US reg­u­la­tors ap­proved Ei­sai and Bio­gen’s Alzheimer’s drug lecanemab, a land­mark mo­ment for the dis­ease and a sec­ond chance for the com­pa­nies af­ter their drug Aduhelm was a com­mer­cial flop in the face of cost and ef­fi­ca­cy con­cerns.

The FDA cleared the mon­o­clon­al an­ti­body un­der its ac­cel­er­at­ed ap­proval path­way, for use in pa­tients with mild cog­ni­tive im­pair­ment from Alzheimer’s who have con­firmed pres­ence of amy­loid be­ta pathol­o­gy pri­or to treat­ment, es­sen­tial­ly the same pop­u­la­tion in clin­i­cal tri­als. Like Aduhelm, which the com­pa­nies brought to mar­ket in June 2021, it claims to slow the pro­gres­sion of the neu­rode­gen­er­a­tive dis­ease. Ei­sai will sell the drug as Leqem­bi.

The drug will be priced at $26,500 per year, Ei­sai said. Ex­ist­ing cov­er­age lim­i­ta­tions from Cen­ters for Medicare & Med­ic­aid Ser­vices mean many pa­tients won’t have ac­cess. CMS said it’s look­ing at avail­able in­for­ma­tion “may re­con­sid­er its cur­rent cov­er­age based on this re­view.” Tra­di­tion­al ap­proval could lead to broad­er cov­er­age, CMS said in a state­ment.

Ivan Che­ung

“It’s not a cure, but I think any dis­ease like on­col­o­gy, HIV and all these ar­eas, you al­ways need that ini­tial, foun­da­tion­al spark,” Ei­sai US leader and glob­al Alzheimer’s chief Ivan Che­ung told End­points News in an in­ter­view be­fore the ap­proval. “I think this could be that mo­ment.”

Aduhelm at one time ap­peared to be that spark. But it quick­ly fiz­zled out. Af­ter the FDA cleared the drug, CMS, which in­sures the US’ 65-and-over pop­u­la­tion, re­fused to pay the $56,000 price ex­cept for use in pa­tients in a clin­i­cal tri­al. The ev­i­dence that the drug ac­tu­al­ly made any dif­fer­ence in slow­ing Alzheimer’s was am­bigu­ous, and even af­ter the price was cut in half to $28,200, it failed to bring in any mean­ing­ful sales.

Un­der the com­pa­nies’ part­ner­ship, Bio­gen was re­spon­si­ble for Aduhelm’s com­mer­cial­iza­tion, which sparked an 18-month con­gres­sion­al in­ves­ti­ga­tion, while Ei­sai will take the lead with Leqem­bi.

De­bate about ef­fi­ca­cy

Leqem­bi is like­ly to face its own ques­tions from doc­tors about whether pa­tients will ac­tu­al­ly no­tice the drug’s im­pact. In Sep­tem­ber, Ei­sai an­nounced that an 1,800-pa­tient Phase III tri­al found the drug slowed the pro­gres­sion of Alzheimer’s dis­ease by 27% over 18 months com­pared with a place­bo, us­ing a scale mea­sur­ing cog­ni­tion and func­tion.

Re­searchers and clin­i­cians have called the drug’s im­pact mod­est and said there’s still no de­fin­i­tive ev­i­dence of clin­i­cal mean­ing­ful­ness, with the de­bate on­go­ing about how big an ef­fect is need­ed. Yet the drug, which aims to clear tox­ic amy­loid pro­tein buildups in the brain, is a step in the right di­rec­tion for a dis­ease with few treat­ment op­tions, doc­tors have said.

“The fact that it is even be­ing dis­cussed as po­ten­tial­ly mean­ing­ful when you’re start­ing a tri­al where there are clin­i­cal symp­toms on board, af­ter a long de­gen­er­a­tive process, is ac­tu­al­ly pret­ty stun­ning, es­pe­cial­ly when you align it with the move­ment of the bio­mark­ers,” Bar­ry Green­berg, an Alzheimer’s re­searcher since the 1980s and an as­so­ciate pro­fes­sor of neu­rol­o­gy at Johns Hop­kins, said in an in­ter­view.

“We worked very, very hard with the FDA to nar­row­ing the pop­u­la­tion to the one in the clin­i­cal tri­als,” Ei­sai’s Alzheimer’s leader said.

