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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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Biocom’s President and CEO, Joe Panetta: Fostering Global Collaboration & COVID-19 Takeaways

Thirty years ago, Biocom was established to accelerate the success of California’s life science community. Today, the medical device and life science trade organization has expanded across the United States and throughout the world; pushing for advocacy, industry collaboration and global networking. What truly sets this multifaceted organization apart from other trade organizations is their unique membership and offices across the state, in Washington, D.C., and in Tokyo. They not only offer membership to biotech, medical device and pharmaceutical companies, but also to service providers. This innovation allows for immediate networking opportunities, where pharma, biotech, research, and academic institutions can collaborate on a global level. Leading Biocom is CEO and President, Joe Panetta. Joe focuses on Biocom’s strategic direction, guiding policy priorities, and advocating for the biopharmaceutical industry at the local, state, national and international level. Recently, Joe sat down with Rich Soll and the WuXi AppTec Content Team to discuss Biocom, their role in the fight against COVID-19 and Joe’s insights into future global preparations. WuXi AppTec: Please take a minute to introduce Biocom to our readers. Joe Panetta: Biocom is the life science trade association for California, headquartered in San Diego, representing 1,300 member companies and another 50 member companies in Japan. Biocom’s mission is to accelerate the success of California’s life science community across the state, across the United States and across the world. We have three main functions: first is to advocate at the local level, in the state capital and in Washington D.C., to work with policymakers in other parts of the world, and to help member companies raise the capital needed to move their products forward. Second, to train the current and future life science workforce, working with universities and other educational institutions to provide the opportunity for people to obtain degrees and certificates, and to share and gain knowledge through conferences, committees and networking events. Third, to provide a whole slew of goods and services, on the purchasing side, at discounts to our members who need to conduct lab research and operate their companies’ payroll, and healthcare benefits. WuXi AppTec: Can you elaborate on your organization’s efforts to combat COVD-19? Joe Panetta: Yes, and I’d like to recognize our 1,300 members who are working non-stop to get the world out of this pandemic. Our member companies are involved in developing diagnostics, therapies, vaccines, protective equipment and other types of products that deal directly with the COVID-19 virus. They also may be involved in other activities, which support initiatives to ensure we have an ongoing healthy population. Our companies need to continue to do the research and development, commercializing, and manufacturing, so success in addressing the virus and in developing products to support susceptible patients can be found quickly. Autoimmune diseases, heart disease, cancer, diabetes – all of these conditions contribute to the declining health of our population, making us more susceptible to the COVID-19 virus. Wuxi AppTec: How does Biocom directly support those companies and what is unique about Biocom? Joe Panetta: We support our stakeholders in multiple ways so I will illustrate four of those: strategic communication, company–industry relationships, advocacy at state and national levels, and cross company purchasing power. The first is we help our companies connect with each other. Our web-based coronavirus resource center, accessible on , allows our membership to match supplies such as personal protective equipment (PPE) with hospitals or other frontline healthcare workers. Second, we are providing the opportunity for companies to promote their technologies – so people know what’s available; to donate supplies they might have on hand; and to share their knowledge or experiences. For example, Illumina shared with us their well-thought out coronavirus emergency plans, which pertained to the safety of their employees and to ensuring their facility qualified as a virus free work environment. Additionally, we have companies that advise our small companies on how to access grant funding and small business administration funding. This comes out of the CARES act which