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2019/12/02

RAPT Therapeutics Sees “Charged” Lung Cancer Tumors as Inviting Targets for Lead Drug FLX475

Lung cancer remains a stubborn disease to treat. Even cutting-edge immuno-therapies have had limited success. Brian Wong, CEO of South San Francisco-based RAPT Therapeutics, believes that the company’s lead drug, FLX475, has potential to overcome the scientific challenges in treating this disease. RAPT’S proprietary discovery platform has identified certain tumors in which the abundance of regulatory T (Treg) cells are likely to be a key cause of immune suppression. RAPT refers to these tumors as “charged” because of their expression of high levels of C-C motif chemokine receptor 4 (CCR4) ligands, Treg  cells and CD8 positive effector cells. These charged tumors include tumor types such as non-small cell lung cancer. RAPT’s approach is designed to enable selective restoration of the immune response within tumors without systemically depleting Treg cells or broadly suppressing the immune system. Dr. Wong is leading RAPT’s programs. He joined RAPT Therapeutics in 2015, bringing more than 15 years of experience leading research and translational medicine organizations. Most recently, he served as Senior Vice President, Research, and Head of Immuno-Oncology at Five Prime Therapeutics, where he led the discovery of novel therapeutics in cancer and inflammation. Prior to Five Prime, Dr. Wong served as Director of Research in the Inflammation Disease Biology Area at Roche Palo Alto from 2005 to 2009. From 2000 to 2005, he held various leadership roles at Rigel Pharmaceuticals, where he identified and developed clinical candidates for allergic, autoimmune and respiratory disorders, including Tavalisse™. Dr. Wong received his M.D. from the Weill Cornell Medical College and his Ph.D. in Immunology from Rockefeller University. WuXi AppTec: What is your opinion about the challenges of early diagnosis of lung cancer? Are there any specific biomarkers? Dr. Brian Wong: The biggest challenges in the early diagnosis of lung cancer are determining which people to screen, and developing methods that can reliably diagnose the disease at a stage when it is still curable, or at least improve overall survival. Finding the right biomarkers to identify and select patients who will best respond to specific immunotherapies is a constantly evolving area. PD-L1 expression and tumor mutational burden are among the most extensively studied and investigated, but are by no means perfect. Through extensive computational analysis of cancer genetic signatures, we have identified tumor types characterized by high levels of effector cells, Treg cells, and CCR4 ligands as being tumors we believe have a higher chance of responding to our drug candidate (FLX475), which targets CCR4 and Treg cell recruitment. We call these “charged” tumors, and non-small cell lung cancer is one of those “charged” tumor types. WuXi App Tec: What are the hot targets in the field of drug development for lung cancer? Dr. Brian Wong: Relevant to immuno-oncology, the anti-PD-(L)1 antibody therapies have revolutionized lung cancer therapy and have become key treatment options for a subset of patients. However, it is clear that a majority of patients do not respond to these therapies, likely due to immune-resistance mechanisms such as Treg cells, which act to suppress the immune response. At RAPT we are developing a novel oral small molecule that is designed to specifically target Treg cells associated with the tumor while not triggering widespread immune suppression, which has historically plagued the field. WuXi App Tec: What treatment modalities show the most potential? Are there any with the potential to treat early stage disease? Dr. Brian Wong: Immunotherapies are showing new potential in the treatment of lung cancer, both as monotherapies as well as in combination with different treatment modalities, including other novel immuno-oncology agents and chemotherapy. With that said, there is still room for significant improvement in this therapeutic area since still only a minority of lung cancer patients are benefiting from checkpoint inhibitors. WuXi AppTec: How is your drug different from existing lung cancer treatments? Is it a new approach? Dr. Brian Wong: We are developing FLX475, our lead drug candidate targeting CCR4, for the treatment of a broad range of “charged” tumors. These “charged” tumors are characterized by high levels of effector cells, Treg cells, and CCR4 ligands, the target for our immunotherapy. “Charged” tumor types include lung cancer and other cancer types we believe are most likely to respond to FLX475. In cancer, the secretion of certain chemokines from tumor cells and tumor-resident immune cells is responsible for recruitment of immunosuppressive Treg cells to tumor sites. Treg cells represent a dominant pathway for downregulating the immune response, and thus may limit the effectiveness of currently available therapies such as checkpoint inhibitors. Therefore, blocking the migration of Treg cells has the potential to restore naturally occurring antitumor immunity as well as to synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, immune stimulators and adoptive T cell therapy. We believe that the inhibition of CCR4 has the potential to bring therapeutic benefit to lung cancer patients (among other tumors) in a manner similar to other immuno-oncology therapies that have been shown to be effective against multiple tumor types, while also potentially deepening or broadening clinical responses to these therapies. The company is conducting a Phase 1/2 study of FLX475 in patients with advanced cancer. The Phase 1 portion of the study will examine the safety and determine the Phase 2 dose of FLX475, both as a monotherapy and in combination with pembrolizumab. The Phase 2 portion will examine the efficacy of FLX475 both as monotherapy and in combination with pembrolizumab in selected types of cancer.   WuXi AppTec: What is the specific mechanism of action? Dr. Brian Wong: FLX475 is an orally-available small molecule drug that blocks the CCR4 receptor on regulatory T cells and thus stops their ability to be recruited into tumors. By cutting off the supply of suppressive regulatory T cells to the tumor microenvironment, FLX475 is predicted to then shift the CD8 effector T cell to regulatory T cell balance toward the anti-tumor effector cells which should promote the eradication of tumor cells. FLX475 could be used either as monotherapy, or in combination with other therapies that can be limited by regulatory T cells such as checkpoint inhibitors, CAR-T cells, vaccines, chemotherapy, and radiation therapy. WuXi AppTec:  How did you choose to focus on lung cancer? It has been a very difficult disease to treat. Dr. Brian Wong: Through our analysis of many types of cancer we identified specific tumors that appear to be much more likely to express high levels of CCR4 ligands and to have high numbers of regulatory T cells and effector CD8 T cells, which we believe have a higher chance of responding to FLX475. Non-small cell lung cancer (NSCLC), both adenocarcinoma and squamous subtypes, came up as being among the most “charged” tumor types in our analysis. WuXi AppTec: Other than participating in clinical trials how have patients been involved in the development of your drug? Dr. Brian Wong: We have incorporated our profiling of cancer patient genetic data to come up with the “charged” tumor profile, which has indicated that NSCLC patients may be more likely to respond to FLX475. So patient data have certainly helped shape our overall development plan. WuXi AppTec: What major challenges have you faced in trying to bring a new drug for lung cancer to patients? Dr. Brian Wong: It is a highly competitive field, with many clinical trials ongoing using all kinds of agents, both novel and follow-on. We see these dynamics as good for patients as it means that the industry is focusing on the unmet needs of this patient population, but it also can mean many clinical trials are recruiting the same types of patients. WuXi AppTec: What lessons have you learned during the development process? Dr. Brian Wong: It is crucial to engage with investigators early on in the process and to communicate the science behind your drug candidate. Patient selection and enrichment strategy as well as a comprehensive biomarker program are critical in increasing the probability of success. WuXi AppTec: What other drug candidates do you have in the pipeline? Dr. Brian Wong: For cancer we are developing inhibitors of general control nonderepressible 2 (GCN2) and hematopoietic kinase 1 (HPK1), both of which limit the immune systems’ ability to recognize and eliminate tumor cells. These programs are in the discovery stage. We are also developing a second CCR4 antagonist called RPT193 as an oral treatment for a broad array of allergic disorders. WuXi AppTec:  What are the top three major impediments in our delivery of “better” medicines “faster” and “better” to patients? Dr. Brian Wong: First, identifying novel targets to meaningfully improve clinical outcomes. Second would be the identification of patient populations or subpopulations that have an increased probability of responding to these novel mechanisms of action, and the third impediment is the high number of clinical trials competing for the limited numbers of patients who actually participate in clinical trials. WuXi AppTec: For lung cancer, what would be the one thing that would have the greatest potential to lead a paradigm shift “from treatment to cure?” Dr. Brian Wong: Finding the right combinations of therapies that can both directly kill tumor cells while unleashing the full capacity of the immune system to develop, expand, and maintain an effective anti-tumor immune response.

