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2020/01/12

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

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

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2019/12/30

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

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

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2019/12/23

SOTIO Arms Dendritic Cells for Immunotherapy Against Cancer

SOTIO has developed a method to generate autologous dendritic cells that express multiple tumor antigens on their surfaces to awaken oncology patients’ immune systems to attack the cancer. Radek Spisek, Ph.D., the company’s Global CEO, observed that cancer cells express many different tumor antigens. In their ongoing effort to elude detection by a patient’s immune system, those tumor cells shed some of their antigens. To counter this evasive strategy, SOTIO arms the patients’ dendritic cells, which Spisek describes as the immune system’s most important cells, with “multiple different tumor antigens,” he explained. “In case two of those antigens disappear from the tumor cell, or five of them, we still have many additional shots on goal. There are still additional targets for the immune response that can be explored and we believe that this is important,” he said. SOTIO is developing its dendritic cell platform for treatment of lung, prostate and ovarian cancers. The Czech company’s most advanced program targets prostate cancer and it expects to complete its Phase III registration trial in Europe and in the U.S. in 2020. Next up is a Phase III trial in ovarian cancer, which will take four years to complete. The company is also in discussions to design a potential registration trial for lung cancer patients. 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 Spisek about his company’s technology and the challenges of developing new drugs for cancer. Spisek participated in the founding of SOTIO in 2010 as Chief Scientific Officer and was appointed Global CEO in March 2018. He received his Ph.D. in immunology from the 1st Faculty of Medicine of Charles University in Prague and is a professor at Charles University’s 2nd Faculty of Medicine. Spisek also worked at the Institute de Biologie of Université de Nantes in France and the Center for Immunology and Immune Diseases at Rockefeller University, New York. WuXi AppTec: Is your immunotherapy targeting early stage treatment of solid tumor cancers, including lung cancer? Radek Spisek: In our cancer immunotherapy program, we already have very intriguing data in ovarian cancer, and initial data in lung cancer, that show positive signs of efficacy in our ongoing clinical trials, especially in patients who are at the stage of either minimal residual disease or minimal tumor burden; or patients who are in remission after the standard of care chemotherapy and have low tumor burden. So, our approach seems to be best suited for patients who are diagnosed early, who have low tumor burden, where the immune system is still fully functional and when there is a great chance that successful immunotherapy might lead to induction of anti-tumor response and subsequently result in improvement of the prognosis of the patient. WuXi AppTec: How much progress has been made in lung cancer drug research over the past 10 to 20 years? Radek Spisek: There has been a revolution in the treatment of many solid tumors after the successful introduction with checkpoint inhibitors. They represent a novel class of treatments that exploit the immune system. The outcome is that you delete the immunosuppressive environment in the patients and you give the immune system a chance to get active, attack the tumor cells and eliminate them. Almost 10 years ago, the introduction of checkpoint inhibitors for the treatment of melanoma, then non-small cell lung cancer and then many other solid tumors really represented a change of paradigm, which for me now signals the addition of a new modality to the three classical modalities of radiotherapy, surgery and chemotherapy. Over the course of the past 10 years, checkpoint inhibitors have found their place in the standard of care treatment protocols, including those for lung cancer. It’s fascinating to see that they basically moved to a front-line treatment for lung cancer, and we now see many clinical trials where checkpoint inhibitors are tested as front-line treatments in head-to-head comparison with standard of care chemotherapy or in combination with chemotherapy. This decade-long process in the development of checkpoint inhibitors for lung cancer really resulted in the substantial improvement in the prognosis of the disease. To me this represents a revolution and rightly so was recognized with a Nobel Prize in 2018 for Jim Allison, of the MD Anderson Cancer at the University of Texas, and Tasuku Honjo, of Kyoto University. WuXi AppTec: How does SOTIO’s active cellular immunotherapy platform work in treatment of lung cancer? Radek