This was my first time at the Clinical Trials in Alzheimer ’s disease (CTAD) conference and I found it an excellent way to get up to speed with global progress in Alzheimer’s treatment development. The majority of talks focused on the search for treatments that can slow down the disease pathology. But there is also an ongoing effort to improve symptomatic treatments, such as those to reduce agitation and aggression to help people with dementia and their families live better with the condition.
In the search to identify the first disease modifying treatment, research efforts are moving to test treatments earlier in the disease process, either intervening at the mild cognitive impairment stage (commonly referred to as prodromal Alzheimer’s) or even earlier in the preclinical stages before any cognitive symptoms can be detected. As you might expect, industry representatives featured prominently on the conference agenda, but encouragingly there were also a large number of academic groups and public-private partnerships presenting their work.
Getting the negatives out of the way
Day one of CTAD 2015 started with discussion of a number of failed or futile trial results. Some of these we knew were coming, such as Roche’s Scarlet RoAD trial of gantenerumab which was terminated last December after an interim futility analysis, and some were findings being presented for the first time.
Sembragilline, also from Roche, failed to show any cognitive benefits in a phase 2 trial of people in the moderate stages of Alzheimer’s disease. There were hints that it may help to reduce the development of behavioural problems but as the MAyflOwer RoAD study was not designed to test this outcome, the findings would need to be reproduced.
The Alzheimer’s Disease Cooperative NGF Study was a tour de force, testing vector delivery of the gene for Nerve Growth Factor directly into the brain of people with mild to moderate Alzheimer’s disease using a blinded, sham surgery controlled Phase 2 trial design. Unfortunately the intervention failed to show any cognitive benefits, as did a trial of the diabetes drug Metformin in mild cognitive impairment and early Alzheimer’s conducted by Penn Memory Centre.
Hints of efficacy from Biogen
To help us avoid the temptation of the Barcelona sunshine, the conference organisers designed the agenda to get progressively more positive as the days progressed. We saw encouraging data from the PRIME study, a Phase 1b of Biogen’s anti-amyloid antibody aducanumab. Looking at just the participants with very early Alzheimer’s disease (MMSE 24-30), they observed a dose-dependant reduction in brain amyloid burden using PET imaging. Although this study was only designed to test safety, there was a significant reduction in cognitive decline (on the CDR sum of boxes test) relative to controls over 52 weeks. This new post-hoc analysis is representative of the patient group currently being recruited into the company’s Phase 3 testing programme.
Non-pharmacological interventions
Two large studies testing multidomain lifestyle interventions presented encouraging cognitive data. The ongoing FINGER study from Finland has previously reported improved cognition in an at-risk elderly population using a combination of physical activity, cognitive training, nutritional guidance and vascular health monitoring. The new data presented showed that those who took part in the intervention were at a 30% reduced risk of experiencing cognitive decline over 2 years compared to the control group who received 10 sessions of general health advice. Relative to the control group, over the two years the intervention group saw a 150% increase in processing speed, an 80% increase in executive function, a 40% increase in memory and a 50% reduction in the likelihood of developing a functional impairment, as determined by performance on the Activities of Daily Living scale.
The Multidomain Alzheimer Prevention (MAPT) Study from France has tested a similar multidomain intervention either with or without omega-3 supplements in 1680 70+ year olds living in the community. Presenting their final results for the first time, Bruno Vellas reported an increase in brain glucose metabolism and prevention of cognitive decline over 3 years in those who participated in the lifestyle intervention compared to the control group. Given how intensive the programme was, a compliance of 71% in this older, at risk population is very encouraging for the possible delivery of such interventions in the population at large. Omega-3 supplements had no effect overall in this study, but a subgroup analysis found that those with low baseline levels needed to have this corrected with supplements if they were to benefit from the lifestyle intervention.
Based on the promising results of these studies and others, the MIND-AD project is now aiming to test a similar multidomain intervention in 10,000 people across Europe with funding from JPND.
Addressing future challenges
Throughout the three days, the plenary speakers gave impressive overviews of major advances and challenges facing the field. There was a key focus on finding disease markers, both that can be used to identify people at risk or in the preclinical stages of Alzheimer’s, or to track disease progression. Simon Lovestone kicked off day one discussing the potential for blood based protein biomarkers to select people most suitable for clinical trials but he acknowledged that we have not yet identified the right set of proteins.
Marilyn Albert presented data from the 20 year long BIOCARD study showing that a composite biomarker panel in healthy middle aged people could predict those that would develop mild cognitive impairment or Alzheimer’s disease within 5 years. The score included ApoE genotype, levels of beta-amyloid and tau in the cerebral spinal fluid, structural MRI measures and performance on a number of cognitive tests. The specificity and sensitivity scores were high for a relatively small group (n=349) but the team are now looking to collaborate with other longitudinal cohorts to increase their power.
Roche’s Scarlet RoAD study demonstrated the value of enriching a trial population for those at greater risk of cognitive impairment using amyloid PET imaging. Twenty percent of participants developed dementia over 2 years compared to an average of 5% in earlier studies without such screening.
One of the conference highlights for me (other than the superb squid ink croquetas at lunch) was a brief history of industry involvement in Alzheimer’s disease treatment development by Eric Siemens from Eli Lilly. He went through the last decade of pharma-led trials in Alzheimer’s disease discussing the 13 compounds that have reached phase 2 or 3 testing and the reasons why we believed they failed. Although he outlined some current, promising trials that are due to report in the next few years, he stressed that the time taken to conduct these trials is far too long. Stating slow patient recruitment as a significant barrier to dementia trials, he nodded to recent efforts to streamline recruitment through patient registries (such as TrialMatch in the US and Join dementia research in the UK) but urged the community to make participating in research a key offering for people with early memory complaints.
So after an intense few days of p-values, numerous sightings of the famed ‘Jack curve’ and some delicious food, I headed back to the UK feeling pleasantly optimistic about what I’d seen and heard. While there was a large number of trial failures presented, we are starting to see hints of disease modification in exploratory studies that I hope will be born out in Phase 3 trials over the coming few years. There are some major challenges in dementia trial recruitment methodology that need to be addressed but the community seems determined to solve them.
Clare Walton
Alzheimer’s Society (UK)
