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2019/10/23

Salarius Believes Children Should Not Be Left Behind in the Fight Against Cancer

Many pharmaceutical and biotech companies shy away from pediatric drug development. While the genomic revolution has resulted in scores of new cancer treatments for adults, children suffering from cancer have been left behind. It takes a spirit of determined commitment to real innovation to overcome the obstacles to developing new pediatric therapies. That is what Salarius Pharmaceuticals CEO David Arthur feels his company and team are all about. At a recent opening session of NASDAQ, Salarius became a public company. Arthur used this as an opportunity to summarize the company’s mission: “Every day we get to come into the office, go to work and take the fight to cancer.” Salarius, based in Houston, is a clinical-stage oncology company targeting the epigenetic causes of cancers. The company’s lead candidate, Seclidemstat, is currently in clinical development for treating Ewing sarcoma, for which it has Orphan Drug designation and Pediatric Rare Disease Designation by the U.S. Food and Drug Administration (FDA). Ewing sarcoma is a devastating pediatric bone cancer and represents a major unmet clinical need. Currently, chemotherapy, radiation and tumor resection surgery are the only options for patients, and in many cases the tumors recur or develop in a location too sensitive to risk surgery. There is a 70 percent five-year mortality rate for patients whose tumors recur after treatment or who are initially diagnosed with metastatic disease. Salarius began enrollment for a Phase 1/2 trial in Ewing sarcoma in 2018.   The need for a new therapy for this disease is critical, as Arthur points out. “There are 400 to 500 children diagnosed with Ewing sarcoma every year in the U.S. and the average age of diagnosis is about 15. These are children and young adults with their whole lives ahead of them. But figures show that roughly 40 percent to 45 percent either do not respond or relapse from the standard of care. With those patients, there is an approximately 70 percent five-year mortality rate.” WuXi AppTec Communications asked Mr. Arthur to share his thoughts on why pediatric drug development has lagged behind development of adult treatments and how Salarius’ drug can make a difference in children’s lives. Mr. Arthur is an industry veteran with 25 years of experience building and leading medical and marketing organizations in product development as well as launching and managing pharmaceutical and device brands. Prior to Salarius, Mr. Arthur was Managing Director of Dacon Pharma, LLC. Additionally, he spent 20 years with Eli Lilly and Boehringer-Ingelheim in executive roles managing product development, business development, US business, global commercialization, European regional marketing and financial planning/analysis. Mr. Arthur earned a BS in Chemical Engineering from North Carolina State University, an MBA from the Duke University Fuqua School of Business, and is a licensed Professional Engineer and Six Sigma Green Belt. WuXi AppTec: Generally speaking, why are there so few pediatric drugs in development? David Arthur: This is an amazing time for drug discovery and development. With the advances in genetic and diagnostic testing, we are entering a new era of medicine that is capable of developing novel treatments for rare diseases and different cancers every day. However, many drug companies remain disinclined to develop medications for pediatric uses due to small market size and the complexity involved in developing drugs for infants and children. Salarius Pharmaceuticals has stepped up to the challenge by focusing on the development of therapies for pediatric and rare cancers with high unmet needs or for which no targeted therapies are available. In the past 40 years, fewer than 10 drugs have been developed for use in children with cancer, a number that pales in comparison to the hundreds of therapies developed for adult cancers. Our understanding of the various childhood cancers has grown, yet roughly one out of every five pediatric cancer patients will die from their disease. Research into many rare pediatric illnesses often lacks the funding necessary to develop therapies and treat patients in clinical trials. So, with many forms of pediatric cancer, medical advances have been slow and mortality rates remain high. WuXi AppTec: How does developing drugs for children differ from adults? Aren’t children just small adults? David Arthur: No, this is a misconception. Children respond to medications in a very different way than adults. Drugs that are generally safe and effective for adults may be unsafe or ineffective — or both— for some or all pediatric age groups. It is truly unfortunate when the only available treatments are harsh and potentially debilitating, such as the standard chemotherapeutic agents. Besides the severe short-term side effects, chemotherapeutic agents are often associated with long-term consequences, and that can be especially troubling when the patients could still have 60 or more years of life expectancy. That is why Salarius is working to develop safer, less toxic treatments for this critical population. WuXi AppTec: What are the barriers to developing drugs for pediatric cancer patients? David Arthur: Childhood cancers represent a relatively small portion of the U.S. oncology market. Of the estimated 1.7 million new cancer diagnoses expected to be made in the U.S. in 2019, 11,060 could involve children age 15 and younger, according to the American Cancer Society. Add the political backlash over high prices for new medications, and some drug industry players see little incentive to invest in pediatric oncology drug development. But the barriers to developing new cancer drugs for children go beyond market size and potential sales. There are also scientific challenges, such as the smaller number of genetic mutations in children that can serve as therapeutic targets. The biological differences between infants, adolescents and young adults make drug development even more complex. And because experimental drug candidates sometime have toxic side effects, researchers and drug companies are reluctant to include children in clinical trials until safety has first been established in adults, a process that can take years. WuXi AppTec: Is this landscape changing? David Arthur: It is, though slowly. President Trump placed pediatric cancer in the national spotlight this year when he promised during his State off the Union address to add $500 million to research funding during the next decade. Also, several pieces of legislation have been passed that not only expand funding and incentives for drug makers to develop therapies for pediatric cancer patients, but also compels the inclusion of children, as well as adults in cancer drug studies starting in 2020. For example, members of the congressional Childhood Cancer Caucus introduced legislation in September 2019 that would reauthorize the Creating Hope Act, making permanent the FDA’s rare pediatric disease Priority Review voucher program. This is a fantastic program, effectively self-funded by the pharmaceutical industry, which incentivizes drug development expressly for children with cancer and other life-threatening illnesses. Yet the rare pediatric disease Priority Review voucher program is the only voucher program created by the