Spisek: It falls into the category of active immunizations, so it means you are trying to actively induce anti-tumor action in the patient’s body. You are trying to get an anti-tumor immune response that recognizes the tumor cells and eliminates the tumor cells, prolonging survival of patients with lung cancer. There are many approaches that fall into this category of active immunization. What we are trying to explore is an approach based on dendritic cells. Dendritic cells are the most important cells in the human immune system. They are necessary for the induction of the immune response. What dendritic cells do very well is present tumor antigens on their surfaces, which become accessible to the effector cells of the immune system, especially T lymphocytes. When T lymphocytes see the tumor antigens on dendritic cells, the T lymphocytes get activated, they proliferate, they amplify and then they can recognize tumor cells that express these tumor antigens and kill them. In our clinical programs, we enroll patients into the clinical trial and then we artificially, in our cell therapy laboratories, generate hundreds of millions of dendritic cells from a particular cell subset in their blood. Patients go to a blood transfusion center and spend two to three hours there while we collect hundreds of millions of white blood cells from their peripheral blood. From these white blood cells, we generate hundreds of millions of dendritic cells within one week. There is one additional step we do in our laboratories and that is we introduce the tumor antigens into the dendritic cells. Our cell therapy laboratories are in Prague, Czech Republic and in Beijing, China. The tumor antigens are known to be present in lung cancer, and the outcome of their introduction is that the dendritic cells take up the tumor antigens and then they express them on the surface and this results in dendritic cells that are fully capable of inducing anti-tumor responses in the patient’s body. Next we freeze the dendritic cells in liquid nitrogen so they remain viable and when the patient comes to the hospital outpatient clinic, the physician takes up the frozen vial of the dendritic cells, thaws the cells and by a subcutaneous injection, injects the cells and they migrate in the body to the lymph nodes of the organ where they interact with the T lymphocytes. They activate the T lymphocytes, which do their job and kill the tumor cells. This a complicated process that we need to do for every patient involved in the trials. WuXi AppTec: How do you introduce the tumor antigens into the dendritic cells? Radek Spisek: This is a specific element of our program that is patent protected, but most of it has been presented and published in scientific journals. What we decided to do a long time ago and what will differentiate our approach from other ones is that the source of the tumor antigens is the tumor cells. We identified a mixture of two specific lung cancer cell lines that express many of the relevant antigens in lung cancer. We take the cell lines and kill them by a specific method called high hydrostatic pressure. This kills them but it also makes them express high levels of the tumor antigens. When they are killed, they are put together with the dendritic cells, which eat up or engulf the dead tumor cells – it’s called phagocytosis. Then they cleave the tumor cells to the individual tumor antigens and the tumor antigens are presented on the surface of the dendritic cells. This is what normally happens in vivo and we can make this process in vitro as well. WuXi AppTec: How is this different from the CAR-T cell immunotherapy? Radek Spisek: CAR-T cells are a totally different approach. They deal with the last component of this chain. I told you that we inject dendritic cells and we hope that in the patient’s body they activate T lymphocytes and the T lymphocytes then kill the tumor. The CAR-T cell industry does something that is very smart. They take the T lymphocytes, which are the last piece of the chain of immune reaction, and they genetically modify the T lymphocytes so they can specifically recognize a tumor antigen in the body. So, the outcome of the CAR-T cell production is hundreds of millions of T lymphocytes that when injected into the body go directly to the tumor and kill it. It’s cancer immunotherapy at a different level. The main difference is that we are using a response against multiple tumor antigens. Through our approach, we inject the dendritic cells into the patient. They express many tumor antigens – let’s say 25 different tumor antigens – and this results in the activation of the immune response against multiple targets on the tumor cell. I personally believe this is extremely important because then you have an immune response that fights many targets on the tumor cell. What very often happens in the development of the tumor is that the tumor tries to escape the immune response and one way the tumor tries to escape is it loses expression of some of its tumor antigens. If