A drug for Alzheimer's disease targeting tau protein pathology failed to demonstrate a benefit in the primary analysis from phase III trial reported at the AAIC meeting. However, in a prespecified subgroup, patients who were not taking symptomatic treatments (e.g., cholinesterase inhibitors), the anti-tau drug therapy did show a statistically significant benefit in terms of cognition, functional ability, and brain atrophy. Patients had mild to moderate AD and the trial lasted 15 months.
We contacted neurology experts via email to ask:
How much of a disappointment are these results?
Was it a mistake not to combine this drug with an anti-amyloid drug, at least in one treatment arm?
Where does this leave the prevailing theories of Alzheimer's disease and the best ways to attack it?
The participants this week are:
Samuel Gandy, MD, PhD, professor of neurology and psychiatry at Mount Sinai Hospital in New York City
Claude Wischik, MD, PhD, study co-author and co-founder of drug sponsor TauRx, professor of psychiatric geratology at Aberdeen University
Lary C. Walker, PhD, associate professor of neurology at Emory University School of Medicine in Atlanta
Douglas Scharre, MD, professor of clinical neurology and psychiatry at The Ohio State University Wexner Medical Center in Columbus
George Grossberg, MD, Samuel W. Fordyce professor and director of geriatric psychiatry at St. Louis University School of Medicine
Disappointing?
Gandy: No surprise, no disappointment.
Wischik: The results are more a source of frustration than disappointment in that the potential of LMTX to provide an effective treatment in this devastating disease was only demonstrated in a small proportion of the trial subjects. However, the results of TauRx's second AD study confirm the findings of this first study and we look forward to the publication and presentation of these results, which is expected later in 2016.
Walker: The results are somewhat disappointing, but not necessarily surprising. Certainly the apparent positive outcome of LMTM monotherapy will need to be replicated in a larger group of subjects. As we learn more about the natural history of Alzheimer's disease, it has become clear that tau aggregation (like Abeta aggregation) is well-advanced in the brain by the time the signs of dementia set in. Hence, it may be that a therapy targeting tau must be administered much earlier in the pathogenic process to be effective.
Scharre: Very disappointing that another phase III trial for dementia treatments has failed. However, we definitely gain knowledge by every failure and that propels us closer to more efficacious treatments. The trial used mild to moderate AD subjects and so it is possible this tau aggregation inhibitor may have been applied to late in the course of the disease and that earlier use of this agent may provide benefit. Anti-amyloid agents are currently being tested in prodromal cases.
Grossberg: These results are quite disappointing, with many trying to sugarcoat the results of this negative study. The field was hoping for a new therapy with a new mode of action but this study is a clear setback for tau-based therapies.
Trial Critiques
Scharre: I think their method of not using anit-amyloid treatments was correct at this stage in their evaluation of their drug. Since anti-amyloid agents are far from proven to help AD subjects, adding another arm would have delayed the recruitment and study completion of this agent.
Gandy: I think that the ideal trial is to identity APOE4 positives in midlife 45-50 follow with annual amyloid scans and when positive, give anti-amyloid or anti-tau or both.
Wischik: It was important for a tau-targeted drug to be able to demonstrate the potential of this particular pathway as distinct from that of the amyloid pathway. Whether there is benefit from a combination of tau- and amyloid-focused treatments remains a valid question that will need to be explored in future studies when effective amyloid-focused treatments become available.
Grossberg: I am not a fan of combining two experimental drugs with different mechanisms of action and different side-effects in one vulnerable, elderly patient (with Alzheimer's disease, especially).
Walker: Eventually such combined therapy might be deemed necessary, but a single treatment would be preferable for a number of reasons. For instance, combining treatments could aggravate the side-effect profile in unexpected ways. Tau alone is a legitimate therapeutic target for AD, and it is possible that inhibition of tau aggregation could be effective later in the pathogenic cascade than are anti-amyloid-beta approaches. In my view, the design of the study was appropriate for this early stage of development of therapeutic strategies.
Future Steps
Grossberg: We still do not know which mechanism/s lead to brain cell death in Alzheimer's disease. This negative study combined with many negative amyloid-based treatment trials should encourage the field to look more aggressively at other than amyloid or tau -focused therapeutic/preventative interventions and in particular life/style and dietary modifications.
Walker: Overwhelming evidence supports the concept that the misfolding and self-assembly of amyloid-beta and tau drive the onset and evolution of Alzheimer's disease. This process begins in the brain many years before the first signs of dementia become apparent. A fundamental principal of alleviating chronic diseases is the importance of treating early; assuming that a therapeutic agent effectively engages the appropriate target in the brain, the largely negative results of AD trials to date may simply be telling us that an ounce of prevention is worth even more than a pound of cure.
Gandy: I think that we have no idea how early we need to intervene. APOE4-positive and amyloid-positive form the highest risk group. We know from autopsy some E4 have amyloid in their 40s.
Scharre: I do not feel that one negative trial regarding this tau aggregation inhibitor would at all change prevailing theories of AD. The fact that a small group of subjects not using symptomatic treatments currently available, improved with this drug, may suggest that further study of these agents or similar anti-tau agents would be worthwhile.
Wischik: I think the results of our two studies of LMTX in Alzheimer's will show that a tau-based approach to disease treatment has the potential to be effective. When we look at the number of patients suffering from the disease, and of the caregivers providing support to them, we clearly need to pursue all possible treatment avenues in parallel.
Friday Feedback: Alzheimer Drug Flop Frustrates Field
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