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2019/11/21

SQZ Biotech’s Unique Technology Squeezes Cells to Transform Them into Therapeutics

SQZ Biotechnologies’ technology platform aims to tap into cells to create the next generation of commercially viable therapeutics with the potential to have an impact treating a broad range of diseases. Unlike current gene and cell therapies, which use viruses to engineer cells for therapeutic purposes, the company’s Cell Squeeze® platform disrupts the membranes of cells to deliver materials that arm them to treat diseases. The company recently received approval from the US Food and Drug Administration (FDA) to begin clinical trials of a cell therapy aimed at activating patients’ immune systems to attack solid tumors caused by human papilloma virus (HPV) infection. SQZ founder and CEO Armon Sharei, Ph.D., explained, “What we have been starting with is this mechanism around antigen presentation. What we do is take PBMCs (peripheral blood mononuclear cells) from the patient’s blood and use the SQZ platform to load them with tumor antigens. We are starting with HPV positive tumors.” The cells, loaded with HPV positive tumor antigens, are injected back into patients, activating the immune system’s killer T cells to attack the cancer. The clinical trials will test the therapeutic cells as a monotherapy and in combination with Roche’s checkpoint inhibitor. SQZ is working with Roche in a collaboration to develop antigen presenting cells to treat cancer. In discussing SQZ’s technology, Sharei observed, “I’m excited about the platform. We think it can overcome a lot of the fundamental issues in the cell therapy field and potentially create a whole host of new products that can make a big impact for people.” As part of an exclusive series spotlighting the insider perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Sharei about his company’s technology and the challenges facing cell and gene therapies. Sharei founded SQZ Biotechnologies in 2013 and has served as the CEO since January 2015. He earned his B.S. from Stanford University and Ph.D. in Chemical Engineering from the Massachusetts Institute of Technology. WuXi AppTec: How has research in gene and cell therapies progressed over the past 20 years? Do you anticipate a wave of new approvals coming over the next 5 to 10 years? Armon Sharei: Gene and cell therapies have advanced by leaps and bounds over the past 20 years and really have started to show the impact people were hoping to see with these concepts. If you think about historically what we’ve done with therapeutics, we had small molecules and then we had biologics. Gene therapies have the potential to be a quantum leap above that relative to what has existed so far, and that is with things like CAR-Ts (chimeric antigen receptor T-cells). With the adoption of some of these AAV (adeno-associated virus) therapies we are starting to see differences in patients that are just a huge delta relative to what was done before in those fields. CAR-Ts having north of a 70 percent response rate in patients who really had no chance of survival at that point is really dramatic. It’s very different from when you have a chemotherapy or targeted therapy come out and give patients a month of extra time versus this, which works to actually completely change your biology, potentially allowing patients to go into remission. When it comes to the next 5 to 10 years that’s where I would start to distinguish the gene therapy and cell therapy definitions a little bit differently. For therapeutics that use viruses—a lot of the gene therapies today administer a virus in vivo—that’s an area that we work less on, but from what I can tell it looks like people have really started to figure it out in a way that’s going to be therapeutically meaningful quickly in the next 5 to 10 years across a few indications. That’s amplified by companies like Novartis and Roche going into this field. After a period of refinement and development, these virus-based therapies are coming into their own and most of their applications are in these rarer genetic disorders. Now for cell therapies I would say we’re still very much at the beginning of what’s possible. Comparatively speaking, injecting a virus in vivo can do an interesting set of things beyond what a biologic could do. But a cell can do more things, by far, than a virus can do. With these cell therapies right now, due to a lack of tools, people use viruses to engineer them. That’s why this whole category of cell and gene therapies has been blurry because so much has relied on viruses to get this far. CAR-Ts, for example, are made with viruses. But ultimately what you can do with a cell is not restricted to genetic change, and I think that’s exemplified by what we’re doing at SQZ. Our platform lets us go after much more diverse biologies within cells, like the program we have partnered with Roche. We don’t make any genetic changes to these cells. We deliver, in this case, peptide materials that leverage these cells’ physiological systems and induce immune responses. Those immune responses have shown a lot of potential pre-clinically and we’re very optimistic about what they’re going to do in the clinic. In contrast to gene therapies, we’re at a point where you are going to see these cell therapies become more commonplace and accepted, and useful across diseases. We’re going to start to see more interesting things happening over the next few years, but it’s going to be decades until cell therapies really reach the height of their impact because I think they can apply to so many more diseases and patients. WuXi AppTec: When you are referring to viruses, you’re talking about the delivery systems, correct? Armon Sharei: Yes, exactly. At the end of the day, for these applications, it comes down to what can you make a cell do; and viruses are pretty limited in what kind of cargo they can bring in and also what kind of cell type they can transduce. But if you are relieved of those constraints, there is a much broader range of what you can do. What illustrates that is most AAV vector gene therapies are being used for relatively rare genetic diseases. WuXi AppTec: What scientific advances are needed to make these therapies more effective?  Armon Sharei: On the viral gene therapy side, one of the biggest things right now is repeat dosing and pre-existing immunity. That is something where people are trying to figure out how to shut down those immune responses against these viral vectors so that you can enable repeat dosing. That has been a challenge so far. In the context of cell therapies, it goes back to those elements we were talking about where right now people are really limited in what they can engineer. Improvements in cell engineering are really going to drive that big differentiation down the line. That’s where you need these newer technology platforms, which can alter many different functions within cells to create these therapeutics. Now to layer on top of that, I would say the challenge is manufacturing. Right now manufacturing for both gene therapy and cell therapy, and particularly for cell therapies, can be really impractical in the sense that it is quite expensive and, from a patient perspective, takes too long. If you are a cancer patient on your last legs, you don’t have a month to just wait for your cell therapy to be prepared. With the SQZ system, for example, our manufacturing process for our program that’s already in the clinic now is under 24 hours. So it is by far faster and more cost effective than what people have been able to achieve so far with cell therapies. And I think these kinds of manufacturing improvements are going to really determine the accessibility of these therapies down the line. A final point on the cell therapies is safety. Right now within cancer there is significant tolerance for safety challenges. CAR-Ts are not safe-based products. They tend to have significant side effects that are currently manageable, but they are still substantial. You can’t tolerate those kinds of side effects as you go into earlier lines of treatment in cancer, or if you go into indications that are not going to be terminal for the patient. Going back to cell engineering, that is the main advance needed. As you can access different biologies, you can start to create therapies that can be really effective, but also are a lot safer because they stay closer to natural physiology in how they work and don’t inadvertently trigger a host of other responses that drive toxicity. WuXi AppTec: Will cell therapies ever be commonplace? Will they become more commonplace than small molecules and biologics? Armon Sharei: I think cell therapies can be a much more rational biological approach to many diseases because you are using a complex biological machine to go and create your treatment as opposed to a relatively simplistic small molecule or biologic. That being said, it will always be easier to swallow a pill than to get an infusion of a cell therapy. So for our more serious diseases cell therapies can become commonplace and will usher in a new era where you can treat terminal illnesses