News

Innovation that Matters

Filter By

2022/09/23

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

Read more

2022/09/22

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.

Read more

2022/09/21

Delivering on the Promise of New Modalities: An Interview with Geoff Hamilton, Co-Founder & CEO, Stemson 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 recently sat down with Geoff Hamilton, Co-Founder & CEO of Stemson Therapeutics, an early-stage company focused on hair regeneration using stem cells to generate healthy new follicles as part of our interview series. Last year, the company secured $15 million in Series A Financing to create a hair loss treatment that makes net-new hair follicles. Stemson’s vision is to provide a solution to all patients battling the emotional trauma or social stigma of hair loss through a novel approach using the patient’s own cells. Thank you for taking the time to join us, Geoff. For cell therapies, what are the challenges in current therapeutic intervention in general? Geoff: The primary industry-wide challenge that cell therapy companies like Stemson face is the fact that we are working with cells as the therapeutical modality. The challenge of working with cells as the actual therapy is the ability to safely and scalability control these cells for the therapeutic endpoints. Cells are alive and have their own activities with a high degree of variability, which can pose huge challenges in establishing a level of control and reproducibility to have the cells perform the functions that we need on a consistent basis. Having tools, processes, and methods for making those cells more uniform, controllable and reproducible are probably the biggest challenges that not only face us here at Stemson, but also folks across the industry working on cell therapy solutions which are now widely in development across the whole industry. A large number of big pharma and biotechs are developing cell therapy-based solutions in their pipeline. What is your new modality approach helping to address these challenges? How is it different from existing approaches? Geoff: Stemson’s new modality uses a cell therapy approach to address the broad problem of hair loss across the human population. Hair loss affects all races, ethnicities, nationalities and genders; it’s very widespread, and has a tremendously negative effect on mental health, self-confidence and well-being. Until now, the therapeutic products brought forward to treat this condition were all small molecule or biologics-based approaches. Hair loss is a degenerative disease in the skin. Much like other degenerative diseases across the body, a cell therapy approach makes a lot of sense in terms of regenerating the tissue that’s been lost in hair. So, the uniqueness of our approach is that we are capable of making the cell types required to regenerate hair follicles. We leverage these cells as the starting materials to bioengineer a new supply of hair follicles to treat folks who have lost their hair. That’s novel. And there is no therapeutic solution available today capable of generating de novo hair follicles. What are critical challenges in realizing the full potential of your regenerative cell therapy? Key milestones anticipated? Geoff: The biggest challenge for Stemson in realizing the full potential of cell therapy to treat hair loss is how we use cells as the building blocks to engineer a functionable, durable hair follicle tissue that can survive once transplanted into the skin. Engineering cells is hard enough but directing that population of cells to work together to form a functional tissue that’s capable of engrafting successfully into a patient’s skin and surviving over the long term is the next big challenge. So, the key milestone driving Stemson’s focus will be the first-in-human clinical trial which we expect to begin following successful completion of our pre-clinical trials. Our initial animal data shows tremendous promise, but we need that first-in-human proof of concept to prove that this is possible and reproducible in humans. With many new modalities advancing into the clinic and getting closer to patients, how will the 2030 class of FDA new approvals look compared to those of today? Geoff: With many new modalities advancing into the clinic, there is a strong push forward across the cell therapy front. Cell therapy, rather than other types of biologics or other drug molecules, is going to prove to be a better approach to treating a number of degenerative diseases. With a robust pharma pipeline of cell therapies in development across many indications, I would expect the 2030 class of FDA new approvals to have a much larger share of these cell therapies making their way out into commercialization to treat broader patient populations. This will be true not just for companies targeting degenerative diseases but for companies attempting to modulate and tune immune cells to unleash the immune system on certain types of diseases such as cancer. For cell therapy development, do you see novel data technologies, AI, or machine learning being used in the next couple of years? Geoff: I do see machine learning and AI being put to heavy use specifically on cell therapies. The challenge of understanding the basic biological mechanisms with which we need to control broad populations of cells is a daunting challenge of biological variability. The complex genetic and proteomic interactions driving cellular behavior is such an enormous amount of data to consume even for a single individual cell. Typical analytical approaches to understand the drivers of cell function and behavior cannot be addressed effectively without the use of big data tools like machine learning and Artificial Intelligence. At Stemson, we collect large amounts of molecular data to tell us what is happening in the cells that we are engineering and what is happening in the tissues that we are engineering. The complexity of this data requires that we write and leverage algorithms with machine learning and AI to pick out patterns and correlations and statistical significance to help us understand what is going on across a broad population of cells and across many molecular mechanisms existing within those cells.   Geoff Hamilton Co-Founder & CEO, Stemson Therapeutics Geoff Hamilton is co-founder and Chief Executive Officer of Stemson Therapeutics. He brings 20 years of product commercialization and business executive experience in life science and biotech companies. Prior to founding Stemson Therapeutics, Geoff spent five years at Illumina, a Fortune 500 company and world leader in DNA sequencing technology, where he held leadership positions in marketing, product management, and strategic partnerships. During his time at Illumina, Geoff launched three instrument platforms and helped the company grow from $1.4B to $3.8B in annual sales. Prior to Illumina, Geoff spent ten years at Life Technologies (now a part of ThermoFisher Scientific) where he held various leadership roles in marketing, global commercial operations, and acquisition integration. He helped build the company from $1.2B to $3.6B in annual sales before the ThermoFisher Scientific acquisition. Geoff earned a Bachelor of Science in Business Administration from the University of North Carolina, Chapel Hill.