you only have a CAR-T cell active against one tumor antigen and that tumor antigen is gone – it’s not present on the tumor cell – the CAR-T cell cannot do anything. It can’t see the tumor any more. What we have is a complex, robust immune response against multiple targets and in case two of those antigens disappear from the tumor cell or five of them we still have 20 shots on goal. There are still 20 targets for the immune response that can be explored and we believe that this is important. We see this benefit for patients in our lung cancer program and our ovarian cancer program. It’s a very significant benefit in terms of prolonging survival. WuXi AppTec: How are you applying your platform to the development of immunotherapies for prostate and ovarian cancer? Radek Spisek: We have a unique opportunity here. SOTIO started in 2010 and from the beginning we were funded by a very large Czech financial institution, called PPF Group. SOTIO is being built as a company that doesn’t want to be focused on a single program. We have been building for the past 10 years an oncology-focused company with a diversified portfolio of programs that all explore different arms of the immune system. At this stage we have six or seven programs at various stages of development. One program is focused on the dendritic cells and the dendritic cell platform has been optimized for lung cancer, ovarian cancer and prostate cancer. We have very interesting data from a Phase II program in ovarian cancer and in lung cancer where we see statistical significance of survival benefit in patients, which is the most important endpoint in oncology studies. This year we also brought to the clinic, after extensive preclinical work, a program where we have a molecule that very efficiently stimulates T lymphocytes and NK cells. It’s a molecule based on interleukin 15 (IL-15). We call it a superagonist of IL-15. This is now a very popular field in oncology research – proteins that can very efficiently activate those T cells, expand them and make them proliferate. This program is at the Phase I clinical trial stage. We are very close to bringing to the clinic one more program that is in the domain of antibody drug conjugates. We have a monoclonal antibody that recognizes tumor cells in gastric cancer and to this monoclonal antibody we attach a few molecules of a very toxic compound that kill the tumor cells. The idea of this approach is that the antibody brings those toxic molecules very specifically to the tumor cells that express the specific target for the antibody. The tumor cell then takes up the antibody, which releases the toxin and the toxin kills the tumor cell. We believe we may have a very interesting program for clinic trials in the next year and a half. SOTIO is looking for other portfolio programs and also doing minority investments into interesting biotech companies we want to cooperate with. WuXi AppTec: What are some of the other ways your cancer immunotherapy differs from other immunotherapies? Radek Spisek:  There is one more difference that is built into our clinical trials. We always incorporate long-term administration of the compound. In other words, our approach is not that the patient comes to the hospital and receives three shots of the vaccine and then that’s it. We have data that show it’s important to continuously boost the immune response. If you boost it once in four weeks, the tumor response goes down because it’s not very strong and it’s important to boost it again. We basically have in our clinical program one year of treatment for the patients where we continuously boost the immune response. It’s our belief, and it’s now supported by the data, that this long-term administration is important for the clinical efficacy of these approaches. WuXi AppTec:  What major challenges have you faced in developing your immunotherapies? What lessons have you learned that you can share with other CEOs? Radek Spisek: There’s an obvious answer to this one. What we are trying to do is very challenging with respect to the logistics of the process. Manufacturing and administering the cells is very complex – we have built a whole logistical system around it. The fact is we need to produce cells for each individual patient. In clinical medicine, people call this an autologous approach. For every single patient involved in your clinical program you need to generate a compound specific for that particular patient. This has significant logistical challenges. We need to have a network of blood transfusion centers where we collect the cells from patients. Then the cells need to make it from the blood transfusion unit to the SOTIO manufacturing site – one of the largest cell therapy facilities in Europe. And because we are working with living cells, we need to ship the cells within 30 hours to keep them alive, so we can work with them and modify them. Then at the end of the manufacturing process we need to get the cells to the hospital and back into patients’ bodies via subcutaneous