Small steps towards effective treatments in neurodegenerative disorders

‘We need to move forward step by step in developing treatments for neurodegenerative diseases,' says Dr Philip Kremer, Research Director Neurology. 'By learning both from successes and failures, we will eventually develop effective treatments.'

Using innovative approaches in collaboration with the Immunology group, the Neurology group can often gain valuable information about target engagement in early clinical studies. Kremer and his team studied for example a drug for the treatment of amyotrophic lateral sclerosis (ALS). In healthy participants, they demonstrated target engagement. Unfortunately, however, a plateau occurred in the pharmacodynamic effect. 'Above a certain concentration, the desired effect did not increase, while we did see evidence of side effects in the liver. So our conclusion is that the molecule does what it is supposed to do, but just not enough. Based on this information, the sponsor can go back to the drawing board to design an improved molecule.'

Target engagement was also demonstrated for a compound developed to inhibit neuroinflammation in conditions such as Alzheimer's disease. Kremer: ‘The compound was a large molecule. It’s always difficult to get such large molecules across the blood-brain barrier. Often, a very high dose is needed to reach sufficient concentrations in the brain. But this compound used a specific transporter to shuttle itself over the blood-brain barrier, increasing CNS exposure.’

The team showed that the drug did indeed have a calming effect on microglia in healthy participants. In the cerebrospinal fluid, they found a decrease in inflammation markers. Unfortunately, further development of this compound had to be halted due to side effects, but according to Kremer, this study still offers hope for future success with this innovative approach to introducing large molecules into the brain.

The first clinical studies can sometimes provide indications of potential success. A good example is the study of an inhibitor of LRRK2, leucine-rich repeat kinase 2, which is a known risk factor for a rare hereditary variant of Parkinson's disease (PD). There are indications that LRRK2 is also involved in the common (idiopathic) variant of PD, so these PD patients may benefit from inhibiting LRRK2.

Among other functions, LRRK2 acts as a kinase: it phosphorylates specific molecules. Animal studies suggest that an overactive kinase function of LRRK2 may play a role in PD. An LRRK2 inhibitor such as the one studied by CHDR therefore may well have beneficial effects in PD patients. The team showed in healthy participants and in PD-patients that the drug can indeed inhibit LRRK2’s kinase function in a dose-dependent manner. Based on these favourable results, the drug's manufacturer decided to start a large phase III study in patients. This clinical trial will show if inhibiting the kinase function of LRRK2 can indeed reduce the progression and/or severity of PD.

Kremer: 'We hope, of course, that this drug will have a therapeutic effect. But even if it does not, that is also valuable knowledge. It may be that another function of LRRK2 is involved in PD. There are drugs in development that remove LRRK2 from the cell, so perhaps these will be the solution. This is a fascinating time in neurology research. There are so many parallel developments, and I’m confident that in the next few years we will see various breakthroughs in the treatment of neurodegenerative diseases.'