Creating Hope Act that is not permanent. Certainly, the majority of Big Pharma remains attracted to adult cancer’s larger market size. But there is support available from other sources, such as not-for-profit organizations and foundations. Salarius has received more than $20 million in non-dilutive capital and in-kind support from The Cancer Prevention and Research Institute of Texas (CPRIT) and the National Pediatric Cancer Foundation (NPCF). Also, we are fortunate to have the support of shareholders who want to do good by putting their money to work to advance the development of cancer therapies for children. WuXi AppTec: What form of pediatric cancer is Salarius targeting and why was it selected? David Arthur: Our lead drug candidate Seclidemstat is being studied in a Phase 1/2 clinical trial for Ewing sarcoma, a rare, devastating and deadly pediatric and adolescent bone and soft-tissue cancer. In the U.S. this year, roughly 500 cases will be diagnosed in patients with an average age of 15 years. And 70 percent of patients who relapse or are initially diagnosed with metastatic Ewing will die within five years. We are talking about adolescents who should have their whole lives ahead of them. Is there any better motivation to support the development of pediatric medicines? At Salarius, we are studying epigenetic-based strategies for the treatment of cancer. Based on that research and the lack of targeted treatments available for patients, we feel that we have a real shot at having a meaningful impact in Ewing sarcoma that could benefit the lives of these children and their families. WuXi AppTec: Can you describe Seclidemstat? What type of drug is it and what is its mechanism of action? David Arthur: Seclidemstat is a reversible inhibitor of lysine specific demethylase 1 or LSD1, which is an extensively-studied epigenetic enzyme that is often highly expressed in cancers. Epigenetics is the study of the regulatory system that controls how gene expression is turned on and off. If the epigenetic enzymes that regulate gene expression become dysregulated, it leads to inappropriate activation and silencing of genes, which can lead to the development and progression of cancer. Drugs that are able to safely modify the activity of these epigenetic regulators may correct the gene changes that are driving disease and provide a new treatment for these cancers. In the case of Ewing sarcoma, a chromosomal translocation produces a fusion oncoprotein. The fusion oncoprotein recruits other proteins to alter gene expression to a cancer promoting state. Unfortunately, the oncoprotein itself is difficult to directly target because it is a highly disordered protein. An alternative strategy is to target proteins that interact with the oncoprotein. This is the approach Salarius is taking. Salarius’ lead compound, Seclidemstat, targets the LSD1 enzyme, which is known to interact with the Ewing sarcoma oncoprotein. Salarius licensed the technology from the University of Utah’s Huntsman Cancer Institute, where it was developed by Dr. Sunil Sharma, Salarius’ scientific founder. By inhibiting LSD1 from associating with the oncoprotein, we have shown the ability to reverse the aberrant gene expression. In animal models, Seclidemstat has been shown to slow down, or stop the growth of Ewing sarcoma tumors, and we hope to have a similar therapeutic impact in our ongoing clinical trials. WuXi AppTec:  What do you mean by a reversible LSD1 inhibitor? David Arthur: There are a number of companies researching LSD1 inhibitors. We believe Seclidemstat is one of only two reversible LSD1 inhibitors now in the clinic, and that is an important distinction. An irreversible inhibitor permanently binds to the FAD cofactor within the LSD1 enzyme. Since LSD1 is required for cell homeostasis, irreversibly inhibiting the protein leads to adverse effects which are considered “on-target” as they are related to the biology of LSD1, such as hematological toxicity. In contrast, Seclidemstat reversibly binds to LSD1 allowing it to maintain some degree of functionality; we have not observed any hematological toxicity to date. This gives us the opportunity to explore more flexible dosing schedules which can potentially allow for a higher chance of therapeutic activity.   WuXi AppTec: How does Seclidemstat differ from the treatments already available to children with Ewing sarcoma? David Arthur: Right now, children and young adults diagnosed with Ewing sarcoma have few treatment options, and to be honest, none of them are good. There are no targeted therapies approved for the disease. The standard of care is surgery to remove the primary tumor, radiation and often multi-regimen chemotherapy. In roughly 40 percent to 45 percent of cases, patients don’t respond to the standard treatment or suffer a relapse. Among these patients, there is around a 70 percent mortality rate within five years. WuXi AppTec: So, Salarius hopes to provide a less toxic, more effective therapy. Am I right? David Arthur: You’re absolutely right. In fact, that is the exact mission of the National Pediatric Cancer Foundation, and it is one of the reasons Salarius has received, and continues to receive, such tremendous support from the organization. WuXi AppTec: What is the clinical path forward for Seclidemstat?  Can it be accelerated? David Arthur: Seclidemstat is now in a Phase 1/2 clinical trial involving patients who have failed to respond to previous treatment or who have suffered a recurrence of their tumors. Right now, we are establishing a maximum tolerated dose and developing a safety profile. Patients will be treated with that maximum tolerated dose in a dose expansion phase of the trial. Early safety and efficacy data should be available in 2020, and once we have compiled full results, Salarius will meet with the FDA and talk about the most efficient and expeditious path forward. Is there an opportunity for accelerated approval? We hope so given the unmet need in Ewing sarcoma. Seclidemstat already has Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA. If proven safe and efficacious in early clinical studies, Seclidemstat could qualify for Breakthrough Status, which provides access to programs that accelerate drug development and FDA approval. Also, Seclidemstat could be eligible for priority review and upon approval, receive a Pediatric Priority Review Voucher. WuXi AppTec: Does Salarius engage patients, their parents and patient advocacy groups in your clinical development programs? If so, how are they involved? David Arthur: As I mentioned earlier, Salarius has been fortunate to receive tremendous financial support from both the Cancer Prevention and Research Institute of Texas (CPRIT) and the National Pediatric Cancer Foundation. In fact, the NPCF is funding a significant portion of our ongoing Phase 1/2 study of Ewing sarcoma. The NPCF has also assisted with the initiation of our clinical studies. Salarius is using the foundation’s network of research hospitals, called Sunshine Project Hospitals. This is a great example of industry and not-for-profit foundations working together to address an unmet need. WuXi AppTec: For the disease area you are working on, what would be the one thing that would have the most potential to lead a paradigm shift “from treatment to cure?” David Arthur: Developing a therapy targeting the root cause of the disease that is safe and effective would be a giant step forward.

