Biomarkers RNA: [2022] What Is ASPYRE Technology?

Biomarkers RNA: [2022] What Is ASPYRE Technology?


How Can This Help Patients With Non-small Cell Lung Cancer (NSCLC)?

I would like to speak with you today and tell you a little bit about ASPYRE and Biofidelity. So Biofidelity recently published a paper in BMC Medical Genomics describing a new technology called ASPYRE, and this really summarizes the low cost. A simple, very rapid assay for multi-molecule detection of multiple gene fusions from RNA.


And the paper describes the assay for how detecting these fusions faster and at a lower cost has the potential to really revolutionize patient care and make precision medicine globally accessible to more people. And importantly, I'll just point out that we published a paper earlier this year on the detection of variants from (tumor) DNA using the same technology as last year. So what I'd like oncologists and my colleagues to understand and know about ASPYRE is that it really has the potential to change the way we currently treat lung cancer patients with non-small cell lung cancer because it enables the detection of actionable genomic (RNA) biomarkers for these patients.

This testing can be performed on both tissue samples and plasma. Should access to tissue be a limiting factor? And importantly, because the assay is ultrasensitive, it's highly specific. It's capable of returning results in as little as two days. So this really cuts down on the time between cancer patients receiving appropriate treatment (and for early detection). The technology can be applied in either a centralized or decentralized fashion. And what I mean by this is that the tissue can either be sent to our lab, which is in North Carolina, or the testing could be performed at your own institution's.


4 Key Takeaways From The ASPYRE Assay

  1. RNA helps oncologists identify actionable mutations. Molecular or antibody-based gene fusion detection technologies are limited to single-gene targeting, insensitive, or slow. Due to the large size of introns, next-generation sequencing DNA-based methods to detect fusions by sequencing intronic sections have varying sensitivity and predictive value. Predicted gene fusions may not be expressed due to the depth of sequencing and input nucleic acid needed.

  2. Using pyrophosphorolysis, we can detect gene fusions from RNA and somatic mutations in DNA in a single instrument run [1].

  3. Detection was under 6 molecules/ 6 μL target volume. From extracted nucleic acid to sample analysis, the workflow and instrumentation are similar to PCR assays.

  4. The 18-plex Seraseq Fusion RNA Mix v4 standard reference sample was acquired from LGC Seracare (Milford, USA). GenScript (Leiden, Netherlands) synthesized RNA oligonucleotides that were diluted in 0.2 g/L polyA carrier RNA (Qiagen, Manchester, UK). Background RNA was obtained from ThermoFisher Scientific (Waltham, USA) and consisted of purified whole lung RNA (AM7968).



What Is The Current Standard of Care In Pts With Non-small Cell Lung Cancer (NSCLC)?

So this is a great question; the standard of care for non-small cell lung cancer has changed dramatically, and I think anybody that's in this field can attest to this. We know that, based on a body of literature, lung cancer (screening) has emerged as essentially the poster child of how precision medicine can dramatically improve patient outcomes over the last couple of decades.


We know that. 85% of patients with non-small cell lung cancer harbor potentially actionable driver mutations, and matching these targeted therapeutics to druggable alterations in the first-line setting may potentially go beyond that, significantly prolonging survival as compared to cytotoxic chemotherapy. And additionally, targeted therapeutics are generally better tolerated than chemotherapy. They have fewer adverse events, so they really have a favorable risk-benefit profile. Dr. Kelly, What are your thoughts on the assay? 


Thank you. As you mentioned, our recent study focused on RNA analysis using ASPYRE, and this is really clinically important because RNA is an under exploited analyte in oncology genomic testing.

So we demonstrated that our ASPYRE technology can provide extremely sensitive detection of multiple clinically significant gene fusions simultaneously and directly from an RNA sample. And this is really important because there are more than 10 quite effective targeted therapies available for patients with non-small cell lung cancer (NSCLC) who have these specific kinds of recurrent fusions.


And principally, we're talking about fusions in genes like ALK, RET, ROS1, and NTRK. So our tests really help to ensure that no patient misses out on the promise of precision medicine. And so when a new test is developed, it's helpful to compare it to existing methods, and so many clinical labs are currently using a method that I'm sure many of you listeners are familiar with called Next Generation Sequencing, or NGS.


