September 27, 2017
7:45 am Registration/Continental Breakfast
8:25 am Chairperson's Opening Remarks
8:30 am The Use of a Multi-modal Pain Test Battery in Early Phase Clinical Drug Development
Human evoked pain models can help to establish the analgesic potential of novel analgesic compounds. We integrated a range of mechanistically different pain tasks such that they can be used as a screening tool for the early drug development of potential analgesics. The "PainCart" yields a unique and reproducible profile of analgesic effects that can be considered a biomarker of the analgesic potential of a drug. The PainCart is currently used in early phase clinical drug studies for dose finding and go no-go decisions prior to phase 2.
Geert Jan Groeneveld, MD, Ph.D., Research Director, CNS, Centre for Human Drug Research
Human evoked pain models can help to establish the analgesic potential of novel analgesic compounds. We integrated a range of mechanistically different pain tasks such that they can be used as a screening tool for the early drug development of potential analgesics. The "PainCart" yields a unique and reproducible profile of analgesic effects that can be considered a biomarker of the analgesic potential of a drug. The PainCart is currently used in early phase clinical drug studies for dose finding and go no-go decisions prior to phase 2.
Geert Jan Groeneveld, MD, Ph.D., Research Director, CNS, Centre for Human Drug Research
9:00 am Using Biased Agonism to Refine the Therapeutic Potential of Opioids
In this presentation, Dr. Bohn will present work on separating signaling events downstream of opioid receptor activation and how this effects diverse physiological responses in vivo.
Laura Bohn, Ph.D., Professor, Departments of Molecular Medicine & Neuroscience, The Scripps Research Institute
In this presentation, Dr. Bohn will present work on separating signaling events downstream of opioid receptor activation and how this effects diverse physiological responses in vivo.
Laura Bohn, Ph.D., Professor, Departments of Molecular Medicine & Neuroscience, The Scripps Research Institute
9:30 am Human Sensory Neurons in Pain Drug Discovery: New Preclinical Strategies for Identifying Clinical Candidates
Historically, pain drug discovery has demonstrated a very low success rate in translating preclinical findings in animal models to human clinical studies.The challenges created by cross-species differences can be bypassed by employing novel preclinical strategies that rely on the use of isolated primary human sensory neurons. The study of drug effects on the target expressed in native tissue, provides an accurate assessment of the potential analgesic efficacy in human. In addition, by profiling drug activity on the different sensory neurons subtypes, both in healthy as well as pathological states, it is possible to obtain information highly valuable for the identification of the most appropriate pain indication.
Andre Ghetti, Ph.D., Chief Executive Officer, AnaBios Corporation
10:00 am Refreshment Break/Exhibit Viewing/Scientific Poster Viewing
10:25 am Opioid Sparing Endpoints: Trial Design, Clinical Relevance and Label Claims
Many analgesic drug developers seek an opioid sparing claim for their drug label. However, the regulatory criteria for this claim can be complex, and the FDA requires extensive experimental backup to allow an opioid sparing label. Additionally, there are multiple tiers of opioid sparing label that can be awarded. Dr. Neil Singla is Chief Scientific Officer of Lotus Clinical Research, a specialty analgesic CRO and research site that has performed over 100 analgesic clinical trials and helped guide several analgesic agents through FDA approval.
Many analgesic drug developers seek an opioid sparing claim for their drug label. However, the regulatory criteria for this claim can be complex, and the FDA requires extensive experimental backup to allow an opioid sparing label. Additionally, there are multiple tiers of opioid sparing label that can be awarded. Dr. Neil Singla is Chief Scientific Officer of Lotus Clinical Research, a specialty analgesic CRO and research site that has performed over 100 analgesic clinical trials and helped guide several analgesic agents through FDA approval.
