Hear­ing loss spe­cial­ists at Fre­quen­cy pin the blame for PhI­Ia flop on tri­al de­sign — but they could­n't stem a freefall in share price

When Fre­quen­cy Ther­a­peu­tics scored $80 mil­lion in cash from Astel­las to jump­start an al­liance, the biotech cau­tious­ly point­ed to Phase I/II da­ta bol­ster­ing hope that they might in­deed have a ground­break­ing re­gen­er­a­tive med­i­cine ap­proach to restor­ing hear­ing, lean­ing on re­search done by Bob Langer and Jeff Karp out of MIT around prog­en­i­tor cell ac­ti­va­tion.

New­ly re­leased Phase IIa re­sults are now keep­ing them away from that lofty goal.

David Lucchi­no

At the in­ter­im analy­sis, four week­ly in­jec­tions of FX-322 failed to im­prove things for pa­tients with mild to mod­er­ate­ly se­vere sen­sorineur­al hear­ing loss, whether they looked at word recog­ni­tion, words-in-noise, pure tone au­diom­e­try and ad­di­tion­al ex­plorato­ry or oth­er mea­sures.

Fre­quen­cy ex­ecs, though, be­lieve the blame lies not with the drug but with the tri­al de­sign. Armed with pre­lim­i­nary da­ta from a sep­a­rate Phase I/II tri­al, they are all but giv­ing up on the four-dose reg­i­men and go­ing back to take a sin­gle-shot ap­proach through fur­ther eval­u­a­tion in­stead — with lessons tak­en from the lat­est mid-stage tri­al.

“I can tell you that we have tak­en a mean­ing­ful step clin­i­cal­ly, though not in the way we an­tic­i­pat­ed,” CEO David Lucchi­no said in an in­vestor call.

Cowen an­a­lyst Phil Nadeau was sym­pa­thet­ic to the ar­gu­ment, not­ing that while the topline read­out brings the bi­o­log­ic ef­fect of the drug in­to ques­tion, Fre­quen­cy may have a point in con­tin­u­ing its de­vel­op­ment:

We agree that the repli­ca­tion of the ini­tial sin­gle dose da­ta sug­gest that ‘322’s pro­file should con­tin­ue to be ex­plored. Though there are nu­mer­ous caveats to sin­gle arm stud­ies (most no­tably the con­tralat­er­al ear in study ‘111 need not have WR deficits at base­line) the con­sis­ten­cy of ef­fect in the two tri­als pro­vides a sig­nal of ef­fi­ca­cy for the sin­gle in­jec­tion reg­i­mens.

In­vestors are less cheery, tank­ing the shares 77.98% Tues­day af­ter­noon.

The first of two main is­sues, Lucchi­no ex­plained, was that the four week­ly in­jec­tions seemed to “tem­porar­i­ly over­whelm the ear.”

“This is a bit of an over­sim­pli­fied anal­o­gy, but one that can pos­si­bly fit: When you re­seed the lawn, you need to stay off the grass,” he said. “In oth­er words, while we can’t see the pre­cise mech­a­nisms in play, mul­ti­ple week­ly in­jec­tions led to con­di­tions that did not al­low FX-322 to achieve its in­tend­ed ef­fect.”

Sec­ond­ly, he im­plied that some pa­tients may have ex­ag­ger­at­ed the ex­tent of their word recog­ni­tion deficit in or­der to get in­to the study, re­sult­ing in an un­ex­pect­ed­ly high lev­el of hear­ing ben­e­fit in the place­bo group — “out­liers” that his team had nev­er seen be­fore.

In the tri­al, all 95 par­tic­i­pants re­ceived four in­jec­tions to­tal, with dif­fer­ent com­bi­na­tions of drug and place­bo. None of the treat­ment groups had dis­cernible ben­e­fit com­pared to place­bo.

The rea­son Fre­quen­cy is hold­ing out hope comes most­ly from pre­lim­i­nary re­sults in an open-la­bel study in which a sin­gle dose of FX-322 was giv­en to 33 pa­tients with se­vere SNHL. With the un­treat­ed ear as the con­trol, in­ves­ti­ga­tors re­port­ed that 34% of par­tic­i­pants saw a 10% or greater im­prove­ment in word recog­ni­tion scores. A sub­set even more than dou­bled their WR scores.

