Chas­ing 'Holy Grail' STAT3 tar­get, Hous­ton start­up re­fu­els with $74M to ze­ro in on liv­er can­cer

Ron De­Pin­ho

Tvar­di launched out of Hous­ton with the promise of fi­nal­ly de­vel­op­ing the right in­hibitors for the Holy Grail tar­get of STAT3 — un­der the guid­ance of se­r­i­al en­tre­pre­neur Ron De­Pin­ho and his col­league David Tweardy, a lead­ing ex­pert in the field. Al­most three years lat­er, they say they have the proof of con­cept da­ta to keep go­ing.

It’s good enough for a $74 mil­lion Se­ries B, a big jump from the $9 mil­lion they got in the last round and, CEO Im­ran Al­ib­hai would add, a re­flec­tion of the rep his team has built.

In Phase I dose es­ca­la­tion stud­ies in­volv­ing pa­tients with sol­id tu­mors who have failed all oth­er treat­ments, the lead com­pound was shown to have down­reg­u­lat­ed the STAT3 ac­tiv­i­ty of in­ter­est: block­ing it from be­com­ing phos­pho­ry­lat­ed by the re­cep­tors it typ­i­cal­ly in­ter­acts with.

“The topline news is that in over half of our pa­tients, we’ve seen clin­i­cal ben­e­fit” in the form of tu­mor sta­bi­liza­tion, shrink­age or even par­tial re­spons­es, he said. “That drove a lot of in­ter­est, but be­yond that what’s been strik­ing has been the safe­ty.”

He be­lieves the se­cret lies in fo­cus­ing on pre­vent­ing the ac­ti­va­tion of STAT3, which dri­ves the nu­clear func­tion re­lat­ed to dis­ease, but not try­ing to re­move it from the sys­tem, de­grade it, or break it too much. The small win­dow, af­ter all, is what makes tar­get­ing STAT3 so tricky de­spite it be­ing a top 5 tar­get for can­cer.

David Tweardy

By the first half of next year, Tvar­di ex­pects to wrap up the Phase I tri­al and ze­ro in on he­pa­to­cel­lu­lar car­ci­no­ma in Phase II tri­als — while al­so start­ing to study the drug for fi­bro­sis.

“When you think about growth and dif­fer­en­ti­a­tion in tu­mors, and metas­tases, there’s prob­a­bly three or four legs to the stool, and STAT3 is def­i­nite­ly one of those. Right? It is a cen­tral node,” Al­ib­hai said. “When it comes to fi­bro­sis, there is one leg to the stool. And STAT3 mod­u­lates that path­way. And so if you could find a safe drug that ac­tu­al­ly tar­gets STAT3, you can po­ten­tial­ly see some re­al­ly beau­ti­ful da­ta.”

Oth­ers have ar­rived at the same con­clu­sion, with a small band of star­tups herald­ing new ap­proach­es such as pro­tein degra­da­tion to tar­get STAT3, Sanofi-part­nered Kymera and Medicxi’s Jan­pix (now part of Centes­sa) among them.

For his part, Al­ib­hai said he wel­comes more op­tions for pa­tients and hopes Tvar­di’s oral dos­ing small mol­e­cule treat­ment can set it­self apart. Be­sides, it is not triv­ial to make drugs that can even get in­to the clin­ic.

“What the true test is: Can you ac­tu­al­ly get in, be safe, and be very very very tar­get­ed in the case of STAT3?” he not­ed. “Be­cause there are mul­ti­ple roles for STAT3 in every cell, and so we need to make sure that we’re tar­get­ing ap­pro­pri­ate­ly for the role that we’re in­ter­est­ed in.”

The small com­pa­ny is al­ready work­ing on a sec­ond-gen­er­a­tion mol­e­cule that will be three to eight times more po­tent than the lead can­di­date, he said. And their new in­vestors are in for the long game, giv­ing them the op­tion to ei­ther jump straight in­to an IPO next or raise an­oth­er crossover round and, more im­por­tant­ly, “do some­thing in­ter­est­ing.”

Slate Path Cap­i­tal, Palkon Cap­i­tal, Ar­row­Mark Part­ners and 683 Cap­i­tal joined the round, with sig­nif­i­cant sup­port from Sporos Bioven­tures and oth­er ex­ist­ing in­vestors.

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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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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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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CBO: Medicare ne­go­ti­a­tions will ham­per drug de­vel­op­ment more than pre­vi­ous­ly thought

As President Biden’s Build Back Better Act — and, with it, potentially the Democrats’ last shot at major drug pricing reforms in the foreseeable future — remains on life support, the Congressional Budget Office isn’t helping their case.

The CBO last week released a new slide deck, outlining an update to its model on how Medicare negotiations might take a bite out of new drugs making it to market. The new model estimates a 10% long-term reduction in the number of new drugs, whereas a previous CBO report from August estimated that 8% fewer new drugs will enter the market over 30 years.

Joshua Brumm, Dyne Therapeutics CEO

FDA or­ders DMD tri­al halt, rais­ing ques­tions about a whole class of promis­ing drugs

Dyne Therapeutics’ stock took a nasty hit this morning after the biotech put out word that the FDA had slapped a clinical hold on their top program for Duchenne muscular dystrophy. And now speculation is bouncing around Biotwitter that there could be a class effect at work here that would implicate other drug developers in the freeze.

Dyne execs didn’t have a whole lot to say about why the FDA sidelined their IND for DYNE-251 in DMD while “requesting additional clinical and non-clinical information for” the drug.

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CEO Lex Rovner (64x Bio)

A George Church spin­out fight­ing the vi­ral vec­tor bot­tle­neck in cell and gene ther­a­py lands $55M

A synthetic biology company spun out of George Church’s lab is set to tackle the gene therapy manufacturing bottleneck, and it just landed $55 million in a Series A financing round to do so.

64x Bio comes out of the Harvard Department of Genetics. CEO Lex Rovner and her team — which right now, sits around 10 people — are looking to tackle a key hurdle for major companies: manufacturing cell and gene therapies.