Disease Analysis: Alzheimer’s Disease
Author: Pammy Spicer
Publisher: Datamonitor Healthcare
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Disease Overview
Alzheimer’s disease is an irreversible, progressive, neurodegenerative disease that slowly affects memory, cognition, and function. It is a continuum of pathological changes in the brain that begin well before clinical symptoms emerge. The hallmark abnormalities of Alzheimer’s disease are beta-amyloid deposits and tau tangles in the brain, while it is also characterized by the loss of neuronal connections. These pathological changes are thought to occur years in advance of the onset of dementia in patients with Alzheimer’s disease. Studies indicate that people aged 65 years and over survive an average of four to eight years after a diagnosis of Alzheimer’s disease, yet some live as long as 20 years or more, indicating the slow, insidious progression of the disease.
Latest key takeaways
- Datamonitor Healthcare estimates that in 2018, there were 74.5 million prevalent cases of Alzheimer’s disease in adults aged 65 years and older worldwide, and forecasts that number to increase to 102.5 million prevalent cases by 2027.
- The landmark approval of Biogen and Eisai’s anti-amyloid antibody Aduhelm (aducanumab) provides the first potentially disease-modifying treatment for patients with early Alzheimer’s disease. The approval came despite Phase III clinical trial data resulting in one positive and one negative study. In its release of this groundbreaking news, the FDA acknowledged that there is still some uncertainty around the data, but reiterated that the treatment is the first to show a benefit in amyloid plaque reduction, thus targeting the underlying disease pathology rather than masking symptoms.
- The FDA’s accelerated approval of Aduhelm based on amyloid reduction rather than cognitive improvement lowered the bar for competitive anti-amyloid antibodies to reach the market sooner. While Roche’s gantenerumab and Eisai’s lecanemab, also partnered with Biogen, are completing Phase III trials in 2022, Eli Lilly plans to file donanemab for accelerated approval in 2021 based on biomarker data from Phase II.
- Donanemab may be able to clear amyloid plaques from the brain the fastest among its competitors, thus enabling a limited treatment duration. Both Aduhelm and donanemab are administered by monthly infusion, which is more convenient than lecanemab’s infusion every other week but may be less favorable than gantenerumab’s monthly subcutaneous formulation. Lecanemab has the lowest rates of amyloid-related imaging abnormalities (ARIA), thus eliminating the need for a dose titration period.
- The high price of these biologics and required imaging to accompany their labels will increase the cost of care and limit accessibility. Regardless, the high unmet need can be expected to drive uptake, creating a lucrative market for any anti-amyloid antibody to gain approval.
- Symptomatic treatments largely consist of four well-established products. The acetylcholinesterase class of drugs will continue to dominate the treatment of mild Alzheimer’s disease, while NMDA receptor antagonist memantine is used primarily as an add-on or second-line therapy in more severe disease stages.
- In 2021, Eli Lilly expects to report topline data from a Phase II trial of anti-tau antibody zagotenemab, while topline results from late-phase studies of atuzaginstat and ALZT-OP1 are also expected.
- The likelihood of approval of a Phase III Alzheimer’s disease asset is 16.8%, compared to 48.1% in the overall neurology space, reflecting the high historical rate of late-stage failures in this indication.
