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.
Achievements & News
When it comes to Alzheimer’s disease (AD), most potential drug candidates fail during clinical trials, resulting in significant setbacks in the development of effective treatments. IMI’s Pharma-Cog project set out to change that.### The project developed a matrix of biomarkers which can be used to study the effect of a drug candidate both in animals and humans, and has the potential to more accurately predict the success of future drugs in early stages of drug development. Pharma-Cog scientists also found a better way to stratify patients with early signs of Alzheimer’s disease, which may lead to more definitive clinical trials. All this has the potential to help pharmaceutical companies conduct more efficient and more precise clinical trials in the future, speeding up the development of AD drugs. At least one biotech company is already using the results of Pharma-Cog to test a promising new drug candidate. ‘We have attracted an SME which didn’t take part in our project’, explained scientific coordinator Régis Bordet, in an interview with the IMI Programme Office. ‘They saw the results of Pharma-Cog and they asked me to help them develop their compound which could be very interesting for AD treatment. The project is worth 3 million euros and has received support from the French government. By early 2019 we will know whether there is a sizeable effect of this compound on Alzheimer’s, and whether it is worth pursuing further in a clinical trial. Thanks to this cooperation, we will have a real-life demonstration that we have done in Pharma-Cog is useful for the development of new compounds for AD patients.’
IMI’s Alzheimer’s disease project PharmaCog has completed the recruitment of 150 patients with mild cognitive impairment for a clinical trial of a matrix of biomarkers.### The human and financial costs of Alzheimer’s disease are growing rapidly as the population ages, but the results of recent clinical trials for Alzheimer’s drugs have been disappointing. The main reason for the failure of these trials is a lack of demonstration of significant efficacy.
The working hypothesis of PharmaCog is that no single physiological, functional or biochemical marker will be sensitive enough to respond to a drug sufficiently to provide the confidence to progress to later clinical phase studies, but that a collection of markers will be necessary. With this in mind, the project is working to develop a biomarker matrix to track disease progression in patients with Alzheimer’s disease and patients with mild cognitive impairment as a novel tool to detect the efficacy of treatments.
PharmaCog’s matrix is a unique tool for the study of Alzheimer’s disease and potential treatments, as it can be applied to laboratory models, human volunteers and patients. By achieving this latest recruitment goal, PharmaCog is on track to test and reach conclusions on the value of the matrix as a tool for tracking disease progression in people with mild cognitive impairment.
IMI project PharmaCog presented some of its key findings at the European Parliament during a lunch hosted by French parliamentarians Françoise Grossetete and Elisabeth Morin-Chartier.### The 40 guests, including 7 Members of the European Parliament (MEPs) learnt about how the PharmaCog project is helping to speed up the discovery of drugs for Alzheimer’s disease. PharmaCog is developing new tools to identify potential drugs (and screen out ineffective ones) early in the drug development process. The project is also working on tests to determine how well a drug is working in individual patients, e.g. through brain scans, blood tests, and cognitive testing.
ParticipantsShow participants on map
- Astrazeneca AB, Södertälje, Sweden
- Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
- Eisai Limited, Hatfield, United Kingdom
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
- H. Lundbeck As, Valby, Denmark
- Institut De Recherches Servier, Suresnes, France
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Merck Kommanditgesellschaft Auf Aktien, Darmstadt, Germany
- Novartis Pharma AG, Basel, Switzerland
- UCB Pharma SA, Brussels, Belgium
Universities, research organisations, public bodies, non-profit groups
- Centre National De La Recherche Scientifique Cnrs, Paris, France
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain
- Fondazione Sdn Per La Ricerca E L'Alta Formazione In Diagnostica Nucleare, Napoli, Italy
- Institut National De La Sante Et De La Recherche Medicale, Paris, France
- Istituto Di Ricerche Farmacologiche Mario Negri, Milano, Italy
- Provincia Lombardo Veneta - Ordineospedaliero Di San Giovanni Di Dio- Fatebenefratelli, Brescia, Italy
- Stichting Vu, Amsterdam, Netherlands
- The University Of Exeter, Exeter, United Kingdom
- Universidad De Murcia, Murcia, Spain
- Universita Cattolica Del Sacro Cuore, Milan, Italy
- Universita Degli Studi Di Foggia, Foggia , Italy
- Universita Degli Studi Di Genova, Genova, Italy
- Universita Degli Studi Di Perugia, Perugia, Italy
- Universita Degli Studi Di Verona, Verona, Italy
- Universitaet Leipzig, Leipzig, Germany
- Universitaetsklinikum Essen, Essen, Germany
- Universite D'Aix Marseille, Marseille, France
- Universite De Lille Ii - Droit Et Sante, Lille, France
Small and medium-sized enterprises (SMEs)
- Diaxonhit SA, Paris, France
- Innovative Concepts in Drug Development (ICDD-sas), Meyreuil, France
- Qualissima, Marseille, France
- SAS Alzprotect, Loos, France
- Alzheimer Europe, Luxembourg, Luxembourg
- Elliniki Etairia Nosoy Alzheimer Kai Syggenon Diatarachon Somateio, Thessaloniki, Greece
- Centre Hospitalier Regional De Marseille Assistance Publique-Hopitaux Marseille, Marseille, France
- Centre Hospitalier Regional Et Universitaire De Lille, Lille, France
- Museum National D'Histoire Naturelle, Paris, France
- Universite Paul Sabatier Toulouse Iii, Toulouse, France
|Name||IHI funding in €|
|Alzheimer Europe||100 000|
|Centre National De La Recherche Scientifique Cnrs||205 000|
|Consorci Institut D'Investigacions Biomediques August Pi I Sunyer||560 973|
|Diaxonhit SA||259 677|
|Elliniki Etairia Nosoy Alzheimer Kai Syggenon Diatarachon Somateio||205 519|
|Fondazione Sdn Per La Ricerca E L'Alta Formazione In Diagnostica Nucleare||62 393|
|Innovative Concepts in Drug Development (ICDD-sas)||298 423|
|Innovative Health Diagnostics (left the project)||121 100|
|Institut National De La Sante Et De La Recherche Medicale||1 010 591|
|Istituto Di Ricerche Farmacologiche Mario Negri||549 000|
|Provincia Lombardo Veneta - Ordineospedaliero Di San Giovanni Di Dio- Fatebenefratelli||767 507|
|SAS Alzprotect||304 377|
|Stichting Vu||44 000|
|Universidad De Murcia||300 000|
|Universita Cattolica Del Sacro Cuore||62 400|
|Universita Degli Studi Di Foggia||448 496|
|Universita Degli Studi Di Genova||176 597|
|Universita Degli Studi Di Perugia||304 400|
|Universita Degli Studi Di Verona||360 000|
|Universitaet Leipzig||176 715|
|Universitaetsklinikum Essen||70 748|
|Universite D'Aix Marseille||1 658 892|
|Universite De Lille Ii - Droit Et Sante||1 066 828|
|Total Cost||9 658 388|