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Stronger Together: Steve Bates, CEO, UK BioIndustry Association Encourages a Fundamental Rethink

The UK BioIndustry Association (BIA) is a trade association focused on promoting the UK life sciences sector as a global hub for leading-edge research and commercialization, enabling the UK’s world-leading research base to deliver healthcare solutions that can truly make a difference to people’s lives. Steve Bates – BIA’s 12-year CEO, chair of the International Council of Biotech Associations, and Board member of Europabio since 2015, champions BIA’s initiatives. He stands as the industry representative for UK life sciences for both the government and the media, and fosters sector collaborations between research charities and academic institutions. Before BIA, Steve worked for Genzyme, as an advisor to the UK Government of Tony Blair and was made Officer of the Order of the British Empire (OBE) for his services to innovation in 2017. Recently, Rich Soll and the WuXi AppTec Content Team sat down with Steve to discuss the work of the BIA, their role in the fight against COVID-19, the UK biotech COVID-19 response, and his insights into the need for collaborative pandemic preparations. WuXi AppTec: Prior to COVID-19, what did you see as the biggest challenge for the life science industry in the U.K.? Steve Bates: As the third global cluster of life science companies in the world, UK efforts have been centered on global finance in Asia ­- China and Hong Kong in particular. The biggest challenge was to make sure that U.K. science could grow at the scale and pace that we see in the real hot spots, like Boston.   WuXi AppTec: What is a distinctive or unique aspect of BIA? Steve Bates: It’s the British approach to understated excellence. Through very deep, collaborative scientific engagement, we keep calm and carry on. The UK ecosystem is well networked, with many of the major global Pharma companies having R&D presence in the UK community. We’re fortunate to have a couple of the global players based in the United Kingdom.. We have links to our friends in Boston and there are many people working with colleagues in mainland Europe and Asia. The uniqueness is that for many people in biotech, their experiences within the UK ecosystem are part of their education. We find many of our friends in China have spent time in UK institutions. Many of the global players look to partner or innovate here in the United Kingdom. They do this through, direct participation, venture investment, or by supplying their presence in London through organizations like J&J Innovation. Many companies in the UK have strong linkages back to their headquarters in America or other countries. Traditionally, ­ the U.K. strengths have been in discovery science and early development, leading to collaboration with most of the major players. For example, Eli Lilly and Company recently announced a collaboration with Oxford-based Sitryx to develop immunometabolic medicines. Another example of U.K. bred innovation is Cambridge Antibody Technology, whose platform formed the core of therapeutics from Medimmune, which in turn was acquired by AstraZeneca. WuXi AppTec: What initiatives did BIA undertake in response to the pandemic caused by the SARS-CoV-2 virus which led to COVID-19? Steve Bates: I have been leading and coordinating efforts against the pandemic on behalf of the BIA, and would like to provide you with an overview of BIA’s contributions as of April 3, 2020. Due to the way we organize our membership, we have a very strong expertise in antibodies. This stems from our experience in understanding immune responses, which is now applied to the discovery aspects of COVID-19. Similarly, our past experiences in the use of antibodies as therapeutics and in prophylactic was embedded within Dr. Jane Osborne’s group who previously headed Medimmune U.K. We have been bringing various sectors and communities together. For example, in the UK there is a public sector effort around genomics, driven in part through collaborative access to the Wellcome Sanger Institute where genomic information is collected and analyzed. We’re gaining deeper understandings and insights which we hope will translate to yet more effective therapies in the battle against COVID-19. We are also working on a vaccine for COVID-19. Although no vaccine is currently available, this is a highly active space with around 40 vaccines or vaccine approaches in development around the world. In the UK there are two major groups. The Oxford vaccine is based on a chimpanzee adenovirus, which is modified to produce proteins in human cells that are also produced by COVID-19. It is hoped the vaccine will teach the body’s immune system to then recognize the protein and help stop the coronavirus from entering the cell. Clinical trials have just started. WuXi AppTec: Can you elaborate on the UK pipeline? I know it is very robust, particularly in biologics like therapies and vaccines. Steve Bates: Yes, that is correct, but there is more. One novel approach from Imperial College bears similarity to Moderna’s technology platform, targeting mRNA approaches to vaccine development. Our contribution has been to link a manufacturing and scale-up community to these efforts. If anything promising should arise from these or similar approaches from other groups around the world, we’re already thinking through and having in place the stages that are needed for the scale-up and manufacture. Our colleagues at WuXi AppTec are key players regarding this process in China. I believe we will be looking to partner and share as we go along, if any of these become of value outside the United Kingdom. I believe we have a really interesting group in antibody development. They are looking at vaccines in novel and mRNA approaches, as well as a promising adenovirus approach. This will help to display a more established route. We’re also keen to learning other approaches around the world. We’ve seen interesting approaches in Singapore on this, and other places which seem to be ahead of us, including China – which has been through COVID-19 for many more months than we have