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2020/05/19

Click is Pioneering and Developing Cutting-edge Digital Therapeutics to Transform Medicine

What is digital health? In broad terms, it is the convergence of digital technologies with medicine, health and society to boost treatment efficacy and deliver more personalized and precise patient care. It is an expansive and growing field, covering everything from mobile health apps to sensors to wearable gadgets. But a key component of digital health is the area of digital therapeutics. Digital therapeutics can deliver interventions directly to patients using evidence-based, clinically evaluated software to treat a wide-range of behavioral, mental, and physical diseases and disorders. Unlike other devices, digital therapeutics are held to the same standard as medication or other therapies. It is an expanding sector with global sales projected to hit nearly $8 billion by 2025, according to Allied Market Research. For this inaugural article of a new series on digital therapeutics, WuXi AppTec Communications spoke with Click Therapeutics CEO David Benshoof Klein about the future of the industry and how Click is developing its technology. Click Therapeutics, based in New York City, is one of the early pioneers in digital therapeutics. David Benshoof Klein is the former Managing Director of Opus Point Partners, which created, financed and operated more than ten life science companies. He has been a guest lecturer at Columbia University and NYU Stern School of Business and has served as a senior consultant at Pfizer and strategic advisor at various publicly traded and private life science companies. He holds a BA from Brandeis University. WuXi App Tec: How would you define digital therapeutics? David Benshoof Klein: Digital Therapeutics, simply defined, are software applications that treat a disease. Just like traditional pharmacologic therapies, they are clinically validated through robust clinical trials, and are developed in accordance with relevant FDA, ISO and IEC standards. This sets them apart from other health apps that focus on supporting wellness, patient education, clinical decision support or enabling live teletherapy. In addition, many digital therapeutics, including Click’s, are meant for use as part of a clinical treatment paradigm as prescription products that can only be accessed via a healthcare practitioner. WuXi AppTec: Will biotech and pharma companies develop digital therapeutics, or do you see this as a separate industry? David Benshoof Klein: I really see the industry as separate from pharma–akin to a new class of biotech company. The expertise required for digital therapeutics is quite distinct from pharma and biotech, so we’ll continue to see traditional players actively seek to access the space through partnerships with digital therapeutics companies. Click’s collaboration with Otsuka in depression is the most significant of such collaborations in the industry to date. WuXi AppTec: Why are digital therapeutics necessary in the practice of medicine today? What are the benefits? David Benshoof Klein: One of the great inefficiencies of medicine over the last twenty years, I believe, has been our tendency to impose purely pharmacological solutions on behavioral problems. In reality, modern healthcare is about more than just biology; it relies on social, cognitive and behavioral interventions to provide truly functional treatment. Across disease areas, treatment guidelines continue to recognize that drugs are only one part of a larger toolkit that physicians must have at their disposal, and in many cases recommend non-pharmaceutical options as a first-line approach. Digital therapeutics are vital to ensuring that this treatment paradigm is successfully delivered. They provide safe, effective and convenient treatment modalities that can be easily scaled to dramatically improve access to care. On top of this, they also bolster classic pharmaceutical approaches by generating real world evidence and facilitating greater adherence. The need for digital therapeutics is clear now more than ever. In the past few months, we have all seen how quickly our healthcare system can be overwhelmed and how limited currently available treatment options can be. The COVID-19 pandemic, as terrible as it has been, has only strengthened the case for digital therapeutics. WuXi AppTec: Can you share how you see COVID-19 affecting the digital therapeutics industry and healthcare as a whole? David Benshoof Klein: I think this pandemic has really forced us, as a society, to reevaluate how and when we interact with others. In medicine, for instance, how do we provide patients with the care that they need without putting them in harm’s way or crowding hospital wards? Already we’ve seen a rapid shift from hospital and clinic-based care towards the use of remote treatment whenever possible. With this change has come increased acceptance and adoption of technologies like telemedicine and digital therapeutics. Importantly, the people driving these shifts are the major stakeholders in our industry: patients, physicians, payers, and policymakers. As a digital