Success in clinical trials of drugs for Alzheimer’s disease seems to hinge in large part on picking the right patients. Recent positive – just – data on Lilly’s project donanemab came from a trial that excluded patients with high tau levels, and dona’s ongoing pivotal trial is using similar enrolment criteria.
Blood tests for tau are thus already in demand, and several groups are developing assays for this and other Alzheimer’s biomarkers for clinical trial “enrichment”. But test developers are looking beyond this niche. Blood tests for tau and even amyloid could come to be used to diagnose Alzheimer’s; should dona, or Biogen’s anti-amyloid therapy aducanumab, reach market, demand for this kind of testing could explode.
Lilly has developed an in-house test capable of picking up a variant of the protein called phospho-tau217 (p-tau217) shed by the brain into the blood. The company uses this in combination with PET imaging to stratify patients into low, medium and high tau groups for its trials of dona. In Trailblazer Alz-2, the MAb’s pivotal study, the best results are expected from the low-tau group (Lilly moves to stack the deck for donanemab, March 16, 2021).
Cheaper and less invasive
But these assays have potential beyond aiding drug development. Last year data published in Jama suggested that Lilly’s test could tell patients with Alzheimer’s apart from those with other neurodegenerative diseases, and its performance was not significantly different from cerebrospinal fluid or PET-based testing.
That said, the test is not sensitive enough on its own to quantify the amount of tau in patients’ brains.
“We can use the blood to find people who have tau in the brain, kind of a yes/no,” says John Sims, senior medical director of neurodegeneration at Lilly. The precision on just how much tau is present is not possible yet, he says, “and I don’t know whether it will be”.
Consequently in the diagnostic context tau tests could be used as a first pass, with those with a positive result being sent for confirmation with PET.
“How [this] will fit into the diagnostic armamentarium is still yet to be determined,” says Mr Sims. “Certainly at minimum it could sit as an initial cheaper step for ensuring that someone has maybe the pathology, if they’re coming in complaining of symptoms.”
The diagnostics group Quanterix also has a tau test. It launched an assay for a different variant of the protein, p-tau181, last year as a way to aid research into Alzheimer’s and to help enrol the right patients into drug trials. This too has shown correlation with CSF and PET scan testing for Alzheimer’s pathology.
Quanterix’s product is therefore comparable to tests that require either a spinal tap or lengthy imaging procedures, which are “probably 500 times more expensive and much more invasive,” says the group’s chief executive, Kevin Hrusovsky.
He adds that the test is “selling off the charts” at the moment – but expects further growth should a tau-based treatment for Alzheimer’s succeed.
“There’s not a lot of people in the world today that would want to know, ‘hey, your biomarker signature is telling us that you’ve got Alzheimer’s, and you’re probably going to get dementia 15 years from now’,” Mr Hrusovsky says. “That’s why in the area of Alzheimer’s all of the focus right now is getting the drug across the goal line.”
Mr Sims agrees, saying that Lilly has always seen the need for tau blood tests increasing once a therapeutic option is available.
All eyes on the tau pipeline, then. The most advanced candidate is Taurx Pharmaceuticals’ tau aggregation inhibitor LMTX, whose Lucidity phase 3 trial is set to conclude at the end of this year. This study does not appear to be stratifying patients by tau levels; its record on clinicaltrials.gov lists the presence of amyloid as an inclusion criterion.
Lilly’s Trailblazer Alz-2 study of donanemab, the most advanced trial that does screen enrolees for tau, will report in 2023.
There is of course a vitally important crunch point fast approaching for a different Alzheimer’s biomarker. The FDA will pronounce on aducanumab’s approvability in June, and the decision will either provide something approaching vindication for the amyloid hypothesis or do it an injury from which it might never recover.
There is in fact a blood test for beta-amyloid already on sale in the US. C2N Diagnostics launched PrecivityAD under a Clia certification last October, in much the same settings as tau tests: to help clinicians diagnose Alzheimer’s in patients experiencing early memory complaints, and to screen patients for drug trials. Its list price is $1,250, but C2N has a financial assistance programme that can lower the cost to between $25 and $400 for eligible patients.
C2N’s chief executive, Joel Braunstein, says that despite the lack of active anti-amyloid drugs demand for PrecivityAD is strong.
“Some people would say, I’m not sure I want to know, and other people are very enthusiastic about having access to this information even in the absence of the disease-modifying therapy,” he says. “There’s a movement of people who want to be very proactive with their health, and are interested in being more informed.”
If the test is positive, the patients can change their lifestyles in ways that have been proven to slow the progression of Alzheimer’s, doing more physical exercise and taking part in cognitive and memory support training, for example.
Still, there is a limit to what can be achieved by these kinds of interventions. Availability of an anti-amyloid drug would change the situation.
“Certainly, if a disease-modifying therapy becomes available, there will be a considerable interest in having additional information to help get a precise diagnosis,” Mr Braunstein says. “The less invasive nature of a blood draw will certainly be helpful for supporting an infrastructure that’s going to presumably have a significant need to identify people with early pathology.”
If – and it is of course a big if – anti-amyloid and anti-tau MAbs make it to market, the setting for blood tests for these biomarkers could shift again.
Jeff Dage, distinguished medical fellow at Lilly, says that some research has suggested that Lilly’s tau test can be used to screen people before symptom onset to identify those with tau pathology who are likely to develop Alzheimer’s.
Quanterix’s Mr Hrusovsky envisions annual or even quarterly screening programmes for healthy people, organised via insurers or other payer groups, as a potential use of the assays, “so that you can see the earliest cascade of amyloidosis or tauopathy”.
This might be a stretch. But it is clear that the utility of blood tests for Alzheimer’s markers – and to some extent the fate of the companies developing them – is tied closely to the success or otherwise of drugs like aducanumab and donanemab.