Ex­pert pan­el re­view on Alzheimer’s drug ad­u­canum­ab be­comes a one-day tri­al by fire as crit­ics turn their guns on Bio­gen — and the FDA

Two days af­ter an en­thu­si­as­tic FDA in­sid­er re­view of Bio­gen’s ad­u­canum­ab pro­vid­ed a $15 bil­lion pop for the big biotech’s mar­ket cap, a pan­el of out­side ex­perts pro­vid­ed some fresh fire­works on the de­bate, with a big ma­jor­i­ty turn­ing thumbs down on the con­tro­ver­sial pitch that there are da­ta to prove the drug is ef­fec­tive — as well as the agency’s per­plex­ing en­dorse­ment.

Most of the ex­perts slapped down 3 ques­tions re­gard­ing whether there was any ev­i­dence to back the ef­fi­ca­cy of the drug — with a lone vote in fa­vor on one of the ques­tions.

The mon­ey ques­tion:

Con­sid­er­ing all the tri­al da­ta, the FDA asked, is it rea­son­able to con­sid­er the pos­i­tive study 302 “as pri­ma­ry ev­i­dence of ef­fec­tive­ness” for the treat­ment of Alzheimer’s dis­ease?

Ten said no, none said yes and there was one ab­sten­tion. Sev­er­al said the FDA pre­sen­ta­tion was heav­i­ly weight­ed in Bio­gen’s fa­vor, with no dis­cus­sion from the agency of the harsh­ly crit­i­cal sta­tis­ti­cal re­view from FDA staffers.

Any­one ex­pect­ing a dry and dis­pas­sion­ate re­view of the da­ta for Bio­gen’s Alzheimer’s drug ad­u­canum­ab at the FDA pan­el meet­ing Fri­day was in for a rude awak­en­ing.

Bil­ly Dunn

Both Bio­gen ex­ecs as well as Bil­ly Dunn, the head of the agency’s neu­ro­sciences di­vi­sion, of­fered a full-throat­ed en­dorse­ment of the drug, out­lin­ing the rea­sons why they found the da­ta back­ing the con­tro­ver­sial ap­pli­ca­tion “com­pelling.”

That ar­gu­ment, though, in­vit­ed a sharp shove back from mem­bers of the ad­vi­so­ry pan­el asked to weigh in on the ap­pli­ca­tion, es­pe­cial­ly from the sta­tis­ti­cians who re­peat­ed­ly probed why Dunn was so sup­port­ive when the FDA’s sta­tis­ti­cal re­view took the com­plete­ly op­pos­ing view, con­clud­ing that the da­ta were con­flict­ing, of­fered clear ev­i­dence that the drug doesn’t work and that Bio­gen’s ar­gu­ment in its fa­vor was hol­low.

“We brought in­no­v­a­tive think­ing to this un­usu­al sit­u­a­tion,” ar­gued Dunn, con­struct­ing sup­port for ad­u­canum­ab that dis­count­ed the ear­ly ter­mi­na­tion of the study due to fu­til­i­ty, of­fer­ing rea­sons why the 1 pos­i­tive late-stage study of­fered “ex­treme­ly per­sua­sive” rea­sons for an ap­proval, why the oth­er failed study could be ex­plained as pro­vid­ing sup­port­ing da­ta and why a small co­hort in an ear­li­er study al­so pro­vid­ed en­cour­age­ment for an OK — es­pe­cial­ly as Covid-19 de­mand­ed reg­u­la­tors to work co­op­er­a­tive­ly in sal­vaging tri­als.

Sev­er­al mem­bers of the pan­el were clear­ly out­raged by that.

G. Caleb Alexan­der, a Johns Hop­kins pro­fes­sor, blast­ed the FDA’s re­view as “strik­ing­ly in­con­gru­ous” which of­fered con­clu­sions that were at best com­pelling­ly con­flict­ed, rais­ing ques­tions on how the FDA could de­ter­mine there was ev­i­dence of ef­fec­tive­ness.

“It just feels like the au­dio and the video on the TV are out of sync,” he said.

For every point that sug­gests sup­port for the drug, he added, there are more that raise con­cerns.

At sev­er­al points, Alexan­der harsh­ly crit­i­cized Dunn’s team for skew­ing the brief­ing doc­u­ments and ques­tions in Bio­gen’s fa­vor. “I’m call­ing out the fact … that this ques­tion is open to elic­it­ing se­lec­tive in­for­ma­tion,” he not­ed at one point.