On an 18-point scale known as the Clin­i­cal De­men­tia Rat­ing-Sum of Box­es, or CDR-SB, place­bo pa­tients had their scores wors­en by 1.66, while Leqem­bi pa­tients de­clined by 1.21 points. That amounts to a 0.45 point dif­fer­ence in Leqem­bi’s fa­vor.

Bar­ry Green­berg

But ex­perts have called a 1-point dif­fer­ence the min­i­mum for clin­i­cal mean­ing­ful­ness. Ei­sai and its in­ves­ti­ga­tors dif­fer. When pub­lish­ing the CLAR­I­TY AD Phase III re­sults in the New Eng­land Jour­nal of Med­i­cine in late No­vem­ber, they claimed that such a de­f­i­n­i­tion “has not been es­tab­lished.”

What has been es­tab­lished is that there’s still plen­ty of de­bate.

“Eigh­teen months of treat­ment pro­duc­ing a dif­fer­ence of that min­i­mal size is not the clin­i­cal ef­fects that pa­tients are hop­ing for,” Matthew Schrag, a Van­der­bilt Alzheimer’s re­searcher un­af­fil­i­at­ed with Leqem­bi, said in an in­ter­view with End­points. “This drug doesn’t give any­one their mem­o­ry back.”

Safe­ty ques­tions

The de­bates about ef­fi­ca­cy are cer­tain to be paired with ques­tions about safe­ty. In the Phase III tri­al, Ei­sai re­port­ed cas­es of brain bleed­ing and swelling. Known as ARIA, the amy­loid-re­lat­ed imag­ing ab­nor­mal­i­ties are de­tect­ed by scans, and have been as­so­ci­at­ed with oth­er an­ti-amy­loid drugs in clin­i­cal stud­ies. The rates of ARIA-E, which can in­di­cate swelling, were 12.6% for those on Leqem­bi and 1.7% for those on place­bo. For ARIA-H, or signs of bleed­ing, the rates were 17.3% and 9.0%, re­spec­tive­ly.

FDA placed a “warn­ing for amy­loid-re­lat­ed imag­ing ab­nor­mal­i­ties (ARIA), which are known to oc­cur with an­ti­bod­ies of this class. ARIA usu­al­ly does not have symp­toms, al­though se­ri­ous and life-threat­en­ing events rarely may oc­cur,” in the re­lease.

In the la­bel, FDA notes MRI mon­i­tor­ing for ARIA should be done pri­or to treat­ment and again be­fore the fifth, sev­enth and 14th in­fu­sions. Un­der the warn­ings and pre­cau­tions sec­tion, the FDA notes, based on the Phase II study, pa­tients on Leqem­bi and an­ti-throm­botics, as­pirin, oth­er an­ti-platelets or an­ti-co­ag­u­lants “did not have an in­creased risk of ARIA-H com­pared to pa­tients who re­ceived place­bo and an­ti-throm­bot­ic med­ica­tion.”

The la­bel in­cludes no boxed warn­ing, no risk eval­u­a­tion and mit­i­ga­tion strat­e­gy (REMS) and no con­traindi­ca­tions, Che­ung said.

“Hav­ing said that, we want to be proac­tive,” the Ei­sai ex­ec­u­tive said. Ei­sai will launch a spon­sored pro­gram called “Un­der­stand­ing ARIA,” which he said will in­clude self-di­rect­ed ed­u­ca­tion­al mod­ules for physi­cians, live in­ter­ac­tive ed­u­ca­tion­al ses­sions for doc­tors and con­tin­u­ing med­ical ed­u­ca­tion spon­sor­ships.

Pub­li­ca­tions have re­port­ed cas­es of three deaths po­ten­tial­ly linked to the drug, in­clud­ing one re­port that came out just weeks be­fore the ap­proval.

Michael Irizarry

Schrag called Ei­sai and Bio­gen’s fail­ure to dis­close the death at a med­ical con­fer­ence in late No­vem­ber dis­turb­ing, and said that “rush­ing this drug to mar­ket would be a mis­take.” Michael Irizarry, Ei­sai’s deputy chief clin­i­cal of­fi­cer for Alzheimer’s and brain health, told End­points the tri­al in­ves­ti­ga­tor hasn’t yet had ac­cess to the hos­pi­tal records and scans that were re­port­ed.

