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Delivering on the Promise of New Modalities: An Interview with Maria Luisa Pineda, CEO and Co-founder, Envisagenics

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. For our next interview as part of our featured series highlighting innovation in our ecosystem, we sat down with Maria Luisa Pineda, CEO and Co-founder, Envisagenics. As a spinout of the world-renowned Cold Spring Harbor Laboratory (CSHL) and an artificial intelligence-driven biotechnology company, Envisagenics focuses on diseases that are driven by splicing deregulation. With this scientific premise, Envisagenics primarily focuses on three therapeutic areas – oncology, neurodegenerative, and metabolic disorders. The company secured Series A financing in 2021 to continue to develop and improve its machine learning based drug discovery SpliceCore® platform and to discover and develop novel RNA splicing therapeutics. In November 2022, Envisagenics announced a multi-year research collaboration agreement with Bristol Myers Squibb for accelerated discovery and development of oncology therapeutic candidates. Greetings Maria, nice to have you today. Could you please introduce Envisagenics’ platform to our readers? What is the top industry-wide challenge your company tries to solve? Maria: As an AI-driven biotech company, we maximize the power and potential of sequencing data for the discovery of targets for therapeutic development. Traditional drug discovery paths are long, expensive, and often fail to reach patients. Envisagenics is capitalizing on the value of RNA sequencing data to identify novel RNA splicing derived targets in-silico and understand the mechanism of action for each target prior to validating the biology in downstream experiments. Another industry-wide challenge is the need for novel therapeutic targets since most biopharma companies are working on the same, stagnant targets. As technologies have advanced, companies like Envisagenics can look beyond the targets at the genetic level by taking an exon-centric approach. With this validated approach, Envisagenics has created one of the largest search spaces of approximately 7 million splicing events, consisting of novel, alternative splicing-derived proteins. Compared with existing approaches, how unique and differentiated is your approach? Maria: Envisagenics’ SpliceCore software platform uses machine learning and AI to re-envision the human genome with a validated exon-centric approach that leads to the discovery of novel targets that gene-centric discovery approaches cannot find. Envisagenics’ technology combines high-performance computing and proprietary ML algorithms to process high volumes of RNA-seq data for the identification of novel targets, at an accelerated rate, in the therapeutic areas of interest—thereby truncating a promising new drug’s time to market. Envisagenics’ technology also addresses the high failure rates of therapeutics in clinical trials by leveraging its scientific expertise in RNA splicing and combining it with SpliceCore’s ability to identify and develop highly specific therapeutics that modulate RNA splicing events involved in the pathogenesis of oncology, neurodegenerative, and metabolic disorders. With innovative technology and rare expertise, Envisagenics is poised to help patients faster than ever before. In your opinion, what are the key challenges in realizing the full potential of your new technologies? Solutions? Do you anticipate any key milestones in the near future? Maria: The primary challenge has been overcoming outdated, preconceived biases against RNA therapeutics and AI, along with a general resistance to change. Historically, the field of RNA therapeutics has had its setbacks, partly due to delivery methods and concerns with efficacy during development. However, the industry’s reluctance to embrace RNA therapeutics fell by the wayside with the advent of successful mRNA vaccines during the COVID-19 pandemic. RNA technologies have now demonstrated enormous promise, and we are energized and excited to be part of that revolution. As the company continues to mature, Envisagenics’ goal is to see one of its RNA therapeutic assets help patients in need faster than ever. There are other AI-based biotechnology companies that are approaching IND and taking drugs into the clinic. Therefore, our goal represents a key, achievable milestone that Envisagenics aspires to reach in the coming years. AI/ML is core to Envisagenics’ platform.  How do you see these novel data technologies becoming the norm in R&D in the next couple of years? Maria: Recently, one of the biggest shifts within Biopharma is that AI/ML has gained a greater following among both scientists and business-minded executives.  