Thinking Outside the Beta-Amyloid Box

Posted on January 9, 2023 by Muzamil Saleem

The dominant amyloid hypothesis of AD has translated into an armada of anti-amyloid biologics in the near-term pipeline—led by Eisai and Biogen’s lecanemab. Last month, lecanemab showed a slowing in the rate of cognitive decline by 27% over 18 months versus placebo. Lecanemab also possesses a relatively improved safety profile among the beta-amyloid mAbs, as a result of lower rates of amyloid-related imaging abnormalities (ARIA) (this was a significant issue with aducanumab). This improved safety profile eliminates the need for a dose titration period. The other notable beta-amyloid mAb drug contenders include Roche’s gantenerumab and Eli Lilly’s donanemab, which may achieve the fastest amyloid plaque clearance among its competitors.

These recent successes, however, come after an approximate 98% failure rate in phase 2 and 3 trials since 2003.¹ For a disease that kills more people than breast cancer and prostate cancer combined,² a modest improvement in cognitive decline is not enough. This has led many labs to pursue other potential targets in AD, with some encouraging early signals of success (Table 1).³

Table 1. Alzheimer’s drug development pipeline: disease-modifying drug candidates with non-amyloid mechanisms of action with corporate sponsor in phase 2 and 3 and select phase 1 drug candidates, grouped by target. Source: Cummings et al (2022).³

Sponsor	Drug candidate	Target	Trial status
Vigil Neuro	VGL101	TREM2	Phase 1
Denali Therapeutics Inc.	DNL919	TREM2	Phase 1
TauRx Therapeutics	TRx0237	Tau	Phase 3; active
AC Immune, Janssen	ACI-35	Tau	Phase 2; recruiting
UCB Biopharma	Bepranemab	Tau	Phase 2; recruiting
Eisai	E2814	Tau	Phase 2; recruiting
Ionis Pharmaceuticals	IONIS MAPTRx (BIIB080)	Tau	Phase 2; active
Janssen	JNJ-63733657	Tau	Phase 2; recruiting
Eli Lilly	LY3372689	Tau	Phase 2; recruiting
Samus Therapeutics	PU-AD	Tau	Phase 2; active
Genentech	Semorinemab (R07105705)	Tau	Phase 2; active
AgeneBio, NIA	AGB101	Synaptic plasticity	Phase 3; active
Cortexyme	Atuzaginstat (COR388)	Synaptic plasticity	Phase 3; active
Anavex Life Sciences	Blarcamesine (ANAVEX2-73	Synaptic plasticity	Phase 3; active
Cassava Sciences	Simufilam (PTI-125)	Synaptic plasticity	Phase 3; recruiting
Tetra Discovery Partners	BPN14770	Synaptic plasticity	Phase 2; active
Neurotrope Bioscience, NIH, NIA	Bryostatin 1	Synaptic plasticity	Phase 2; recruiting
Cyclerion Therapeutics	CY6463	Synaptic plasticity	Phase 2; recruiting
Toyama Chemical	Edonerpic (T-817MA)	Synaptic plasticity	Phase 2; active
Cognition Therapeutics	Elayta (CT1812)	Synaptic plasticity	Phase 2; recruiting
Athira Pharma	Fosgonimeton (ATH-1017)	Synaptic plasticity	Phase 2; recruiting
Neurokine Therapeutics, et al.	MW150	Synaptic plasticity	Phase 2
EIP Pharma	Neflamapimod (VX-745)	Synaptic plasticity	Phase 2; recruiting
Biohaven Pharma, ADCS	Troriluzole (BHV4157)	Synaptic plasticity	Phase 2; active
KeifeRx	Nilotinib BE	Proteostasis/ proteinopathies	Phase 3
QR Pharma, ADCS	Posiphen	Proteostasis/ proteinopathies
Pharmazz	Sovateltide (PMZ-1620)	Neurogenesis	Phase 2; recruiting
Novo Nordisk	Semaglutinide	Metabolism and bioenergetics	Phase 3; recruiting
Cerecin	Tricaprilin	Metabolism and bioenergetics	Phase 3
T3D Therapeutics, et al.	T3D-959	Metabolism and bioenergetics	Phase 2; recruiting
NewAmsterdam Pharma	Obicetrapib	Lipids and lipoprotein receptors	Phase 2
Neurmedix	NE3107	Inflammation	Phase 3; recruiting
Alector, AbbVie	AL002	Inflammation	Phase 2; recruiting
Novartis	Canakinumab	Inflammation	Phase 2; recruiting
GMP BIO, BHT Lifescience Australia	GB301	Inflammation	Phase 2
IntelGenx Corp.	Montelukast	Inflammation	Phase 2; recruiting
Vaccinex, ADDF, Alzheimer’s Association	Pepinemab (VX15)	Inflammation	Phase 2; recruiting
TrueBinding, Inc	TB006	Inflammation	Phase 2; recruiting
Mindful Diagnostics and Therapeutics	Tdap vaccine	Inflammation	Phase 2
Northwell Health, Janssen	Daratumumab	Inflammation	Phase 2; recruiting
Shanghai Green Valley	GV-971	Gut-brain axis	Phase 3; recruiting
Actinogen Medical	Xanamem	Growth factors and hormones	Phase 2; active
GemVax & Kael	GV1001	Epigenetic	Phase 2
Neuroscience Trials Australia	Deferiprone	Cell death	Phase 2; active