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2019/10/22

DelMar Developing Drug to Cross the Blood Brain Barrier to Treat Deadly Glioblastoma Disease

Glioblastoma Multiforme (GBM) is the most common and most lethal form of brain cancer. GBM affects an estimated 12,000 new patients each year in the US alone. The median survival in newly diagnosed patients with the best available treatments is 20.5 months. After diagnosis, today’s standard treatment includes surgical resection of the tumor followed by radiotherapy and chemotherapy with temozolomide (TMZ). Nearly all GBM patients relapse following first-line treatment, and those patients have a one-year survival rate of approximately 25 percent. The average five-year survival rate is less than 3 percent. Treating glioblastoma is very difficult due to several complicating factors: the tumor cells are very resistant to current approved treatments, the brain is susceptible to damage from conventional therapy, the brain has a very limited capacity to repair itself and, perhaps most important, many drugs cannot cross the blood–brain barrier to act on the tumor. The brain is the only organ known to have its own defense system, a network of blood vessels that allows the entry of essential nutrients while blocking others. Ironically, this barrier effectively prevents life-saving drugs from being able to repair the injured or diseased brain. DelMar Pharmaceuticals President and CEO Saiid Zarrabian believes its lead drug, VAL-083 can penetrate this barrier and deliver an effective treatment. “VAL-083 has the potential to treat newly diagnosed patients as a ‘front-line’ treatment in conjunction with radiotherapy, as a ‘maintenance’ treatment after patients complete radiotherapy, and as ‘salvage’ therapy after treatment with temozolomide,” said Zarrabian. “VAL-083 is a small molecule DNA targeting therapeutic that has been proven to cross the blood brain barrier, and to have tumor effecting properties in multiple PH1 and PH2 clinical studies. The biological and tumor effecting activity has been demonstrated in numerous clinical trials and in a prior glioma study has shown extension of median survival rates nearly double that of radiation alone,” he added. WuXi AppTec Communications has begun a new series looking at novel and potentially breakthrough drugs which can make a difference in people lives, especially treating a disease as deadly as glioblastoma. We discussed with Zarrabian the challenges drug developers have had finding an effective therapy for this disease and why he believes the drug will become a successful treatment. Zarrabian is an industry veteran who has served as San Diego based DelMar’s Chief Executive Officer since November 3, 2017, and President since January 1, 2018. Since October 2016, Zarrabian has served as an advisor to Redline Capital Partners, S.A., a Luxembourg based investment firm. From 2012 to 2014 he was Chairman and member of the Board of La Jolla Pharmaceutical Company. From 2012 to 2013 he was President of the Protein Production Division of Intrexon Corporation, a synthetic biology company. He has also been CEO and member of the Board of Cyntellect, Inc., President and COO of Senomyx, Inc., a company focused on discovery and commercialization of new flavor ingredients, and COO of Pharmacopeia, Inc. WuXi AppTec: What are the challenges involved in diagnosing and treating brain cancers? How important is early detection? Saiid Zarrabian: Diagnosis is not the major issue. This disease is hard to treat due to its rapid growth rate of 1.5 percent per day at peak growth, challenges with removing the tumor surgically, as well as the possibility of random cancer cells elsewhere in the brain. Unlike many other solid tumors where the tumor body and sufficient margin tissue can be removed without life threatening or debilitating results, it is not possible to remove the whole tumor mass in GBM both because it infiltrates micro capillaries in the brain and because of our inability to remove tissue surrounding the tumor given its location in the brain. All of this requires a systemic approach to GBM vs. a local solution, which creates the critical necessity of the drug’s ability to cross the blood brain barrier. WuXi AppTec: Why has it been so difficult to find druggable targets for glioblastoma? Saiid Zarrabian: Despite decades of effort to identify and develop novel drug candidates for GBM, most if not all have failed in clinical trials. There are many reasons for this including the impact of the blood brain barrier which limits the exposure of chemicals to protect the brain against toxicities. In addition, many potential biological targets and pathways identified for GBM are vulnerable to mutations that cause the tumors to become resistant to the potential anticancer effects of the therapy. Recently, it has been confirmed that GBM is an immunologically “cold tumor” due to the lack of T cells infiltrating the tumor and as such is a challenging target for novel immunotherapy (I-O) treatments. This creates a much tougher challenge for many existing and new I-O treatment options as the human body’s immune defense mechanisms cannot be effectively exploited for successful brain tumor therapies. WuXi AppTec: Has genomic analysis of glioblastoma improved drug discovery? If so, how? Saiid Zarrabian: Yes, modern genomic analytical techniques have identified various gene expression patterns and mutations in GBM which have been the subject of drug development efforts. These include EGFR viii, IDH wild type versus mutations, and the identification of the expression of MGMT (methyl guanine methyl transferase) a critical