In this talk Dr. Singla will outline:
♦ The criteria required for each type of opioid sparing label
♦ Examples of recently approved drugs for which opioid sparing claims were sought, both successfully and not
♦ A review of labels, protocol designs and endpoints, and resulting publications for these drugs
♦ The types of opioid sparing label the FDA awards
Neil Singla, MD, Chief Scientific Officer, Lotus Clinical Research
10:55 am Clinical Progress with Selective Blockers of the Nav1.7 Sodium Channel
It has been well over a decade since channelopathies in the SCN9a gene (which encodes for the Nav1.7 channel), were first implicated in human pain states. Many pharmaceutical companies have sought selective molecules targeting the Nav1.7 channel, as potential new drugs in the treatment of chronic pain. As we move towards larger phase 2 and pivotal phase 3 trials, this talk will review the clinical progress that has been made with the first generation of selective Nav1.7 blockers, highlighting the challenges observed, the most successful indications to date and thoughts for future studies.
Simon Tate, Ph.D., Chief Scientific Officer, Convergence Pharmaceuticals, Non-Executive Director, Biogen
It has been well over a decade since channelopathies in the SCN9a gene (which encodes for the Nav1.7 channel), were first implicated in human pain states. Many pharmaceutical companies have sought selective molecules targeting the Nav1.7 channel, as potential new drugs in the treatment of chronic pain. As we move towards larger phase 2 and pivotal phase 3 trials, this talk will review the clinical progress that has been made with the first generation of selective Nav1.7 blockers, highlighting the challenges observed, the most successful indications to date and thoughts for future studies.
Simon Tate, Ph.D., Chief Scientific Officer, Convergence Pharmaceuticals, Non-Executive Director, Biogen
11:25 am Development Update on Erenumab, an Anti-CGRP Receptor Monoclonal Antibody for Migraine Prevention
Erenumab is a human monoclonal antibody that targets and blocks the calcitonin gene-related peptide (CGRP) receptor. The presentation will focus on Phase 1, 2 and 3 clinical trial results, including results that describe the safety and efficacy of erenumab in prevention of episodic and chronic migraine.
Daniel Mikol, MD, Ph.D., Executive Medical Director, Global Neuroscience Development, Amgen
Erenumab is a human monoclonal antibody that targets and blocks the calcitonin gene-related peptide (CGRP) receptor. The presentation will focus on Phase 1, 2 and 3 clinical trial results, including results that describe the safety and efficacy of erenumab in prevention of episodic and chronic migraine.
Daniel Mikol, MD, Ph.D., Executive Medical Director, Global Neuroscience Development, Amgen
11:55 am Question/Answer Session with the Morning's Speakers
12:20 pm Luncheon
1:20 pm Variability in the Response to Non-steroidal Anti-inflammatory Drugs (NSAIDs)
Inhibitors of the cyclooxygenases (COXs), the non-steroidal antiinflammatory drugs (NSAIDs), relieve inflammatory pain, but are associated with gastrointestinal and cardiovascular complications. Given the widespread use of NSAIDs there has been a longstanding interest in optimizing their risk-benefit ratio for example by reducing the gastrointestinal risk. More recently, the focus has shifted toward the cardiovascular complications of NSAIDs and very large prospective studies have been performed to compare cardiovascular risk across distinct NSAIDs. Surprisingly, much less attention has been paid to the efficacy side of the risk-benefit ratio. There is marked variability in the degree of pain relief by NSAIDs due to the complex interplay of molecular mechanism contributing to the pain sensation, variability in the disposition of NSAIDs and imprecision in the quantification of human pain. This presentation will discuss how variability in the response to NSAIDs may be parsed, and how this may inform the interpretation of clinical trials assessing cardiovascular risk and perhaps clinical practice.