Read more

2022/09/20

Delivering on the Promise of New Therapies for Rare Diseases: An Interview with Lili Mao, Director of Clinical Development Unit and Head of Project Management Office at GEXVal

Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will accelerate development of breakthrough treatments to address the healthcare challenges of rare diseases. As we continue on this exciting journey to bring transformational medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases”. Thanks for taking the time to join us today, Lili! Before we start, could you please introduce yourself to our audience? Lili: My name is Lili Mao, Director of Clinical Development Unit and Head of Project Management Office at GEXVal. I’m a biochemist by training. After finishing research in academia as a postdoc fellow, I started my career in the pharma industry in drug discovery at Takeda, where this was the first time I realized the beauty of drug repurposing. GEXVal was founded in 2018 as a spin-out company from Takeda, focusing on rare diseases. We hope to deliver cost-effective and innovative treatment options to help improve the health and quality of life for patients and their families who are affected by rare diseases. What inspired you to work on Fragile X, and what issues are you trying to address? Lili: Access to medicine is extremely important in the area of rare diseases. We believe that all patients who are living with Fragile X syndrome should have accessibility to all the innovative drugs, but the current R&D approaches in the industry sometimes may not be a very good fit for drug discovery for Fragile X. As you hear from major media that research and development costs per approval has grown significantly in the past two decades. The current emerging therapies as treatment options, such as gene therapy or cell therapy, may further increase the R&D cost. In the current fast-moving pharma industry, there are so many shelved assets. Probably they are discontinued or put on hold for development, just due to changes in corporate strategy. So these shelved assets or shelved drug candidates are usually of high quality, and are brushed up, ready for clinical development. What we are trying to do here is to address this issue by repurposing the shelved assets, and reinvent alternative use of these assets to seek every opportunity, deliver an innovative and affordable drug for Fragile X syndrome patient. What unique approaches are you taking in the context of drug repurposing for Fragile X? Lili: When we think about to develop a drug for Fragile X syndrome, we believe that it is very important to deliver user-friendly medicine when we consider the daily life of patients and the caregivers. Our approach, or our drug candidate, is an orally-available small molecule. The mechanism of action has been proven to be clinically very safe. And actually the compound we are working on is a new chemical entity which was previously developed for non-rare neuropsychiatric disease, and IND-approved in the US for safety tolerability study. Now through our internal repurposing activity, we redirect the compound to Fragile X syndrome. What is the greatest and differentiated value of your modality or technical approach to the treatment of Fragile X patients? Lili: So when we study the publications or the current treatment regimen for Fragile X patients, we noticed that existing treatment options or drug candidates are very target limited. So we discovered that our candidate, GXV-001, preclinically has triple actions on the axis of hormone, neurotransmitter and the neurotrophic factors. And in fact, we also found this compound quite efficacious in addressing anxiety, autistic behavior symptoms, and social stress in non-rodent and rodent animal models. So with this data, we want to aim to develop a drug that has impact on a broad spectrum of symptoms in Fragile X syndrome, thereby to provide the patients with better treatment options, and hope to avoid polypharmacy. Could you share with us your progress with this candidate so far? What is the next milestone? Lili: Yeah, so we are very happy to announce that in June 2022 we received the approval for a phase I trial in Australia and we have started the enrollment of healthy volunteers for the study. We hope to have the first dose in human in July, or the third quarter this year. The next milestone will be, of course, safety, the first priority. So we want to first demonstrate the safety, tolerability in human, and also to prove that this compound has a favorable PK profile in human. We also want to obtain biomarker data, which will help us define the starting dose in phase II study, at which pharmacological effect can be affected in the patient population. In your view, how can we better address the complexity of Fragile X disease biology using biomarkers? Lili: So from my personal opinion and during my experience in drug discovery for Fragile X syndrome, I feel biomarkers studies are of high value. Ideally, I hope that there will be a biomarker that has a very good translatability from animal studies to clinical trials. So this biomarker, it can be a soluble biomarker, or a passive biomarker, and can be measured by