with few side effects. They will be the most meaningful therapeutic modality. But when you can take a pill to ease your joint pain you’ll probably do that over a cell therapy. WuXi AppTec: How far away are we from that day? Armon Sharei: I think we are over a decade away from (cell therapy) being that commonplace. Over the next 10 years people are going to have to show that future world is possible. By taking the dramatic progress made already in cell therapies and starting to implement cell therapies across more diseases, in a safer way, with much faster manufacturing, that will be the tipping point which can lead to a proliferation of cell therapies across many disease areas. It will take a while to get there, but it will be a very interesting world when we do get there. WuXi AppTec: What are the risks and limitations of these therapies? Armon Sharei: For gene therapies, which you are delivering with viruses, the limitations are that there are not that many diseases that will ultimately be addressed by that kind of the therapeutic strategy. There are some very serious diseases that relate to a genetic deficiency, but there are many diseases that are not rooted in that kind of cause. Gene therapy will certainly have an impact for patients who really need it, but it’s not going to be a huge proportion of the population. For cell therapies, the limitations right now are those points we talked about. They are limited in what diseases they can be used for, there are safety issues, and it’s very impractical to administer them. And as we improve on methods of how to engineer these cells and have new platforms that can engineer a much broader range of function in a quick and practical way, you will start to see significant change, which makes this a lot more accessible. WuXi AppTec: How does your cell therapy work and what diseases are you targeting? Armon Sharei: Our company is built around this platform where we have shown that by squeezing cells at high speeds in a microfluidic channel you can disrupt their membranes and enable the delivery of all kinds of different materials. This has really opened up the doors as far as what cell types you can use and what you can engineer about them while implementing a simple, rapid, and cost-effective manufacturing format. We think this can ultimately be used as the basis for creating many different cell therapies. Our goal for the company is to create that next wave of much more impactful cell therapies. What we have been starting with is a mechanism around antigen presentation. We take PBMCs (peripheral blood mononuclear cells) from the patient’s blood and use the SQZ platform to load them with tumor antigens. We are starting with HPV (human papilloma virus) positive tumors. When we load these cells with the tumor antigens, what they’re going to do once we inject them in vivo is present those antigen components on their surface. That will activate the patient’s own endogenous CD8 T cells, which are the killer T cells, and they will proliferate and try to destroy the tumor. It’s really a mechanism of trying to tell the immune system what to target in the context of cancer. If we can show success in these HPV positive tumors, it should be pretty plug and play to then implement this for many different tumor types. And the manufacturing time for our Phase I trial is under 24 hours for creating the product, so it’s by far faster than what people currently do. WuXi AppTec: How would you contrast your approach with that of others attempting to create cell therapies? Armon Sharei: Our platform can address virtually any cell type and deliver any materials to alter its function. And we can do this all without otherwise causing undesirable changes to the cell function. It has broadened our ability to go after many different biologies and concepts that others can’t implement. So the contrast I would say right now is that a lot of the field of cell therapy in oncology has been focused on CAR-Ts, which thus far have been limited to B cell malignancies (i.e. specific blood cancers) and haven’t been able to translate effectively to other tumor types. Also they are associated with significant toxicity issues. In our case, we are from the beginning going into these solid tumors, which are HPV positive tumors, and based on the mechanism we’re pursuing we would expect a much better safety profile; certainly have a much faster manufacturing time; and know that it will be much simpler to implement in other tumor types relative to the mechanisms that the CAR-Ts have pursued. WuXi AppTec: Will your technology be able to treat early stage cancer? Armon Sharei: In principle, yes. Our trial is starting with later stage cancer, but the mechanism is very applicable to early stage cancers, and because we expect it to be a lot safer, it would be quite desirable to implement it in earlier stages. Whereas some of the systems that exist today for cell therapies you would not want to treat early stage cancers because the toxicity issues would be difficult to make it justifiable. But we should be able to go in earlier as well as in a broader range of cancer types. WuXi AppTec: What major regulatory and commercial challenges do you face, now that you have begun clinical development? Armon Sharei: We have had productive interactions with the FDA, and from a regulatory perspective I think we all recognize that this is a newer field and everybody is learning as we go. We have a strong case. Given the simplicity of our platform, and given the types of mechanisms we go after–and our expectations for it being safer than what’s out there–we haven’t had challenges per se from the regulatory side. There is a challenge because it’s a new field–and relatively unknown–and the regulators and companies like ourselves are trying to be thoughtful, deliberative, and creative about how we approach it. On the commercial front, because we’ve solved a lot of the manufacturing problems, we can make cell therapy much more feasible, much more broadly implementable, and it should be successful in trials. I think the main challenge is going to end up being that no one has been able to implement a broad cell therapy commercially right now. That’s going to be interesting because this is going to end up being different from a biologic. Our first program uses autologous cells. You need to think about implementation at a really broad scale, tracking individual patient material and the manufacturing chain, and scheduling the patient follow-up visits. It is more complex than a biologic or a small molecule, but ultimately we believe our approach is a lot more tractable than what people do today in cell therapy. WuXi AppTec: As with other new medicines, the prices for some gene and cell therapies generate “sticker-shock” among patients. Will gene therapies be widely accessible for patients? What changes are needed to ensure universal accessibility to these potential disease cures? Armon Sharei: It’s a great debate that’s going on right now. We’re in favor of outcome-based pricing because these new modalities, like the gene therapies and the cell therapies, should have an impact that is disproportionate to what a small molecule or biologic could have achieved. That would be the justification for the added cost. In the end, if you are actually making these new modalities do what they are capable of, it should actually be a net benefit and cost-savings to society because you’re treating or potentially curing diseases that previously would result in much less desirable personal and economic outcomes. When we are used to paying for a treatment that is going to prolong your life for a month or two and be really expensive, that is one mindset. But when you’re talking about a treatment that could potentially cure the disease, that is a very different proposition. Ultimately, I think there will be a solution to pricing that recognizes the impacts of these therapies and has an economic incentive to continue to create them. WuXi AppTec: Have you determined how you are going to value your therapy? Armon Sharei: We have not. It will be determined by how much of an impact we’re having. Obviously there have been certain precedents set by where CAR-Ts have been priced, but we want to see what our cell therapy does in the clinic and how truly differentiated it is before trying to figure out pricing. WuXi AppTec: In general, what are the top 3 impediments to delivery of better medicines, faster and cheaper to patients?  Armon Sharei: In our context, the biggest impediments are the breadth of biology people can access today. It has been limited and we feel platforms like ours can overcome this. That will make a big difference. The manufacturing and turn-around time involved with our field right now are problems, and if we can resolve those it will really make these (cell therapies) much more accessible. And then finally—this actually goes to your point on pricing and incentives—we do need a more rational incentive and pricing structure that motivates the right kinds of innovation and demotivates the much more incremental or repetitive pieces that might encourage inefficiencies in the system.

