Are scientists closing in on vaccines for Alzheimer’s and Parkinson’s?

Pfeifer, Andrea

article

Are scientists closing in on vaccines for Alzheimer’s and Parkinson’s?

4 April 2022

Protecting against conditions that appear in older generations is increasingly becoming a focus of the medical industry. In this article, Dr Andrea Pfeifer, CEO and Director of AC Immune, discusses the current landscape of vaccine development for neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Alzheimer’s disease (AD), Parkinson’s disease (PD) and certain related neurodegenerative diseases are a silent pandemic that is spreading in lockstep with the ageing of our global population. Neurodegeneration occurs when nerve cells in the brain or elsewhere in the nervous system lose function and die. Between 2000 and 2019, while deaths from stroke, heart disease and HIV decreased, deaths from AD increased by over 145 percent. In the US, total payments for health care, long-term care and hospice services for people aged 65 and older with dementia were estimated to cost $355 billion in 2021 and unpaid dementia caregiving was valued at $256.7 billion in 2020.^1,2 The rising incidence of neurodegenerative diseases presents us with a moral and economic situation that must urgently be addressed.

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Scientists have been exploring vaccination strategies for neurodegenerative diseases for decades”

The pathophysiology of neurodegenerative diseases shares some hallmark characteristics that make them amenable to active immunisation strategies. For example, specific neurotoxic species of three endogenous proteins – amyloid beta (Aβ), tau and alpha-synuclein (α-syn) – namely pyroglutamate amyloid beta (pyroGlu‑Aβ), phosphorylated-tau (pTau) and oligomeric alpha‑synuclein (oligomeric α-syn), respectively, are believed to be key drivers of neurodegeneration in AD, PD and related proteinopathies.

Amyloid plaques, formed of misfolded Aβ species, like neurotoxic pyroGlu-Aβ and oligomeric Aβ, are one of the early hallmarks of AD, first appearing while people are pre-symptomatic and proliferating as disease progresses.³ Tau, a protein that normally stabilises brain cell microtubules, forms neurofibrillary tangles, rich in aggregated pTau or enriched paired helical filaments (ePHF), which multiply in a spatiotemporal pattern that tracks with loss of cognition, function and neurodegeneration.⁴

Vaccine	Target	Statues	Company
ACI 7104	α-synuclein	PD Phase II	AC Immune
UB-312	α-synuclein	PD Phase I	Vaxxinity
ABvac 40	Amyloid	AD Phase II	Araclon Biotech
ACI-24	Amyloid	AD Phase II; AD in Down’s syndrome Phase Ib	AC Immune
UB-311	Amyloid	Amyloid	United Neuroscience
Lu AF20513	Amyloid	AD Phase I	Lundbeck, Otsuka
AADvac1	Tau	AD Phase II; Progressive non-fluent aphasia Phase I	Axon Neuroscience
Axon Neuroscience	Tau	AD Phase I/II	AC Immune, Janssen

Table 1 Neurodegenerative disease vaccine candidates in development

Similarly, in PD, protein aggregates known as Lewy bodies are formed principally of misfolded oligomeric α-syn,⁵ which is present in even greater quantities in the rare condition known as multiple system atrophy (MSA).⁶

Scientists have been exploring vaccination strategies for neurodegenerative diseases for decades and early attempts, not focused on the neurotoxic misfolded sub-species of these proteins, disappointed due to lack of efficacy.^7-9 Vaccine technologies have since evolved and new targeted approaches could not only slow disease progression but also, perhaps, delay or prevent disease onset.

New vaccines that target these hallmark proteinopathies of AD and PD are entering mid‑stage clinical development; we will soon know if they can prevent progression or even onset of symptoms in people living with AD, PD and related diseases.

Assuming advances in diagnostics allow earlier detection, therapeutics that target neurotoxic species could offer not only a way to slow the loss of function associated with disease progression but also, perhaps, extend the period of time before symptoms appear. Furthermore, because vaccines are required less frequently than monoclonal antibody (mAb) or small molecule therapeutics, they may provide significant compliance and cost advantages.

Will these vaccines work?

The recent advances of passive immunisation approaches, namely mAbs, targeting Aβ, tau and α-syn, serve not only to validate the therapeutic targets being pursued but also immunotherapy, including active immunisation, ie, vaccination, to induce the body’s own targeted antibody response. Over time the body may evolve its polyclonal antibody response to higher affinities, meaning potentially enhanced efficacy compared to mAbs, possibly with fewer side effects and less frequent administration.