therapeutics company, we’ve always expected this would happen, but never this quickly. Ultimately, we’ll be feeling the effects of this pandemic for years to come. The steps that we have taken as a community to combat the spread of COVID-19 will give rise to a host of behavioral conditions like depression, anxiety and insomnia being treated almost exclusively remotely, while also highlighting underlying disease areas that may exacerbate the virus, like obesity. All of these conditions are extremely well suited for digital treatments. Given that payers and providers are quickly realizing the benefits of digital therapeutics, I think we will be well prepared to tackle this next wave of post-COVID healthcare challenges. WuXi AppTec: Even with all of the benefits, are there any risks associated with Digital Therapeutics, such as privacy? David Benshoof Klein: Yes, of course privacy should be a central focus of any organization, especially a technology-enabled digital therapeutics company. At Click, our privacy team is dedicated to ensuring that we adhere to all of the relevant laws and industry guidelines and to incorporate privacy by design as we develop our products. At the end of the day, though, digital therapeutics actually lack many of the safety risks associated with traditional pharmaceuticals, positioning them even more strongly in cases where polypharmacy may be an issue. WuXi AppTec: What are the regulatory guidelines for digital therapeutics? Are they still evolving, and if so, what needs to be clarified? David Benshoof Klein: Digital therapeutics that make treatment claims, like Click’s, require marketing authorization from applicable regulatory bodies (e.g. via 510(k) or de novo pathway in the US, or CE marking in the EU). Overall, the regulatory landscape is definitely still evolving, but recent guidance has been extremely encouraging–the FDA recently issued new guidance in response to the COVID-19 pandemic geared specifically towards digital therapeutics and digital health products, further evidencing how regulatory bodies are embracing the immense potential of digital therapeutics. WuXi AppTec: Are business challenges for digital therapeutics different from biopharma drug development? David Benshoof Klein: As a digital therapeutics company, we sit at the intersection of technology and biopharma. This unique position brings with it a unique set of business opportunities and hurdles. One huge benefit is that we can develop our treatments at a much lower cost and shorter time to market than a small or large molecule, and often with a significantly higher probability of technical and regulatory success and potentially even greater upside. The main challenge, and an area in which I think Click really excels, is balancing the diverse expertise (e.g., technology, product, design, science, clinical development and operations, quality management systems, privacy and security, etc.) required to agilely develop a digital therapeutic that drives outcomes and is in accordance with applicable regulatory and quality standards. You also need to build a product that patients actually want to use, which is part and parcel to achieving those clinical outcomes. This is not something that just any digital health or pharma or biotech player can do overnight, or in some cases, ever. WuXi AppTec: How will patients access digital therapeutics and how will they be reimbursed? Will they have more impact on certain groups? David Benshoof Klein: Traditional approaches like pharmacy and medical benefits definitely are one option, but there is also potential for more innovative value-based models, direct-to-payer models and direct-to-consumer prescription models via telemedicine. It’s also possible that reimbursement will vary based on the product area. In any event, the positive impact that digital therapeutics will have is clear: without geographic and distribution barriers, the most at risk and underserved populations will have unprecedented access to the healthcare they need. WuXi AppTec: What kind of digital therapeutics is your company pursuing? What diseases are you targeting? Why? David Benshoof Klein: Click is developing a portfolio of digital therapeutics designed to treat a wide range of disease areas. We are highly evidence-driven in our selection of therapeutic areas to target, focusing on high burden diseases where clinical data support the use of non-pharmacologic approaches and our clinically validated engagement platform can drive meaningful outcomes for patients. Click’s pipeline includes Smoking Cessation, Major Depressive Disorder (MDD), Acute Coronary Syndrome, Chronic Pain, Migraine, Insomnia, Obesity and more. WuXi AppTec: How do your digital therapeutics work? What do they accomplish? Is your approach different from other digital companies? David Benshoof Klein: Click’s digital therapeutics are intended to treat diseases either alone or in combination with pharmacotherapy. To do this, they leverage a growing library of proprietary, clinically validated translational and discovery cognitive and neurobehavioral mechanisms. As a “mobile-first” company, our products are designed from the ground up by our