Hopes and Questions raised by Alzheimer’s drug Leqembi (lecanemab)

The FDA has approved Leqem­bi, the first dis­ease-mod­i­fy­ing treat­ment for ear­ly-stage Alzheimer’s and a pre­cur­sor con­di­tion, mild cog­ni­tive impair­ment. Medicare has said it will pay for the ther­a­py. Med­ical cen­ters across the coun­try are scram­bling to final­ize poli­cies and pro­ce­dures for pro­vid­ing the med­ica­tion to patients, pos­si­bly by summer’s end or ear­ly autumn.

It’s a fraught moment, with hope run­ning high for fam­i­lies and oth­er promis­ing ther­a­pies such as donanemab on the hori­zon. Still, med­ical providers are cau­tious. “This is an impor­tant first step in devel­op­ing treat­ments for com­plex neu­rode­gen­er­a­tive dis­eases, but it’s just a first step,” said Ronald Petersen, direc­tor of the Mayo Clinic’s Alzheimer’s Dis­ease Research Cen­ter in Rochester, Minnesota.

Unan­swered ques­tions abound as this new era of treat­ment begins for mild cog­ni­tive impair­ment and ear­ly-stage Alzheimer’s. Will Leqembi’s pri­ma­ry ben­e­fit — a slight slow­ing of decline in cog­ni­tion and func­tion­ing — make a sig­nif­i­cant dif­fer­ence to patients and fam­i­ly mem­bers or will it be dif­fi­cult to dis­cern? Will its effects accel­er­ate, decel­er­ate, or flat­ten out over time?

Will demand for Leqem­bi (the brand name for lecanemab), a mon­o­clon­al anti­body that requires infu­sions every two weeks, be robust or restrained? How many old­er adults in their 70s and 80s will be able and will­ing to trav­el to med­ical cen­ters for infu­sions twice a month and have reg­u­lar MRI scans and physi­cian vis­its to mon­i­tor for poten­tial side effects such as brain bleeds or swelling?

Even with Medicare cov­er­age, how many peo­ple will be able to afford the suite of med­ical ser­vices required, includ­ing cog­ni­tive tests, infu­sions, doc­tors’ appoint­ments, MRI scans, genet­ic tests, and spinal taps or PET scans to ver­i­fy the pres­ence of amy­loid plaques, a hall­mark of Alzheimer’s and a pre­con­di­tion for receiv­ing this therapy?

Will pri­ma­ry care physi­cians start rou­tine­ly screen­ing old­er adults for mild cog­ni­tive impair­ment, some­thing that doesn’t hap­pen currently?

These ques­tions aren’t sur­pris­ing, giv­en that these demen­tia treat­ments are open­ing unchart­ed ter­ri­to­ry. Here’s some of what peo­ple should know:

Leqem­bi basics. Leqem­bi is very effec­tive at remov­ing amy­loid plaques (a pro­tein that clumps between neu­rons) from people’s brains. But it doesn’t reverse cog­ni­tive decline or pre­vent future deterioration.

In a brief­ing doc­u­ment, Eisai, the com­pa­ny that makes Leqem­bi, said clin­i­cal tri­als showed a 27% slow­er rate of decline for peo­ple tak­ing the drug. But when raw scores on the cog­ni­tive scale used to mea­sure results are con­sid­ered (4.41 for the Leqem­bi group at the end of 18 months ver­sus 4.86 for the place­bo group), the rate of improve­ment was 9%, accord­ing to Lon Schnei­der, a pro­fes­sor of psy­chi­a­try, neu­rol­o­gy, and geron­tol­ogy at the Uni­ver­si­ty of South­ern California’s Keck School of Medicine.

Ben­e­fits may be hard to detect. Research sug­gests that patients notice a “clin­i­cal­ly mean­ing­ful” change in cog­ni­tive per­for­mance — a notice­able alter­ation in their abil­i­ty to think, remem­ber, and per­form dai­ly tasks — when scores rise at least 1 point on an 18-point scale used to mea­sure Leqembi’s impact. But the change detect­ed after 18 months for patients tak­ing this med­ica­tion was only 0.45%.

That’s a min­i­mal dif­fer­ence, and peo­ple are unlike­ly to per­ceive any real alter­ation in cog­ni­tive func­tion­ing,” said Alber­to Espay, a pro­fes­sor of neu­rol­o­gy at the Uni­ver­si­ty of Cincin­nati Col­lege of Medicine.

Petersen has a dif­fer­ent per­spec­tive since many patients have told him they’d be hap­py to put off get­ting worse. “If we can keep these patients sta­ble for a some­what longer peri­od of time, that’s mean­ing­ful,” he told me.

Side effects are com­mon. The drug­mak­er report­ed 17% of patients tak­ing Leqem­bi expe­ri­enced swelling in the brain and 13% had brain bleeds. Most of these side effects occurred dur­ing the first three months of treat­ment and resolved with­out seri­ous con­se­quences four months later.