“We do think that it does high­light that ARIA-E is an im­por­tant ad­verse event with Leqem­bi and can be a se­ri­ous ad­verse event,” Irizarry said.

Re­searchers like Schrag want more an­swers.

“As we as a field wres­tle with the ap­pro­pri­ate role of these drugs, we need to be work­ing with all of the da­ta. This episode un­der­mines my trust in Ei­sai and Bio­gen and falls in­to the same pat­tern of frus­trat­ing be­hav­ior that we wit­nessed around the ap­proval and post-ap­proval mar­ket­ing of” Aduhelm, Schrag said.

Cov­er­age ne­go­ti­a­tions

Leqem­bi’s ac­cel­er­at­ed ap­proval means that the com­pa­nies will still need to ap­ply for full FDA ap­proval, which will hap­pen in mere days, Che­ung told End­points.

The US-Japan­ese drug­mak­er has been in di­a­logue with CMS to open up pay­ment for the med­i­cine af­ter the agency lim­it­ed cov­er­age of Alzheimer’s drugs in the wake of Aduhelm’s ap­proval. Cur­rent­ly, to get cov­ered by the pro­gram, most pa­tients must be in a clin­i­cal tri­al. Con­ver­sa­tions with the gov­ern­ment thus far are “very pro­duc­tive,” Che­ung said, and he not­ed many pay­ers are in line with CMS’ de­ci­sion, but that “doesn’t mean we’re not go­ing to try our best to work with oth­er pay­ers.”

Ei­sai and oth­er an­ti-amy­loid drug­mak­ers got the back­ing of the Alzheimer’s As­so­ci­a­tion in mid-De­cem­ber, when the ad­vo­ca­cy group called on CMS to re­verse the cov­er­age de­ci­sion, call­ing it “not ac­cept­able.”

Ei­sai said the com­pa­ny doesn’t ex­pect CMS’ na­tion­al cov­er­age de­ci­sion to be lift­ed or loos­ened ahead of a full ap­proval. In the in­ter­view, Che­ung ac­knowl­edged some hos­pi­tal sys­tems might not put any pa­tients on Leqem­bi be­cause of the CMS re­stric­tion, call­ing it a “mixed emo­tion of a launch,” but that oth­er pa­tients might have ac­cess, such as those un­der the age of 65, or those who are cov­ered by Vet­er­ans Af­fairs or the De­part­ment of De­fense. The VA did not cov­er Aduhelm.

“This ini­tial phase, our goal at Ei­sai is not gen­er­at­ing de­mand or gen­er­at­ing sales. It’s re­al­ly get­ting the ecosys­tem ready,” Che­ung said. The “true launch” will come when changes are made to the NCD, he said.

Ap­proval fil­ings in Japan and the Eu­ro­pean Union are ex­pect­ed by the end of March. An ap­pli­ca­tion was ini­ti­at­ed in Chi­na in De­cem­ber, and oth­er coun­tries on the hori­zon in­clude Aus­tralia, Cana­da, UK and Switzer­land, Che­ung said. Lecanemab in­ven­tor BioArc­tic is al­so work­ing with Ei­sai on prepar­ing for fil­ings in the Nordics, a spokesper­son said. The Eu­ro­pean Med­i­cines Agency could be more strin­gent, as the bloc’s drug reg­u­la­tor like­ly seeks con­fir­ma­tion of clin­i­cal rel­e­vance.

Price and da­ta

Leqem­bi’s price is high­er than the $9,000 to $21,000 per year “cost-ef­fec­tive” range cal­cu­lat­ed by the In­sti­tute for Clin­i­cal and Eco­nom­ic Re­view, the pric­ing watch­dog which re­leased a draft re­port on the drug in De­cem­ber. Once pa­tients reach the main­te­nance phase, though, the an­nu­al price would be less than $15,000, Che­ung said.

Ei­sai pre­vi­ous­ly cal­cu­lat­ed an “an­nu­al val­ue-based price” range of $9,200 to $35,600 based on Phase II re­sults, and that price in­creased to $37,000 af­ter fac­tor­ing in the Phase III da­ta as part of the “so­ci­etal val­ue of med­i­cine,” the Ei­sai ex­ec­u­tive ex­plained.

In­fla­tion in the US and re­sults from stud­ies of a sub­cu­ta­neous ver­sion of Leqem­bi will be tak­en in­to con­sid­er­a­tion in the fu­ture, as well, Che­ung said, not­ing ICER’s draft and the Con­gres­sion­al re­port re­leased in the last week of 2022 were not fac­tored in­to the pric­ing analy­sis.

