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Review of Alzheimer’s Association International Conference (AAIC16) Part 1: Focus on Tau

Posted on August 10th, 2016 by in Pharma R&D

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I have just returned from the Alzheimer’s Association International Conference (AAIC16) in Toronto, Canada. Toronto is a beautiful cosmopolitan city and a perfect setting for scientists from across the globe to come and share their latest research on Alzheimer’s disease.

Here are some of the highlights of the conference from my perspective on tau research. A subsequent post will discuss highlights on amyloid research.

Tau Therapy Fails to Impress.

The most anticipated presentation at the conference was on a small molecule tau aggregation inhibitor LMTM (leuco-methylthioninium-bis(hydroxymethanesulfonate) from TauRx. In it, they discussed the results from the Phase 3 trial of LMTM in Alzheimer’s disease (AD). Disappointingly, the tau aggregation inhibitor failed to reach significance in its two primary outcome measures (ADAS-Cog for cognition, and ADCS-ADL for function) following 15 months of treatment of mild-to-moderate AD patients.

Despite this failure on the co-primary outcomes, the investigator suggested that there was indeed a significant and robust effect of LMTM in a small subset of patients who were on “mono-therapy”; in others words, not taking other approved symptomatic drugs such as memantine or cholinesterase inhibitors.  There was considerable consternation over these claims as secondary analyses, even pre-specified, tend to be looked at with skepticism until confirmed in follow-up studies. In addition, the statistical treatment of data was flawed as it compared subjects on monotherapy to all placebo controls regardless of drug status. The investigators indicated this was necessary due to the small numbers of patients taking placebo only, but statisticians were quick to point out that this invalidates the comparison.

Finally, there’s no biological rationale for why this drug would work as a monotherapy but not when combined with standard of care symptomatic drugs. Additional clinical trials with LMTM are ongoing and may provide some clarity, but for now, it would seem that the first large Phase 3 trial of a tau-directed therapy failed to provide any significant benefit to mild-to-moderate AD patients. However, these results should not be taken as evidence that tau is not a good target for AD. Rather the take-away for me is that this molecule offers no benefit to patients at this stage of disease. It remains to be seen whether other tau-directed therapies (see below) will offer benefits.

In the Tau Pipeline

One promising tau-directed molecule that has entered early clinical trials is Merck’s MK-8719, a small molecule inhibitor of the O-GlcNAcase (OGA) enzyme. This compound inhibits the removal of a sugar moiety, O-GlcNAc from tau (and numerous other proteins), which in preclinical cellular and animal models is associated with reduced tau aggregation and pathology. In the Tg4510 tau transgenic model, treatment with MK-8719 produced a dose-dependent increase in brain O-GlcNAc-modified proteins that was associated with dose-dependent decreases in the accumulation of pathologic tau.

In addition, the subsequent downstream neuroinflammation and neurodegeneration associated with tau pathology was blunted by OGA inhibition. Phase 1 clinical data showed MK-8719 to be safe and well tolerated at doses up to 1200 mg given to subjects. The amount of O-GlcNAc-modified protein in peripheral blood mononuclear cells (PBMCs) is being used as a biomarker for OGA inhibition, and the investigators noted a dose-related increase in the amount of O-GlcNAc-proteins after a single dose. To assess target engagement in brain, Merck has developed a PET ligand for OGA (18F-MK-8553). At some undefined dose, they showed a significant decrease in 18F-MK-8553 binding in brain. MK-8719 is being developed for the treatment of Progressive Supranuclear Palsy (PSP), one of the neurodegenerative tauopathies related to AD.

Space constraints limit a discussion of other tau-directed molecules in early stage development, but these include active and passive immunotherapy approaches. Unlike OGA, where target engagement can be monitored by the increase in O-GlcNAc-modified proteins and by displacement of active-site directed PET ligands, determining target engagement with tau immunotherapy is more challenging and limited to attempting to quantify antibody binding to tau. Thus, the development of tau PET tracers (see below) could not be better timed to support clinical development of tau therapies.

Imaging Tau Pathology

All of the tau-directed therapies going forward will benefit from the development of Tau PET tracers. 18F-AV-1451 from Lilly is the most advanced, but other PET-ligands, e.g, the THK series from Tohuku and 11C-PBB-3 are fast followers. These tracers show the progressive spread and accumulation of neurofibrillary tangles (NFTs) reminiscent of the Braak and Braak staging. Moreover, unlike amyloid PET imaging, the patterns of tau deposition are more strongly linked with cognition in AD. Thus, these tau PET ligands may prove to be invaluable imaging biomarkers for tracking the disease progression of AD patients on active drug therapy versus placebo. While the performance of these tau PET ligands appears to be robust in AD, the jury is still out on whether the same tau PET ligands will be useful for tracking tau pathology and disease progression in other tauopathies.


 

All opinions shared in this post are the author’s own.

For more information and research on Alzheimer’s disease visit ScienceDirect.

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