After repeated failures with anti-amyloid drugs, targeting tau protein was the next big idea in Alzheimer's disease. But a setback with one of tau's first big tests suggests that progress with this mechanism might not come any easier.
News of the failure of Roche and AC Immune’s anti-Tau MAb semorinemab will have set nerves jangling at the likes of Biogen and Lilly – stalwarts of the amyloid years that are now heavily invested in tau. But with few details available on semorinemab’s flop, the host of companies developing tau-targeting agents will have to wait to see if glimmers of hope can be found among the wreckage.
For now, all Roche and AC Immune are saying is that the phase II Tauriel trial in prodromal to mild Alzheimer’s did not meet its primary endpoint, change in the clinical dementia rating-sum of boxes score, with semorinemab showing no benefit over placebo. The companies did not disclose the p value.
The study also missed two secondary endpoints, the ADAS-Cog13 and the ADCS-ADL.
More data should be presented at the CTAD meeting in November, according to Leerink analysts. Attendees will be particularly keen to see tau biomarker data – if semorinemab is shown not to be effective at clearing tau, this could explain the failure, meaning the tau hypothesis might still be in play.
Even if this turns out to be the case, there are reasons to be cautious about other late-stage anti-tau projects. The most advanced, Taurx Pharmaceuticals’ LMTX, has already failed twice in phase III. And Axon Neuroscience’s AADvac1 failed to show a benefit on clinical efficacy endpoints in its phase II trial.
Furthermore Abbvie and Biogen’s anti-tau MAbs, ABBV-8E12 and gosuranemab, failed last year in progressive supranuclear palsy which, like Alzheimer's, is characterised by the build-up of tau in the brain.
There is a question mark over whether antibodies will be effective therapies given that they target extracellular tau, and pathologic tau largely accumulates within neurons. However, extracellular tau could have a role in the spread of pathologic tau between neurons.
AC Immune is taking different approaches with its two other anti-tau projects. The vaccine ACI-35.030 is being developed in collaboration with J&J, while Lilly is partnered on ACI-3024, a small molecule designed to be able to pass through cell membranes to inhibit intracellular tau aggregates.
Semorinemab is not dead yet, with the phase II Lauriet study in moderate Alzheimer’s ongoing. However, hopes are now low, reflected by the fact that AC Immune lost nearly half its value yesterday.
|Selected tau-targeting projects in clinical development|
|LMTX||Taurx Pharmaceuticals||Tau aggregation inhibitor||AD trial to complete Dec 2021|
|Semorinemab/RG6100||Roche/AC Immune||Anti-tau MAb||Tauriel in prodromal/mild AD failed; Lauriet in moderate AD ongoing|
|Tilavonemab/ABBV-8E12||Abbvie||Anti-tau MAb||Failed in PSP; study in early AD completes Apr 2021|
|Zagotenemab/LY3303560||Lilly||Anti-tau MAb||Study in early symptomatic AD completes Aug 2021|
|Gosuranemab/BIIB092||Biogen/Bristol Myers Squibb||Anti-tau MAb||Failed in PSP; Tango in early AD completes Mar 2024|
|BIIB080||Biogen/Ionis Pharmaceuticals||Tau antisense oligonucleotide RNAi therapeutic||Study in mild AD completes May 2022|
|ACI-35.030||Johnson & Johnson/AC Immune||Anti-tau vaccine||Study in early AD completes Oct 2022|
|BIIB076||Biogen/Eisai||Anti-tau MAb||Volunteer & AD study completed Mar 2020; no data yet|
|E2814||Eisai||Anti-tau MAb||Volunteer study completed Aug 2020|
|PNT001||Pinteon Therapeutics||Anti-tau agent||Volunteer study completes Nov 2020|
|ACI-3024||Lilly/AC Immune||Tau aggregation inhibitor||Volunteer study data due 2020|
|Lu AF87908||Lundbeck||Anti-tau aggregation MAb||Volunteer & AD study completes Mar 2021|
|BEY2153||Beyondbio||Beta-amyloid & tau aggregation inhibitor||Volunteer study completes Oct 2021|
|UCB0107||Roche/UCB||Anti-tau MAb||PSP trial ongoing, AD deal signed Jul 2020|
|Source: EvaulatePharma, clinicaltrials.gov.|