Blocking tau appears to be just as fruitless as clearing amyloid buildup when it comes to helping Alzheimer’s disease (AD) patients.
That’s the top-line verdict, anyway, after another setback in the field, this time from the phase 2 Tauriel trial of Roche and partner AC Immune’s anti-tau antibody, semorinemab, in early (prodromal to mild) AD.
The results were poor: The Swiss partners’ drug did not meet its primary efficacy endpoint of reducing decline on Clinical Dementia Rating scale Sum of Boxes scores compared to placebo.
On top of this, two secondary endpoints, Alzheimer’s Disease Assessment Scale cognitive subscale 13 and Alzheimer’s Disease Cooperative Study Group – Activities of Daily Living Inventory, were also not met. The drug was tested across nearly 500 patients.
These three are typical measurements of whether a drug can help AD patients. The only bright spot: The safety endpoint was met.
A full data set was not published, but “additional data analyses are ongoing and Genentech plans to present the results from TAURIEL at an upcoming medical congress,” it said in a statement.
The second phase 2, known as Lauriet, which is studying semorinemab in patients with moderate AD, “remains ongoing,” the partners said, with the drug clearly not being tossed out just yet. Data from this are expected next year, although analysts at Jefferies said “we see potential negative read-across given the more advanced disease population.”
“Today’s news is surprising and disappointing, given what we as a field know about Tau and its strong spatiotemporal correlation with both symptoms and pathology in AD,” said Andrea Pfeifer, CEO of AC Immune.
“We believe the full data analysis of this first-of-its-kind study will yield information about this promising target that will advance our understanding and inform future efforts to successfully develop effective therapeutics for neurodegenerative diseases (NDD). We would like to thank the patients, caregivers and investigators who participated in this important, ground-breaking trial and look forward to the final results from our partner, Genentech.”
“Although we are disappointed by the topline results, we believe these data will contribute to the scientific understanding of the role of tau in this complex and difficult-to-treat disease,” said Rachelle Doody, MD, Global Head of Neurodegeneration at Roche, in a statement to Fierce Biotech.
“We remain committed to following the science and exploring multiple approaches and molecules that aim to address key pathways of Alzheimer’s disease, including tau and beta-amyloid, with the hope that our collective scientific research will lead to impactful progress for millions of people with this disease. We gratefully acknowledge the efforts of everyone involved in this program, especially the trial participants and their families.”
Like the amyloid theory, Tau, which had high hopes at one point and causes deposits of tangles in the brain, has also endured a rocky path, with coming data over the next two years likely to prove pivotal to whether it is worth pursuing, or not.
Late last year Biogen, which still believes it can achieve an approval for its failed AD drug aducanumab, said its humanized monoclonal antibody that targets N-terminal tau also flopped in a midstage test.
One of the furthest along the development path had been TauRx’s tau aggregation inhibitor LMTX (hydromethylthionine mesylate), but this also failed to show a benefit over placebo when added to Aricept therapy in a phase 3 trial reported in 2016.
Undeterred, TauRx started a new phase 2/3 trial called Lucidity in 2018 with a lower dose of LMTX used on its own, with data expected next year, or 2022.
AbbVie has an antibody called ABBV-8E12 in phase 2 testing that binds to the abnormal tau tangles, trying to block spread from neuron to neuron.
But while the therapy failed a phase 2 in progressive supranuclear palsy (PSP) last year, that shortfall didn’t affect the AD research. Patients in the PSP trial were at an advanced stage at diagnosis, an investigator told Alzheimer’s Forum, while the stage of “tauopathy” in the AD trial is “relatively early,” the researcher said. Results from ABBV-8E12’s phase 2 in Alzheimer’s are due next year.
This also isn’t Roche’s only skin in the game: It has another partnered tau-targeting drug in the mix with its recent $120 million deal to develop a UCB antibody. The drug, UCB0107, is designed to block or reduce the buildup of tau proteins.
UCB is already testing the candidate in the uncommon neurodegenerative disorder PSP, but under its deal with Roche, the Belgium-based drugmaker will fund and carry out a proof-of-concept study in Alzheimer’s. If all goes well, Roche can take over development from there, and the deal could yield up to $2 billion total for UCB if all the milestones involved pay out.
Roche also has several other non-Tau prospects in AD, including MorphoSys-partnered gantenerumab, an anti-beta-amyloid antibody which finished up enrolment in a phase 3 in July, but has in the past already chalked up a major phase 3 failure before Roche tried again.
It’s a similar story for crenezumab, an investigational anti-amyloid monoclonal antibody, currently in a phase 2/3 Alzheimer's prevention Initiative test for those at risk for autosomal dominant AD.
This, also partnered with AC Immune and also the victim of a 2014 phase 2 flop, saw its phase 3 stopped last year after an interim analysis found they were unlikely to hit their primary endpoint in patients with sporadic, prodromal-to-mild Alzheimer’s.
What does this mean for tau theory? If it’s anything like the amyloid hypothesis, it will likely continue on, despite years and multiple failures, indicating just how little R&D works on AD and the desperate need for any glimmer of hope against the memory-wasting disease.
And what does this mean for AC Immune? It means its shares were down around 50% on the news Wednesday morning, despite it also using the press release of the failure to talk up its pipeline hopes and cash reserves.
Jefferies added that while it saw expectations as “muted” into these data, the failure is likely “to be a hit to sentiment” after numerous setbacks with amyloid-targeted therapies.
“Our 20% probability of success reflects the high risk nature of AD drug development, with the Tau hypothesis as yet unproven.”