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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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Harvard’s Francisco Quintana Explores the Impact of Environmental Factors on the Pathogenesis of Multiple Sclerosis

Multiple sclerosis, an autoimmune disorder, is one of the more prevalent rare diseases worldwide. An estimated 2.3 million people are living with multiple sclerosis, whose cause remains unknown. Francisco J. Quintana, Ph.D., professor of neurology at Harvard Medical School and the Ann Romney Center for Neurologic Diseases at Brigham & Women’s Hospital, is researching the role immune system cell signaling pathways play in the progression of multiple sclerosis and other neurodegenerative diseases. His exploration of these pathways has yielded targets for potential therapeutic intervention in treatment of secondary progressive multiple sclerosis, which is a primary focus of his research, and also in other neurodegenerative diseases. Progressive multiple sclerosis is a later, more debilitating stage of the relapsing and remitting form of the disease that affects most multiple sclerosis patients.  Another unique element of Quintana’s research is the identification of environmental factors, such as herbicides, that can affect central nervous system inflammation and neurodegeneration involved not only in multiple sclerosis, but also Alzheimer’s and Parkinson’s diseases. “When we look into any immunologic or neurologic diseases it is very clear it’s not only genes that drive their development, but also environmental factors like exposure to chemicals,” Quintana explained. As part of an exclusive series spotlighting rare diseases and the challenges of developing new drugs for these illnesses, WuXi AppTec Communications spoke with Quintana about his Harvard laboratory’s research efforts. Quintana earned his undergraduate degree from the University of Buenos Aires and his doctorate in immunology from the Weizmann Institute of Science. In addition to his post as professor at Harvard Medical School, he is an associate member of the Broad Institute at Harvard and MIT, and he is the president-elect of the International Society of Neuroimmunology. WuXi AppTec: How does researching new drugs for rare diseases differ from research into more common diseases? Francisco Quintana: There are two main differences. On one hand you have a more limited number of clinical samples you can access in order to identify mechanisms of disease pathogenesis. That ultimately makes it more difficult for you in terms of the things you can access from the scientific community. Those samples are more precious, so not everyone has access to them. The second point, which I think plays a critical role, is if you are working with a rare disease then you probably have fewer patients available on which to test your drug candidate. WuXi AppTec: How much progress has been made in multiple sclerosis drug research and development over the 20 years? Francisco Quintana: There have been significant advances, but those have been limited to a very specific phase of the disease. The reason is that multiple sclerosis initially presents in most patients as the relapsing, remitting form of the disease, in which patients endure a neurologic attack and then they will do better. This is a cycle that can go on for years. However, eventually most patients transition into progressive multiple sclerosis in which they accumulate a neurologic disability without recovering from attacks. And that’s important because over the past 25 years we have developed, as a community, multiple drugs that target and benefit patients affected by relapsing-remitting multiple sclerosis, yet there is still a huge unmet clinical need for drugs that target the progressive phases of the disease. WuXi AppTec: How did you get involved in research on multiple sclerosis? Why did you choose this particular disease? Francisco Quintana: I think it has to do with a history of neurologic disease in my family together with my interest in immune and autoimmune diseases. WuXi AppTec: What is the focus of your research? Francisco Quintana: Basically we are interested in mechanisms of regulating immune pathways that regulate T-cell responses. As part of those studies we have identified multiple signaling pathways involved in that, including the aryl hydrocarbon receptor (AHR) for which we developed a nanoparticle that can therapeutically target the receptor. The nanoparticle has been developed as novel therapies targeting central nervous system (CNS) autoimmunity and also autoimmunity targeting other tissues besides the CNS. In addition, we have also identified other pathways that play the same role in controlling effector T cell responses. One of the most exciting things we are doing is being very focused on trying to identify mechanisms that control inflammation in the CNS driven by resident cells, such as microglia and astrocytes. That’s important because the mechanisms that control those cells are thought to drive inflammation and neurodegeneration in progressive phases of multiple sclerosis and other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. We believe that by identifying what regulates and controls astrocytes and microglia we can identify therapies for the secondary progressive stage of multiple sclerosis and for other neurodegenerative diseases. As part of our