Alzheimer’s disease: Despite failures, hope for new treatment by 2025
Neurodegenerative treatments are particularly difficult to develop, because of the difficulty in delivering any therapy in sufficient quantities across the blood-brain barrier.
One disease area, in particular, has proved especially complex in the discovery of new treatments: Alzheimer’s disease (AD).
Last week, Roche’s crenezumab joined the list of treatments that did not succeed at the clinical trial stage. Preliminary data collected by an independent monitoring committee suggested that there was little likelihood of trials into the treatment reaching their primary endpoints.
It means that another treatment failure will have to be chalked up in the battle against the disease, with Roche not the only large pharma company struggling after numerous companies have failed to show clinical success in recent years.
However, when BioPharma-Reporter (BPR) spoke to Elliot Goldstein (EG) and James Kupiec (JK), CEO and CMO of biotech, ProMIS Neurosciences, they expressed confidence that the string of clinical failures would end in the not-too-distant future.
Roche will continue trials into crenezumab in patients who do not express symptoms of AD but have a familial risk, with the hope that earlier intervention may prove more beneficial. On this front, the experts from ProMIS were less optimistic.
BPR: Could you outline the focus of ProMIS’ work?
EG: We're exclusively focused on neurodegenerative conditions, and 'the big three' of these: Alzheimer’s disease (AD), Parkinson's disease, and amyotrophic lateral sclerosis (ALS). We have other target areas, but these are our big drivers.
Our technology is based on a very deep understanding of the root causes of these diseases. There's a commonality among them – a toxic oligomer or a misfolded toxic form of an otherwise normal protein that's killing neurons and propagating throughout the brain.
JK: There are a number of different species of these proteins in each of these diseases – it's all the way from a monomer, a single protein, to higher molecular weight groupings of 100. There are also the insoluble protein aggregates that get deposited in the brain of the patients, for all three conditions.
We're trying to find a very selective target to go after on toxic oligomers, and we've developed antibodies for this task that we will take into the clinic.
BPR: Why do you believe your technology will succeed where others have failed?
EG: Our technology is focused on creating antibodies to neutralise only the toxic form of these proteins and not the healthy form. This a key understanding why crenezumab, and all the failures we've been following in the field for the last decade or so have occurred – they're not selective and they waste ammunition on the normal forms of amyloid beta, in the case of AD.
The important thing is to have an antibody that is highly selective for the toxic oligomer and then have little or no binding to the normal forms. We know today that monomers and plaque are not toxic, there's only one form that is toxic, which is the one you have to neutralise and that's what we do.
BPR: How is the technology able to achieve this specificity?
EG: Our technology results from work done over a dozen years at the University of British Colombia, and we're the only company that has a chief physics officer, in addition to the chief scientific officer. Why is it that? The challenge here is that the normal techniques used to create antibodies to target selectively large molecules, such as amyloid beta toxic oligomers, don't work. You can't physically isolate these oligomers.
We use two proprietary algorithms, running on supercomputers, which allow us to actually pinpoint where these molecules misfold, because that's what makes them toxic and there is a loop that is usually hidden inside. [Using the algorithms] these loops stick out and we can make our antibodies target nothing but these misfolded loops. You won't find these loops on the monomers, you won't find them the larger aggregates that aren't misfolded and you won't find them on plaques – our technology is able to create antibodies that are highly specific.
What's exciting about it is that we can apply it to any misfolded proteins, and there's half a dozen or more that have this root cause.
BPR: The recent failure of crenezumab saw Roche continue a study carried out an earlier stage of AD – in your view, will this still suffer from a lack of specificity?
EG: In my opinion, it doesn't matter how early you are in a disease stage, if you're not knocking out or selectively targeting the right thing then it's hard to expect it to work. Stage of the disease is an important factor but what's important is knocking out what's killing neurons. Crenezumab binds all three forms of amyloid beta: the monomer, the toxic oligomer and the plaque. So, I would be doubtful.
Antibodies don't cross the blood-brain barrier well so having a product that is highly selective is probably the only way to go. For every thousand monomers in the brain, there's approximately one toxic oligomer – unless you're very precise, you have no chance of having an impact.
JK: I would agree. I think it's doubtful it's going to be successful but we won't find out for five years. There'll be many years until we know the answer to the question.
BPR: Despite doubts about the potential of this particular study, what is your view on targeting AD at an earlier stage?
EG: Generally, in chronic diseases, not just neurodegenerative cases, you want to intervene early. Before the first symptoms of AD, it's been estimated you need to lose about 10 billion of your neurons, out of 100 billion or so in a healthy adult, for any symptoms to occur. It seems to make practical sense to treat patients before there's so much damage and there's very little left to save.
JK: This is a disease that we know begins two to three decades before symptoms are manifest. There's been a big push in the academic community, embraced by the pharmaceutical industry, that treating earlier will lead to better outcomes. The question is whether the prevention studies, which have already started and are using compounds that have failed elsewhere in development, are going to work.
The jury is out but, based on what we know, it seems doubtful. Based on our science, and the science that has emerged over the last five years on toxic oligomers, it seems unlikely this trial will ultimately be positive. Though the rationale is fantastic, the question is whether they're using the right tools.
BPR: After the number of failures, is the future still looking bright for Alzheimer's research?
EG: For every company that has pulled out, new ones have come in. For larger pharma companies, after investment failures, and the fact that many have multiple investment options, then they get a little wary. That's pretty traditional behaviour.
There are new players that are taking up the baton, and it's interesting that almost all of the products have come from small biotechs, such as ourselves. We are also coming into a much more mature understanding of the game and have been able to learn from the failures what not to target.
JK: The whole field is changing so dramatically and so quickly. For the last few years, I've been very enthusiastic about the field – our understanding of the molecular biology, biomarkers have been developed and there's going to be a real focus on combination therapies. I expect by 2025 there will be one or two disease-modifying therapies for AD approved, and there will be a panel of biomarkers that can be used to determine if there is a biologic pathology of AD going on in a patient's brain.
Elliot Goldstein is the CEO of ProMIS Neurosciences. He began his career with Sandoz Pharmaceuticals, working for 14 years at the company and becoming head of clinical R&D in the US, before working at GSK, British Biotech and Maxygen.
James Kupiec is CMO of ProMIS Neurosciences. He most recently served as VP and clinical head of the neuroscience research unit for Pfizer.
