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CTAD 2022 | The diagnostic and prognostic performance of U-p53AZ as a blood-based biomarker for AD
Paul Kinnon, CEO, Diadem SpA, Brescia, Italy, introduces the unfolded conformational variant of the p53 protein, U-p53AZ, as a blood-based biomarker for Alzheimer’s disease (AD). In the search for a biomarker that could be used to prognose AD in its earliest stages, U-p53AZ was identified as a potential candidate. It was found to be unique to AD and present very early on. Furthermore, its unfolded conformation allows for a region of p53 to be targeted using antibodies that is not otherwise present, enabling easy detection. Kinnon discusses two major longitudinal studies utilizing the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort that demonstrated U-p53AZ as a successful blood-based biomarker to identify present and future symptomatic AD. U-p53AZ outperformed amyloid PET imaging in predicting progression to AD, achieving an area under the curve of over 98% for identifying progression to symptomatic AD up to six years prior to diagnosis. This rapid and non-invasive test can not only identify patients likely to develop symptomatic AD, but can classify the stage of current disease as well e.g. cognitively normal, mild cognitive impairment (MCI) or AD. This interview took place at the Clinical Trials on Alzheimer’s Disease Congress 2022 in San Francisco.
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Transcript (edited for clarity)
Like most scientific discoveries, it was developed out of the University of Brescia by a little bit of serendipity. The scientists there had been working at The Weizmann Institute in Israel for a number of years, came back to Italy, continued doing research into P53 and Alzheimer’s. And then they were looking for specific markers to try and predict early what was going on with Alzheimer’s...
Like most scientific discoveries, it was developed out of the University of Brescia by a little bit of serendipity. The scientists there had been working at The Weizmann Institute in Israel for a number of years, came back to Italy, continued doing research into P53 and Alzheimer’s. And then they were looking for specific markers to try and predict early what was going on with Alzheimer’s. And they were looking at blood, and plasma, and other such materials and mediums.
They identified that unfolded P53, or a unfolded variant, was present very early and that it was specific to Alzheimer’s compared to other markers that were present at the same time. And what we then determined with further research and investigation was that, basically this unfolded variant is unique to Alzheimer’s, and this unfolded variant is caused by the breakdown of the post translational modification of the P53.
And basically, it’s an unfolded variant of the P53, which enables us to target really a region that is not normally present with antibodies so we can bind to it. And that marker therefore tells us that the P53 breakdown is changing the pathway, is causing an increased probability of Alzheimer’s being caused.
And we’ve done two major studies. We used a 224 patient study from the AIBL cohort longitudinal. That gave us our original discovery cohort and the performance targets that we were looking at, which were very high. Over 90% for a PPV and NPV.
Then we took a completely new cohort of over 482 patients, again longitudinal, with data from 10 years worth of patient studies, analyzed that, and we still got a PPV over 95% for the risk of decline within six years. And an NPV over 95% saying, “You will not decline into Alzheimer’s in that six-year period.”
Now, that data’s phenomenally powerful. We’re replicating that now. We’re doing that in ADRC and the ADNE cohort, and we hope to have published that before the end of the year, maybe next year, where we’ve got maybe another 600 or 700 patients from each cohort showing the same performance in different demographics.
So obviously, the data I just discussed is the prognostic performance and that gives us fantastic AUCs, which means that we can use those with patients, clinicians, and also in the clinical market to help pharmaceutical companies look at their buried treasures, their fallen angels, find new products and new targets, and basically accelerate the development of drugs, because we can enable you to identify the progressors, so that you’ll know for your clinical trial, which patients are going to be used and who are going to decline.
But additionally, one of the byproducts of this test is that it classifies the stage of the disease, in terms of are you cognitive normal, are you MCI, or are you AD at the time of our treatment? Our test I should say. So basically, you get told you’re a progressor or not. If you are a progressor, the results of our test also gives you a binary readout, which says you’re either a cognitive normal, MCI, or AD patient, even if you’re symptomatic or asymptomatic.
So you don’t need a PET scan, you don’t need a CSF analysis. Basically, the readout from a prognostic point of view is accurate. Then additionally, you get a diagnostic of what stage you are at the time of testing, even though you may not be showing symptoms.