in-house discovery and technology teams to maximize clinical efficacy and engage users natively through their phone. Our algorithms can then learn from user activity to personalize the experience, tailoring the therapeutic to each patient’s specific needs. This has enabled us to build the strongest patient engagement platform in the space with a proven ability to scale (our first marketed product, Clickotine, is available in over 11.5 million lives and counting). With these approaches, Click is really well positioned to tackle new diseases quickly and agilely and drive the growth of the digital therapeutics industry as a whole. WuXi AppTec: Some closing thoughts please. What will be the lasting impact of digital therapeutics on new medicines? David Benshoof Klein: I believe that digital therapeutics will fundamentally change the way medicine is developed, perceived, delivered and monitored. WuXi AppTec: And finally how will digital therapeutics change over the next 5-10 years? David Benshoof Klein: Over the next several years, as patient and provider adoption accelerates, I see digital therapeutics becoming standard of care across a wide variety of disease areas. And for those areas where traditional therapeutics are necessary, I firmly believe that digital treatments and traditional biopharmaceuticals will not be viewed as separate approaches, but rather two sides of the same coin.

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2020/05/19

Vaccinex’s Cancer Research May Lead to Effective Treatment for Deadly Huntington’s Disease

Huntington’s disease (HD), also known as Huntington’s chorea, is an inherited genetic disorder that kills brain cells. The Huntington Disease Society of America describes the disease as “a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain.” The symptoms of HD are described as having ALS, Parkinson’s and Alzheimer’s simultaneously. Symptoms usually appear during prime working years – between the age of 30 and 50 – and worsen over a 10- to 25-year period. Over time, HD affects the individual’s ability to reason, walk and speak. The disease affects men and women equally and children born to a parent with HD have a 50/50 chance of inheriting the faulty gene. There is currently no cure or treatment which can halt, slow or reverse the progression of the disease. Full-time care is required in the later stages of the disease. Treatments can relieve some symptoms and, in some, improve quality of life. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Disease complications and injury from falls reduce life expectancy. Suicide is the cause of death in about 9% of cases. Death typically occurs 15–20 years from when the disease was first detected.  According to the Huntington Disease Society of America,“there are approximately 41,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease.” While only a handful of biopharmaceutical companies are researching new therapies for HD, Maurice Zauderer, President and CEO of Vaccinex, a clinical stage biotech company based in Rochester NY is optimistic the company’s late stage drug pepinemab may be the first effective therapy for HD patients. Ironically, cancer research led Vaccinex to utilize the same technology to target HD. As part of its ongoing series exploring the challenges of rare disease research, Wuxi AppTec Communications spoke with Dr. Zauderer about why he believes pepinemab can make a difference. Dr. Zauderer, Ph.D. has served as President and Chief Executive Officer and a member of the Vaccinex’s board of directors since its inception in April 2001. Prior to founding the company, Dr. Zauderer was an Associate Professor at the University of Rochester and has also held senior faculty positions at Columbia University. During his academic career, Dr. Zauderer held the position of visiting scientist at the Laboratory of Cell Biology, the Ontario Cancer Institute and the National Cancer Institute. Dr. Zauderer received a B.S. in Physics from Yeshiva University and a Ph.D. in Cell Biology from the Massachusetts Institute of Technology. WuXi AppTec: What are the major  differences between developing drugs for rare diseases and for more common diseases? What are some of the unique rare disease regulatory and business challenges? Maurice Zauderer: In general, larger clinical trials and greater financing are required to achieve regulatory comfort for indications that affect large numbers of people. To a large extent, this reflects the inherent diversity of large human populations. In principle, identification of biomarkers that allow functional segmentation could facilitate development. On the science and investment side, there is usually not as much research and knowledge to draw on for rare and orphan diseases, and, importantly, there is often no precedent for therapeutic success. As a result, investors may not be confident that the reward merits the risk. Fortunately, greater pricing tolerance on the part of payers for rare and orphan diseases alleviates some of these concerns. WuXi AppTec:  Many biotech companies are involved in cancer research how did you choose to target Huntington’s? Maurice Zauderer: We are actually