CEO Virginia Burger (New Equilibrium Biosciences)

Bet­ting ear­ly on an AI niche, RA Cap­i­tal seeds a young founder's quest to un­lock 'Holy Grail' tar­gets

Ar­ti­fi­cial in­tel­li­gence, with its grandiose claims and sweep­ing promis­es to rev­o­lu­tion­ize drug dis­cov­ery, may seem om­nipresent in bio­phar­ma now. But Vir­ginia Burg­er and RA Cap­i­tal be­lieve there are nich­es it has yet to touch.

Pe­ter Tom­pa

Af­ter tak­ing up res­i­den­cy at the star-stud­ded Boston ac­cel­er­a­tor Petri, Burg­er’s start­up — named New Equi­lib­ri­um Bio­sciences — has scored $10 mil­lion in seed cash from the VC firm to prove that by reach­ing in­to those cor­ners, they could un­cov­er drugs against “Holy Grail” tar­gets in every­thing from can­cer to neu­rode­gen­er­a­tive dis­eases.

Specif­i­cal­ly, the biotech is in­ter­est­ed in a class of pro­teins called in­trin­si­cal­ly dis­or­dered pro­teins that doesn’t have a sin­gle fold­ed struc­ture. MYC, for in­stance, is a can­cer-caus­ing IDP.

“They break this par­a­digm of se­quence to struc­ture to func­tion be­cause it’s re­al­ly se­quence to mul­ti­ple of dif­fer­ent con­for­ma­tions which have many dif­fer­ent func­tions,” she told End­points News.

They can al­so range from ful­ly un­struc­tured to par­tial­ly struc­tured ones con­tain­ing a dis­or­dered re­gion, some­thing con­den­sate play­ers like Dew­point are fo­cused on.

Nathaniel Brooks Hor­witz

Crack­ing this spe­cial class, RA Cap­i­tal prin­ci­pal Nathaniel Brooks Hor­witz said, re­quired a new breed of com­pa­ny that in­te­grates AI in physics mod­eel­ing for drug dis­cov­ery, be­yond what the pi­o­neers — he counts Schrödinger, Re­lay, Sil­i­con  Atom­wise, Re­cur­sion and Ex­sci­en­tia among oth­ers — are do­ing.

“What we’re re­al­ly ex­cit­ed about is when a com­pa­ny like New Equi­lib­ri­um can en­able a tar­get about which we can say the fol­low­ing — ‘If on­ly we could de­vel­op a drug for this tar­get’ — we’re con­fi­dent it will be suc­cess­ful,” he said.

As a PhD in Pitts­burgh and lat­er post­doc at MIT, Burg­er would read pa­pers high­light­ing their im­por­tance as drug tar­gets. But they were so hard to tar­get that un­til mid­way through her post­doc, sci­en­tists weren’t even sure if lig­ands could bind to them — they wig­gle around too quick­ly to be even seen in ex­per­i­ments. Even when they did find mol­e­cules that bound weak­ly to the pro­teins, there was no re­al way to op­ti­mize them in­to drug can­di­dates.

Im­mersed in the en­tre­pre­neur­ial en­vi­ron­ment at MIT, it seemed nat­ur­al to build a start­up around the com­pu­ta­tion­al meth­ods she had been de­vel­op­ing to iden­ti­fy the set of con­for­ma­tions the pro­teins would switch be­tween. First, though, she took a job at XtalPi, the US-Chi­na AI biotech start­up backed by Ten­cent and lat­er Soft­Bank and Morn­ing­side.

It was dur­ing that two-year stint that she met Pe­ter Tom­pa, a pro­fes­sor at Flan­ders In­sti­tute for Biotech­nol­o­gy who’s de­vot­ed his ca­reer to study­ing IDP struc­ture and func­tion. He was in­ter­est­ed in start­ing a com­pa­ny to­geth­er.

Two weeks lat­er, she was out.

The first thing she did af­ter re­ceiv­ing fund­ing from Petri — an ac­cel­er­a­tor set up to tai­lor to the needs of young founders — was to buy quan­tum chem­i­cal soft­ware and start gen­er­at­ing their own train­ing da­ta for a new kind of physics mod­el.