Envisagenics is proud to be a part of this innovation. We announced our collaboration with Bristol Myers Squibb on November 29, 2022. The multi-year partnership aims to leverage our proprietary AI technology, SpliceCore, to identify alternative splicing derived targets for therapeutic development in the oncology pipeline at BMS. While we hope to continue to see similarly structured partnerships between Big Pharma and Biotech AI, at the same time, novel data technologies continue to be introduced to the market that improve R&D insight, efficiency, and speed in the pursuit of better treatments. At some point, companies that fail to embrace AI/ML will be left behind, and the industry has taken notice. Therefore, in the next few years, AI/ML will become a standard component of Biopharma R&D pipelines. Many Biopharma companies already partner with agile, specialized AI/ML companies in order to gain access to next-gen technologies while also standing up small, internal Data Science teams. Big Pharma has also begun to reserve capital and infrastructure for the pursuit of internal in-silico capabilities to maximize the value of internal, proprietary databases. While we are still in the early days of Biopharma AI/ML, we have already seen new technology embraced both internally and externally throughout the Biopharma industry. We expect these adoption trends to continue in pursuit of innovation, and we predict that R&D pipelines will transform permanently, to the benefit of patients around the world. Thank you, Maria, for your insights. You mentioned collaboration between big pharma and biotechs. What does global collaboration mean to your company? Maria: Diseases affect patients worldwide, and effective treatment development requires a global outlook. For Envisagenics, “global collaboration” means working with likeminded companies to take an expansive, inclusive approach to problem solving. Internally, it means that we must seek and develop diverse datasets that train ML models and do so in concert with diverse scientific expertise while recruiting the best talent from around the world to work for us. It also means that we must support and strive for equal access to treatments among patients. Externally, it requires us to seek input, ideas, and data sources from around the world and push ourselves to adopt new approaches without bias, regardless of where those ideas originate. As a result, Envisagenics maintains a focus on making the biggest impact it can for patients. Fortunately for Envisagenics, our principal technology—the cloud-agnostic SpliceCore software platform—can be deployed to collaborate with anyone, anywhere, in a secure and compliant manner. This has allowed us to work with some of the pre-eminent global Biopharma companies, such as Bristol Myers Squibb, Johnson & Johnson, and Biogen. Thanks again Maria! Maria Luisa Pineda, Ph.D. CEO and Co-founder, Envisagenics; Secretary, The Alliance for Artificial Intelligence in Healthcare Dr. Maria Luisa Pineda started as a high school Intel International Science Fair winner.  For her undergraduate studies, Dr. Pineda was awarded an endowment of $2 million dollars from the Goizueta Foundation and an NIH fellowship with the Minority Access to Research Careers (MARC U*STAR) program. Dr. Pineda received her Doctorate from the prestigious Cold Spring Harbor Laboratory School of Biological Sciences as an Arnold and Mabel Beckman graduate student and a William Randolph Hearst foundation scholar.  After graduating, she acquired investment experience in technology and life-sciences startup companies at Canrock Ventures and Golden Seeds, LLC. Under her leadership, Envisagenics has received non-dilutive SBIR grants from the National Institutes of Health, raised capital from investors, won several prestigious artificial intelligence competitions, and formed multiple research collaboration partnerships with Biopharma.

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Delivering on the Promise of New Modalities: An Interview with SJ Lee, CEO, Orum Therapeutics

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. In our latest interview, we’re joined by SJ Lee, CEO of Orum Therapeutics. Orum is a biotech company pioneering the development of targeted protein degraders to treat cancer. In June 2021, the company closed $84 million Series B financing to advance the company’s lead therapeutic candidates into clinical trials. Orum’s proprietary platform merges the power of protein degraders with the precise cell delivery mechanisms of antibodies. Unlike traditional ADCs, the targeted protein degrader (TPD) payloads of Orum’s TPD2 approach can specifically degrade intracellular target proteins within cancer cells via the E3 ubiquitin ligase pathway. ORM-5029, one of its lead candidates, was dosed in its first patient last October. By selectively delivering