Interview: Hope for those with degenerative brain disease PSP
Like Alzheimer’s disease, PSP is caused by a build-up of tau in the brain damaging cells. Build-up of the protein requires the activity of enzymes that act on it called tau kinases, which causes the tau protein to misfold and clump, forming neurofibrillary tangles.
Tau is a small protein that occurs naturally in the brain and usually exists as a soluble protein. In people with PSP, it forms harmful clumps in brain cells.
The disease is finally attracting some attention after a number of larger trials which have unfortunately been unsuccessful[DB1] .
A collaboration was formed in February this year (2023) which saw Swiss clinical stage biotechnology company Asceneuron sign a licensing agreement which gave Ferrer exclusive worldwide rights to develop and commercialize Asceneuron’s ASN90 drug.
Keen to find out more, OSP interviewed Dirk Beher, CEO and co-founder of Asceneuron alongside Óscar Pérez, chief marketing officer, pricing and market access and business development officer for Ferrer.
OSP: There seems to have been an increase in awareness of PSP, has this made people recognise the symptoms sooner?
Óscar Pérez Albet: I was pleased to be invited to this interview because I believe we need to keep highlighting, investigating, and developing a treatment for PSP. PSP is a degenerative brain disease, and the cause is still unknown.
Tau eventually starts to deposit in certain areas of the brain, and because of that the brain cells/neurons are damaged and affected, and this is when the symptomatology starts..
There’s a whole bunch of different symptoms, a variety of them, but those that are much more specific to this condition are loss of balance, the slowing of movement, difficulty in moving the eyes along the vertical axis, and it can even impair the cognitive function of our brain. What's important to understand is that in normal physiological conditions tau protein exists in the body and has a crucial role, an architectural one stabilising the neural network in the brain crucial for our normal functioning and for our brain activity.
Dirk Beher: A particularly unusual characteristic of this disease is falling backwards as well as all the ones Óscar described so well.
To expand upon tau a bit more, it is a protein that's required for neurons to function and for the brain too. If you see it precipitating or depositing, something is clearly wrong. We now have a chance to develop drugs - and that’s our mandate – to prevent deposition of this protein. With our ASN90 molecule we have shown with laboratory experiments that we can prevent the precipitation, and that's our whole hypothesis. We don’t know the cause and we don’t know why it precipitates but what we do know is that we want to block it.
We're quite hopeful that we have a potential treatment and the reason for that is because of what we have seen in Alzheimer's disease - seeing beta-amyloid precipitating and removal of precipitated beta-amyloid being efficacious.
OSP: Is this a treatment you’re trying to develop for the early stages of PSP, or can it be applied to patients whose disease has already progressed?
Dirk Beher: We begin when people already have symptoms, but with the future identification of disease biomarkers we could start earlier and earlier. With PSP we are at the beginning of this, but for Alzheimer’s disease we have a huge data set for biomarkers already available. For future studies, we would try to catch patients earlier, but we are dependent on patients showing PSP symptoms for the trials so that we can categorise them as PSP patients - and not as having other rare diseases - and quantify treatment effects.
Óscar Pérez Albet: The point is that this is a devastating condition, and like in many other rare diseases and rare conditions, it is easy to find under-served patients because of the lack of researchand the lack of existing treatments. This is a particular issue with disease showing syndromic symptoms, a collection of symptoms not specific to a certain disease.
Because of the lack of diagnosis it can be misled or delayed. We need to do much more and part of our conjoined strategy is to keep working with patient associations and many of the disciplines in the medical setting to help them learn more about early symptoms.
OSP: Is there any reason why it targets people or is it just completely random?
Dirk Beher: It's non-discriminatory and can happen in men or women, and there's no racial, geographical or any other factors. As with all neurodegenerative diseases, the main risk factor is age.
That's why the onset usually comes between 60 or 70 years of age. Why this is we don't know, but it it's very common across all neurodegenerative diseases.
Óscar Pérez Albet: There are specific symptoms, and this is probably what is much more important, like backwards falls and the difficulty in moving the eyes along the vertical axis, as well as feeling muscular stiffness.. As long as we promote awareness, we are going to increase diagnosis and find a meaningful treatment which is the combination we are all striving for.
A meaningful treatment would be the success that we are all waiting for.
OSP: How long do you think a patient could be suffering from PSP without realising they have it?
Dirk Beher: It's difficult to assess. We started this project 2013 and the disease was relatively unknown, but now I think physicians are becoming more aware and I think that is because in part since drug companies have run larger trials in PSP.
Óscar Pérez Albet: We know that is that is a rare disease, but I would say beyond prevalence, that there is not as much data available and the kind of questions that you are raising are proper ones.
OSP: We have had trials that have been done and the discovery of your treatment. Do you know the plans, where are we going next with this?
Dirk Beher: I can speak about how we have developed ASN90 and would pass on the discussion on the future to Óscar. We have developed this in our company which we started in 2013. It has taken a considerable time with a small team of highly experienced experts. And we looked time and time again for the most suitable disease to develop a tau drug, and where we know we can find tau pathology.
When you look at Alzheimer's disease, I mentioned earlier that where you find beta-amyloid, you find tau, you even find other pathologies. That's a very complex situation so when thought about the most suitable indication for the drug, we considered a disease where only tau is the driver and ended up with PSP. I don't want to go into too much detail of the full development plan because it gets very complicated. However, what has been done with the molecule so far is that we have been able to run three trials in healthy volunteers.
We have shown the drug gets into the body by entering into the blood stream and what's exciting is that we have shown with an imaging technique that the drug goes into the living human brain and really binds to its target, the OGA enzyme.
That was the most important data set generated, and the next step will be to go to patients.
Óscar Pérez Albet: We plan to start a phase two of our clinical development plan and that will be followed by phase three. This is the traditional pathway, and we will demonstrate what potential an asset like the ASN90 molecule has, especially based on efficacy and safety. We also need to look at the profile of the patient and their many different needs - not only the pharmacological ones and we need to start having early conversations with regulators.
OSP: What other therapies have been proven to be helpful before?
Dirk Beher: I think trying to moderate the symptoms but that depends on the patients. You can use some of the dopaminergic drugs that may provide some benefit for a certain period of time, but I think it is fair to say there is no treatment that can really change the disease, it is mainly to ease the patient’s life.
It was important for us to find a partner who can take this on to develop it further because we are a small company. I think we have found our forever partner here because Ferrer is committed to patients, they also have rare disease experience, and this was very comforting for us and you can see the excitement here when Oscar's speaks about moving this into patients knowing we will be making a difference.
Óscar Pérez Albet: It's so important to help raise the voice of the patients and to spread the word to generate increasing awareness.
The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted orphan drug designations to ASN90 for the treatment of PSP. The OGA inhibitor was evaluated in three clinical studies including a double-blind, placebo-controlled, randomised phase 1 trial and human positron emission tomography (PET) CNS target engagement study.