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.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

FDA ad­vi­sors unan­i­mous­ly rec­om­mend ac­cel­er­at­ed ap­proval for Bio­gen's ALS drug

A panel of outside advisors to the FDA unanimously recommended that the agency grant accelerated approval to Biogen’s ALS drug tofersen despite the drug failing the primary goal of its Phase III study, an endorsement that could pave a path forward for the treatment.

By a 9-0 vote, members of the Peripheral and Central Nervous System Drugs Advisory Committee said there was sufficient evidence that tofersen’s effect on a certain protein associated with ALS is reasonably likely to predict a benefit for patients. But panelists stopped short of advocating for a full approval, voting 3-5 against (with one abstention) and largely citing the failed pivotal study.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,500+ biopharma pros reading Endpoints daily — and it's free.

Sanofi, Re­gen­eron boast PhI­II win with Dupix­ent in COPD, clear­ing first bar for ex­pan­sion

Dupixent, the blockbuster anti-inflammatory drug from Sanofi and Regeneron, has cleared a high-stakes Phase III study in chronic obstructive pulmonary disease, the companies announced Thursday morning.

If they hold up in a second, identical trial, the data pave the way for Dupixent to become the first biologic to treat patients whose COPD remains uncontrolled despite being on maximal standard-of-care inhaled therapy — the patient population studied in the pivotal program. The companies had spotlighted this as a key readout as they look to expand the Dupixent franchise and explore its full potential.

Chat­G­PT with phar­ma da­ta de­buts for med­ical meet­ings, be­gin­ning with AACR

What do you get when you combine ChatGPT generative AI technology with specific pharma and clinical datasets? A time-saving tool that can answer questions about medical conference abstracts and clinical findings in seconds in one new application from ZoomRx called FermaGPT.

ZoomRx is debuting a public version of its generative AI product specifically for medical conferences beginning this week for the upcoming American Association for Cancer Research (AACR) annual meeting that runs April 14-19.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,500+ biopharma pros reading Endpoints daily — and it's free.

Alaa Halawa, executive director at Mubadala’s US venture group

The ven­ture crew at Mubadala are up­ping their biotech cre­ation game, tak­ing care­ful aim at a new fron­tier in drug de­vel­op­ment

It started with a cup of coffee and a slow burning desire to go early and long in the biotech creation business.

Wrapping up a 15-year discovery stint at Genentech back in the summer of 2021, Rami Hannoush was treated to a caffeine-fueled review of the latest work UCSF’s Jim Wells had been doing on protein degradation — one of the hottest fields in drug development.

“Jim and I have known each other for the past 15 years through Genentech collaborations. We met over coffee, and he was telling me about this concept of the company that he was thinking of,” says Hannoush. “And I got immediately intrigued by it because I knew that this could open up a big space in terms of adding a new modality in drug discovery that is desperately needed in pharma.”

Endpoints Premium

Premium subscription required

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

FDA re­jects Ab­b­Vie's in­fu­sion ther­a­py for Parkin­son's, re­quests more in­fo on pump de­vice

The FDA rejected AbbVie’s 24-hour infusion therapy for Parkinson’s, saying it needs more information on a device used to administer the treatment before it can clear it.

The Chicago-area drugmaker said in a press release that the complete response letter from the agency didn’t include any requests for more efficacy or safety trials related to the drug, known as ABBV-951. The company said it aims to “resubmit the NDA as soon as possible.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,500+ biopharma pros reading Endpoints daily — and it's free.

In­cyte wins ac­cel­er­at­ed ap­proval for PD-1 in rare skin can­cer

Incyte touted an accelerated approval for its PD-1 retifanlimab in a rare skin cancer on Wednesday, roughly a year and a half after the drug suffered a rejection in squamous cell carcinoma of the anal canal (SCAC).

Retifanlimab, marketed as Zynyz, was approved for metastatic or recurrent locally advanced Merkel cell carcinoma (MCC), a fast-growing skin cancer typically characterized by a single, painless nodule. It’s roughly 40 times rarer than melanoma, according to the nonprofit Skin Cancer Foundation — but incidence is growing, particularly among older adults, Incyte said in its announcement.

FDA in­di­cates will­ing­ness to ap­prove Bio­gen ALS drug de­spite failed PhI­II study

Ahead of Wednesday’s advisory committee hearing to discuss Biogen’s ALS drug tofersen, the FDA appeared open to approving the drug, newly released briefing documents show.

Citing the need for flexibility in a devastating disease like ALS, regulators signaled a willingness to consider greenlighting tofersen based on its effect on a certain protein associated with ALS despite a failed pivotal trial. The documents come after regulatory flexibility was part of the same rationale the agency expressed when approving an ALS drug last September from Amylyx Pharmaceuticals, indicating the FDA’s openness to approving new treatments for the disease.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,500+ biopharma pros reading Endpoints daily — and it's free.

Genen­tech to stop com­mer­cial man­u­fac­tur­ing at Cal­i­for­nia head­quar­ters

Genentech is halting commercial manufacturing at its California headquarters — and laying off several hundred employees.

The move is the result of a decision Genentech made in 2007 to relocate manufacturing operations from its South San Francisco headquarters location to other facilities or move the work to CDMOs, said Andi Goddard, Genentech’s SVP of quality and compliance for pharmaceutical technical operations, in an interview with Endpoints News. Genentech has made changes in capabilities and invested more in technology, so it doesn’t need as many large-scale manufacturing facilities as it did in the past, she said.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 163,500+ biopharma pros reading Endpoints daily — and it's free.