Throughout the Alzheimer's and Parkinson's Disease (AD/PD) Congress 2017, there were a number of recurring topics providing insight into the current and future focus of Alzheimer's disease (AD) research and development (R&D) efforts.
In particular, consultant to multiple pharmaceutical companies including Eli Lilly and Eisai Jeffrey Cummings claims that we are in the pre-combination era, where we will soon be studying combinations of drug classes. This shift in the way we conceptualise the future AD treatment arises from the fact that many large trials have recently failed due to lack of efficacy, which could indicate that it is unlikely that a single drug will ever achieve a high enough effect on the brain to improve patient's cognition considerably.
For instance, future trials may test a monoclonal antibody drug (such as Biogen's aducanumab) against a BACE-1 inhibitor drug (such as Merck's verubecestat) to test whether the combinatory effect is superior to the effect of the current investigational drugs as monotherapy. However, such a paradigm shift depends on first finding a drug compound with sufficient efficacy and mechanism of action based on clear scientific rationale and second the current challenges being met.
A number of prevailing challenges exist. Possible solutions were presented by a number of lead researchers and industry executives in an industry symposia and forum discussion:
Challenge 1: A number of biomarkers have become available such as b-Amyloid, total tau, and phosphorylated tau in cerebrospinal fluid, but it is still unclear which biomarkers should be used for what purpose.
Possible solution: Gain further understanding into the pathway through which proteins such as tau and b-amyloid cause AD so that we know what the biomarker correlates with, for example, neuro-inflammation, AD-specific pathology, andneuronal damage.
In addition, include imaging biomarkers such as tau positron emission tomography (PET) and cognitive tests such as visuo-spatial tests during patient enrollment to test the validity of these tools alongside the investigational drugs.
Challenge 2: We have recently seen consecutive late-phase failures due to insufficient effect sizes on the cognitive performance of AD patients.
Possible solution: Identify a patient group where the drug is effective (for example, amyloid-targeting drugs should be studied in prodromal or mild cognitive impairment (MCI) patients). In addition, incorporating more objective endpoints such as electroencephalogram and magnetic resonance imaging endpoints in clinical trials is likely to aid in detecting therapeutic effect.
Challenge 3: There is a lack of Phase I drugs in the pipeline and it is unclear what other targets remain to be tested.
Possible solution: Repurposing of currently marketed drugs should be explored. AD has been found to have links to multiple metabolic pathways, which suggests that treatments currently used in metabolic conditions may be useful in mitigating AD-associated symptoms.
Challenge 4: There are no animal models for AD, making it difficult to translate findings from animal studies into clinical studies.
Possible solution: Facilitate more discussion on what models can be used (such as primates) and what ethical challenges exist.
Success in addressing these urgent problems will be key to finding a drug or combination of drugs that can eventually reverse or slow the progress of AD.