DNA repair protein which limits the efficacy of temozolomide first-line therapy for GBM. VAL-083 is active for patients who have been identified through genomic diagnostics to have an unmethylated promoter for MGMT. WuXi AppTec: How did you choose to focus on glioblastoma? Saiid Zarrabian: Although VAL-083 has been studied by the National Cancer Institute (NCI) in approximately 40 Phase 1 and Phase 2 studies in multiple indications the GBM program was the most advanced and the most likely to reach early success vs. other indications like ovarian cancer and non-small cell lung cancer. WuXi AppTec: How did you develop your drug candidate? Saiid Zarrabian: VAL-083 was originally developed at NCI, where close to 40 PH 1 and PH 2 trials in multiple indications were completed. DelMar’s founder and current CSO obtained the right to reference the IND for the drug, including all the preclinical and clinical study information that was developed prior to DelMar’s IND submission. DelMar has been advancing the drug since that time. WuXi AppTec: What is the mechanism of action? Saiid Zarrabian: VAL-083 is a DNA targeting agent that readily crosses the blood-brain barrier and has been shown to preferentially accumulate in brain tumor tissue. VAL-083 exhibits a unique bi-functional DNA crosslinking cytotoxic mechanism creating cross-links at the N7 guanine position. This mechanism is different from existing chemotherapeutic agents used in the treatment of GBM, such as temozolomide, and is not susceptible to the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair pathway. This results in the potential for VAL-083 to be more effective, initially in treating the approximately 60 percent of GBM patients whose tumors are MGMT unmethylated, and for whom the current treatment of temozolomide has limited clinical benefit. In the future, we hope to also include the remaining GBM patients without the MGMT unmethylated status as the drug is agnostic to this biomarker. The choice to go after this biomarker identified population is purely to help accelerate the process and get to the goal line of providing a better treatment option for this grossly underserved GBM patients first, before we extend the study for the remaining patients. WuXi AppTec: What regulatory challenges do you face in clinical development? Saiid Zarrabian: The typical challenges of making sure you have the right study design, the right efficacy endpoints, and are treating the right patient population. Fortunately, DelMar has fast track status with the FDA for VAL-083, so we can benefit from ongoing discussions with the agency on these types of issues. WuXi AppTec: Have you worked with patients in developing your drug development strategy? If so, how? Saiid Zarrabian: Our clinical studies involve extensive pharmacokinetics (PK) analysis. This is important to determine optimized patient dosing and scheduling. In addition, measurement of VAL-083 in the CSF (cerebrospinal fluid) which some patients have consented to, has helped determine the sufficient extent of drug penetration in the brain. WuXi AppTec: What lessons have you learned during the drug development process? Saiid Zarrabian: The importance of working with the right partners. From the manufacturing process where we work with STA Pharmaceutical Co., Ltd. (a WuXi AppTech company) and Italfarmaco, to conducting clinical trials with M.D. Anderson Cancer Center and Sun Yat-sen University Cancer Center, we have seen how important it is to work with the best possible collaborators. WuXi AppTec: How soon will we have an effective treatment for glioblastoma? Will effective treatments require combinations of drugs? Saiid Zarrabian: We expect the completion of both our current Phase 2 trials in approximately a year. The current trials are single agent trials with VAL-083. The Phase 3 registration study timeframe somewhat depends on the results from our current trials, but we are optimistic that we can initiate a trial in 2021, with a drug reaching the market as early as 2023. WuXi AppTec: Can you comment on the specific progress or lack of progress in treating this disease in the last ten or 20 years? Saiid Zarrabian: The development of new therapies for GBM has been extremely disappointing. Many promising approaches have not realized survival benefits for patients due to challenges in developing drugs that effectively cross the blood-brain-barrier, and the inherent aggressiveness of the tumor. There have been extensive clinical trials for drugs affecting unique cellular targets and biologics for immunotherapy that have not met the appropriate clinical trial efficacy outcomes for FDA approvals. In addition, interest and investment by large pharmaceutical companies has been very limited. The creation of novel therapeutics with those unique attributes for brain tumors has not been a high priority. WuXi AppTec: What are the top three impediments to delivery of better medicines faster and cheaper to patients? Saiid Zarrabian: Access to capital, ability to enroll an adequate number of patients quickly into clinical trials, and necessary regulatory hurdles. WuXi AppTec: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure for cancer patients? Saiid Zarrabian: Cancer prevention and early detection will probably provide the greatest impact to solve the cancer problem. The modern genomic screening tools and other diagnostics will continue to provide valuable support to identify patients at risk and potentially more effective therapeutics. Being able to target specific populations of patients, such as DelMar’s approach for MGMT unmethylated GBM patients, can lead to better outcomes.