experienced thus far. WuXi AppTec: It’s terrific to see cutting-edge science on this translational path. What are the lessons learned thus far with respect to COVID-19? Steve Bates: I think it’s the extreme altruism and the coming together to face the challenge that we’ve seen from the community. People have put aside commercial differences, they have rapidly come together, and they are deeply interested in working at pace. I think the other aspect is that it is interesting how fast advancements are moving. WuXi AppTec: How important is collaboration? Steve Bates: We believe that ­ science is a team sport. We are used to working collaboratively with partners from around the world. We’re delighted to have been able to benefit from the Chinese experience of putting the genome into the public domain, and people have been working on that in the U.K. We’re always keen to collaborate with partnership in the US, and I think there is an opportunity through COVID-19 for other groups across the world to embrace a collaborative mindset. We’re seeing that happen at a pace and scale in the U.K. community and beyond, even at a time when it is difficult to do this, especially without travel.       WuXi AppTec: What do you see as the biggest need within COVID-19, is it in the diagnostics area, in therapeutics or vaccines? Steve Bates: I think we see that we’re going to need a combination of approaches. The immediate need is three fold: (1) social distancing to enable the health service, which has stepped up tremendously to take the increase in patients; (2) the need to increase testing, which is based on swab testing for active virus; (3) the ability to do clinical trial work on COVID-19. We still need an effective daily template to be rolled out in the U.K., which allows us to be keen to stay up with global developments; I would really like to track and visualize these changes on an almost day by day basis. Mapping out the entire process across vaccine development, diagnostics and therapies will be essential in our communication to the community. There is at least one other emerging area of importance in regards to the COVID-19 infection: antibody testing from recovered patients or patients who were resistant. The insights learned here may be beneficial to developing more reliable and faster diagnostics, therapies, and effective vaccines. This could represent an important part of the armory against the virus.          WuXi AppTec: Can we better prepared for the next pandemic? Steve Bates: There will be a lot of fundamental rethinks in the UK and Europe. These will include much closer workings between digital health and diagnostics. We will see the healthcare system move to much more preventative measures and screenings. Additionally, all fundamental underpinnings of our healthcare system must be diligently assessed and improved upon where necessary. I consider it a bright future. By collaborating internationally, we will continue to play a significant global role.

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Turning the Tides on Neurodegeneration the Denali Way, A Conversation with Ryan Watts, CEO.

While striving towards success in an area of imperative medical need, Denali Therapeutics looks to set a new bar in neurodegenerative clinical research. Established in 2015, Denali has built an impressive product pipeline, with over 30 partnerships, 15 pipeline programs, 5 clinical stage programs and multiple modalities – a notable accomplishment in light of the difficulty associated with neurodegenerative treatments. The company develops approaches to neurodegeneration using three principles: (1) genetic disease linkage – which highlights the important disease pathways for therapeutic intervention; (2) targeted approach to crossing the blood-brain barrier for optimal brain delivery of small and large molecules, and (3) biomarker-driven clinical trials to enhance the probability for success. As a company that is dedicated to a single disease area–neurodegeneration in diseases such as Parkinson’s, Alzheimer’s, ALS, and Hunter Syndrome–Denali credits over 30 collaborative partnerships covering industry and academia as a key element to its success. Rich Soll, Senior Advisor, Strategic Initiatives, and WuXi AppTec’s Content Team had an opportunity to discuss neuroscience, Denali and personal perspectives with Ryan Watts, CEO and co-founder of Denali Therapeutics. WuXi AppTec: Your thoughts on the “State of Innovation,” where are we? Ryan Watts: Having founded a company five years ago, and having been in the industry for twenty years, what’s pretty incredible is seeing new technologies enormously accelerate the drug development process. Within five years at Denali, for example, we now have five clinical stage programs. I think what’s happened with the speed of invention is that we can develop clinical candidates much faster and begin clinical trials sooner. WuXi AppTec: The FDA approves forty to nearly sixty new drugs per year. Do you think over the next ten years we’ll get approval for 100 new drugs? Do you think this is realistic? Ryan Watts I think the challenge in neurodegeneration is that the time to see a clinical benefit remains long and the costs remain high. Nevertheless, we have a deeper understanding of disease now, and have been developing molecularly targeted medicines in neurodegeneration that have the potential to be transformative. I certainly hope that new approvals will soon include a number of medicines for Alzheimer’s disease, Parkinson’s disease and other neurodegenerative diseases. WuXi AppTec: Do you see current approaches taken across the industry as incremental or transformative in your view? Ryan Watts: I think there’s great diversity across the industry, but certain approaches have become transformative. We’ve introduced new modalities to treating disease like antisense oligonucleotides and gene therapy. We have gotten so much better at molecular therapies and biologics and so you’re starting to see better and more transformative medicines. In neurodegenerative diseases, the ability to bring drugs across the BBB in therapeutic concentrations will be transformative. WuXi AppTec: How does technology shape the future and what kind of technological breakthroughs might be game changing in the next five years for you? Ryan Watts: I’d like to talk about what happened in the last five years and what’s been game changing, which is the ability to engineer the genome not only for a therapeutic approach, which still is a ways off, but also for research tools that are critical to developing medicines. Being able to generate cell lines or mouse models has been one major advantage; the ability to do high-content imaging and assess thousands of compounds rather than hundreds; and we can generate a variety of cells that are genetically engineered. In the last five years we’ve been able to do much more than we’ve been able to do in the previous twenty-five years. In the next five years I see these applications becoming translational. WuXi AppTec: What we see for the drug approvals today is kind of the fruits of what happened ten plus years ago so you can imagine that the work done today will translate into yet more transformative medicines. Thank you for your perspectives. Let’s discuss Denali itself, a company formed around neurodegeneration in an era where companies were just basically bailing out of the neurosciences. Ryan Watts: Yes. There are three broad buckets of neuroscience: neuropsychiatry, pain, and neurodegeneration and they’re all distinct in terms of their biology and genetic underpinnings. For us at Denali, we are looking to tackle big problems. Denali was founded with a singular purpose: defeat degeneration. Marc Tessier-Lavigne, Alex Schuth and myself previously worked together and founded the company in 2015. We have a very clear goal to invent medicines that slow or halt or cure Parkinson’s disease, Alzheimer’s disease, and ALS. As a smaller company that takes bigger risks while maintaining focus on the underlying mechanisms, we built the company around three principles. First is genetic pathway potential. So using genetics to define the targets and the pathways we work on, and most of that information is new within the last decade. The second is engineering brain delivery, or inventing medicines that cross the blood-brain barrier (BBB). Engineering small molecules and large molecules (antibodies and proteins) to cross the BBB is foundational. To do it, we have a biology team that’s focused on the BBB that teams up with the engineering team. Together this group is focused on technologies to help small and large molecules cross the BBB. We think that this is critical and in fact some of the disease areas we work on, like rare neurodegenerative diseases or liposomal storage diseases, have less biology risk. We know that in fact, the enzymes that are deficient in these diseases can be delivered systemically to treat as enzyme replacement therapy, but they don’t get across BBB. We see demonstrating that as one step toward a bigger challenge of solving Parkinson’s and Alzheimer’s. The third principle that we focus on is biomarker-driven development to show target engagement, pathway engagement, and or patient phenotyping; this is essentially integrated into everything we do. Developing and utilizing biomarkers allows us to de-risk and better predict success for our therapeutic programs. Now we are at a point where we have five clinical stage programs, four of which are small molecules and one is a biotherapeutic, and we’re expanding our biotherapeutic platform. WuXi AppTec: Can you elaborate? Ryan Watts:   LRRK2 is a gene that has been shown to be mutated in a subset of Parkinson’s patients resulting in hyper-activation of the kinase. We’ve developed kinase inhibitors that can cross the BBB that enter the brain, coupled with a biomarker-driven development plan. We also have RIP kinase inhibitors that are engineered to cross the BBB and are currently testing these in Alzheimer’s disease and ALS, and multiple inflammatory indications that are being developed in partnership with Sanofi. We have an EIF2B activator program, focused on ALS and maybe a subset of Alzheimer’s and vanishing white matter disease. It’s a modulator of RNA stress granule formation as a result of the integrated stress response. Again, it’s a small molecule engineered to cross the BBB. Denali has an enzyme containing biologic that we are testing for Hunter’s syndrome, in which about 70% of the patients have neurological disease with an early onset of neurodegeneration. Leveraging our transport vehicle (TV) technology, our investigational biologic has been shown to cross the BBB in animal models. This year is exciting for us as we have just read out our first Parkinson’s disease study. We plan to have four indications in which our medicines have been in patients. We’re planning on smaller biomarker studies initially, so that we can collect dose-related data to inform larger efficacy studies. WuXi AppTec: How did those partnerships arise? Ryan Watts: Partnering has been at the heart of building Denali. We’ve entered into over thirty partnerships. We have a number partnerships where we’ve brought technologies, molecules, or biomarkers into Denali from academic groups and other biotech companies. We have, for example, a license agreement with Genentech around LRRK2, which enabled us with intellectual property and molecules. WuXi AppTec:  This is a very significant pipeline. Given that the company came together in 2015, this is a very short time to have such a rich pipeline. Ryan Watts: We had a solid five-year incubation period. When we thought first about Denali in 2010, we didn’t feel like the time was right, for a number of reasons. The biggest is that we were just at the beginning of this uptick in genomic discovery for neurodegenerative diseases. We were just at the beginning of technologies to help therapeutics cross the BBB, and it was also early days with new CNS biomarkers such as imaging biomarkers in Alzheimer’s disease. That was the state of the field in 2010. Within five years, we have seen this incredible acceleration of genetic understanding of disease and new technology and that meant it was the right time for Denali. WuXi AppTec: Denali has a very rich and a very exciting pipeline. I