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(Source:Alamy)

While its US Food and Drug Administration approval and $56,000 price tag have been controversial, Biogen Inc./Eisai Co. Ltd.’s Aduhelm (aducanumab) still represents a lot of firsts as the first disease-modifying drug approved for Alzheimer’s disease and the first amyloid-targeting therapy to make it all the way across the drug development finish line. But it was far from the first attempt.

Scrip took a look through the history of the Alzheimer’s drug pipeline, drilling down into the anti-amyloid drug candidates, to put the US Food and Drug Administration approval of Aduhelm in early June into perspective.

Phase III failures across the amyloid class have been high-profile flops, but what is striking about the data – detailed in the infographic below – is exactly how many therapeutic candidates attempting to target amyloid, directly and indirectly, ultimately failed to move into later-stage development or succeed in Phase III: 93 drugs and biologics.

Nevertheless, even companies like Eli Lilly and Company, with multiple failed anti-amyloid programs, continue to pursue the amyloid hypothesis, buoyed by Aduhelm’s regulatory success and the new precedent it set for accelerated approvals.

The broader Alzheimer’s pipeline (symptomatic and disease-modifying treatments) still has significant numbers of programs in various stages of preclinical and clinical development, although the percentages of amyloid-targeting therapies relative to the overall pipeline are lower in the earlier stages of development. For instance, 37% of the 17 programs in Phase III target amyloid, but only 16% of the 37 candidates in Phase I are anti-amyloid programs.

Drug developers have given up on some mechanisms of action for clearing amyloid from the brains of Alzheimer’s patients altogether, such as small molecules targeting beta-amyloid precursor protein-cleaving enzyme (BACE). Highlighted below, BACE inhibitors previously were among many closely watched amyloid-targeting drug classes.

The Alzheimer's Pipeline, At It Stands Now

Biomedtracker lists 493 Alzheimer’s drug candidates in the pipeline, including symptomatic treatments and disease-modifying therapies, preclinical through Phase III candidates and suspended programs.

Approaching Amyloid From Many Angles

The 93 amyloid-targeting drug candidates suspended between 2002 and 2021 included multiple mechanisms of action.

52 different companies led development of the 93 discontinued programs

The programs were suspended at every stage, from preclinical through Phase III due to trial failures, safety issues, R&D pipeline reprioritization and company shutdowns. Some candidates were quietly removed from developers’ pipelines with no reason given or companies just stopped providing public updates. 

Amyloid Snapshot: BACE Inhibitors

Scrip took a look at one high-profile segment of amyloid-targeting drugs to show what happened to BACE inhibitors, all of which have failed in Alzheimer’s disease, during the past decade.

Drug &
Developer		 2012 Status 2021 Status
AZD 3839
 AstraZeneca		 A Phase I was completed in November 2011. Development discontinued in 2012 due to safety and efficacy issues. AZ and partner Lilly advanced another BACE inhibitor, Ianabecestat, into two Phase III studies but ended the trials early due to lack of efficacy.
Elenbecestat (E2609)
Eisai		 A Phase I study was completed in March 2012 and two additional Phase I studies were ongoing. Eisai and partner Biogen Inc. ended two Phase III studies in 2019 due to safety.
HPP 854
 High Point Pharmaceutical		 The company planned to complete a Phase Ib study in the first half of 2012. The trial was suspended in the second half of 2012.
Atabecestat (JNJ-54861911)
Johnson & Johnson		 J&J's Janssen partnered with Shionogi on BACE inhibitors. The partners ended a Phase IIb/Phase III trial and Phase II extension study in 2013 due to liver safety concerns.
LY2886721
Lilly		 A Phase I/Phase II trial was completed in March 2012. Enrollment in a Phase II trial was suspended in 2013 due to liver toxicity. Lilly developed two other BACE inhibitors that it terminated in preclinical and Phase II.
Verubecestat (MK-8931)
Merck		 Phase I data reported in April 2012; two other Phase I studies were ongoing. A Phase II/Phase III study in patients with mild cognitive impairment was stopped in 2017 due to lack of efficacy and a Phase III trial in prodromal Alzheimer's disease was ended in 2018 for futility.
RG7129
Roche		 A Phase I study in France completed in January 2012 with a US Phase I trial planned to start in May. The company took the drug out of its pipeline in 2013, still in Phase I.

Note: Novartis and Amgen started development of umibecestat in 2014 and ended two Phase II/Phase III studies in 2019 due to worsening cognitive function in some patients.

Source: Biomedtracker

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