studies we also have identified pathways by which the environment, the gut flora, metabolism, microglia and T cells control astrocytes and microglia for inflammatory responses. WuXi AppTec: Have you licensed any of your research for clinical development? Francisco Quintana: We have established a start-up company from our laboratory which is focused on the development of nanomedicine for antigen specific T cell modulation, and that was established initially in partnership with Pfizer. Pfizer already has in-licensed one of our products, which is targeted at Type 1 diabetes. We’re in the process of partnering with other companies. We have developed products that will be useful for T cell specific modulation in other diseases, including celiac disease and multiple sclerosis. In addition, we have novel inventions/targets that are available for licensing. WuXi AppTec: What kind of environmental factors are you investigating in relation to inflammatory responses? Francisco Quintana: When we look into any immunologic or neurologic disease, it is very clear it’s not only genes that drive their development, but also environmental factors like exposure to chemicals in the environment, which go to the gut microbiome. That can affect the development of autoimmune disease and neurologic disease in individuals who have specific genetic backgrounds. What my laboratory has done is to identify many of these factors and use these environmental chemicals as probes to identify novel mechanisms that regulate CNS inflammation. That has also led us to identify novel pathways that regulate CNS inflammation, which in turn has led to the identification of potential novel approaches and therapeutic targets. WuXi AppTec: What specific environmental chemicals have you identified? Francisco Quintana: We identified an important role for herbicides in triggering CNS inflammation, and that led us to identify a role for a specific receptor as part of the physiological control of inflammation. That’s important because if we know the receptors then we can use small molecules to modulate their functions. WuXi AppTec: What major challenges do you face in bringing new drugs to multiple sclerosis patients? Francisco Quintana: I would say there are two types of challenges associated with the two types of drugs you might want to develop. For drugs targeting the relapsing and remitting phase of the disease, the challenge is that there are many other drugs out there that seem to be doing quite well. So your new drug has to do extremely well side by side with other drugs, and getting enough patients to test it would be one big challenge. The second challenge involves developing drugs for secondary progressive multiple sclerosis; at that stage the disease manifests differently. At this stage, you do not detect well-defined attacks; instead the disease is driven by chronic, progressive neurodegeneration. The outcomes you should focus on at this progressive stage probably are not going to be classic multiple sclerosis disease activity in terms of attacks. The outcomes actually are more MRI (magnetic resonance imaging) based markers and other outcomes. That is a different type of clinical trial, and there you have to start thinking about what it is you are going to specifically measure. WuXi AppTec: What advice would you give drug companies in developing new drugs for multiple sclerosis and other rare diseases? Francisco Quintana: For progressive multiple sclerosis, we should develop drugs that target CNS resident cells – astrocytes and microglia – and that means we need to have more basic research and closer interactions with basic researchers to find what are the candidate drugs that target intervention with those cells. That would be my first piece of advice. Then this is more of an open question: how and where would we be able to even analyze the efficacy of drugs useful for the progressive phase of the disease? WuXi AppTec: In 10 years, can we get to FDA approval of 100 new drugs per year at half of today’s drug development costs? If not, what are the impediments to reaching this goal? Francisco Quintana: It seems new models of clinical trial design might optimize our ability to increase the rate of new drug approvals; I think we have to come up with different outcomes, at least for progressive multiple sclerosis. WuXi AppTec: Overall, do you see our current approaches to tackling diseases as incremental improvements or are we getting more and more transformative? Francisco Quintana: It’s all driven by the science. In some diseases we are studying new paradigms as in multiple sclerosis, where we are starting to study the role of CNS resident cells in inflammation. That no doubt will guide new drug discovery. The question is will the same apply to many other diseases. WuXi AppTec: What technological breakthroughs might be game-changing in the next five years?  Francisco Quintana: One of those breakthroughs is probably the use of single cell technologies in order to characterize patient samples and mechanisms of disease pathogenesis. The other thing I would say is probably the use of CRISPR approaches as a way of quickly modelling in animal experimental systems some of the things we detect in patients so we can understand mechanisms of disease pathogenesis and identify candidate targets for therapeutic intervention. Those two would be the ones I think would make a significant contribution.