wish you a lot of luck with that. Ryan Watts:  I think what’s great is even though some big pharma partners or pharma players are exiting neurodegeneration, I don’t think they’re exiting permanently. I think they’re expecting that companies like Denali are going to solve many of the foundational issues and look to future partnerships to be able to commercialize the medicines that we and others invent. WuXi AppTec: What do you see coming down the future? What’s the next breakthrough? Ryan Watts: I would foresee a world of more prevention. In Parkinson’s disease, for instance, it’s amazing how effective exercise is in helping slow progression. There will always be a role for medicines in disease management but I would hope that those medicines would be really focused on maintaining health and prevention, and then to the other extreme, to basically correcting disease. What does that mean for neurodegeneration? Right now the number one risk factor for neurodegeneration is aging. And then, combined with that, are the genetic and environmental factors. We don’t know yet what the environmental factors may be that are a risk for neurodegeneration. What we do know is that there are over fifty genetic associations in Alzheimer’s and fifty to seventy in Parkinson’s and maybe forty or fifty in ALS; genomics allows us to understand the pathways that are dysfunctional. WuXi AppTec: What do you see are your challenges? Or where do you see Denali five years from now? Ryan Watts: I would hope five years from now that we’re at the point where we are about to have our first medicine approved. Then we would be able to basically continue to invest in the discovery of these tailored medicines for neurodegeneration using, obviously, the success of those early programs. I also think a goal is to solve the BBB challenge in delivering drugs to the brain. To have technologies and enable medicine to readily cross the brain vasculature to treat neurological diseases including Alzheimer’s disease, Parksinson’s disease and ALS but also other diseases like glioblastomas, cancer metastasis, and neuropsychological diseases. WuXi AppTec: An exciting story, I must say and a great set of accomplishments. Ryan Watts: Thank you. We’re just getting started.

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Aridis Trying to Improve Infection Control for Cystic Fibrosis Patients with Alternative to Antibiotics

Aridis Pharmaceuticals is developing new drugs for infections prone to antibiotic resistance, including bacteria that regularly invade the lungs of cystic fibrosis patients. Cystic fibrosis is a rare disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, which leaves patients’ lungs susceptible to persistent infections and makes it difficult for them to breathe. The life-threatening disease affects about 30,000 people in the US and more than 70,000 worldwide, according to the Cystic Fibrosis Foundation. Aridis CEO Vu L. Truong said rare diseases present more challenges for drug developers than common illnesses, but cystic fibrosis “is one rare disease where the patients can feel very optimistic.” Truong explained that recently new drugs (such as Vertex Pharmaceuticals’ Trikafta), which target the underlying genetic defect in cystic fibrosis, have improved lung function, raising hopes of a cure. “But we also know there isn’t an on and off switch for cystic fibrosis,” Truong added. “Patients who have progressed from moderate to severe disease – and have lived with chronic lung infections and inflammation – have a lot of fibrotic (damaged) tissue in their lungs,” meaning they are still susceptible to severe infections. Inhaled antibiotics are the standard of care, Truong observed, but because patients must use them three times daily there is a high risk of the infections developing resistance. Aridis’ drug candidate is an inhaled alternative to antibiotics that kills bacterial infections through a different mechanism of action. Not only is the risk of resistance low, but also patients only need to take the drug once a week. As part of an exclusive series spotlighting rare diseases and the challenges of developing new drugs for these illnesses, WuXi AppTec spoke with Truong about his company’s innovative anti-infective therapy for cystic fibrosis patients. Truong is a founder of Aridis and was named CEO in 2015 after serving as chief scientific officer since 2005. He earned his Ph.D. in pharmacology and molecular sciences at Johns Hopkins University School of Medicine, and he has more than 20 years of experience in biopharmaceutical drug development. WuXi AppTec: What are the major differences in developing drugs for rare diseases compared with more common illnesses? What are some of the unique regulatory and business challenges you face in developing drugs for rare diseases? Vu L. Truong: In the rare disease area, there obviously are benefits and challenges that are quite different from that of common diseases, such as understanding the patient population, the unmet medical need, and the market opportunity. Scientifically the challenge is understanding if there are rational mechanisms of action in the disease that could be addressed to change the patient’s clinical outcome. With common diseases usually there are a number of solutions that have been examined and there are drugs in the marketplace. An understanding of some of the underlying disease mechanisms that would impart a positive outcome is reasonably established. And, of course, the patient population is relatively well-defined, as is the market opportunity. You have a good understanding of who is doing what among your peer companies. In rare diseases, typically you don’t have that luxury. You have less of an opportunity to leverage existing data on disease mechanisms and interventional approaches that could possibly help reverse the outcome. WuXi AppTec: Is clinical trial design more problematic? Is it more challenging to identify the outcomes you want to achieve? Vu L. Truong: That is part of the regulatory challenge because in rare diseases you often don’t have good clinical endpoints that are clear and pre-established. You have to do your best scientific work