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 Medicare Coverage-In-Clinical-Trials Policy For Alzheimer’s Drugs Could Stifle Access For Years
35 New Body Blow For Aducanumab As Japan Asks For More Data
35 Aducanumab: Biogen Is The Latest Firm To Preempt A Negative EU Opinion On Approval
36 FDA Grants Breakthrough Therapy Designation For Gantenerumab
36 No REMS Required: Aduhelm’s ARIA Risks, MRI Guidance Conveyed In Labeling, Voluntary Communications
37 Aduhelm’s Revised Labeling Could Help Payers Navigate Reimbursement
37 US FDA Issues Alzheimer’s Disease Breakthrough Therapy Designations
37 Biogen Gets ‘Almost Shockingly Broad’ Label For Alzheimer’s Drug Aducanumab
38 Aducanumab Accelerated Approval Reflects US FDA Flexibility But Raises Doubts About Confirmatory Trial
38 Nuplazid Complete Response Letter For Dementia Psychosis Driven By Effectiveness Concerns In Subgroups
39 Acadia’s Nuplazid Hits A Review Roadblock, But Not A CRL (For Now)
39 Aducanumab Approval Decision Delayed: Could This Be Good News?
41 PROBABILITY OF SUCCESS
42 LICENSING AND ASSET ACQUISITION DEALS
42 Zai Lab Pays $35m Up Front For Karuna’s KarXT In Greater China
42 Well-Funded Chinese Venture Races To Clinic Amid Reviving CNS Interest
42 IMM Licenses MultiTEP Platform Technology To NuraVax
42 Sumitomo, Otsuka Both Stand To Gain From CNS Partnership
43 Shape Scores Big Pharma Dollars In Roche Deal For AI-Driven AAV Technology
43 BMS To Increase Focus On Neurology And Neurodegenerative Disease
43 Simcere Acquires License To Develop Vivoryon’s Alzheimer’s Medicines
44 Hoth Therapeutics Signs Sponsored Research Agreement With Washington University
44 Denovo Dusts Down Lundbeck’s Failed Alzheimer’s Drug
44 GSK Looks To Immuno-Neurology In $700m Alector Tie-up
44 Core One Takes In Akome Biotech In All-Stock Deal
45 Italfarmaco To Market Luye’s Dementia Patch Product In Four EU Nations
45 Lilly Broadens Its CNS Reach With Rigel RIPK1 Deal
46 CLINICAL TRIAL LANDSCAPE
47 Sponsors by status
48 Sponsors by phase
49 Recent events
56 DRUG ASSESSMENT MODEL
56 Genericized symptomatic treatments
57 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 Atuzaginstat for Alzheimer’s Disease (January 25, 2022)
72 Atuzaginstat for Alzheimer’s Disease (October 26, 2021)
74 Semorinemab for Alzheimer’s Disease (August 31, 2021)
76 BIIB080 for Alzheimer’s Disease (July 26, 2021)
77 Aduhelm for Alzheimer’s Disease (June 7, 2021)
79 ANVS-401 for Alzheimer’s Disease (May 21, 2021)
80 AR1001 for Alzheimer’s Disease (March 29, 2021)
81 Atuzaginstat for Alzheimer’s Disease (February 15, 2021)
82 Troriluzole for Alzheimer’s Disease (January 18, 2021)
84 LY3002813 for Alzheimer’s Disease (January 11, 2021)
87 KEY UPCOMING EVENTS
88 UNMET NEEDS
88 Anti-amyloid antibodies need to validate cognitive effect and prolonged survival
88 Symptomatic therapies display modest efficacy at best
88 Beyond cognition and function, Alzheimer’s disease also involves behavioral deficits
89 BIBLIOGRAPHY
90 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
46 Figure 7: Clinical trials in Alzheimer’s disease
46 Figure 8: Top 10 drugs for clinical trials in Alzheimer’s disease
47 Figure 9: Top 10 companies for clinical trials in Alzheimer’s disease
47 Figure 10: Trial locations in Alzheimer’s disease
48 Figure 11: Alzheimer’s disease trials status
49 Figure 12: Alzheimer’s disease trials sponsors, by phase
56 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
74 Figure 16: Atuzaginstat for Alzheimer’s Disease (October 26, 2021): Phase II/III – GAIN
76 Figure 17: Semorinemab for Alzheimer’s Disease (August 31, 2021): Phase II – LAURIET (Moderate)
77 Figure 18: BIIB080 for Alzheimer’s Disease (July 26, 2021): Phase I/IIa – MAD
80 Figure 19: ANVS-401 for Alzheimer’s Disease (May 21, 2021): Phase I/II – AD/PD
81 Figure 20: AR1001 for Alzheimer’s Disease (March 29, 2021): Phase II – ADP2-US01
84 Figure 21: Troriluzole for Alzheimer’s Disease (January 18, 2021): Phase II/III – T2 Protect AD (ADCS)
86 Figure 22: LY3002813 for Alzheimer’s Disease (January 11, 2021): Phase II – TRAILBLAZER-ALZ (w/LY3202626)
87 Figure 23: 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), 2022–26
71 Table 8: Atuzaginstat for Alzheimer’s Disease (January 25, 2022)
72 Table 9: Atuzaginstat for Alzheimer’s Disease (October 26, 2021)
75 Table 10: Semorinemab for Alzheimer’s Disease (August 31, 2021)
76 Table 11: BIIB080 for Alzheimer’s Disease (July 26, 2021)
78 Table 12: Aduhelm for Alzheimer’s Disease (June 7, 2021)
79 Table 13: ANVS-401 for Alzheimer’s Disease (May 21, 2021)
80 Table 14: AR1001 for Alzheimer’s Disease (March 29, 2021)
82 Table 15: Atuzaginstat for Alzheimer’s Disease (February 15, 2021)
83 Table 16: Troriluzole for Alzheimer’s Disease (January 18, 2021)
84 Table 17: LY3002813 for Alzheimer’s Disease (January 11, 2021)
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