Congress recently passed. So we are very much engaged in ensuring our members are connected, especially during perilous times like we’ve seen during COVID-19. Third, we’re also very involved in working with state and local governments to ensure we are having a dialogue that relates to the essential needs of our companies. We must allow employees who need to be in the office or in the lab into the buildings to do their work. Some of it is research that can’t be stopped and restarted again. ­Empty labs today mean fewer therapies tomorrow. Therefore, we are advocating for a smart way to allow our companies to let people come to work on the things they need to do. Fourth, we have a purchasing program. Our most prominent member is Thermo Fisher Scientific. Their subsidiary, Fisher Scientific is providing many of the technologies being utilized to develop the coronavirus tests as well a lot of laboratory protective equipment (PPE). The scope and depth of this relationship gives us enormous buying power, which benefits our members.                                                                                                             WuXi AppTec: Is the San Diego life science community skewed towards segments – small molecules therapeutics, biologics, and diagnostics vaccines? Joe Panetta: I think one of the advantages we have in San Diego is that we have a broad distribution of every type of company, and a broad distribution of therapeutic areas. We have a number of companies with expertise in anti-infectives and antivirals. In fact, one of the first antiviral drugs was developed here by Agouron Pharmaceuticals to treat HIV and AIDS. There is a high level of innovative start-ups in San Diego, which is why we attract large biotech and pharma companies, many of which arrived via acquisition of the local innovative companies. Finally, we are known as the genomics capitals of the world, with Illumina’s headquarters here. Their presence attracts other companies and researchers interested in working on therapies derived from genetic sequencing. WuXi AppTec: How important is collaboration in San Diego? Joe Panetta: At our heart really, we’ve been an organization that came together to allow people to collaborate in a network. When we talk about the San Diego community, the first word that comes to mind, and I hear it from everybody here, is collaboration. It’s a community of collaboration. Biocom has about 15 different committees that have actively worked together for many, many years to share best practices, connect with investors, and interact with government officials. They’re actually continuing to work together vigilantly throughout this pandemic. They’re holding video teleconferences, sharing advice, and then allowing us to access the advice and post it on our website. Our coronavirus website is another example of how we encourage collaboration by providing this exchange, this opportunity for people to share information and to access the technologies they have. We held a virtual breakfast meeting about two weeks ago, right after everyone went under the stay-at-home order; the event was successful. Additionally, we are now providing that information through webinars we’re doing now and into the future on different aspects of the pandemic and other topics that would be educational to our members. WuXi AppTec: The COVID-19 outbreak—what did we learn from this? Joe Panetta: I think the most important thing we’re learning from this is that we have to be vigilant all the time when it comes to the potential threat of any kind of viral or bacterial disease. The things we’re doing now are things we should have been doing before, like washing our hands, covering our mouths, getting our children vaccinated, eating healthy, and getting the flu shot, since most likely there will be a vaccine for coronavirus. Another lesson learned is the importance of collaboration that goes beyond partnership, technology acquisition and licensing. It is realizing the role that larger companies have in ensuring a healthy business community. WuXi AppTec: Can we better prepare for a future epidemic? Joe Panetta: We must make sure we learn from this experience from many angles. We need to have a coordinated effort at the local, state, and federal levels with a coronavirus czar to orchestrate and coordinate these efforts to improve preparedness, efficiency, effectiveness, and impact. We were not well prepared for this pandemic—no vaccine or therapeutic— so we must do better preparation in advance of the storm. We should turn these challenges of today into collaborative opportunities for solutions.  

