DAY ONE - OCTOBER 19, 2016
7:30 am Registration/Continental Breakfast
8:10 am Chairperson's Opening Remarks
William K. Schmidt, Ph.D., President, NorthStar Consulting, LLC
8:15 am Imaging-based Pain Neurosignatures
Pain is a complex experience that arises from cohesive patterns of neuronal activity distributed across vast regions of the brain representing pain’s somatosensory, emotional and cognitive dimensions. In this presentation, Dr. Roy will present results from recent brain imaging studies using machine-learning to identify pain-predictive signatures, and how these may be modified by interventions that influence pain perception, such as self-regulation, expectations, emotions, or drugs. Implications for drug development will be discussed.
Mathieu Roy, Ph.D., Assistant Professor, Department of Psychology, McGill University
Pain is a complex experience that arises from cohesive patterns of neuronal activity distributed across vast regions of the brain representing pain’s somatosensory, emotional and cognitive dimensions. In this presentation, Dr. Roy will present results from recent brain imaging studies using machine-learning to identify pain-predictive signatures, and how these may be modified by interventions that influence pain perception, such as self-regulation, expectations, emotions, or drugs. Implications for drug development will be discussed.
Mathieu Roy, Ph.D., Assistant Professor, Department of Psychology, McGill University
8:45 am Exploring the Interplay between Rescue Drugs, Data Imputation and Study Outcomes in Analgesic Clinical Trials
In placebo-controlled pain studies, provisions for study subjects to receive adequate analgesic therapy must be made. As such, most protocols allow study subjects to receive a prespecified regimen of rescue drugs as-needed. The selection of a rescue regimen is a critical experimental design choice. Despite the importance of rescue as a study design feature, there exist no published review articles or meta-analysis focusing on the impact of rescue therapy on experimental outcomes. In this talk, Dr. Singla will discuss his research and findings relevant to rescue therapy, data imputation and study outcomes.
In placebo-controlled pain studies, provisions for study subjects to receive adequate analgesic therapy must be made. As such, most protocols allow study subjects to receive a prespecified regimen of rescue drugs as-needed. The selection of a rescue regimen is a critical experimental design choice. Despite the importance of rescue as a study design feature, there exist no published review articles or meta-analysis focusing on the impact of rescue therapy on experimental outcomes. In this talk, Dr. Singla will discuss his research and findings relevant to rescue therapy, data imputation and study outcomes.
Neil Singla, MD, Chief Scientific Officer, Lotus Clinical Research
9:15 am Pain, Policies and Predicaments: Who is to Blame and What are the Real Solutions?
Every day, dozens of media reports surface that decry a worsening opioid crisis in America. These reports are accurate, but they've had unintended consequences. Governmental agencies have reacted to these reports with policies and regulations that are causing harm for vast numbers of people in pain. Payers have been conspicuously absent from the discussion and have not been held accountable for their contribution to the problem. Ironically, Pharma has been criticized for creating the opioid crisis when, in fact, they are the industry that can bring about the solutions to the epidemic. Pharma alone can bring about safer and more effective therapies. People in pain and physicians look to Pharma for answers. The discussion will highlight the major problems that have led to the current crisis and what must be done to solve it.
Lynn Webster, MD, FACPM, FASAM, Vice President of Scientific Affairs, PRA Health Sciences, Past President, American Academy of Pain Medicine
9:45 am Morning Break/Exhibiting Viewing/Poster Session Viewing
10:10 am Pain, Policies and Predicaments - Follow-Up Panel Discussion
In this panel session, Dr. Lynn Webster will engage panelists in a discussion revolving around the current opioid crisis in America and what they see are the challenges the pharmaceutical industry is trying to meet and the obstacles they are encountering in the development of new pain drugs. This session will also provide an opportunity for the larger audience to participate and add their thoughts to the discussion.
CHAIR: Lynn Webster, MD, FACPM, FASAM, Vice President of Scientific Affairs, PRA Health Sciences, Past President, American Academy of Pain Medicine
Carl L. Roland, PharmD, MS, Senior Director, Pfizer, Inc.
Joe Stauffer, DO, MBA, Chief Medical Officer, Cara Therapeutics
Alexander Kraus, Ph.D., Vice President of Product Development, Technical & Government Affairs, Grunenthal USA, Inc.
Joe Stauffer, DO, MBA, Chief Medical Officer, Cara Therapeutics
Alexander Kraus, Ph.D., Vice President of Product Development, Technical & Government Affairs, Grunenthal USA, Inc.