catalytic GSPT1 protein degraders to the cancer cells, the candidate has the potential to treat HER2-expressing tumors via a novel MoA. Congratulations on your progress in clinical programs and thank you for joining us. Orum is developing innovative drugs to treat cancer. In your opinion, what are the challenges in current therapeutic intervention, or current modalities? SJ: An industry-wide challenge is targeting “undruggable” targets. Targeted protein degraders are a powerful modality that have the potential to address undruggable targets. However, like all small molecules, there are safety concerns as they are unable to distinguish between targets in healthy and diseased cells. Moreover, heterobifunctional degraders also hold a lot of promise in terms of broadening the range of proteins to target but can be stifled by issues such as low cell permeability, bioavailability, PK, and the hook effect. Antibody drug conjugates (ADCs) have been successful in oncology by making cytotoxic agents safe and effective, but the biggest challenge in the field is highly toxic payloads wiping out normal cells that expresses express the target cell antigen of interest such as CD33. This restricts the use of ADCs to certain tumor types and disease indications. How is Orum’s platform helping to address these challenges? How is it different from existing approaches? SJ: We have developed an approach that we call TPD² – or dual-precision targeted protein degradation – to generate antibody-enabled targeted protein degraders. We’re merging the aspects of these modalities. Orum’s TPD² drug candidates offer novel payloads with a new cell-killing mechanism of action to target proteins that are considered undruggable. Furthermore, by conjugating protein degraders to an antibody, TPD² drug candidates are designed to specifically target diseased cells to increase efficacy and safety to overcome the challenges inherent to small molecule degraders. In addition, the degrader payload itself has lineage dependant activity. For example, GSPT1 degraders can kill leukemia cells while sparing normal hematopoietic stem cells. Orum’s lead candidate already has been dosed in its first patient this year. To fully realize the potential of your new platform, what are the critical challenges remain to be solved? SJ: The challenge of realizing the full potential of our TPD² approach is there are almost an unlimited number of combinations possible via cell surface antigen and TPD target protein pairings. We are engaging partners that either have expertise in a disease area, or degrader or antibody assets that can be conjugated to its counterpart. While we are currently focused on oncology, Orum’s TPD2 approach is agnostic to therapeutic areas. We have a unique opportunity to partner with others who have deep expertise in non-oncology indications, such as immunology, to explore TPD2 projects, where we can design degraders to be delivered to specific immune cells. Orum is still a relatively young biotech. What does global collaboration mean to your company? SJ: Orum is a global company with wet labs in the US and South Korea. We benefit from that by accessing diverse and skilled talent pools. We also work with high-quality partners, such as WuXi AppTec, in East China that are two hours flight away from Seoul. This shaves days off the lead optimization cycle, speeding up drug discovery efforts significantly. Thanks for your insights! If we were to gather here again in 10 or 15 years’ time, what do you think we’re going to be talking about in terms of what we have already achieved in the industry? SJ: We will see more creative fusions of established modalities. ADCs are chemotherapy agents on antibodies, CAR-Ts are antibody fragments on T cells. More innovation will come from the novel fusion of such validated components. A good example is Enhertu, which is a novel fusion of validated approaches – topoisomerase 1 inhibition on an approved antibody. We think TPDs on antibodies will become mainstream 15 years from now, and we believe Orum is a leader in this field. SJ Lee, Ph.D. CEO, Orum Therapeutics SJ Lee is the CEO of Orum Therapeutics, a clinical stage biotech pioneering the development of tumor-directed targeted protein degraders. Before founding Orum to address the undruggable target problem, he was at Sanofi as the head of research for Asia Pacific R&D. He oversaw teams and projects around a virtual biotech model to co-invent drugs with biotech and academia teams for Asia related diseases such as hepatocellular carcinoma. SJ has led international teams to improve the therapeutic landscape for various diseases, including oncology and infectious diseases. He earned a Ph.D. in Biophysics from the University of California, Berkeley, and worked as a postdoctoral scholar at Stanford University.

