After repeated failures with agents targeting amyloid, tau is the new hot ticket in the Alzheimer’s world. Yesterday’s tie-up between Merck & Co and Teijin Pharma came just over a month after Biogen licensed another anti-tau antibody, from Bristol-Myers Squibb.
But, as with any Alzheimer’s project, there are reasons to be cautious. The tau-targeting approach was dealt a blow in December when Taurx Pharmaceuticals quietly slipped out the failure of a second phase III trial of LMTX. The company is persevering with this project, but so far the omens are not good.
Taurx had hoped that statistical tinkering would help it get a result after the failure of its initial TRx-237-015 phase III study in mild to moderate Alzheimer’s (TauRx touts second chance to prove success, July 28, 2016).
But the TRx-237-005 study, in mild disease, also failed to show a difference between the treatment and placebo groups in the original, as-randomised analyses. A confounding factor might have been that the placebo group received a low dose of LMTX to stain bodily effluents blue and thus maintain blinding, which could have been effective, Taurx claims.
The company has said it plans to press ahead with this low 4mg dose in a new trial in Alzheimer’s patients not receiving cholinesterase inhibitors or memantine; however, it has not given any details of this study and it does not appear to have been listed on Clinicaltrials.gov.
LMTX has also failed in a phase III trial in frontotemporal dementia, another neurodegenerative disease.
How soon is tau?
Taurx’s tribulations have obviously not put off Merck, which now has exclusive worldwide rights to Teijin’s unnamed preclinical tau antibody. The group kept the value of the deal under wraps, but Teijin will retain an option to co-promote in Japan.
The project works differently from LMTX, a tau aggregation inhibitor. Among the tau-targeting agents antibodies are the most popular, with seven such projects in clinical development, according to EvaluatePharma – including BMS-986168, which Biogen recently licensed from Bristol (For $300m Biogen beefs up its Alzheimer’s attack, April 13, 2017).
This is in phase II for progressive supranuclear palsy, although at the time of the deal Biogen said it would start phase II development in Alzheimer’s soon.
With Merck and Teijin’s project lagging behind, the hope has to be that it shows an advantage over the other antibodies once in the clinic – that is, assuming that this approach has merit.
|Clinical stage tau-targeting Alzheimer's disease projects|
|Project||Company||Mechanism||Trial details (if available)|
|LMTX||Bayer/TauRX Pharmaceuticals||Tau aggregation inhibitor||TRx-237-005; NCT01689233|
|AADvac1||Axon Neuroscience||Tau vaccine||Adamant; NCT02579252|
|ABBV-8E12||Abbvie/C2N Diagnostics||Anti-tau MAb||NCT02880956|
|BMS-986168||Biogen/Bristol-Myers Squibb||Anti-tau MAb||PSP study; NCT03068468|
|Posiphen||QR Pharma||Amyloid precursor protein, a-synuclein & tau inhibitor||Discover; NCT02925650|
|AADvac2||Axon Neuroscience||Anti-tau MAb||-|
|ACI-35||Johnson & Johnson/AC Immune||Anti-tau vaccine||-|
|NPT088||Proclara Biosciences||Abeta, tau & a-synuclein aggregation inhibitor||NCT03008161|
|RG7345||Roche/AC Immune||Anti-tau pS422 MAb||-|
|Tau MAb Research Program||Lilly||Anti-tau MAb||-|
Others are using different methods to hit tau, and there are two vaccines in clinical development: Axon’s AADvac1 and Johnson & Johnson/AC Immune’s ACI-35. This is another hot area of research, although most Alzheimer’s vaccines target beta-amyloid (Therapy focus – Early beginnings for Alzheimer’s vaccines, March 7, 2017).
The amyloid hypothesis has been called into question after a string of late-stage failures, including that of Merck’s Bace inhibitor verubecestat. The company is awaiting data from a study in prodromal disease, and the hope is that earlier treatment could lead to a better outcome.
With other amyloid-targeting approaches coming up short this is far from assured. Merck now has another shot on goal in Alzheimer’s with tau, but this is probably no less risky.
(This article has been corrected to show that QR Pharma is developing posiphen.)