CONTENTS
7 OVERVIEW
7 Latest key takeaways
8 DISEASE BACKGROUND
8 Definition
8 Symptoms
8 Risk factors
8 Patient segmentation
11 TREATMENT
11 Cholinesterase inhibitors are recommended for mild-to-moderate Alzheimer’s disease
11 Memantine is reserved for moderate-to-severe disease
11 Aduhelm becomes the first anti-amyloid antibody approved for early Alzheimer’s disease
12 EPIDEMIOLOGY
16 MARKETED DRUGS
20 PIPELINE DRUGS
35 KEY REGULATORY EVENTS
35 Aduhelm’s Revised Labeling Could Help Payers Navigate Reimbursement
35 US FDA Issues Alzheimer’s Disease Breakthrough Therapy Designations
35 Biogen Gets ‘Almost Shockingly Broad’ Label For Alzheimer’s Drug Aducanumab
36 Aducanumab Accelerated Approval Reflects US FDA Flexibility But Raises Doubts About Confirmatory Trial
36 Nuplazid Complete Response Letter For Dementia Psychosis Driven By Effectiveness Concerns In Subgroups
37 Acadia’s Nuplazid Hits A Review Roadblock, But Not A CRL (For Now)
37 Aducanumab Approval Decision Delayed: Could This Be Good News?
38 Aducanumab Filed In Japan Despite Recent US Setback
38 Biogen’s Aducanumab: Why Accelerated Approval Might, And Might Not, Be An Option For US FDA
38 Biogen’s Aducanumab Falls Hard At Panel Review, Leaving US FDA In A Tight Spot
39 What Did US FDA Do Wrong In Its Review Of Aducanumab? AdCom Members Have A List
39 Biogen’s Aducanumab: One Positive Phase III Trial Is Good Enough For Demonstrating Efficacy, US FDA Says
39 US FDA Gives Biogen Big Hand In Effort To Get Its Alzheimer’s Treatment On The Market
40 Adu-CAN-umab? Reading The Tea Leaves For Biogen’s US Filing For Alzheimer’s Drug
41 PROBABILITY OF SUCCESS
42 LICENSING AND ASSET ACQUISITION DEALS
42 BMS To Increase Focus On Neurology And Neurodegenerative Disease
42 Simcere Acquires License To Develop Vivoryon’s Alzheimer’s Medicines
42 Hoth Therapeutics Signs Sponsored Research Agreement With Washington University
42 Denovo Dusts Down Lundbeck’s Failed Alzheimer’s Drug
43 GSK Looks To Immuno-Neurology In $700m Alector Tie-up
43 Core One Takes In Akome Biotech In All-Stock Deal
43 Italfarmaco To Market Luye’s Dementia Patch Product In Four EU Nations
43 Lilly Broadens Its CNS Reach With Rigel RIPK1 Deal
44 Grifols Buys Remaining Interest In Alkahest It Didn’t Own Already
45 CLINICAL TRIAL LANDSCAPE
46 Sponsors by status
47 Sponsors by phase
48 Recent events
55 DRUG ASSESSMENT MODEL
55 Genericized symptomatic treatments
56 Disease-modifying therapies
62 Other pipeline drugs
65 Agitation in Alzheimer’s disease
66 MARKET DYNAMICS
67 FUTURE TRENDS
67 Anti-amyloid antibodies to drive the market
67 Accelerated approval pathway hastens substantial increases in market size
67 Generic symptomatic therapies remain relevant for Alzheimer’s dementia
68 CONSENSUS FORECASTS
71 RECENT EVENTS AND ANALYST OPINION
71 BIIB080 for Alzheimer’s Disease (July 26, 2021)
72 Aduhelm for Alzheimer’s Disease (June 7, 2021)
74 ANVS-401 for Alzheimer’s Disease (May 21, 2021)
75 AR1001 for Alzheimer’s Disease (March 29, 2021)
76 Atuzaginstat for Alzheimer’s Disease (February 15, 2021)
77 Troriluzole for Alzheimer’s Disease (January 18, 2021)
79 LY3002813 for Alzheimer’s Disease (January 11, 2021)
81 Masitinib for Alzheimer’s Disease (December 16, 2020)
82 Azeliragon for Alzheimer’s Disease (December 15, 2020)
84 Aducanumab for Alzheimer’s Disease (November 6, 2020)
85 Aducanumab for Alzheimer’s Disease (November 4, 2020)
87 Semorinemab for Alzheimer’s Disease (September 23, 2020)