injections. The major complication – and the major drawback – of these autologous therapies is the need to produce a specific cellular product for each individual patient. That’s the biggest challenge that we overcame. We have a very sophisticated network of fully functional blood transfusion units. We have very sophisticated software solutions for the logistics of cell shipment. We manufacture the cells in the Czech Republic then ship them and store them in facilities that are close to the clinical side. But this, of course, represents an additional cost of goods that complicates the process and makes it more expensive. WuXi AppTec: How will you maximize the value and benefit of your therapies for patients globally? Radek Spisek: If our clinical trial programs are successful and these cell therapies are approved, the vision of the company leadership and investors is to commercialize them – and we believe that can be done globally. We can already serve the U.S., the Europe and China with the existing process. We are doing a large, global prostate cancer clinical trial that includes sites in the U.S. and Europe. There are almost 1,200 patients enrolled in the trial and there has never been a single mistake in the logistics and the processing of the cells. We have also done all sorts of financial analyses that show us this program might be commercially viable if it gets on the market at a similar price point to other oncology products. WuXi AppTec: How soon will your immunotherapy reach the market? Radek Spisek: We will have the results of the prostate cancer trial in 2020. The next program, is in ovarian cancer. The timeline from the beginning of the registrational trial to the analysis of the results is four years from now. We now have two shots on goal: next year with prostate cancer and four years from now with ovarian cancer. We are still discussing the design of the potential registrational trial for the lung cancer program. WuXi AppTec: What are the top impediments for delivery of better medicines faster and cheaper for patients? Radek Spisek: The biggest issue is one that cannot be solved easily. In SOTIO we’ve been screening more than 300 new oncology programs a year. We are trying to identify oncology programs at the stage of preclinical studies and there are very few approaches, I think, that have a reasonable chance to make it to the market and be successful. This is not an impediment that is caused by the regulatory environment. It is also not caused by the lack of financial resources. It’s really the nature of oncology – of tumor cell biology. We are at the stage where many mechanisms of the tumor cell have been explored. There are many drugs out there and the prognoses of many cancers have improved significantly. And I think what we’ve seen over the past 10 years is there are a very limited number of programs that can be game changers. This is an inherent problem of oncology research at this stage. I see very few effective programs at the preclinical level that make me believe they can become new drugs in oncology. Then, of course, what I see from our experience is the financial need required for text book development in oncology. The cost per patient in clinical trials is increasing tremendously. I have seen a 30 percent to 40 percent increase in the clinical trial costs in the past five years. This is really getting to the point where many companies are struggling to find the financial resources to follow the clinical development program. For me, this is currently the biggest hurdle. You often hear people comment on the complicated regulatory environment in oncology. I don’t share this opinion. I think that regulators, especially the US Food and Drug Administration, are actually trying to create an environment that facilitates the approval of compounds that look promising at the stage of early clinical data. When the compounds look interesting, there are mechanisms to speed up development and accelerate approvals. But really, the financial burden of increasing clinical trial costs is currently the biggest hurdle in the development of new compounds. WuXi AppTec: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure in cancer? Radek Spisek: I am on the more skeptical side of this. From the 15 years of experience I have in oncology research, it’s very rare to see complete game changers that lead to a cure. I am more a believer in incremental improvements and in the combination of the different treatment modalities. This is what you see in most of the solid tumors. Incremental improvements in the prognosis of the disease come from introduction of new drugs that provide some benefit and then combining these novel treatments with pre-existing ones. This leads to a gradual improvement in the prognosis of the patients. I don’t expect to see a dramatic shift in the case of lung cancer that would result in 100 percent survival from the 20 percent survival you currently see in advanced patients. I doubt there will be a treatment like this.

