Nan Ji (PAQ Therapeutics)

Dis­cov­ery by Shang­hai sci­en­tists in­spires new plan of AT­TEC for pro­tein degra­da­tion

In a re­view penned weeks ago, Craig Crews — the Yale sci­en­tist cred­it­ed with the dis­cov­ery of PRO­TACs — re­flect­ed on how, in the two decades since he helped launch the field, tar­get­ed pro­tein degra­da­tion has moved be­yond the pro­tea­some in­to “nov­el and ex­cit­ing” strate­gies.

“For ex­am­ple, Lyso­some Tar­get­ing Chimeras (LY­TACs) har­ness the lyso­so­mal degra­da­tion path­way to in­duce degra­da­tion of ex­tra­cel­lu­lar pro­teins and the Macroau­tophagy Degra­da­tion Tar­get­ing Chimera (MAD­TAC) plat­forms, AU­TACs and AT­TECs hi­jack the au­tophagy path­way, thus po­ten­tial­ly en­abling the tar­get­ed de­struc­tion of en­tire or­ganelles and pro­tein ag­gre­gates,” he and co-au­thor Michael Bond wrote.

One of those ap­proach­es they spot­light­ed is now hav­ing a com­ing-out par­ty.

Sher­pa Health­care Part­ners is lead­ing the $30 mil­lion Se­ries A for PAQ Ther­a­peu­tics, which is promis­ing to chart a dif­fer­ent route for de­grad­ing dis­ease-caus­ing sub­strates.

CEO Nan Ji was head of chem­istry at Kymera, the At­las-backed start­up whose take on pro­tein degra­da­tion would lead in­to a Sanofi part­ner­ship, when he no­ticed a pa­per in Na­ture de­scrib­ing au­tophago­some-teth­er­ing com­pounds, or AT­TECs, in late 2019. While the de­graders he had been work­ing on lever­aged the ubiq­ui­tin-pro­tea­some sys­tem (UPS), the au­thors went with the oth­er ma­jor degra­da­tion path­way: au­tophagy, which lit­er­al­ly means “self-eat.”

Specif­i­cal­ly, the re­searchers fig­ured out a way to ap­pro­pri­ate the process by which a vesi­cle en­gulf­ing cer­tain sub­strates, dubbed au­tophago­some, is formed. By pulling to­geth­er an au­tophago­some struc­ture and a dis­ease-caus­ing sub­strate, they could nudge the au­tophago­somes to gob­ble up those prob­lem­at­ic mol­e­cules, in their case the pro­tein to blame for Hunt­ing­ton’s dis­ease. A good vi­su­al­iza­tion ex­er­cise may be the game of Pac-Man, with the lit­tle yel­low PAC head chew­ing up all the dots — at least that’s where PAQ would even­tu­al­ly get its name.

“Be­cause au­tophagy is the most ver­sa­tile mech­a­nism in the hu­man body to ini­ti­ate degra­da­tion, it ac­tu­al­ly has a much wider va­ri­ety of sub­strates that it can take care of, such as lipids, such as pro­tein ag­gre­gates, de­fec­tive mi­to­chon­dria,” Nan Ji told End­points News.

He wasn’t alone. Co­in­ci­den­tal­ly, Nest.Bio Ven­tures and Ma­trix Part­ners Chi­na saw po­ten­tial in that tech­nol­o­gy and got in touch with the sci­en­tists at Shang­hai’s Fu­dan Uni­ver­si­ty who wrote the pa­per to seed a spin­out.

“So in that sense, this com­pa­ny ac­tu­al­ly speaks to the grow­ing pres­ence of the sci­en­tif­ic dis­cov­ery from Chi­na,” he said, adding that Box­un Lu, the sci­en­tif­ic co-founder, “ac­tu­al­ly is trained in the US, at UPenn, and then he did his post­doc at No­var­tis.”

Box­un Lu (R) and his stu­dent (Cred­it: Fu­dan Uni­ver­si­ty)

Ji, who shares a sim­i­lar back­ground (he got his bach­e­lor’s at Peking Uni­ver­si­ty be­fore pur­su­ing a PhD at Har­vard), was re­cruit­ed to be CEO about a year ago.