developing our lead drug, pepinemab, both as a combination therapy with a checkpoint inhibitor in cancer and as a single agent in neurodegenerative disease. What we learned about the mechanism of action of our drug in cancer actually informed our understanding of its potential in Huntington’s and other neuroinflammatory/neurodegenerative diseases. Our lead antibody, pepinemab, blocks the activity of SEMA4D, a molecule that binds to high affinity plexin receptors to trigger dissociation of the cell cytoskeleton. The cell cytoskeleton gives cells shape, but, more importantly, it makes it possible for cells to change shape. Cells need to change shape in order to extend projections that enable movement in a desired direction. This is, for example, essential for immune cells to infiltrate and attack tumors. Tumors have learned to exploit this pathway as one of several means of evading anti-tumor immune responses. They express high levels of SEMA4D at their margin and this serves to immobilize immune cells that constitutively express the plexin receptors for SEMA4D. Wuxi AppTec: So how did this discovery lead to a potential therapy for Huntington’s? Maurice Zauderer: Based on our understanding of the biochemistry and cell biology of the SEMA4D/plexin pathway, we came to recognize that similar cytoplasmic projections are required for cells to make contacts that enable direct interactions with other cells. Such contacts are central to the normal function of astrocytes in the brain. Astrocyte projections completely cover blood vessels that feed the brain. These projections express glucose transporters, the main source of energy for the brain, and facilitate uptake of glucose from circulation. Similar astrocyte projections cradle synapses and express glutamate receptors that recycle and allow efficient use of the free excitatory transmitter. In response to brain injury, the astrocyte cytoskeleton collapses, they abandon these normal functions and switch over to secretion of inflammatory cytokines. This is an interaction mediated by diffusion of soluble molecules rather than direct cellular contact. We asked what might trigger this important inflammatory transformation, and we wondered whether the SEMA4D/plexin pathway could be involved. Indeed, we discovered that SEMA4D is upregulated on neurons in response to stress or damage during underlying disease progression, and that astrocytes express plexin receptors that, in response to SEMA4D, trigger inflammatory transformation. We determined that SEMA4D blocking antibody ameliorated disease pathology in several animal models of neuroinflammatory/neurodegenerative disease, including Huntington’s, Alzheimer’s and multiple sclerosis. WuXi AppTec: Were there other factors that led to looking at Huntington’s? Maurice Zauderer: In addition to these mechanistic insights, we were motivated to focus on Huntington’s disease because it is an important unmet medical need with unambiguous diagnostic clarity of clinically manifest and asymptomatic gene carriers. The clinical trial experience of our colleagues in the Department of Neurology at the University of Rochester School of Medicine and in the Huntington Study Group were important support for the soon to be completed, potentially pivotal, SIGNAL study of pepinemab as a treatment for Huntington’s disease. WuXi AppTec: How important are government regulatory incentives to encourage rare disease research in general? And as a follow-up, are patient groups also an important driver in Huntington’s?   Maurice Zauderer: It is very important that regulatory agencies recognize the special difficulties of performing clinical trials in rare or orphan diseases and make reasonable accommodation to facilitate such studies. The rare disease community has been historically overlooked and under-researched, and we’re pleased to see that regulatory incentives have played a role in beginning to change this. In addition to the fact that HD is an important unmet need that is devastating to patients and families, a more rapid regulatory pathway motivated us to initially focus on HD, rather than a more prevalent neurodegenerative disease such as Alzheimer’s. The favorable regulatory environment has allowed us to safely and efficiently develop and advance pepinemab, with the hope of being able to rapidly deliver this new therapy to a community that currently has no treatment options, beyond those that address some symptoms of the disorder. Additionally, choosing to address HD first has enabled us to expand our research and help more patients than might not have been possible otherwise. Our promising data in HD has led to welcome support from the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation for a phase 1 Alzheimer’s study that we plan to initiate in the second half of 2020. WuXi AppTec: Why is it so difficult to develop effective therapies for Huntington’s Disease? Maurice Zauderer: All neurodegenerative diseases are challenging because there are numerous important but not well understood interactions between different cell types in the brain. As an orphan disease, HD does not enjoy the concentration of research invested in other slowly progressive neurological diseases such as Alzheimer’s and multiple sclerosis. Fortunately, much can be learned from common pathways and parallel mechanisms in these different brain diseases. A broader perspective can accelerate therapeutic development. WuXi AppTec: How do you overcome patient recruitment challenges in rare disease research when you have much smaller patient populations?  