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2019/10/18

Paving the Way to a New Generation of CNS Drugs: Karuna CEO Steve Paul, Neuroscience’s Renaissance Physician, Psychiatrist, Neuroscientist and Executive

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team There are few who have Steve Paul’s perspective, experience and track-record in the neurosciences. A former scientific director at the NIMH/NIH, Paul was formerly President of Lilly Research Laboratories and an accomplished entrepreneur at Third Rock Ventures. Additionally, he co-founded two CNS-focused companies, Sage Therapeutics and Voyager Therapeutics (a gene therapy company). Now, Paul is CEO and Chairman of Karuna Therapeutics. Throughout his multi-decade career, Paul’s interest in the neurosciences and drug discovery, particularly for psychiatric and neurological disorders, never diminished – despite a shrinking emphasis on neuroscience worldwide.          His latest entrepreneurial endeavor is with Karuna, a neuroscience startup developing first-in-class therapeutics to improve quality of life for people living with schizophrenia, Alzheimer’s disease and pain. Rich Soll and the WuXi content team recently caught up with Paul to discuss Karuna and the revitalization of the neuroscience field in general. “In the neurosciences, antipsychotics and Selective Serotonin Reuptake Inhibitors (SSRIs) once dominated the commercial pharmaceutical market; they dwarfed oncology and most other therapeutic areas,” explained Paul. “However, the collapse of the CNS market was attributable to several factors, including limited efficacy, tough clinical trials due to large placebo effects, and nothing better in the pipeline—a dearth of innovation.” That has been changing in recent years. There’s an incredible amount of basic genetic and biological understanding of the etiology of many neurological disorders, especially diseases such as Parkinson’s disease, Alzheimer’s disease, MS, ALS, and Huntington’s. For psychiatric disorders, there’s little that is well understood with respect to genetics, and even those that are clearly inherited are highly polygenic disorders, which makes it very difficult to identify and validate drug targets based on genetics alone. “Our knowledge about the intricacies and complexity of chemical neurotransmission, on the other hand, has advanced considerably over the last decade,” exclaimed Paul. “And we have capitalized on this knowledge with my first company, Sage Therapeutics, where we have developed a rich pipeline of drugs targeting GABA and glutamate receptors, including a recently launched drug for treating postpartum depression, and now with Karuna. These developments are happening primarily in small companies who work in the neurosciences.” Karuna’s lead compound, xanomeline, was originally developed at Lilly in the 1990s for improving cognition in advanced Alzheimer’s patients. Although cognition was only modestly improved in this Phase 2 study, other neuropsychiatric symptoms, for example agitation and psychotic symptoms such as hallucinations and delusions (observed in 40-50 percent of advanced Alzheimer’s disease patients) were substantially improved, and this was accomplished without many of the troublesome side effects of traditional antipsychotic drugs, such as sedation and weight gain. However the elderly population did not tolerate the drug well due to peripheral cholinergic side effects. In another Phase 2 study in another form of psychosis that occurs in patients with schizophrenia, the drug once again appeared to be active. “The drug stimulates preferentially two of the five G-protein coupled muscarinic receptors, M1 and M4 receptors, which led to both the beneficial and side effects. Although xanomeline was not developed further by Lilly, the drug nevertheless had a remarkable antipsychotic profile,” said Paul. “A simple, but elegant solution to this dilemma unfolded: Formulate xanomeline with a generic, non-brain penetrating, peripherally-acting muscarinic antagonist, specifically trospium.” Trospium had other favorable features, including a long elimination half-life enabling it to cover the presence of xanomeline around the clock. Moreover, it’s not metabolized by the same liver enzymes as xanomeline, which meant likely fewer drug-to-drug interactions. The combination product is tagged KarXT. Two Phase 1 studies have been conducted with KarXT and the combo has shown good tolerability. Currently, a large Phase 2 schizophrenia study is ongoing and by year’s end we will know if we see the same antipsychotic effects of xanomeline while attenuating its side effects. “Based on feedback from three independent safety monitoring reviews of our unblinded Phase 2 data, we are cautiously optimistic that we have improved the tolerability of xanomeline through this reformulation,” proclaimed Paul. “We are very focused on M1 and M4 receptors and hope to eventually have other exciting drugs that stimulate these and other GPCRs and in different ways.” Paul was a senior author on the initial Lilly paper describing xanomeline’s antipsychotic effect in Alzheimer’s disease. “People ask me all the time ‘Why didn’t you think of this or do this when you were back at Lilly?’” Paul shared. “It’s interesting. I think we, in our zest to get the purest and cleanest kind of molecules, sometimes ignore data that’s sort of sitting right in front of us. Even if we had thought of this combination strategy, I don’t think we would have pursued it. It was just too inelegant for a large company. What we did was to go back to the labs to try to come up with a single molecule that had fewer of these peripheral cholinergic side effects and still retained the therapeutic benefits. We worked on that for 20 years, and we couldn’t do it.” Paul believes Karuna’s approach has the potential to produce a differentiated therapy relative to current D2 dopamine receptor-based antipsychotic drugs, whose roots date back to the 1950s, and to beneficially impact the lives of millions of patients with schizophrenia and other psychotic and cognitive disorders. Antipsychotics are often used by physicians to address a wide range of neuropsychiatric disorders but are associated with modest efficacy and significant side effects. Karuna believes the preferential stimulation of M1 and M4 muscarinic receptors in the CNS may also address the negative symptoms of schizophrenia, such as apathy, reduced social drive and loss of motivation, as well as cognitive deficits in working memory and attention, all of which currently lack any approved treatments. Other beneficial properties of xanomeline have also been uncovered. It has been known for years that nonselective muscarinic agonists have analgesic properties. Scientists at AstraZeneca published a paper a few years ago showing that xanomeline has very potent analgesic effects across a broad range of animal pain models. “We know that the pathway that mediates the analgesic effects are mediated via muscarinic receptors, instead of opiate receptors,” said Paul. “The drug reduces pain in various animal models distinct from the opiate receptor, so this could be a non-opioid pain medicine. To me, that’s remarkable that you can take an old drug that has been ignored, but you need to ask the right questions at the right time. If it works, we’ll also have good IP protection on the co-formulated product.” Karuna, initially a PureTech-incubated biotech, completed its IPO in early July, raising approximately $102.6 million. So far, it has built its pipeline on the broad therapeutic potential of its lead product candidate KarXT as an oral modulator of muscarinic receptors. However, its intent is to commercialize in the U.S. and partner for all other regions. In five years, Paul’s plan is to have launched its first medicine, KarXT for acute psychosis in schizophrenia and Alzheimer’s disease, to have something in pain, and to have a very full mid-stage and early stage pipeline. All of these plans are being conducted from a virtual organization, no labs. “In today’s ecosystem, this is possible because of organizations like WuXi AppTec, where many parts of the value chain can be accessed with high quality and with people every bit as good as we had in the glory days of big pharma,” stated Paul. “Currently, there are literally hundreds of smaller companies discovering and developing medicines in a very different way than we had traditionally done at big pharma. Gaining access to these critical components was not possible 20 years ago but now they are available, and they are cost-effective solutions.” Paul also discussed two potentially game-changing technologies. The first relates to the availability of reliable, high throughput, in-silico chemistry approaches where biological targets with structural information, including crystal or Cryo-EM structures, are used to find chemical hits and leads much quicker; in many cases the compounds have already also have been prescreened for drug-like properties. The second relates to screening behaviorally complex disorders such as depression or schizophrenia, essentially using phenotypic screening in mice, coupled with artificial intelligence and machine learning analytics, which allow for the design molecules that can modulate complex behavioral biology in a predictable way. Paul concluded with this thoughtful insight: “Looking to the industry’s future there will definitely be more effective CNS drugs approved and more affordable drugs to boot. In the case of Karuna, we’re focusing on psychotic disorders and hope to introduce the next generation of antipsychotic drugs, arguably the first new generation in half a century. That makes me feel good.”