And these labs use NGS to look at patient samples for things that happen in the DNA that affect the genome. These are known as translocations. And all of these things lead to the creation of RNA fusions, so many of these NGS tests are aimed at very large, very complicated parts of the genome. Called introns, these are non-coding regions, and so there's a lot of real estate to sequence where these translocations occur, so sometimes they're missed, and when an event is detected, they have to infer that it ultimately leads to the production of an RNA fusion.

So it's really an indirect method. The bottom line is that the strategy is insensitive, resulting in maybe 1 in 4 actionable fusions being missed. And missed fusions mean that a lot of patients who could benefit won't get the targeted therapy that is most likely to give them a treatment plan that is clinically effective.


What Led To The Development Of ASPYRE Technology And It's Use For Patients With Non-small Cell Lung Cancer (NSCLC)?

That is a great question. Patient access to genomic testing is an ongoing problem, and access to biomarker data lags far behind the therapeutic advances made over the last few years. But this biomarker data is absolutely required for the effective and informed use of these kinds of targeted therapies, and I'll just give you some statistics. Approximately 60–70% of people with metastatic lung cancer in the US start treatment before getting the recommended biomarker test results. And these figures are even worse outside of the US.


As I said before, about one in four targetable gene fusions is missed when DNA sequencing alone is the testing strategy. And another problem is the time to result from these kinds of genomic tests. Typically, it takes around 4 weeks from the initial cancer diagnosis to the final results of the biomarker tests.

So, this delay could mean that a less-than-ideal treatment is started before the results of genomic testing are known. So as you can see with these problems and issues, there's a tremendous unmet need for a solution that enables faster clinical decision-making at a lower cost and with a shorter test turnaround time.

And this decreased time to treatment would result from a reduced testing turnaround time with ASPYRE. We are very confident that this will ultimately lead to better patient care and, ultimately, better outcomes. And then a further benefit of our ASPYRE technology is that it's very easily deployed in a decentralized fashion.


And so by "decentralized," I mean at local labs near the patients. This will allow for testing in different settings, locations, and countries, for example in lower resource settings. Where the barriers to NGS-based biomarker testing that are currently in place have left patients with very few options.


Key Data Points From The ASPYRE Assay

We have a lot of data coming out around ASPYRE, including the paper and BMC Genomics that Dr. Levin mentioned that we've already discussed. We also presented a poster at the recent Association for Molecular Pathology annual meeting, and I'll just briefly summarize that data set.


So in that study, we evaluated over 1200 contrived plasma and tissue samples for variants or mutations in DNA infusions in RNA. We made well over 100,000 distinct variant calls with the assay, and our goal was to derive the assay performance characteristics. With that in mind, we showed that the assay specificity was 99.9% for both tissue and plasma samples.


We also showed that the assay sensitivity was over 96% for tissue, and this dataset included many very low-level and very difficult-to-detect variants, so 96% is quite impressive. In plasma samples, our sensitivity was approximately 92%, and that data set also included many challenging very low-level samples. So the take-home message here is that we've shown that ASPYRE has very compelling performance characteristics.

And we believe it would be extremely effective in a clinical laboratory. We can analyze genomic variance from both tissue and plasma, and we can test both DNA and RNA. Dr. Levin, what are some of the other features of ASPYRE that you think are important?

Finally, because tissue can be small once you actually do get it, it insufficient for both histologic evaluation and genomic testing. And so again, one of the key advantages of ASPYRE is that it can be used on both tissue and blood, and clearly the latter is recommended and has been validated when tissues are not available.

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Interesting Information About the ASPYRE Assay

So as an oncologist and a healthcare provider myself, I'm really excited about ASPYRE and its potential to revolutionize patient care. We know that precision medicine has had a remarkable impact on patient treatment, particularly in the field of oncology. Over the past decade, researchers have discovered (biomarker discovery) that many cancers are caused by specific mutations in genes, and biopharmaceutical companies have developed drugs to specifically target these mutations. And these mutations are redundant and in fact seen in many other types of cancers. In addition to non-small cell lung cancers, they offer targeted treatments as an alternative to chemotherapy regimens, often with less harsh side effects and better results in terms of both response rates and potentially better survival. And in fact, 5 year survival rates for lung cancer (non-small cell lung cancer (NSCLC)) have tripled since targeted therapeutics have become available since about 2010.