to estimate the primary and secondary endpoints that would be clinically meaningful and that can be objectively measured and robust enough to allow the regulators to have confidence the drug is going to result in a positive outcome when it is launched to a wider patient population. WuXi AppTec: On the business side of the challenges, is it more important to work closely with the patient advocacy groups when you’re trying to develop a drug for rare diseases? Is the relationship with patient groups different than when developing a drug for a more common illness, such as heart disease? Vu L. Truong: Absolutely. The rarer the disease, especially neglected rare diseases, the greater the challenges in terms of educating the public, the investment community, and the regulators of the pain points that the patient population is going through. Oftentimes you have diseases that are so rare it is hard to get even drug developers’ attention because the perceived market opportunity is not there. The rarer the disease the harder it is to get everybody’s attention, which adds to the importance of working with patient advocacy groups. WuXi AppTec: Aridis Pharmaceuticals is developing new drugs for infectious diseases. So how did you choose to focus on cystic fibrosis? Vu L. Truong: We felt that treating the chronic infectious diseases affecting cystic fibrosis patients was a well understood need with a defined clinical development pathway and clinical endpoint. When we looked at the dependency of these patients on chronic inhaled antibiotics – or even intravenous (IV) antibiotics – we knew there was a need for an alternative because chronic use of antibiotics eventually leads to a rise in antibiotic resistance and gradual decline in effectiveness. We noted an anti-infective with a novel mechanism of action and a low drug resistance profile would be differentiating. We also sought to improve the patient’s dosing regimen by developing something the patient would take less frequently. Current standard of care for these patients involves being tethered to an inhaler for about 20 or 30 minutes, three times a day. If you add up all time it takes these patients to administer their antibiotics and compound the time over their life span, the incremental years in life extension afforded by the antibiotics are spent by the patients treating themselves. So we sought to develop a differentiating anti-infective that has a combination of a novel mechanism of action (it is completely different from any antibiotic), a very low to no drug resistance profile, and a much less frequent dosing regimen such as once a week versus three times a day. WuXi AppTec: How important are US government incentives, such as the Orphan Drug Tax Credit, for developing rare diseases? Is that a critical component of getting drugs to these patients? Vu L. Truong: Absolutely. It is of critical importance because of the many challenges rare disease drug developers have to contend with. For example, some of the analytical assays used to define drug potency in vitro or in vivo are sometimes not well defined and the regulatory requirements to demonstrate fitness of a drug candidate to be tested clinically can be burdensome. Also by definition rare disease patient populations are smaller and therefore clinical trial enrollment is oftentimes a great challenge. This affects the requirement for patient sample size to demonstrate efficacy. A lot of times in rare diseases you barely reach statistical significance because there are just not enough patients to test and you may have to do a study that lasts three, five or seven years. That puts a lot of strain on the capital resources of companies, especially smaller companies like us. The selection of the clinical trial’s primary endpoint also is very important, and you need to have buy-in from the regulator. Sometimes the requirement of the U.S. Food and Drug Administration (FDA) for outcome measures may make it overwhelmingly difficult to obtain the patient population to achieve a magnitude of difference between the drug candidate and the placebo to get approval. So regulatory incentives are critical for drug developers to take a risk on rare diseases. And then of course there is also the risk of drug pricing. There is an increase in government pressure that filters down to the FDA, and that affects how much a drug developer should charge. Just the increased pressure on reimbursement has given drug developers pause for certain rare diseases. WuXi AppTec: How much progress has been made in developing drugs for cystic fibrosis? Vu L. Truong: There has been substantial progress. This is one rare disease where the patients can feel very good of the prospect of a cure. The (chloride) channel correctors (that address the underlying genetic cause of cystic fibrosis) have given these patients more hope than they have ever had. They are starting to work, and the life extension data are starting to come in. The data on moderate decline in dependency on chronic inhaled anti-infectives also are starting to come in. There is a great sense of optimism that a cure already has arrived. With channel correctors, such as the drug (Trikafta) that Vertex Pharmaceticals makes and the drugs other companies are developing, there is a steady improvement in channel function and these patients are starting to have fewer pulmonary exacerbations. They are starting to feel healthier. I wouldn’t say there is a complete cure. The data are still being accumulated. But certainly there has been a dramatic impact on clinical outcome. But we also know there isn’t an on and off switch for cystic fibrosis. Patients are not cured right away. Those who have progressed from moderate to severe disease – and have lived with chronic lung infections and inflammation – have a lot of fibrotic tissue in their lungs that may be very difficult to reverse. You may be able to correct the genetic defect, which is the function of the chloride channel, but as the disease accumulates over years and decades, patients’ lungs become more fibrotic; that is, the lung tissue becomes damaged and scarred. So there always is a set of conditions that cannot be reversed even