Ex­ist­ing com­pu­ta­tion­al mod­els, Burg­er said, were built on what’s al­ready known about fold­ed struc­tures, which ren­ders them the wrong fit for in­trin­si­cal­ly dis­or­dered pro­teins. By us­ing AI to learn quan­tum chem­istry — the en­er­gies and forces on each atom that give rise to a shape at any giv­en mo­ment — New Equi­lib­ri­um’s al­go­rithms can “see,” in sil­i­co, thou­sands or even mil­lions of pos­si­ble struc­tures over time.

“We’re re­do­ing how sim­u­la­tions have been done in the past by re­build­ing the un­der­ly­ing sim­u­la­tion ar­chi­tec­ture to use AI for each step in­stead of in­tro­duc­ing a sin­gle — the stan­dard cal­cu­la­tion for each step,” she said.

The next step is to ze­ro in on the struc­tures that are more sta­ble or ap­pear more fre­quent­ly, screen lig­ands against them in a wet lab, and then fuse the frag­ments bind­ing to dif­fer­ent struc­tures in the same mol­e­cule. Burg­er can’t yet re­veal how many frag­ments they’d need for each drug made this way, but not­ed that the seed fund­ing will get them clos­er to pre­clin­i­cal can­di­dates.

For RA Cap­i­tal, the deal marks an­oth­er move in their shift to­ward ear­li­er stages of ven­ture fi­nanc­ing.

Quan­tum com­put­ing, Hor­witz not­ed, is loom­ing on the hori­zon with hard­ware start­ing to take shape. And the tech­nol­o­gy will ul­ti­mate­ly make it pos­si­ble to “ful­ly mod­el the true bio­phys­i­cal state of even the most com­plex mol­e­c­u­lar in­ter­ac­tions.”

“Which will be the com­pa­nies that are the first to use quan­tum com­put­ing and all the pow­er that brings to ra­tio­nal­ly de­sign med­i­cines for mean­ing­ful tar­gets?” he said. “I think New Equi­lib­ri­um can be that com­pa­ny.”

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In­no­v­a­tive MedTech De­mands Spe­cial­ist Clin­i­cal Tri­al Reg­u­la­to­ry Af­fairs and De­sign

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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.

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Uğur Şahin, BioNTech CEO (Kay Nietfeld/picture-alliance/dpa/AP Images)

De­spite falling Covid-19 sales, BioN­Tech main­tains '22 sales guid­ance

While Pfizer raked in almost $28 billion last quarter, its Covid-19 vaccine partner BioNTech reported a rise in total dose orders but a drop in sales.

The German biotech reported over $3.2 billion in revenue in Q2 on Monday, down from more than $6.7 billion in Q1, in part due to falling Covid sales. While management said last quarter that they anticipated a Covid sales drop — CEO Uğur Şahin said at the time that “the pandemic situation is still very much uncertain” — Q2 sales still missed consensus by 14%.

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Anna Protopapas, Mersana CEO

In $1.36B biobuck deal with GSK, Mer­sana touts 'biggest pre­clin­i­cal ADC deal ever'

Days after Enhertu reeled in another FDA nod, with the first-ever green light for HER2-low breast cancer, another antibody drug conjugate biotech claims it has secured the largest preclinical ADC pact to date for a single asset.

AstraZeneca and Daiichi Sankyo made waves with their nearly $7 billion collaboration back in spring 2019, but at that point, Enhertu was already nearing the FDA’s doors with clinical data. The latest ADC tie-up to enter the biopharma fray centers around a preclinical asset, Mersana Therapeutics’ XMT-2056.

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

With drug pric­ing al­most done, Con­gress looks to wrap up FDA user fee leg­is­la­tion

The Senate won’t return from its summer recess until Sept. 6, but when it does, it officially has 18 business days to finalize the reauthorization of the FDA user fee programs for the next 5 years, or else thousands of drug and biologics reviewers will be laid off and PDUFA dates will vanish in the interim.

FDA commissioner Rob Califf recently sent agency staff a memo explaining how, “Our latest estimates are that we have carryover for PDUFA [Prescription Drug User Fee Act], the user fee funding program that will run out of funding first, to cover only about 5 weeks into the next fiscal year.”

Pascal Soriot, AstraZeneca CEO (David Zorrakino/Europa Press via AP Images)

As­traZeneca and Dai­ichi Sankyo sprint to mar­ket af­ter FDA clears En­her­tu in just two weeks

Regulators didn’t keep AstraZeneca and Daiichi Sankyo waiting long at all for their latest Enhertu approval.