But really, the challenge is identifying which patients might respond best to these therapies. And you can't do that without testing. You need to identify which patients have the specific mutation, and this again is why biomarker testing at diagnosis is really critical for all patients, including those with non-small cell lung cancer (NSCLC cancer cells) and other cancers as well. Because these pathways tend to be redundant, in addition, there's been a lot of justified excitement about immunotherapy, so drugs like Keytruda and other PD1s, PDL1 inhibitors, which stimulate the immune system and work to attack the tumor cells. But, more importantly, even these Even though these have moved into the first-line setting, in many cases, it's still important to test for genomic driver mutations prior to starting IO, as the presence of these types of mutations informs the use and timing of immunotherapeutic agents. And this is really consistent with current clinical practice guidelines. As a result, this is the first time ASPYRE has been used to treat non-small cell lung cancer (NSCLC tumor cells), which is very important, and we're really excited about rolling this out to our cancer patients. But we're also working to bring it to other disease areas that have action genomic markers.


Plans For The Further Development Of ASPYRE Technology

ASPYRE is really built on Biofidelity's technology platform, and this platform removes the noise from genomic data. This provides the critical information needed to make clinical decisions faster with increased confidence and makes the whole process much less complex. Ultimately, we think ASPYRE technology and our platform will make genomics more widely accessible. And by reducing genomic complexity and eliminating uninformed genomic data, we can significantly lower the cost of genomic analysis and accelerate clinical decision-making. So ASPYRE is the first application of the Biofidelity technology.


It enables fast clinical decision-making. It's simple, precise, and allows for targeted identification of whole panels of genomic (RNA) biomarkers. And one important thing that we haven't yet mentioned is that our ASPYRE technology utilizes readily available quantitative PCR instrumentation. These qPCR instruments are ubiquitous in labs everywhere, especially since the purchases for COVID testing, and our technology has a very simple workflow. So our goal is to help ensure that all patients have the information needed to receive the treatment that is right for them at the right time, in keeping with that goal. Our plan is to make ASPYRE available for the detection of actionable (RNA) biomarkers in as many other cancer types as we can.


Final Thoughts On The ASPYRE Assay 

So what I'd like oncologists and other healthcare providers to know is that at Biofidelity, we're working very hard to deliver this breakthrough genomic technology that really fits between this gap of next-generation sequencing and PCR testing. And the goal of this is to enable fast clinical decision-making through simple, precise, and targeted identification of panels of genomic markers, and again, the goal here is really patient-centric to identify those patients most likely to respond to targeted therapeutics. In terms of that, making genomic data more accessible and easier to interpret, in addition to being more cost-effective, helps ensure that all patients globally have equitable access to the information needed to receive the right treatment at the right time. Dr. Kelly, do you have any final comments? 

I'd like to add that we're excited to keep improving the ASPYRE technology so that more patients can benefit from it. From precision oncology through easier access to decentralized, faster, and easier biomarker testing, we look forward to using ASPYRE to enable more patients with cancer to benefit from all of the cutting-edge personalized therapies that are available to them.


Wendy J. Levin, MD, MS - About The Author, Credentials, and Affiliations

Dr. Levin is a board-certified oncologist and hematologist who went to school in the United States. She has worked in the pharmaceutical industry for more than 15 years and is an expert in translational medicine, drug development, and managing clinical development, medical affairs, and business development. She has led interactions with health authorities and regulators, set up clinical advisory boards, and been in charge of the clinical side of studies from first-in-human to Phase 3 registration trials. She has also helped start-ups before they went public and Fortune 500 companies with their business plans.


Todd W. Kelley MD, MS, Executive Director of Medical Affairs  - About The Author, Credentials, and Affiliations

Todd got his MS and MD from the Ohio State University and then completed his residency and fellowship at the Cleveland Clinic. The American Board of Pathology has granted him certification in Anatomic Pathology, Clinical Pathology, and Hematology.


Associate Professor of Pathology at the University of Utah Health Sciences Center, Medical Director of Hematopathology, and Co-Scientific Director of Next Generation Sequencing and Biocomputing at ARUP Laboratories; Laboratory Director/Head of Scientific Affairs at Navican Genomics. Medical Director/Director of Medical and Scientific Affairs at Beckman-Coulter Diagnostics.


Dr. Kelley has spent his entire career focusing on research, development, validation, and clinical application of molecular and conventional diagnostic (biomarker) test techniques in a variety of clinical and Medical Affairs leadership roles. He is a member of many professional groups, such as the Association for Molecular Pathology and the American Society of Hematology, and has written over seventy research articles, reviews, and book chapters.

Biomarkers RNA: [2022] What Is ASPYRE Technology?

Dr. Levin and Dr. Kelley Speak About Biomarkers RNA: [2022] What Is ASPYRE Technology?