Maurice Zauderer: In our experience, it has been important to work with a CRO that has well-established relationships with investigators and clinical coordinators at a large number of sites. The Huntington Study Group has served us well. WuXi AppTec: How much progress has been made in Huntington’s disease drug research and development over the last 20 years?  Maurice Zauderer: Not enough. The only currently approved drugs for HD are symptomatic treatments like tetrabenazine that suppresses involuntary movements but does not slow disease progression. WuXi AppTec: We have been talking about Huntington’s research in general. I would like to switch to your specific drug program. What phase is it in? What results have you seen so far? And will it treat all stages of the disease? Maurice Zauderer: As discussed above, the SIGNAL study is based on the relatively recent understanding of the key role of astrocytes in neuroinflammation. Much of this work was pioneered by the outstanding late neuroscientist, Ben Barres and his colleagues at Stanford University. Our contribution has been to identify a specific molecular pathway that activates astrocytes. The Vaccinex drug, pepinemab, blocks this pathway and ameliorates the pathology. The soon to be completed SIGNAL study in HD enrolled 265 subjects of whom two thirds had manifest disease and one third were prodromal, that is they were known to have inherited the Huntingtin mutation but did not yet have diagnostic symptoms. Subjects were randomized 1:1 drug to placebo and received 18 monthly treatments of a relatively high concentration of pepinemab antibody administered intravenously. The antibody concentration was calibrated to achieve a targeted biologically effective dose in the brain even though antibodies do not efficiently pass through the blood-brain barrier. This avoided the need for more invasive interventions like intrathecal injections into the spinal cord or intavesicular injection directly into the brain. WuXi AppTec: What were the results you saw first? Maurice Zauderer: In an initial 36 subject phase 2 arm of this study, we determined that pepinemab treatment has a dramatic effect on preserving and even increasing glucose transport as reflected in FDG-PET imaging. This was an exciting observation because we know that glucose transport is a normal function of astrocytes that is abandoned upon inflammatory transformation. Our interpretation, supported by a variety of other evidence, is that our drug blocks reactive transformation of astrocytes. The SIGNAL study will now determine whether pepinemab treatment confers clinical benefit to subjects with early HD including both manifest disease and, potentially, prodromal subjects. WuXi AppTec: When do you think it may be available to patients? Maurice Zauderer: We anticipate completing the SIGNAL study in late June/early July 2020, at which time we will begin the process of locking the database, leading to analysis and topline data in the Fall. This is a potentially pivotal study for FDA registration, and we have already begun to prepare to scale up manufacture and the infrastructure for commercialization should results prove to be positive. Pepinemab has the potential to be the first disease-modifying therapy for HD. WuXi AppTec: Why do you think your approach can be more successful than other companies’ drug programs in this disease?  Maurice Zauderer: I think that what is most important about the Vaccinex treatment strategy for HD is that it targets a pathogenic mechanism rather than just a biomarker of the disease. Biomarkers are useful to identify disease susceptibility and progression, but, as we have seen in many failed trials in Alzheimer’s disease, they are not necessarily effective targets. There is a lot of evidence for the pathogenic role of astrocytes and chronic inflammation in multiple neurodegenerative diseases and these research advances have informed our strategy for HD. WuXi AppTec: Do you see a time when we will have a cure for this disease? What scientific advances are needed to reach this goal? Any predictions when this might happen? Maurice Zauderer: There are multiple new approaches employing novel technologies in development. A lot of good things could happen in the next few years, including potential combination therapies. I am optimistic. WuXi AppTec: Anything we haven’t touched on that you would like to add?  Maurice Zauderer: One of the very rewarding aspects of working in HD is that the Huntington’s disease community, patients and their families, have seen and understand the devastation of this disease. They are wonderfully supportive of each other and of efforts to develop new and effective treatments. It is inspiring to experience and share in the determination and commitment of this community.