wearable or portable devices. And with the biomarker studies, we hope to further expedite clinical trials in the future with such validated biomarker that may help to monitor advancing Fragile X syndrome disease biology. What do you hope the field will do differently in order to advance better medicines faster for Fragile X patients? What do you hope to see in Fragile X R&D in maybe the next 10 years? Lili: Yeah, so clinical feasibilities sometimes can be a challenge, such as access to the right patient population, and how to measure the endpoints or the outcomes, especially we have some interaction with our local clinicians in Japan. So to address such a challenge in terms of feasibility, we hope that our effort as a biotech or venture startup, together with the Fragile X community, can get this issue resolved by, for example, engaging in global study or employment of wearable electronic device, or having more validated or regulatory-approved evaluation tools to optimize the clinical trials. So eventually, I think we have the same goal; we want to deliver a better drug faster in the next 10 years, so I hope to see the first drug approval for Fragile X syndrome. And with this approval, I believe it’ll further raise awareness of the Fragile X syndrome. And then I think more Fragile X syndrome patients will get diagnosed and get treated at the earliest time point. Are there any innovative collaborations or partnerships models that the Fragile X community can follow in order to advance the field faster? Lili: That’s a very good question. So collaboration and partnerships are always appreciated, particularly that we are venture startups. As always, we require additional fundraising to move the project forward. So for this purpose, it’s very important for us to prove that we do have the right partnership with the patient advocacy groups and the clinical community to ensure we have the clear and correct path to deliver a drug. We also require a clear target product profile based on appropriate understanding of the unmet needs from the patients’ caregivers or clinicians. So it is always the best for us to have a long-term relationship with the patient advocacy group, and we hope to get support on say, clinical strategy, execution of the trials, and of course, fundraising. Patient centricity is important in ensuring high quality healthcare for patients. So what does patient-centric drug development mean for the Fragile X field? Lili: Yeah, so for Fragile X, patient-centric drug development means that we have to carefully understand the patients’ needs and then deliver the clinical strategy to address the needs. That is the basic principle. It also show me the shortest path to deliver an innovative and affordable drug accessible to anyone who are affected by Fragile X syndrome and are waiting for better treatment options. Finally, let’s think beyond Fragile X, in 2021 the FDA approved 50 new drugs. If we now imagine in 2030, do you think we will collectively be able to achieve 100 or more new drug approvals at half of today’s cost? And in doing so, will there be any major gaps to bridge? Are there any upcoming breakthroughs which you are most excited about? Lili: I am very confident that we can achieve such goal. I think the gap would be the R&D cost; however, I think this is something that can be solved. We’re very excited about the combination of strategically providing shelved assets, together with AI-assisted drug discovery. So we want to uncover the hidden value of such assets in a very unbiased manner. By doing this, we will definitely increase the R&D efficiency to finally successfully deliver a good, innovative drug to the patients. In fact, we have already been taking such approach at GEXVal for rare disease drug discovery. Now we are very excited in entering the next stage to prove that such a strategy will be one of the solutions to address the access issue to medicines in rare diseases. Thank you for your insights, Lili! Lili: You are welcome!     Lili Mao HEAD OF PROJECT MANAGEMENT OFFICE AND DIRECTOR, CLINICAL DEVELOPMENT UNIT, GEXVAL Dr. Lili Mao has extensive knowledge and experience in drug discovery for rare diseases. After receiving her PhD from University of Medicine and Dentistry of New Jersey, she continued basic research in Rutgers University and University of Minnesota as a postdoctoral fellow. Dr. Mao completed her doctoral degree in biochemistry and postdoctoral training in anti-viral drug development, where she achieved publications of research articles and book chapters including a chapter in Encyclopedia of Biophysics (2013), as well as two patents issued in the U.S. In 2015, she joined Takeda and started her career in extra value generation research unit for early drug discovery. In 2018, she started a new career as an entrepreneur and spun out from Takeda to focus on the rare disease drug discovery. At GEXVal, Dr. Mao is intensively engaged in business planning, fundraising, and served as CSO for two terms during startup phase leading the research unit to successfully complete the IND-submission. She is now Director of Clinical Development and Head of Project Management of GEXVal based in Fujisawa, Kanagawa, Japan.

