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.

Janet Woodcock (AP Images)

End­points poll: Janet Wood­cock takes the (in­ter­im) helm at the FDA. And a large ma­jor­i­ty of our read­ers want her to stay there

It’s official: Janet Woodcock is now the acting chief of the FDA.

And — according to an Endpoints poll — most industry readers would like her to stay there, although a significant minority is strongly opposed.

To recap: Joe Biden is reportedly choosing between Woodcock and former deputy FDA commissioner Joshua Sharfstein as his nominee for the permanent position. Given their respective track records, the decision is set to determine the agency’s lodestar for years to come.

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5AM Ven­tures: Fu­el­ing the Next Gen­er­a­tion of In­no­va­tors

By RBC Capital Markets
With Andy Schwab, Co-Founder and Managing Partner at 5AM Ventures

Key Points

Prescription Digital Therapeutics, cell therapy technologies, and in silico medicines will be a vital part of future treatment modalities.
Unlocking the potential of the microbiome could be the missing link to better disease diagnosis.
Growing links between academia, industry, and venture capital are spinning out more innovative biotech companies.
Biotech is now seen by investors as a growth space as well as a safe haven, fuelling the recent IPO boom.

An Endpoints Zoom meeting; and the email header employees will see if your company is a Premium subscriber

What’s next for End­points — and how to sup­port our in­de­pen­dent bio­phar­ma news mis­sion

The firehose of biopharma news is gushing these days.

That’s why broader and deeper is the theme for 2021 at Endpoints. You can expect new coverage outside our core R&D focus, with deeper reporting in some key areas. When John Carroll and I launched Endpoints nearly five years ago, we were wading in waist-high waters. Now we’re a team of 25 full-time staffers (and growing) with plans to cover the flood of biopharma news, Endpoints-style.

Janet Woodcock and Joshua Sharfstein (AP, Images)

Poll: Should Joshua Sharf­stein or Janet Wood­cock lead the FDA from here?

It’s time for a new FDA commissioner to come on board, a rite of passage for Joe Biden’s administration that should help seal the new president’s rep on seeking out the experts to lead the government over the next 4 years.

As of now, the competition for the top job appears to have narrowed down to 2 people: The longtime CDER chief Janet Woodcock and Joshua Sharfstein, the former principal deputy at the FDA under Peggy Hamburg. Both were appointed by Barack Obama.

Eli Lil­ly's an­ti­body cuts risk of Covid-19 by up to 80% among the most vul­ner­a­ble — but will it have a place next to vac­cines?

Eli Lilly says bamlanivimab lowered the risk of contracting symptomatic Covid-19 in a first-of-its-kind trial involving nursing home residents and staff, paving the way for a new option to protect against the virus.

But how big of an impact it might have, and what role it will play, at a time vaccines are being rolled out to the exact population it is targeting still remains unclear.

Among 965 participants in the study — all of whom tested negative for the coronavirus at baseline — the number of symptomatic cases reported in the bamlanivimab arm was 57% lower than that in the placebo arm (odds ratio 0.43, p=0.00021). In addition to that primary endpoint, all secondary endpoints reached statistical significance.

Michelle McMurry-Heath, BIO CEO (BIO via YouTube)

BIO looks to re­struc­ture, lay­ing off staff amid chal­lenge to the trade org's nor­mal face-to-face style

The biopharma industry, on the whole, had a red-letter year in 2020 amid Covid-19, with fundraising at an all-time high and major players speeding vaccines ahead to approval. But for BIO, the industry’s leading trade organization, the pandemic has prompted a reconsideration of the game plan.

BIO will pivot to digital as the Covid-19 pandemic continues to rage, making “some staff reductions” as it looks to bring its roughly 37,000 in-person meetings each year to the web, the organization said Thursday.

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Covid-19 roundup: Italy won­ders aloud if it can sue Pfiz­er for vac­cine short­falls; US recom­mits to WHO un­der Biden ad­min­is­tra­tion

As reports crop up that deliveries of Pfizer and BioNTech’s Covid-19 vaccine are being unexpectedly cut, Italy wonders if it can take the vaccine developers to court, according to the Wall Street Journal. 

After its shipment for this week was cut by 29%, the Italian government consulted its attorney general about taking legal action, the WSJ reported. Pfizer and BioNTech had warned the EU and Canada last week that their allocations would be reduced as Pfizer upgrades its Belgium factory. What Italy says it doesn’t appreciate, though, is the short notice.

Hal Barron, GSK R&D chief (GSK via YouTube)

Glax­o­SmithK­line's $4B bis­pe­cif­ic can­cer drug al­liance with Mer­ck KGaA hit by big set­back with a PhI­II fail­ure on NSCLC

Close to 2 years ago, GSK’s R&D team eagerly agreed to pay up to $4 billion-plus to ally itself with Merck KGaA on a mid-stage bispecific called bintrafusp alfa, which intrigued them with the combination of a TGF-β trap with the anti-PD-L1 mechanism in one fusion protein.

But today the German pharma company says that their lead study on lung cancer was a bust, as independent monitors said there was no reason to believe that the experimental drug — targeting PD-L1/TGF-Beta — could beat Keytruda.

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Mike Grey, Plexium chairman (Horizon Therapeutics)

Plex­i­um adds in­dus­try vet Mike Grey to the brain trust with new in­vestor cash fund­ing its pro­tein degra­da­tion play

About 15 months since closing a $28 million Series A, a San Diego protein-degradation upstart returned to the venture well Thursday with an extension of that round and some new hires, including one of the city’s best-connected biotech execs.

Plexium has bagged an additional $35 million in financing, the biotech said, money that will push undisclosed oncology and immuno-oncology programs into the clinic. In addition, longtime industry vet Mike Grey is jumping on as chairman of the board, and two others from Thursday’s leads — Adam Goulburn from Lux Capital and Rob Hopfner from Pivotal BioVentures — joined the board too.