To start, Rehan, can you share a bit about your background and Precede Bio?
I studied biochemistry and following a Master’s degree, I joined a rapidly growing global biopharma company. I started in medical affairs, moved into global clinical development, transitioned to commercial roles, and ultimately took on executive leadership responsibility that spanned both R&D and commercial – making decisions on which medicines to develop on the R&D front and at the same time, managing a commercial P&L and launching new medicines into clinical practice.
My collective experiences working across both R&D and commercial are the inspiration for what I am doing today. We all know and appreciate that developing new medicines is hard, and it is certainly made harder by the lack of insight we so often have into relevant disease biology at the scale we would want. This impacts interpretation of early phase trial results and our ability to design trials that maximize probability of success. On the commercial front, so much of the sales and marketing spend could be optimized if the patient profile for a given therapy could be biologically defined.
Today, I lead Precede Biosciences, a company I co-founded with three leading researchers and clinicians from the Dana Farber Cancer Institute (DFCI) and a well-known VC firm here in Boston, 5AM ventures. We have taken on the development and scaling of a liquid biopsy platform that profiles the key epigenomic regulators of gene expression using both advanced molecular techniques and sophisticated machine learning in order to impact precision use of medicines.
Your group’s work combines two rapidly evolving fields: liquid biopsy and epigenomics-based diagnostics. Could you tell us about Precede Bio’s liquid biopsy platform and its approach to leveraging epigenomics?
Every single one of us started as a single cell, a fertilized egg, and we grow from this single cell to about 30 trillion cells that contain the same genetic instructions, the same genome. And, yet we end up with so many different specialized cells and organs that play very specific roles. The emerging thinking is that there may be more than 500 specialized cells in the human body. Epigenomics is the system of controls that ensures the required genes for any specific cell are expressed at the required level and time for healthy functioning.
When cells die, they often release their cellular contents into the blood stream, and this includes their DNA and its associated epigenomic features. This is what we assay at Precede Bio, giving us unique insight into the near-real time biology of cancer cells, immune cells, and other diseased and dying cells.
More specifically, we profile three highly informative epigenomic controls, one associated with active transcription of a gene, one associated with modulating the active transcription of a gene, and one associated with transcriptional repression of a gene. Together they form a very comprehensive picture of what genes, pathways, and programs are active in disease and how they change undertreatment.
This is distinct from genomics where one is specifically interested in detecting changes in the actual sequence of DNA. What we reveal is what DNA is being targeted for expression by a given cell. It’s this view of the genome, through the lens of the epigenome, that enables us to open up new therapeutically relevant applications for liquid biopsy in cancer and other diseases.
Are there specific applications of this approach you find particularly promising?
The potential applications are broad and we are fully focused on advancing precision medicine. Getting patients on the therapy that is right for them is associated with far better outcomes, so what we want to enable are rational biology-based treatment decisions from a simple blood test.
An example application area would be the many cell surface protein targets that are the focus of the next wave of precision medicines in cancer, medicines such as antibody-drug conjugates, radio-ligand pharmaceuticals, immunotherapies such as BiTEs, and other next generation antibody formats. There is a huge wave of investment into these medicines and their targets. There are close to 300 programs alone against the top 15 targets, about half of which are in the clinic, with more than 100,000 patients actively enrolled in clinical trials.
Understanding target expression is relevant for each of these medicines. For some, it’s relevant in their core indication (e.g., the recent approval of Claudin18.2-targeting zolbetuximab in gastric cancer) while for others, it’s relevant for indication expansion (e.g., HER2 3+ determination for pan-tumor use of trastuzumab deruxtecan). Our platform can resolve target expression using the epigenomic features of circulating tumor DNA and we have shown that we can do this in a quantitative way (e.g., our recent data on resolving prostate-specific membrane antigen (PSMA) expression in advanced prostate cancer that correlates with quantitative PET imaging for PSMA expression). What makes this even more exciting is that we can resolve many targets of interest from the same blood sample, enabling a future triage of patients to the most appropriate therapy.
Beyond cancer, there is a real opportunity to inform on disease biology in any condition where cell-free DNA is enriched with DNA from relevant dying cells. Auto-immune conditions fit well into this broad area of opportunity, and we have some exciting pilot data in conditions such as multiple sclerosis and lupus, conditions that could really benefit from biology-informed decision-making in both drug development and clinical practice.
How would you characterize the current state of adoption of epigenomics in the diagnostics space, specifically with regards to therapy selection, early detection and monitoring?
I would say that it’s a very exciting time, that we are in the early innings, and that we are starting to see the real power of epigenomics, blood-test based epigenomics, to inform patient care.
Starting with early cancer detection, we have seen the recent FDA approval of the first blood-based test for colorectal cancer screening, a test that’s significantly powered by detecting DNA methylation patterns, an important epigenomic control that is widely dysregulated at the earliest stages of cancer. There are also tests emerging for lung cancer screening and even multi-cancer screening that are powered by different epigenomic technologies.