11:00 am Kappa Opioid Receptor Agonists (KORA’s) A Novel Approach to Managing Acute and Chronic Pain
In this presentation, Dr. Stauffer will present the following:
♦ Review of the Kappa Opioid Class
♦ Human Abuse Liability Data of CR845 a Novel KORA
♦ Post-operative and Chronic Pain Data of CR845
Joe Stauffer, DO, MBA, Chief Medical Officer, Cara Therapeutics
11:30 am An Exploratory Clinical Phase 2 Study With a Dual Inhibitor on 5HT2A and GlyT2 in Post-operative Pain
In animal studies, VVZ-149, a dual inhibitor on 5HT2A and GlyT2, had shown morphine comparable analgesic effects in formalin model and incision model as well as anti-allodynic effect in a rat model of neuropathic pain. In a human proof of concept study with laparoscopic gastrectomy patients, the VVZ-149 Injection (8 hours IV infusion) could reduce the opioid consumption up to 57.5% (P<0.05) depending on the post-dosing time compared to placebo group, however, the opioid saving effect of VVZ-149 seemed to be confounded with a flooring effect due to high usage of opioid during the first 2 hrs and weak pain intensity of the laparoscopic surgery. Limitations in post-operative pain study and PK/PD correlation will be discussed.
Doo H. Lee, Ph.D., Chief Executive Officer, Head of Research and Development, Vivozon, Inc.
12:00 pm Luncheon
1:00 pm Clinical Development of a Novel Opioid Molecule with Inherent Anti-abuse Properties, Less Sedation and Less Respiratory Depression
Discuss the clinical development of NKTR-181, a first-in-class, full mu-opioid agonist molecule with slow rate of CNS entry which is in Phase 3 as a twice-daily oral tablet to treat chronic pain. NKTR-181 has a novel molecular structure designed to maintain full mu-opioid receptor activity in order to provide potent pain relief while also having a slow rate of entry into the brain to eliminate euphoria. In preclinical and clinical studies, NKTR-181 also exhibited much less traditional opioid side effects such as sleepiness, dizziness and respiratory depression.
Carlo Di Fonzo, Ph.D., Vice President, Drug Development & Regulatory Affairs, Nektar Therapeutics
1:30 pm A Novel Endomorphin Analog Providing Pain Relief Comparable to Morphine with Substantially Reduced Side Effects
Opioid prescription painkillers are the gold standard for alleviating pain but are associated with several adverse side effects. Abuse liability is particularly important as it results in major medical, societal, and economic problems that have led to an epidemic of abuse and a quadrupling of painkiller overdoses since 2000. In addition, respiratory depression is the cause of death from overdose, and tolerance complicates treatment and increases the risk of side effects. Motor and cognitive impairment are especially problematic for older adults. We have taken a novel approach to these problems by testing analogs of endomorphin, a brain peptide selective for the mu (morphine) opioid receptor. After screening numerous analogs, a lead compound emerged that provided equal or greater pain relief relative to morphine in the rat, while showing significantly reduced: a) respiratory depression, b) impairment of motor coordination, c) impairment of cognitive function, d) tolerance, e) inflammation/glial activation associated with tolerance and pain hypersensitivity and f) abuse liability in several complementary tests that correlate well with human results, indicating that it is highly unlikely to be abused. The presentation will discuss these results and recent demonstrations that the analog is very effective at relieving pain in multiple models of pain in animals.
James Zadina, Ph.D., Senior Research Career Scientist, SE LA Veterans Health Care System, Director, Neuroscience Laboratory; Professor of Medicine, Pharmacology and Neuroscience, Tulane University School of Medicine
2:00 pm Chasing Men on Fire: Sodium Channels and Pain, from Squid to Clinic
Beginning with a short discussion of peripheral sodium channels as potential therapeutic targets, this lecture will explore the functional roles of Nav1.7 and Nav1.8 in pain signaling. It will then describe inherited erythromelalgia, a genetic model of neuropathic pain in humans, followed by a discussion of the roles of Nav1.7 and its variants in “the rest of us”, in broad populations. Finally, it will discuss recent translational studies on Nav1.7 blockers in human subjects with pain, and pharmacogenomic approaches to pain therapy with existing medications.
