2013 Agenda

THURSDAY, NOVEMBER 7, 2013

7:45 Registration/Continental Breakfast

8:10 Chairperson's Opening Remarks

William K. Schmidt, Ph.D., President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical & Regulatory, Api Genesis, LLC, VP Clinical Development, EicOsis, LLC

8:20 New Approaches for Preclinical Assessment of Analgesic Efficacy and Side Effects
The treatment of acute and chronic pain continues to present an enormous challenge to physicians and other healthcare professionals. In many cases, current pharmacotherapies offer incomplete efficacy and/or produce self limiting side effects. Development of new (novel) analgesics has been limited and disappointing from the patient, practitioner and pharmaceutical perspectives. Assessment of analgesic efficacy in preclinical animal models is one area that needed careful reevaluation and change to help address the overall lack of progress. This talk will present some of the latest approaches in inducing nociceptive (pain) states in animals, measuring the consequences of the pain on behavior and other relevant endpoints, and assessing analgesic candidates as part of the drug development process. The presentation will include new methods for measuring spontaneous and affective components of pain, as well as pain suppressed behaviors.

Edward Bilsky, Ph.D., Vice President for Research and Scholarship; Professor of Pharmacology, Director of the Center for Excellence in the Neurosciences, University of New England

8:55 Failed Analgesic Studies: 10 Factors Diminishing Translation
Pain is the #1 reason patients seek a physician.  Chronic pain is becoming increasing recognized as a disease, and accounts for substantial suffering and disability world-wide. While there have been numerous attempts by the industry to development novel pain therapeutics, why is it that there is little to show for regarding treatments that improve efficacy, side-effects or positively impact quality of life (QoL)? This presentation highlights 10 challenges faced by stakeholders, and actions that need to be collectively taken to advance our ability to make a paradigm shift in delivering new pain relievers.

Stephen Arneric, Ph.D., Senior Research Fellow, Eli Lilly & Co.

9:30 The G Protein Biased Mu-opioid Ligand TRV130: A Developmental-stage Analgesic with an Improved Tolerability Profile
TRV130 is a potent, selective G protein biased ligand at the mu-opioid receptor. The compound is active in several preclinical models of pain with an improved tolerability profile compared to morphine. TRV130 was dosed intravenously to normal volunteers and has dose-proportional levels of exposure. Subjects dosed with TRV130, experienced a dose dependent increase in pupil constriction, a classical effect of mu opioid receptor activation. The compound was well tolerated and plans are now being made to evaluate the efficacy and tolerability of TRV130 compared to morphine in an experimental medicine study in healthy volunteers.

Jonathan Violin, Ph.D., Director of Biology and Co-Founder, Trevena, Inc.

10:05 Refreshment Break/Poster Viewing

10:35 Pain Models and Methods to Reduce Experimental Error in Analgesic Clinical Trials
Falsely negative analgesic clinical trials are not only a squandered societal burden, but also are a waste of precious time and resources. Pharmaceutical companies spend large amounts of time perfecting their protocol and selecting quality sites so that the efficacy of their drug can be statistically demonstrated. However, an equal amount of effort is rarely placed on other aspects of clinical trials that may lead to optimizing their success such as patient education and analgesic model manipulations. This talk will discuss techniques for site education, subject placebo response training, and other mechanisms to mitigate variability in analgesic clinical trials.

Neil Singla, MD, Founder & Chief Scientific Officer, Lotus Clinical Research, LLC

11:10 Diode Laser Selective Stimulation as a Potential Biomarker for Preclinical and Clinical Analgesic Development
Neuropathic pain (NP) is a common clinical problem that poses a considerable challenge because it is difficult to diagnose and response to current treatments can be inconsistent. Radically significant improvement could be achieved if the underlying mechanisms in individual patients could be assessed and documented by specifically studying the functional status of C and A-delta fibers, the nerve fibers involved in pain mechanisms. Diode laser selective stimulation (DLss) achieves this objective.

Several distinct classes of medication have demonstrated efficacy in neuropathic pain but thus far clinicians do not possess tools to select treatments for individual patients and are often forced into a “trial and error” approach. A clinical or laboratory tool that can predict response to a specific treatment with a distinct mechanism of action would represent a major advance in the treatment of neuropathic pain. One such advance would be the ability to identify differential involvement of C and A-delta fibers, as there is recognized evidence that specific interventions affect fiber types differently.
 
Dr. Nemenov will discuss application of DLss as a potential biomarker for preclinical and clinical analgesic development based on the ability of DLss to specifically activate TRPV1 positive C- or A-delta fibers in healthy subjects and patients with NP. The discussion will include demonstration of safe and differential activation of C or A-delta fibers in single unit recordings in rodents, and plantar and orofacial animal models. It will also include demonstrations of quantitative sensory testing (QST), laser evoked potentials (LEP), and fMRI in healthy human volunteers. Additionally, he will present new data on the differential involvement of C and A-delta fibers in patients with diabetic NP. Experimental data showing lacking responses to noxious stimulation after depletion of TRPV1 positive A delta and C fibers will be discussed.

