Ad­comm splits slight­ly in fa­vor of FDA ap­prov­ing Chemo­Cen­tryx’s rare dis­ease drug

The FDA’s Arthri­tis Ad­vi­so­ry Com­mit­tee on Thurs­day vot­ed 10 for and 8 against the ap­proval of Chemo­Cen­tryx’s $CCXI in­ves­ti­ga­tion­al drug ava­co­pan as a treat­ment for adults with a rare and se­ri­ous dis­ease known as an­ti-neu­trophil cy­to­plas­mic au­toan­ti­body (AN­CA)-vas­culi­tis.

The vote on whether the FDA should ap­prove the drug was pre­ced­ed by a split vote of 9 to 9 on whether the ef­fi­ca­cy da­ta sup­port ap­proval, and 10 to 8 that the safe­ty pro­file of ava­co­pan is ad­e­quate enough to sup­port ap­proval.

John Sperati

There was a con­tentious de­bate over whether the one, rel­a­tive­ly small Phase III tri­al com­par­ing ava­co­pan with pred­nisone was ro­bust enough for a full ap­proval. FDA raised con­cerns about the sta­tis­ti­cal analy­ses of the da­ta in the tri­al and what ef­fect the use of glu­co­cor­ti­coids on top of cy­clophos­phamide or rit­ux­imab in both treat­ment arms had on the ava­co­pan ef­fi­ca­cy. Chemo­Cen­tryx de­fend­ed its tri­al de­sign and ex­plained how it met its pri­ma­ry end­point and showed a re­duc­tion in the use of steroids with ava­co­pan.

Those vot­ing against ap­proval raised con­cerns about re­ly­ing on the sin­gle tri­al as ev­i­dence, the in­suf­fi­cient amount of safe­ty da­ta, and ques­tions on whether the tri­al was sta­tis­ti­cal­ly ro­bust enough. Some pan­elists called for Chemo­Cen­tryx to run an­oth­er tri­al.

AAC pan­elist John Sperati, as­so­ciate pro­fes­sor of med­i­cine at Johns Hop­kins Uni­ver­si­ty School of Med­i­cine, vot­ed no on whether the FDA should ap­prove the drug and said he had con­cerns with the study de­sign and per­sua­sive­ness of the da­ta. He ex­plained how if ava­co­pan is ap­proved by the FDA, one would have to use it in a sim­i­lar fash­ion as in the tri­al, but where its true ef­fi­ca­cy lies re­mains un­clear from that tri­al da­ta.

Ju­lia Lewis

An­oth­er pan­elist Ju­lia Lewis, pro­fes­sor of med­i­cine at Van­der­bilt Uni­ver­si­ty Med­ical Cen­ter, al­so vot­ed against ap­proval and said the in­di­ca­tion is too broad and far ex­ceeds the da­ta pre­sent­ed.

Those vot­ing in fa­vor of ap­proval not­ed that the tri­al just cleared the bar to meet its pri­ma­ry end­point and that tri­als in this pop­u­la­tion are dif­fi­cult to con­duct.

AAC pan­elist Wal­ter Kraft, pro­fes­sor of med­i­cine and surgery at Sid­ney Kim­mel Med­ical Col­lege of Thomas Jef­fer­son Uni­ver­si­ty, vot­ed for ava­co­pan to be ap­proved, say­ing reg­u­la­to­ry de­ci­sions are not made in a vac­u­um, but with ex­ist­ing ther­a­peu­tics in mind, and that the tri­al met its goal. He al­so raised con­cerns about de­lays in ac­cess to ava­co­pan if the FDA re­quires an ad­di­tion­al tri­al.

Fel­low pan­elist Margrit Wiesen­dan­ger, as­so­ciate pro­fes­sor at Ic­ahn School of Med­i­cine at Mount Sinai, al­so vot­ed in fa­vor of ap­prov­ing the drug, but said ju­di­cious use of it will be war­rant­ed and ad­di­tion­al guid­ance will be nec­es­sary to ex­plain who ex­act­ly should re­ceive it.

Wal­ter Kraft

Those vot­ing in fa­vor of ap­proval fol­lowed a se­ries of con­cerns raised by FDA sta­tis­ti­cal re­view­er Yu­ra Kim on the com­pa­ny’s as­sess­ments of the da­ta, not­ing, “Sta­tis­ti­cal analy­ses of the pri­ma­ry end­point us­ing the In­ves­ti­ga­tor as­sess­ment of BVAS [a clin­i­cal scor­ing sys­tem of dis­ease ac­tiv­i­ty to iden­ti­fy ac­tive vas­culi­tis in nine or­gan sys­tems] re­mis­sion re­sult­ed in small­er mag­ni­tude of treat­ment ef­fect and would not sup­port su­pe­ri­or­i­ty of ava­co­pan.”