The partners pulled a win on Friday in HER2-low breast cancer patients who’ve already failed on chemotherapy, just two weeks after submitting a supplemental BLA. While this isn’t the FDA’s fastest approval — Bristol Myers Squibb won an OK for its blockbuster checkpoint inhibitor Opdivo in just five days back in March — it comes well ahead of Enhertu’s original Q4 PDUFA date.

David Reese, Amgen R&D chief

UP­DAT­ED: In a fresh dis­ap­point­ment, Am­gen spot­lights a ma­jor safe­ty is­sue with KRAS com­bo

Amgen had hoped that its latest study matching its landmark KRAS G12C drug Lumakras with checkpoint inhibitors would open up its treatment horizons and expand its commercial potential. Instead, the combo spurred safety issues that blunted efficacy and forced the pharma giant to alter course on its treatment strategy, once again disappointing analysts who have been tracking the drug’s faltering sales and limited therapeutic reach.

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Bernhardt Zeiher, outgoing Astellas CMO (Astellas)

Q&A: Astel­las' re­tir­ing head of de­vel­op­ment re­flects on gene ther­a­py deaths

For anyone who’s been following discussions about the safety alarms surrounding the adeno-associated viruses (AAV) commonly used to deliver gene therapy, Astellas should be a familiar name.

The Japanese pharma — which bought out Audentes Therapeutics near the end of 2019 and later built a gene therapy unit around the acquisition — rocked the field when it reported three patient deaths in a trial testing AT132, the lead program from Audentes designed to treat a rare muscle disease called X-linked myotubular myopathy (XLMTM).

When the company restarted the trial, it adjusted the dose and instituted a battery of other measures to try to prevent the same thing from happening again. But tragically, the first patient to receive the new regimen died just weeks after administration. The therapy remains under clinical hold, and just weeks ago, Astellas flagged another safety-related hold for a separate gene therapy candidate. In the process of investigating the deaths, the company has also taken flak about the way it disclosed information.

Big questions remain — questions that can have big implications about the future of AAV gene therapies.

Bernhardt Zeiher did not imagine any of it when he first joined Astellas as the therapeutic area leader in inflammation, immunology and infectious diseases. But his ascent to chief medical officer and head of development coincided almost exactly with Astellas’ big move into gene therapy, putting him often in the driver’s seat to grapple with the setbacks.

As Zeiher prepares to retire next month after a 12-year tenure — leaving the unfinished tasks to his successor, a seasoned cancer drug developer — he chatted with Endpoints News, in part, to discuss the effort to understand what happened, lessons learned and the criticism along the way.

The transcript has been lightly edited for length and clarity.

Endpoints: I want to also ask you a bit about the gene therapy efforts you’ve been working on. Astellas has really been at the forefront of discovering the safety concerns associated with AAV gene therapy. What’s that been like for you?

Zeiher: Well, I have to admit, it’s been a bit of a roller coaster. We acquired Audentes. Huge amount of enthusiasm. What we saw with AT132 — that was the lead program in XLMTM — was just remarkable efficacy. I mean, kids who went from being on ventilators, not able to eat for themselves, sit up, do things like that, to off ventilators, walking, you know, really — one investigator called it this Lazarus-like effect. It was just really dramatic efficacy. And then to have the safety events that occurred. So they actually occurred within that first year of the acquisition. So we had the three patient deaths. Me and my organization became very, very much involved. In fact, Ed Conner, who had been the chief medical officer, he left after some of the deaths, but I stepped in as the kind of acting chief medical officer, we had another chief medical officer who was involved, and then we had a fourth death, and I became acting again for a period of time.

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Steve Paul, Karuna Therapeutics CEO (Third Rock)

Karuna's schiz­o­phre­nia drug pass­es a close­ly-watched PhI­II test, will head to FDA in mid-2023

An investigational pill that combines a former Eli Lilly CNS compound with an overactive bladder drug was better than placebo at reducing a scale of symptoms experienced by patients with schizophrenia in a Phase III trial.

Karuna Therapeutics’ drug passed the primary goal in EMERGENT-2, the Boston biotech said early Monday morning, alongside quarterly earnings. The study is the first of Karuna’s four Phase III clinical trials to read out in schizophrenia and will provide the backbone to the biotech’s first drug approval application, slated for mid-2023.

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