Are we close to Alzheimer’s cure?

BioSpectrum (India) - - BIO CONTENT - Aish­warya Venkatesh aish­warya.venkatesh@mmac­tiv.com

The need is great, bar­ri­ers are many and re­wards high- this is the cur­rent sce­nario of Alzheimer’s drug de­vel­op­ment. It’s been 14 years since the last new drug was ap­proved for Alzheimer’s by the FDA and for long Alzheimer’s disease has been a grave­yard for ex­per­i­men­tal re­search. Amid all this, Bio­gen’s re­cent suc­cess­ful trial of an in­ves­ti­ga­tional can­di­date for Alzheimer’s has brought back hope for mil­lions of pa­tients. World Alzheimer’s Day is on Septem­ber 21, BioSpec­trum analy­ses the chal­lenges and op­por­tu­ni­ties in de­vel­op­ing a drug for Alzheimer’s disease.

Im­proved health­care fa­cil­i­ties, bet­ter ac­cess to qual­ity health in­fra­struc­ture and grow­ing aware­ness of good life­style is help­ing peo­ple live longer. Yes, that is good news! But with old age comes age re­lated dis­or­ders like de­men­tia that rob elders of their cog­ni­tive abil­i­ties, se­verely im­pact­ing their day to day life. To­day, across ge­ogra­phies, many el­derly suf­fer from dis­or­ders that fall un­der the um­brella term de­men­tia and de­spite con­certed ef­forts from the sci­en­tific com­mu­nity and phar­ma­ceu­ti­cal in­dus­try, re­searchers have frus­trat­ingly failed to de­velop drugs for some of the most fright­en­ing age re­lated dis­eases. Alzheimer’s is one of the most com­mon type of de­men­tia. Alzheimer’s disease is in­creas­ing rapidly in fre­quency as the world’s pop­u­la­tion ages and more peo­ple en­ter the ma­jor risk bracket for this age-re­lated dis­or­der. From the 5.3 mil­lion US cit­i­zens af­fected now, ex­perts pre­dict that the num­ber of vic­tims will in­crease to 13 mil­lion or more by 2050 and world­wide the to­tal num­ber of af­fected in­di­vid­u­als is ex­pected to in­crease to a stag­ger­ing 100 mil­lion. The cost of care in the

US, cur­rently more than $200 bil­lion an­nu­ally, will grow to an un­sup­port­able $1 tril­lion an­nu­ally by 2050.

Alzheimer’s is a neu­rode­gen­er­a­tive, pro­gres­sive disease of the brain, which leads to loss of mem­ory and cog­ni­tive func­tions. It also in­volves parts of the brain which con­trol thought, mem­ory, and lan­guage and over time can se­ri­ously af­fect a per­son’s abil­ity to carry out daily ac­tiv­i­ties. Alzheimer’s ac­counts for 60-80 per cent of de­men­tia cases. The disease was first dis­cov­ered in 1906 by Alois Alzheimer and since then, has been dif­fi­cult to treat. Alzheimer’s is a pro­gres­sive disease, in

which

symp­toms of the disease grad­u­ally worsen over a num­ber of years. This disease has no cur­rent cure; there are drugs that only treat symp­toms and these drugs are highly pa­tient de­pen­dent.

For the pharma in­dus­try, it’s been a bumpy ride to fight Alzheimer’s disease. Alzheimer’s is a for­mi­da­ble foe for a num­ber of rea­sons. The brain isn’t easy to ac­cess, an­i­mal models for test­ing are dif­fi­cult and it is es­ti­mated that nearly 99.6 per cent of the clin­i­cal tri­als have failed in the course of 2002 to 2012. A re­cent study looked at how 244 com­pounds in 413 clin­i­cal tri­als fared for Alzheimer’s disease be­tween 2002 and 2012. The study find­ings paint a gloomy pic­ture. Of those 244 com­pounds, only one was ap­proved.

De­spite this sky-high fail­ure rate, phar­ma­ceu­ti­cal com­pa­nies are leav­ing no stone un­turned to find a cure for this de­bil­i­tat­ing disease, pre­sum­ably be­cause of the lu­cra­tive and largely un­tapped drug mar­ket. Wall Street thinks that a medicine for Alzheimer’s could rake in a monstrous $20 bil­lion in sales by 2030, given that over 5 mil­lion Amer­i­cans al­ready suf­fer from this de­bil­i­tat­ing disease, com­bined with the fact that there are no treat­ments avail­able right now.

