UP­DAT­ED: Pan­el of neu­ro­science ex­perts lays out the com­pli­ca­tions with us­ing Bio­gen's new Alzheimer's drug

Treat­ment of ear­ly Alzheimer’s pa­tients with Bio­gen’s new drug Aduhelm should close­ly re­sem­ble how the drug was stud­ied in its piv­otal clin­i­cal tri­als, ac­cord­ing to new rec­om­men­da­tions from a pan­el of neu­ro­science ex­perts led by UN­LV’s Jef­frey Cum­mings.

Jef­frey Cum­mings

“Those con­sid­er­ing ad­u­canum­ab ther­a­py should un­der­stand that the ex­pect­ed ben­e­fit is slow­ing of cog­ni­tive and func­tion­al de­cline; im­prove­ment of the cur­rent clin­i­cal state is not an­tic­i­pat­ed,” they wrote Tues­day in The Jour­nal of Pre­ven­tion of Alzheimer’s Dis­ease, not­ing that some of their rec­om­men­da­tions are more spe­cif­ic or more re­stric­tive than the in­for­ma­tion pro­vid­ed in the FDA’s pre­scrib­ing in­for­ma­tion.

Cum­mings has re­ceived more than $45,000 in pay­ments from Bio­gen since 2014, ac­cord­ing to Open Pay­ments da­ta. Sec­ond au­thor Paul Aisen of the Alzheimer’s Treat­ment Re­search In­sti­tute at the Uni­ver­si­ty of South­ern Cal­i­for­nia, who’s al­so ed­i­tor in chief of the Jour­nal of Pre­ven­tion of Alzheimer’s Dis­ease, al­so re­ceived more than $38,000 in pay­ments from Bio­gen in 2014. Third au­thor Alireza Atri of the Ban­ner Sun Health Re­search In­sti­tute took more than $32,000 in pay­ments from Bio­gen since 2014.

An aca­d­e­m­ic in neu­ro­science who asked to re­main anony­mous told End­points News that these rec­om­men­da­tions are es­sen­tial­ly an ex­ten­sion of Bio­gen’s mar­ket­ing arm.

One of the biggest is­sues with ad­u­canum­ab is that it sub­stan­tial­ly in­creas­es the rate of amy­loid-re­lat­ed imag­ing ab­nor­mal­i­ties, al­so known as ARIA, com­pared to rates ob­served in nat­ur­al his­to­ry stud­ies or tri­al place­bo groups.

And while ARIA on­ly led to about 6% of pa­tients on ad­u­canum­ab stop­ping their in­volve­ment short in the tri­als, com­pared to 0.6% of pa­tients on place­bo, ARIA (ARIA-E and ARIA-H) oc­curred in about 35% of pa­tients on the high dose of ad­u­canum­ab com­pared to about 3% of those in the place­bo group, the pan­elists note.

“If pa­tients with ARIA (ARIA-E or ARIA-H) have symp­toms, treat­ment should be sus­pend­ed, and a clin­i­cal as­sess­ment and neu­ro­log­i­cal ex­am­i­na­tion per­formed. MRI should be re­peat­ed in 1 month; if the ARIA-E has re­solved or the ARIA-H is sta­bi­lized, treat­ment can be re­sumed. If ARIA-E has not re­solved and ARIA-H is wors­en­ing, treat­ment is with­held, and month­ly MRIs ob­tained un­til treat­ment can be re-ini­ti­at­ed or a de­ci­sion is made to ter­mi­nate treat­ment … Ad­u­canum­ab should not be re-ini­ti­at­ed in pa­tients with se­vere symp­to­matic ARIA (e.g., seizure, stroke-like syn­dromes),” they wrote.

But ARIA-E was most com­mon­ly ob­served in par­tic­i­pants who were APOE-4 gene car­ri­ers (43%) and least of­ten in those with­out the APOE-4 gene (20.3%).

While the FDA-ap­proved pre­scrib­ing in­for­ma­tion for us­ing ad­u­canum­ab do not re­quire APOE geno­typ­ing, the ex­pert pan­el “rec­om­mends that pa­tients and care part­ners be en­gaged in a pa­tient-cen­tered dis­cus­sion of the risk that an APOE-4 geno­type con­fers for the risk of ARIA. This dis­cus­sion will de­ter­mine if geno­type in­for­ma­tion would in­flu­ence their de­ci­sion to be treat­ed with ad­u­canum­ab and if they wish to pur­sue APOE geno­typ­ing,” par­tic­u­lar­ly as ge­net­ic test­ing to de­ter­mine the APOE geno­type of the par­tic­i­pants was re­quired in the piv­otal tri­als.