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2019/10/08

Halozyme Utilizing Unique Tumor Microenvironment Pathway to Fight Pancreatic Cancer

In WuXi AppTec’s latest series on novel drug development for pancreatic cancer, most of the companies featured have concentrated on ways to directly stimulate the patient’s own immune system to fight this stubborn disease. Halozyme, a clinical stage oncology company based in San Diego, has adopted a different, unique strategy based on the tumor’s microenvironment. The company is testing its lead drug candidate, investigational drug pegvorhyaluronidase (PEGPH20), in a Phase 3 trial in patients with HA-high metastatic pancreatic cancer. PEGPH20 targets the area around the tumor rather than the tumor itself, increasing the delivery of oxygen and chemotherapy to the immune cells of the tumor. The tumor microenvironment (TME) includes the malignant cancer cells as well as the many non-malignant cells within a tumor (for example fibroblasts and immune cells), blood vessels, and extracellular matrix components, such as collagen and the polymeric carbohydrate hyaluronan (HA). The cancer cells within the tumor can recruit other cell types into the TME and then stimulate them to generate growth factors, signaling molecules and other matrix components that can further optimize the TME for malignant cell growth and result in an immunosuppressive microenvironment. Decades of investigation have led to the current mechanism-based hypothesis for the role of HA in the TME. Accumulation of HA and associated water within some solid tumors can lead to increased pressure within the tumor microenvironment. The increased pressure can lead to blood vessel compression, restricting blood flow, leading to increased areas of hypoxia, and impeding access of therapeutic intervention into the tumor.   WuXi AppTec communications asked Halozyme’s Senior VP of Research and Development, Dr. Alison Armour, to explain why the company decided to take this unique approach and how PEGPH20 works. Dr. Armour has over 15 years of practice as a clinical oncologist and a strong record of overseeing successful regulatory submissions. Dr. Armour joined Halozyme in May 2019 and she is responsible for Halozyme’s research, clinical development, regulatory, safety and pharmacovigilance efforts. Prior to Halozyme, Dr. Armour served as the Chief Medical Officer at Endocyte, where she was responsible for the company’s clinical division, including all medical operations, clinical operations, regulatory, data management and pharmacovigilance activities. Prior to this role, she served as Vice President of Development and team lead for TYKERB® at GSK and then at Novartis. Earlier in her career Dr. Armour also served as global medical science director at AstraZeneca. Dr. Armour received her B.Sc. in Biochemistry, her M.B., Ch.B. MSc, and Doctorate of Medicine from the University of Glasgow; her FRCR at the Royal College of Radiologists London, UK and her FRCP at the Royal College of Physicians in London, UK, for contributions to the field of oncology. WuXi: Dr. Armour, what is your opinion about the challenges in pancreatic cancer early screening and diagnosis? Are there any specific biomarkers? Alison Armour: It is incredibly challenging to screen for pancreatic cancer at its early stages. A robust biomarker for example hasn’t been developed yet. The pancreas is deep within the abdomen. It’s not easy to detect on routine clinical examination and the symptoms can be non-specific. For example nausea, vomiting, weight loss or pain, which can often be misdiagnosed as other conditions. The current blood biomarker tests are not specific, but CA19 or CEA may sometimes be elevated. Standard tests include CT, MRI and tissue via ERCP, which is an invasive procedure. Panels of potential diagnostic biomarkers are currently being explored. WuXi: What are the hot targets in the field of drug development for pancreatic cancer? Alison Armour: Pancreatic cancer is an extremely resistant cancer in the world of drug development, but so was melanoma until we found the right target. There are multiple targets being explored for pancreatic cancer, including KRAS and CTHRC1. At Halozyme, we believe there’s great promise in targeting hyaluronan (HA)—let me explain why. Pancreatic cancer is known to be surrounded by very dense fibrous tissue. In fact, only around 10 percent of the cells are tumor. We also know that pancreatic tumor cells surround themselves with HA. That’s what we are targeting at Halozyme. HA is a large, complex carbohydrate molecule. It accumulates on the surface of tumor cells and the space around them. It provides a barrier to immune cells from infiltrating the tumor and compresses the blood vessels, which impedes the delivery of chemotherapy to the tumor. PEGPH20 breaks down the large molecule and has been shown in preclinical models to increase the perfusion of oxygen and chemotherapy to the tumor. The breakdown products may also have a role in recruiting immune cells into the tumor. That’s an area that we are actively researching now. WuXi: In recent years, what breakthroughs have been made in drug development for pancreatic cancer? Alison Armour: Sadly, not many. The first real breakthrough came with chemotherapy in the 1970s, then along came gemcitabine in the ‘90s. Since then, people have just combined drugs. There really haven’t been any significant breakthroughs in pancreatic cancer, and that’s why we must keep trying and explore the tumor microenvironment in its entirety. We are starting to target the molecular defects in all cancers though and PARP inhibitors showed some interesting data in the small numbers of patients whose tumors had a DNA repair defect. WuXi: How is your drug (PEGPH20) different from existing pancreatic cancer treatments? Is it a new approach? What are the results of your research so far? Alison Armour: Our lead therapeutic candidate, PEGPH20, utilizes a unique mechanism of action compared to standard anti-cancer therapies. Our preclinical research shows that it doesn’t target the cancer cells, but instead it targets a component of the microenvironment. It breaks down HA in the tumor itself and makes it easier for the blood vessels to deliver oxygen and chemotherapy as well as immune cells in the tumor area. In our Phase 2 study, PEGPH20 plus standard chemotherapy of ABRAXANE and gemcitabine suggested meaningful clinical trends in OS and PFS in patients whose tumors expressed high levels of HA. We are waiting for the results of a confirmatory Phase 3 study later this year. WuXi: What is the specific mechanism of action? Alison Armour: PEGPH20 targets the accumulation of HA in the tumor microenvironment. When HA accumulates, it creates a significant barrier to drug delivery. Enzymatically degrading this accumulated HA has been shown in animal models to reduce tumor pressure, improve vascular perfusion and decrease hypoxia, enabling increased access of anti-cancer therapeutics and immune cells. WuXi: How did you choose to focus on pancreatic cancer? It has been a very difficult disease to treat. Alison Armour: Pancreatic tumors have very high levels of HA, the prime target for PEGPH20. This makes pancreatic cancer an ideal indication for Halozyme to pursue. WuXi: Are you planning to develop the drug through regulatory approval and market it? Alison Armour: Absolutely. We fully intend to commercialize PEGPH20 for the treatment of pancreatic cancer pending the results of our Phase 3 data readout. WuXi: Have patients been involved in the development of your drug, other than participating in clinical trials of course? Alison Armour: Our work with patients predominantly surrounds advocacy and support groups including the Pancreatic Cancer Action Network (PanCAN). WuXi: What major challenges have you faced in trying to bring a new drug for pancreatic cancer to patients? Alison Armour: The biggest challenge in drug development for pancreatic cancer is that we haven’t been able to target the pathways that really drive the development and growth of pancreatic cancer, but as drug developers we will keep trying. Patients are often very ill by the time they present and they succumb quickly to their disease, so we need to find agents that are effective and work rapidly. WuXi: What other drug candidates do you have in the pipeline? Alison Armour: Right now, we are concentrating on developing PEGPH20. Beyond pancreatic cancer, we are conducting studies across multiple solid tumor types to examine if PEGPH20’s demonstrated ability to degrade accumulated HA may help increase the effectiveness of anti-cancer and immuno-oncology therapeutics. WuXi: What are the top impediments in our delivery of “better” medicines “faster” and “cheaper” to patients? Alison Armour: We work tirelessly to create the best treatment options we can, as quickly as possible, because patients are waiting. People often rush through the early stages of development to see if the molecule works, but when a drug gets into trouble, the signs are usually there in the data and the science. We must not underestimate the value of really understanding the target and the drug. WuXi: For the disease area you are working on, what would be the one thing that would have the most potential to lead a paradigm shift “from treatment to cure?” Alison Armour: It’s the biology of the disease. There are many mutations in pancreatic cancer, but if we could define one or two pathways that really drive the growth of the disease, we could unlock it.