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Biotechnology Innovation Organization’s (BIO’s) COVID-19 Lead George Scangos: The Call To Action

George Scangos was appointed on February 26, 2020, by BIO, biotech’s largest industry trade group, to lead the battle against COVID-19 – the highly contagious, deadly viral disease declared a global pandemic by the World Health Organization (WHO). His appointment coincided with Vice President Pence’s acceptance as Chair of the White House’s Coronavirus Task Force. Scangos assumes this role amidst an urgent need to address the swiftly spreading pandemic that has already infected more than 2.6 million people across the globe. Scangos will help BIO in its efforts to accelerate therapeutics, vaccines and diagnostics as scientists, public health experts, and policy makers seek to contain and mitigate the spread of the virus. Scangos is President and CEO of Vir Biotechnology, a clinical-state immunology company based in San Francisco, California. He was previously CEO of Biogen Inc., CEO of Exelixis Inc. and President of Bayer Biotechnology. Scangos discussed his new role at BIO and shared thoughtful perspectives regarding the challenges and opportunities faced today with Rich Soll, Senior Advisor for Strategic Initiatives and Head of WuXi AppTec’s Boston office, along with members of the WuXi AppTec’s Content Division. WuXi AppTec: Your new role is a huge undertaking. Can you tell us how you were approached about it and why you decided to take it on? George Scangos: BIO, for which I serve as a board member, was monitoring the rapidly spreading deadly virus attack (later named COVID-19) caused by a novel coronavirus (later called SARS-CoV-2) that the WHO decreed on January 30, 2020, to be “A Public Health Emergency of International Concern” after its initial detection in December 2019. BIO wanted to facilitate biotech’s efforts to find better diagnostics and to develop vaccines (prevention) and therapies (treatments) because none existed. I told BIO, they knew what VIR was doing in that regard, that we would like to be involved in BIO’s efforts. Then, I was asked by Jeremy Levin, Chairman of the BIO Board, if I would lead the efforts. I knew it would be an enormous undertaking, but I also think it is very important. WuXi AppTec: It’s still early in your tenure, but can you share more details about your responsibilities? George Scangos: Well, I don’t ever recall a pandemic like this in my lifetime that has had such a profound global impact. Furthermore, we were handicapped in our ability to prevent or fight the virus, because we had nothing to battle it with; no diagnostic, no vaccine to prevent infection, and no therapies for treatment. So I see my responsibilities really are to work with the BIO staff and the other members of the Board to accomplish our objectives. The first is to make it easier for members of BIO to bring forward potential treatments, cures, vaccines, and diagnostics. Second is to promote collaboration around technologies, skill sets and people. Third is to inform member companies in BIO of what the regulatory agencies are thinking, and what the government funding opportunities might be. Fourth is to promote the positive impact that our efforts are producing. WuXi AppTec: Through its leadership and member companies, BIO’s resources include some of the top scientists and academics in the industry. How does BIO leverage this knowledge base in its approach to such an enormous public health emergency from your perspective? George Scangos: BIO is doing a number of things but I will cite three. One, BIO organized a virtual meeting with government officials and BIO members to have a two-way dialog on what is needed and what companies have to offer. Two, a bulletin board to facilitate collaboration, and three, most pre-commercial biotech companies lack extra cash, so BIO helps in seeking appropriate funding. WuXi AppTec: Biopharma and biotech companies in particular have been highly engaged in the coordinated response to COVID-19. What in your mind has been notable and important regarding developments in recent months? George Scangos: Perhaps the two most notable would be how they have responded to a lack of PPE (Personal Protective Equipment) for healthcare workers on the frontlines, testing reagents and materials. The second is the dramatic increase in the number of big pharma and biotech companies working together on this specific problem, compared to the coronavirus diseases SARS and MERS. WuXi AppTec: Why such an interest in light of the shift away from infectious disease by Big Pharma? George Scangos: There was enthusiasm to do something for SARS and MERS but both were contained. SARS infected less than 10,000 people around the world but it could be millions of cases of COVID-19 by the time this is over. This should have been a wakeup call that there could be a coronavirus pandemic. And so, as this became clear in January that this was likely to be a huge epidemic, potentially a pandemic, a few companies started working. We at Vir already had been working on coronaviruses, so we had a running start. I think among the pharma companies there has been some efforts, but not all the pharma companies have expertise in infectious disease. Of those that do, it is hard for larger companies to simply shift on a dime in many cases. As this disease progresses, it increasingly seems that it will become endemic and not just be a single epidemic this year. It could be with us for a while, I am sure there will be more efforts. Currently there are lots of efforts around various approaches to treatment and prevention.       