NR Times reports on how the pioneering work of Aprinoia Therapeutics could influence better patient outcomes in neuro-rehab; in conversation with chief medical officer Bradford Navia.
‘Precision neuroscience’ is a term which encapsulates the ceaseless drive for more targeted and effective brain treatments and diagnoses.
Not to be confused with Elon Musk’s neuro-tech startup of the same name, it sits at the intersect between two emergent health innovation trends; the rise of precision medicine – tailored interventions that consider genes, environments and lifestyles – and an acceleration of our understanding of the neurological world.
On the frontline of the precision neuroscience movement is Aprinoia, a clinical-stage biotech headquartered in Boston which is opening up new possibilities for the diagnosis and treatment of neuro conditions including Alzheimer’s and Parkinson’s.
Its lead programme, APN-1607, represents the next generation of tau positron emission tomography (PET) tracers. It’s a line of research and development that could ultimately enable more effective and efficient diagnoses and delivery of treatment in neurological conditions.
Its success could essentially enable increased certainty that therapeutics, when tested, are treating the right patient population at the right time in their disease.
Pharma firms Biogen and Bristol Myers have already licenced APN-1607 to use in their own trials, while the company is collaborating with AbbVie and Lundbeck on a second tracer for alpha-synuclein, which would hope to be used in the setting of Parkinson’s Disease and/or Multiple System Atrophy.
NR Times spoke to Bradford Navia, chief medical officers of the company, to find out more.
‘Precision neuroscience’ is presenting exciting possibilities in neuro-rehab. Tell us about how Aprinoia is helping to progress this movement.
Precision neuroscience is an important theme that drives the mission that drives much of our work. We have two to two platforms – a diagnostic platform and a therapeutics platform.
Our diagnostic platform has been centred on developing a positron emission tomography [PET] imaging tracer. This is a tracer that binds to tau – an incredibly important protein involved in the pathogenesis of a host of neurological and neurodegenerative diseases, including Alzheimer’s, as well as some rare conditions, such as progressive supranuclear palsy [PSP] and frontotemporal dementia [FTD].
What progress has been made so far on this area of work?
Our tracer, we have shown through various studies done by investigators outside of the company, binds to different forms of tau. Different forms of tau are implicated in different diseases.
These forms are related to repeat structures within the protein – the 3R and 4R forms. Our tracer, unlike other tracers, shows good selectivity for both forms of tau activity – for example 4R in PSP and Corticobasal syndrome [a condition that causes changes in movement and/or language skills] and 3R in Picks disease [a form of FTD]. Alzheimer’s is a mix of 3R and 4R. We are currently advancing a phase three programme for PSP.
Having been in discussions with the FDA recently, we have their permission to advance our programme to approval based on the result of a single pivotal phase three trial, which is very exciting.
Approval for the use of that tracer will be based on a single trial. That is an important, remarkable achievement for the team to get alignment with the agency.
How significant could the successful development of the tracer be in terms of future PSP diagnosis and treatment?
There are currently no approved diagnostic markers for PSP and PSP can be very difficult to diagnose during its early stages. There are diseases where patients present with Parkinson’s like symptoms, including problems of balance, walking, swallowing or speech, and they can resemble each other clinically. But the underlying pathology is different.
So today, there is no clear way to diagnose and differentiate PSP from other syndromes that can mimic it clinically.
We’re hoping to show that with APN1607 we can diagnose PSP in its earliest stages. When patients present for the first time to the clinic, physicians could use the tracer to reliably arrive at a diagnosis or not, to say they have PSP or to exclude that possibility.
That’s the end game. Showing that we can use the tracer to help with that diagnosis will have a huge impact in the clinical field we believe.
So it could drive much earlier diagnosis of PSP?
On average it will take a clinician somewhere between three to four years to establish a diagnosis of PSP.
Sometimes it is not until the patient has died and there is an autopsy when the definitive diagnosis is made.
