July was a month of very mixed fortunes for Alzheimer’s disease (AD) compound development. On the positive side EnVivo Pharmaceuticals announced at the Vancouver AAIC event positive effects of their nicotinic alpha 7 compound EVP-6124 (see the slide deck presentation and Dr. Dana Hilt’s press presentation). Nutricia were also at AAIC to present the results of their investigation of Souvenaid, a medical food that has shown positive effects on memory in patients with early AD (see Dr. Philip Scheltens’ AAIC presentation).
Much less encouraging was the news from Pfizer and Janssen AI that Bapineuzumab has not shown positive effects in treating AD. These disappointing results for Bapineuzumab have reignited discussions about the time course of the disease and raised the question of whether intervening in already diagnosed AD is just too late. Consequently the focus of many of the discussions I had in Vancouver were about intervening in at the prodromal stage (secondary prevention), i.e. before patients are diagnosed with AD. Dr. Reisa Sperling described the planned ‘A4’ study and made the point that increases in amyloid are often seen as early as 15 years before the onset of AD (see her presentation).
Although the AAIC meeting is an AD event, in the restaurants and cafes around the convention centre there was much discussion of other neurodegenerative diseases, and particularly Parkinson’s disease (PD). The hallmarks of this disease are the cardinal signs that present as difficulties with movement, including tremor and bradykinesia (slowness of movement). Remedies for PD have tended to focus on the movement component of the disease and it is interesting to note that for many patients one of the most troubling aspects of PD is the cognitive problems they suffer. Dr. Alexander Tröster makes the point that "mild changes may be present as early as the time of diagnosis" and "at any one time about one quarter to one third have mild cognitive impairment (MCI) while another one quarter to one third have dementia" (see here). See also his very informative webcast on this topic.
Cognitive difficulties in PD were the focus of my PhD and I have maintained a strong interest in this area. I have also witnessed a marked recent increase in seeking to remedy these cognitive difficulties with pharmaceuticals. This is hardly a new idea; some years ago Rivastigmine was investigated for rescuing cognitive deficits in PD and showed some improvements on general tests of cognition, tests, reaction time and executive function (see here).
Recent experience of participating in clinical drug trials of new therapies for remedying the signs and symptoms of PD has reminded me just how ‘busy’ these protocols have become. The need to monitor behavioral, psychiatric, cognitive and the myriad other signs and symptoms of PD requires the inclusion of often as many as 20 different scales and measures, placing a significant burden on study teams. Many of the cognitive areas of interest, such as memory and executive function are often measured using traditional ‘paper-and-pencil’ tests, whilst cognitive skills such as attention and psychomotor speed are best indexed using computerised tests such as those employed in the above referenced Rivastigmine trial. Given the number of other assessments in a typical protocol it is tempting to employ computerised versions of the standard scales, such as the UPDRS, Zarit Caregiver Burden, MMSE, etc. Building on the other documented benefits of electronic data capture, this approach can greatly reduce the burden on study staff.
I’m sure that caregivers, patients and clinicians would welcome the development of drugs to remedy the movement difficulties associated with PD. A legacy of current medication is often the emergence of dyskinesia, uncontrolled athetoid and choreic movements. Drugs that remedy tremor and bradykinesia without this unfortunate legacy would doubtless be welcomed. It is tempting to suppose that patients free of the burden of tremor, dyskinesia and difficulties with initiating movement would be better able to focus on remembering things, concentrating and problem solving, so whilst new compounds might not have ‘direct’ effects on cognition, the control of movement difficulties might well be reflected as benefits to cognition.
It would be nice to see the development of drugs to rescue the cognitive consequences of PD. License extensions of drugs such as Rivastigmine are of course important, but new therapies targeted on the often distinctive cognitive deficits seen in patients with PD would be very welcome. Current EMA guidance notes for PD drug developers refer to the current guidance notes for AD and other dementias for advice regarding the assessment of cognition. However, specific assessments based on tests known to be sensitive to cognitive deficits in PD, with links to the pathological neural substrates of the disease, seem a more satisfying approach. One possible solution is to employ a similar assessment to that used in a recent trial of a gene therapy for PD. Interestingly, the concern in this trial was primarily cognitive safety, but the same measures would likely function just as well as measures of efficacy.
Rescuing cognitive impairments in a variety of neurological and psychiatric disorders is an area of clear unmet need. Current treatments for PD focus on the movement disorder component of the disease and the development of compounds designed to rescue the cognitive components of the disorder would surely be welcomed by patients, caregivers and healthcare professionals alike. Hopefully we can bring the same level of sophistication to cognition measurement and trial conduct as we do to the search for new treatments.
John Harrison, PhD
Scientific Consultant, CRF Health