The 2 anti-Aβ monoclonal antibodies, in treatment for Alzheimer disease, are currently being tested in 2 phase III trials.
Geoff Kerchner, MD, PhD
Geoff Kerchner, MD, PhD, senior medical director of neuroscience, Genentech, sat with NeurologyLive at the 2018 Alzheimer’s Association International Conference in Chicago, Illinois, to talk about 2 investigational anti-Aβ monoclonal antibodies being studied for treatment of early Alzheimer disease: gantenerumab and crenezumab. Currently, both gantenerumab and crenezumab are under evaluation in 2 phase III studies, GRADUATE 1 and 2, and CREAD 1 and 2, respectively.
The GRADUATE studies aim to recruit up to 750 patients with early-stage Alzheimer disease to evaluate the efficacy and safety of gantenerumab. Subjects will receive either subcutaneous injection gantenerumab or placebo for 2 years, followed by an optional 50-week open-label extension study. Subjects will receive doses about 5 times higher than that in the Marguerite RoAD and Scarlet RoAD studies.
The CREAD studies, currently ongoing, aim to evaluate the safety and efficacy of crenezumab versus placebo in 813 recruited participants with prodromal to mild Alzheimer disease. Subjects will be randomized to receive either intravenous infusion of crenezumab or placebo every 4 weeks for 100 weeks. The final efficacy and safety assessment will be performed 52 weeks after the last dose.
Geoff Kerchner, MD, PhD: Gantenerumab is an investigational antibody against beta-amyloid. It’s actually 1 of 2 investigational antibodies against beta-amyloid that we’re developing as a company, the other one’s called crenezumab. Why are we developing 2? These are actually different antibodies targeting different versions of beta-amyloid, and in the case of gantenerumab it binds most strongly to plaques in the brain. And part of what we’re showing here at the conference, based on some prior studies that were run with gantenerumab where patients went on to an open-label extension and were treated for a couple of years with this drug.
We were able to show evidence that gantenerumab was able to lower amyloid plaque levels in the brain. As many as half of the people exposed to the drug for a couple of years actually showed complete clearing, so evidence that there was no more detectable plaque in the brain by amyloid PET, and that extends some further findings that we had shown before, showing that in patients treated in as little as 9 months up to 30% of those patients showed a lowering of amyloid plaque levels. So, we’re really excited, because the intended purpose of this antibody is to reduce plaques, and we’ve been able to show that in the data.
GK: SCarlet RoAD and Marguerite RoAD were 2 prior phase III studies that we ran with gantenerumab. Those studies were stopped prematurely because there was evidence they were not going to meet their primary endpoint. At that point we turned those studies into open-labeled extensions to allow patients to continue to receive the drug, and patients receiving placebo switched on to active drug.
Importantly, the studies were stopped not because of any safety concern, but because there wasn’t clear evidence of efficacy and we learned a lot from that experience. We learned that we need to dose higher, so right now the current phase III studies that we have going on we’re dosing at about 5 times the dosing that were given in those prior studies. Based on what we learned and based on those open extension labels that I’ve described, we have really solid evidence that this higher dose is going to be successful in lowering plaque levels in the brain.
GK: The 2 phase III trials for gantenerumab they’re called GRADUATE, they’ve just started so they’re enrolling patients right now and we don’t have exact projections, it depends on a lot of things like when they’re going to read out, but patients will be on double-blind treatment for 2 years.
GK: So, where gantenerumab is targeting the form of beta-amyloid that is in plaques in the brain, crenezumab is targeting the form of beta-amyloid that’s called oligomers. This is a form of beta-amyloid that is dissolved in the fluid that’s inside the cortex of the brain, and there’s been evidence for a lot of years that Aβ oligomers are the toxic form of amyloid, and they exert a lot of negative effects on synapses and probably directly on neurons as well, and so, crenezumab is actually the leading investigational therapy that directly targets that toxic form of Aβ, and CREAD 1 and 2 are the 2 phase III trials of crenezumab which are both fully enrolled now. It will take a couple of years for the double-blind portion of that study to be over and for us to get a readout.
GK: I think this is one of the most exciting times to be in Alzheimer disease therapeutic research. We’re standing on the foundation of a lot of years, of a lot of clinical trials, that have given us a lot of important insights into the biology of Alzheimer disease and also how therapies, especially therapies targeting beta-amyloids, how they work. We’ve learned things like you have to dose high with these antibodies in order to get a therapeutic effect. We’ve learned you have to target patients that are in the earlier stages of their illness, we call this the prodromal stages or mild cognitive impairment stages of Alzheimer disease and mild dementia. Treating at a high dose and treating early are critical and we’ve also learned about the really important use of biomarkers to characterize our patients, to understand how our therapies are targeting the molecular targets they’re aimed to go for in the brain, and so, we’re standing on this wealth of knowledge and that has helped us to improve the design of our clinical trials, to maximize the chances that we can show benefit for patients. I still treat patients in a memory clinic, and I’m tired of having to tell them we don’t really have anything that could help you, and I’m really optimistic, again, I think it’s an exciting time in the field and I’m hoping among the therapies that are in trials now, hopefully, some of them will end up succeeding and we can change what we tell our patients.
GK: The entire field of Alzheimer disease is challenging, it’s a complex chronic illness and there are a lot of factors in the disease besides just beta-amyloid, we’re standing on the foundation of many years of deep basic science and also clinical science investigation on the biology of the illness. We still have a lot to learn and I think we have therapies in development that are going to make an important difference, and I also think that there’s a lot of exciting research that’s coming up behind that. As an example, we’re not just developing the 2 anti-amyloid antibodies that I mentioned, crenezumab and gantenerumab, but we also have an antibody targeting tau that’s in a phase II study that just started up a few months ago.
Alzheimer disease is not just defined by the presence of beta-amyloid plaques, but also tau tangles in the brain. Tau the other neuropathology hasn’t been as much of a focus of the field in the past years but more recently has become an increasing area of focus, and we’re excited that we have a therapy in a phase II trial now that targets that.
Transcript has been edited for clarity.