Masterstudiengang "Drug Regulatory Affairs"
Master-Thesis
Development of a New Active Substance for Treatment of Alzheimers Disease Development from Preclinical Testing to Proof-of-Concept ***
Dr. Susanne Manhart (Abschlußjahr: 2009)
Language: English
The successful development of a drug consists of three main exploration areas: chemical-pharmaceutical, preclinical and clinical research. This also applies to the development of a QC inhibitor as a new medication to treat Alzheimers Disease. In general, preclinical and clinical development of a new AD medication follows the approach as for other new chemical entities. Some specific aspects of the conventional development program need to be tailored for the development of the new AD medication considering the particularities of the target organ brain, the elderly patient population to treat and the mechanism of QC inhibition. A specific approach is described in this master thesis.
In the screening phase, compounds were optimised regarding their efficacy (in vitro and in vivo) and their general suitability for development as a new treatment expressed by favourable properties of the molecules regarding their physicochemical characteristics, ADME/PK and safety. Owing to the mechanism of QC inhibition, compounds were examined for their CYP and off-target liability early in the screening cascade. A specific prerequisite for a successful AD medication is the optimisation of compounds to display good blood/brain permeability. Therefore, the determination of the brain penetration potential in combination with unbound drug concentrations in plasma and brain of several animal species were essential screening parameters. The PK data from mouse, rat and monkey in combination with relevant in vitro data were the basis for a human PK prediction to select candidates suitable for once a day dosing in humans.
During exploratory development phase some toxicological, genotoxicity and safety pharmacology studies were frontloaded from the regulatory development phase to estimate general toxicity of selected QC inhibitors.
The preclinical screening process was paralleled by a chemical-pharmaceutical development process evaluating the economy of the synthesis process, up-scalability of potential APIs and formulation feasibility. A key quality aspect for QC inhibitors was the chemical and chiral stability of the selected QC inhibitors.
A specific problem in the preclinical development of a new AD treatment is the availability and relevance of AD related pharmacological animal models to demonstrate the proof-of-concept in animals and to perform pharmacodynamic studies in the foreseen therapeutic application. To overcome the drawbacks of existing animal models, which only reflect aspects of human pathology and show a late onset, the development of new transgenic animal models specifically addressing the formation of pyroGlu-Aß was initiated.
On the basis of the data set resulting from compound screening and exploratory development studies, the clinical candidate will be nominated and the regulatory preclinical development phase begins. During this highly regulated development phase, in-depth understanding of the pharmacodynamic, pharmacokinetic and toxicological characteristics of the clinical candidate is acquired to pursue the planned clinical program.
The clinical program up to proof-of-concept in humans is planned to be covered by three clinical phase I trials. Three phase I trials consisting of the FiM trial in healthy volunteers, a single dose, bioavailability trial in young and elderly volunteers and a multiple dose trial in young and elderly volunteers should give a sound data base to start a phase IIa/POC trial in mild to moderate patients. Specific AD related key aspects in therapeutic clinical trial designs are related to the complexity of the disease and the target organ. Biomarkers from brain homogenate to measure efficacy in transgenic mice cannot directly be adopted into clinical trials due to ethical and practical reasons. To support the POC trial, a biomarker program was initiated to establish progression sensitive biomarkers in plasma and CSF as a complement to imaging techniques like PET and/or MRI. To claim for disease modification, efficacy has to be demonstrated by combination of clinical and biomarker endpoints.
It was the objective of this thesis to suggest a strategy for the development of a new active substance from preclinical testing to proof-of-concept for a new AD treatment. Regulatory requirements and experience from more than two decades of AD drug development provide the framework for a product-specific development approach. It was tried to identify the AD specific hurdles during the compound screening/exploratory development phase and during the preclinical and early clinical development phases. In summary, the development of a new treatment for Alzheimers Disease remains a challenge. The future will show whether the suggested development program is the right program for a new AD modifying medication.
Pages: 81