89 Aducanumab for Alzheimer’s Disease (August 7, 2020)
91 KEY UPCOMING EVENTS
92 UNMET NEEDS
92 Anti-amyloid antibodies need to validate cognitive effect and prolonged survival
92 Symptomatic therapies display modest efficacy at best
92 Beyond cognition and function, Alzheimer’s disease also involves behavioral deficits
93 BIBLIOGRAPHY
94 APPENDIX
LIST OF FIGURES
15 Figure 1: Trends in prevalent cases of Alzheimer’s disease, 2018–27
20 Figure 2: Overview of pipeline drugs for Alzheimer’s disease in the US
20 Figure 3: Pipeline drugs for Alzheimer’s disease, by company
21 Figure 4: Pipeline drugs for Alzheimer’s disease, by drug type
21 Figure 5: Pipeline drugs for Alzheimer’s disease, by classification
41 Figure 6: Probability of success in the Alzheimer’s disease pipeline
45 Figure 7: Clinical trials in Alzheimer’s disease
45 Figure 8: Top 10 drugs for clinical trials in Alzheimer’s disease
46 Figure 9: Top 10 companies for clinical trials in Alzheimer’s disease
46 Figure 10: Trial locations in Alzheimer’s disease
47 Figure 11: Alzheimer’s disease trials status
48 Figure 12: Alzheimer’s disease trials sponsors, by phase
55 Figure 13: Datamonitor Healthcare’s drug assessment summary for Alzheimer’s disease
66 Figure 14: Market dynamics in Alzheimer’s disease
67 Figure 15: Future trends in Alzheimer’s disease
72 Figure 16: BIIB080 for Alzheimer’s Disease (July 26, 2021): Phase I/IIa – MAD
75 Figure 17: ANVS-401 for Alzheimer’s Disease (May 21, 2021): Phase I/II – AD/PD
76 Figure 18: AR1001 for Alzheimer’s Disease (March 29, 2021): Phase II – ADP2-US01
79 Figure 19: Troriluzole for Alzheimer’s Disease (January 18, 2021): Phase II/III – T2 Protect AD (ADCS)
81 Figure 20: LY3002813 for Alzheimer’s Disease (January 11, 2021): Phase II – TRAILBLAZER-ALZ (w/LY3202626)
82 Figure 21: Masitinib for Alzheimer’s Disease (December 16, 2020): Phase III – Add-On Therapy (Spain)
84 Figure 22: Azeliragon for Alzheimer’s Disease (December 15, 2020): Phase II/III – Elevage (Mild Alzheimer/T2D)
89 Figure 23: Semorinemab for Alzheimer’s Disease (September 23, 2020): Phase II – TAURIEL (Prodromal to Mild)
91 Figure 24: Key upcoming events in Alzheimer’s disease
LIST OF TABLES
9 Table 1: Alzheimer’s disease severity, by rating scale
10 Table 2: FDA stages by disease attributes
13 Table 3: Prevalent cases of Alzheimer’s disease, 2018–27
17 Table 4: Marketed drugs for Alzheimer’s disease
22 Table 5: Pipeline drugs for Alzheimer’s disease in the US
68 Table 6: Historical global sales, by drug ($m), 2016–20
69 Table 7: Forecasted global sales, by drug ($m), 2021–25
71 Table 8: BIIB080 for Alzheimer’s Disease (July 26, 2021)
73 Table 9: Aduhelm for Alzheimer’s Disease (June 7, 2021)
74 Table 10: ANVS-401 for Alzheimer’s Disease (May 21, 2021)
75 Table 11: AR1001 for Alzheimer’s Disease (March 29, 2021)
77 Table 12: Atuzaginstat for Alzheimer’s Disease (February 15, 2021)
78 Table 13: Troriluzole for Alzheimer’s Disease (January 18, 2021)
79 Table 14: LY3002813 for Alzheimer’s Disease (January 11, 2021)
81 Table 15: Masitinib for Alzheimer’s Disease (December 16, 2020)
83 Table 16: Azeliragon for Alzheimer’s Disease (December 15, 2020)
84 Table 17: Aducanumab for Alzheimer’s Disease (November 6, 2020)
86 Table 18: Aducanumab for Alzheimer’s Disease (November 4, 2020)
88 Table 19: Semorinemab for Alzheimer’s Disease (September 23, 2020)
90 Table 20: Aducanumab for Alzheimer’s Disease (August 7, 2020)
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