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2019/11/08

Avalon Venture’s Jay Lichter Discusses COI, Community of Innovation, a Different Way for Drug Discovery and Development

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team Tucked away in the life science corridor of San Diego’s famed Torrey Pines Road is an unconventional incubator with an unconventional name, COI Pharmaceuticals. This facility is not really a pharmaceutical company but rather a Community of Innovation, according to its CEO, Jay Lichter. Established in 2013, COI is a fully integrated incubator that streamlines its operations through shared key resources including finance, planning, facility and more. Unlike most incubators, this is not a real estate play but rather is part of the Avalon Ventures’ investment portfolio, where Lichter is a Managing Director responsible for life science related investments. Lichter perceived it as a pragmatic way of operating various small businesses. Lichter brings an unusual combination of business acumen and deep scientific/technical knowledge together, resulting in licensing or merger/acquisition deals valued in excess of $3B. He started 25 companies; for example, he was a co-founder of Sequana Therapeutics and Synthorx (a synthetic biology company whose genetic alphabet expanded to six base pairs makes novel protein therapeutics with improved pharmacological properties). He also led investments in Sitari, Calporta, Otonomy, Aratana and Fortis amongst many others. A hands-on executive leader with more than 25 years of experience, he holds more than 300 patents (issued or application). His investment and management style and that of his senior staff is “operational capital,” meaning that he invests in companies, his team runs the companies, and he keeps track of them daily. In a recent discussion with Rich Soll and the WuXi AppTec Content Team, Lichter identified his main motivation: pushing the frontiers of technology to satisfy unmet medical needs. Most of Lichter’s startups are first in mechanism, “no me too’s.” This philosophy is partly inspired by his own experience with a balance disorder and hearing loss, which connected directly to the funding of Otonomy, a company that pioneered new treatment options to patients with otic (ear) disorders whose therapy is now in Phase 3. “There’s certain risk with first in mechanism,” Lichter admitted. “How is the FDA going to go, how to set up clinical trials necessarily, whether or not your approach is going to have efficacy with a successful safety profile when you finally get to the clinic… (But) when you do win, you’re going to get it at a premium for that particular molecule because nobody else is doing it. Anybody else is years behind you.” However, Lichter stressed that investing considerations are not solely based on good science. Given the extensive experiences of Avalon and its expertise, the portfolio companies are required to have a specific financial picture of the amount of money they need to put in over the life of the startup, which highlights the importance of running a business. “There are plenty of things where it is great science but terrible business. I’m not doing it. So that business piece is super important,” Lichter said. “I’m making investment decisions and coaching people on business strategy.” All Avalon portfolio life science companies stay in COI for further discoveries and development; there are 12 companies currently. When the company grows up and has a full-time management team, it leaves the incubator. This usually happens when a Series B get raised and when its own dedicated team is needed. Otonomy did, Synthorx did, and a few others are going on that path. COI’s pipeline is as abundant as its portfolio. “We have Avelas in Phase 3 for breast cancer treatment during surgery, a bunch of companies in the clinic testing new molecules, and companies that are manufacturing right now, promising a near future to be in the clinic,” Lichter continued. “In addition, one healthcare IT company with monthly revenue growth by 20% and two companies going to be acquired. We’re excited by that.” When looking into the Intellectual Property within all the funded companies, a third of it is homemade and two-thirds come from universities. GlaxoSmithKline (GSK) installed a unique early-stage partnership model with Avalon Ventures in 2013, with a goal of 10 investments. They have formed eight companies incubated by COI as part of that partnership. These included Iron Horse Therapeutics, whose focus is on amyotrophic lateral sclerosis, PDI Therapeutics, an immune-oncology company, and Sitari. On September 11, 2019, GSK announced it would acquire Sitari Pharmaceuticals for its transglutaminase 2 (TG2) small molecule program for the treatment of celiac disease, where TG2 is thought to play multi-factorial role in autoimmune response to the disease as well as catalyzing a reaction with dietary gluten peptides that drive pathogenesis of the disease. The acquisition occurred six years after Sitari’s founding and $10M in Series A financing. “Our batting average for delivering clinical candidates is about 60-70%, which is not only quite remarkable for a first-in-class molecule, it is higher than industry average,” stated Lichter. “Part of it is that we make sure we have all the assets and reagents needed, hope for a little luck, and good contractors like WuXi AppTec to make sure that experiments get done right.” Lichter was a big fan of virtual companies before it became popular. “We were outsourcing a lot of stuff; if there was a key complex biological asset, we kept that in house, Lichter stated. “With Fortis we raised $28 million yet had no full-time employees; everything was outsourced. We could not do that fifteen years ago.” WuXi AppTec has had a long-time partnership with Avalon’s portfolio companies. In the development of these startups, WuXi AppTec enabled COI through manufacturing, general chemistry, process, PK and other kinds of capabilities. Lichter viewed it as a privilege of keeping small teams and working on multiple projects. According to him, it helps companies put emphasis on innovation and plan, rather than the size of chemical libraries. Lichter’s senior team has seen more than 1500 proposals over the last 5 years. To be considered for entrance into COI, an entrepreneur’s proposal must have innovative science that addresses an unmet medical need, possess a clear regulatory and clinical strategy to the market, and the product must be disruptive rather than incremental in terms of benefit to the patients. Lichter also commented on innovation impediments or barriers to delivering medicines faster and cheaper to patients. “You can get some grant money and small capital from friends and family. Identify a target. Make your laboratory-based antibody and you can even engineer it a little bit. Get to your final form without a lot of money. Then it’s minimally nine months and five million dollars, often more, to have it made and manufactured. In today’s funding world that’s really difficult,” said Lichter. “This is an industry-wide hurdle.” As a seasoned former researcher, he also wished to see improved manufacturing technologies. “If there was a machine that I could take a cell or a group of cells from a clonal population with novel antibody in it, and in two weeks out pops enough GMP materials, I could run my first Phase 1. That would change a lot of things. You’d see a lot more of these things in the clinic quickly,” he said. Lichter concluded with the following: “There are already many cancers that can be treated and cured, and that number will increase dramatically,” said Lichter. “It will be like infections. Until you first started to understand what antibiotics were, people would die quickly from infections. Now there’s therapy and the vast majority of people who get infections don’t die. And I think in cancer you’re going to see the same thing in the next ten to twenty years.”

