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.”

MedTech clinical trials require a unique regulatory and study design approach and so engaging a highly experienced CRO to ensure compliance and accurate data across all stages is critical to development milestones.

In­no­v­a­tive MedTech De­mands Spe­cial­ist Clin­i­cal Tri­al Reg­u­la­to­ry Af­fairs and De­sign

Avance Clinical is the Australian CRO for international biotechs providing world-class clinical research services with FDA-accepted data across all phases. With Avance Clinical, biotech companies can leverage Australia’s supportive clinical trials environment which includes no IND requirement plus a 43.5% Government incentive rebate on clinical spend. The CRO has been delivering clinical drug development services for international biotechs for FDA and EMA regulatory approval for the past 24 years. The company has been recognized for the past two consecutive years with the prestigious Frost & Sullivan CRO Best Practices Award and a finalist in Informa Pharma’s Best CRO award for 2022.

Mathai Mammen (Rob Tannenbaum, Endpoints News at BIO 2018)

Math­ai Mam­men makes an abrupt ex­it as head of the big R&D group at J&J

In an after-the-bell shocker, J&J announced Monday evening that Mathai Mammen has abruptly exited J&J as head of its top-10 R&D group.

Recruited from Merck five years ago, where the soft-spoken Mammen was being groomed as the successor to Roger Perlmutter, he had been one of the top-paid R&D chiefs in biopharma. His group spent $12 billion last year on drug development, putting it in the top 5 in the industry.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 147,500+ biopharma pros reading Endpoints daily — and it's free.

Robert Califf, FDA commissioner (Tom Williams/CQ Roll Call via AP Images)

Hop­ing to ex­pand mon­key­pox vac­cine sup­ply, US paves the way for new route of ad­min­is­tra­tion

After making it clear that the US’ current monkeypox vaccine supply is insufficient, the FDA on Tuesday authorized a new route of administration that should increase the number of available doses by five-fold.

Regulators cleared Bavarian Nordic’s Jynneos vaccine for intradermal injection in adults older than 18. Unlike subcutaneous injection — the current method by which vaccine is delivered under the skin — an intradermal jab goes directly into the skin. It’s believed that this method requires less vaccine, since the dermis is rich in dendritic cells which specialize in taking up foreign antigens and presenting them to the immune system, according to Daniel Kuritzkes, chief of infectious diseases at Brigham and Women’s Hospital in Boston.

Samantha Du, Zai Lab CEO

Any­one still look­ing for a CD47? Zai Lab shelves PhI pro­gram af­ter re­view­ing 'com­pet­i­tive land­scape'

Over the past few years, the promise of blocking CD47 — a “don’t eat me” signal co-opted by cancer cells — has sent drugmakers big and small into a frenzy. But one biotech is now bowing out.

Zai Lab is deprioritizing ZL-1201, its CD47 inhibitor, scrapping plans for a Phase II trial. It will now “pursue out-licensing opportunities,” the company said in its Q2 update. The decision was based on a review of the competitive landscape, it added, without going into further details.

Illustration: Kim Ryu for Endpoints News

Why non-opi­oid pain drugs keep fail­ing — and what's next for the field

In 1938, Rita Levi-Montalcini was forced to move her lab into her bedroom in Turin, as Mussolini’s facist government expelled Jewish people from studying or working in schools in Italy. Levi-Montalcini, then just a few years out of medical school and using sewing needles as scalpels in her makeshift lab, would soon discover nerve growth factor, or NGF, in chicken embryos.

Her discoveries formed the basis of our understanding of the peripheral nervous system and how cells talk to each other, and Levi-Montalcini went on to win the Nobel Prize in 1986. Much later, NGF was hailed as a promising target for new pain therapies, with some analysts quoting an $11 billion market. However, the latest anti-NGF candidate, Pfizer and Eli Lilly’s tanezumab, was rejected by the FDA last year because of a side effect that dissolved bone in some of its patients.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Ted Love, Global Blood Therapeutics CEO

Up­dat­ed: Pfiz­er scoops up Glob­al Blood Ther­a­peu­tics and its sick­le cell ther­a­pies for $5.4B

Pfizer is dropping $5.4 billion to acquire Global Blood Therapeutics.

Just ahead of the weekend, word got out that Pfizer was close to clinching a $5 billion buyout — albeit with other potential buyers still at the table. The pharma giant, flush with cash from Covid-19 vaccine sales, apparently got out on top.

The deal immediately swells Pfizer’s previously tiny sickle cell disease portfolio from just a Phase I program to one with an approved drug, Oxbryta, plus a whole pipeline that, if all approved, the company believes could make for a $3 billion franchise at peak.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 147,500+ biopharma pros reading Endpoints daily — and it's free.

HHS Secretary Xavier Becerra (Patrick Semansky/AP Images)

US weighs new route of ad­min­is­tra­tion for mon­key­pox vac­cine as cas­es climb — re­port

Less than a week after HHS Secretary Xavier Becerra declared monkeypox a national health emergency, reports have emerged that the US plans to extend its vaccine supply by opting for a different route of administration.

Officials are expected to call for intradermal injection of Bavarian Nordic’s Jynneos vaccine — the only shot approved specifically for monkeypox in the US — as opposed to subcutaneous injection, unnamed sources told both the New York Times and Washington Post on Tuesday.

'Messy at best': Is the US re­peat­ing the same Covid mis­steps with mon­key­pox mes­sag­ing?

When Kyle Planck first suspected he might have monkeypox in late June, he went to the CDC website and found six photos of different types of lesions. And that was about it for general public information.

Planck, who is a sixth-year PhD pharmacology researcher at Weill Cornell, kept looking though and found a separate part of the CDC website meant for healthcare professionals. There he found a medical slide deck with more pictures, professional journal articles and more details about symptoms and diagnosis.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Andy Jassy, Amazon CEO (Isaac Brekken/AP Images for NFL, File)

Up­dat­ed: FDA slaps Ama­zon with a warn­ing let­ter for sell­ing OTC mole re­moval prod­ucts

The FDA’s Center for Drug Evaluation and Research on Tuesday released a warning letter sent last week to Amazon CEO Andy Jassy in Seattle for selling mole removal products over-the-counter, or, as the FDA explains, “introducing, delivering, or causing the introduction or delivery into interstate commerce of products that are unapproved new drugs.”

“There are no over-the-counter (OTC) drugs that can be legally sold for mole or skin tag removal, and FDA has safety concerns about drugs marketed OTC directly to consumers for these uses,” the agency said in its Aug. 4 warning.