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2019/09/19

Finch Therapeutics Taps into the Human Microbiome to Find Disease Causes and Cures

Finch Therapeutics is developing microbial therapies designed to alter the microbiome for treatment of patients suffering from diseases as varied as bacterial infections and autism. In 2019, the company received a Breakthrough Therapy designation from the US Food and Drug Administration (FDA) for its microbial therapy CP101, a treatment for recurrent Clostridium difficile (C. difficile) infections (CDI), which can cause extreme diarrhea and life-threating inflammation of the colon. CP101 is the lead drug candidate derived from a technology platform designed to explore the microbiome, the community of micro-organisms that exists throughout the human body, particularly in the gastrointestinal tract. Imbalances and disruptions of the microbiome are linked to a wide variety of diseases. Finch CEO Mark Smith, Ph.D., said C. difficile infections are usually treated with antibiotics, “which often disrupt the balance of the gut microbiome, leaving patients susceptible to additional CDI episodes.” A 2017 clinical trial showed CP101 prevented recurrence of CDI in 88 percent of the 49 patients enrolled, earning the drug its breakthrough designation. A Phase 2 trial of CP101 is underway and, if successful, could serve as a pivotal study expediting FDA approval. 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 Smith about the company’s new CDI therapy, the impact of the FDA’s Breakthrough Therapy designation and the role of the human microbiome in diseases. Smith co-founded Finch to develop the next generation of microbiome-based therapies. He earned his Ph.D. in microbiology from Massachusetts Institute of Technology and his B.A. in biology from Princeton University.   WuXi: How did CP101 qualify for Breakthrough Therapy designation? Mark Smith: CP101, our microbiome-based investigational drug for recurrent C. difficile infections (CDI), received the FDA’s Breakthrough Therapy designation because it is intended to treat a serious or life-threatening condition, and the preliminary clinical evidence indicates that CP101 may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. CDI is certainly a serious and sometimes life-threating condition. CDI is the most common hospital-acquired infection in the US, but it also affects individuals with limited or no contact with a hospital setting. In the US alone, an estimated 500,000 individuals suffer from CDI each year, and sadly, CDI is associated with close to 30,000 deaths per year. The US Centers for Disease Control and Prevention (CDC) categorizes CDI as an “urgent threat” to public health, the highest possible threat categorization. CP101 is intended to prevent recurrent CDI; in other words, it is designed to prevent patients from experiencing additional CDI episodes. After an initial CDI episode and treatment with antibiotics, up to 20 percent of patients will experience a second episode. After a patient has experienced two or more CDI episodes, 40-65 percent experience yet another episode. With antibiotics alone it can be extremely difficult to break the cycles of CDI, and the negative impact on patients, their families and the health care system is enormous. The preliminary evidence for CP101 is very exciting — in a preliminary clinical study, 88 percent of patients battling recurrent CDI that received CP101 did not experience a CDI recurrence over a two-month period. Beyond this study, other clinical studies have also shown that transferring a diverse microbial community into the gut of patients suffering from recurrent CDI may be significantly more effective than utilizing antibiotics alone to treat recurrent CDI.   WuXi: How does your drug candidate differ from existing therapies for clostridium difficile infection? What is the mechanism of action? Mark Smith: CDI has traditionally been treated with antibiotics alone, which often disrupts the balance of the gut microbiome, leaving patients susceptible to additional CDI episodes. To combat this, many clinicians are now using fecal microbiota transplants (FMT), an investigational treatment derived from the stool of human donors, to treat patients with recurrent CDI that have failed antibiotic therapy. While many of the FMT treatments used in the US come from OpenBiome, a nonprofit stool bank that rigorously screens its donors, there is wide variation in the donor screening protocols and processes used by other organizations preparing FMT treatments. FMT treatments are often delivered using clinically invasive methods, such as naso-enteric tubes, enemas, or most commonly in the US, via colonoscopy, which requires bowel preparation beforehand, a process that can be quite uncomfortable and difficult for patients.  We consider CP101 the next generation of microbiome-based therapies because it addresses the limitations of currently available options. Specifically, CP101 is an oral capsule, produced under applicable GMP (Good Manufacturing Practices) controls, which contains a diverse community of lyophilized microbiota from human donors that have undergone rigorous screening and testing. The oral delivery method has the potential to significantly improve the patient experience. And, unlike FMT treatments that must generally be kept frozen, the lyophilization of the microbiota avoids the need for CP101 to be kept frozen, simplifying the supply chain and making it much easier for hospitals to store CP101. WuXi: How did you demonstrate the potential clinical benefit beyond existing treatments to secure the breakthrough designation? Mark Smith: We submitted data from a clinical study conducted at the University of Minnesota, which describes the clinical experience with CP101 used to treat patients with recurrent CDI. In the study 88 percent of patients achieved clinical success, defined as no recurrence of CDI over a two-month period. Compared to the published recurrence rates seen after antibiotic therapy, this is a large, and very clinically relevant, decrease in the rate of recurrence. This data allowed