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2019/12/16

Refuge Biotechnologies: Developing “Smart Cells” to Fight Cancer Inside the Human Body

Cell therapy is an emerging treatment with great potential because, unlike small molecules, cells are dynamic. They can migrate, proliferate, differentiate, and respond to their environment both in vitro and in vivo. Cell therapy company Refuge Biotechnologies, based in Menlo Park, CA is leveraging gene engineering technologies known as CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) to develop therapeutic cells that are programmed to make decisions inside the patient’s body. This commitment is aptly summarized by the company’s mission statement: Designing Intelligent Cell Therapies to Fight Cancer. Refuge’s platform connects cell membrane receptors to CRISPR a/i systems, creating a genetically programmable switch that can control multiple gene expressions. Refuge is seeking to enable the integration of multiple therapies into a single type of therapeutic cells, one that combines greater efficacy with fewer side effects. Refuge’s technology enables cells to sense their surroundings and conditionally activate or repress multiple genes when they encounter specific external antigens. In particular, with receptor-dCas, immune cells can now be engineered to conditionally turn on/off certain genes, such as PD-1, to generate more potent CAR-T immune cells when it senses the presence of a tumor cell. Leading Refuge’s research programs is CEO and Co-founder Dr. Bing Wang. Dr. Wang co-founded the company following nearly a decade of life science investment banking experience. He most recently served as director of healthcare investment banking at Barclays Capital. Dr. Wang, a cancer survivor who is passionate about bringing forth “smarter” medicines that will transform cancer care, earned a B.S. in Applied Physics from Columbia University, an MBA from Columbia Business School, and a Ph.D. in Electrical Engineering from Princeton University. WuXi AppTec communications asked Dr. Wang to explain how Refuge’s unique cell therapy platform can fight cancer in vivo and the future benefits of and challenges in developing cell therapies. WuXi AppTec: How has cell therapy research progressed over the past 10 years? Do you anticipate a wave of new approvals coming over the next five to 10 years? Dr. Bing Wang: Absolutely, the expectation is that cell therapies will become much more prominent as a treatment modality across many diseases over the next five to ten years. There has been an immense amount of progress in the cell therapy field over the last decade building on original research into using cells to treat diseases, especially as the Novartis and Kite/Gilead products have come to the forefront to treat hematological malignancies. At Refuge, we are building on this progress and hope to further apply the cell therapy modality with other mechanisms to make cell therapies more effective in oncology and beyond. WuXi AppTec: What kinds of diseases are targeted with cell therapies? Dr. Bing Wang: Recently, cell therapies have been most prominently linked to oncology, but there is a wide range of applications for which cell therapies can be targeted, including regenerative medicine, rare diseases, and metabolic and cardiovascular diseases. Refuge initially focused on furthering cell therapy efficacy in solid tumors, but now we are exploring the potential ways to utilize the Refuge platform beyond oncology indications. WuXi AppTec: What scientific advances are needed to make cell therapies more effective? Dr. Bing Wang: As research progresses further into how cell therapies work and act within the tumor microenvironment, it is expected that better control over these mechanisms will improve the efficacy of cell therapies. Refuge is uniquely positioned to be able to tackle these issues together as its platform technology has the ability to target multiple pathways that underpin these mechanisms at the same time by modulating multiple genes simultaneously in addition to a cell therapy itself, such as CAR-T. This effectively designs an intelligent cell that is fitter and can react to its environment. WuXi AppTec: Will cell therapies ever be commonplace? If so, how soon? Dr. Bing Wang: At the current rate of advancement across various cell therapy fields, it would be expected that cell therapies would become much more common in the clinic and industry. Within the next five to ten years, cell therapies could likely become a common treatment modality in addition to traditional small molecule medicines and antibody-based therapies. WuXi AppTec: What are the risks and limitations of cell therapies? Dr. Bing Wang: As with all medical treatments, there are safety and efficacy risks that need to be managed for cell therapies. With further use in the clinic, as we have seen with the evolution of therapy management in dealing with CRS (Cytokine Release Syndrome), many of the risks can be effectively managed so that patients can really benefit from curative cell therapies. For current cell therapy products on the market, the obvious limitation today is that they are only indicated in hematological malignancies. There are various challenges for getting CAR-T (cell surface chimeric antigen receptor) therapy to perform better in solid tumors, including improving the ability to have CAR-T get into the tumor microenvironment and improving the persistence and fitness of CAR-T therapy cells, which many research and development institutions, including Refuge Biotech, are working towards solving. The field of oncology presents a highly complex range of biology and manifestations that are still being discovered and understood today. It is likely that there are unknown