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2020/05/05

GeNeuro Believes its New and Unique Pathway in MS Research Can Lead to a Truly Effective Treatment

Multiple Sclerosis (MS) is a long-term, degenerative disease that affects the central nervous system in which the immune system attacks the myelin sheath that protects nerve fibers, causing neuroinflammation and neurodegeneration. Without the protection of myelin, nerves lose functionality, become damaged and are ultimately destroyed, which leads to the formation of scar tissue (sclerosis). Symptoms tend to vary depending on the nerves affected and the damage caused. MS is most commonly diagnosed between the ages of 20 and 30, however most patients will have evidence of prior, inflammatory CNS damage at diagnosis, as seen via Magnetic Resonance Imaging (MRI). In 85% of the cases, MS presents itself at the original diagnosis in a form called relapsing-remitting MS (RRMS), which will usually degenerate after 10-20 years into a more aggressive form of the disease: the secondary progressive form (SPMS) during which the loss of neuronal function increases. Approximately 10% of patients present from the outset with a form of the disease called primary progressive MS (PPMS). There is currently no cure for MS. Treatment options interfere at the level of the patient’s immune system, reducing partially or almost completely the number of inflammatory relapses (one of the manifestations of the disease). However, there is no treatment presently available that has shown a determining impact on the progression of long-term disability resulting from the disease. Despite these challenges researchers at GeNeuro, a Geneva, Switzerland based clinical stage biopharmaceutical company has completed a MS Phase 2 clinical trial with encouraging results. GeNeuro CEO Jesus Martin-Garcia believes that GeNeuro’s ground-breaking approach can ultimately lead to an effective treatment. The company’s lead drug, temelimab, centers on the causal factors of MS rather than treating the symptoms. In a new MS series WuXi AppTec Communications discussed the causes of MS and how GeNeuro’s drug can make a real impact for MS sufferers. Martin-Garcia began his career in 1983 at the World Economic Foundation, and later at McKinsey & Co where he led studies in the pharmaceutical and food industries. By 1993, he chose the entrepreneurial path by creating, investing and leading start-ups in Switzerland and the United States. In 2003 he created Eclosion, a public-private partnership for translating scientific discoveries in the field of life sciences into innovative drugs with disruptive potential. This unique structure was instrumental in the creation of GeNeuro, which Martin-Garcia has led since its founding in 2006. Martin-Garcia holds a bachelor’s degree in industrial sciences, a master in law from Geneva University and an MBA from Harvard Business School. He serves on the board of several biotech companies and industrial and business associations. WuXi AppTec: Are there any major differences between developing drugs for multiple sclerosis (MS) compared with other diseases? Are there unique regulatory and business challenges? Jesus Martin-Garcia: As with any other neurological disorder, the development of medicines to treat MS remains cumbersome, as access to target tissue in situ is literally impossible. Therefore, development relies on surrogate biomarkers, such as imaging or fluid biomarkers. In addition, the different clinical manifestations of MS and the variable long-term evolution of clinical disability make it difficult to develop therapies for MS. Today we have an arsenal of approved drugs that are very effective against relapses. The effectiveness of these drugs can be measured over two years, i.e. relatively short periods of time compared to the duration of the disease. What we lack are solutions to slow underlying neurodegeneration that drives disability progression over the long term. Anti-inflammatory and immunosuppressive drugs, which are very effective against relapses, have unfortunately been demonstrated to have limited impact on long-term neurodegeneration. As disability progression is a long-term phenomenon, developing drugs against neurodegeneration is certainly challenging. WuXi AppTec: Many MS drugs started out as cancer drugs. Why did you decide to target MS directly? Jesus Martin-Garcia: You make an interesting observation, which is right. Most drugs effective against MS relapses were initially developed for oncology and organ transplant, where immunomodulation and/or immunosuppression can have benefits. Some of these drugs have also been utilized in treating other autoimmune diseases, with