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2019/11/08

The Prostate Cancer Foundation: A Tireless Worker and Voice in the Development for Better Treatments

Prostate cancer is the second most common cancer in men.It is a cancer that occurs in the prostate — a small walnut-shaped gland in men that produces the seminal fluid that nourishes and transports sperm. While some types of prostate cancer grow slowly and may need minimal or even no treatment, others are aggressive and can spread quickly. Prostate cancer that’s detected early, when it’s still confined to the prostate gland, has a better chance of successful treatment. But malignant growths can be a threat to life as they can spread to nearby organs and tissues, such as the bladder or rectum, and can also metastasize to other parts of the body like lymph nodes or bone. Although it can be removed, sometimes it grows back. Treatment side effects can lead to incontinence, erectile dysfunction, depression, fatigue, and infertility. WuXi AppTec Communications has been highlighting companies conducting novel research into different diseases, but another key to finding treatments for unmet medical needs are active disease research organizations and patient advocacy groups, which help provide financial support for research, provide useful patient information on how to get help, and represent the patients in an advocacy role. To coincide with a new WuXi AppTec series about prostate research, we spoke with Jonathan W. Simons, MD, President and CEO of the Prostate Cancer Foundation (PCF), for an overview about the current state of prostate research and the pathways to future treatments and cures. Dr. Simons is an internationally recognized physician-scientist, oncologist and acclaimed investigator in translational prostate cancer research. Prior to joining the PCF in 2007, he was Distinguished Service Professor of Hematology and Oncology at the Emory University School of Medicine and Professor of Biomedical Engineering and Materials Sciences at the Georgia Institute of Technology. Dr. Simons is the Founding Director of the Winship Cancer Institute at Emory University in Atlanta and Co-Director of the National Cancer Institute Center for Cancer Nanotechnology Excellence at Emory and Georgia Tech. WuXi AppTec: What progress has been made in diagnosing and treating prostate cancer since the founding of the Prostate Cancer Foundation (PCF) 25 years ago? Dr. Simons: The PCF has supported the research leading to every major practice-changing advance against prostate cancer since its founding in 1993. This includes early research and development for nearly every life-extending drug approved by the U.S. Food and Drug Administration (FDA) for prostate cancer since 2004. Without a doubt, the prognosis for men diagnosed with prostate cancer at any stage has never been more encouraging. Recent advances enable men with prostate cancer to live longer, more productive lives – and when detected early through routine physical exams and minimally invasive blood tests, prostate cancer is nearly 100 percent treatable. Nearly 100 percent of men diagnosed with prostate cancer in the local or regional stages will be disease free after five years. Equally important is the fact that discoveries in prostate cancer now extend to saving lives in more than 18 other forms of cancer, including breast, myeloma, colon, lung, ovarian, melanoma, pediatric neuroblastoma, bladder, and thyroid cancers. Because the PCF is focused on precision medicine, we are funding research that targets cancers based on their genomic alterations and not the organs from which they came, and therapies that help men with metastatic prostate cancer have been shown to be effective in more than 73 other forms of human cancer. Over the last two decades, the PCF has worked tirelessly and effectively to promote public awareness about the disease to the reduction in the U.S. death rate from prostate cancer by more than 50 percent. WuXi AppTec: And as a follow up, there seems to be a lot of confusing advice coming from the community about what type of prostate testing is most effective. Can you comment?  Dr. Simons: The PCF has always stressed that the question of screening is a personal and complex one, and we believe in strategic and personalized screening. The decision to undergo routine prostate specific antigen (PSA)-based screening in men with a normal risk aged 55 to 69 should be an individual one that includes a discussion about the potential benefits and harms of screening. The PCF believes that every man should be able to talk with his doctor about whether prostate cancer screening is right for him. Additionally, it is the PCF’s position that for men with a family history of lethal breast cancer, ovarian cancer, or pancreatic prostate cancer in a first-degree relative, 40 is the age at which a conversation with a health provider to discuss the potential benefits and harms of prostate cancer screening should begin. In the African-American community, we encourage men at 45 to pay attention to their prostate health and prostate cancer risk and take the opportunity to talk with their doctors about the pros and cons of prostate cancer screening. Above all, the PCF believes there is no ‘one-size-fits-all’ approach to screening. We generally support the recommendation made by the United States Preventive Services Task Force against prostate cancer screening in men over the age of 70, although we acknowledge that this age-based recommendation may not be appropriate for all men over the age of 70 and advocate for a personalized approach that takes into account health, values, and preferences. WuXi AppTec: What are the hot targets today in the field of drug development for prostate cancer? Dr. Simons: Poly-ADP ribose polymerase (PARP) and prostate-specific membrane antigen (PSMA) are two of the “hottest targets” in the field of drug development for prostate cancer today. A study presented recently at the 2019 European Society for Medical Oncology (ESMO) Congress reported positive results from a Phase 3 clinical trial testing the PARP inhibitor olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) who have alterations in certain DNA damage repair (DDR) genes, a result which will likely lead to a new FDA approval. Roughly 20 to 30 percent of mCRPC patients harbor these DDR gene mutations in their tumors and thus may benefit from PARP-inhibition. This trial of olaparib is the first positive Phase 3 “precision medicine” clinical trial testing a targeted therapy in men with advanced prostate cancer with defined mutations. PARP inhibitors were first approved by the FDA as treatments for BRCA1/2-deficient breast and ovarian cancer in 2014. However, PCF-funded studies demonstrated that BRCA1/2 and PARP are also important in prostate cancer. Prostate-specific membrane antigen is a protein on the surface of prostate cancer cells, and is a compelling cell surface drug target. The PCF is supporting research into many new treatments for prostate cancer that target PSMA, including radionuclide therapy, a treatment that brings radiation directly to tumors, and chimeric androgen receptor (CAR) T cells, a form of personalized immunotherapy. Prostate-specific membrane antigen is also a very good target for PET imaging tracers, and PSMA-PET imaging has been demonstrated to be significantly more sensitive than current imaging methods for detecting sites of prostate cancer throughout the body. The PCF anticipates that PSMA-PET imaging will likely be FDA approved by 2020. WuXi AppTec: What are the prospects for treating the disease in its early stages? Will drugs ever be a substitute for surgery and radiation? Dr. Simons: Early potentially lethal prostate cancer if untreated can be cured by not one but two different modalities: radiation therapy or surgery. Eventually, the PCF believes most advanced prostate cancer can be intercepted when it is micro-metastatic and the total burden of cancer in a patient’s body is at its lowest number. If caught early, prostate cancer is 100 percent treatable. Early, strategic detection is thus so important. Early prostate cancer can be treated by not one but two modalities: radiation and surgery. Surgery and radiation therapy remain the standard treatment for localized prostate cancer. But other experimental treatment options have recently become available. As time goes on and the benefits of these treatment options are better understood, it’s possible that they may be reasonable alternatives for certain patients. For now, none of these are seen as standard treatment for localized prostate cancer because they lack support from large randomized clinical investigations in comparison with successful radiation or surgery. WuXi AppTec:  What are the regulatory challenges in evaluating early stage prostate cancer treatments? Dr. Simons: The process of discovering, developing, and delivering new therapies has myriad challenges. In order for the FDA to approve a new therapy, an improvement in length or quality of life due to the therapy must first be demonstrated in clinical trials. The “overall survival” (OS) endpoint, which measures the length of time from randomization to death from any cause, is the gold standard for measuring the impact of a treatment on length of life and the goal line for calling a new treatment curative. However, in localized prostate cancer, reaching an