The AD therapeutic landscape appears to be shifting away from symptomatic drugs and focusing more on disease-modifying drugs (DMDs)—a report by the Alzheimer’s Association (AA) showed that 68% of agents in phase 3 trials are DMDs (Figure 2).³ Most of these DMDs target beta-amyloid (29%); however, the remainder represent innovative new directions in targeting the multifactorial, complex pathology of AD.

Figure 2. Mechanisms of action of agents in phase 3.³

The discovery that mutations in “triggering receptor expressed on myeloid cells 2” (TREM2) can increase the risk of AD by up to threefold, suggested the involvement of inflammatory pathology in AD.^4-6 TREM2 is a transmembrane protein located on the surface of microglia, the resident immune cells of the brain. Microglia are dynamic, innate immune cells of the brain: functioning to constantly sense extracellular cues (e.g., cellular debris, invading viruses or bacteria) in the central nervous system (CNS). In the absence of extracellular cues, the microglia are in a homeostatic conformation. When cellular debris binds to TREM2, homeostatic microglia are activated and transition to disease-associated microglia (DAM). Microglia in the DAM state also function to clear proteins that aggregate in neurodegenerative diseases—such as amyloid plaques in AD. Because TREM2 loss-of-function mutations are associated with the inability of microglia to transition to the DAM phenotype, they are a rational target in AD. Dysfunctional microglia expressing mutated TREM2 are unable to clear cellular debris, and this leads to a perpetuation of neuroinflammation and subsequent neurodegeneration.

Further research bridging pathologies has revealed that TREM2 biology directly involves beta‑amyloid: TREM2 binds to beta-amyloid, and this binding is compromised in the presence of AD‑associated mutations.⁷ Moreover, TREM2 has been linked to the long-established genetic risk factor of the late-onset (after age 60) form of AD: the ε4 allele of apolipoprotein E (APOE).⁸

Targeting TREM2 is particularly attractive because it is restricted to the area of pathology—the brain. Denali Therapeutics’ TREM2-targeted therapy, DNL919, uses a proprietary antibody delivery technology to deliver drug across the protective blood-brain barrier and activate the receptor. DNL919 was this year placed on a clinical hold before it entered human trials due to issues surrounding the preclinical toxicology assessment. Denali is working to provide the FDA with the information needed to restart the clinical trial.