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Delivering on the Promise of New Modalities: An Interview with Christopher Thanos, President, CEO & Co-Founder, Actym Therapeutics

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. We continue our interview series with Christopher Thanos, President, CEO & Co-Founder of Actym Therapeutics, Inc., a biotechnology company focused on the discovery and development of novel therapies intended to transform the treatment of cancer. They have developed a systemically dosed therapeutic platform that can overcome the solid tumor immune microenvironment, which is hostile to T-cells. The platform, called STACT™ (S.Typhimurium-Attenuated Cancer Therapy) is based on a gene-edited, immunologically cloaked microbe capable of enriching in solid tumors. Once there, payload combinations are delivered directly to tumor-resident, antigen-presenting cells to generate antitumor immunity. Actym raised a $34 million Series A financing to advance development of immunotherapies from this platform. They recently announced a manufacturing pact with Wacker Biotech to produce Actym’s lead clinical candidate, ACTM-838, for the treatment of solid tumors. Thanks for joining us, Chris, and congratulations on being named one of the “Top 25 BioTech CEOs of the year!” For cancer therapy drug discovery and development, what are the challenges in current therapeutic intervention, or current new modality solutions? Christopher: Thank you for the kind words and the invitation to discuss new modalities. Unfortunately, treatment of solid tumors remains a big challenge, with the FDA-approved checkpoint therapies providing benefit in only a fraction of patients. To generate durable responses in this setting, new modalities must overcome several challenges. First, they must be systemically administered, but with tumor-specific effects, which is particularly critical in a metastatic setting. Tumor-specific target engagement will be required to limit systemic immunotoxicities. Second, new modalities must safely pack more of a therapeutic punch. Multi-pathway target engagement is a likely prerequisite to reverse the known immunosuppressive cascades within the tumor microenvironment (TME), which prevent antitumor immunity. Finally, new modalities must be technically and economically feasible to develop, manufacture, and distribute, without being increasingly burdensome to patients and caregivers. We specifically designed STACT with attributes to overcome these challenges. Could you please share more details of your new modality, STACT? Christopher: STACT is an IV-dosed, programmable, avirulent, microbial-based modality, which naturally enriches in tumors, selectivity delivering payload combinations in a single therapeutic composition. To facilitate systemic dosing, we used gene-editing to eliminate a number of inflammatory components on the surface of STACT, resulting in dramatically improved tolerability through the reduction of inflammatory cytokine responses. We have dosed up to 3 billion CFUs intravenously in NHPs with no impact on tolerability. STACT has a designed auxotrophy for multiple tumor-specific metabolites of the adenosine pathway, which are elevated in many types of tumors. This engineering enables STACT to naturally expand in the extracellular milieu of the TME, an environment well-known to be hospitable for the growth of all kinds of bacteria. Many types of tumors possess an elevated adenosine pathway signature, suggesting this approach may have broad utility. Once enriched in the tumor, STACT is naturally and selectively internalized by tumor-resident myeloid cells, such as macrophages and dendritic cells, through a process called phagocytosis. After internalization, STACT is rapidly destroyed and cytoplasmic, facilitating payload delivery. We are exploiting this unique mechanism to engage intractable “big-lever” immunomodulatory pathways of interest to pharma by deploying payloads in STACT that are known to be too inflammatory and too toxic if dosed systemically via conventional modalities (such as biologics and small molecules). We plan on entering the clinic next year with our lead STACT candidate, ACTM-838, which encodes an IL-15 cytokine and an engineered STING variant. Both the IL-15 and STING pathways are clinically validated, which significantly reduces risk in our approach. In preclinical, difficult-to-treat, checkpoint refractory tumor models, the STACT IL-15 + STING combination generates durable anti-tumor immunity, repolarizes tumor-resident myeloid cells, and is synergistic with anti-PD1 therapy. How is your technology different from other new modalities attempting to achieve the coveted “systemic delivery, tumor-specific effect” mechanism of