varying success and efficacy. In GeNeuro’s case, it’s probably more accurate to say that MS chose us! GeNeuro was founded based on 25 years of research conducted on human endogenous retroviruses (HERVs), including 15 years within Institut Mérieux and the French National Institute for Health (INSERM). These HERVs are the remnants from viral infections in our primate ancestors that, over the millennia, have integrated themselves into our genome. In fact, the DNA from these ancient viruses make up about 8% of the human genome! This HERV research showed that there is a link between these viral genes and certain diseases, paving the way for us to uncover and understand the action of a potential causal factor of multiple sclerosis, an envelope protein (Env) that is produced by a pathogenic member of the human endogenous retrovirus-W family (pHERV-W). pHERV-W Env is systematically found post-mortem in the brain lesions of MS patients, but neither in the normal appearing white matter of MS patients, nor in the brains of patients with other neurological disorders. WuXi AppTec: How do you overcome patient recruitment challenges in MS research?  Jesus Martin-Garcia: Treatment of MS has been well established over the past several years – a positive consequence of the advances in treatment options. There are specialist clinics and centers around the world that treat MS patients. By collaborating with these we are able to reduce the challenge of recruitment. Yet, as most patients experience increasing disability despite their MS treatment, there is an aspiration by those patients for experimental drugs that hold promises to slow down the underlying neurodegeneration. WuXi-AppTec: How much progress has been made in MS drug research and development over the last 20 years?  Jesus Martin-Garcia: Over the past 20 years, there has been significant progress in our ability to treat the symptoms of MS; however, treating the underlying cause and stopping the progression of the disease has proven to be much more difficult. Today there is a good understanding of the immune mechanisms of relapses, with T and B cells penetrating into the brain and causing a local edema. The clinical manifestation of this edema will depend on its localization in the brain, and can take many forms, such as muscle weakness, loss of muscle coordination, pain, loss of vision, etc. But these symptoms will generally disappear with the resolution of the edema. This knowledge has been the basis for the development of the very effective drugs available today to reduce the frequency and severity of relapses, which is a great benefit for the patients. We have also made very good progress in understanding some of the mechanisms that lead to long term neurodegeneration and disability. Among those, two interesting areas of research on progression in MS are the potentially damaging role of pro-inflammatory microglial cells and the impaired function of oligodendrocyte precursor cells (OPC), the latter being key for myelin repair. There are also a number of new biomarkers being developed to be able to measure disease progression over time, such as the measure of brain atrophy, myelin density, and the differentiation of lesions that appear to be specific to long-term progression. Neurofilament light chain biomarkers in the periphery and the CSF are also an interesting new avenue to measure the inflammatory state of MS patients. But slowing down and hopefully stopping disability progression over time remains an unmet medical need in MS, and there is still much more research to be done to help these underserved patients, and GeNeuro is playing its part! WuXi AppTec: We have been talking about MS research in general. I would like to switch to your specific drug program. What phase is it in? What is its MOA? and what results have you seen so far? And will it treat all stages of the disease? Jesus Martin-Garcia: GeNeuro is currently evaluating temelimab, a monoclonal antibody designed to neutralize the pathogenic envelope protein, pHERV-W Env. This protein, which is specific to MS in the brain of patients, has been shown to activate microglial cells into an aggressive phenotype, causing direct damage to brain tissue, and to inhibit the differentiation of oligodendrocyte precursor cells, which are key to myelin repair. Neutralizing pHERV-W Env is thus expected to stop these two key mechanisms that are involved in fueling long term neurodegeneration and disability. GeNeuro has completed a 1-year Phase II on 260 remitting MS patients followed by a one-year extension study. The two-year results, announced in March 2019, showed a continued, positive impact on key MRI measures of disease progression