Haruo Naito, Eisai CEO (Shoko Takayasu/Bloomberg via Getty Images)

Break­ing: FDA clears sec­ond Alzheimer's drug in 'foun­da­tion­al spark' for field

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.

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