us to meet the FDA’s requirement that breakthrough therapies must have preliminary clinical evidence that indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. WuXi: What impact does the breakthrough designation have for your company? Mark Smith: The increased communication and support that the FDA offers to companies with Breakthrough Therapy designation is incredibly valuable and will enable us to accelerate our efforts to make CP101 available to patients fighting recurrent CDI. Just recently, we had a very productive conversation with the FDA in which we learned that it may be possible for PRISM3, our currently enrolling Phase 2 clinical trial, to be considered a single pivotal trial if the statistical results meet the FDA’s highest bar. If we meet this very high, but achievable bar we would be able to submit for FDA approval without needing to conduct a Phase 3 clinical trial. Having a therapy with Breakthrough Therapy designation was also helpful during our last fundraising round, where we raised $53 million dollars to advance our portfolio of therapies. WuXi: What role, if any, have patients played in your drug development and clinical trials, aside from participating in clinical trials, of course? Mark Smith: Patients are always at the center of our work. They inspire us and motivate us to work with tenacity and urgency. We’ve worked closely with many individuals that have battled C. difficile as well as C. difficile patient advocacy groups to understand the needs of those we seek to serve. Their input has helped inform the design of our product and clinical trials. WuXi: What other drugs are you developing based on your technology platform? Mark Smith: We use our Human-First Discovery™ platform to develop therapies for a wide range of diseases and conditions linked to a disrupted gut microbiome. Rather than following the traditional drug discovery process, we begin with proof-of-concept data from human interventional studies to identify meaningful microbial signatures. We have a Full-Spectrum Microbiota® (FSM®) product platform that allows for the development of therapies that contain a diverse community of microbiota from healthy human donors, as well as a Rationally-Selected Microbiota® (RSM™) product platform that allows for the development of therapies containing select microbes, grown in pure culture, that we believe are driving successful clinical outcomes.     In addition to recurrent CDI, we also have a pediatric Autism Spectrum Disorder program that recently received Fast Track designation from the FDA, and a partnership with Takeda Pharmaceutical Company to develop a Rationally-Selected Microbiota therapy for ulcerative colitis. Beyond that we continue to evaluate and advance microbiome research to identify additional areas where our platform can address unmet patient needs. WuXi: What role does the microbiome play in diseases and what kinds of diseases are linked to it? Mark Smith: Scientists are discovering that the microbes inside us are having a much bigger impact on our health than previously thought. In addition to the areas we are currently focused on, researchers have found that the microbiome is linked to the response patients have to cancer therapies, as well as the development of autoimmune conditions, such as rheumatoid arthritis and multiple sclerosis, central nervous system disorders such as Parkinson’s disease, and even the development of food allergies and obesity, just to name a few areas of promising research. To further our understanding of the microbiome’s therapeutic potential, we are currently supporting a number of investigator-initiated clinical studies that span a wide variety of neurological, hepatic, infectious disease, and gastrointestinal conditions.     WuXi: What lessons can other companies learn from your drug development experience? Mark Smith: We believe that focusing on bringing clinical data into the development process as early as possible is critical to retire risk and inform product strategy. Because of the favorable safety profile of our microbial therapies we have been able to rapidly generate proof-of-principle clinical data. This approach enabled us to quickly move into the clinic with CP101 and obtain data that allowed us to secure Breakthrough Therapy designation and initiate a potentially pivotal trial. While other companies may not share the unique features of our discovery platform, the principle of tying decisions to clinical data early in development is an important one. WuXi: Have FDA initiatives such as Breakthrough Therapy and Fast Track designations, changed the paradigm of clinical drug development? If so, how? Mark Smith: The FDA plays a pivotal role in the development of effective therapies. Fast Track and Breakthrough Therapy designations increase our ability to interact with the FDA’s multidisciplinary team of experts. These designations allow sponsors to design better trials and more smoothly navigate the necessary regulatory processes that exist to ensure that safe, effective drugs reach patients. WuXi: What are the top three major impediments in our delivery of better medicines, faster and cheaper to patients? Mark Smith: If you consider the biopharma industry as a whole, there are a few main challenges. As we all know, it’s very costly and time consuming to identify a promising drug candidate. And, many drug candidates that show promise in a pre-clinical setting are found to be ineffective once clinical trials start. These factors drive up the cost of drugs and increase the time it takes for new therapies to enter the market. With our product platform and strong partnerships with clinicians studying the gut microbiome in a clinical setting, we are uniquely positioned to overcome many of the traditional challenges. By starting with microbial data sets from human interventional studies, we can reverse engineer successful clinical outcomes to identify the microbial community driving patient outcomes, significantly decreasing the time, cost, and risk associated with our drug discovery process.     

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