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Apitope’s Research Seeks to Put Cause of Multiple Sclerosis into Remission

The National Organization of Rare Diseases (NORD) describes multiple sclerosis (MS) as a chronic neuroimmunologic disorder involving the brain, spinal cord and optic nerves. MS is just one of 7000 known diseases categorized as a “rare disease,” but in addition to its rare disease classification, it is also autoimmune – meaning the body’s immune system wrongfully targets its own healthy tissue when initiating an immune response. In the case of MS, the targeted healthy tissue is the central nervous system, which sustains an ongoing series of inflammatory attacks. These attacks lead to the scarring of the myelin sheath – the protector of the nerves around the brain and spinal cord. These attacks occur unpredictably, vary in intensity and affect multiple locations of the nervous system tissue – hence the name multiple sclerosis. During the course of MS, patients may have attacks (relapses or exacerbations) that gradually worsen or stabilize. Some people with severe MS may lose the ability to walk independently or at all. 2.3 million people worldwide have an MS diagnosis, for which there is currently no cure. However, there are biotech companies searching for new therapies as well as a cure, including Apitope based in the UK and Belgium. Apitope is developing potential first-in-class antigen-specific immunotherapeutics targeting the immunological basis of autoimmune diseases. Apitope researchers use their novel, proprietary discovery platform to select and develop highly specific peptide-based therapies, known as apitopes®, which restore the natural balance (immune tolerance) of the immune system. This mechanism of action avoids global immune suppression which protects against autoimmune diseases such as MS. Apitope’s lead product candidate, currently in Phase II clinical development, is ATX-MS-1467. It is the first potential therapeutic for MS that combines high efficacy with an excellent, and thereby differentiating, safety profile. Leading Apitope is their Chief Executive Officer Hayley French. Dr. French has over 20 years’ experience in the life sciences sector. Before joining Apitope, Dr. French spent three years at Novartis, based at their Basel headquarters. Prior to Novartis, Dr. French worked in the Life Sciences Group of Bird & Bird, London. Previously she was Head of Commercial Legal Affairs at the Centre for Applied Microbiology and Research (CAMR) in Salisbury UK. Dr. French has a B.Sc. in Microbiology from the University of Liverpool, as well as a PhD in Microbiology and a M.Sc. in intellectual property from the University of London. As part of a new series on rare diseases, WuXi AppTec Communications explored the issues and challenges of rare disease research with Dr. French and why her company’s lead drug could become the first cure for MS. WuXi AppTec: What are the differences between developing drugs for rare diseases and for more common diseases? Hayley French: Developing drugs for rare diseases has additional challenges, especially in the recruitment of patients in rare disease populations. There is generally a lack of knowledge about such diseases, and this presents diagnostic problems as well as challenges in clinical design, such as a lack of clinical end-points. WuXi AppTec: Following up on what you said, can you speak to the specific regulatory and business challenges to drug development for rare diseases? Do regulatory incentives help encourage rare disease research? Hayley French: First there are a limited number of patients for trials. A rare disease in the EU is defined as one that affects less than one in 2000. In the US a rare disease is defined as affecting fewer than one in 200,000. In fact, most rare diseases affect far fewer people. With such small patient populations, it becomes more complicated and more costly to recruit for randomized clinical trials. Another challenge is a lack of knowledge of the history of the disease, which also adds to the complexity in designing a clinical trial. Most rare diseases are genetic diseases, which can make it even harder to research because there are different versions of the same disease. An additional difficulty is that almost 50 percent of patients suffering from a rare disease are children. This results in added ethical considerations and limits in designing clinical trials. Fortunately, both EU and US regulatory agencies along with rare disease