duchenne muscular dystrophy, died last October just eight days after receiving the therapy in a clinical trial in which he was the only participant. The case raised questions about the safety of certain gene therapies and what would happen to other drug programs under a nonprofit that Horgan created, called Cure Rare Disease.

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Bio­phar­ma's 20 high­est-paid CEOs of 2022, each bring­ing in $20M+ pay­days

Even in a down year for much of the biopharma market, 20 CEOs brought in pay packages valued at more than $20 million, an Endpoints News analysis found.

Endpoints collected data on more than 350 CEO compensation packages, covering a wide range of pharma, biotech, and life sciences companies. All told, the 20 largest earners made over $725 million in 2022 — an average package of $36.4 million. Three brought in paydays over $50 million, and one CEO broke the $100 million mark.

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Mi­rati’s drug sitra­va­tinib flops PhI­II in com­bo with Op­di­vo for cer­tain lung can­cer

Mirati Therapeutics’ path to a second drug approval will likely have to wait. The San Diego biotech company said Wednesday that its investigational lung cancer drug failed a Phase III trial testing it in combination with Bristol Myers Squibb’s Opdivo.

The drug, sitravatinib, and Opdivo weren’t better than the chemo drug docetaxel at keeping patients alive, Mirati said in a press release. The spectrum-selective kinase inhibitor missed the primary goal of overall survival in patients with second- or third-line advanced non-squamous, non-small cell lung cancer.

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The 20(+2) un­der 40: Your guide to the next gen­er­a­tion of biotech lead­ers

This year’s list of 20 biotech leaders under the age of 40 includes a huge range of ambitions. Some of our honorees are planning to create the next big drug giant. Others are pushing the bounds of AI. One is working to revolutionize TB testing. All are compelling talents who are still young in age, but already far along in achievement.

And, as in years past, we went over. The 20 are actually 22 because of two double profiles that reflect how important teamwork is in the industry. As one of our honorees, Joe Illingworth of DJS Antibodies, told me in our interview, “It takes a village to raise a biotech.”

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Athena Countouriotis, Avenzo Therapeutics CEO (website via Nasdaq)

Ex-Turn­ing Point ex­ecs plan to have their next bet, Aven­zo, on the Nas­daq next sum­mer

The crew at Turning Point Therapeutics is back together for a new biotech that wants to acquire early-stage oncology small molecules, including antibody drug conjugates, and potentially form partnerships with China-based drug developers for ex-China rights as it eyes a speedy leap onto the Nasdaq around this time next year, CEO Athena Countouriotis told Endpoints News.

After selling Turning Point to Bristol Myers Squibb, announced at the onset of last year’s ASCO confab, she and colleague Mohammad Hirmand founded Avenzo Therapeutics. The CEO and CMO already have approximately $200 million in seed and Series A financing from five big-name investors to evaluate which drugs to bring into its pipeline. That includes SR One, OrbiMed, Foresite Capital, Citadel’s Surveyor Capital and Lilly Asia Ventures. Bidding wars for assets have led Avenzo to miss out on some deals in recent months, but the biotech has three active term sheets and hopes to bring in its first asset in the third quarter, Countouriotis said in a Friday morning interview.

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FDA ap­proves Lex­i­con’s heart-fail­ure drug af­ter de­feat in di­a­betes

The FDA on Friday approved Lexicon’s heart failure drug sotagliflozin following a string of setbacks for the pharma company, including an FDA rejection in diabetes and the loss of a development deal with Sanofi.

The dual SGLT1 and SGLT2 inhibitor will be marketed as Inpefa and is a once-daily tablet. It’s been approved to reduce the risk of cardiovascular death and heart failure-related hospitalization or urgent visits in adults with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. The label spans the range of left ventricular ejection fraction, including preserved ejection fraction and reduced ejection fraction, as well as patients with or without diabetes, Lexicon said Friday.

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Eu­ro­pean Com­mis­sion to re­ceive few­er Pfiz­er-BioN­Tech vac­cine dos­es un­der amend­ed con­tract

The European Commission has made a few changes to its vaccine contract with Pfizer and BioNTech, reducing the dose volume while extending the delivery timeline to cope with “evolving public health needs.”

The Commission previously struck a contract in May 2021 for 900 million doses, with the option to purchase another 900 million. Of those, 450 million were expected to be delivered in 2023, though an amendment now calls for fewer doses. While neither the Commission nor Pfizer and BioNTech have revealed an exact amount, an unnamed source told Reuters that the amendment reduces the remaining expected doses by about a third.

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