In the past decade or two, global drug pow­er­houses like Eli Lilly, Ei­sai, Roche, Pfizer, As­traZeneca, Bio­gen, and Merck have de­voted bil­lions of dol­lars into projects. Among this di­verse list of clin­i­cal hope­fuls, Eli Lilly and Bio­gen’s be­taamy­loid plaque-bust­ing an­ti­bod­ies -- solanezumab and ad­u­canumab, re­spec­tively -- have gar­nered the most at­ten­tion, in part be­cause of the ad­vanced state of their de­vel­op­ment. While the lu­cra­tive mar­ket is at­tract­ing pharma com­pa­nies, so is re­peated fail­ures and bil­lions of dol­lars spent, prompt­ing sev­eral pharma giants to end their re­search ef­forts to­wards find­ing a cure for the disease.

2018 be­gan with pharma gi­ant Pfizer an­nounc­ing that it was end­ing its in­ter­nal ef­forts to de­velop new drugs for Alzheimer’s and Parkin­son’s dis­eases. Ax­o­vant Sci­ences also an­nounced that it is pulling plug off its Alzheimer’s drug af­ter a key study fail­ure. These set­backs pile on to an al­ready de­press­ing sit­u­a­tion: more than 400 failed clin­i­cal tri­als since the last Alzheimer’s drug — which only treats the symp­toms of the disease, tem­po­rar­ily — was ap­proved more than a decade ago.

“I was sur­prised, be­cause I knew Pfizer had in­ter­est­ing com­pounds in the pipe­line,” said Dr. Jeff Cum­mings, director of the Cleveland Clinic Lou Ruvo Cen­ter for Brain Health in Las Ve­gas as quoted by the CNBC. For Cum­mings, though, it was ul­ti­mately just one more ad­di­tion to a long record he has main­tained, doc­u­ment­ing the fail­ure of Alzheimer’s treat­ments. “It is an­other state­ment that de­vel­op­ment of drugs, par­tic­u­larly for neu­rode­gen­er­a­tive dis­eases like Alzheimer’s and Parkin­son’s, has proven to be enor­mously dif­fi­cult.”

It takes on av­er­age 13 years for a can­di­date for Alzheimer’s treat­ment to move from lab­o­ra­tory to Food and Drug Ad­min­is­tra­tion (FDA) re­view and 10 years for an agent to nav­i­gate the clin­i­cal de­vel­op­ment pe­riod from start of phase I to end of FDA re­view, elab­o­rates a re­cent study. This means that un­der cur­rent cir­cum­stances, an agent must now be in phase II to pos­si­bly be ap­proved by 2025. Although there are few promis­ing agents in the clin­i­cal trial pipe­line with the high rate of fail­ure of Alzheimer’s disease drug de­vel­op­ment, the aim of hav­ing a reper­toire of agents that could re­spond com­pre­hen­sively and in­di­vid­u­ally to a pa­tient’s clin­i­cal cir­cum­stances within the 2025 time­frame is not easy. Also, Alzheimer’s pa­tients are gen­er­ally di­ag­nosed in the late stage, mostly due to de­layed ap­pear­ance of symp­toms. Hence, de­vel­op­ing the early di­ag­nos­tic de­vices that can de­tect the disease early is also a sig­nif­i­cant chal­lenge.

A new ray of hope

Amid these string of fail­ures and trial clo­sures, comes Ja­pan’s Ei­sai and Bio­gen’s an­nounce­ment bring­ing in hope to mil­lions of pa­tients. The com­pa­nies an­nounced pos­i­tive topline re­sults from the Phase II study with BAN2401, an an­ti­amy­loid beta protofib­ril an­ti­body, in 856 pa­tients with early Alzheimer’s disease. The study achieved sta­tis­ti­cal sig­nif­i­cance on key pre­de­fined end­points eval­u­at­ing ef­fi­cacy at 18 months on slow­ing pro­gres­sion in Alzheimer’s Disease Com­pos­ite Score and on re­duc­tion of amy­loid ac­cu­mu­lated in

the brain as mea­sured us­ing amy­loid-PET.