Stephen Waxman, MD, Ph.D., Bridget Marie Flaherty Professor of Neurology, Neurobiology, and Pharmacology, Yale University School of Medicine, Director, Center for Neuroscience and Regeneration/Neurorehabilitation Research, VA Connecticut
2:30 pm Intrathecal Substance P-Saporin for the Treatment of Intractable Cancer Pain
Substance P-Saporin (SP-SAP), a non-opiate, chronic pain-focused biological that when delivered directly into the spinal fluid, seeks out and destroys a specific subpopulation of pain pathway neurons. Because of its size (and rapid degradation of both Substance P and Saporin), this drug does not travel far from the site of administration, hence its safety profile and lack of side effects. Treatment is one injection and the results are permanent. The presentation will cover the method of delivery of SP-SAP and the options for lumbar placement and the correlation to the location of pain. A brief summary of the results of the ongoing clinical trial will be discussed.
Carl Noe, MD, Professor, Department of Pain Management and Anesthesiology, UT Southwestern Medical Center, Medical Director, Eugene McDermott Center for Pain Management
Substance P-Saporin (SP-SAP), a non-opiate, chronic pain-focused biological that when delivered directly into the spinal fluid, seeks out and destroys a specific subpopulation of pain pathway neurons. Because of its size (and rapid degradation of both Substance P and Saporin), this drug does not travel far from the site of administration, hence its safety profile and lack of side effects. Treatment is one injection and the results are permanent. The presentation will cover the method of delivery of SP-SAP and the options for lumbar placement and the correlation to the location of pain. A brief summary of the results of the ongoing clinical trial will be discussed.
Carl Noe, MD, Professor, Department of Pain Management and Anesthesiology, UT Southwestern Medical Center, Medical Director, Eugene McDermott Center for Pain Management
3:00 pm Afternoon Refreshment Break/Exhibit Viewing/Poster Viewing
3:25 pm Is There a Future for Fatty Acid Amide Hydrolase Inhibitors in Neuropathic Pain?
Increasing the endocannabinoid and fatty acid amide levels by the inhibition of fatty acid amide hydrolase (FAAH) has been a promising therapeutic strategy in inflammatory and neuropathic pain; however, the one clinical trial in the literature was unable to confirm an analgesic effect in osteoarthritis. Dr. Sang will present the results of a clinical trial evaluating a reversible inhibitor of FAAH Type 1 in central neuropathic pain.
Christine Sang, MD, MPH, Director, Translational Pain Research, Brigham and Women's Hospital, Associate Professor, Harvard Medical School
3:55 pm Agonists for the A3 Subtype of Adenosine Receptor are Potent Analgesics for Neuropathic Pain and Adjuncts that Improve Opiate Analgesic Therapy
It has been known for over a decade that an IV infusion of adenosine yields remarkable analgesia in patients with neuropathic pain. Of course, adenosine itself is metabolized too quickly to be of practical use. Adenosine is known to activate four GPCR receptor subtypes, A1AR, A2AAR, A2BAR, and A3AR. Work with A1 and A2A agonists shows analgesia but also dose-limiting cardiovascular and renal side-effects. Dr. Bennett and his team have investigated agonists that are over 10,000-fold selective for A3, a receptor subtype with very low expression in heart and kidney. They find that A3 agonists are potent analgesics at doses that produce no obvious side effect in all models of neuropathic pain studied to date, and have remarkable effects when combined with an opiate analgesic, including a complete block of analgesic tolerance and opioid-induced hyperalgesia, a reversal of the neuropathic pain’s relative resistance to opiates, block of the opiate’s positively rewarding effects, and a significant reduction in naloxone-evoked withdrawal symptoms.
Gary Bennett, Ph.D., Chief Executive Officer, Biointervene, Inc., Adjunct Professor, UC San Diego
It has been known for over a decade that an IV infusion of adenosine yields remarkable analgesia in patients with neuropathic pain. Of course, adenosine itself is metabolized too quickly to be of practical use. Adenosine is known to activate four GPCR receptor subtypes, A1AR, A2AAR, A2BAR, and A3AR. Work with A1 and A2A agonists shows analgesia but also dose-limiting cardiovascular and renal side-effects. Dr. Bennett and his team have investigated agonists that are over 10,000-fold selective for A3, a receptor subtype with very low expression in heart and kidney. They find that A3 agonists are potent analgesics at doses that produce no obvious side effect in all models of neuropathic pain studied to date, and have remarkable effects when combined with an opiate analgesic, including a complete block of analgesic tolerance and opioid-induced hyperalgesia, a reversal of the neuropathic pain’s relative resistance to opiates, block of the opiate’s positively rewarding effects, and a significant reduction in naloxone-evoked withdrawal symptoms.