in MS patients, confirming and extending the data reported at year one. This includes reductions in brain atrophy, particularly in the cortex and thalamus, and maintenance in myelin integrity, as measured by magnetization transfer ratio (“MTR”) imaging. Also, for the first time, encouraging dose-dependent effects were seen on clinical measures of disease progression. The study also showed that temelimab had only a modest effect on B and T-cell driven neuroinflammation, indicating that the positive results observed on MRI measures associated with disease progression maybe specific to neurodegeneration mechanisms independent of relapse-associated inflammation. GeNeuro announced on November 20, 2019 an agreement with the Karolinska Institutet / Academic Specialist Center (ASC) of Stockholm to launch a new Phase II clinical study specifically targeting patients whose disability progresses without relapses. It will document the safety and tolerability of temelimab following higher doses as well as measures of efficacy based on the latest biomarkers associated with disease progression. The study aimed to start enrolling patients in Q1 2020, with last patient out and expected top line results in H2 2021; however, due to the COVID-19 crisis, we announced on March 19, 2020 that we were temporarily postponing this trial to prioritize healthcare resources against the pandemic. Assuming recruitment can still be completed by the end of 2020, the company expects that results would still be communicated in H2 2021. WuXi AppTec: When do you think it may be available to patients? Jesus Martin-Garcia: If the results of the trial at the Karolinska Institutet confirm temelimab’s activity against disability progression in the absence of relapses, we would expect a rapid development based on the results of this trial through Phase III pivotal trials. Temelimab may be developed as a monotherapy for “non-active” progressive patients, or as an adjunctive therapy for remitting patients in combination with existing immunomodulatory drugs addressing neuroinflammation, such paths being non-exclusive. WuXi AppTec: Why do you think your approach can be more successful than other companies’ drug programs in this disease?  Jesus Martin-Garcia: Today, there are many drugs that are effective against relapses in MS through modulating and/or suppressing key parts of the immune system of the patients. But long-term disease progression, which is the focus of GeNeuro, remains a very urgent unmet medical need. GeNeuro’s approach is very unique as it tries to neutralize a causal factor fueling disability progression. We do know that temelimab is very well tolerated, with no safety flags thus far, and we do need to continue our evaluations in larger clinical studies to confirm its unique potential. WuXi AppTec: Do you see a time when we will have a cure for this disease? What scientific advances would be required to reach this goal? Any predictions when this might happen? Jesus Martin-Garcia: Our knowledge of MS and other neurological diseases is expanding every day. The research into HERVs shows that they could be one of the key missing links that scientists have been seeking for many years. Whether they result in a cure remains to be seen, but they are certainly a step in the right direction. As with many other diseases, we still don’t know enough about MS to predict when there will be a cure, but we have made great progress in our ability to help support and treat patients in the meantime. WuXi AppTec: Anything we haven’t touched on that you would like to add?  Jesus Martin-Garcia: The role of HERVs and their effect on human health are still being explored. Despite the accumulation of mutations and various mechanisms to silence their genetic expression, HERVs are still contributing to the human transcriptome. A growing number of studies suggest that HERV expression products may play pathogenic roles in a number of diseases. As well as MS, GeNeuro has research programs in Type 1 diabetes, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease), in partnership with the US National Institutes of Health, and chronic inflammatory demyelinating polyneuropathy (CIDP), a rare neurological disorder. We believe that our pioneering work in MS will open a new avenue for the effective treatment of many other poorly understood diseases.

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2020/05/05

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

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

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2020/05/04

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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