Tilo Grosser, MD, Research Associate Professor, Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania
1:50 pm Potassium Channels as Pain and Migraine Targets: Challenges and Path Forward
This presentation will cover nociceptive pathways and potassium channels and pain signaling with emphasis on Voltage-gated potassium channels and Two pore domain channels drug discovery
Narender Gavva, Ph.D., Scientific Director, Amgen
This presentation will cover nociceptive pathways and potassium channels and pain signaling with emphasis on Voltage-gated potassium channels and Two pore domain channels drug discovery
Narender Gavva, Ph.D., Scientific Director, Amgen
2:20 pm Diode Laser Fiber Selective Quantitative Sensory Test (DLss-QST) for Testing the Efficacy of Neuropathic Pain Treatments
Dr. Nemenov and his team at LasMed LLC have developed a method that allows for selective activation of silent C mechano-insensitive (CMi) fibers and -A delta fibers. An assessment of CMi fibers underlie spontaneous pain and A-delta fibers denervation in patients with all peripheral neuropathy types. DLss-QST is an easy to use, and safe in both animals and humans. Because of these capacities, DLss can be instrumental in determining efficacy of novel therapeutics for neuropathic pain, and uniquely, spontaneous neuropathic pain.
Dr. Nemenov and his team at LasMed LLC have developed a method that allows for selective activation of silent C mechano-insensitive (CMi) fibers and -A delta fibers. An assessment of CMi fibers underlie spontaneous pain and A-delta fibers denervation in patients with all peripheral neuropathy types. DLss-QST is an easy to use, and safe in both animals and humans. Because of these capacities, DLss can be instrumental in determining efficacy of novel therapeutics for neuropathic pain, and uniquely, spontaneous neuropathic pain.
Mikhail "Mike" Nemenov, Ph.D., Founder and Chief Scientist, LasMed LLC, Senior Research Scholar, Stanford University
2:50 pm Refreshment Break/Exhibit Viewing/Scientific Poster Viewing
3:15 pm Two-stage, GI Enzyme Activated Opioid Prodrugs and Combination Products for Abuse Prevention and Overdose Protection
A recently completed clinical trial demonstrated safety and efficient oral activation of BIO-MDTM oxycodone prodrug, PF614. The BIO-MDTM prodrug platform provides abuse deterrence for inhalation, injection and chewing of single agent products. The Human Abuse Liability approach to development will be discussed along with the Multi-Pill Abuse Resistant (MPARTM) technology overdose protection that can be applied to this pipeline of products.
D. Lynn Kirkpatrick, Ph.D., President and CEO, Ensysce Biosciences
A recently completed clinical trial demonstrated safety and efficient oral activation of BIO-MDTM oxycodone prodrug, PF614. The BIO-MDTM prodrug platform provides abuse deterrence for inhalation, injection and chewing of single agent products. The Human Abuse Liability approach to development will be discussed along with the Multi-Pill Abuse Resistant (MPARTM) technology overdose protection that can be applied to this pipeline of products.
D. Lynn Kirkpatrick, Ph.D., President and CEO, Ensysce Biosciences
3:45 pm Development of Innovative DNA Medicine for Diabetic Neuropathy: Scientific Basis and Results from Phase I and II Studies in the US
A new concept medicine has been developed for diabetic neuropathy, based on naked plasmid DNA (VM202) engineered to express two isoforms of human hepatocyte growth factor. In Phase I and II studies done for painful diabetic peripheral neuropathy (DPN), i.m. injection of VM202 demonstrated excellent safety profile and highly effective pain relieving effects for a long period of time, with a suggestion of recovery of sensory function. The scientific basis of using HGF and the data from clinical studies will be presented.
Sunyoung Kim, D.Phil., Founder and Chief Scientific Officer, ViroMed, Professor, Seoul National University
A new concept medicine has been developed for diabetic neuropathy, based on naked plasmid DNA (VM202) engineered to express two isoforms of human hepatocyte growth factor. In Phase I and II studies done for painful diabetic peripheral neuropathy (DPN), i.m. injection of VM202 demonstrated excellent safety profile and highly effective pain relieving effects for a long period of time, with a suggestion of recovery of sensory function. The scientific basis of using HGF and the data from clinical studies will be presented.