Massachusetts-based Vigil Neuro is developing disease-modifying therapeutics to restore the microglia DAM phenotype by activating TREM2 signaling in order to treat neurodegenerative diseases such as AD. Vigil is targeting the activation of TREM2 with VGL101, a drug currently in a phase 1 healthy volunteer trial that is slated to read out by the end of the year.

The potential role of gut microbiota in AD pathogenesis⁹ has culminated in the discovery of a plant-based compound, sodium oligomannate (GV-971), by Shanghai Green Valley Pharmaceutical. GV-971 contains an active ingredient derived from brown algae and was recently shown to therapeutically remodel gut microbiota, resulting in the suppression of inflammation and inhibition of AD progression¹⁰. China’s drug regulator approved marketing of GV-971 following encouraging results from a 36-week phase 3, multicenter, randomized, double-blind, placebo-controlled parallel-group clinical that revealed significant improvements in cognition.

Deficits in axonal transport—a cellular process that mediates the movement of diverse cargoes along axons—has been shown to be a contributing pathology in the neurodegeneration seen in AD (as well as other neurological diseases).^11,12 Buntanetap, a drug being developed by Annovis Bio, inhibits multiple neurotoxic aggregating proteins—including beta-amyloid, tau, α-synuclein and TAR DNA-binding protein 43 (TDP-43)—to restore axonal transport to normal levels. Annovis recently reported positive safety data and a statistically significant improvement in cognition from its phase 2a Alzheimer’s study, and this month received FDA authorization to initiate a phase 2/3 clinical trial of buntanetap in moderate AD.

It appears that the AD field is now refocusing on pathologies outside of aberrant amyloid and tau protein, and looking more closely at diverse biological processes including inflammatory cascades, gut-brain signaling, and axonal transport. It’s likely that ongoing translational research will eventually lead to a better understanding of these diverse pathologies and that overall treatment of AD will ultimately be multifactorial.

Muzamil Saleem, PhD
Associate Scientific Director, ProEd Regulatory
Muz is a trained neuroscientist with a diverse skillset, combining a ten-year neurology-focused research career, scientific consulting experience and a three-year tenure in healthcare equity research on Wall Street before joining ProEd Regulatory—all supported by a passion for written and visual scientific communication. Connect with Muz on LinkedIn.

References

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Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368(2):117-127.
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Fitz NF, Wolfe CM, Playso BE, et al. Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice. Mol Neurodegener. 2020;15(1):41.
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The Alzheimer’s Conundrum

Posted on November 22, 2022 by Muzamil Saleem

The United States is facing an avalanche of Alzheimer’s disease (AD). An estimated 12.7 million Americans over the age of 65 are projected to suffer from AD dementia by 2050,¹ and yet, despite more than 30 years of intensive research, we have yet to develop a drug that provides a clinically meaningful slowing in cognitive decline. There are only 6 AD drugs currently approved in the US. Five of these are symptomatic treatments, such acetylcholinesterase drugs for mild AD and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, which is used as an add-on or second-line therapy in more severe cases. Aduhelm, a beta-amyloid monoclonal antibody (mAb) therapy, represented the sixth US Food and Drug Administration (FDA) approval in AD and is the first to target the underlying pathology of the disease. However, the beta-amyloid mAbs have failed to live up to the promise of delivering a curative, disease-modifying drug (DMD). We examine directions in research and development that contribute a set of diverse pathological targets—illuminating Alzheimer’s disease as a conundrum that will likely be solved with a multifactorial treatment approach.

The Alzheimer’s Conundrum

So, why have effective AD therapeutics been so elusive? A key factor is the cavernous deficiency in our pathologic understanding of AD. In the amyloid hypothesis, plaques composed of toxic beta-amyloid and phosphorylated tau protein are hypothesized to cause neurodegeneration leading to cognitive decline. This hypothesis has dominated the last 20 years of AD research and carries with it a storm of controversy, to the extent that two camps have formed (those who support the amyloid hypothesis, and those who don’t). At issue is the failure of a long line of drugs targeting beta-amyloid in clinical trials dating back to 2003. Interviews with multiple scientists suggest that any research that fell outside of the amyloid field was suppressed,² likely slowing progress in the field. In addition, the dire unmet need for AD therapeutics has put a strain on translational research, such that biotech companies have scrambled to move drugs into clinical trials, perhaps before the science was fully baked.