though you have corrected the genetic defect. The lung damage that has accumulated over the years means that the patients’ lungs are always going to be compromised. WuXi AppTec: Now let’s talk about your research and drug develop program. What is your drug candidate and how does it work? What will it accomplish? Vu L. Truong: When we looked at the anti-infective standard of care that these patients are using – and we were also keeping an eye on these channel correctors that were being developed – we asked, if you’re going to develop an anti-infective where are the unmet needs? Standard of care has been the inhaled antibiotics. Two drugs of note are TOBI, inhaled tobramycin, which was commercialized by Novartis. The other one is Cayston (sold by Gilead Sciences), which is inhaled aztreonam. These are off-the-shelf antibiotics that have been reformulated for inhaled delivery. These drugs are prone to antibiotic resistance just like all antibiotics. They have a demanding dosing regimen – three times a day, every day, for a month and then a month off. So these patients get the antibiotic treatment for a month and then they have a drug holiday month. The month-long drug holiday is imposed because of the worry of chronic exposure to antibiotics and development of antibiotic resistance. When the patients are on the drug holiday month, the bacteria begin to build right back up in their lungs and they feel terrible. We asked, how can we make a difference? We wanted to find a drug candidate that uses a different mechanism of action and is less vulnerable to drug resistance, eliminating the need for a drug holiday. The drug also would have to be effective throughout the patients’ lives whenever they show a high bacterial burden in their lungs. So we sought to develop gallium citrate, which is not an antibiotic. It’s a small molecule anti-infective. It works very differently from all antibiotics in that this drug acts as an iron analog to starve bacteria of iron. All microbes require iron as a key nutrient. If you withhold iron from bacteria, both gram negative and gram positive, they all die. So wherever iron binds to bacterial cells, the drug also binds, blocking the iron. The drug may even dislodge iron. Iron is involved in many enzyme mechanisms in the bacteria, and gallium citrate is one drug that hits multiple gene products inhibiting these mechanisms, such as cell wall synthesis, protein synthesis, and metabolic maintenance. For bacteria to mount an effective mutation leading to drug resistance, the mutations would have to occur simultaneously in multiple enzyme pathways. Antibiotics, however, target only one pathway. All the bacteria have to do is develop resistance to that one target and the antibiotic is ineffective. We call our drug candidate, AR-501, and it is currently in Phase 1/2 clinical testing. We are working with the Cystic Fibrosis Foundation, which is sponsoring the clinical study. The patients receive inhaled AR-501 once a week, instead of three times a day every day. We think the combination of a much more convenient dosing regimen, much lower drug resistance risk, and no month-long drug holiday, will be a game-changer for inhaled anti-infectives for cystic fibrosis patients. We expect to submit a new drug application for approval with the FDA some time in 2026. Even with all the channel correctors rolling out, these patients are still going to be dependent on inhaled antibiotics or inhaled anti-infectives for decades to come before we know for sure whether there is a complete cure for cystic fibrosis. WuXi AppTec: This last question is aimed at getting your insights on drug development in general. What technological breakthroughs in the drug development process might be game-changing in the next 5 years? Vu L. Truong: CRISPR will continue to provide the next revolution in the drug development process. Rare diseases will likely have among the most benefit from CRISPR because of the ease with which gene editing can be applied to correct genetic defects.

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WuXi Healthcare Forum 2020 – Solving Tomorrow’s Health Challenges

To Be Determined|The St. Regis Shanghai Jingan, Shanghai, China Dear Colleagues and Friends, Given current efforts to address the coronavirus outbreak, the organizing committee of the WuXi Healthcare Forum has decided to postpone this event, originally scheduled for February 25-27, 2020. We are closely monitoring the situation and will provide an update regarding new dates for the Forum, pending further assessment of the situation and in compliance with guidance from the relevant authorities. This situation, which continues to evolve daily, reminds us that we must continue to do the right thing for patients, both individually and collaboratively. We look forward to prioritizing these efforts with you at the WuXi Healthcare Forum in the near future. Best regards, WuXi Healthcare Forum Committee —————————————————————————— The second annual WuXi Healthcare Forum will take place once again at The St. Regis Shanghai Jingan in 2020. The Forum 2020 will expand upon the successful inaugural event in 2019, which attracted 6500+ global applicants, 2500+ senior executives, and 90+ speakers from 25 countries. This global event, themed “Solving Tomorrow’s Health Challenges” , will focus on 3 distinctive subthemes: 1) State of Innovation – Global and Regional Perspectives; 2) Race to the Cure – Transforming the Way We Treat Diseases; and 3) Innovation 2030 – How Technologies will Shape the Future of Healthcare . It will bring together innovators, entrepreneurs, clinicians, healthcare providers, and future technologists from the world to promote new thinking that will shape future healthcare solutions. From disruptive technologies to precision diagnostics, from breakthrough therapies to preventive care, and from new players to new collaboration models, the forum provides unparalleled access to our industry’s most respected movers and shakers – delivered through 3 days of visionary keynotes, 300 intimate CEO roundtables, private 1-1 meetings, and a world of networking opportunities. Global challenges need global solutions. Hosted