limitations that will cap the ability to have a single solution for all cancers, so combination therapy across cell therapies and other treatments may still be needed. WuXi AppTec: What cell therapies are you developing? Dr. Bing Wang: Our mission at Refuge Biotech is to “Design Intelligent Cell Therapies To Fight Cancer” based on Stanley Qi’s original research in CRISPR interference and activation to allow cells to make decisions in vivo. When the cell therapy comes in contact with a tumor, different genes within the T cell are expressed to react and enhance the attack against cancer cells. To do this, we are leveraging a synthetic biology circuit that combines cell surface signaling with specific multiplexed gene modulation through use of a deactivated CRISPR system. This capability enables us to combine many different cancer therapeutic mechanisms in a single therapy. As it relates to our initial clinical developments, we are applying known cancer biology, combining CAR-Ts against targets such as HER2, among others, with simultaneous modulation of genes responsible for various pathways involved in cancer pathogenesis. This includes checkpoint genes as well as targets in various other co-immunostimulatory and co-immunoinhibitory pathways. Our lead pipeline asset is a HER2 CAR-T plus PD-1 knockdown system for various solid tumor indications. We are also developing various additional pipeline assets focused on other CAR-T targets, with modulation of different genetic target combinations derived through intensive bioinformatics analysis to treat a wide range of cancers. Additional oncology indications will be disclosed in due course. WuXi AppTec: How does your approach differ from other cell therapy companies? Dr. Bing Wang: Our technology platform connects cell membrane receptors to CRISPR interference / activation to facilitate inducible gene modulation of multiple genes simultaneously with cell therapies such as CAR-T therapy. CRISPR interference / activation is very different from standard gene editing technology, such as standard CRISPR, Talens and Zinc fingers, etc., in which there is no cutting of the genome. The CRISPR is “deactivated” to mute the cleavage site while maintaining all the gene targeting specificity through short guide RNA (sgRNA). At the same time a transcription that either down-regulates or up-regulates gene expression is combined to the deactivated CRISPR, so that the cell therapy can use the GPS mechanism of the CRISPR to pinpoint a targeted strand of DNA and switch that gene on or off to varying degrees. This structure is tethered to the cell surface so that it is released only in response to engagement of tumor antigen through activation of a CAR-T on the T-cell surface. On release, the structure travels to the cell nucleus guided by sgRNA to effect specific gene modulation, where gene targeting can be multiplexed through adding multiple sgRNAs. Most DNA editing technologies snip out genes entirely and have an all-or-none effect, but we are able to control gene modulation and up-or-down-regulate multiple gene expressions at different levels. This will be important in combination therapy situations where you may not want to completely knockout endogenous genes since doing so can lead to long term permanent changes to the genome after tumor cells disappear. The advantages of our platform consist of no cutting of genetic material, the ability to multiplex gene modulation through the addition of more sgRNAs, and the capability to simultaneously versus sequentially enhance this process, thereby providing better efficiency for manufacturing. Comparable editing technologies need to be more careful with concurrent edits due to potential translocation and genotoxicity risks, which are irrelevant issues for our technology. By effectively being able to combine multiple cancer treatment modalities together, the Refuge platform will be able to provide better efficacy in the treatment of various cancers while simultaneously achieving a better safety profile. WuXi AppTec: What are your major regulatory and commercial challenges? What lessons have you learned? Dr. Bing Wang: We have a very novel approach to treating cancer that effectively incorporates synthetic biology, cell therapy and gene engineering. Therefore, familiarizing health authorities and regulatory bodies with our technology is essential, especially before we increase the complexity by using multiplexed targets. In parallel, we need to be diligent in manufacturing, as it is central to development and commercialization, alongside impeccable planning. WuXi AppTec: The drug industry is already under enormous pressure in Congress to hold down prices.  And as with other, new medicines, prices for some cell therapies seem to generate “sticker-shock” among patients. What are ways can we make new cell therapies more accessible to patients especially in these times? Dr. Bing Wang: As with any new and complex class of treatments, we must find ways make them effective and ensure patients can access them. One key element to consider is manufacturing. The complexity of manufacturing and delivering cell-based therapies, compared to traditional biologics and small molecules, leads to higher costs. Cell therapies require greater precision and regulatory inspections to ensure quality grade practices, and we face a shortage of capacity in GMP-grade manufacturing facilities to support new cell-based products coming to market. But as more products advance toward the market, the resulting growth in manufacturing capacity and other innovations may help reduce cost.

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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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