The pathology of AD, best represented as a continuum (Figure 1),¹ presents another challenge. Researchers and clinicians believe that therapeutic intervention stands the best chance of success in patients with mild cognitive impairment, but without a reliable biomarker, it can be challenging to identify an appropriate patient population for clinical studies.

Figure 1. Alzheimer’s disease continuum.

The pathological changes in the brain that cause the first noticeable symptoms of AD—related to memory, language, and cognition—are thought to start 2 decades or more prior.^3-10 During this asymptomatic phase there may be measurable changes in a biomarker that could indicate future progression to clinical AD. Hence, there is a crucial need for a biomarker sensitive enough to detect AD in early stages. To date, the best available biomarker of AD is the assessment of abnormal beta-amyloid deposits in the brain by positron emission tomography (PET) imaging.

The Lumipulse^® beta-amyloid test (Fujirebio Diagnostics) was FDA approved earlier this year and could potentially substitute for the use of PET scans to detect amyloid pathology; however, the test requires collection of cerebrospinal fluid (CSF), which is an unpleasant procedure. The search for a minimally invasive, blood-based biomarker has been at the center of a fervent research effort over the past decade.¹¹ The PrecivityAD^® is a blood test developed by C2N Diagnostics that has been shown to be 81% accurate in predicting the level of beta-amyloid in the brain; however, it is not yet FDA approved.

The First Drug to Address the Underlying Biology of Alzheimer’s Disease

The accelerated approval of aducanumab (Aduhelm™), an antibody that binds to and clears beta-amyloid plaques in the brain, in 2020 was a landmark in the treatment of AD, signaling the first new drug in 18 years. Aduhelm was studied in two large, randomized, controlled trials in patients with mild cognitive impairment and evidence of amyloid pathology by PET imaging. However, both trials were prematurely stopped for futility. The first trial (EMERGE) ultimately met its primary endpoint—patients on high-dose aducanumab showed a significant slowing of cognitive decline from baseline. The second trial (ENGAGE) did not meet its primary endpoint; however, patients from this trial who received sufficient exposure to high-dose aducanumab showed efficacy results supporting the findings of EMERGE. Both trials also showed a statistically significant, dose-dependent decrease in beta-amyloid and phosphorylated tau protein by PET imaging, which was the basis for accelerated approval.

Controversy ensued when an independent panel of scientific and clinical experts was assembled at an FDA Advisory Committee meeting to deliberate over the approval of Aduhelm. The committee advised unanimously against the approval of aducanumab. Despite convincing evidence that Aduhelm effectively removes beta-amyloid plaques from the brain, experts argued that the two large phase 3 clinical trials— one positive and one negative—did not conclusively demonstrate a slowing in cognitive decline.

The approval of Aduhelm has not quelled any of the controversy surrounding the amyloid hypothesis. There remains a significant unmet need for disease-modifying AD therapeutics that result in a slowing—or indeed a reversal—of cognitive decline. The following post in this Alzheimer’s series will explore the next wave of AD drug development. We will place our focus beyond aberrant amyloid and tau protein pathology, and examine a multifactorial set of disease mechanisms, including inflammatory cascades, gut-brain signaling, and axonal transport.

References

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Reiman EM, Quiroz YT, Fleisher AS, et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012;11(12):1048-1056.
Jack CR, Jr., Lowe VJ, Weigand SD, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain. 2009;132(Pt 5):1355-1365.
Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804.
Gordon BA, Blazey TM, Su Y, et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 2018;17(3):241-250.
Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70(11):960-969.
Shi L, Baird AL, Westwood S, et al. A Decade of Blood Biomarkers for Alzheimer’s Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication. J Alzheimers Dis. 2018;62(3):1181-1198.