WuXi AppTec: Right. Actually, what is also interesting is the level of collaborations amongst these companies. It’s gone up significantly. For example, Vir aligned with Alnylam for its cutting-edge technology in drug delivery of short interfering RNA (siRNA) and with GSK on a multi-faceted effort to develop antibodies, therapeutics and vaccines. George Scangos: Right. There have been several announcements of companies joining together to understand and tackle the threat of COVID-19. So, the question is, what role does collaboration among companies and industries play in addressing the outbreak and protecting patients? For one thing, it is not business as usual. This is a pandemic, and people are dying, and they are dying now. More will die in the future. The sooner we can get something that actually reduces the disease or eliminates it, the better off the world will be. So we’ve put aside many of the normal constraints to push something quickly during this perilous period. We’ve just said, as have others, let’s start working together during this tough period while constraining matters are dealt with. And it seems to be working. I have to give companies a lot of credit because it is not clear if there will be financial returns– we’re spending money and diverting resources but it is the right thing to do. Most people I know who work in these industries are doing so because they are motivated by bringing medicines forward, which helps make patients better and saves lives. WuXi AppTec: This requires sustainability. George Scangos: It’s got to be sustainable at the end of the day but there are many scientific challenges with respect to this virus. For vaccines, will it be like measles, smallpox, etc.? Which work very well or will it be like the flu, which works only some of the time? We can’t predict that. One challenge with antibodies is that you have to make sure that the antibodies have a broad enough range and that the particular portion of the virus they interact with doesn’t really change much over time. So it’s difficult for the virus to become resistant. Small molecules have their challenges too because they need to be efficacious without toxicity. WuXi AppTec: Any other thoughts on COVID-19? George Scangos: Take social distancing seriously. You need to protect yourself as well as others and keep yourself from being infected. We need to slow down the spread of the virus so that we do not overwhelm our healthcare system.

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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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Tackling COVID-19 at a Potential Achilles Heel, siRNA: A Conversation with Alnylam’s CEO John Maraganore

Having recent success in lung delivery, short interfering RNA (siRNA) is poised to be a powerful new modality to treat COVID-19. Alnylam and Vir Biotechnology expanded their 2017 partnership earlier this month – leveraging Alnylam’s lung delivery technology of novel conjugates of siRNA with Vir’s expertise and extensive capabilities in infectious disease – to target SARS-CoV-2. Alnylam has already identified siRNA that targets highly conserved regions of coronaviruses, thus offering the prospects of broad coronavirus application. Because the discovery of RNA interference (RNAi) was considered so profound in understanding how genes are regulated in cells, a Nobel Prize in Medicine was awarded to Craig Mello and Andrew Fire just eight years later. Yet the translation of these fundamental findings into the first FDA-approved RNAi-based therapeutic, patisiran, took more than a decade. Discovered and developed by Alnylam, patisiran’s approval represented a crucial milestone for this transformational technology.                               John Maraganore is CEO of Alnylam, which he co-founded in 2002 with Phil Sharp, Phil Zamore, Paul Schimmel, Dave Bartel, and Tom Tuschl. Under his leadership, Alnylam has built a deep portfolio of drugs and drug candidates created by the platform—and has formed numerous alliances using RNAi to solve industry-wide problems. Rich Soll and the WuXi AppTec Content Team discussed Maraganore’s quest to apply this technology to stop the COVID-19 pandemic. WuXi AppTec: What motivated you to apply your RNAi experience to the fight against the coronavirus? John Maraganore: We have a technology that is very exciting and has great potential to target RNA as a way of developing novel therapies, and we’ve been successful in bringing these medicines to the market. Because our technology targets RNA and because the SARS-CoV-2 virus (the virus that mediates COVID-19), is an RNA virus, our technology is incredibly well-suited for developing a direct antiviral therapy. As the outbreak was being reported in China very early in the year, our scientists already began to start an effort to develop RNAi therapeutics that target the SARS-CoV-2 genome with the goal of developing a therapeutic for the treatment of COVID-19. The SARS-CoV-2 program builds a lot on what we learned from earlier experiences in virology programs on Hepatitis B and RSV. WuXi AppTec: Your Covid-19 program is partnered with Vir Biotechnology. Can you describe the relationship and recent expansion of Alnylam’s partnership with Vir in more detail?                                                                         