The agency al­so ques­tioned if the oth­er drugs used in the study may have con­tributed to the ef­fi­ca­cy seen for ava­co­pan.

“In this case, both treat­ment arms re­ceived back­ground ther­a­py in the form of cy­clophos­phamide or rit­ux­imab. The ben­e­fit of glu­co­cor­ti­coids on top of cy­clophos­phamide or rit­ux­imab is not well un­der­stood,” Kim said. “As a re­sult, it is dif­fi­cult to de­ter­mine if sim­i­lar re­mis­sion rates ob­served on both arms can sup­port a con­clu­sion that ava­co­pan is ef­fec­tive or if sim­i­lar­i­ties can be pri­mar­i­ly at­trib­uted to both arms re­ceiv­ing rit­ux­imab or cy­clophos­phamide.”

Margrit Wiesen­dan­ger

The com­pa­ny de­fend­ed its study de­sign, not­ing that when rit­ux­imab won ap­proval in this in­di­ca­tion, it was pri­mar­i­ly based on re­sults from a sin­gle tri­al of about 200 pa­tients, and was de­signed as a non-in­fe­ri­or­i­ty, com­para­tor tri­al over 26 weeks.

Fol­low­ing that lead, Chemo­Cen­tryx in Ju­ly 2016 ini­tial­ly pro­posed a 26-week ran­dom­ized, dou­ble-blind tri­al com­par­ing ava­co­pan to pred­nisone in 232 pa­tients re­ceiv­ing ei­ther rit­ux­imab or cy­clophos­phamide, Pirow Bekker, the clin­i­cal lead for the ava­co­pan clin­i­cal de­vel­op­ment pro­gram, ex­plained.

The Eu­ro­pean Med­i­cines Agency agreed to the non-in­fe­ri­or­i­ty study, ac­cord­ing to Bekker, with the demon­stra­tion of su­pe­ri­or­i­ty in a sec­ondary end­point, such as glu­co­cor­ti­coid tox­i­c­i­ty.

But in the US, FDA said a 26-week non-in­fe­ri­or­i­ty study was not suf­fi­cient, he not­ed. In or­der to ad­dress both FDA and EMA’s feed­back, Chemo­Cen­tryx re­vised the study to be a 52-week study in about 300 pa­tients, with the su­pe­ri­or­i­ty as­sess­ment built in as well.

FDA’s Rachel Glaser con­firmed that there was an ex­pec­ta­tion agreed to in the pre-sub­mis­sion dis­cus­sions that su­pe­ri­or­i­ty would need to be con­firmed for ava­co­pan and that non-in­fe­ri­or­i­ty would not be enough.

The FDA is not re­quired to fol­low the ad­vice of its ad­vi­so­ry com­mit­tee on Chemo­Cen­tryx’s ava­co­pan, but in gen­er­al, the agency usu­al­ly does.

In­side Track: Be­hind the Scenes of a Ma­jor Biotech SPAC

Dr. David Hung and Michelle Doig are no strangers to the SPAC phenomenon. As Founder and CEO of Nuvation Bio, a biotech company tackling some of the greatest unmet needs in oncology, Dr. Hung recently took the company public in one of this year’s biggest SPAC related deals. And as Partner at Omega Funds, Doig not only led and syndicated Nuvation Bio’s Series A, but is now also President of the newly formed, Omega-sponsored, Omega Alpha SPAC (Nasdaq: OMEG; oversubscribed $138m IPO priced January 6, 2021).

Barry Greene, Sage CEO

UP­DAT­ED: Sage's sec­ond chance at de­pres­sion hits the PhI­II pri­ma­ry, but ques­tions re­main over dura­bil­i­ty, side ef­fects

Looking to make a comeback after a big Phase III flop, Sage Therapeutics revealed data they believe could change the entire depression treatment landscape, given the vast array of failures in the field. But some results are spooking investors, sending Sage $SAGE shares down early Tuesday.

First, the primary: Sage and Biogen reported Phase III data for once-daily zuranolone Tuesday morning, saying the experimental drug hit its primary endpoint by spurring a statistically significant change from baseline in the 17-item Hamilton Rating Scale for Depression total score. After 15 days, patients in the drug arm saw an average change of -14.1 points, compared to -12.3 on placebo.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 109,500+ biopharma pros reading Endpoints daily — and it's free.

Bio­gen sig­nals a big PhI­II fail­ure as the lead gene ther­a­py in their $800M Night­star buy­out goes down in flames

That $800 million buyout of Nightstar has turned into a bust for Biogen as the lead therapy in the deal failed a pivotal study, signaling a severe setback for the biotech’s ambitions in gene therapies.