“This is the first late-stage anti-amy­loid an­ti­body study to suc­cess­fully achieve sta­tis­ti­cally sig­nif­i­cant re­sults at 18 months, fur­ther val­i­dat­ing the amy­loid hy­poth­e­sis,” said Lynn Kramer, M.D., Chief Clin­i­cal Of­fi­cer and Chief Med­i­cal Of­fi­cer, Neu­rol­ogy Busi­ness Group, Ei­sai in its press re­lease on July 5. “We will dis­cuss these very en­cour­ag­ing re­sults with reg­u­la­tory au­thor­i­ties to de­ter­mine the best path for­ward. We con­tinue to work to­wards the goal of de­liv­er­ing BAN2401 to pa­tients and health­care pro­fes­sion­als as early as pos­si­ble.”

Ear­lier many pharma giants have also fo­cused on ad­dress­ing the is­sue of amy­loid pro­tein buildup in Alzheimer’s pa­tients. Many of these clin­i­cal tri­als flopped and this has cast doubt on amy­loid hy­poth­e­sis. The lat­est re­sults for BAN2401, how­ever, showed im­prove­ment on two key fronts. First, the drug slowed pro­gres­sion in Alzheimer’s disease by a sta­tis­ti­cally sig­nif­i­cant amount. Sec­ond, it re­duced the amount of amy­loid ac­cu­mu­lated in the brains of pa­tients by a sta­tis­ti­cally sig­nif­i­cant amount.

This aside, the more promis­ing late-stage Alzheimer’s disease drug for Bio­gen is ad­u­canumab, which it is co-de­vel­op­ing with Neurim­mune Hold­ing. Bio­gen has three can­di­dates in phase 3 clin­i­cal test­ing. Two of them, like BAN2401, tar­get the treat­ment of Alzheimer’s disease. And both, also like BAN2401, seek to re­duce amy­loid ac­cu­mu­la­tion in the brain. Ad­u­canumab ranked third on mar­ket re­search firm Eval­u­atePharma’s list of top pipe­line as­sets in the bio­phar­ma­ceu­ti­cal in­dus­try.

Huge un­tapped mar­ket

Statis­ti­cians es­ti­mate that more than 2 bil­lion peo­ple will be above 60 years by 2026. Ris­ing old age pop­u­la­tion and higher in­ci­dences of neu­rode­gen­er­a­tive dis­eases are two sig­nif­i­cant fac­tors that sup­ple­ment the mar­ket growth. More­over, in­creas­ing R&D in­vest­ment, global ini­tia­tives and en­cour­age­ment to find a cure for Alzheimer’s is fur­ther ex­pected to fuel the mar­ket growth.

A re­cent mar­ket re­port sug­gests that global Alzheimer’s drugs mar­ket was val­ued at ap­prox­i­mately $3.42 bil­lion in 2016 and is ex­pected to gen­er­ate rev­enue of around $5.09 bil­lion by end of 2022, grow­ing at a CAGR of around 8 per cent be­tween 2017 and 2022.

Alzheimer’s is one of the lead­ing causes of death in the United States. The huge disease bur­den with very few ther­a­peu­tic al­ter­na­tives in­di­cates an im­pend­ing mar­ket need that would pro­vide lu­cra­tive growth op­por­tu­ni­ties to the in­dus­try play­ers.

Asia Pa­cific is also a key mar­ket for Alzheimer’s in­ter­ven­tions. Growth in Asia Pa­cific mar­ket is ex­pected to be driven due to grow­ing aware­ness about the treat­ment of Alzheimer’s in the re­gion.

This re­gion is likely to be a key con­trib­u­tor to the global Alzheimer’s drugs mar­ket in the com­ing years. Some of the key play­ers in Alzheimer’s Drugs are Ono Phar­ma­ceu­ti­cal, John­son & John­son, Dai­ichi Sankyo, H Lund­beck A/S, Ei­sai, and among oth­ers.

Global Data an­a­lyst Tom Moore thinks that Bio­gen’s BAN2401 could gen­er­ate peak an­nual sales of more than $1 bil­lion if it earns FDA ap­proval. Hence, though the risks, fund­ing chal­lenges and bar­ri­ers for com­pa­nies work­ing in Alzheimer’s are huge, but so too, po­ten­tially, are the re­wards.

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