In 2021, the US Food and Drug Administration (FDA) signalled that clinical efficacy on validated biomarkers of neurodegenerative progression, ie, Aβ plaques, can be used as pivotal endpoints; this precedent may significantly reduce projected timelines (and costs) for developing therapeutics to treat neurodegenerative diseases. While Aβ antibodies, like aducanumab, donanemab, gantenuremab and crenezumab have had their ups and downs, only aducanumab is approved and reimbursement by payors remains the centre of some controversy. Nevertheless, the opportunity of using this regulatory pathway remains intact, while most experts and mounting evidence suggest that Aβ-targeting therapeutics will be important in future combination therapies, especially in treating early disease or for prevention.

Also, in 2021, Phase II data for donanemab demonstrated that this mAb, which specifically targets the toxic species pyroGlu-Aβ, slowed cognitive decline and loss of function in mild AD patients.¹⁰ In addition, although larger Phase III pivotal trials of donanemab have yet to report results, currently expected in late 2023, the sponsor may finish filing for regulatory approval this year.

Separately in 2021, a mAb targeting tau, semorinemab, showed robust Phase II results, with a statistically significant reduction in memory loss but, puzzlingly, no reduction in the loss of function in moderate AD patients. It was the first time a tau antibody had shown statistically significant slowing of cognitive decline and the first time such a result had been observed in moderate AD patients.¹¹

Another 2021 result in PD for the α-syn antibody prasinezumab in a Phase II blind extension study showed that it significantly slowed decline on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III or the digital motor score by one-quarter to one-third and participants with more severe and faster-progressing symptoms benefitted more from treatment.¹²
These passive immunisation approaches have not stopped progression or reversed the loss of function in these patients, yet these trial results are highly encouraging as they represent, in rapid succession, the first real evidence of tangible progress in decades – and for three distinct therapeutic targets.

Figure 1

As a result, the new class of conformation targeted vaccines in development now enjoy enhanced risk profiles, improved regulatory pathways and better-informed development.

Why vaccines?

The newer vaccines against endogenous “self” proteins preferentially target the toxic misfolded forms of those proteins. We wrote last year in this publication about how liposomal discovery technologies allowed the presentation of Aβ and tau epitopes in conformations similar to the physiological forms of their neurotoxic species, thereby yielding vaccines that generate polyclonal responses that are biased or targeted towards the specific misfolded protein species driving neurodegeneration (see Figure 1).¹³

Vaccines offer four potential advantages:

They generate a polyclonal response against the target – more shots on goal
The immune system may iteratively optimise its antibodies for the target over time – more precise shots on goal
Vaccine-induced antibodies are not immunogenic and will not lead to an inappropriate immune response – safer shots on goal
They provide long-lasting immune activation – more and consistent shots on goal – affording both cost and compliance advantages.

Vaccine progress

Significant progress was made over the last year in demonstrating the potential of conformation-targeted vaccines and three such vaccines are entering mid-stage proof-of-concept studies this year.

Data published in February this year in Brain Communications showed that an Aβ vaccine‑candidate designed using liposomal presentation of Aβ (ACI-24), induced a broad polyclonal anti-Aβ response, including high titers of antibodies specifically targeting pyroGlu-Aβ variants and was well tolerated in non-human primates and mice.¹⁴ The vaccine’s specificity for pyroGlu-Aβ and oligomeric Aβ, the most toxic forms of Aβ, suggest that the vaccine may have similar, or, due to polyclonality, a stronger impact than anti-Aβ antibodies.

Significant progress was made over the last year in demonstrating the potential of conformation-targeted vaccines”

Additionally, the anti-pyroGlu-Aβ immune response observed was shown to be substantially stronger in animals vaccinated with the ACI-24 vaccine compared to those vaccinated (in the same contemporaneous experiments) with previously clinically tested (and terminated) Aβ vaccines less targeted for this toxic sub-species of Aβ, AN1792 and ACC-001.11,12 Three early-stage clinical trials of ACI-24 have revealed it can generate targeted immunogenicity with appropriate safety and the sponsors are advancing it into mid- to late‑stage clinical proof-of-concept testing this year.

