Safety and Immunogenicity of the Tau Vaccine AADvac1 in Patients with Alzheimer’s Disease

MedicalResearch.com Interview with:

Petr Novak, MD, PhD AXON Neuroscience Bratislava, Slovakia

Dr. Petr Novak

Petr Novak, MD, PhD
AXON Neuroscience
Bratislava, Slovakia

MedicalResearch.com: What is the background for this study?

Response: Alzheimer’s disease is a complex, multifactorial disorder, with many-faceted neuropathology. A hallmark finding is the co-existence of neurofibrillary pathology (such as neurofibrillary tangles) composed of tau protein, and amyloid-β pathology (plaques) [1].

Neurofibrillary pathology is closely correlated with cognitive impairment in Alzheimer’s disease [2], while support for the role amyloid in the disease pathogenesis comes from the ability of certain mutations to induce AD in an autosomal-dominant fashion [3].

The field has explored various anti-amyloid therapies to great extent, and continues to do so with undiminished effort [4]; meanwhile, there is a noticeable paucity of investigated therapies aimed at neurofibrillary tau protein pathology, despite the ability of tau protein dysfunction to cause a multitude of neurodegenerative disorders, collectively named “tauopathies” [5].

AADvac1 is the first tau-targeted immunotherapy investigated in humans [6], a pioneering effort to target the component of AD neuropathology that is proximal to neuronal damage and cognitive loss, and thus to halt or slow the progression of Alzheimer’s disease.

MedicalResearch.com: What are the main findings?

Response: AADvac1 is an active vaccine that uses the patients’ own immune system to produce antibodies that target pathological tau protein, with the aim to prevent tau aggregation and to label pathological tau protein for removal by immune cells [7]. The first-in-man study that is the topic of the present article primarily aimed to assess the safety and immunogenicity of the vaccine.

A beneficial safety profile was observed, with generally mild reversible injection site reactions being the only side effect clearly linked to treatment; such reactions are commonly observed with a range of adjuvanted vaccines. The importance of this finding becomes apparent when one considers the problematic safety profiles of many investigational Alzheimer’s disease drugs [4, 8].

We were able to induce an IgG-type antibody response against the tau peptide component of the vaccine in 29/30 treated patients, and an antibody response against pathological AD tau protein (as found in the brains of AD patients) in 25/30 treated patients; the antibodies displayed a pronounced preference for AD tau in comparison to healthy tau. This is an encouraging finding, especially considering immune senescence, and the difficulties it causes in vaccinations for the elderly [9]. Furthermore, we have performed a range of haematological assessments to identify aspects of patient immune competence that influence the antibody response.

MedicalResearch.com: What should readers take away from your report?

Response: The first-in-man study of AADvac1 has successfully laid foundation for further development of AADvac1, such as the ongoing phase 2 study “ADAMANT”, a combined safety-efficacy study (NCT02579252).

By extension, seeing that a range of immunotherapy programs have been launched in the recent years, the initiation of the AADvac1 program may actually have spurred the development of other tau-targeted immunotherapies for Alzheimer’s disease:

http://www.alzforum.org/therapeutics/search?fda_statuses=&target_types%5B%5D=177&therapy_types%5B%5D=161&therapy_types%5B%5D=162&conditions=&keywords-entry=&keywords=#results

Regardless, the takeaways from the AADvac1 phase 1 study are fairly obvious:

  • it is possible to target neurofibrillary pathology in the brain via immunotherapy safely
  • it is possible to raise high titres of specific antibodies even in the elderly
  • the immune response to novel antigens administered to the elderly is tied to identifiable factors; characterising these early in the development program opens an avenue to eventual optimisation of the compound or inclusion criteria of further studies if necessary

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: First of all, it is important to highlight that neurofibrillary pathology is exceedingly complex, a fact that is often overlooked in the Alzheimer’s disease field. In disease, the AD tau proteome can consist of a plethora of pathologically modified tau protein forms (estimates of 1012 different forms could be realistic). These forms do have common denominators, but they differ in truncation points, phosphorylation patterns, conformation, and many other aspects. The present study highlights one aspect of this: anti-tau response raised by the 13-meric tau peptide component of AADvac1 labels a range of insoluble tau forms extracted from human AD brains, from low molecular weight fragments to high molecular weight aggregates. In the development of tau-targeted immunotherapy, one should always keep in mind the question: “Which forms of tau does the compound target? Which forms does it not target?”

Based on the distribution of antibody titre values observed in the study, it appears wise to use at least 30 patients for the characterisation of antibody response to every dose strength of an active vaccine.

Finally, our recommendation is to implement a broad range of biomarker endpoints early in any  Alzheimer’s disease drug development program. 

MedicalResearch.com: Is there anything else you would like to add?

Response: In relation to the abovementioned complexity of tau pathology, it is important to add that similarly, the compounds that interact with tau protein, and their functions can be highly varied. Early in our research, we have identified antibodies that can prevent tau aggregation, but also those that can promote it [10]. It goes without saying that only the first kind should be selected for further development [7], and the latter not (though they still can be valuable tools for in vitro assays).

Finally, we’d like to highlight that there is a large body of tau protein research that has been accumulating since the 80’s [6, 11, 12], and numerous of these findings should be brought back to light to inform the nascent field of clinical development of tau-targeted immunotherapy, but also other related fields, such as development of tau PET ligands.

References

  1. Braak, H. and E. Braak, Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol, 1991. 82(4): p. 239-59.
  2. Nelson, P.T., et al., Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol, 2012. 71(5): p. 362-81.
  3. Hardy, J. and D. Allsop, Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci, 1991. 12(10): p. 383-8.
  4. Schneider, L.S., et al., Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med, 2014. 275(3): p. 251-83.
  5. Spillantini, M.G. and M. Goedert, Tau pathology and neurodegeneration. Lancet Neurol, 2013. 12(6): p. 609-22.
  6. Iqbal, K., F. Liu, and C.X. Gong, Tau and neurodegenerative disease: the story so far. Nat Rev Neurol, 2016. 12(1): p. 15-27.
  7. Kontsekova, E., et al., First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther, 2014. 6(4): p. 44.
  8. Gilman, S., et al., Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 2005. 64(9): p. 1553-62.
  9. Siegrist, C.A. and R. Aspinall, B-cell responses to vaccination at the extremes of age. Nat Rev Immunol, 2009. 9(3): p. 185-94.
  10. Kontsekova, E., et al., Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res Ther, 2014. 6(4): p. 45.
  11. Wischik, C.M., et al., Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A, 1988. 85(12): p. 4506-10.
  12. Grundke-Iqbal, I., et al., Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A, 1986. 83(13): p. 4913-7.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase 1 trial
Novak, Petr et al.
The Lancet Neurology , Volume 16 , Issue 2 , 123
Published: 09 December 2016

DOI: http://dx.doi.org/10.1016/S1474-4422(16)30331-3

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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