A challenging disease
Over 4 million Europeans suffer from Alzheimer’s disease (AD), and the cost of the disease in the EU amounted to more than 100 billion in 2008. Currently approved drugs for patients with Alzheimer's disease only treat symptoms (symptomatic approach) and their effect is limited or absent in many patients. No drugs have been approved yet that can actually slow the progression of the disease (disease modifying approach). Trials with candidate drugs take years and cost tens of millions of euros. Furthermore, a number of AD drugs which showed promise in the laboratory didn’t translate into success in the clinic, resulting in a high number of costly drug failures.
The Pharma-Cog project aimed to develop and validate new tools to test candidate drugs for the treatment of symptoms and disease in a faster and more sensitive way. By bringing together results from blood tests, electroencephalography (EEG) recording of brain activity, magnetic resonance imaging (MRI) scans, and behavioural tests, the scientists set out to develop a more comprehensive matrix of clues (biomarkers) that may give more accurate information on the progression of the disease and the effect of candidate drugs than current approaches. The project worked in three core areas: preclinical work with animal models; experimental medicine work involving healthy volunteers that undergo a challenge, such as sleep deprivation; and patients with mild cognitive impairment (MCI), an early sign of Alzheimer’s.
Improving translatability between animals, healthy volunteers and patients
In order to find biomarkers which could help predict the effectiveness of a new drug candidate in the early stages of drug development, Pharma-Cog scientists measured the effect of known Alzheimer’s drugs in all three core areas above. By cross-checking the results, they identified and validated a matrix of biomarkers, such as EEG recordings of brain activity and MRI scans, which could help predict the effect of drugs more accurately. For example, they demonstrated that some changes in the rhythm of brain activity observed via EEG are a good marker to detect the effect of a new drug in early studies involving both human and animal models. This important discovery could help pharmaceutical companies make better decisions on which drugs are worth pursuing in clinical trials, and do this much earlier, before starting the more costly studies in patients. A French biotechnology small and medium-sized enterprise (SME) is already using some of these findings to evaluate a promising new AD drug candidate.
Improving stratification of patients
An important part of the project was a study involving more than 150 patients with MCI. MCI is one of the early signs of Alzheimer’s but not all patients who have it will go on to develop the disease. In clinical studies involving MCI patients, the effect of a potential drug candidate can be masked by this variability among patients.
By monitoring a group of MCI patients over a longer period of time, and taking measurements such as EEG readings, MRI scans and blood tests, Pharma-Cog scientists were able to identify a set of biomarkers which signal whether a patient is likely to progress to Alzheimer’s or not. This important discovery has the potential to improve the stratification of AD patients in future clinical trials, making it more sensitive and effective.
In addition to improving translatability between animal and human studies, and improving the stratification of patients, the project recorded a number of other achievements, including:
- Reconciling the symptomatic and disease modifying approaches to AD therapy, and highlighting the need for improved symptomatic drugs despite the emphasis on disease modification.
- Building a large database which contains data on the effect of AD drugs on a matrix of biomarkers. As some studies are still ongoing, this database is currently open to only Pharma-Cog partners, but it will eventually be opened up to other researchers.
- Demonstration that healthy humans and animals who have been sleep-deprived for one night show some of the same changes in brain activity as AD patients, and can be used in early studies to predict the effectiveness of new drug candidates.
- Thanks to Pharma-Cog, a French SME was able to validate a diagnostic kit for AD, which they had developed before the project. The kit contains inflammatory proteins which show correlation with the worsening of the disease. A patent application is pending.
- As the European Medicines Agency was a full partner in the project, the findings could have an impact on the revision of EMA guidelines on medicines for Alzheimer’s. Discussions with the agency are still ongoing.
- Strengthening collaboration between key players in the Alzheimer’s disease field, including industry, academia and SMEs. The collaboration is continuing and could result in future projects.
For the benefit of industry, academia, and patients
The academic partners benefited from the project by gaining international visibility, strengthening their collaboration with industry and learning more about the drug development process, including the high standards of robustness and rigour of data that industry requires before further investment into novel drugs or technologies. Many publications and communications have also resulted from the project.
The industry also benefited from the collaboration with academia, SMEs and other industry partners. In the long term, the outputs of Pharma-Cog could help pharmaceutical companies make better decisions on which drugs are worth pursuing in clinical trials, saving them money and resources. Additionally, the stratification of patients devised in Pharma-Cog could make clinical trials more sensitive.
But it will be the patients who will benefit the most. Thanks to Pharma-Cog, future clinical trials may require smaller sample sizes and shorter duration, which could speed up the development of new AD drugs for the benefit of patients.
Thanks to the participation of a patient organisation, Alzheimer Europe, as a full partner in the project, Pharma-Cog also enabled patients to gain a better understanding of the drug development process and the challenges of predicting the safety and efficacy of new molecules.
Even though the project has officially ended, several studies are still ongoing and further publications are anticipated. Furthermore, some of the partners within the project are continuing to collaborate and apply for new projects.