Ad­u­canum­ab’s la­bel, tight­ened by the agency a month af­ter the ac­cel­er­at­ed ap­proval, notes on ARIA: “En­hanced clin­i­cal vig­i­lance for ARIA is rec­om­mend­ed dur­ing the first 8 dos­es of treat­ment with ADUHELM, par­tic­u­lar­ly dur­ing titra­tion. If a pa­tient ex­pe­ri­ences symp­toms which could be sug­ges­tive of ARIA, clin­i­cal eval­u­a­tion should be per­formed, in­clud­ing MRI test­ing if in­di­cat­ed.”

The pan­el added: “Dose in­ter­rup­tion or treat­ment dis­con­tin­u­a­tion is rec­om­mend­ed for symp­to­matic ARIA and for mod­er­ate-se­vere ARIA. The Ex­pert Pan­el rec­om­mends MRIs pri­or to ini­ti­at­ing ther­a­py, dur­ing the titra­tion of the drug, and at any time the pa­tient has symp­toms sug­ges­tive of ARIA.”

The pan­elists al­so not­ed that their guide­lines were writ­ten de­spite the cur­rent lack of peer-re­viewed pub­li­ca­tions about ad­u­canum­ab’s Phase III piv­otal stud­ies, which the com­pa­ny re­cent­ly said it ex­pect­ed to do. Changes in the guide­lines may be re­quired once all the da­ta is avail­able in the pub­lic do­main, they not­ed.

As far as what to do if a pa­tient miss­es one of his month­ly dos­es of ad­u­canum­ab, the pan­el notes that this co­nun­drum has not been stud­ied.

“The Ex­pert Pan­el rec­om­mends that if a pa­tient miss­es a dose, the next in­fu­sion should be ad­min­is­tered as soon as pos­si­ble at the dose ad­min­is­tered in the pre­vi­ous in­fu­sion. If a pa­tient miss­es three or more dos­es and re­quires con­tin­ued treat­ment, titra­tion should be re-ini­ti­at­ed be­gin­ning at a dose lev­el one step be­low that pre­vi­ous­ly ad­min­is­tered (e.g., if the pa­tient was at 6 mg/kg pre­vi­ous­ly, they would re­sume at a dose lev­el of 3 mg/kg) with the dose in­creased every oth­er month as de­scribed for treat­ment ini­ti­a­tion,” they wrote.

They al­so not­ed cer­tain pa­tients who were ex­clud­ed from Bio­gen’s clin­i­cal tri­als and might need fur­ther con­sid­er­a­tion:

“Pa­tients with ev­i­dence of mi­cro­he­m­or­rhage on MRI or with clot­ting ab­nor­mal­i­ties or who were on an­ti­co­ag­u­lants were ex­clud­ed from the piv­otal tri­als. It is not known if these ex­clu­sions af­fect­ed the rate of mi­cro­he­m­or­rhage as­so­ci­at­ed with ad­u­canum­ab ther­a­py. The risk of se­vere ARIA in a per­son re­ceiv­ing an­ti­co­ag­u­lants or with a clot­ting dis­or­der is suf­fi­cient to ex­clude them from treat­ment with ad­u­canum­ab. Platelet an­ti-ag­gre­ga­tion agents are al­low­able as con­comi­tant ther­a­py. Lum­bar punc­ture for con­fir­ma­tion of amy­loid sta­tus should not be per­formed on pa­tients be­ing treat­ed with an­ti­co­ag­u­lants; the oc­cur­rence of perispinal he­m­or­rhage and spinal cord com­pres­sion are low but can oc­cur and the risk should be avoid­ed.”

As far as when to even start amy­loid imag­ing, or when such imag­ing is ap­pro­pri­ate, the neu­ro­sci­en­tists point to three con­di­tions: “a) there is a cog­ni­tive com­plaint and cog­ni­tive im­pair­ment has been ob­jec­tive­ly con­firmed im­pair­ment; b) AD is a pos­si­ble di­ag­no­sis, but the di­ag­no­sis is un­cer­tain af­ter a com­pre­hen­sive eval­u­a­tion by a de­men­tia ex­pert; and c) knowl­edge of the pres­ence or ab­sence of amy­loid-be­ta pathol­o­gy is ex­pect­ed to in­crease di­ag­nos­tic cer­tain­ty and al­ter man­age­ment.”