in Asia, which accounts for 60% of the world’s population with huge unmet healthcare needs, there cannot be a more fitting location. Please click HERE to enjoy a 2 min video of the inaugural event that captures the sheer energy as we collectively seek new solutions to global healthcare challenges. The 2020 Forum ( will build upon the successful inaugural event in 2019 which attracted 6500+ global applicants, 2500+ senior executives, and 90+ speakers from 25 countries. Highlights of WuXi Healthcare Forum 2020 Main Forum: 3000+ attendees engaging with 150 global leaders and dynamic new voices will deliver 3-days of visionary keynotes and 30 wide-ranging panel tracks. Complimentary to all attendees upon confirmation of registration. CEO Roundtables: 300 innovative companies will showcase their innovative products, and technologies. C-level executives can apply to host a roundtable. Hosting is complimentary upon approval. Satellite Forums: 12 independent satellite events co-located with the main forum. Organized by our sponsoring partners. Exclusive One-on-One Partnering Meetings: three days of private 1-1 discussions with leading investors and pharma/biotech partners. By-invitation from our sponsoring partners. Receptions and Networking: many networking opportunities built around the 3-day forum. By-invitation from our hosts and sponsoring partners. This event is by invitation-only and complimentary. Please request attendance ONLINE, or click HERE to contact us if you would like to inquire about hosting a CEO roundtable or sponsoring opportunities. The Forum agenda will be announced in January. We welcome you to join the conversation!

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TDI Serves as a Bridge Between Academia and Industry, Leveraging All It Needs for Innovation

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team The translation of academic discoveries into therapeutic products remains an issue despite passage of the Bayh-Dole Act (or Patent and Trademark Law Amendments Act) in 1980.  That Act, for first time, allowed academic institutions to capitalize on discoveries that emerged from their faculty’s labs.  Boston, San Francisco and San Diego nurtured cutting-edge entrepreneurial environments for spin-outs from academic science, but New York City, one of biggest recipients of NIH funding, lagged far behind the big-3 bioclusters. Tri-institutional Therapeutics Discovery Institute (TDI) was born in New York City as a not-for-profit research center to explore the early steps of advancing scientific breakthroughs from bench to bedside.  The goal of the Institute is to advance ground-breaking discoveries from scientists at the Memorial Sloan Kettering Cancer Center, The Rockefeller University and Weill Cornell Medicine through preclinical studies. Leading TDI as the Sanders Director since 2018 is Dr. Peter Meinke, a 20+ year industry veteran from Merck Research Laboratories with broad experiences associated with multiple facets of drug discovery and development. He was a recipient of the coveted American Chemical Society’s Heroes of Chemistry team award in 2017 for his leadership in the discovery of the antiviral NS5A inhibitor found in the fixed-dose combination product known as Zepatier,® a therapy for the treatment of Hepatitis C. Dr. Meinke recently sat down with Dr. Rich Soll and members of the WuXi Content Team to share his experience managing a unique organization like TDI as well as provide insights on drug development and observations of the industry’s dynamics and trends over the years. Rich Soll: How does TDI work toward its goal? Peter Meinke: TDI provides industrial-scale technical support for academic projects, making it possible to rapidly assess the utility of specific therapeutic targets in disease-relevant contexts in ways that are unprecedented in scale and scope for an academic environment. This is accomplished through a series of highly favorable academic-industry partnerships established through TDI, as well as our Innovation & Education Initiative, which provides community-wide training and support in order to maximize the impact of these partnerships on academic drug discoveries. We achieve our mission by leveraging the infrastructure, staff and intellectual capital of our academic and industry partners, as well as the generous support of philanthropists. Rich Soll: How many projects do you have and what is the process for selection? Peter Meinke: Currently, we have twenty-three therapeutic programs, almost equally split between biologics and small molecules, and our programs are structured as collaborations so we are able to leverage the expertise of the labs.  And we have built an early portfolio of about twenty-five Early Stage programs, using about 10 percent of our resources, so we now have a pipeline of projects. To decide which programs to undertake, we have an annual RFP process, but we also take in programs on a rolling basis over the course of the year. We have an independent scientific advisory board made up of people who are often former C-Level executives from Pharma and Biotech, all of whom have international reputations. Our SABs look at potential programs and use their best technical judgments, rank ordering them just as in an NIH grant review process, and then we set a funding line. We probably accept somewhere between a quarter and a third of all applicants on a historical basis. We also have project-specific advisory boards to provide technical expertise that we, or the Tri-I labs, lack. Rich Soll: So what about the historical success rates? Peter Meinke: We’ve accepted 60 biologics programs in just about six years, and 68 small molecule programs. Our total output to this date is we’ve contributed to two NewCos (new companies) and licensed six programs to biotech or pharma. We had one program where the PI declined to accept the license because he’s an MD/PhD with unique skills who recognized he could take it close to the NewCo stage and clinical validation before partnering. We have three programs that are available for license, which we validated in animal models. We have 12 additional programs for which we have obtained