Gary Bennett, Ph.D., Chief Executive Officer, Biointervene, Inc., Adjunct Professor, UC San Diego
4:25 pm An Open Dialogue and Q&A with the Day's Presenters
5:10 pm Cocktail Reception
7:45 am Continental Breakfast
8:30 am Ricolinostat, a Clinical Stage HDAC6 Inhibitor, Induces a Rapid, Persistent Reversal of Established Peripheral Neuropathic Pain in Rodent Models
Ricolinostat is a phase 2, orally bioavailable, selective, and well tolerated HDAC6 inhibitor that is currently in clinical trials for multiple myeloma. Low doses of ricolinostat reversed tactile allodynia in rodent models of peripheral neuropathy. The effect of the drug persisted after washout, suggesting that HDAC6 inhibition may produce a sustained effect on neuropathic pain. Ricolinostat is a promising and potentially disease modifying therapeutic candidate for neuropathic pain.
Matthew Jarpe, Ph.D., Associate Vice President of Biology, Acetylon Pharmaceuticals
9:00 am AYX1, An EGR1 Decoy Oligonucleotide, Provides Long-term Reduction of Postoperative Pain and Prevention of Chronic Pain After TKA
AYX1, an EGR1 decoy oligonucleotide, provides long-term reduction of postoperative pain and prevention of chronic pain after TKA. This presentation will summarize the preclinical and phase 2 clinical data for the transcription factor decoy AYX1. AYX1 is a 23 base-pair, unprotected, double-stranded DNA transcription factor decoy drug candidate designed to inhibit the activity of the trauma-induced transcription factor EGR1 by binding to and preventing EGR1-triggered gene transcription that results in central sensitization. AYX1 is delivered via a single bolus intrathecal injection immediately prior to surgery and efficiently and dose-dependently prevents the maintenance of mechanical allodynia and hyperalgesia in multiple animal models without altering basal neuronal function. Results to date have demonstrated that a single preoperative intrathecal administration of AYX1 added to standard of care postoperative analgesic regimen in total knee arthroplasty was well tolerated and significantly reduced both movement-evoked pain and pain at rest with a treatment effect persisting through the 42-day follow-up period. The incidence of clinically significant pain was dramatically decreased at day 42 compared to placebo that strongly support AYX1’s ability to prevent postoperative chronic pain.
Donald Manning, MD, Ph.D., Chief Medical Officer, Adynxx
9:30 am The Integration of Artificial and Human Intelligence for Differentiated Pain Therapeutics
The use of Big Data Analytics such as the real-time, predictive, Artificial Intelligence platform (PharmGPS®), has brought us to a new chapter in the identification of a multitude of indications for a specific target by making complex associations often unattainable by the human mind alone. However, the requirement for human Intelligence or domain expertise is an essential component in reviewing the resultant data output and its relevance. An assessment of compounds with respect to the best fit for efficacy and safety within indications can be considered for internal alignment of strategy, ability to execute the development program, relevance of regulatory precedence and obstacles and competition in the development space. In addition, commercial consideration, cost and time lines which need to be taken into account to decide an indication and target population can be prioritized. It is clear that both artificial and human intelligence have to work in unison to extract therapeutic value and create differentiated products that have a higher probability of clinical an
Randall Stevens, MD, Chief Medical Officer, Centrexion Therapeutics
10:00 am Morning Refreshment Break/Exhibit Viewing/Poster Viewing
10:25 am Panel Session: Transformational Change in Pain and Migraine
The treatment of pain and migraine is more than ready for transformational change. Innovation in tools and advances in understanding of disease biology promise to advance a standard of care that is decades to centuries old, and leaves a meaningful percentage of patients with inadequately addressed pain, intolerable side effects, safety and abuse issues. This panel will discuss advances in our understanding of disease biology, and in the development of new imaging, biomarker, and big data analytics tools that are leading to the identification of mechanisms and approaches to address unique needs for unique patient populations. These advances should tilt the risk/reward balance toward the positive from a scientific, clinical and commercial perspective. Join us as we explore transformation in the pain drug development space and what will defined commercial success:
♦ Are we truly entering a new era in pain and migraine drug development?
♦ What factors are driving the forward momentum? Where are the potential speed bumps?
♦ What are the emerging tools/approaches to improve potential for clinical and commercial success?