The big biotech put out the word after the market closed on Monday that the gene therapy they picked up in the deal for a degenerative blindness called choroideremia failed the Phase III study, just a month after their #2 drug in the deal also flopped in a mid-stage study.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 109,500+ biopharma pros reading Endpoints daily — and it's free.

Lynn Fitch, Mississippi Attorney General (Rogelio V. Solis/AP Images)

Mis­sis­sip­pi sues Eli Lil­ly, Sanofi and No­vo over in­sulin prices as in­ter­change­able biosim­i­lars may ar­rive soon

Mississippi Attorney General Lynn Fitch last week sued the top three insulin manufacturers, which collectively cover almost the entire US insulin market, alleging that they’ve colluded to raise their prices in lockstep, and in some cases by more than 1,000% for drugs that are decades old.

“Because of Manufacturer Defendants’ collusive price increases, nearly a century after the discovery of insulin, diabetes medications have become unaffordable for many diabetics,” the lawsuit says.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 109,500+ biopharma pros reading Endpoints daily — and it's free.

CEO Harith Rajagopalan (Fractyl)

Af­ter a decade in the type 2 di­a­betes game, Fractyl Lab­o­ra­to­ries recharges with a fresh $100M and a new name

Harith Rajagopalan compared the way type 2 diabetes is managed to sticking your fingers in a dam that’s leaking from a number of places.

You can take drugs to lower your blood sugar, cholesterol, or blood pressure, but you’re not addressing what he says is the core issue — the metabolic abnormality that causes the disease.

“We’re so busy plugging the holes in the dam, we don’t have time to see that the whole infrastructure is at risk,” he said. “That infrastructure is a full-body systemic metabolic abnormality called metabolic syndrome, that we’re ignoring while we’re so busy trying to treat all of the individual symptoms of the condition.”

Michel Sade­lain puts his name and new cell en­gi­neer­ing tech be­hind 'ag­nos­tic' CAR-T start­up chas­ing epi­ge­net­ic anti­gens

It felt natural for Alain Maiore and Sebastian Amigorena to bring in Michel Sadelain as a co-founder of Mnemo Therapeutics. A CAR-T pioneer, Sadelain had been involved as an advisor since the early days — enthusiastic about Amigorena’s work in a genetic knockout that could enhance T cell memory and a new class of potential targets he’s discovered — and could introduce some well-known technologies to the toolbox. So they got the initial cash from Sofinnova Partners to plant roots in Paris and New York in early 2019; within a few months, they began to see more clearly just what the antigen discovery platform might unlock.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 109,500+ biopharma pros reading Endpoints daily — and it's free.

Patrizia Cavazzoni, CDER

FDA’s Cavaz­zoni calls for ad­comms to ‘get back to the sub­stance’

While her comments were recorded prior to the FDA’s recent approval of Biogen’s controversial Alzheimer’s drug, CDER Director Patrizia Cavazzoni presciently called for substantial reforms to the advisory committee process at the agency.

Short on examples of the adcomms she was referring to, Cavazzoni said at a BIO event aired on Monday that some recent committees show “how they can be swayed by emotion in the face of hard facts,” but they need to “get back to the fundamentals, which is listening to thoughtful input from experts in response to thoughtful questions that we ask them.”

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

Andrew Hopkins, Exscientia CEO

Ex­sci­en­tia spends Soft­Bank's cash in bid to edge out AI ri­vals

Exscientia is sprinting to win the great AI biotech race.

The UK company, having long labored on small discovery deals with large pharmas, raised up to $525 million in a Series D led by the infamous Japanese conglomerate SoftBank in April and followed it up less than a month later with a Bristol Myers Squibb deal that paid $50 million cash and $1.2 billion in milestones.

Now, the Oxford spinout is splurging on a shiny new tool. On Monday they announced they purchased the three-year-old molecule-screening biotech Allcyte, a longtime collaborator, for $60.6 million in cash and stock.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 109,500+ biopharma pros reading Endpoints daily — and it's free.

Hal Barron, GSK R&D chief (Endpoints News)

Hal Bar­ron gam­bles $625M cash on high-wire TIG­IT act, throw­ing Glax­o­SmithK­line in­to heat­ed race and com­plet­ing next-gen I/O trin­i­ty

Count Hal Barron and GlaxoSmithKline in for the TIGIT fight.

The stakes are as high as the risks: While a growing pack of Big Pharma rivals is lending credence to the hypothesis that TIGIT will be the next big immune checkpoint and cancer drug target, the first clinical trials have shown response rates that can be described as modest at best. But Barron’s bet is on the whole “axis” that the receptor sits on, with an eye on testing its new anti-TIGIT antibody not just in combo with PD-1 but also in triplets.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 109,500+ biopharma pros reading Endpoints daily — and it's free.