Read more

2022/09/20

Delivering on the Promise of New Therapies for Rare Diseases: An Interview with Xinyu Zhao, Professor, Waisman Center and Department of Neuroscience, University of Wisconsin-Madison

Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will accelerate development of breakthrough treatments to address the healthcare challenges of rare diseases. As we continue on this exciting journey to bring transformational medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases.” Hello and thank you for joining us, Professor Zhao! Before we begin the interview, could you please introduce yourself to our audience? Xinyu: Hi, my name is Xinyu Zhao, I’m a professor of neuroscience. I’m also an investigator at the Waisman Center at the University of Wisconsin-Madison. This is a public university funded by NIH and private foundation and also the State of Wisconsin. What has inspired or led you to research on Fragile X? What issues are you trying to address? Xinyu: So I started working on Fragile X when I was a new assistant professor starting my lab in New Mexico. During my post-doc training, I was working on neural stem cells and plasticity and regeneration. And because of my interest in regeneration, I was working on adult neurogenesis. Adult neurogenesis is important for learning and memory and in lifelong learning memory. And so when I ran into this question about the Fragile X syndrome, I become really interested in knowing how the lifelong learning deficit… Basically, I became interested in answering the question, whether the lifelong learning memory deficit might be rooted from defect neurogenesis. And also at the time I had three little children myself, and so I became really interested in knowing the basis of a genetic neurodevelopmental disorders and try to find a way to treat that, from the point of view of a parent. And so that’s how I started working on Fragile X syndrome. So the first question I tried to answer using the mouse model was whether neurogenesis is defective in the Fragile X mice, and indeed we found that. Using that model, we identified the number of molecular targets and potential drug targets that might be feasible for developing therapies for Fragile X syndrome. And more recently I became interested in extending the mouse study into human studies. The reason is that many of the research based on mouse models have not really translated successfully into clinical trial and the treatment. Since I moved to Wisconsin 11 years ago, I’ve been working on human stem cell models derived from Fragile X patients. And that’s our more recent discoveries and research. What approaches are you taking in regard to gene therapies, targeted therapies, drug repurposing, or others? Xinyu: We kind of have a two-pronged approach. In my lab, we actually use parallel mouse models and the human patient-derived iPS cells. The reason we use these two models is because, in the mouse model we have, we could test some of the potential drug targets and for the purpose of drug repurposing. And we can use behavior outcome as a readout for some of this drug effect. Because of the limitation of the mouse model, we also use the human iPSC, induced pluripotent stem cell, models. Using those models, we try to understand the molecular mechanism underlying the function of a Fragile X gene, FMR1. From that, we can identify novel pathways and the novel altered mechanisms, providing the knowledge basis for drug development. What is the greatest and differentiated value of your modality or technical approach towards the treatment of Fragile X patients? Xinyu: One of the most important works we are doing recently is to derive iPSCs from patients with a distinct behavior and brain electric activity phenotypes. The reason we want to do that is because there’s a really diverse kind of representation and severity among Fragile X patients, and this diversity has contributed to a lot of the complexity in clinical trial design and the readout. So because of that, we decided to derive the iPSC stem cells from the patient with a distinct representation in their severity and drug response. And this is a collaboration with clinicians, basic scientists and computation scientists. Our goal is to try to identify, what are the underlying mechanism for these differences in severity, and can we develop an in vitro model in the cell culture model that we can test some of these drugs before they need to be applied to human clinical trial or patient treatment? So this is really exciting, because this is highly relevant to what actually need to be applied to patient in future and highly relevant to some of the more pressing and fundamental questions in Fragile X research and treatment. Could you tell us your research progress so far? What is the next milestone? Xinyu: Using mouse models we actually made a lot of interesting discoveries. We published quite a few papers and some of those mouse studies are now being tested in human stem cell models. We also collaborated with other people testing some of their discoveries in our human stem cell models. In terms of the human stem cells, we derive them into neurons in culture. And though we measure their electric activity, their molecular changes, we have actually discovered some very preliminary data showing differences among different Fragile X patient-derived neurons. And we are not sure even these are the underlying molecular differences among patient diversity, but