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.”

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.

Graphic: Kathy Wong for Endpoints News

What kind of biotech start­up wins a $3B syn­di­cate, woos a gallery of mar­quee sci­en­tists and re­cruits GSK's Hal Bar­ron as CEO in a stun­ner? Let Rick Klaus­ner ex­plain

It started with a question about a lifetime’s dream on a walk with tech investor Yuri Milner.

At the beginning of the great pandemic, former NCI chief and inveterate biotech entrepreneur Rick Klausner and the Facebook billionaire would traipse Los Altos Hills in Silicon Valley Saturday mornings and talk about ideas.

Milner’s question on one of those mornings on foot: “What do you want to do?”

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Hal Barron, Endpoints UKBIO20 (Jeff Rumans)

'Al­tos was re­al­ly a once-in-a-life­time op­por­tu­ni­ty': Hal Bar­ron re­flects on his big move

By all accounts, Hal Barron had one of the best jobs in Big Pharma R&D. He made more than $11 million in 2020, once again reaping more than his boss, Emma Walmsley, who always championed him at every opportunity. And he oversaw a global R&D effort that struck a variety of big-dollar deals for oncology, neurodegeneration and more.

Sure, the critics never let up about what they saw as a rather uninspiring late-stage pipeline, where the rubber hits the road in the Big Pharma world’s hunt for the next big near-term blockbuster, but the in-house reviews were stellar. And Barron was firmly focused on bringing up the success rate in clinical trials, holding out for the big rewards of moving the dial from an average 10% success rate to 20%.

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Executive Director of the EMA Emer Cooke (AP Photo/Geert Vanden Wijngaert)

Eu­ro­pean Par­lia­ment signs off on strength­en­ing drug reg­u­la­tor's abil­i­ty to tack­le short­ages

The European Parliament on Thursday endorsed a plan to increase the powers of the European Medicines Agency, which will be better equipped to monitor and mitigate shortages of drugs and medical devices.

By a vote of 655 to 31, parliament signed off on a provisional agreement reached with the European Council from last October, in which the EMA will create two shortage steering groups (one for drugs, the other for devices), a new European Shortages Monitoring Platform to facilitate data collection and increase transparency, and on funding for the work of the steering groups, task force, working parties and expert panels that are to be established.

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FDA+ roundup: FDA's neu­ro­science deputy de­parts amid on­go­ing Aduhelm in­ves­ti­ga­tions; Califf on the ropes?

Amid increased scrutiny into the close ties between FDA and Biogen prior to the controversial accelerated approval of Aduhelm, the deputy director of the FDA’s office of neuroscience has called it quits after more than two decades at the agency.

Eric Bastings will now take over as VP of development strategy at Ionis Pharmaceuticals, the company said Wednesday, where he will provide senior clinical and regulatory leadership in support of Ionis’ pipeline.

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Sec­ondary patents prove to be key in biosim­i­lar block­ing strate­gies, re­searchers find

While the US biosimilars industry has generally been a disappointment since its inception, with FDA approving 33 biosimilars since 2015, just a fraction of those have immediately followed their approvals with launches. And more than a handful of biosimilars for two of the biggest blockbusters of all time — AbbVie’s Humira and Amgen’s Enbrel — remain approved by FDA but still have not launched because of legal settlements.

Hal Barron (GSK via YouTube)

GSK R&D chief Hal Bar­ron jumps ship to run a $3B biotech start­up, Tony Wood tapped to re­place him

In a stunning switch, GlaxoSmithKline put out word early Wednesday that R&D chief Hal Barron is exiting the company after 4 years — a relatively brief run for the man chosen by CEO Emma Walmsley in late 2017 to turn around the slow-footed pharma giant.

Barron is being replaced by Tony Wood, a close associate of Barron’s who’s taking one of the top jobs in Big Pharma R&D. He’ll be closer to home, though, for GSK. Barron has been running a UK and Philadelphia-based research organization from his perch in San Francisco.

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Chamath Palihapitiya and Pablo Legorreta

Bil­lion­aires Chamath Pal­i­hapi­tiya and Pablo Legor­re­ta hatch an $825M SPAC for cell ther­a­py biotech

Three years after Royalty Pharma chief Pablo Legorreta led a group of investors to buy up a pair of biotechs and create a new startup called ProKidney, the biotech is jumping straight into an $825 million public shell created by SPAC king and tech billionaire Chamath Palihapitiya.

ProKidney was founded 6 years ago but really got going at the beginning of 2019 with the $62 million acquisition of inRegen, which was working on an autologous — from the patient — cell therapy for kidney disease. After extracting kidney cells from patients, researchers expand the cells in the lab and then inject them back into patients, aiming to restore the kidneys of patients suffering from CKD.

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Troy Wilson, Kura CEO

FDA lifts par­tial hold on Ku­ra's Phase Ib AML pro­gram as biotech re­dou­bles mit­i­ga­tion ef­forts

Kura Oncology is clear to resume studies for its early-stage leukemia program after the FDA lifted a clinical hold Thursday afternoon.

Regulators had placed the hold on a Phase Ib study of KO-539, an experimental oral treatment for some genetic subsets of acute myeloid leukemia last November after a patient died while taking the drug. Kura expects to begin enrolling patients again imminently, CEO Troy Wilson told Endpoints News.