OS endpoint can require 10 to 15 years – a prohibitive timeframe for pharmaceutical companies. This fact has translated into only limited improvements being made in the treatment of early, aggressive prostate cancer in the last decade. For patients urgently awaiting treatments and cures, addressing these regulatory challenges is vital. For this reason, the PCF identified this issue as a critical unmet need, and in 2012, supported the establishment of a working group called ICECaP (Intermediate Clinical Endpoints of Cancer of the Prostate). Led by Dr. Christopher Sweeney of the Dana-Farber Cancer Institute, this is an international collaborative initiative to undertake the arduous task of identifying an intermediate clinical trial endpoint that can accurately predict OS but can be obtained much earlier in the course of the disease. WuXi AppTec: Is clinical trial participation by patients a challenge? If so, how does the PCF encourage participation? Dr. Simons: The first 1,000 men cured of incurable advanced prostate cancer will be in a clinical trial. The road to cures runs through clinical trials. The PCF is the go-to source for information about the latest investigational clinical trials driven by PCF-funded science. In addition to publishing the Prostate Cancer Patient Guide, a comprehensive health guide for prostate cancer patients compiled with the contributions of top-tier doctors and researchers in prostate cancer, PCF.org is the center for must-have resources for prostate cancer patients. It focuses all of the information available about contemporary prostate cancer research, treatment, lifestyle factors, and precision clinical trials. To further improve access to information that can improve outcomes by getting patients on “the right track” as soon as possible, the PCF has also launched a prostate cancer clinical trial finder in collaboration with Smart Patients. Because finding a trial can be confusing for patients, the PCF has custom-curated trials that may be specifically relevant to men with prostate cancer. The tool allows men to search based on their disease state, stage, and their geographical location. WuXi AppTec: What are researchers learning about the causes of prostate cancer? How is it different from other cancers? Dr. Simons: Over the past 25 years, more than 50 hereditary DNA mutations (genetic mutations that run in families) have been discovered that may increase the risk of developing certain cancers. The most famous that you may have heard of are the BRCA1 and BRCA2 mutations that increase risk for breast and ovarian cancer. Prostate cancer has long been recognized to have a familial component. In fact, of all human cancers, prostate cancer is the most common running by hereditary 57 percent among family members, with 40 percent of prostate cancer attributable to genes that run in families. If you have received a prostate cancer diagnosis, it’s important to speak with your family about risk, prevention, and screening. Having a father or brother with prostate cancer increases a man’s risk of developing prostate cancer. The genes that cause this risk have been extensively studied and are complex and need more research. WuXi AppTec: How does the PCF support research and drug development? Dr. Simons: The PCF is unique in its innovative approach to medical research funding. The PCF identifies the most promising “first-in-field” early research ideas and attracts brilliant individuals and teams of scientists early in their careers to the PCF’s Global Research Enterprise. By channeling resources directly to the world’s top scientific minds, the PCF is able to cut through red tape, speed scientific breakthroughs, and deliver new treatments to patients. The PCF funds a variety of different kinds of projects that vary in focus, scope, and duration: PCF Challenge Awards fund teams of scientists working on critical unmet needs for advanced prostate cancer; PCF Young Investigator Awards jumpstart research programs for early-career scientists and researchers; and, PCF researchers connect globally to exchange information and share scientific data in real time. Since its inception the PCF has been a pioneer in new drug development, providing key funding for FDA-approved treatments that improve survivorship. Having recruited more than 5,000 of the best physician-scientists in more than 21 countries, many of the most important discoveries in the fight against prostate cancer since 1993 have resulted from PCF funding or coordination. Thanks in large part to the work of PCF-funded researchers, the number of drugs approved to treat prostate cancer doubled – from just six drugs approved in nearly 30 years to another nine drugs approved in just nine years. Of those nine medicines, eight were FDA-approved because they actually prolong patients’ lives, rather than simply ease their symptoms. As of early 2019, there are now a total of 21 drugs approved by the FDA for treatment of prostate cancer, with even more in the pipeline. WuXi AppTec:  What are some of your most recent research funding efforts? Dr. Simons: Prostate cancer is the most frequently diagnosed cancer among veterans. In 2016, the PCF committed $50 million over five years to create Veterans Affairs (VA) Centers of Excellence that deliver innovative, best-in-class prostate cancer care to veterans. More than half of the PCF’s Precision Oncology funds have already been used to stand up ten Centers of Excellence and fund the research of numerous VA physician-scientists. The platform created by the PCF will be used to build Centers of Excellence for other cancers as well. WuXi AppTec: What is the best strategy for developing new prostate cancer drugs? Dr. Simons: Collaborative teams comprised of young scientists is the fastest route for research and development to end death and suffering from a disease. The contribution, or loss, of even the single greatest researcher, isn’t likely to make or break the attainment of a cancer cure. That achievement will come from the global community of a great team of researchers. These repositories of accumulated intellectual, physical, and financial resources represent the “social capital” of medical progress. The PCF has laid the cornerstone for at least four major social capital initiatives involving this community. The PCF has changed how research is funded to harness the power of teams. Our research awards are designed to attack major problems in prostate cancer biology and treatment by creating synergistic teams of individuals with diverse intellectual capabilities who otherwise might simply conduct isolated research in their own silos they require constant unpublished data sharing. The PCF began seeding this field with individual research awards in 1993. As traditional funding sources have picked up these programs, we’ve adopted a strategy of directing current and future PCF funding to more effective team science. This strategy has resulted in the formation of collaborative teams who are able to take research from bench to bedside rapidly.    WuXi AppTec: What are the top three impediments to delivery of better medicines, faster and cheaper to patients? Dr. Simons: Our greatest challenge of all of the many challenges is less than five percent of men with advanced prostate cancer participate in clinical trials. Our second challenge for advanced disease is that we still need to better understand how to stop prostate cancer cells from evolving in real time to become resistant to our new promising therapies. Cancer cell “evolutionary” resistance is the killing mechanism of fatal cancers. WuXi AppTec: What are your thoughts relating to focal therapy and prostate cancer? Dr. Simons: “Focal” therapies are treatments that target just a region of the prostate thought to have the tumor, instead of treating the entire prostate gland. None of these therapies have yet been proven in large randomized clinical trials to have the same long-term success as surgery or radiation therapy in clinical trials. Claims about them must be viewed with caution. They are still considered experimental treatments. The likelihood of recurrence is high with focal therapy due to the fact that in more than 60 percent of cases prostate cancer is actually “multi-focal,” meaning even if the biopsy and/or MRI showed the cancer to be in only one area, there is likely tumor in many areas of the prostate. WuXi Apptec: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure in prostate cancer drug development? Dr. Simons: One of the most promising areas that has the potential to lead a paradigm shift from treatment to cure is the field of immunotherapy. Historically, the problem with curing cancer has been the uncanny ability of cancer cells to reprogram themselves after treatment and hide from the immune system. The promise behind immunotherapy is that when properly activated, the immune system has the potential to evolve as quickly as the tumor and seek out and kill tumor cells anywhere they are hiding in the body. In many types of cancer, immunotherapy has resulted in long-term remissions and even cures in patients with advanced metastatic disease who would otherwise have died from their disease. Numerous ongoing research studies and clinical trials are being conducted around the world trying to discover newer immune cell activations and optimize immunotherapy to treat the many forms of advanced prostate cancer.  