this is the first step. So we’re really excited about this discovery. As for the next step, this work is right now ongoing, and we hope to have publications in the next couple years and to really contribute to the knowledge of Fragile X field. How do you think we can better address the complexity of Fragile X disease biology in order to identify new targets and biomarkers? Xinyu: So, Fragile X syndrome is, wow, a really complex disorder, even though there is, in most cases, a single gene mutation. The outcome and the representation of the symptom severity is quite different. Based on what I see, I would say that the kind of approach that may actually help us to develop better understanding and treatment is to use multiple different models. I talked about the mouse models and human stem cell models in my lab, but I also know people are using rat models and other type of models. I think in the future, if possible, we really should try to include more than one type of model, because each of the experiment model has its strength. If we can actually achieve our knowledge from using different models, we’ll be able to achieve our goal much easier. In addition to that, I really do think that we need to study the relevant cells from the patients, actually iPS cells, because we can differentiate them into neurons. Of course, if we have access to neurons directly, it will always be the best model, but that’s not possible. So when we derived iPS cells from blood, or skin fibroblasts, we can differentiate them into different neuronal types. And that give us models to study how and what kind of molecular pathways have gone wrong in different Fragile X patients. And then we can also identify convergent molecular changes and drug targets that may be in subpopulation patients, because it is possible that the diverse phenotype and representation of severity is rooted from a molecular mechanism that’s somewhat different in different patients. In your view, what would you recommend the Fragile X researchers to do differently in order to advance better medicine faster for the patients, and what do you hope to see in the Fragile X R&D in the next 10 years? Xinyu: I know there are a lot of talking about reactivating or reintroducing the gene into patients as a therapy, and I feel that before we know the function of the gene and what kind of off-target effect it can have when you overexpress it, we really need to know more about how this gene can be reactivated or reintroduced and the impact of misexpression. In addition to the current models, large animal models will be really useful. And so far other than mostly mouse models, rat models and human stem cell models, there’re really not that many large animal models for studying Fragile X syndrome. I think, even for gene delivery and drug delivery, large animal models will be really useful. And the other thing is, the Fragile X patient-derived iPS cells are actually very useful for us to understand the mechanism underlying the different symptoms, different phenotypical diversity among patients, and for us to test the drugs, because not all the patients respond to the same drug the same way. If we can have the iPSC models, we can address this issue and that will give us knowledge of which path we could target for which set of patients. So we have started on that with our work, which was initially funded by FRAXA and also by John Merck Fund. Now, we are expanding that work to study and unveil the mechanism underlying these differences. I think more of this type of work should be carried out. Are there any innovative collaboration and partnership models that the Fragile X community can pursue to advance the field faster? Xinyu: Definitely. Without that pilot funding from FRAXA and also from John Merck Fund, we would never have been able to derive these iPS cells from this group of patients. I’m referring specifically to our collaboration with Dr. Craig Erickson at Cincinnati. He has patients from this group and also extensive clinical information of these patients. So the partnership with John Merck Fund and with FRAXA have made a huge difference in terms of progress in this area. Now we have the system, there are pharmaceutical or biotech companies getting interested in working with us to test some of their drugs, because we have a good readout for neuronal excitability and mitochondria deficit or the different kinds of molecular changes we have detected in Fragile X neurons. So I think this type of a partnership and the pilot grant from non-federal funding will be very important to initiate this type of exploratory projects. And in the future, I think it’ll be really nice to have collaborative funding from multiple modalities, including federal and private foundation and pharmaceutical companies, and putting the money with academia to investigate specific questions together, because each part have their own goal, but together we can actually form this unified goal to try to answer this really important question and help the patients and the treatment development. Patient-centric drug development is very important in achieving high quality healthcare. What does it mean for you in the Fragile X field? Xinyu: Of course our primary goal is to help the patients eventually. I’m a basic scientist, so my first question is always, what is the mechanism behind this? Then once you discover the mechanism, you want to know, can we use this mechanism to help the patient in