The NAi platform is digitalizing patient biology – using clinically annotated unbiased patient samples and Bayesian methodologies to identify biological signals within the noise of billions of patient data points; revealing hidden cause and effect relationships that fuel drug discovery and de-risk drug development.
NAi provides a validated platform that is fully scalable to meet the needs of any drug development journey.
The NAi platform consists of an industry leading and clinically annotated proprietary biobank, with purpose-built Bayesian causal AI and is using one of the world’s fastest supercomputers, Frontier, at Oak Ridge National Laboratory (ORNL), making it a pioneer in fully integrated high-performance computing (HPC) in the biopharmaceutical industry for AI-driven target nomination, development, and molecule design. Additionally, the NAi platform takes advantage of cutting-edge spatial mass spectrometry imaging (MSI) to create decision-grade data that informs drug distribution, target engagement, and biomarker discovery.
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The Power of NAi
The NAi platform is unprecedented in the volume of information that it outputs. Not only does it identify high-confidence targets, it also provides high-confidence biomarkers – two for the price of one. The target lists feeds our drug discovery pipeline; the biomarkers, our diagnostic pipeline.
A great example is BPGbio’s pstateDx diagnostic panel. Roughly 50% men aged 50-50 and 80% of men aged 70+ suffer from a condition known as benign prostate hyperplasia (BPH). When these men receive screening for prostate cancer, they commonly generate a false positive – many diagnostic tests rely upon measuring levels of prostate specific antigen (PSA), a biomarker which is elevated in both BPH and prostate cancer. The result? Roughly one million men annually are required to undergo an invasive prostate biopsy to confirm a prostate cancer diagnosis. At BPGbio we are bringing to fruition a better option for patients – an innovative diagnostic test, pstateDx.
In partnership with the Department of Defense (DoD), we used the NAi platform to discover a novel driver of prostate cancer, Filamin A. With the guidance from the NAi platform, our scientists identified a fragment of Filamin A that functions as a biomarker of prostate cancer. Crucially, aggressive prostate cancer has highly elevated levels of Filamin A observed in men with BPH – allowing for BPH and aggressive prostate cancer to be distinguished at an early stage during annual screening. This innovation represents a much-needed advancement in prostate cancer diagnostics, one that can distinguish between a common benign condition (BPH) and aggressive prostate cancer that’s life threatening.
The NAi platform is in a class of its own – its differentiated ability to generate new knowledge from real patients unlocks previously hidden cause and effect relationships. A causal map generated by the platform identified mitochondrial dysregulation as the cause of many disparate diseases in oncology, wound healing, aging. In the cell, mitochondria play an essential role in generating energy. Dysregulation of mitochondrial metabolism can cause energy deficits and damage to cellular components. BPM31510, a nanostructure delivering CoQ10, acts at the source of these conditions to rebalance mitochondrial metabolism. Interestingly, in the unique metabolic environment of the tumor, this triggers cancer cell death. With these insights from the NAi platform, BPGbio expanded its original topical form of BPM31510 into an IV formulation and an oral formulation for a suite of clinical trials in mitochondrial medicine:
Topical BPM31510: Completed a Phase 1 trial for Epidermolysis Bullosa, and Phase 2 for Squamous Cell Carcinoma;
BPM31510IV: Currently in phase 2b for Glioblastoma and phase 2a for Pancreatic cancer (Ph2) and exploring phase 3 in Primary Q10 Deficiency (Ph2);
BPM31510 Oral: Completed a phase 1 trial in sarcopenia.
Using multiomic data from tissue, blood, and urine samples collected from patients in a Phase I trial, NAi’s can help trial sponsors map patient biology and better understand the mechanism of action and safety—not just for the population as a whole, but also how the drug interacts with patients with specific germline or somatic genomic profiles.
As an example, BPGbio team tested our BPM31510 compound with a broad mechanism that targeted the mitochondria in a large Phase I trial with 104 patients with different cancers. Leveraging our multiomic data we could better understand how BPM31510 induced a shift in metabolism and see that its effect was limited to those with more aggressive tumors. Knowing this helped us prioritize future studies to more narrow clinical indications, select patients with these types of cancer, and better understand the pharmacodynamic biomarkers predictive of success before beginning Phase II studies.
NAi can also help scientists understand the relationship between patient biology and adverse events and modify clinical protocols to limit toxicities and optimize trials for patient safety.
In one of our trials, our AI modeling identified toxicity markers for patients with previously unknown bleeding and clotting abnormalities leading us to add dosing of vitamin K to the clinical trial protocol in a subsequent trial.
NAi increases the predictability of clinical trial outcomes. With NAi, BPGbio has run three successful trials in oncology and two in rare disease.
In the search for novel drug targets, BPGbio combined the data generated by their proprietary Bayesian causal AI models in oncology, neurology and inflammatory disease, and against this backdrop of trillions of data points, they identified a little-known target: a Ubiquitin-Conjugating Enzyme (E2s) that was a critical biological node in disease biology. While E2s are known to be crucial in the protein degradation pathway, they had long been considered undruggable due to the lack of druggable binding pockets.
BPGbio’s next move was to validate their in-silico E2 insight in their wet lab. By employing conventional gene manipulation tools (siRNA,) and disease relevant cell types ( cancer cells, neuronal cells), BPGbio observed cell cycle effect in cancer cells leading to anticancer effect, and improved cell survival in neuronal cells.
To overcome the traditional E2 druggability challenge, BPGbio designed their ligands to bind a modified form of E2 with a deeper binding pocket, enabling discovery of selective ligands. The E2 based drug discovery program was initiated as a wet lab exercise of identifying fragment based hit molecules and growing them into drug like small molecules. In the process the team identified 2 unique E2 based discovery opportunities – Novel Small Molecule Therapeutic for Huntington Disease and a scaffold for Targeted Protein Degradation of undruggable targets.
BPGbio’s unique E2-based TPD approach is differentiated from the typical E3-based approach, with several inherent advantages, including potentially higher efficacy, potency, broader disease scope, and reduced drug toxicity.
BPGbio very quickly confirmed TPD was possible via their novel E2 scaffold approach, opening up white space in disparate therapeutic areas and indications. BPGbio is beginning exploration of their E2 TPD Platform starting with several programs in oncology.
The company is ready for collaborative and partnered pipeline engagement with pharma partners. BPGbio holds proprietary protein structures, computational models, and assays for rapidly attaining selectivity and specificity to a class of E2s. Structural data has enabled the creation of chimeric targeting molecules or Bi functional degraders, that combine exit vector knowledge, linker and Protein of Interest (POI) ligands. The company is now leveraging proprietary chemo proteomics probe sets and cutting-edge proteomics platforms to address degradability of hitherto undruggable protein substrates.
Prior to the E2 discovery by BPGbio’s NAi Platform, no one had focused on developing an E2-based TPD approach, let alone leveraging it into multiple therapeutic programs. The NAi Platform truly unlocked a hidden biological insight that will hopefully improve the human condition for all.