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2019/11/05

OncoSenX Developing New Gene Therapy Approach that Kills Cancer Cells by “Suicide”

Gene therapy faced many challenges in its early days, but scientific advances, drug approvals and millions in investment have accelerated research in the gene therapy field. WuXi AppTec Communications has begun a new series profiling some of the companies developing novel and unique approaches to making gene therapy even more effective in treating intractable diseases. One such company is OncoSenX, based in Seattle. OncoSenX believes “The next generation in cancer therapies will be more targeted with fewer side effects….and should be fought with genetic information.” The company is using brand new technology to develop transient gene therapies for solid tumors in cancers such as lung and prostate. They work by delivering genetic programs (DNA) that cause cancerous cells to commit suicide via apoptosis and/or express immunotherapeutic proteins that “flag” them for the immune system to aid in their removal. WuXi discussed OncoSenX’s new gene therapy technology, and what this technology could offer in the future, with company CEO, Chairman and co-founder Matthew Scholz. A serial entrepreneur with a background in computer security and immunology, Matt is also the founder and CEO of Oisín Biotechnologies and former CEO of Immusoft, a biotech firm developing a breakthrough technology that will turn a patient’s B cells into miniature drug factories. He’s a graduate of the University of Washington and a frequent speaker at the UW School of Business. WuXi: The promise of gene therapy has been around for decades. How has gene therapy research progressed over the past 20 years? Do you anticipate a wave of new approvals coming over the next 5 to 10 years? Matthew Scholz: People have wanted to manipulate DNA ever since they knew what DNA was, of course – but as with any new technology, it took a long time for the field to develop. The last 20 years in particular have borne witness to extraordinary progress. They weren’t without challenging circumstances, of course: the 2000s began with the field reeling from the death of Jesse Gelsinger, a sobering event that would chill research and funding for some time, but most recently, we’ve seen the approval of several gene therapies, billions of dollars of investment and renewed excitement about what is possible. There are currently hundreds of gene therapies in clinical trials and I fully expect a commensurate wave of approvals in the future. WuXi: What kinds of diseases are targeted with gene therapies? Matthew Scholz: The first wave of treatments mostly targeted rare monogenic diseases, but now the field is largely dominated by oncology therapeutics. There aren’t many limits on what diseases could be treated with gene therapies, but given their expense and risk, today they are primarily focused on life-threatening or severely debilitating diseases. The gene therapies we’re developing have compelling advantages in these respects. They should be far less expensive to produce at scale. This is largely due to the fact that we don’t need to grow viruses and that it’s an off-the-shelf product with no ex vivo cell culture. Our therapies should be far less toxic than chemotherapies and more broadly applicable & scalable than CAR-T cell therapies. In many respects what we’re building can really be thought of as the next generation of I-O therapeutics. WuXi: What scientific advances are needed to make gene therapies more effective? Is delivery still one of the major challenges? Matthew Scholz: Despite therapeutic developers’ best efforts, delivery remains the Achilles heel of gene therapy. It is less of a challenge for ex vivo gene-modified cell therapies, but there are many tissues one cannot take out of the body to modify. Viruses – adeno-associated viruses specifically – are the primary way of delivering DNA in vivo, and they are fraught with problems. They are exceedingly expensive to manufacture at scales needed for systemic delivery in adults. They have a very limited DNA cargo capacity and they’re also immunogenic, so repeat dosing isn’t feasible. The emergence of a delivery vector that addresses these limitations would be a transformative development for the field. WuXi: Will gene therapies ever be commonplace? If so, how soon? Matthew Scholz: Maybe not commonplace in the near future, but certainly more common. I think we’ll continue to see people preferring pills containing small molecule drugs that can be taken easily and mass produced cheaply. With that said, I think we are approaching the limit of what small molecule drugs can do. The more we learn about human biology, the more personalized and targeted our treatments become. At the root of biology is the code of life – DNA – so one way or another, I think we’ll end up increasingly building treatments that manipulate genes and their expression. If we look further into the future, say 20-50 years, I think it’s possible that gene therapies will start to be used prophylactically and therefore become quite commonplace. WuXi: What are the risks and limitations of gene therapies? Matthew Scholz: The primary risk of gene therapies in general is an unintended integration event that leads to uncontrolled cell proliferation (cancer), though every treatment will have its own set of attendant risks. Some of the more significant limitations of today’s technologies are: the small payload capacity of the delivery vectors, inefficient transduction of the target cells (especially in vivo), immunogenicity of the delivery vectors and manufacturing constraints. WuXi: What gene therapies are you developing and how do they work? Matthew Scholz: We’re developing transient gene therapies for solid tumors – cancers such as lung and prostate. They work by delivering genetic programs (DNA) that cause cancerous cells to commit suicide via apoptosis and/or express immunotherapeutic proteins that “flag” them for the immune system to aid in their removal. Our first therapeutics will directly kill cancerous cells with a suicide gene, whereas our second-generation treatments will also actively engage the patient’s immune system. This is a radically different approach than traditional cancer therapeutics or even other gene therapies for