action? Christopher: STACT is distinct from other experimental modalities such as protease-activated prodrug approaches, engineered T-cells, and cationic lipid nanoparticles containing encoded mRNAs. As a microbe, STACT can naturally enrich in tumors and be internalized by macrophages and dendritic cells, facilitating tumor-specific delivery of payload combos. For tumor-specificity, STACT does not rely on a protease-activated prodrug approach, where the cleaved, active therapeutic product can enter circulation and induce toxicities, and multiplexing options are limited. While T-cell based therapies can encode multiplexed payloads, they poorly infiltrate into tumors, are inactivated by the hostile TME, have on-target toxicities in healthy tissue, and are a significant challenge to manufacture. Furthermore, T-cell therapies require lymphodepletion, which is poorly tolerated, or high dose IL-2, which is even more poorly tolerated, and have an extended vein-to-vein time. Unfortunately, cancer patients often succumb to their disease before their engineered T-cells are ready. Approaches utilizing payload-encoding mRNAs encapsulated within cationic lipid nanoparticles can be multiplexed, but lack systemic delivery and have an unproductive inflammatory profile, limiting their utility as cancer treatments. STACT was designed to be technically and economically feasible to develop, manufacture, and distribute. STACT will be delivered in an IV bag and is reversible with standard antibiotics. Many thousands of doses can be produced via fermentation in a single 24-hour manufacturing run, with a stable shelf life. The platform is now codified such that multiple product candidates can be generated in a similar manner. What are the critical challenges in realizing the full potential of your new modality? Any key milestones anticipated in near-term? Christopher: We’ve received clear feedback from the FDA on our approach. The near-term milestones for the company are production of GMP material, completion of GLP tox studies, regulatory submissions, and expansion of our pipeline. The value-creating inflection point for Actym is demonstration of proof-of-concept in a Phase I clinical trial. A key challenge for this type of modality is making sure that we identify patients with tumor types that are most amenable to STACT’s mechanism of action. To that end, we’ve performed a detailed analysis that revealed a number of high unmet-need cancers predicted to have elevated of levels of adenosine pathway metabolites, which are necessary for STACT tumor-specific enrichment. Many new modalities have been approved by the FDA recently. Do you think the 2030 class of new FDA approvals may look similar or different from those of today? Christopher: I am bullish on the next ten years in the immuno-oncology field. We’re going to see novel modalities emerge with improvements in both durable responses and safety. Additional immuno-modulatory targets will become validated, traditionally intractable targets will become druggable, exciting new treatment combinations will emerge, and cancer vaccines will make a big push forward as well. Thanks for your insights! One last question, how important is global collaboration to your company? Christopher: It’s difficult to survive in the biotechnology industry without global collaboration. First, in terms of access to capital, we’re strongly supported by an international set of top tier investors. Despite being a small and new biotechnology company, Actym is engaged in R&D activities across multiple continents, including several countries in the EU, as well as China and Australia. You have to go to where the subject matter experts are, regardless of the country or continent. I can’t imagine where we’d be without our global network of investors, advisors, and collaborators! Christopher Thanos, Ph.D. President, CEO & Co-Founder, Actym Therapeutics, Inc. Chris assembled the founding team at Actym, raised initial capital, and co-invented Actym’s therapeutic technology platform. Chris has 30 years of R&D experience, and is an inventor on over 30 issued patents. Previously, Chris was Head of Biotherapeutics Discovery at Halozyme (NASDAQ: HALO) leading Molecular Biology, Immunology, Protein Engineering and Cell Biology Groups at the company. Prior to that, Chris was Head of Protein Engineering at Sutro Biopharma (NASDAQ: STRO), and Cofounder of Catalyst Biosciences. He was a National Cancer Institute Postdoctoral Fellow under Professor Jim Wells at UCSF and Sunesis. Chris earned a Ph.D. in Molecular Biology and Biochemistry from UCLA, where he was an NIH Chemistry/Biology Interface Predoctoral Fellow. Chris was named one of the top 25 CEOs in Biotech for 2022 by Healthcare Technology Report.