patient groups have increased regulatory and financial incentives for drug companies to target and develop therapies for these long-underserved patient populations. WuXi AppTec: How much progress has been made in multiple sclerosis drug research and development over the last 20 years? Hayley French: While the past 20 years have brought many significant advances in the management of multiple sclerosis, with the approval of over a dozen disease modifying therapies (DMTs) and numerous palliative treatment options, significant unmet needs still remain in the market. There has been a lot of activity in a busy market and many approvals of blockbusters with increasing levels of efficacy. However, with increasing efficacy we have observed safety and side effect issues. Also, there is still a need to slow down neurodegeneration and halt disease progression. Furthermore, drugs for progressive forms of the disease have been under-researched for this underserved patient population. This has led to pharmaceutical companies focusing research and development efforts on their currently marketed relapsing MS products to treat this form of the disease. WuXi AppTec: Your lead drug is aimed at MS, can you tell us what you have seen so far in your clinical research? Hayley French: Apitope’s lead product candidate ATX-MS-1467 is currently undergoing Phase II clinical development. It is a potential first in class treatment specifically for MS that combines high efficacy with an excellent safety profile. Clinical studies performed so far by Apitope have demonstrated a significant reduction in brain lesions as well as the volume of brain lesions, both of which are associated with the disease. It has also demonstrated a highly favorable safety profile. Importantly, in addition to its safety and efficacy profile, Apitope’s drug has the potential to be differentiated from other therapies in halting disease progression and improving cognition. WuXi AppTec: Different companies use different targets to treat a disease. How is your approach to MS different from other companies? Hayley French:  Our approach is focusing on correcting the cause of the disease by acting to downregulate the specific T lymphocytes that destroy the myelin insulation of the nerves. To target a very specific T cell population the rest of the immune system is left to fully function to protect the patient from other issues, e.g. infections and cancer. Current therapies are addressing a broader cell population or a cell function which induces a general immune suppression, which results in increased susceptibility to opportunistic infections as a consequence. By inducing immune tolerance by establishing a specific set of T regulatory lymphocytes known to be missing in autoimmune diseases, the aggressive myelin-specific T cells are silenced and the disease goes into remission. WuXi AppTec: Dr. French you mentioned the importance of your drug’s safety profile. Can you elaborate? What is the advantage to the patient? Hayley French: The treatment has been demonstrated to be very safe with no severe adverse events, which will allow for the treatment of  newly diagnosed patients. With a continuous maintenance treatment after establishing the immune tolerance, the Apitope peptide drug can prevent the progress of  MS into more severe forms of the disease. WuXi AppTec: Why do you see ATX-MS-1467 as a possible cure for MS? What other approaches could also be a cure for MS? Hayley French: From our perspective, Apitope therapies treat the underlying cause of the disease by selectively reinstating immune tolerance to the self-antigen target. We believe our MS therapeutic. ATX-MS-1467 has the potential to halt disease progression rather than just slowing down the disease. Additionally, further development is being pursued on re-myelination, which could create new myelin sheaths to protect the brain and spinal cord cells. WuXi AppTec: As a closing thought, Dr. French you have a long and successful record in drug development. What do you see as the best new technology that can really shape the future of healthcare? Hayley French: Although still in its infancy, pharmacogenomics and its role in personalized medicine is likely to be a game-changer  and become routine standard of  medical care over the coming years. Utilizing genomics technology in drug development in the future will determine how individuals respond to drugs and have the potential to provide more effective, safe and well-tolerated individualized drug therapies.