Two oth­er ear­ly-stage, place­bo-con­trolled tri­als on the sin­gle in­jec­tion are on­go­ing, fo­cus­ing on age-re­lat­ed hear­ing loss and se­vere SNHL, re­spec­tive­ly. Re­sults should be in lat­er this year — when Fre­quen­cy al­so ex­pects to re­port fi­nal num­bers from the flopped Phase IIa.

“We rec­og­nized when we start­ed and con­tin­ue to rec­og­nize to­day that achiev­ing such a bold goal would not be with­out un­ex­pect­ed turns along the way,” Lucchi­no said. “We be­lieve in the tech­nol­o­gy, we be­lieve in the da­ta, and we will fol­low the sci­ence.”

BY­OD Best Prac­tices: How Mo­bile De­vice Strat­e­gy Leads to More Pa­tient-Cen­tric Clin­i­cal Tri­als

Some of the most time- and cost-consuming components of clinical research center on gathering, analyzing, and reporting data. To improve efficiency, many clinical trial sponsors have shifted to electronic clinical outcome assessments (eCOA), including electronic patient-reported outcome (ePRO) tools.

In most cases, patients enter data using apps installed on provisioned devices. At a time when 81% of Americans own a smartphone, why not use the device they rely on every day?

Chris Gibson (Photo By Vaughn Ridley/Sportsfile for Web Summit via Getty Images)

Re­cur­sion founders gin for­tunes as IPO back­ers show­er $436M on one of the biggest boasts in AI -- based on some very small deals

In the AI drug development world, boasting often comes with the territory. Yet few can rival Recursion when it comes to claiming the lead role in what company execs like to call the industrialization of drug development, with promises of continued exponential growth in the number of drugs it has in the pipeline.

On Friday, the Salt Lake City-based biotech translated its unicorn-sized boasts into a killer IPO, pricing more than 24 million shares at the high end of its range and bringing in $436 million — with a large chunk of that promised by some deep-pocket backers.

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Covid-19 vac­cine halt drags on, an FDA ap­point­ment at long last, the great CRO con­sol­i­da­tion, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Conference season is upon us, and while we’d much prefer to be wandering down the hallways and presentation rooms in person, the team is ready to cover the most consequential data coming out of these scientific meetings. Get in touch early if you have news to share.

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Eli Lil­ly asks FDA to re­voke EUA for Covid-19 treat­ment

Eli Lilly on Friday requested that the FDA revoke the emergency authorization for its Covid-19 drug bamlanivimab, which is no longer as effective as a combo therapy because of a rise in coronavirus variants across the US.

“With the growing prevalence of variants in the U.S. that bamlanivimab alone may not fully neutralize, and with sufficient supply of etesevimab, we believe now is the right time to complete our planned transition and focus on the administration of these two neutralizing antibodies together,” Daniel Skovronsky, Lilly’s CSO, said in a statement.

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Ex­clu­sive in­ter­view: Pe­ter Marks on why full Covid-19 vac­cine ap­provals could be just months away

Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, took time out of his busy schedule last Friday to discuss with Endpoints News all things related to his work regulating vaccines and the pandemic.

Marks, who quietly coined the name “Operation Warp Speed” before deciding to stick with his work regulating vaccines at the FDA rather than join the Trump-era program, has been the face of vaccine regulation for the FDA throughout the pandemic, and is usually spotted in Zoom meetings seated in front of his wife’s paintings.

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Near­ly a year af­ter Au­den­tes' gene ther­a­py deaths, the tri­al con­tin­ues. What hap­pened re­mains a mys­tery

Natalie Holles was five months into her tenure as Audentes CEO and working to smooth out a $3 billion merger when the world crashed in.

Holles and her team received word on the morning of May 5 that, hours before, a patient died in a trial for their lead gene therapy. They went into triage mode, alerting the FDA, calling trial investigators to begin to understand what happened, and, the next day, writing a letter to alert the patient community so they would be the first to know. “We wanted to be as forthright and transparent as possible,” Holles told me late last month.