The Uni­ver­si­ty of Wash­ing­ton’s Scott Emer­son was an­oth­er per­sis­tent crit­ic with point­ed crit­i­cism of the drug and the da­ta used to back the ap­pli­ca­tion.

And Joel Perl­mut­ter, a pro­fes­sor of neu­rol­o­gy, warned the pan­el that if the FDA ap­proved some­thing with­out strong ev­i­dence of ef­fi­ca­cy they would pre­vent a good and ef­fec­tive treat­ment from be­ing ap­proved “for more than a cou­ple of years, for many years.”

The friend­liest ques­tion the pan­el faced con­cerned whether tri­al 302, count­ed as the on­ly pos­i­tive study of the 2 Phase III ef­forts, pro­vid­ed strong ev­i­dence of ef­fi­ca­cy — if you al­so ig­nore 301, the failed tri­al.

That went down hard, with 8 ‘no’ votes, 1 ‘yes’ and 2 ab­sten­tions. Even the ab­stain­ers, though, of­fered ob­jec­tions.

How about the small­er study 103, the Phase II tri­al Dunn cit­ed for of­fer­ing some sup­port­ive da­ta for the drug? Was it sup­port­ive in some way?

The ex­perts shot that one down as well, by a vote of 7 no, 0 yes and 4 un­cer­tain.

The one up­beat re­sult was on patho­phys­i­ol­o­gy, but sev­er­al not­ed ques­tions whether the drug’s abil­i­ty to re­duce amy­loid would ever trans­late in­to ef­fi­ca­cy or an im­pact on symp­toms. That earned some sup­port: 5 yes and 6 un­cer­tain.

“I view the ques­tion nar­row­ly,” said Chia­di Onyike, say­ing there was clear ev­i­dence it mopped up amy­loid be­ta. And oth­ers not­ed ques­tions whether that was enough to gain clin­i­cal ef­fi­ca­cy, or if it’s the cor­rect bio­mark­er to use at all.

The FDA doesn’t have to con­sid­er the pan­el vote in mak­ing its de­ci­sion. In this case, giv­en the heat­ed ob­jec­tions, it would be hard to ig­nore. But giv­en Dunn’s ear­li­er de­ci­sions sup­port­ing Sarep­ta, there is still a dis­tinct pos­si­bil­i­ty of an ap­proval.

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?

Image: Shutterstock

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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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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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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Pascal Soriot (AstraZeneca via YouTube)

Af­ter be­ing goad­ed to sell the com­pa­ny, Alex­ion's CEO set some am­bi­tious new goals for in­vestors. Then Pas­cal So­ri­ot came call­ing

Back in the spring of 2020, Alexion $ALXN CEO Ludwig Hantson was under considerable pressure to perform and had been for months. Elliott Advisers had been applying some high public heat on the biotech’s numbers. And in reaching out to some major stockholders, one thread of advice came through loud and clear: Sell the company or do something dramatic to change the narrative.

In the words of the rather dry SEC filing that offers a detailed backgrounder on the buyout deal, Alexion stated: ‘During the summer and fall of 2020, Alexion also continued to engage with its stockholders, and in these interactions, several stockholders encouraged the company to explore strategic alternatives.’

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PDU­FA VII to ex­pand FDA’s re­al-time on­col­o­gy re­views to sup­ple­ments for all ther­a­peu­tic ar­eas

The FDA’s popular program to speed up its reviews of new oncology drugs and supplemental applications by months will be expanded into a larger program for efficacy supplements across all therapeutic areas.

The new program, to be known as Split Real-Time Application Review (STAR), first came to light in the minutes of a December meeting of the premarket subgroup working on the negotiation of the latest iteration of the Prescription Drug User Fee Act (PDUFA VII).

Emmanuel Hanon (Viome)

Glax­o­SmithK­line’s head of vac­cine R&D is jump­ing to a well­ness com­pa­ny con­cen­trat­ing on the mi­cro­bio­me as re­ports of an ex­o­dus start to spread

Back in the fall of 2019, GlaxoSmithKline vaccine R&D chief Emmanuel Hanon had plenty of good things to say about a wellness company called Viome and CEO Naveen Jain. He was particularly interested in Viome’s technology for analyzing the gut microbiome and how that could intersect with new vaccine research.

Today, Hanon is jumping ship to join his collaborator as R&D chief as reports circulate of an exodus at GSK’s big vaccine group.

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