Dave Ricks, Eli Lilly

Eli Lil­ly bets on an RNA base edit­ing out­fit lever­ag­ing the body's own en­zymes to re­verse mu­ta­tions

With its con­tro­ver­sial Alzheimer’s med do­nanemab near­ly ready for FDA scruti­ny, Eli Lil­ly has grown more em­bold­ened in its ef­forts to be­come the top dog in neu­ro­science. A new part­ner­ship with a qui­et RNA edit­ing play­er fo­cused around neu­ro­science could now add even more bite to Lil­ly’s bark.

Lil­ly will pay $50 mil­lion in up­front cash and eq­ui­ty and up to $1.25 bil­lion in down­stream mile­stones for ac­cess to five RNA edit­ing can­di­dates from Dutch biotech Pro­QR Ther­a­peu­tics, which is us­ing edit­ed oligonu­cleotides to kick off an RNA base edit­ing sys­tem ini­ti­at­ed by the body’s own en­zymes, the part­ners said Wednes­day.

Pro­QR’s oligonu­cleotide plat­form, dubbed Ax­iomer, re­cruits “en­doge­nous” en­zymes in the cell — which are known as adeno­sine deam­i­nas­es act­ing on RNA, or ADARs — to at­tach to tar­get RNA and in­duce an adeno­sine to in­o­sine base switch, what’s called A-to-I.

When that edit­ed RNA is tran­scribed, the in­o­sine is in­ter­pret­ed as guano­sine, ef­fec­tive­ly cre­at­ing an A-to-G switch. That’s im­por­tant be­cause Pro­QR thinks its plat­form could ad­dress around 20,000 known G-to-A mu­ta­tions that are as­so­ci­at­ed with hu­man dis­ease. The first tar­gets in the col­lab are liv­er and ner­vous sys­tem dis­eases, Pro­QR said, and rep­re­sent a change of pace for the biotech’s pipeline, which is cur­rent­ly fo­cused on ge­net­ic eye dis­ease with a lead can­di­date in late-stage clin­i­cal test­ing.

An­drew Adams

“RNA edit­ing is an ex­cit­ing emerg­ing tech­nol­o­gy, which al­lows tran­sient, re­versible edit­ing, which in some in­di­ca­tions may be an ex­treme­ly at­trac­tive ther­a­peu­tic ap­proach,” said An­drew Adams, Lil­ly’s VP for new ther­a­peu­tic modal­i­ties, in a state­ment. “Through this col­lab­o­ra­tion with Pro­QR, we hope to uti­lize this tech­nol­o­gy to un­lock nov­el treat­ments to im­prove the lives of pa­tients across a spec­trum of dis­eases.”

It’s an ap­proach sim­i­lar to the tech­nol­o­gy for which Roche re­cent­ly ear­marked more than $3 bil­lion in a tie-up with Shape Ther­a­peu­tics, al­so tar­get­ing ADARs. That fam­i­ly of en­zymes is par­tic­u­lar­ly at­trac­tive for brain cell RNA edit­ing, po­ten­tial­ly due to nat­u­ral­ly high lev­els of ex­pres­sion there. Roche and Shape say they’re go­ing af­ter Alzheimer’s and Parkin­son’s, among oth­er dis­eases, and it’s not a stretch to say that Lil­ly — with Alzheimer’s can­di­date do­nanemab near fil­ing — could be in­ter­est­ed in those tar­gets as well.

This part­ner­ship rep­re­sents a con­tin­ued ef­fort on Lil­ly’s part to ex­pand its next-gen RNA ther­a­peu­tics wing as well as its work in neu­ro­science, which has re­ceived a big shot in the arm from do­nanemab’s res­ur­rec­tion af­ter the con­tro­ver­sial Aduhelm ap­proval. Late last month, Lily an­nounced it would spin its um­brel­la Bio­Med­i­cines unit off in­to two new busi­ness ar­eas — neu­ro­science and im­munol­o­gy — in­di­cat­ing the com­pa­ny’s re­newed fo­cus on the cen­tral ner­vous sys­tem.

Mean­while, Lil­ly has inked deals in RNA ther­a­peu­tics and gene edit­ing, tak­ing a broad swing at next-gen meds. In April 2019, the drug­mak­er signed a deal with Avid­i­ty Bio­sciences worth $35 mil­lion up­front and $405 mil­lion per opt-in for the biotech’s plat­form that com­bines mon­o­clon­al an­ti­bod­ies and oligonu­cleotide-based ther­a­pies tar­get­ing RNA. The ini­tial fo­cus area for the part­ner­ship was im­munol­o­gy, the part­ners said at the time.

More than a year lat­er, in No­vem­ber, Lil­ly agreed to a part­ner­ship with Pre­ci­sion Bio­Sciences worth $100 mil­lion up­front for mol­e­cules out of that biotech’s in vi­vo gene edit­ing plat­form based on the I-Crel en­zyme with an ini­tial fo­cus in Duchenne mus­cu­lar dy­s­tro­phy.

Pro­QR, mean­while, has been work­ing on edit­ed oligonu­cleotides, what it calls EONs, for quite some time but pri­mar­i­ly fo­cused on ge­net­ic eye dis­ease. The biotech’s lead drug, se­po­farsen for Leber con­gen­i­tal amau­ro­sis 10, is cur­rent­ly in Phase II/III test­ing with an in­ter­im read­out sched­uled for the first half of 2022.

Daniel de Boer

Ac­cord­ing to CEO Daniel de Boer, Pro­QR’s plat­form can touch a range of ge­net­ic mu­ta­tions across or­gans, putting liv­er and brain dis­ease well with­in range. Those cer­tain­ly aren’t easy ther­a­peu­tic ar­eas and ones that re­quire a high de­gree of tis­sue speci­fici­ty, but de Boer thinks hav­ing Lil­ly on board will help in terms of re­fin­ing ar­eas of ther­a­peu­tic need.

“We said, ‘what if we can en­able oth­ers to use this tech­nol­o­gy but for oth­er ther­a­peu­tic ar­eas that are non-core to us?'” de Boer said. “That’s what led to this part­ner­ship with Lil­ly where we will help on the RNA side but they will even­tu­al­ly take the drugs in­to de­vel­op­ment. So it’s re­al­ly com­bin­ing our ex­per­tis­es where we con­tribute all our know-how on the RNA sci­ence and they bring in the ther­a­peu­tic area ex­per­tise.”

With its plat­form “ready for prime­time,” Pro­QR will like­ly de­clare its first can­di­date in this part­ner­ship with­in the next 12 months, de Boer said.

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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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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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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UCB buys its way to epilep­sy show­down with Jazz with $1.9B Zo­genix ac­qui­si­tion

Zogenix’s epilepsy drug Fintepla may only have brought in around $100 million of sales in its first year, but UCB clearly believes it can go much, much higher.

The Belgian pharma has inked a $1.9 billion deal to buy out Zogenix, paying $26 per share in cash and offering a contingent value right worth $2 more per share if Fintepla lands an extra EU approval by the end of 2023.

But even the upfront marks a 72% premium to California-based Zogenix’s shares, which were trading just north of $15 on Tuesday.

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