The brief letter noted two other patients also suffered severe reactions after receiving a high dose of the therapy and were undergoing treatment. One died a month and a half later, at which point news of the deaths became public, jolting an emergent gene therapy field and raising questions about the safety of the high doses Audentes and others were now using. The third patient died in August.

“It was deeply saddening,” Holles said. “But I was — we were — resolute and determined to understand what happened and learn from it and get back on track.”

Eleven months have now passed since the first death and the therapy, a potential cure for a rare and fatal muscle-wasting disease called X-linked myotubular myopathy, is back on track, the FDA having cleared the company to resume dosing at a lower level. Audentes itself is no more; last month, Japanese pharma giant Astellas announced it had completed working out the kinks of the $3 billion merger and had restructured and rebranded the subsidiary as Astellas Gene Therapies. Holles, having successfully steered both efforts, departed.

Still, questions about precisely what led to the deaths of the 3 boys still linger. Trial investigators released key details about the case last August and December, pointing to a biological landmine that Audentes could not have seen coming — a moment of profound medical misfortune. In an emerging field that’s promised cures for devastating diseases but also seen its share of safety setbacks, the cases provided a cautionary tale.

Audentes “contributed in a positive way by giving a painful but important example for others to look at and learn from,” Terry Flotte, dean of the UMass School of Medicine and editor of the journal Human Gene Therapy, told me. “I can’t see anything they did wrong.”

Yet some researchers say they’re still waiting on Astellas to release more data. The company has yet to publish a full paper detailing what happened, nor have they indicated that they will. In the meantime, it remains unclear what triggered the events and how to prevent them in the future.

“Since Audentes was the first one and we don’t have additional information, we’re kind of in a holding pattern, flying around, waiting to figure out how to land our vehicles,” said Jude Samulski, professor of pharmacology at UNC’s Gene Therapy Center and CSO of the gene therapy biotech AskBio, now a subsidiary of Bayer.

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Severin Schwan, Roche CEO (Georgios Kefalas/Keystone via AP Images)

Look­ing to ce­ment its lead in packed MS mar­ket, Roche's Ocre­vus un­corks new da­ta in ear­ly-stage pa­tients

Among a positively jam-packed multiple sclerosis market, Roche’s Ocrevus has managed to stand out for what the Swiss drugmaker is calling the most successful launch in its long history. But in order to press its advantage, Ocrevus is looking to earlier-stage patients, and new interim data should help build its case there.

After 48 weeks on Roche’s Ocrevus, 85% of newly diagnosed primary progressing or relapsing MS patients without a history of disease modifying therapy posted no disease activity, including disease progression or relapse, according to interim data set to be presented this weekend at the virtual American Academy of Neurology meeting.

J&J faces CDC ad­vi­so­ry com­mit­tee again next week to weigh Covid-19 vac­cine risks

The CDC’s Advisory Committee on Immunization Practices punted earlier this week on deciding whether or not to recommend lifting a pause on the administration of J&J’s Covid-19 vaccine, but the committee will meet again in an emergency session next Friday to discuss the safety issues further.

The timing of the meeting likely means that the J&J vaccine will not return to the US market before the end of next week as the FDA looks to work hand-in-hand with the CDC to ensure the benefits of the vaccine still outweigh the risks for all age groups.

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Osman Kibar (Samumed, now Biosplice)

Os­man Kibar lays down his hand at Sa­mumed, step­ping away from CEO role as his once-her­ald­ed an­ti-ag­ing biotech re­brands

Samumed made quite the entrance back in 2016, when it launched with some anti-aging programs and a whopping $12 billion valuation. That level of fanfare was nowhere to be found on Thursday, when the company added another $120 million to its coffers and quietly changed its name to Biosplice Therapeutics.

Why the sudden rebrand?

“We did that for obvious reasons,” CFO and CBO Erich Horsley told Endpoints News. “The name Biosplice echoes our science much more than Samumed does.”

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