The head of the Non-Invasive Brain Stimulation Lab at the Santa Lucia Foundation discussed the phase 2 findings and offered takeaways on rotigotine’s possible place in Alzheimer treatment.
Giacomo Koch, MD, PhD, neurologist, and head, Non-Invasive Brain Stimulation Lab, Santa Lucia Foundation
Giacomo Koch, MD, PhD
This is the first of a 2-part interview. For Part 2, click here.
Recently, phase 2 data were published suggesting that rotigotine (Neupro; UCB pharma), a dopaminergic agonist, may be able to improve frontal cognitive function and activities of daily living for patients with mild to moderate Alzheimer disease.
Although the agent showed no significant effects on memory and other cognitive tasks, the results of the randomized clinical trial—Effects of Dopaminergic Therapy in Patients with Alzheimer's Disease (DOPAD)—hold some promise for the therapy, particularly in the sense of a possible combination approach to treating Alzheimer.
The data showed that the application of a 2-mg transdermal rotigotine patch for 1 week and a 4-mg patch for 23 weeks (n = 47) was associated with an estimated mean change in Alzheimer Disease Cooperative Study—Activities of Daily Living score of −3.32 (95% CI, −4.02 to −2.62) compared with a change of −7.24 (95% CI, −7.84 to −6.64; P = 0.4) for placebo (n = 47). As well, Frontal Assessment Battery score changes were significantly favorable for rotigotine (0.48; 95% CI, 0.31 to 0.65) compared to placebo (−0.66; 95% CI, −0.80 to −0.52; P = 0.2).
The study was conducted by Giacomo Koch, MD, PhD, neurologist, and head, Non-Invasive Brain Stimulation Lab, Santa Lucia Foundation. To find out more about how the work came to be and what the findings might suggest for clinicians, NeurologyLive inquired with Koch.
Giacomo Koch, MD, PhD: Actually, it is quite a long story. We started almost 10 years ago by evaluating the effects of dopaminergic agonists on cortical activity in patients with Alzheimer's disease. This series of neurophysiological studies were actually based on previous neuropathological observation showing that in Alzheimer's disease, there is a remarkable reduction of dopaminergic receptors across the cerebral cortex. Not only in the temporal lobe, but remarkably in the prefrontal cortex, for instance.
Therefore, we decided to systematically investigate the effects of dopamine and dopaminergic agonists. Namely, we were waiting first the effects on central cholinergic transmissions by means of specific neurophysiological tools such as transcranial magnetic stimulation. We published a paper in 2009, in which we show that a single dose of dopamine was able to restore cholinergic transmission in the brain, which was interesting at the time. Then, we sort of extended this observation by investigating the effects not only on cholinergic transmission, but also on cortical plasticity—long-term potentiation— which is an important marker of memory and learning in cortical function.
We found in another paper that we published a few years ago that actually not only dopamine, but also rotigotine, which is a dopaminergic agonist, was able to enhance cortical plasticity, while actually cholinesterase inhibitors were not. This was something rather specific and this is before because actually dopamine and the dopaminergic system is the strongest modulator of long-term plasticity in the brain. On the basis of this evidence, we applied for grants and luckily, we have the opportunity to work with the Alzheimer’s Drug Discovery Foundation, and we set up a phase 2 clinical trial in order to see whether these neurophysiological effects could also have a clinical impact.
What we found in this clinical trial was that there were some important effects in terms of improving the activity of the frontal cortex, and this was measured by different specific battery of tests for frontal lobe activity—cognitive activity—and it was also supported by neurophysiological examination combining transcranial magnetic stimulation with electroencephalography. At the same time, this improvement of frontal lobe cognitive function was also a combined by an improvement in the activities of daily living, so these patients compared to patients with placebo, after 6 months, were more independent, which was important.
On the other end, the primary outcome of the study was not met because we didn't find any effect on general cognitive function, including memory, which is the usually the primary outcome in these studies’ performance in Alzheimer disease patients. Although, I must say that our background and our hypothesis was clearly directed towards the frontal lobe activity, but we decided to put the ADAS-Cog and the general cognitive function as primary outcome in order to be aligned with other clinical trials.
We think that take-home message here is that by using a combination—because actually, this was an add-on study, so all patients were taking rivastigmine, which is the most very common drug in patients with Alzheimer's disease. Our idea is that while the inhibitor against cholinesterase increased cholinergic activity and mainly involves the temporal lobe activity, here, we try to add another small piece of evidence suggesting that combining different neurotransmission systems may be efficient in improving different cognitive function.
The key issue is that when Alzheimer's disease is evident, not only in the early phase, but we investigate patients with mild to moderate some disease—when the disease is manifested. It is not only limited to the memory system, but involves, broadly, other cognitive functions.
We have some interesting interactions with the APOE4 genotype, but we didn't publish the data because the sample size was not sufficient to fully support the hypothesis. But there is something that it's really important, suggesting that the dopaminergic drugs may be more effective in patients with APOE4 genotype. That's something that will need to be explored further in future studies.
We are deciding where to go because there are several interesting pathways that we need to be exploring. First of all, as I mentioned, we would like to better understand who are the patients that could benefit from this specific treatment—for instance, the APOE genotype could be a serious variable.
Moreover, we would be very interested in in observing what happens if we used this drug early in the disease, during mild cognitive impairment or even preclinical or prodromal Alzheimer disease. Our idea is that the dopaminergic system is improving and is involved in cortical plasticity, and if you increase the level of cortical plasticity since the beginning of the disease, maybe this could be transferred into a delay of the onset of dementia. That's also another interesting new policy we would like to work on.
Transcript edited for clarity.
Koch G, Motta C, Bonni S, et al. Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease: A Randomized Clinical Trial. JAMA Netw Open. 2020;3(7):e2010372. doi: 10.1001/jamanetworkopen.2020.10372.