Sunyoung Kim, D.Phil., Founder and Chief Scientific Officer, ViroMed, Professor, Seoul National University
4:15 pm Efficacy and Safety of CNTX-4975 in Subjects With Moderate to Severe Osteoarthritis Knee Pain
The presentation will review the efficacy and safety of a single intra-articular injection of CNTX-4975 over a 24 week double-blind trial. Efficacy brings a patient group with severe pain, on average, to mild pain, on average, at the 12 week primary, with statistical separation in pain at 1 week and durability out to 6 months.
Randall Stevens, MD, Chief Medical Officer, Centrexion Therapeutics
The presentation will review the efficacy and safety of a single intra-articular injection of CNTX-4975 over a 24 week double-blind trial. Efficacy brings a patient group with severe pain, on average, to mild pain, on average, at the 12 week primary, with statistical separation in pain at 1 week and durability out to 6 months.
Randall Stevens, MD, Chief Medical Officer, Centrexion Therapeutics
4:45 pm Question/Answer Session with the Afternoon's Speakers
5:10 pm Cocktail Reception
September 28, 2017
8:00 am Continental Breakfast
8:45 am The Use of Multi-molecular Profiling of Skin Biopsies to Detect Disease and Patient Specific Novel Pathologies and Therapeutic Targets for Personalized Treatment of Chronic Pain
A major challenge in pain research has been a lack of objective biomarker criteria from which to effectively diagnose many types and subtypes of chronic pain afflictions and to identify mechanistic differences that can be used for more rational strategies for personalized treatment. Punch biopsies have been introduced as an approved means of detecting alterations in the cutaneous innervation in patients with a wide variety chronic pain affliction, but their potential has been under-utilized in detecting actionable diagnostic and therapeutic targets. The presentation will document proof-of-principle examples of how multi-molecular profiling has led to the discovery of novel pathologies and therapeutic targets involving subtypes of vascular innervation and neural signaling properties of keratinocytes in human patients with fibromyalgia and diabetic neuropathy. Examples will also be shown of how this profiling can be used in reverse translation research to discover pre-clinical animal models of chronic that are more relevant to human afflictions.
Frank Rice, Ph.D., President and Chief Scientist, Integrated Tissue Dynamics
A major challenge in pain research has been a lack of objective biomarker criteria from which to effectively diagnose many types and subtypes of chronic pain afflictions and to identify mechanistic differences that can be used for more rational strategies for personalized treatment. Punch biopsies have been introduced as an approved means of detecting alterations in the cutaneous innervation in patients with a wide variety chronic pain affliction, but their potential has been under-utilized in detecting actionable diagnostic and therapeutic targets. The presentation will document proof-of-principle examples of how multi-molecular profiling has led to the discovery of novel pathologies and therapeutic targets involving subtypes of vascular innervation and neural signaling properties of keratinocytes in human patients with fibromyalgia and diabetic neuropathy. Examples will also be shown of how this profiling can be used in reverse translation research to discover pre-clinical animal models of chronic that are more relevant to human afflictions.
Frank Rice, Ph.D., President and Chief Scientist, Integrated Tissue Dynamics
9:15 am Blockade of TARP g-8-containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain
Central sensitization of glutamatergic synaptic transmission in spinal and supraspinal somatosensory pathways is postulated to underlie many of the symptoms common to chronic pain disorders. Non-selective ionotropic glutamate receptor antagonists have demonstrated efficacy in chronic pain clinical trials, but are accompanied by significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the CNS. Recently, a glutamate receptor antagonist, LY3130481, has been identified which selectively blocks TARP 8-containing AMPA receptors. Results support the hypothesis that LY3130481 may provide a novel approach to chronic pain conditions.
Eric S. Nisenbaum, Ph.D., Group Leader Neurophysiology, Neuroscience Division, Eli Lilly and Company
9:45 am Developing a U.S. Pain Drug for Europe Takes Some Translation
Taking a drug from a U.S. program and developing it for commercialization in Europe often requires some translation to the local European trial, regulatory, and payer environments to be successful. 505(b)2 programs rarely make a successful journey, yet there can be clever shortcuts to a full NDA/MAA and ways to get an adequate price. Know what is needed and prepare for success.
