Extending the team-up against AD

Alzheimer’s is thought to be caused by “tangles,” or twisted fibers of certain proteins. The oligomeric forms of these misfolded beta-amyloid and tau proteins play a pivotal role in the pathophysiology of the disease.

“The quantification of amyloid beta oligomers is challenging because of the very tiny amounts in which they are present in the CSF [cerebrospinal fluid], but we believe [ourselves] to be uniquely and very well positioned to be successful because our partnership brings together the key elements to find optimized alternatives to currently available Abeta oligomer assays,” says Inge Lues, chief development officer of Probiodrug.

The companies first established the partnership in 2016 to harness Crossbeta’s capacity to stabilize oligomers and further Probiodrug’s search for a breakthrough in AD treatment. Research specific to oligomers is very challenging due to the inherent instability of their protein aggregates. Crossbeta’s proprietary stabilization technology generates pure and functional preparations of oligomeric protein species and thereby overcomes this problem, enabling highly reproducible and well-controlled assays for preclinical and clinical research and development related to therapeutics, biomarkers and diagnostics.

“We are very pleased [at] the collaboration with Crossbeta. The potential of Crossbeta’s unique technology has significant impact to overcome the challenge of establishing and validating sensitive and specific assays for Abeta- and pGlu-Abeta-oligomers to be used in the clinical studies of Probiodrug’s lead candidate, Glutaminyl Cyclase (QC) inhibitor PQ912,” commented Lues in 2016.

Probiodrug has focused on targeting a key neuro/synaptotoxic component of the pathology, pyroglutamate-Abeta (pGlu-Abeta), as a therapeutic strategy to fight AD. Probiodrug’s lead candidate for the treatment of the disease is PQ912, a first-in-class small-molecule inhibitor of the enzym glutaminylcyclase. Mechanistically, the inhibitor prevents the formation of pGlu-Abeta, a modified Abeta version leading to the formation of synaptotoxic Abeta oligomers. Having successfully completed the Phase 2a SAPHIR trial, Probiodrug announced recently the preparation of a Phase 2b core program which will include this new biomarker assay.

Since the partnership began, the program has made excellent progress and has successfully met all critical milestones, the companies say. By leveraging the pivotal role of protein oligomers in AD pathology, the partners are aiming to develop a biomarker assay that allows users to detect and quantify the Abeta and pGlu-Abeta oligomer content in CSF, which would serve as a truly disease-specific AD biomarker and diagnostic with prognostic clinical value.

“Our partnership with Crossbeta has granted us access to a truly unique technology which has proven to be crucially important for the development of high-quality biomarker assays, with adequate sensitivity and specificity to support and further the clinical program of Probiodrug’s QC inhibitor PQ912,” asserts Lues.

According to Lues, Probiodrug is now able to measure the amyloid beta plaque burden by PET imaging, which gives information on the insoluble amyloid plaque load. They are also able to assess the amyloid beta content in CSF, but this does not relate to the oligomers of amyloid beta, which are the main neurotoxic species and represent only a very small fraction of the total amount of amyloid beta that is present in the brain. Having a tool that specifically quantifies the soluble oligomer content would open the possibility to test and selectively include patients in clinical studies, thereby helping to improve the likelihood that these people would benefit from the treatment.

“Another important aspect is that it would help to see the effect of disease-modifying treatments on the Abeta oligomer content. This would add important information regarding the efficacy of the treatment because oligomers are playing a critical role in the pathology. In addition, it could also help to better diagnose other diseases by ruling out the involvement of these ‘Alzheimer’s oligomers,’” notes Lues.

Guus Scheefhals, CEO of Crossbeta, added: “We are very pleased about the extension of our partnership with Probiodrug. It is an honor being able to contribute to Probiodrug’s exciting and encouraging therapeutic program in AD with our proprietary technology. In case of successful achievement of our goals, not only will many other scientists and companies benefit from the availability of this novel, prognostic biomarker and diagnostic, but it will bring urgently needed benefit to AD patients.”