animal proof of concepts for new mechanisms, five of these are under active licensing discussions and they’re split almost equally between small molecules and biologics. This is a pretty remarkable output. I think it’s about 20 percent overall. Rich Soll:  External collaborations and partnerships are vital, especially in today’s R&D. How is that implemented at TDI? Peter Meinke:  Because of the way we’re structured, we can only work with faculty from these three communities.However, many of the programs that we work on also have a collaboration with faculty from other New York, US or international universities. Takeda is our general partner, but many of the programs that we support do not align with Takeda’s interest and Takeda is happy for that because they get access to cutting edge research in areas that they are of strategic focus. For projects not within Takeda’s strategic interest, the institutions created a for-profit, virtual company called Bridge Medicines to continue translational development of the asset. Being a virtual development company, Bridge Medicines relies heavily on the use of providers, particularly WuXi AppTec. Rich Soll:  How has TDI used WuXi AppTec? Peter Meinke: Currently, we have over 100 providers and platforms under contract with TDI and we have a wide range of specialists that we work with for new things. With respect to WuXi AppTec, we make very heavy use of chemistry services. We do use a lot of biological profiling, but that ebbs and flows depending on the nature of the programs. We use WuXi AppTec very commonly to build assays and miniaturize them for high throughput screenings.  WuXi AppTec has counterscreens for key off-targets which are very important to TDI because we learn more about our compounds’ profiles. We also will perform animal pharmacology studies to support projects. For example, we encountered a situation on one mechanism where an off-target liability required a sophisticated animal study that is in the suite of experience that WuXi AppTec offered.  We worked with WuXi AppTec senior scientists to make sure that we designed the study to de-risk this mechanism-based liability in animals as a key component of advancing the program. If that had been a negative result it would result in program termination, so it was important that study be done right and with appropriate standards. WuXi AppTec scientists were instrumental in ensuring that it was designed properly and appropriately controlled, so that we know it was executed to a high technical standard. Our molecules did not have the adverse signals. We couldn’t possibly do that internally. And we have variations of that on the biologic side in terms of antibody generation, antibody maturation, and so forth. Rich Soll: What is different leading an organization like TDI in comparison to previous positions? Peter Meinke: Leading an organization like TDI has been very different, incredibly enjoyable and very rewarding for me. The environment here is filled with experienced and creative scientists in different scientific disciplines with diverse expertise. TDI is well-resourced, but it is not pharma, so everything we do matters. We continuously ask ourselves “what is the key impediment that stops a program or asset from progressing.” It’s all about quick decision-making and devoting resources to solve the problem, even if deemed risky.  We leverage our externalized networks to augment anything we can’t do internally. I can do that today because of the way industry has evolved. I have a working relationship with WuXi AppTec that goes back to its earliest days. I’ve seen the type of complexity that they can handle on both small molecule and biologic fronts. TDI has its internal labs but, importantly, does not need to build a large chemistry or biologics department because we can leverage the capabilities of WuXi AppTec. Rich Soll: When you take a look at the world of R&D and pharmaceutical discovery, how has it evolved? What trends have you observed? Peter Meinke: The growing role of biotech and academia is clear. There is an increasing amount of large pharma’s pipelines coming from small biotechs and academia. People with real talent and drug discovery experience who once worked for pharma have migrated to the sea of small companies that are doing innovative and highly risky programs that address a recognized unmet need. These small organizations typically only have one, or a few, projects. They have very limited time and bandwidth to be successful, so they are incredibly focused on trying to show that “yes, this hypothesis has legs” and “yes, it will help treat some disease or another.” And then, when they get to a certain point, pharma, which has the resources and the wherewithal, will swoop in and often acquire/partner with these smaller organizations to really move it fast into clinical applications and real-world use. Rich Soll: If you had access to one technology that could make a difference, what would that be? Peter Meinke: One of the greatest challenges in the small molecule world is actually getting a suitable starting point of high quality. So, I pay a great deal of attention to computational technologies that allow me to generate this starting point. We pretty much have unrestricted access to Schrodinger’s software, and we have three full-time computational scientists using these tools, which lets you understand how valuable it is for TDI. Rich Soll:  Do you see opportunities here for cancer to go from treatment to cure? Peter Meinke: It’s pretty clear to everybody that immuno-oncology, for example, is as profound a change for treating cancer as was the discovery of antibiotics, and you know the use of IO is extending past oncology applications. This has led to the development of the Car-T platform which you can view as the next generation, and from this are emerging even more and more changes. People are really starting to learn how the human body’s immune system actually controls disease states, so if you can modulate this in an appropriate fashion, it has really profound impacts, which are already extending beyond cancer treatments.

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