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Amicus Therapeutics: A Patient-First Approach to Treating Rare Diseases

Rare diseases have long posed a dual challenge. First, since there are relatively few patients by definition, they are not the highest priority for most drug makers. Second, many of them have proven quite difficult to effectively treat, let alone cure. The passage of the Orphan Drug Act in 1984 succeeded in spurring greater interest in the field. Amicus Therapeutics is one of the companies focusing on developing drugs for these hard to treat illnesses, one with a unique beginning. Amicus was founded in 2002 and went public in 2007. Leading the company is founder and CEO John Crowley, who has a very personal stake in treating rare diseases. In the middle of an early, successful career at Bristol-Myers, Crowley’s children received a terrible diagnosis: Pompe Disease, a devastating neuromuscular disease. At that time, there was no treatment, so Crowley quit his job, co-founded his own company Novazyme, and then raced against the clock to find a way to help his children. In the end, Novazyme and later Genzyme worked to develop a successful enzyme replacement therapy that saved the Crowley children’s lives. This real-life story has landed the Crowley family on the front page of The Wall Street Journal and served as the basis of the major motion picture “Extraordinary Measures,” starring Harrison Ford. In addition to his highly acclaimed career in the biopharmaceutical industry, Crowley also served as a commissioned Navy Reserve Officer who has served with a special operations team in Afghanistan. He graduated with a B.S. in Foreign Service from Georgetown University, earned a J.D. from the University of Notre Dame Law School, and also completed an M.B.A. from Harvard. Once he’d succeeded in his mission to find a treatment for his kids, Crowley took time to contemplate what to do next. Reflecting on his personal experiences led him to build a new company focused on providing a patient-centered approach to treating rare diseases. This is what gave rise to Amicus Therapeutics, which is named for the Latin word for “friend” to represent the company’s commitment to be the most patient-focused and patient-friendly company in the industry. One key aspect of the culture is for employees to consider and make major decisions from the perspective a patient (or parent of a child) with a rare disease. Although Crowley is optimistic about the current state and future progress of the industry, he identified three main obstacles to treating diseases in a way that serves the best interests of patients. The first is regulation. He praised regulators for moving quickly to work across many facets of treating rare disease, especially regarding incorporating patient voices into the process, but he believes that the regulatory framework has not kept up with the pace of scientific development. The second major concern he has is policy. Specifically, policies that govern patient access to drug companies. Again, he identified the current state as mixed, with some policies (both current and proposed) really ensuring access to patients and others hindering it. “We need to ensure 100% access to all patients in need,” Crowley emphasized. “A number of us have tried to be pretty assertive with our views in terms of what will drive innovation and what’s in the best interests of patients in moving these medicines forward.” However, in his view, there’s still too much that hinders access. The last major concern he has is the biopharmaceutical industry’s commitment to always acting in the best interests of patients. “We have a moral obligation to develop and manufacture the highest quality therapies for patients. We also have the obligation to ensure the broadest access [to needed medicines] possible,” he forcefully stated. He cited this year’s Gallup survey about public perception of various industries and organizations. “For the first time ever this year the biopharmaceutical industry ranked last. We ranked below the federal government and below Big Tobacco,” he said. He believes that the industry needs to improve how it serves patients or else this negative public perception will continue to impede the industry. Shifting his focus from the industry at large to treating rare diseases in particular, Crowley also acknowledged significant challenges even as he maintained his overall positive outlook. Using Pompe Disease as an example, he stated that understanding a disease mechanism does not guarantee the development of a cure. Pompe Disease is an enzyme deficiency resulting in lost function. Replacing lost function is much more difficult in his view. Though there is no cure, Pompe and Fabry now have treatments which Crowley considers an important initial step. “But there are risks and challenges inherent in any small disease population – recruitment of clinical studies for instance.  Even where we do have a first-generation approved therapy, sometimes the harder challenge is to come up with the next generation therapy.” He mentioned that the target for Pompe Disease is particularly tricky. And he cited that in some ways the Orphan Drug Act, while doing a substantial amount of good, has put up huge barriers to second generation therapies on top of the challenge of recruiting study participants. However, he also cited that, despite the challenges, we are truly entering a golden age for medicine and technology. “35 years ago, before the Orphan Drug Act, there were just a handful of approved therapies for rare diseases. Today we have hundreds,” he said. “But it’s still been a tough fight. When we look at some of the results of these approvals in spinal muscular atrophy, in rare eye diseases, I believe we’ve finally turned the corner in gene therapy. When I look at gene therapies, RNA technologies, and also at the promise of a field like gene editing, over the next couple of decades we truly have the chance to change the course of disease and profoundly impact the course of human history to alleviate an enormous amount of suffering. That’s a great, great opportunity for