In minimal residual disease and recurrence monitoring, there are so called tumor-naïve tests (tests that do not require a sample of the patient’s tumor tissue) that are starting to play an important role in informing clinical decisions having received positive coverage determinations in some cancer contexts.
Finally, in therapy selection, there is so much opportunity to expand beyond the limited focus on promoter hypermethylation in select use cases (e.g., MGMT promoter hypermethylation in glioblastoma that sensitizes the tumor to alkylating agents) with a broader set of epigenomics technologies, and this is exactly what we are focused on doing at Precede Bio with our comprehensive and interpretable epigenomics platform.
What are current challenges in leveraging epigenomic information for therapy selection, early detection and monitoring? How is Precede Bio solving them?
In therapy selection, where we are focused, one of the most important challenges to date has been the interpretability of epigenomics technologies such as DNA methylation. Beyond promoter hypermethylation that is associated with transcriptional repression, DNA methylation changes aren’t generally interpretable. In contrast, our platform focuses on three distinct epigenomic controls (including promoter hypermethylation) that are very interpretable at the gene level giving us the opportunity to assign meaning to what we see much more directly. For instance, going back to the PSMA example, when we profile samples from advanced prostate cancer patients, we can see a strong functional activation of the enhancer associated with the PSMA gene in a large proportion of patients, which tells us that the PSMA gene is transcriptionally active. It’s this direct interpretability that is enabling us to take epigenomics into the domain of therapy selection in a powerful and efficient way.
Beyond the interpretability, for any emerging diagnostic technology, one has to meet the expected technical performance criteria, and do so at scale for a reasonable cost. Many technologies struggle to emerge for these reasons alone. This is where our team spent considerable effort after our founding and before we launched in October of 2023.
What are your thoughts on the emergence of 6-base genome sequencing technologies that allow for variant and methylation detection in the same assay? Are you anticipating the adoption of these technologies in diagnostics workflows?
The emergence of these technologies is yet another validation of the opportunity we have to further our understanding of the molecular basis of disease by profiling the epigenome. With regards to the 6-base genome, I think there are still questions about the degree to which it will be informative for diagnostic use, and there are companies and academic labs actively involved in exploring its potential.
After oncology, what would you say is the next frontier in terms of indications to leverage epigenomic information?
The epigenome controls gene expression for every cell in the body, and dysregulation of these controls is a hallmark of every disease. Consequently, there is a real opportunity for epigenomics to inform diagnostic and therapeutic approaches within and outside of cancer. We are particularly excited to leverage the epigenome to elucidate opportunities to inform therapy selection in auto-immune conditions, and the emerging science tells us there are many more opportunities including in conditions receiving a lot of investment attention today such as obesity.
What are your thoughts on multi-omic approaches? Are we at a point where we should leverage more approaches (e.g., epigenomics + proteomics) together or is less more?
It’s very context and goal dependent. For example, in early cancer detection, we've seen approaches to combine analytes (such as methylated DNA and key proteins) in an effort to improve test performance. At the same time, we have also seen approaches that have made great use of a single analyte, resulting in robust and encouraging performance. The key message is – more is not always better. Ultimately, one wants to have the desired performance with as robust and parsimonious a set of analytes as possible.
Do you anticipate regulatory challenges associated with developing novel testing platforms given LDT regulations? What are your thoughts as to how this has affected the epigenomics diagnostics landscape thus far?
At a general level, there is a movement to ensure that marketed tests used in clinical practice are sufficiently validated for their specific intended use. We all want to live in a world where we can trust the results of the tests we receive. At this stage, the FDA has been clear on its future expectations, and the industry is preparing accordingly. As with all major changes, adjustment to the new framework could be challenging for both established and emerging players. From a Precede Bio perspective, our approach has always centered on garnering an FDA approval for our platform and tests, and so the proposed changes do not impact our clinical strategy.
What key considerations are helping Precede Bio bolster its position in the liquid biopsy space competitively?
The most important one to emphasize is strategic clarity. The team and I are very focused on expanding the reach of precision medicine and this means a clear focus on impacting therapeutic decision-making. This is a validated opportunity – validated in terms of the unmet need and validated in terms of the opportunity to create a high-value, revenue generating business that can be self-sustaining by meeting that need. In addition, we are very focused on partnering with biopharma on the journey to clinical practice. This means in many cases enabling their candidate medicines in trials before we enable their approved medicines in practice. This clarity of strategic focus is important for any emerging company with an exciting platform technology like ours and is a reason why, over the last 12 months, we have generated the momentum we have.
What trends or developments do you anticipate in the epigenomic liquid biopsy space over the next five years?
We really are in the early innings for epigenomics-based diagnostics, and given the role that epigenomic dysregulation plays across disease, the potential is significant. I am very “bullish on the blood” as there is so much untapped information that can be easily accessed, and with increasingly powerful computational approaches, we will only gain in our ability to resolve the important and informative signals. All-in-all, the future of precision medicine will most certainly be shaped by the continued progress of epigenomic and blood-based diagnostic technologies.
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