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Delivering on the Promise of New Modalities: An Interview with Zachary Hornby, President & CEO, Boundless Bio

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. We’re joined for our latest interview by Zachary Hornby, President and CEO of Boundless Bio, a next-generation precision oncology company who raised an oversubscribed $105 million in Series B Financing last year to develop innovative therapeutics directed against extrachromosomal DNA (ecDNA) in aggressive cancers. Earlier this month, Boundless Bio announced a partnership with Sophia Genetics to further develop Boundless’s proprietary precision diagnostic method called ECHO (ecDNA Harboring Oncogenes) to detect ecDNA in a patient’s routine tumor sequencing data to select appropriate patients for treatment in the in clinical trials of the first ecDNA-directed therapies (ecDTx). Greetings Zachary! In your opinion, what are the top therapeutic challenges in the field of oncology? Zachary: Within the field of oncology, the top therapeutic challenge is the fact that patients with oncogene amplified tumors, which account for 400,000 new patients per year in the US, have no standard of care therapies and have significantly worse survival than the cancer population at large. The underlying biology that accounts for this poor prognosis of patients with oncogene amplified tumors is the phenomenon that oncogene amplifications, in contrast to other types of oncogenic alterations, frequently do not occur on linear chromosomal DNA and instead occur on circular extrachromosomal DNA (ecDNA). ecDNA are large (1-3 mega base pair), circular units of nuclear DNA that are physically distinct from chromosomes, highly transcriptionally active, and do not adhere to Mendelian principles of genomic inheritance. They are the primary site of high copy number focal oncogene amplifications, and they propel primary tumor oncogenesis and secondary tumor resistance through rapid amplification and genetic evolution. ecDNA are observed only in cancer cells and not in healthy cells. Until now, the industry has not previously understood ecDNA biology and its role in cancer nor how to appropriately treat cancers that leverage this biology for growth and resistance. Indeed, ecDNA is becoming a new focus of the cancer field. How might your approaches lead to better cancer therapeutics? Zachary: Boundless Bio’s novel technological approach to treating patients with oncogene amplified cancers is to therapeutically exploit the unique cellular vulnerabilities associated with cancer cells’ reliance on ecDNA. Boundless has built an only-in-class platform called Spyglass that allows us to exquisitely characterize oncogene amplified cancer models and determine how, when, and why they rely on ecDNA for growth and survival. In thoroughly interrogating ecDNA’s role in these cancer cells, we have learned the lifecycle of ecDNA—how they form, replicate, transcribe, segregate, and degrade. Through our understanding of the ecDNA lifecycle, we have identified nodes of vulnerability that represent pharmacological intervention points where we can develop small molecule inhibitors that disrupt the formation and function of ecDNA and render them inaccessible to cancer cells’ benefit. No other company in the biopharma industry is dedicated to improving and extending the lives of patients with oncogene amplified cancers, and no other company is exploiting ecDNA biology to develop novel therapeutics. To realize the full potential of your ecDNA platform, do you anticipate any critical challenges? What about recent milestones? Zachary: One key challenge is that ecDNA represents novel biology that has not previously been therapeutically targeted. Most of the targets that Boundless is pursuing are novel or have not been successfully drugged to date. A second challenge is that ecDNA is a novel biomarker for which no clinical detection methods exist. Boundless is developing a novel companion diagnostic clinical trial assay (CTA) called ECHO (ecDNA Harboring Oncogenes) that uses routine clinical NGS (next generation sequencing) data to detect ecDNA in patient tumor specimens. A key milestone for Boundless will be to demonstrate clinical proof of concept with our first ecDNA directed therapy (ecDTx), BBI-355, in its first in human (FIH) clinical study, due to begin in Q1:2023, which will be a precision oncology trial leveraging ECHO to select appropriate patients for treatment. If we were to gather here again in 10 or 15 years’ time, what do you think we’re going to be talking about in terms of what we have already achieved in the industry? Zachary: In 10-15 years, we will be discussing the first drugs ever designed specifically for, and approved and commercialized for, patients with high unmet need oncogene amplified cancers. We will talk about how an advanced understanding of the underlying molecular biology, not just the genetic driver (e.g., EGFR amplification), but the genetic topology (i.e., circular extrachromosomal DNA) afforded insight into cancer specific synthetic lethality. We will eagerly look forward to the additional indications, possibly beyond cancer, that our new understanding of topology-dependent synthetic lethality enables for targeted treatment. In your opinion, what will be the next big scientific breakthrough in life science industry? Zachary: The next big scientific breakthrough is the concept of topology-dependent synthetic lethality (i.e., where genes are architecturally located in the nuclear genome); this concept is in