us.” How exactly does Amicus take advantage of this unique turning point? Crowley pointed to Amicus’ patient-centric culture as the key to making the strongest possible scientific and social impact. At the core of this effort is Amicus’ patient advocacy department. “Leading that effort is Jayne Gershkowitz, our chief patient advocate,” Crowley shared. “Her job is to be the voice of patients within the company and (along with the management team) the external face of Amicus to the patient community as well.” Even as the company has grown rapidly, it has stayed true to this commitment. In the nearly fifteen years since its founding, Amicus has grown from five to 600 people across 27 countries while maintaining its patient-centric focus. Indeed, Crowley credited that focus for the company’s success thus far. Amicus has reached the commercial stage with Galafold, which is a precision medicine used to treat Fabry Disease. “Beyond Galafold, in the last year alone we’ve built what is now the largest portfolio of rare disease gene therapies in the industry,” Crowley said. “We still have a very large vision. We decided years ago that at the end of our careers we don’t want people to look back on Amicus and think that we dreamed too small.” It’s a vision driven by the company’s fundamental commitment to patients. Amicus is also currently pursuing a “second generation” treatment for Pompe disease: AT-GAA. “We think it has the potential to become the next standard of care. It is the crown jewel of our portfolio and the only ever second-generation therapy for any lysosomal storage disease to received Breakthrough Therapy Designation,” he stated. AT-GAA is designed to be more highly targeted to muscle cells. This protein with this glycosylation is highly phosphorylated. The mannose 6-phosphate receptor is the uptake mechanism. So, with the higher degree of phosphorylation Amicus has seen much higher penetration into muscles. It is combined with a small molecule to stabilize it in plasma, which appears add some stability and enhanced potency to the protein. Amicus believes that once it’s in the muscle it contributes to the breakdown of the glycogen that’s stored in muscles of Pompe patients. To take this research to the next step Amicus is in the midst of their “PROPEL” study. This phase III study, which is due to complete enrollment by the end of 2019, looks at more than 100 adults living with Pompe Disease. “It is the largest lysosomal disease study ever conducted,” Crowley shared. “We are enrolling more than one hundred patients at more than eighty sites around the world on five continents. It’s also the most expensive study ever done in lysosomal disease field.” As a sign of their commitment to patient welfare, they’re now treating children and, to the best of their ability, meeting requests for expanded access or compassionate use of this still experimental treatment. Being able to produce enough medicine to meet this demand is a challenge. Crowley credits Amicus’ success here (and indeed in many other areas) to excellent collaboration with its partners. “In some areas we needed the expertise and the infrastructure of partnerships, and I think the very best example is our partnership with WuXi AppTec, which began almost six years ago when we only had a cell line in Pompe. Once we saw the early results in animals, we knew manufacturing would be our greatest challenge at that point. And that’s where together with our teams at WuXi AppTec, we really built the processes, ultimately even facilities, geared toward scaling up this product.” Another challenge he cited was how to support the PROPEL study with commercial scale material. “Our team together with our partners and WuXi AppTec really rose to the occasion. It’s because of WuXi AppTec’s manufacturing capabilities that we’ve been able to answer so many [compassionate use] requests for AT-GAA.” Crowley also cited their partnership with Dr. Jim Wilson and the University of Pennsylvania around gene therapy as being particularly important. “We combine our protein engineering expertise and technologies with the gene therapy and vector expertise of Dr. Wilson and UPenn.  And it has just been an extraordinary collaboration and partnership for us.” In this context he also mentioned Brammer (now part of Thermo Fisher Scientific) and Paragon (now part of Catalent) as keys to helping advance several of their programs.           When asked what he would have done differently if he could, Crowley took the time to reflect back on his previous experience with Novazyme. “There we were laser focused on a specific medicine and developing a treatment for Pompe, getting into clinical studies. And that certainly was a noble pursuit. But there were times where I lost perspective of the big picture. Maybe it was partly because we were under such time pressure.” For Amicus he took a different approach. “I instructed the team not to tell me what we’re going to do over the next couple of quarters. Instead I asked, ‘What do you want us to look like in ten or twenty years?’ I told them to dream and dream big. And then think about Amicus. And we ended up brainstorming and thinking really big. So, what I would have done differently is to lay out that bigger vision, that larger purpose to what we’re doing. I think that helps frame the smaller details.” He concluded by expressing his full confidence in his team to achieve these big goals. “We are a persistent and resilient bunch at Amicus.  And I think that’s a great trait for anybody in this industry.” By 2030 Crowley is hopeful that we will get to a world with a complete understanding of mutations, universal (in the U.S. at least) childhood screening, and continuing growth in the number and efficacy of treatments – a world where parents can take full advantage of amazing new treatments to help their children avoid succumbing to an otherwise fatal disease. That, he believes, is a world where we are truly putting the patient first.

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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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