In slight­ly more than 1 in 4 cas­es, there were also infu­sion-relat­ed side effects — chills, aches, nau­sea, vom­it­ing, a spike or drop in blood pres­sure, and more.

A lit­tle-dis­cussed side effect is a reduc­tion in brain vol­ume asso­ci­at­ed with Leqem­bi and oth­er anti-amy­loid ther­a­pies. “We don’t know what this will mean to patients long term, and that’s con­cern­ing,” Espay said.

Because peo­ple with the APOE4 gene vari­ant, which rais­es the risk of Alzheimer’s, are also at high­er risk of Leqem­bi side effects, physi­cians at major med­ical cen­ters will rec­om­mend genet­ic test­ing as they eval­u­ate poten­tial patients.

Not all patients will qual­i­fy. “I’m very care­ful­ly select­ing the patients I think will be appro­pri­ate, focus­ing on peo­ple with mild cog­ni­tive symp­toms who are oth­er­wise healthy,” said Erik Musiek, an asso­ciate pro­fes­sor of neu­rol­o­gy at the Wash­ing­ton Uni­ver­si­ty School of Med­i­cine in St. Louis.

He has about 20 patients ready to start treat­ment once Wash­ing­ton Uni­ver­si­ty starts offer­ing Leqem­bi, per­haps by ear­ly autumn. Deliv­er­ing this ther­a­py “is going to be chal­leng­ing, and I think we need to err on the side of cau­tion,” he said.

In Los Ange­les, UCLA Health has set up a mul­ti­dis­ci­pli­nary group of spe­cial­ists, sim­i­lar to a can­cer tumor board, to under­take com­pre­hen­sive reviews of patients who want to take Leqem­bi, said Kei­th Vos­sel, direc­tor of UCLA’s Mary S. Eas­t­on Cen­ter for Alzheimer’s Research and Care. They will dis­qual­i­fy peo­ple with evi­dence of more than four microb­leeds on brain MRIs, those tak­ing blood thin­ners, and those with a his­to­ry of seizures.

At the Mayo Clin­ic in Min­neso­ta, a new Alzheimer’s ther­a­peu­tics clin­ic will care­ful­ly assess poten­tial patients over three to four days and treat only peo­ple who live with­in a 100-mile radius. “We’ll start with patients who are fair­ly healthy and fol­low them very close­ly,” Petersen said.

At Mount Sinai School of Med­i­cine in New York City, Mary Sano, direc­tor of Alzheimer’s Dis­ease Research, is con­cerned about old­er patients with mild cog­ni­tive impair­ment who want to take Leqem­bi but don’t have evi­dence of amy­loid plaque accu­mu­la­tion in their brains. “We’ll only treat peo­ple who are amy­loid-pos­i­tive, and I’m afraid this could lead to peo­ple feel­ing like we’re not tak­ing care of them,” she said. About 40% to 60% of patients 58 and old­er with mild cog­ni­tive impair­ment are amy­loid-pos­i­tive, research indicates.

Also of con­cern are patients who have mod­er­ate Alzheimer’s or ear­ly-stage cog­ni­tive impair­ment due to vas­cu­lar demen­tia or var­i­ous meta­bol­ic caus­es. They, too, would not be able to take Leqem­bi and may well be dis­ap­point­ed, Sano noted.

Costs could be con­sid­er­able. Costs for Leqem­bi are dif­fi­cult to cal­cu­late since Medicare offi­cials haven’t announced what the gov­ern­ment will pay for ser­vices. But the Uni­ver­si­ty of South­ern Cal­i­for­nia esti­mates that a year’s worth of care, includ­ing the $26,500 cost of the med­ica­tion, could total about $90,000, accord­ing to Schneider.

A sep­a­rate analy­sis by the Insti­tute for Clin­i­cal and Eco­nom­ic Review sug­gests that all the med­ical ser­vices nec­es­sary to admin­is­ter the drug, mon­i­tor patients, and under­take need­ed test­ing could total an aver­age of $82,500 year­ly on top of Leqembi’s direct cost.

Assum­ing a patient copay­ment of 20%, that would mean at least $18,000 in out-of-pock­et spend­ing. While many old­er adults have sup­ple­men­tal insur­ance (a Medi­gap plan or employ­er-spon­sored retiree cov­er­age) to cov­er these costs, near­ly 1 in 10 Medicare ben­e­fi­cia­ries lack this type of pro­tec­tion. And it remains to be seen what poli­cies pri­vate Medicare Advan­tage plans will put in place for this medication.

Kaiser Health News con­tribut­ing colum­nist Judith Gra­ham focus­es on med­ical issues and advice asso­ci­at­ed with aging and end-of-life care, help­ing America’s 45 mil­lion seniors and their fam­i­lies nav­i­gate the health care system.

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About SharpBrains

SHARPBRAINS is an independent think-tank and consulting firm providing services at the frontier of applied neuroscience, health, leadership and innovation.
SHARPBRAINS es un think-tank y consultoría independiente proporcionando servicios para la neurociencia aplicada, salud, liderazgo e innovación.

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