As the pro­tein degra­da­tion space booms, di­ver­si­ty is al­so grow­ing. In­trigued by the pos­si­bil­i­ty of com­plete­ly flush­ing out, and not just block­ing, mu­tant or ex­ces­sive mol­e­cules that cause dis­ease, Big Phar­ma and VCs have wa­gered big on all sorts of new tech­nolo­gies. Some play­ers are stak­ing their names on new E3 lig­as­es while oth­ers bank on dif­fer­ent ways to re­cruit the pro­teins for dis­pos­al, such as mol­e­c­u­lar glues or mono­va­lent binders. Car­olyn Bertozzi and Ver­sant have teamed up at Ly­cia Ther­a­peu­tics to pur­sue LY­TACs, which lever­ages the lyso­some to de­grade ex­tra­cel­lu­lar pro­teins (where­as PRO­TACs can on­ly get rid of in­tra­cel­lu­lar ones).

Work­ing with a small team of six in the Boston/Cam­bridge area, Ji thinks of the com­pa­ny as glob­al with a net­work of CRO and three sci­en­tif­ic ad­vi­sors: David Ru­bin­sztein, pro­fes­sor of mol­e­c­u­lar neu­ro­ge­net­ics at the Uni­ver­si­ty of Cam­bridge; Jared Rut­ter, a can­cer re­searcher at the Uni­ver­si­ty of Utah; and Jin-Quan Yu at Scripps.

The Se­ries A cash, which al­so came from Hua­gai Cap­i­tal, MSA Cap­i­tal and MRL Ven­tures Fund, is ex­pect­ed to push the lead can­di­date for an un­spec­i­fied ge­net­ic neu­rode­gen­er­a­tive dis­or­der in­to pre­clin­i­cal de­vel­op­ment. Two oth­er pro­grams are be­ing lined up, and the hope is to be in the clin­ic with­in three years. But Ji is al­so re­al­is­tic.

“We do ex­pect there are gonna be chal­lenges along the way,” he said. “We have to build as­says, we have to build know-hows. It could take us longer but we are ready.”

Adap­tive De­sign Meth­ods Of­fer Rapid, Seam­less Tran­si­tion Be­tween Study Phas­es in Rare Can­cer Tri­als

Rare cancers account for 22 percent of cancer diagnoses worldwide, yet there is no universally accepted definition for a “rare” cancer. Moreover, with the evolution of genomics and associated changes in categorizing tumors, some common cancers are now characterized into groups of rare cancers, each with a unique implication for patient management and therapy.

Adaptive designs, which allow for prospectively planned modifications to study design based on accumulating data from subjects in the trial, can be used to optimize rare oncology trials (see Figure 1). Adaptive design studies may include multiple cohorts and multiple tumor types. In addition, numerous adaptation methods may be used in a single trial and may facilitate a more rapid, seamless transition between study phases.

Matt Gline (L) and Pete Salzmann

UP­DAT­ED: Roivant bumps stake in Im­muno­vant with a $200M deal. But with M&A off the ta­ble, shares crater

Roivant has worked out a deal to pick up a chunk of stock in its majority-owned sub Immunovant $IMVT, but the stock buy falls far short of its much-discussed thoughts about buying out all of the 43% of shares it doesn’t already own.

Roivant, which recently inked a SPAC move to the market at a $7 billion-plus valuation, has forged a deal to boost its ownership in Immunovant by 6.3 points, ending with 63.8% of the biotech’s stock following a $200 million injection. That cash will bolster Immunovant’s cash reserves, giving it a $600 million war chest to fund a slate of late-stage studies for its big drug: the anti-FcRn antibody IMVT-1401.

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Sanofi preps a multi­bil­lion-dol­lar buy­out of an mR­NA pi­o­neer af­ter falling be­hind in the race for a Covid-19 jab — re­port

It looks like Sanofi CEO Paul Hudson is dead serious about his intention to vault directly into contention for the future of mRNA vaccines.