contrast to genomic synthetic lethality (i.e., what genes encode). Topology-dependent synthetic lethality is an utterly new concept and is based on the observation that circular ecDNA creates profound accessibility of the DNA encoded on the circle and those DNA remain accessible throughout the cell cycle. Open accessible DNA is available to the cellular machinery for DNA replication and for RNA transcription. Normally, these processes are tightly coordinated so that cells don’t try to replicate and transcribe regions of DNA at the same time. When they do occur at the same time, transcription-replication collisions also occur. These collisions damage the DNA and cause a shortage of precursors for synthesizing new DNA. Consequently, tumor cells that have ecDNA are under a great deal of replication stress, which creates a unique, druggable, cancer-specific liability.     Zachary Hornby President & CEO, Boundless Bio Zachary (“Zach”) Hornby has served in executive and director roles for multiple private and public biotechnology companies. He is currently a Director at Aardvark Therapeutics, Novome Biotechnologies, and Radionetics Oncology. Prior to joining Boundless Bio, Zach was Chief Operating Officer at Ignyta, where he oversaw development of the company’s portfolio of four clinical stage therapeutics and was the team leader for the company’s lead program, RozlytrekTM (entrectinib), which was the first drug in pharmaceutical history to garner the coveted BTD (FDA), PRIME (EMA). and Sakigake (PMDA) designations. In that role, he also led the business development process that resulted in Ignyta’s acquisition by Roche for $2 billion; after the Roche acquisition, Zach served as the Ignyta site head where he was responsible for overseeing the integration into Roche. Before assuming the COO role, Zach was Ignyta’s Chief Financial Officer, helping the company go public and raise $120 million in capital. Prior to joining Ignyta, Zach served in roles of increasing responsibility across business development, marketing, new product planning, finance, and regulatory affairs at Fate Therapeutics, Halozyme Therapeutics, Neurocrine Biosciences and Transkaryotic Therapeutics (“TKT;” now the Human Genetic Therapies division within Takeda/Shire) and was a life sciences consultant at L.E.K. Consulting. Zach holds B.S. and M.S. degrees in biology, with a concentration in neuroscience, from Stanford University and an MBA from Harvard Business School

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Delivering on the Promise of New Modalities: An Interview with Nikole Kimes, CEO & Co-Founder, Siolta Therapeutics

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. In our latest interview, we’re joined by Nikole Kimes, CEO & Co-Founder of Siolta Therapeutics, a clinical-stage biotech company that was awarded an NIH grant earlier this year and has raised $35 million to date for the development of live biotherapeutic products (LBPs) for the prevention and treatment of diseases of high unmet medical need. Siolta’s proprietary Precision Symbiotics platform has allowed the company to build a robust pipeline of potential first-in-class microbiome-based medicines and diagnostics for allergic diseases, women’s health, and rare pediatric indications. Congratulations on your recent NIH grant funding and thank you for joining us, Nikole. For drug discovery & development related to allergic diseases, what are the challenges in current therapeutic intervention, or current modality solutions? Nikole: Current medicines are exceptionally good at alleviating the symptoms of diseases; however, most approaches fail to address the underlying causes of disease and do not provide long-term benefits, particularly when dealing with complex multifactorial diseases that dominate modern society. Traditional pharmaceuticals typically involve a single molecule that targets a well-defined pathway and results in the alleviation of a specific symptom. Although the pharmaceutical industry’s investments in this approach have been successful in many ways, it leaves a lot to be desired if our ultimate goal is to cure diseases with modalities that do not require lifelong chronic treatments or better yet to prevent diseases from happening in the first place. To address these more challenging goals, we are currently witnessing a shift towards more dynamic approaches in the world of biologics. At Siolta Therapeutics, we aim to utilize the vast repertoire of genes and functionality that the human microbiome contributes toward maintaining human health to develop a new class of biologics, called live biotherapeutic products (LBPs), that offer long-term clinical benefit in disease areas where existing modalities have failed. What is your new modality or technological approach helping to address the challenges? How is it different from existing approaches? Nikole: We are embracing the dynamic and complex nature of human biology to develop next-generation microbiome-based medicines capable of addressing difficult diseases driven by multiple mechanisms of action. Improving upon food-grade probiotics and donor-derived fecal microbiota for transplantation (FMT) approaches, we are developing LBPs that contain defined bacterial consortia. To do this we isolate beneficial microbes from the human microbiome (i.e., fecal, vaginal, and other sample types) and combine synergistic organisms capable of reshaping and redirecting human physiology to maintain the metabolic and immunological balance required to support human health. Our approach initially incorporates human