Allen Downs, CLP, Senior Corporate & Business Development Lead, Corporate & Business Development, Mundipharma International Limited
Taking a drug from a U.S. program and developing it for commercialization in Europe often requires some translation to the local European trial, regulatory, and payer environments to be successful. 505(b)2 programs rarely make a successful journey, yet there can be clever shortcuts to a full NDA/MAA and ways to get an adequate price. Know what is needed and prepare for success.
Allen Downs, CLP, Senior Corporate & Business Development Lead, Corporate & Business Development, Mundipharma International Limited
10:15 am Refreshment Break/Exhibit Viewing/Scientific Poster Viewing
10:40 am Time, Neural Regeneration and Opiates in the Refined NeuroDigm GEL™ Model
Use of opiates for chronic pain may have contributed to the developing opiate crisis. Most current animal models depict opiates as analgesic for neuropathic pain. Animal models are needed to reflect the opiate response of patients’ to enable treatments for neuropathic pain. The NeuroDigm GEL™ Model has markedly less opiate analgesia over time, not related to opiate tolerance. A closer look at study results of this refined tissue model reveal the possible role of neural regeneration in neuropathic pain and in opiate resistance.
Mary Hannaman, MD, President, Co-Founder, NeuroDigm
Use of opiates for chronic pain may have contributed to the developing opiate crisis. Most current animal models depict opiates as analgesic for neuropathic pain. Animal models are needed to reflect the opiate response of patients’ to enable treatments for neuropathic pain. The NeuroDigm GEL™ Model has markedly less opiate analgesia over time, not related to opiate tolerance. A closer look at study results of this refined tissue model reveal the possible role of neural regeneration in neuropathic pain and in opiate resistance.
Mary Hannaman, MD, President, Co-Founder, NeuroDigm
11:10 am Question/Answer Session with the Morning's Speakers
11:35 am Cholinergic Constraint of Sensory Nerves as a Therapeutic Target for Peripheral Neuropathy
Peripheral sensory neurons have the capacity to produce acetylcholine (ACh) and express muscarinic type 1 ACh receptors (M1R). In vitro studies using adult sensory neurons employ an autocrine cholinergic loop that constrains neurite outgrowth via the M1R and suppression of mitochondrial function. Disruption of this endogenous cholinergic constraint mechanism by M1R antagonists or receptor deletion enhanced respiration and neurite outgrowth. Systemic or topical delivery of specific, selective or non-selective M1R antagonists to rodent models of diabetic neuropathy attenuated biochemical markers of mitochondrial dysfunction and prevented and reversed assorted structural, functional and behavioral indices of degenerative peripheral neuropathy and neuropathic pain without impacting severity of diabetes. Treatment with M1R antagonists was also effective in animal models of peripheral neuropathy caused by chemotherapeutic agents or HIV-associated proteins. These studies identify a novel mechanism that regulates growth of peripheral nerves and reveal novel therapeutic targets to protect nerve from metabolic stress or promote recovery from injury in diverse peripheral neuropathies. Clinical studies are in progress.
Peripheral sensory neurons have the capacity to produce acetylcholine (ACh) and express muscarinic type 1 ACh receptors (M1R). In vitro studies using adult sensory neurons employ an autocrine cholinergic loop that constrains neurite outgrowth via the M1R and suppression of mitochondrial function. Disruption of this endogenous cholinergic constraint mechanism by M1R antagonists or receptor deletion enhanced respiration and neurite outgrowth. Systemic or topical delivery of specific, selective or non-selective M1R antagonists to rodent models of diabetic neuropathy attenuated biochemical markers of mitochondrial dysfunction and prevented and reversed assorted structural, functional and behavioral indices of degenerative peripheral neuropathy and neuropathic pain without impacting severity of diabetes. Treatment with M1R antagonists was also effective in animal models of peripheral neuropathy caused by chemotherapeutic agents or HIV-associated proteins. These studies identify a novel mechanism that regulates growth of peripheral nerves and reveal novel therapeutic targets to protect nerve from metabolic stress or promote recovery from injury in diverse peripheral neuropathies. Clinical studies are in progress.