A year after paying Translate Bio a whopping $425 million in an upfront and equity payment to help guide the pharma giant to the promised land of mRNA vaccines for Covid-19, Sanofi is reportedly ready to close the deal with a buyout.

Translate’s stock $TBIO soared 78% after the market closed Monday. A spokesperson for Sanofi declined to comment on the report, telling Endpoints News that the company doesn’t comment on market rumors.

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Anthony Sun, Zentalis and Zentera CEO (Zentalis)

With clin­i­cal tri­als lined up for Zen­tal­is drugs, Chi­na's Zen­tera sets its sights on more deal­mak­ing and an IPO

As Zentalis geared up for an AACR presentation of early data on its WEE1 inhibitor earlier this year, its Chinese joint venture Zentera wasn’t idle, either.

Zentera, which has headquarters in Shanghai, had already nabbed clearance to start clinical trials in China for three of the parent company’s drugs. In May — just a month after Zentalis touted three “exceptional responses” out of 55 patients for their shared lead drug, ZN-c3 — it got a fourth CTA approval.

Thomas Soloway, T-knife CEO

What hap­pens when you give a mouse a hu­man self-anti­gen? In­vestors bet $110M to find out

T-knife Therapeutics launched last August on a mission to isolate T cell receptors not from human donors, but from mice. Now, with a new CEO and a candidate bound for the clinic, the Versant-backed company is reloading with a fresh $110 million.

“What we are trying to do for the field of TCR therapy and solid tumor therapy is very analogous to what the murine platforms have done in antibody development,” CEO Thomas Soloway told Endpoints News. 

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UP­DAT­ED: Watch out Glax­o­SmithK­line: As­traZeneca's once-failed lu­pus drug is now ap­proved

Capping a roller coaster journey, AstraZeneca has steered its lupus drug anifrolumab across the finish line.

Saphnelo, as the antibody will be marketed, is the only treatment that’s been approved for systemic lupus erythematosus since GlaxoSmithKline’s Benlysta clinched an OK in 2011. The British drugmaker notes it’s also the first to target the type I interferon receptor.

Mirroring the population that the drug was tested on in late-stage trials, regulators sanctioned it for patients with moderate to severe cases who are already receiving standard therapy — setting up a launch planned for the end of August, according to Ruud Dobber, who’s in charge of AstraZeneca’s biopharmaceuticals business unit.

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Not all mR­NA vac­cines are cre­at­ed equal. Does it mat­ter?; Neu­ro is back; Pri­vate M&A af­fair; 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.

As part of our broader and deeper drive, Endpoints has been pairing webinars with our special reports to cover more angles on a given topic. In conjunction with Max Gelman’s neuroscience feature, Kyle Blankenship moderated an insightful panel to discuss where the field is headed. You can register to watch it on demand here.

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Bris­tol My­ers pulls lym­phoma in­di­ca­tion for Is­to­dax af­ter con­fir­ma­to­ry tri­al falls flat

Amid an industrywide review of cancer drugs with accelerated approval, Bristol Myers Squibb had to make the tough call last month to yank an approval for leading I/O drug Opdivo after flopping a confirmatory study. Now, a second Bristol Myers drug is on the chopping block.

Bristol Myers has pulled aging HDAC inhibitor Istodax’s indication in peripheral T cell lymphoma after a Phase III confirmatory study for the drug flopped on its progression-free survival endpoint, the drugmaker said Monday.

Rick Pazdur (via AACR)

FDA's on­col­o­gy head Rick Paz­dur de­fends the ac­cel­er­at­ed ap­proval path­way, claim­ing it is 'un­der at­tack'

The FDA is sounding the alarm over its accelerated approval pathway as backlash continues over the recent nod in favor of Biogen’s Alzheimer’s drug Aduhelm, and an ODAC meeting on six such approvals that could potentially be pulled from the market — two of which already have.

“Do you think accelerated approval is under attack? I do,” Rick Pazdur, head of FDA’s Oncology Center of Excellence, said at a Friends of Cancer Research webinar on Thursday.

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