If a therapy targets an important cause of a condition, and does so effectively, there should be little ambiguity in the results that emerge from clinical trials. The size of effect will be large, there will be no need to frown and interpret and try to find subgroups in the which the results are enough to declare some sort of success. Sadly, this latter position is much the state of the Alzheimer's clinical development community, still largely focused on immunotherapies targeting amyloid-β. Such an enormous amount of funding is devoted to these efforts that there is considerable incentive for the sponsoring entities to find some way to declare success, any success, at the end of the day. But are patients doing any better? Not really.
The trend in the field is towards an ability to measurably reduce aggregated amyloid-β and tau in the brain, as well as other biomarkers associated with neurodegeneration, but to see no benefit to cognitive function as an outcome. Why this is the case remains an open question, given the very robust evidence for amyloid-β and tau to be driving the progression of the condition. Or are they? Perhaps Alzheimer's disease is a self-sustaining inflammatory condition in which the immune cells of the brain have been driven into sufficient dysfunction that removing the trigger of aggregated amyloid-β and tau will do little. Or perhaps vascular dysfunction is a lot more important than has been thought, and success will be elusive until it is also addressed. It is with this in mind that one has to parse remarks on trial data.
At the virtual AAT-AD/PD Focus meeting, clinicians and funders involved in the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) discussed results from the first DIAN-TU treatment and prevention trial of the monoclonal antibodies solanezumab and gantenerumab. DIAN-TU's principal investigator had presented topline data analyses of the primary outcome, which was head-scratchingly negative. He also presented the first analyses of several of the trial's biomarker measures, which were robustly positive. What does it all mean?
"It was gratifying to see all biomarkers that were presented moving toward normal. Brain amyloid down, cerebrospinal fluid (CSF) Aβ42 up, tau and p-tau down, and the neurofilament light protein (NfL) increase prevented. This shows the biology of the antibody is working. The whole field is witnessing that antibodies designed to remove amyloid do their jobs and are followed by other biomarkers going in the right direction. Why did this not translate into clinical benefit? Is there a threshold we need to hit? Do we need to go down to zero? Or is it dose exposure over time?"
Topline data suggest that the first two drug arms of the DIAN-TU trial platform - solanezumab and gantenerumab - were not a complete bust. Instead, the analyses finished to date point to nuanced effects of dose, time, disease stage, and biology. To be sure, the data did substantiate the earlier announcement that both therapeutic antibodies had fallen short on the trial's primary endpoint, the DIAN-TU multivariate cognitive endpoint. What happened? In short, symptomatic participants had descended into moderate dementia even before they could be titrated up to a high dose, whereas asymptomatic participants stayed stable throughout the trial regardless of whether they were on drug or placebo. This left the trial's main question unanswered.
For solanezumab, a monoclonal antibody targeting soluble amyloid-β, this indeed marks the end of its exploration within DIAN, the global research network for families with autosomal-dominant Alzheimer's disease. But all is not lost for gantenerumab, a monoclonal targeting aggregated forms of amyloid-β. Besides removing amyloid plaques from the brain and normalizing CSF Aβ42, this antibody reversed toward normal the elevated levels of CSF total tau and p-tau181, an AD-specific, pathological form of this neuronal protein. Gantenerumab further stemmed the rise of the general neurodegeneration marker CSF neurofilament light.
The effect sizes of this biomarker response were so large that they prompted the DIAN investigators to invite DIAN participants - who have devoted four to seven years of their lives to this trial, depending on when they enrolled - to join an open-label extension. It will explore high-dose gantenerumab therapy for several additional years. Its goal? To see if sustained gantenerumab therapy near the highest tolerated dose removes both plaques and tangles all the way down to a hypothesized, yet-to-be-defined threshold at which cognition and function might start to benefit.