♦ What have we learned from past transformations that inform the future (e.g., triptans, QD opioids, gabapentin)?
♦ What are the important collaborative efforts/partnerships to advance the field and absorb risk?
♦ Which particular programs are most promising in terms of value proposition to all stakeholders (patients, physicians, payers)?
♦ What is your advice for early-stage programs/companies?
Chair: Ginger Johnson, Ph.D., Vice President, Defined Health
The treatment of pain and migraine is more than ready for transformational change. Innovation in tools and advances in understanding of disease biology promise to advance a standard of care that is decades to centuries old, and leaves a meaningful percentage of patients with inadequately addressed pain, intolerable side effects, safety and abuse issues. This panel will discuss advances in our understanding of disease biology, and in the development of new imaging, biomarker, and big data analytics tools that are leading to the identification of mechanisms and approaches to address unique needs for unique patient populations. These advances should tilt the risk/reward balance toward the positive from a scientific, clinical and commercial perspective. Join us as we explore transformation in the pain drug development space and what will defined commercial success:
♦ Are we truly entering a new era in pain and migraine drug development?
♦ What factors are driving the forward momentum? Where are the potential speed bumps?
♦ What are the emerging tools/approaches to improve potential for clinical and commercial success?
♦ What have we learned from past transformations that inform the future (e.g., triptans, QD opioids, gabapentin)?
♦ What are the important collaborative efforts/partnerships to advance the field and absorb risk?
♦ Which particular programs are most promising in terms of value proposition to all stakeholders (patients, physicians, payers)?
♦ What is your advice for early-stage programs/companies?
Chair: Ginger Johnson, Ph.D., Vice President, Defined Health
William K. Schmidt, Ph.D., President, NorthStar Consulting, LLC
Randall Stevens, MD, Chief Medical Officer, Centrexion Therapeutics
Marcelo E. Bigal, MD, Ph.D., Senior Vice President, Head of Global Specialty Development, Teva Pharmaceuticals
Aimee Crombie, Ph.D., Senior Director of Research, Trevena, Inc.
11:15 am Implementing Central Statistical Surveillance in Clinical Trials
The FDA’s Risk-Based Monitoring Guideline sets forth a vision of performing central statistical surveillance to support early detection and correction of threats to data quality. A number of studies in the literature have supported the role of central statistical surveillance to provide complementary control of data quality beyond human monitoring. Analgesic Solutions has developed a method for central statistical surveillance that focuses on variables known to impact assay sensitivity of clinical trials, and utilizes statistical process control methods borrowed from manufacturing to maximize early detection of aberrant data while at the same time minimizing false positive signals. In this presentation will review the theoretical basis for central statistical surveillance for assay sensitivity, and review practical learnings from our first several implementations of this system in regulated clinical trials.
Nat Katz, MD, MS, Chief Executive Officer, Analgesic Solutions
11:45 am Voltage Gated Na Channels as Targets for Pain Therapy - Is there Light at the End of the Tunnel?
Voltage gate sodium (Nav) channels have been a target for the development of pain therapies for more than 50 years. Targeting specific members of the voltage gated sodium channel is a much more recent endeavor that has been driven by advances in the genetics of human pain conditions, better understanding of the regionally specific expression of many Nav channel subtypes as well the fundamental processes underlying pain transmission and the role of Nav channels in these processes. While much of the recent focus has been on Nav1.7 channels, there has been increased interest in other Nav channel subtypes including Nav1.8 and Nav1.9. This talk will provide an overview of the current status of development of newer Nav channel targeted therapeutics and some of the challenges that still remain.
Neil Castle, Ph.D., Director of Biology, Icagen
12:15 pm Luncheon
1:15 pm First-in-class Melatonin MT2 Agonists in Neuropathic Pain
Melatonin is a neurohormone acting through two G-Protein coupled receptors called MT1 and MT2. The pharmacological properties of these two receptors have not yet been exploited in therapeutics. Here we present a novel class of melatonin MT2 receptors having antinocieptive properties for neuropathic and inflammatory pain. Melatonin MT2 receptors agonists act through modulation of brainstem descending antinociceptive pathways and are functionally coupled to opioid receptors, but without addiction liability. They represent a novel target for pain treatment.
Gabriella Gobbi, MD, Ph.D., Associate Professor, Department of Psychiatry, McGill University
1:45 pm An Open Dialogue and Q&A with the Day's Presenters
2:45 pm End of Conference