Similar human immunogenicity was demonstrated in clinical testing of a vaccine targeting pTau. This vaccine led to “strong” induction of antibodies selective for pTau and its aggregated form, enriched paired helical filaments (ePHF), according to the sponsors’ 2021 CTAD presentation.¹⁴ In the trial, median anti-pTau antibody titers increased from baseline by approximately two orders of magnitude at week two after a first injection and the anti-pTau/anti‑tau IgG ratio continued to increase over time up to week 10. Median levels of antibodies reactive with ePHF were boosted with both the first and second injections of the vaccine. Safety was adequate with no serious adverse events reported. They also indicated, notably before the completion of the ongoing Phase II trial, that they will be advancing the pau vaccine into more clinical trials.

A third targeted vaccine, this time targeting α-syn and designed using a different technology for making conformation targeted vaccines, is scheduled to enter mid-stage clinical testing in 2022. This α-syn vaccine was made by replacing individual amino acids in the target epitope to bias the polyclonal antibody response towards its pathological forms. Initial clinical testing indicated that the targeted α-syn vaccine successfully induced a long-lasting antibody response against pathological forms of oligomeric α-syn that were accompanied by target engagement and signals of clinical efficacy in initial testing.

All three of these targeted vaccines are entering Phase II clinical proof-of-concept studies in 2022 and data will inform the field about the potential therapeutic value of conformation targeting vaccine technologies for the treatment of neurodegenerative diseases.

About the author

Dr Andrea Pfeifer is the CEO and Director of AC Immune SA, having co-founded the company in 2003. Previously, she was the Head of Nestle Research Centre, Switzerland where she led the scientific development of several innovative products from laboratory to market and co-founded the Life Science-focused Nestle Venture Capital Fund. She is currently a key member of the CEOi initiative on Alzheimer’s Disease and the Davos Alzheimer’s Collaborative (DAC). Andrea holds a PhD in toxicology (cancer research) from the University of Wurzburg, Germany and is a registered Toxicologist and Pharmacist. She is also an Honorary Professor at the Ecole Polytechnique Federale de Lausanne (EPFL).

References:

2021 Alzheimer’s disease facts and figures. Alzheimer’s Dement., 17: 327-406
Golics, C. J., Basra, M. K., Finlay, A. Y., & Salek, S. (2013). The impact of disease on family members: a critical aspect of medical care. Journal of the Royal Society of Medicine, 106(10), 399–407
Buchhave, P. et al. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch. Gen. Psychiatry 69, 98–106 (2012).
Peng, C., Trojanowski, J. Q. & Lee, V. M. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16, 199–212 (2020).
Alam P, Bousset L, Melki R, Otzen DE. alpha-synuclein oligomers and fibrils: a spectrum of species, a spectrum of toxicities. J Neurochem 2019; 150: 522–34.
Prusiner SB, Woerman AL, Mordes DA, et al. Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci USA 2015; 112: e5308–17.
Vukicevic M., Fiorini E., Siegert S., et al. An amyloid beta vaccine that safely drives immunity to a key pathological species in Alzheimer’s disease: pyroglutamate amyloid beta. Brain Communication, 2022 ; 4(1)
Gilman S, Koller M, Black RS, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64(9):1553–1562.
Pasquier F, Sadowsky C, Holstein A, et al. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS‑21 adjuvant in mild-to-moderate Alzheimer’s disease. J Alzheimers Dis. 2016;51(4):1131–1143.
Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med. 2021;384(18):1691-1704.
AC Immune presents full top line data from its Phase 2 LAURIET trial for AD [Internet]. Alzheimer Europe. 2022 [cited 16 March 2022]. Available from: https://www.alzheimer-europe.org/news/ac-immune-presents-full-top-line-data-its-phase-2-lauriet-trial-ad
Pagano G, Boess FG, Taylor KI, et al. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson’s Disease (PASADENA): Rationale, Design, and Baseline Data. Front Neurol. 2021; 1(12).
Pfeifer A. An integrated vaccination approach to neurodegeneration. Drug Target Review. 2021; 8(3):10-14
CTAD Alzheimer Congress | 15th Clinical Trials on Alzheimer’s Disease [Internet]. Ctad-alzheimer.com. 2022 [cited 16 March 2022]. Available from: https://www.ctad-alzheimer.com/

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