the long run? I don’t run clinical trials, but when I think about the long term goal, that actually motivates me to work really hard in my research projects. However, we realize that when we are doing basic research, we need to think about patients, and not just your knockout gene or inactive gene, then you have this consistent changes in every single individual, since we are very diverse in our genetic background and in our environmental exposure. So to develop that kind of patient-centric drug development, we actually have to treat the patients. We really need to think about that; they are not uniform. There are subgroups and there are differences in us. There’s severity and there are phenotypic presentation, and we need to consider that from the basic development of a molecular mechanism and identifying drug target all the way to clinical trial. If we don’t do that, we may end up with a very complex outcome that we cannot interpret. So, what I’m saying is that, we really need to develop this kind of patient-originated cells and the models. One reason why the Alzheimer field is advancing so fast is because they have a lot of postmortem brain tissue. Whatever they discovered in animal model, they can go into the human brain tissue to check if those changes really are there. But in the Fragile X field, we have very limited access to postmortem brain tissues, so those patient-derived iPS cells are good, but they’re cultured cells. They’re not from those patients who have suffered from those condition. So it would be really good to have an expansion of the brain bank. I know this is very challenging. We have worked with the Maryland brain bank trying to get some of the tissues and it’s really, really difficult. There’re very limited number of tissues available. So if we want to make a really big push for advancement of this field, we need to think about all the challenges. We obtain a lot of information from animal models, and one of the most challenging part in our work is to check that information in human neurons and human postmortem brain tissues. If we think beyond Fragile X for a moment, in 2021 the FDA approved 50 new drugs. Now let’s imagine 2030, do you think we would collectively be able to achieve 100+ new drug approvals at half of today’s costs? And if so, would there be any major gaps to bridge or any upcoming breakthroughs that you are most excited about? Xinyu: So I think drug discovery will actually become cheaper, in the sense that for many of the studies, we can use patient-derived iPS cells as a model to test before actually testing in human. So the advancement of human genetics and single cell analysis in recent years has unveiled many molecular pathways and many cell types that either share between humans and animal models, and also identify molecular pathways that can be unique to humans. Some of those pathways are important for drug targets. In the past, we have depended on animal models or cultures, like for example, white blood cells, as a model to testing our theories and our experimental hypothesis. And the limitation is animal models do not always represent the genetic background, the genetic changes in humans, and blood cells are not neurons. So the patient-derived iPS cells and human neurons really provide this unique opportunity for us to test a lot of our hypothesis. And also the single cell genetics and the extensive fast advancement of human genetics can actually identify all those changes we didn’t even realize. With the gene network analysis indicating what pathways might be changed in a disease versus a control healthy group, in cell type specific manner, this is really powerful development. I know many people already take advantage of this advancement and they develop novel software and methods to identify drug targets and potential ways to manipulate the disease conditions, so we can achieve a treatment. It would be really exciting to work in this field in the next few years to see how this develops. We are also working with computation scientists and bioinformaticians to use sophisticated computation method, including machine learning, to identify the changes at the different type of neurons in the brain, in the context of not just Fragile X, but also other diseases. So, I think this is really exciting time for drug development. Thank you so much for your inspirational insights, Professor Zhao! Xinyu: Thank you.     Xinyu Zhao JENNI AND KYLE PROFESSOR, WAISMAN CENTER AND DEPARTMENT OF NEUROSCIENCE, UNIVERSITY OF WISCONSIN-MADISON Dr. Xinyu Zhao graduated from Peking (Beijing) University with a B.S. degree in Biology and then earned her Ph.D. degree in Pharmacology from the University of Washington (Seattle). She obtained postdoctoral training on neural stem cells from Dr. Fred Gage at the Salk Institute for Biological Studies (La Jolla, California). Dr. Zhao started her own independent research at the University of New Mexico School of Medicine in 2003 and then moved to the University of Wisconsin-Madison in 2011. She is currently a Jenni and Kyle Professor in the Department of Neuroscience and an investigator of the Waisman Center. Dr. Zhao’s research focuses on understanding the molecular mechanisms that regulate brain development with the goal of developing novel treatment strategies for neurodevelopmental disorders including fragile X syndrome. She was recognized with a Research Award from the National Fragile X Foundation in 2018.

Read more