Rachelle S. Doody, MD, PhD, on DIAN-TU Study Analysis, Additional Insights on Gantenerumab and Crenezumab
The global head of Neurodegeneration at Roche/Genentech offered her insights on additional analysis of the DIAN-TU trial of gantenerumab and perspectives on biomarker data.
Rachelle S. Doody, MD, PhD
In addition to presentations on a subset of patients enrolled in 6 clinical trials Roche conducted that used its Elecsys NeuroToolKit in Alzheimer disease (AD), the company offered up a number of other data at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30.1
These data included analysis of gantenerumab from the DIAN-TU trial (NCT01760005) of the investigational AD agent, which originally showed that both it and solanezumab (Eli Lilly) failed to reach the primary end point in patients with early-onset dominantly inherited AD based on topline data from February 2020,2,3 and additional data published in July 2021.4 These new data from AAIC were in line with Roche’s NeuroToolKit findings, revealing insights about important biomarkers of AD.
To find out more about these data and presentations of research, NeurologyLive spoke with Rachelle S. Doody, MD, PhD, global head, Neurodegeneration, and franchise head, Alzheimer’s Disease Neurodegeneration, Roche/Genentech. She offered her perspective on the company’s analyses and opinions on what they mean for the clinician community and the patients they treat.
NeurologyLive: Could you offer an overview of the phase 2/3 data on gantenerumab that were presented at AAIC 2021?
Rachelle S. Doody, MD, PhD: The things that that we wanted to share include some of the biomarker data, done in collaboration with our colleagues at Washington University, and we were very encouraged to see that gantenerumab has an effect on not only lowering amyloid in the brain, but on downstream biomarkers as well, including tau and neurogranin. Now, what we talked about in this meeting—and these investigations were led by our colleagues—was that we all wonder: Does it matter what tracer you use? There was an opportunity to investigate that question because several of the DIAN-TU subjects—this is the Dominantly Inherited Alzheimer's Network project—are people who, in this particular part of the trial, are all carriers have familial Alzheimer disease. Many of these carriers had both PiB-PET and Aß45-PET.
It turns out that it does make a difference. Amyloid reduction due to the drug was clearly seen with both tracers, but regionally, the amount of amyloid reduction differed by tracer, particularly in the striatum and in the cingulate gyrus. This was better seen with PiB than with a Aß45. This is important for the field to know. I also think it's important to realize that the placebo increases in amyloid are the same with both tracers, so there's something about the therapeutic effect that different.
The other observation that was reported was about ARIA (amyloid-related imaging abnormalities). Familial Alzheimer disease is largely like sporadic Alzheimer disease, but it's different in that a monogenic disorder can really drive amyloid production and drive the onset and progression of the disease. ARIA was seen as we expected it to be seen in that study. There was 1 patient on solanezumab who had ARIA and 10 patients on gantenerumab. We don't talk about the 1 patient on solanezumab because we don't want to unmask that subject, but with the gantenerumab patients who experienced ARIA, we learned a lot. We learned that APOE4 increases the risk in familial AD, as it does in sporadic AD. We learned that it doesn't last long, about 10 weeks; that it's mostly asymptomatic; that when it occurs, it often occurs in the occipital lobes and that it's often associated with ARIA-H; and, really importantly, whether or not the patient had ARIA-E did not affect the amyloid-lowering result of the drug. Amyloid went down whether you got ARIA or not.
What should the physician communities pay attention to as DIAN-TU continues to provide insights? Were there other insights that you're planning on implementing for future assessments of this therapy?
The DIAN studies are sort of a world unto themselves. These are people whose disease is driven by mutation and amyloid production. We are currently continuing to study patients who were in the DIAN-001 study (NCT01760005), either those on solanezumab or those on gantenerumab have all now been offered an exploratory experimental, open-label extension with gantenerumab. We'll continue to see what happens to these biomarkers over time.
This is very important. Some things can be generalized from familial to sporadic or vice versa. Perhaps some not as well, we'll have to see. We're also talking about additional trials in the DIAN-002 study, the possibility of prevention and introducing gantenerumab quite early. Our modeling is based on the study that's already taken place and would suggest that gantenerumab would likely reduce the accumulation of amyloid, as well as lower amyloid once it's already present.
We continue to work on that universe with gantenerumab, but most importantly, we have 2 large, double-blind, placebo-controlled global trials running in parallel that should replicate each other that we'll read out next year. Those will tell us whether in sporadic Alzheimer disease—patients who are prodromal to mild, or in other words, early AD—are benefited by gantenerumab. We think that this is incredibly, incredibly important, both to the familial population and to the sporadic patients as well.
What was found regarding the tau biomarker data from the phase 2 TAURIEL study of semorinemab?
This is another example of Roche and Genentech using our clinical trial data to try and advance the field. We often wonder what's the difference between using CSF measures of tau and Aß, versus PET. We did some correlations between GTP1 PET reflections of tau and CSF—and to some extent, plasma biomarkers of tau—in a small number of patients who participated in the semorinemab trial. What we found is that GTP1 does correlate with most of the tau biomarkers, even plasma, but the correlations are best with P-tau217. This is convergent with other data from other populations and other researchers, but it's important to get replicable results and perspectives. We found that there's really a very good, high level of correlation and sensitivity and specificity of P-tau217 for predicting elevated tau in the brain, in the 0.8+ range. This is important information because someday we would like to be using one or the other biomarker, and we might even get lucky and be able to use plasma biomarkers as those assays improve, and we and others are working on that.
Is there anything else that you wanted to note?
One other presentation, specifically, at AAIC was about our GRADUATE study (NCT03443973). I think it's worth mentioning that, even though we are currently the only subcutaneous monoclonal antibody directed against Aß, we want to really explore what works for people. This study is using biomarkers—amyloid reduction on PET imaging—to determine whether we could give the drug on a weekly regimen. For some people, it's probably easier to do something every week than it is to do it on any alternative, less-frequent schedule. This is a creative approach. We're looking forward to the comparisons of amyloid lowering and pharmacokinetic/pharmacodynamic, and to the feasibility of caregivers giving this medication at home on a weekly basis.
In the broader picture, I think it's really important to realize how much is going on in Alzheimer in our organization. In addition to late-stage, phase 3 investigations with gantenerumab in sporadic AD, we do have this very active program with our collaborators at Washington University in familial AD.
Our API Generation study with our collaborators at Banner Health and Colombia University is still ongoing, with crenezumab, which was given in that study so early that, in fact, half the patients didn't even have amyloid in the brain. We still have a readout coming sometime in a year or so that will tell us whether that made a difference. The commitment is there for both the familial and sporadic AD, we have a brain shuttle version of gantenerumab in phase 2, which gets considerably more antibody into the brain—a problem for every antibody, no matter how it's given—and we have earlier-stage drugs with other targets. We do have a very broad commitment in Alzheimer disease, not only in diagnostics but also in pharmaceuticals.
Transcript edited for clarity.