Mikhail “Mike” Nemenov, Ph.D., Founder, President and Chief Scientist, Lasmed, LLC, Consulting Professor, Pain Research Center, Anesthesia Department, Stanford University

11:45 Assay Sensitivity in Pain Clinical Trials
Over the last few decades, there have been numerous failed clinical studies with analgesic drugs otherwise known to be effective in the treatment of pain. This session has been designed to provide attendees with an overview of the issues potentially leading to the trend of negative clinical trials in the CNS-pain therapeutic area. Sponsor-level, site-level, subject-level insights will be discussed. The presentation will provide attendees with an understanding of the meaning of assay sensitivity in the context of conducting clinical trials, an understanding of the determinants of poor assay sensitivity, thoughts on plausible means of mitigating this trend to facilitate improved assay sensitivity – positive clinical trial outcome if in fact the drug under study is effective for the condition being studied, and the operational components needed to be considered/employed to support assay sensitivity.

Ernest Kopecky, Ph.D., MBA, VP, Clinical Development, Head, Neuroscience TA, Collegium Pharmaceutical, Research Fellow, Division of Clinical Pharmacology/Toxicology, Hospital for Sick Children

12:20 Luncheon

1:30 Designing Clinical Development Programs with the Goal of Commercialization and Reimbursement in Mind
In this dual presentation, Dr. Katz and Dr. Hankin will focus on what payers need, and how these data generation goals can be incorporated into clinical development programs.

Nathaniel Katz, MD, President, Analgesic Solutions

Cheryl Hankin, Ph.D., President and Chief Scientific Officer, BioMedEcon, LLC

2:40 New Understanding of Migraine Leads to New Opportunities for Therapy
Migraine is one of the most prevalent and disabling medical disorders worldwide. The understanding of its basic mechanisms is evolving rapidly, and with this evolution comes new opportunities for therapy based on  a variety of novel approaches. I will discuss current concepts in the basic and clinical science of migraine, and how those concepts are leading to new nutritional, pharmaceutical, and neuromodulatory therapies.

Andrew Charles, MD, Professor, Meyer and Renee Luskin Chair in Migraine and Headache Studies, Director, Headache Research and Treatment Program, Department of Neurology, UCLA School of Medicine

3:15 Refreshment Break/Poster Viewing

3:45 KP201: A Novel Opioid Pain Therapy with Reduced Abuse Potential and Improved Safety
Although a small number of pain drugs with abuse deterrent features has been introduced in recent years, the common method to reduce the abuse potential of opioids thus far has been through special formulations. This approach, however, has drawbacks and offers only a partial answer to alleviate the problem. 

The inherent physicochemical and pharmacological properties of KP201, a prodrug of hydrocodone, provide a differential and superior approach to address narcotic abuse. Preclinical studies suggest that KP201 exhibits unique abuse deterrent properties by significantly limiting the narcotic exposure upon intranasal administration and being resistant to chemical and physical extraction methods. The poor solubility of KP201 in aqueous media also makes it less suitable for intravenous injection. In this presentation, Dr. Mickle will cover the following:

• Description of the chemical structure and pharmacology of KP201
• Clinical data regarding the pharmacokinetic properties of KP201
• Preclinical data regarding abuse-deterrent properties of KP201
• Preclinical data regarding the prevention of opioid-induced constipation with KP201
• The first disclosure of the tamper resistant properties of KP201

Travis Mickle, Ph.D., President, CEO, KemPharm, Inc.

4:55 TRPV1 Agonists and Allosteric Modulators for Pain Control
The TRPV1 receptor-ion channel has been the subject of studies into pain mechanisms and pharmacological development ever since the algesic actions of capsaicin were initiated. Once TRPV1 was cloned in 1997, it instantaneously became a major molecular target for analgesic development, mainly of antagonists at the capsaicin orthosteric binding site. A role for TRPV1 agonists as an analgesic manipulation has also been articulated and developed. Early efforts concentrated on capsaicin. While capsaicin is an excellent agonist higher potency agonists like resiniferatoxin (RTX) appear to have a mechanistic advantage. This talk will discuss (a) RTX and its actions as an agonist and analgesic and (b) an allied approach, which is the use of positive allosteric modulators of TRPV1 to produce the same neuronal deactivation as RTX but in an activity dependent fashion.