Nigel Calcutt, Ph.D., Professor, University of California San Diego, Co-Founder, WinSanTor
12:05 pm Luncheon
1:00 pm Structure Enabled Discovery of Safer Opioid Analgesics
Despite two centuries of medicinal chemistry since the isolation of morphine from the opium poppy, the ideal opioid analgesic devoid of key liabilities like addiction and respiratory depression remains elusive. I will describe our recent efforts to understand the structural and biophysical basis of opioid receptor activation using X-ray crystallography coupled with NMR and fluorescence spectroscopy. Using these insights, we recently embarked on structure-based discovery campaigns to identify novel opioid analgesics. I will discuss the identification and optimization of a selective, Gi biased μOR agonist that elicits analgesia without inducing respiratory depression or a conditioned place preference response and will outline our current efforts to elucidate the structural basis for the remarkable efficacy of such compounds.
Aashish Manglik, MD, Ph.D., Stanford Distinguished Fellow, Department of Molecular and Cellular Physiology, Stanford University School of Medicine
Despite two centuries of medicinal chemistry since the isolation of morphine from the opium poppy, the ideal opioid analgesic devoid of key liabilities like addiction and respiratory depression remains elusive. I will describe our recent efforts to understand the structural and biophysical basis of opioid receptor activation using X-ray crystallography coupled with NMR and fluorescence spectroscopy. Using these insights, we recently embarked on structure-based discovery campaigns to identify novel opioid analgesics. I will discuss the identification and optimization of a selective, Gi biased μOR agonist that elicits analgesia without inducing respiratory depression or a conditioned place preference response and will outline our current efforts to elucidate the structural basis for the remarkable efficacy of such compounds.
Aashish Manglik, MD, Ph.D., Stanford Distinguished Fellow, Department of Molecular and Cellular Physiology, Stanford University School of Medicine
1:30 pm SV250 - A Novel Therapeutic for Neuropathic Pain
Sensitization of peripheral nociception has been implicated as a cause of hypersensitivity in chronic pain conditions. The pathophysiology of the sensitization is not well understood; however, induction of pain via increased activity of the peripherally restricted enzyme, cystathionine γ-lyase (CSE), has been demonstrated. The enzyme produces the gaso-transmitter hydrogen sulfide (H2S) and studies have demonstrated that H2S contributes to a painful sensitization in animals. Dr. Madigan’s team has demonstrated that CSE is upregulated in human pain conditions and that H2S acts as an agonist or sensitizer at several ion channels known to be involved in pain recognition. In this presentation he will focus on their development candidate, SV250, which inhibits the ability of CSE to produce H2S in vivo and is efficacious in various animal models of pain.
Sanford J. Madigan, Ph.D., Chief Executive Officer, Sova Pharmaceuticals
2:00 pm Selective Kappa Opioid Receptor (KOR) Antagonists as Potential Therapeutics for Migraine
Migraine affects > 10% of the adult population, and stress is the most common trigger. The dynorphin/KOR system is engaged under conditions of stress, and KOR antagonists are being evaluated for stress-related neurobehavioral disorders. Blackthorn Therapeutics is investigating the effects of selective and short-acting KOR antagonists as non-addictive migraine prevention therapeutics and will discuss novel findings from preclinical paradigms.
Migraine affects > 10% of the adult population, and stress is the most common trigger. The dynorphin/KOR system is engaged under conditions of stress, and KOR antagonists are being evaluated for stress-related neurobehavioral disorders. Blackthorn Therapeutics is investigating the effects of selective and short-acting KOR antagonists as non-addictive migraine prevention therapeutics and will discuss novel findings from preclinical paradigms.
Tanya Wallace, Ph.D., Head of Biology, Blackthorn Therapeutics
2:30 pm Question/Answer Session with the Afternoon's Speakers
2:55 pm End of Conference