A bright future for CNS and Alzheimer's?

Swiss biotech Asceneuron is developing what could be the first treatment for progressive supranuclear palsy (PSP), a rare CNS condition that can impair balance, movement, vision, and speech. We spoke to CEO and founder Dirk Beher to get his views on the remaining challenges of tackling diseases like PSP and Alzheimer's.

Tell us about ASN120290. Why are you targeting PSP?

ASN120290 is a small molecule inhibitor of the O-GlcNAcase enzyme. In preclinical models inhibiting this enzyme can essentially prevent toxic tau tangles from forming.

We are now preparing to move the molecule into progressive supranuclear palsy (PSP). PSP is a small enough indication that we could look at efficacy with a patient population that is relatively well defined. Also, PSP is one of the very few CNS diseases which is exclusively driven by tau. At the level of pathology, it is so to speak a “cleaner” disease compared to Alzheimer’s disease.

Needless to say, PSP is terrible disease. When you talk to people who are looking after loved ones with PSP you see that it's a very disheartening disease for them to watch.

What barriers have prevented there from being other treatments available for PSP in the past?

Historically, there haven't been an awful lot of trials compared to a large indication such as Alzheimer’s because it's an orphan disease. It's also only recently that patients have become more organised, that diagnostic criteria have become fully established and that knowledge and awareness have generally increased. I think this is why PSP was neglected beforehand. Also, it’s fair to say that with the more recent interest of the industry in tau that more drugs are worth exploring in this indication.

What kind of trial results have you seen so far?

In phase 1 studies we have seen substantial drug exposure in the central nervous system, in the range that predicts target engagement required for efficacy. We are also currently wrapping up a PET tracer study for target engagement. We expect to present the results at the Alzheimer's International Conference in Los Angeles in July.

Asceneuron is focused on tau. Many companies have been dropping Alzheimer's drugs related to beta-amyloid build-up. Do you see that trend continuing, and do you think tau is going to be the priority for researchers over the next few years?

Yes. I’ve worked on a number of beta-amyloid programmes and I think people have been attracted to this by the strong genetics underlying beta amyloid. There is a clear link to disease, but we still have to work out what exactly it is at the end of the day.

We have seen a couple of antibodies fail in the clinic targeting soluble entities which do not remove plaques. Unfortunately, antibodies that remove plaques did not fare better either. Hence, we like to spread our bets broader these days. I think tau is certainly one of the key areas here.

One of the reasons why people are really excited about tau is because we now have a greater understanding of how it is closely linked to disease progression. Essentially, there are imaging agents (PET tracers) which specifically bind to the neurofibrillary tangles, the tau aggregates in the brains. The amount of tau tracer binding and the increase over time is closely linked to the clinical stage and progression in Alzheimer’s disease. Then you can also ask the question of where is the tau deposition happening. We now know how to look at both the quantity of tau and where it happens. It is worth pointing out that this seems to work well for Alzheimer’s disease whereas for PSP and other tauopathies it appears that novel tau tracers will need to be developed.

There are quite a few companies out there that are deprioritising CNS, and the burden of it is falling on smaller companies like yourself. Do you think it will become a priority again for bigger companies, or will it remain something that is perhaps better served by smaller companies?

I think we need the larger companies to be engaged in the CNS space given the unmet need and interdependencies. Even for smaller companies, when we do our fundraising, if it's only us it's very difficult to build excitement if we’re kind of the lone wolf. It’s always useful to point to bigger companies that are doing studies, that have a network and could become a future partner.

Hopefully the area will evolve similarly to immuno-oncology. As soon as someone has positive data, even with a small effect size, the pendulum might swing around again. We have seen some very big companies going out, but given the competitive nature of areas like immuno-oncology, people may want to get back to CNS when they see that there is something there.

Are there any other areas in CNS that you feel are underserved at the moment?

There are still quite a number of underserved diseases out there. Neuropsychiatric indications such as schizophrenia are one example. Overall, when you think about unmet need, CNS scores pretty high in my view.

Were there any other more general challenges of working in the area that still need addressing?

One is finding and treating the patients early enough. We need more early diagnostics criteria and tools. The challenge is that when people become symptomatic, they have already lost a large number of the functionality in the brain. Parkinson's disease is a good example. Patients have already lost over half of their dopaminergic neurons by the time they become symptomatic.

Are you hopeful for the future of CNS and Alzheimer's?

I'm hopeful that by diversifying, we may find therapies that show some kind of efficacy. Then the area can develop in a similar way to immuno-oncology. My hope is that we can take some of those drugs and can combine these things to really get to a meaningful treatment.

About the interviewee

Dirk Beher is the chief executive officer, a founder and a member of the Board of Directors of Asceneuron. Dirk has more than 25 years of experience in the field of Alzheimer's disease/neurodegeneration and spent over 19 years in pharmaceutical drug discovery including senior research positions around the globe at Merck Sharp & Dohme, Amgen and Merck KGaA.