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.

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.

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.