With the tracer, because it is a pathological marker that binds to collections of tau in specific brain regions for that disease that are known to be implicated in PHP, it will provide evidence that this could be a useful clinical marker for diagnosis.
What is the history of this line of investigation and when might it realistically be available to make an impact on patient outcomes?
The idea is based on data published from our some of our collaborators and investigators in different regions. The first publication on the tracer was worked on by Makoto Higuchi, the founder of the tracer and a co-founder of Aprinoia.
He published an important paper which showed that the uptake of the tracer, the intensity of the signal, correlated with the severity of the disease as measured by clinical scale.
Other groups since that work was published have shown similar findings. In 2017 we were granted an orphan disease designation [ODD] which enables the accelerated development of a product, in this case 1607.
We now have a plan to advance the programme into a global single phase three trial for the eventual approval for this tracer for diagnosis. Our plan is to start the study by the end of this year and complete it in approximately 18 months. So we’re talking about 2025 as an overarching goal.
How does 1607 compare to other Context of what is out there
The only [FDA] approved tau is Tauvid, marketed by Lilly, but it is limited in its use because of what’s known as ‘off target binding’. It binds to other proteins and branch structures, which limits its amplification. It’s approved for the diagnosis of Alzheimer’s Disease.
There are second generation tracers that are generally more selective and other first-generation ones. Ours differs because of the selectivity for the 4R and 3R forms of tau.
The fact that we can visualise different forms of tau across different tau-related disorders is one of the key differentiating features of our tracer compared to others in development.
Neurons damaged by Alzheimer’s disease.
What are some of the key milestones you’re working through as company to advance your work?
We have a phase three trial for Alzheimer’s in China. We also have a phase two study for the condition in the US. The goal is to develop 1607 as a diagnostic marker for diagnosis and for staging patients with Alzheimer’s.
That is important because tau accumulates over time and if the tracer is as effective as we believe it is, it should allow us to stage patients in the course of their disease. This gets to the top of precision neuroscience.
We want to be able to treat patients that are more likely to respond to a treatment. The response to the treatment may be partly predicated by what stage they’re in at the time the intervention is started.
This is probably true for the recent successes – the approval of Lecanemab [an immunotherapy drug designed for people with early-stage Alzheimer’s and marketed as Leqembi] and more recently the positive phase three results of Donanemab [which was shown to significantly slow cognitive and functional decline in early Alzheimer’s disease].
These results suggest that patients need to be at a certain stage of tau accumulation to benefit from treatment. I imagine we’ll soon be in a position to use tau tracers like 1607 to identify patients at the right stage of their disease that are more likely to respond to treatment.
The 1607 tracer will enable the early diagnosis of Alzheimer’s disease, and enable the more accurate staging of patients but the staging is where I feel the true value lies.
It clearly takes a huge amount resources to commercialise the types of innovations you are developing. As well as the well publicised ‘blank cheque’ SPAC deal [read more here], what other developments have been significant on this journey?
We recently received funding from the Alzheimer’s Drug Discovery Foundation, which supports research in neurodegenerative diseases and with a particular focus on Alzheimer’s disease.
They awarded Aprinoia funds to support the phase three trial for PSP, as well as to support the further preclinical development of one of our therapeutic programmes.
The company is gaining more attention as it grows and we advance our programmes. We are in a good position as we advance the company to the next stage of the SPAC deal.
What’s happened recently is that there is a greater awareness of our company in the US and importantly of our tracer and degrader programmes. As we continue to make progress the company is incrementally growing. So it’s an exciting time.
You’ve also been involved in Parkinson’s-related projects
We’re developing a tracer that is still in its early stages and, in terms of treatment, we’re developing a novel approach to protein degradation.
It’s a platform to target aggregates or proteins like tau and alpha-synuclein that play a role in the pathogenesis of diseases like Parkinson’s.
We have now developed platforms to target both proteins in preclinical models. We’re advancing those programmes hopefully to a clinical stage over the next two years.
That’s an exciting, transformative therapeutic approach that will break some serious ground if successful in terms of how to treat these neurodegenerative conditions.
