Adam Gridley, Allay Therapeutics CEO

A non-opi­oid pain start­up be­lieves it can top the bupi­va­caine mar­ket — and it's think­ing in terms of weeks, not days

The road to non-opi­oid pain man­age­ment has swal­lowed biotech play­ers for years as drug de­vel­op­ers have smacked their heads against safe­ty flags. A Cal­i­for­nia biotech that spent a long time work­ing in stealth mode now has ear­ly da­ta sug­gest­ing it may have found a break­through — and the com­pa­ny is ready for its close-up.

Al­lay Ther­a­peu­tics launched Thurs­day with Phase I da­ta show­ing their poly­mer­ized bupi­va­caine im­plant helped 80% of pa­tients get off opi­oids 14 days af­ter a to­tal knee re­place­ment, the com­pa­ny said.

The biotech, found­ed in 2017 by The Foundry in­cu­ba­tor and Light­stone Ven­tures’ Sin­ga­pore fund, looks to craft tai­lored-re­lease ther­a­pies for long-last­ing pain man­age­ment with­out the need for ag­gres­sive opi­oid use af­ter surgery. Its lead com­pound, ATX-101, is a quar­ter-sized im­plant that re­leas­es lo­cal anal­gesic bupi­va­caine com­bined with pro­pri­etary biopoly­mers to match pa­tients’ pain lev­els in the days and weeks af­ter a knee re­place­ment.

Ac­cord­ing to da­ta from a Phase Ib/IIa dose-es­ca­la­tion study in 22 Aus­tralian pa­tients, ATX-101 cut the num­ber of opi­oids pa­tients took af­ter 14 days by half to two-thirds com­pared with stan­dard of care and place­bo. Mean­while, 80% of pa­tients were off opi­oids at the 14-day mark com­pared to around 50% on stan­dard of care.

In terms of pain score, ATX-101 “sig­nif­i­cant­ly out­per­formed” stan­dard of care in terms of du­ra­tion and mag­ni­tude of ef­fect, Al­lay said, and kept pa­tients’ pain in the “ze­ro to mild range” for at least two weeks. Mean­while, pa­tients on stan­dard of care tend to have se­vere short-term pain fol­lowed by mod­er­ate pain for weeks.

Even more promis­ing­ly, the im­plant showed “mean­ing­ful sys­temic lev­els” of bupi­va­caine in pa­tients af­ter 14 days, where­as oth­er bupi­va­caine-based treat­ments are no longer de­tectable af­ter five days, Al­lay said.

Those re­sults are promis­ing enough for Al­lay, which is plot­ting a 300-pa­tient Phase IIb study in the US by the end of the year and set­ting its sights on a fol­low-up Phase III study and pos­si­ble NDA by 2024. That study will test pa­tients on the two high­est dos­es in the Phase I — 750 mg and 1,500 mg.

Crack­ing the code on last­ing non-opi­oid pain man­age­ment has left a slew of wrecked biotechs in re­cent years, but Al­lay thinks its plat­form can churn out tun­able im­plants that pro­vide last­ing pain al­le­vi­a­tion with­out the side ef­fects com­mon to sus­tained high use of lo­cal anes­thet­ics, CEO Adam Gri­d­ley told End­points News. The ATX-101 im­plant car­ries 70 times the drug den­si­ty of oth­er drug-poly­mer con­fig­u­ra­tions, a mas­sive pay­load that sets Al­lay’s prod­uct apart, Gri­d­ley said.

There are, of course, oth­er play­ers in this game, but those ther­a­pies work on the scale of days, not weeks. In Feb­ru­ary, the FDA ap­proved Durect’s 72-hour bupi­va­caine so­lu­tion Posimir for use af­ter shoul­der surgery. Mean­while, Heron is await­ing FDA ap­proval for its 72-hour for­mu­la dubbed HTX-011, and Paci­ra is chas­ing its own can­di­date.

So what is Al­lay bring­ing new? Well, it’s not bupi­va­caine or the biopoly­mers used in the im­plant, but in­stead the way the im­plant is man­u­fac­tured that gives it an edge, CTO Patrick Ru­ane told me.