The pan­el rec­om­mends that pro­grams of­fer­ing ad­u­canum­ab and us­ing amy­loid PET to con­firm the di­ag­no­sis of AD should en­sure its em­ploy­ees are prop­er­ly trained in amy­loid PET in­ter­pre­ta­tion, as all pa­tients in­clud­ed in the piv­otal tri­als had pos­i­tive amy­loid PET.

The pan­el al­so says that pa­tients with neu­ro­log­i­cal dis­or­ders, such as Parkin­son’s dis­ease, ev­i­dence of stroke or rapid­ly pro­gres­sive de­men­tia, should not be treat­ed with ad­u­canum­ab.

“Ad­u­canum­ab has not been test­ed in pa­tients with mod­er­ate or se­vere AD and pro­gres­sion in­to the more ad­vanced phas­es of AD will prompt re­assess­ment of treat­ment con­tin­u­a­tion,” they note. “The Ex­pert Pan­el rec­om­mends that clin­i­cians care­ful­ly re­view the ev­i­dence of ben­e­fit and the po­ten­tial risk in pa­tients who progress to mod­er­ate de­men­tia af­ter ap­pro­pri­ate use of ad­u­canum­ab in ear­ly AD.”

Over­all, the pan­el ex­plains how ad­u­canum­ab re­quires “sub­stan­tial in­fra­struc­ture” to ap­pro­pri­ate­ly ad­min­is­ter the drug, as well as ex­pert clin­i­cians skilled in recog­ni­tion of ear­ly AD; amy­loid PET or lum­bar punc­ture ca­pa­bil­i­ty; ex­perts in amy­loid PET in­ter­pre­ta­tion or CSF analy­sis; in­fu­sion cen­ter avail­abil­i­ty; and ac­cess to MRI and ex­perts in recog­ni­tion and man­age­ment of ARIA.

In an ac­com­pa­ny­ing com­men­tary, Serge Gau­thi­er of the De­part­ment of Neu­rol­o­gy and Neu­ro­surgery at McGill Uni­ver­si­ty in Mon­tre­al, called for an­oth­er place­bo-con­trolled tri­al.

“Fu­ture rec­om­men­da­tions could ad­dress the need of con­fir­ma­to­ry da­ta on clin­i­cal ef­fi­ca­cy, tak­ing ad­van­tage of the FDA re­quire­ment for an­oth­er place­bo-con­trolled study: it is an op­por­tu­ni­ty to es­tab­lish if an­ti-amy­loid ther­a­py can be stopped once the amy­loid load has been rec­ti­fied, through a re­peat PET amy­loid scan af­ter 12 or 18 months, fol­lowed by ran­dom­iza­tion to con­tin­u­a­tion of ad­u­canum­ab, to place­bo, to an an­ti-tau drug or a com­bi­na­tion of the two drug class. This ran­dom­ized de­layed start fac­to­r­i­al de­sign may go a long way in in­flu­enc­ing fu­ture ther­a­py of AD,” he wrote.

Ed­i­tor’s note: Ar­ti­cle up­dat­ed with the ex­pert pan­el’s fi­nan­cial con­flicts with Bio­gen.

Big Phar­ma's Twit­ter ex­o­dus; Mer­ck wa­gers $1.35B on buy­out; $3.5M gene ther­a­py; 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.

As you start planning for #JPM23, we hope you will consider joining Endpoints News for our live and virtual events. For those who are celebrating Thanksgiving, we hope you are enjoying the long weekend with loved ones. And if you’re not — we’ll see you next week!

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

Paul Perreault, CSL Behring CEO

CSL lands FDA ap­proval for he­mo­phil­ia B gene ther­a­py, sets $3.5M list price

The FDA has approved the world’s first gene therapy for hemophilia B, ushering into the market a treatment that’s historic in both what it promises to do and how much it will cost.

CSL will be marketing the drug, Hemgenix, at a list price of $3.5 million — which sets a new record for the most expensive single-use gene therapy in the US.

In a statement provided to Endpoints News, the Australian company noted that the current costs of treating people with moderate to severe hemophilia B can be significant over a lifetime. By some estimates, healthcare systems could spend more than $20 million per person.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

Elon Musk (GDA via AP Images)

Biggest drug com­pa­nies halt­ed Twit­ter ad buys af­ter Lil­ly in­sulin spoof

Almost all of the drug industry’s biggest advertisers cut their spending on Twitter to zero or near-zero over the last two weeks amid worries about impersonation of their brands by pranksters and the future of the social media company.