John Maraganore: The Vir collaboration was started a couple years back when Vir was being established. ARCH Venture Partners, whom we know well through their investment in Alnylam was an investor in Vir. Vir CEO, George Scangos is a friend dating back to when he was at Exelixis and Biogen. The concept was to partner our infectious disease programs to Vir’s dedicated effort on antivirals. We can’t do everything at Alnylam, so Vir was the right fit for us. The key thing about this 50/50 partnership is that we give them development candidates, they do all the clinical testing through to the end of Phase II where we have the right to opt into the program on a 50/50 basis for free. Basically, we’re retaining half the value of the program to go into that collaboration after a lot of the risk is taken out of the program in even Phase I and Phase II. WuXi AppTec: Alnylam had designed and synthesized more than 350 siRNAs that target SARS-CoV and SARS-CoV-2 genomes in 48 hours, and Alnylam had been expecting to deliver 50-100 potent molecules. Did you achieve your goal and how was this enabled? John Maraganore: It’s the power of a platform that uses RNA sequence as a design element. We hope to select a development candidate within the next few months. As soon as that RNA sequence is around, we can begin to design these molecules and find very, very close molecules very quickly. WuXi AppTec: So it is clear you can design potent siRNA, but delivery has been a problem until more recently? John Maraganore: Yes, that’s fair to say. The company was started in 2002 yet up until 2010 or so, we were working on delivery and not really building our pipeline. However, when we finally conquered delivery to the liver, we learned a lot about how this delivery could be achieved to other cell types and other tissues in the body; for example, the CNS (central nervous system) and more recently the lungs. Fortunately, the lung delivery results came in recently so the timing was good with respect to siRNA therapy in COVID-19. The fact that our scientists were able to solve delivery to the lungs in animal models gave us high confidence that we could do this in humans, and therefore gave us high confidence to advance the SARS-CoV-2 program. WuXi AppTec: Persistence and patience paid off here. John Maraganore: It really did in our case. I mean, we’re really lucky that it turned out the way it did, and obviously we couldn’t be happier about the success we’ve been able to have. But it did include a number of near-death moments in the company. WuXi AppTec: What will be the regulatory pathway? John Maraganore: We will be dealing with the Center for Drug Evaluation and Research, CDER – the arm of the Food and Drug Evaluation (FDA), as the siRNA are prepared via a synthetic process for manufacturing. Once we have our developing candidates in hand, we’re going to engage with the FDA, the NIAID and the CDC to have the right discussions about what they want to see. We think a relatively truncated approach is going to be important. This will allow for us to bring a molecule into clinical testing as quickly as possible. It’s worth saying that the way we think this technology may work best is to give it as a preventative agent to people who are or have  been exposed, or to health care workers. As a result, it’s not likely a vaccine that will be given to everybody, but rather to a smaller part of the global population. WuXi AppTec: We’ve had 3 coronavirus outbreaks in two decades (SARS, MERS, and now COVID-19). How can we use Alnylam’s platform to be better prepared for the next virus?   John Maraganore: We’re targeting highly conserved sequences that have been 100 percent preserved all the way back to 2003 and the SARS outbreak that happened in 2003. This gives us incredibly high confidence that these molecules that we’re generating will be useful in the future for the next SARS epidemic. I say, the “next” one because I think that at this point we’ve got to realize that history is going to repeat itself. One thing that we’ve done in the past as a society is that we started initiatives in response to an event like SARS, MERS or Ebola, which then results in a big effort to try to find new therapies. However, in cases where the problems go away, so too does the interest of society – leaving projects in limbo and incomplete. I hope this time that is not the case. We need to finish the job. WuXi AppTec: For the last few minutes perhaps you can share your perspectives on 2 timely topics: state of innovation, can we reach 100 drugs/year approval rate in 10 years and are these incremental or transformative therapies? John Maraganore:  My impression on the state of innovation is that we indeed are operating at higher levels of innovation than before, in regards to gene and cell therapies. RNAi technology is a new modality that did not exist even 5 years ago and only now is being realized as novel medicines. The Center for Biological Evaluation and Research (CBER,) the arm of the FDA that approves biologics, has hundreds of applications under review. I would not be surprised if we hit one hundred or more approvals annually based on all the science that I’m seeing in the pipeline, perhaps in as little as 5 years.  

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