German biotech Probiodrug is hoping its lead candidate can make a difference in this notoriously tough disease area. We asked CEO Konrad Glund what the future might hold for Alzheimer’s treatment

What is the company’s background?

Probiodrug is a German biotech, founded in 1997 by Hans-Ulrich Demuth and Konrad Glund as an academic spin-out – so it’s more than 20 years old now. Our first programme was in diabetes.

What is the company’s background?

The scientific emphasis of the team was always on  posttranslational peptide modifications involved in diseases paired with scientific curiosity. Analysis of senile plaques in the brain revealed that, besides normal amyloid beta (Abeta), they contain shortened and modified Abeta forms among which pyroglutamate Abeta (pGlu-Abeta) was a prominent proportion. We wanted to find out  how this chemically unfavoured modification was  brought about.

We discovered and characterised the enzyme that forms it, called glutaminylcyclase (QC), which led to two questions – does the modified Abeta have something to do with Alzheimer’s disease, and if you have the enzyme that makes the modification, could you stop the formation by inhibiting that enzyme?

Probiodrug has done a lot of research work on the modified Abeta showing that it is indeed involved in the initiation and progression of Alzheimer’s pathology.

The key negative impact of pGlu-Abeta is its feature to force Abeta molecules to cling together forming soluble aggregates, so-called oligomers, which are highly toxic to synapses, the contact points between nerve cells and the basis of cognitive skills. The unique, innovative concept of inhibiting QC activity and thereby the production of pGlu-Abeta has been validated in comprehensive preclinical studies.

Our small molecule inhibitor developed in-house from identification, characterisation down to the current stage of preparing phase IIb. We recently completed a phase IIa (SAPHIR) clinical trial with PQ912 and obtained highly encouraging results in Alzheimer’s patients, which are in line with our unprecedented concept.

The company has also a monoclonal antibody (PBD-C06, preclinical stage) that binds specifically to pGlu-Abeta and promotes its removal. So the aim is to lower this toxic Abeta by two means – firstly by preventing formation with the small molecule inhibitor of the enzyme, and secondly by binding and removing it with the antibody. We were financed by a strong venture consortium until 2014, and we then went public in October 2014.

We are first in class with the small molecule, and we are second to Eli Lilly with this kind of antibody. Lilly’s drug is currently in clinical trials.

There have been many failures in Alzheimer’s drug development across the industry. What have you learnt from them? Do you hope to be an exception?

Though painful and costly, the lessons learned from these failures and the progress made in the field have been enormous – for example the diagnosis of stage of the disease, inclusion criteria for clinical studies, cognitive and functional measurements, the importance of biomarkers etc.

All that knowledge was put into the design of Probiodrug’s first patient trial in which a high dose of PQ912 (a high QC inhibitor) was used to find early-on tolerability and first signals of exploratory outcome measures during a relatively short (3 months) treatment duration.

With respect to the secondary exploratory endpoints, PQ912 showed a very strong target engagement (QC inhibition) as measured in the spinal fluid.

Regarding exploratory biomarkers in the spinal fluid, encouraging positive results on synaptic (neurogranin) and inflammatory (YKL40) CSF markers were obtained. At the functional level a very significant positive effect was found on the EEG theta power.
Applying the neuropsychological test battery, significant improvements of one test of working memory (one back test) and a clear trend in detection test (attention domain) were obtained.

So we have a proof of mechanism and our data strongly support-the hypothesis of pGlu-Abeta being synaptotoxic and the therapeutic concept pursued by Probiodrug. Now we can build on that and go forward.

Are you optimistic for the future of the disease area?

I’m optimistic, yes. With Biogen’s Aducanumab we have seen for the first time efficacy of a disease-modifying Alzheimer’s drug targeting Abeta oligomers which, dose-dependently, was delaying disease progression.

The field has focused mainly on Abeta until now; we know a lot about Abeta which clearly is part of the pathology. Drug development on novel concepts with Abeta as a target need to be and will be progressed  despite the failures.

Tau is also a big part of the pathology, and the research around tau is really developing. A third big theme is inflammation – the path of the disease is associated with inflammation so we also need drugs to tackle that. The simple reason we need to look at all these different paths is that we need more players to be able to combine treatments. In our own experiments with animal models, we have combined our small molecule with  the antibody and we’ve seen an additive effect on  brain pGlu-Abeta and Abeta lowering, showing the potential of combining treatments.

It is obvious that further research efforts will advance our knowledge of the disease and will bring up new mechanisms and targets for drug development.

Is it challenging for smaller companies to break into this disease area?

Developing a treatment for Alzheimer’s is a challenge for everybody involved, as we can see from the current situation. Importantly, a novel, differentiated concept can only be validated with clinical data. The challenge for a smaller company is driving research, pre- and clinical development to this stage and financing it. Probiodrug has a great venture consortium which accompanied this development. We very much look forward to further the clinical development of PQ912 and explore collaborations with pharma companies.