Che­ung said Ei­sai is work­ing on get­ting an­oth­er pa­per pub­lished to in­clude analy­ses of pre-spec­i­fied ar­eas that Sharon Co­hen, a Uni­ver­si­ty of Toron­to neu­rol­o­gist, pre­sent­ed at an Alzheimer’s con­fer­ence the same day the NE­JM pa­per went live.

“Our slope analy­sis [of CLAR­I­TY AD] sug­gests that place­bo reach­es a point af­ter about 12 months that lecanemab doesn’t reach un­til 18 months and that kind of change in­creas­es over time,” Irizarry told End­points. “So we’re try­ing to put all this in­for­ma­tion to­geth­er to sup­port the clin­i­cal mean­ing­ful­ness of the ef­fect on the pri­ma­ry end­point.”

Short­ly af­ter Ei­sai’s Phase III topline read­out, a ma­jor set­back came to the field as Roche’s an­ti-amy­loid gan­tenerum­ab flunked a late-stage study. An­oth­er late-stage can­di­date is still in the works at Eli Lil­ly, whose do­nanemab is in mul­ti­ple clin­i­cal tri­als, in­clud­ing one in which it proved bet­ter than Aduhelm. The FDA is ex­pect­ed to de­cide on that drug in the com­ing months.

A Lil­ly spokesper­son told End­points in an emailed state­ment that the Big Phar­ma has “nev­er been more ex­cit­ed about the promise of our Alzheimer’s dis­ease port­fo­lio and the dif­fer­ence that we be­lieve do­nanemab could make for pa­tients suf­fer­ing from this dis­ease.”

Lars Lan­n­felt

The go-ahead for Leqem­bi is a high point for the drug’s 17-year jour­ney at Ei­sai. The Tokyo-based drug­mak­er ini­tial­ly inked arms with BioArc­tic in 2005 and then signed an ex­clu­sive li­cense in De­cem­ber 2007 for an an­ti­body at the time known as BAN2401.

The ap­proval is a “recog­ni­tion of the many sci­en­tists and doc­tors who have, over many years, pa­tient­ly and per­sis­tent­ly worked to find a treat­ment for this high­ly com­plex dis­ease,” Chris Viehbach­er, the re­cent­ly in­stalled Bio­gen CEO who took over for Michel Vounatsos, told End­points in a state­ment.

The drug’s name hon­ors BioArc­tic founder Lars Lan­n­felt, rep­re­sent­ing the L; e for Ei­sai; and the moniker’s re­main­der rough­ly trans­lates to healthy, el­e­gant and beau­ti­ful in the biotech’s na­tive lan­guage, Che­ung said, not­ing Ei­sai want­ed to in­cor­po­rate “some pos­i­tive mean­ing in the Japan­ese her­itage.”

Bio­gen is re­spon­si­ble for man­u­fac­tur­ing lecanemab at its Solothurn, Switzer­land, fa­cil­i­ty, the part­ners said in March 2022, when they ex­tend­ed the sup­ply agree­ment from five to 10 years.

Ed­i­tor’s note: This sto­ry was up­dat­ed to in­clude in­for­ma­tion from Cen­ters for Medicare & Med­ic­aid and an Eli Lil­ly state­ment.

DC District Court Judge Christopher Cooper today granted Vanda Pharma’s request to require the FDA to disclose more info on the complete response letter for its sleep disorder drug Hetlioz.

The melatonin receptor agonist is approved by the FDA to treat non-24-hour sleep-wake disorder, a circadian rhythm disorder. But in 2018 Vanda filed a supplemental application to market Hetlioz as a treatment for jet lag, which the FDA rejected in August 2019, with few details on what Vanda needed to correct course, according to the company.

Republican leaders of the House Committee on Energy & Commerce sent a five-page letter yesterday announcing an investigation into the ongoing drug shortages that have rankled the US during the pandemic and the FDA’s response to it.

The letter, signed by Chair Cathy McMorris Rodgers (R-WA), explains how shortages have become more common over the past decade, while pointing to a report from the National Academies of Science, Engineering and Medicine finding that drug shortages have been “on the rise” over the past several decades and are lasting longer, with new drug shortages in the US seeing a 30% increase from 2021 to 2022.