Among 18 of the biggest pharmaceutical advertisers in the US market, 12 cut their Twitter ad spending to nothing for the week beginning Nov. 14, according to Pathmatics, which tracks data on prescription drug ad spending as well as general corporate advertising. The list of drugmakers cutting spending to zero includes Merck, AstraZeneca, Eli Lilly, Novartis, Pfizer and others.

Rob Davis, Merck CEO

Up­dat­ed: No Seagen here: 'Do more' means a small $1.35B pur­chase of Ima­go for Mer­ck

Merck is making an acquisition, the Big Pharma announced before Monday’s opening bell. No, Seagen is not entering the fold, as had been speculated for quarters.

Folding under Merck’s wings will be Pfizer-backed Imago BioSciences. For nearly a year, Merck CEO Rob Davis has been saying the pharma giant needs to “do more” on the business development front after its 2021 $11.5 billion acquisition of Acceleron.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

FDA preps for DMD drug gener­ics as Sarep­ta has yet to fin­ish its con­fir­ma­to­ry tri­al

The FDA typically releases guidance to help generic drug manufacturers develop new copycats of small molecule drugs, oftentimes in preparation for a brand name product’s patents or exclusivity to expire.

This week, FDA released such bioequivalence guidance for any generic drugmakers looking to take on Sarepta’s Duchenne muscular dystrophy (DMD) drug Exondys 51 (eteplirsen), even though the drug’s sponsor has yet to convert the accelerated approval to a full approval, showing clinical benefit.

Image: Shutterstock

MIT re­searchers re­veal DNA "Paste" tech be­hind lat­est gene edit­ing start­up

MIT scientists have developed a tool that they say can insert large gene sequences where they want in the genome.

In a paper published Thursday in Nature Biotechnology, MIT fellows Omar Abudayyeh, Jonathan Gootenberg and colleagues detail a technology they call PASTE, which they say can potentially be used to insert long strands of DNA and treat genetic diseases caused by many different mutations, such as cystic fibrosis and Leber congenital amaurosis, a rare eye disorder that causes blindness.

J&J's Spra­va­to pulls a PhI­II win against Sero­quel XR in treat­ment-re­sis­tant de­pres­sion

A day before Thanksgiving, J&J’s Janssen has a new cut of Phase III Spravato data to be grateful for.

The pharma giant announced on Wednesday that its nasal spray, also known as esketamine, beat extended-release quetiapine, previously sold by AstraZeneca as Seroquel XR, in treatment-resistant depression (TRD). Of 676 adults, a significantly higher number of patients on Spravato were able to achieve remission and avoid relapse after 32 weeks, according to J&J.

Dermavant Sciences' first consumer TV ad for its Vtama psoriasis med shows people ready for a new topical treatment.

Roivant’s Der­ma­vant de­buts first-ever TV com­mer­cial for pso­ri­a­sis cream Vta­ma

Dermavant Sciences has been marketing its first product, psoriasis med Vtama, to dermatologists for months, but on Tuesday it rolled out its first consumer campaign. The debut DTC effort including a streaming TV commercial encourages patients to a “Topical Uprising” in a nod to Vtama being a topical cream.

In the new commercial, a swell of people discards scarves and jacket coverings, gathering in the street to converge on a pharmacy to demand a steroid-free prescription. A moment of levity follows when a pharmacist says, “You know you can just talk to your doctor, right?” The gathered crowds collectively says, “Oh.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 154,000+ biopharma pros reading Endpoints daily — and it's free.

Isao Teshirogi, Shionogi president and CEO (Kyodo via AP Images)

Sh­ionogi's Covid an­tivi­ral lands first ap­proval in Japan's new emer­gency ap­proval path­way

Japanese regulators on Tuesday signed off on Shionogi’s homegrown antiviral for Covid-19, known as Xocova (ensitrelvir), making it the first approval under Japan’s emergency regulatory approval system.

The emergency approval, following a back-and-forth with regulators since last February, is based on a safety profile with more than 2,000 patients who have accessed the pill, and clinical symptomatic efficacy for five typical Omicron-related symptoms (primary endpoint) and antiviral efficacy (key secondary endpoint) in patients with mild to moderate SARS-CoV-2 infection, regardless of risk factors or vaccination status, and during the Omicron-dominant phase of the pandemic.