“We’re re­al­ly stand­ing on the shoul­ders of gi­ants — us­ing drugs that are well-es­tab­lished, us­ing poly­mers that are off the shelf,” Ru­ane said. “It’s re­al­ly how we con­fig­ure it and put it to­geth­er. There’s some re­al­ly neat man­u­fac­tur­ing tech­niques where we can con­trol it, and that’s val­i­dat­ed in our clin­i­cal da­ta that it re­al­ly does work.”

Af­ter years in de­vel­op­ment and a raft of ear­ly ex­per­i­ments in the rearview — rough­ly 203, to be ex­act — Al­lay wait­ed un­til it was sure its Phase I tri­al was a suc­cess to un­cloak. There were a num­ber of rea­sons for that de­lay, Gri­d­ley said, but the biggest was be­ing able to prove to in­vestors ear­ly that the plat­form could show promise where so many oth­ers have failed.

“It re­al­ly was, let’s make sure we got some­thing be­fore we come out of stealth,” he said. “This has been such a hard area, no one has got­ten past a cou­ple of days at least do­ing so safe­ly, so that’s where the com­pa­ny has his­tor­i­cal­ly just been pret­ty qui­et. It was that abil­i­ty to show in the most re­cent clin­i­cal tri­al that we were on to some­thing that pre­cip­i­tat­ed the com­ing-out par­ty.”

But now, with the cork popped, Al­lay is ready to make a quan­tum leap for­ward.

On top of its ramped-up clin­i­cal plans for ATX-101, Al­lay has a pipeline un­der de­vel­op­ment to take its drug-biopoly­mer com­bos in­to oth­er post-sur­gi­cal set­tings — in­clud­ing hips, shoul­ders, bunions and her­nias, to count a few — as well as look­ing at a sec­ond-gen fol­low-up to ATX-101. The clin­i­cal pro­gram al­so in­cludes more pa­tient-friend­ly for­mu­la­tions, in­clud­ing an in­jectable.

Mean­while, the biotech is al­so work­ing on what Ru­ane called its “moon­shot” — a re­mote-con­trolled im­plant that would al­low pa­tients and physi­cians to di­al up or down an anes­thet­ic based on pain lev­el with a tap of a phone screen. That par­tic­u­lar project is a ways off, but Al­lay plans to add one new can­di­date in­to hu­man tri­als each year, Gri­d­ley said.

The team will al­so look to great­ly ex­pand in the com­ing years as it ap­proach­es a po­ten­tial NDA, go­ing from its cur­rent work­force of about 40 — 25 in the US and 15 in Sin­ga­pore — to more than 50 by the end of the year. In the next few years, Gri­d­ley said, the biotech could dou­ble in size as it brings more prod­ucts in­to the clin­ic.

In the short term, how­ev­er, Al­lay is look­ing to bring on a chief med­ical of­fi­cer as well as build out its clin­i­cal and sci­en­tif­ic ad­vi­so­ry boards. Pri­or to emerg­ing from stealth, the biotech re­lied on fund­ing from The Foundry and Light­stone from seed to Se­ries B, but Gri­d­ley said Al­lay is cur­rent­ly look­ing to piece to­geth­er a $60 mil­lion Se­ries C to ad­vance its lead pro­gram, with new in­vestors hope­ful­ly jump­ing on board.

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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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.

A Sen­ate bill wants to even an 'un­lev­el play­ing field' for do­mes­tic, for­eign in­spec­tion drop-ins amid back­log

Amid geopolitical tensions between the US and China, two Republican senators are calling for a bill that would aim to strike a balance on domestic and foreign inspection requirements from the FDA.

Sens. Mike Braun (R-IN) and Joni Ernst (R-IA) have penned a bill called the Creating Efficiency in Foreign Inspections Act. It contains a bit of rhetoric, highlighting “communist China” not once, but twice in the release, but states that the goal is to even the playing field between foreign and American manufacturers.

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