cancer. The data we’ve generated so far is really astounding! We can reduce the size of solid tumors in rodents by 90 percent with a single systemic IV injection without any detectable off-target toxicity. It’s also well-tolerated in non-human primates even at massive doses and, unlike viruses, our therapeutic can be administered repeatedly. WuXi:  How does your approach differ from other gene therapy companies? Matthew Scholz: We are killing cells based on their genetics, specifically their transcriptional activity. We deliver the DNA in vivo systemically with a unique lipid nanoparticle (LNP). The LNP is neutrally charged so it doesn’t have the toxicity associated with other LNPs on the market today. It gains entry into cells with a fusogenic peptide on its surface that mixes the lipids of the LNP with the lipids in a cell’s membrane. This results in the DNA being deposited directly in the cytoplasm, bypassing the endocytotic pathway entirely. Since the peptide fuses with cellular membranes, its delivery is indiscriminate – it dumps the DNA payload into any cell in comes in contact with. The DNA payload itself determines which cells are killed. For example, our first therapeutic targets cells have elevated levels of p53 transcription factors. P53 is a tumor suppressor; a cell will typically activate p53 when it detects something, like DNA damage, that needs to be addressed before the cell should be allowed to divide. Since p53 prevents cells from dividing and cancerous cells divide uncontrollably, many cancers have mutated or otherwise broken the p53 gene in the process of becoming cancer. What’s important about this from our perspective is that when p53 is mutated or ablated, the cell often tries to rescue it by making more p53 transcription factors – this is analogous to a person smashing a button harder or repeatedly when it doesn’t work. Our DNA payload encodes a suicide gene that is controlled by a synthetic p53 promoter. That means that damaged cells with elevated levels of p53 transcription factors will read our DNA payload (the suicide gene) and die, whereas healthy cells with normal levels of p53 transcription factors will not read the DNA payload and remain unharmed. We’ve effectively taken targeting out of the realm of chemistry and into the realm of information. This approach allows us to even go a step further and implement Boolean logic in DNA. We can build logic gates in DNA (such as IF /AND/NOT) and make the targeting very specific based on the transcriptional activity of the cells – it’s a radically different approach than others are taking. Our LNP is also far less expensive to produce than viral vectors: the most expensive part is the DNA itself. It can also be made very rapidly at enormous scales, and it can carry relatively large payloads. So far, we’ve administered it to animals for over a year without any detectable immunogenicity, and it is well tolerated at doses that are two orders of magnitude higher than traditional LNPs. WuXi: What are your major regulatory and commercial challenges? What lessons have you learned? Matthew Scholz: We’re pioneering a new class of treatment, and with that, we need to go above and beyond when it comes to demonstrating safety and specificity. It’s early days in the regulatory process of course, but we’re putting a lot of emphasis on those two points. On the commercial side, we’ve needed to educate our audiences on the fact that this is a unique approach to targeting and delivery with an LNP, and that we’re distinct from past LNP approaches that have had their setbacks. In this respect we’ve already started to see progress with a compelling set of data and taking the time to walk people through the merits of the approach. WuXi: As with other new medicines, the prices for some gene therapies generate “sticker-shock” among patients. Will gene therapies be widely accessible for patients? What changes are needed to ensure universal accessibility to these potential disease cures? Matthew Scholz: I’m optimistic that as the industry works through the manufacturing and delivery issues, the costs will come down. In just the last decade we’ve actually seen a tremendous increase in the scale at which these treatments can be produced. As these therapies continue to target diseases with ever-larger patient populations, economies of scale will help drive down costs. Some of the technologies in use today might also simply need to be replaced with next generation versions before gene therapies can be widely accessible, much like vacuum tubes had to be replaced with transistors before computational technologies could be made widely available. Gene therapies won’t ever be as cheap as aspirin, but I do think they will become widely accessible. WuXi: In general, what are the top 3 impediments to delivery of better medicines, faster and cheaper to patients? Matthew Scholz: I’d say first of all is the science itself – there is a lot we don’t know about biology, and it takes a lot of time and resources to create a better medicine in the first place. Second, in gene therapy specifically, we’re also quite limited by the technology: culturing patient cells and growing viruses involves processes and equipment that are clumsy, mostly manual, and nowhere near as mature as say the semiconductor industry. And finally, the entire medical system seems optimized to do the exact opposite of “better, cheaper, faster.” From a regulatory perspective we prioritize safety of medicines over speed to market or cost – especially with new classes of treatments. People may argue over this balance that the regulators have struck in mitigating the dangers of drugs versus the affliction of disease, and I do think the system is delivering progressively better medicines, but I think everyone would agree that the current process is slow and exceedingly expensive. Furthermore, patients, the ones who care most about these goals, have little to no influence over the system, and have to navigate layers and layers of bureaucracy, from the payors and benefit managers to the provider institutions themselves. The science and technology will continue to improve, but other key components of the healthcare system will need to evolve as well to truly make good on those advancements.

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