clinical data to direct early product design and requires an in-depth understanding of each microbe’s functionality (e.g., barrier function, pathogen inhibition, and immune modulation) and their complex downstream metabolic signaling to select the ones that provide the greatest therapeutic benefit for a given patient population. What are some critical challenges in realizing the full potential of your new modality or technologies? What are the solutions and do you anticipate any recent milestones? Nikole: Integrating the complexity of systems biology into more traditional drug development processes presents a number of challenges, including novel regulatory considerations, complex manufacturing, and unique clinical trial approaches. To address these challenges, we had to be creative throughout the entire R&D continuum to expand the in-house expertise needed to develop this novel treatment modality. From a regulatory perspective, we continue to work with the FDA to align expectations around the unique aspects of LBP development that make traditional toxicology, pharmacokinetic, and pharmacodynamic measures irrelevant. Our internal expertise was also essential from a manufacturing perspective, allowing us to overcome the difficulties associated with large-scale manufacturing of strict anaerobic organisms. Having overcome the many challenges of this exciting emerging field, we have safely and efficiently advanced our lead program STMC-103H into Phase 2, a proof-of-concept study in the US and Australia, for the prevention of allergic diseases (atopic dermatitis, food allergy, asthma, and allergic rhinitis) in at-risk newborns. Do you see novel technologies, AI or machine learning being used in the next couple of years? Nikole: Absolutely, machine learning is an important tool we use to identify and predict key features of a given system, and it plays an important role in our platform by supporting diagnostic development and informing patient stratification methods. This is an area that we believe will continue to have important contributions in our design of new consortia for a wide range of indications. Progressing beyond current machine learning methods to even more advanced AI-driven drug design (e.g., deep learning) will require incredible amounts of data across various populations and longitudinal timepoints. As we strive to move towards a precision medicine model in our healthcare system, we believe that developing diagnostic tests associated with the diseases we are targeting and recognizing factors that drive patient response are essential components of this equation, and core to our strategy. This approach can be iterative and allows us to identify new consortia combinations that could improve patient responses in distinct subsets of the population in order to have the most profound therapeutic impact. What do you think we will achieve as an industry in the next 10-15 years? What do you think are going to be some game changers in the future? Nikole: I would like to think that we will look back and appreciate a multitude of advances, including the incorporation of precision medicine concepts to improve efficacy standards and a focus on early intervention and prevention. Going from a symptomatic relief approach to disease-modifying will likely be one of the biggest changes we will observe. In addition, targeted approaches, such as gene editing (whether human or microbial) to treat genetic disorders, cell therapies for the management and potential cure of cancer, and microbes designed to prevent diseases before they start will transform our understanding of the human health. Interestingly, as we continue to embrace more complex approaches to drug development as evidenced in the world of biologics, I also believe we will begin to see even more transformative approaches through the combination of emerging modalities. There is a lot to be excited about!   Nikole Kimes, Ph.D. CEO & Co-Founder, Siolta Therapeutics Nikole E. Kimes, Ph.D., is Chief Executive Officer and co-founder of Siolta Therapeutics, a clinical-stage biotech company developing targeted live biotherapeutic products (LBPs) for the prevention and treatment of diseases of high unmet medical need. Siolta’s growing pipeline of first-in-class LBPs focuses on inflammatory conditions, women’s health, rare pediatric indications, and more. Dr. Kimes leads a talented and passionate team of researchers and clinicians with expertise in microbiology, immunology, bioinformatics, clinical operations, diagnostics, and manufacturing. An inventor of Siolta’s technology, her research in Dr. Susan Lynch’s lab at UCSF, also a co-founder of Siolta, provided the foundational translational research for the company’s formation. In addition to her scientific and entrepreneurial pursuits at Siolta, Dr. Kimes is the chairwoman of the Microbiome Therapeutics Innovation Group (MTIG) board, an independent 501(c)(6) coalition of companies leading the research and development of FDA-approved microbiome therapeutics and microbiome-based products to address unmet medical needs, improve clinical outcomes, and reduce health care costs. Dr. Kimes was also a member of the Springboard Health Innovation Hub: Life Sciences Track 2018 and participated in the 2017 California Life Sciences Institute’s FAST Program. She has over a decade of research experience in microbial ecology and host/microbe interactions, previously supported by a National Science Foundation (NSF) Fellowship and a postdoctoral scholar position at UCSF.

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