Michael Iadarola, Ph.D., Senior Research Scientist, Anesthesiology Research Laboratories, Department of Perioperative Medicine, Clinical Center, National Institutes of Health

5:30 Extended Question & Answer Session/Cocktail Reception

6:15 End of Day's Sessions


FRIDAY, NOVEMBER 8, 2013

7:45 Continental Breakfast

8:15 Chairperson's Opening Remarks

William K. Schmidt, Ph.D., President, NorthStar Consulting, LLC, VP Clinical & Regulatory, Arcion Therapeutics, VP Clinical & Regulatory, Api Genesis, LLC, VP Clinical Development, EicOsis, LLC

8:20 Microelectrode Arrays for Pain Research and Drug Development
Large amounts of information on the cellular and molecular mechanisms involved in sensory processing in the peripheral nervous system were gained in vitro using neurons isolated from dorsal root ganglia (DRG). Electrophysiological recordings from cultured DRG neurons were mainly obtained by the use of patch-clamp, an approach offering a level of throughput often incompatible with the objectives of the pharmaceutical industry. Higher throughput electrophysiological approaches are possible by using automated patch-clamp, but its current design limits its use to cell lines or cells in suspension.

To fill this gap Dr. Cesare and his team have implemented the use of high-density microelectrode arrays (MEA) as a new tool to investigate modulation of sensory neuron excitability in vitro. He will show how this approach, allowing to record extracellularly from thousands of adherent DRG neurons per day, can accelerate the process of target identification and lead optimization in preclinical pain research. He will also discuss some of the unique features of this approach, such as the possibility it offers to perform continuous or repeated non-invasive measurements, as this may be of great importance for the evaluation of substances involved in inflammation. Finally, he will demonstrate the possibility to combine MEA and microfluidics for developing novel assays to investigate synaptic activity in nociceptive circuits.

Paolo Cesare, Ph.D., Dept. of Electrophysiology, Natural and Medical Sciences Institute at the University of Tübingen, NMI

8:55 Soluble Epoxide Hydrolase Inhibitors Reduce Neuropathic Pain in Diabetic Models and in Companion Animals
Epoxides of long chain omega – 6 and omega – 3 fatty acids are anti – hypertensive, anti – inflammatory and reduce both inflammatory and neuropathic pain. These natural compounds abbreviated EETs and EDPs are rapidly degraded by the soluble epoxide hydrolase in multiple species. Dr. Hammock and his team have developed several classes of transition state inhibitors of the sEH with Ki’s as low as 20 pM and with good oral PK – ADME. The compounds have been found to reduce inflammatory and neuropathic pain using a variety of rodent models including choice placement assays with diabetes driven enhanced pain perception. As expected there is a correlation among blood levels of the inhibitors, levels of EETs and EDPs in the blood and pain reduction indicating target engagement. The compounds also synergize dramatically with some NSAIDs extending their utility to treatment of neuropathic pain. The compounds have been found effective in canine and feline patients. Of note is success in treating severe equine laminitis. This is a usually fatal condition involving intractable neuropathic pain and morbid hypertension.

Bruce Hammock, Ph.D., Distinguished Professor, Department of Entomology & UCD Comprehensive Cancer Center, PI, NIH Biotechnology Training Program, UC Davis

9:30 Monoclonal Anti-lysophosphatidic Acid Antibodies for the Treatment of Neuropathic Pain
The bioactive lipid, lysophosphatidic acid (LPA), is a key extracellular signaling molecule that has a central role in the development of neuropathic pain (NPP) and neurotrauma. Through the action of cognate GPCRs and TRPV1 calcium channels, LPA is responsible for long-lasting mechanical allodynia and thermal hyperalgesia as well as demyelination and upregulation of pain-related protein expression patterns in a variety of animal models. Evidence supports the hypothesis that antagonism of the LPA signaling pathways would benefit the treatment of neuropathic pain. Lpath has developed the first monoclonal antibody targeting LPA (anti-LPA mAb). Importantly, systemic administration of the anti-LPA mAb has demonstrated efficacy in ameliorating pain behaviors in rodent models of diabetic NPP, chemotherapy pain, arthritis pain, and sciatic nerve injury induced-NPP. In the STZ model of diabetic NPP, Lpath has demonstrated that decreasing the levels of LPA with our anti-LPA antibody is sufficient to ameliorate the tactile allodynia. Similar long-lasting, durable mitigation of mechanical allodynia was seen in the CAIA model of arthritic pain. Their data suggests that anti-LPA mAb treatment in the acute setting may serve as a novel therapeutic strategy in the treatment of a wide variety of neuropathic pain responses.

Roger Sabbadini, Ph.D., Vice President & Founder, Lpath, Inc.

10:05 Refreshment Break/Poster Viewing

10:35 Potent Opioid Analgesics Lacking Traditional Side-effects
The opioid receptor, a member of the G-protein coupled receptor family, undergoes significant alternative splicing to generate a variety of receptors from the same gene.  Traditional opioid analgesics act through full length, seven transmembrane domain (7TM) receptors.  However, recent work has also identified another set of truncated variants containing only six transmembrane domains (6TM) under the control of a different promoter associated with exon 11.  Targeting these exon 11-associated 6TM splice variants yields drugs with high potency, as much as 50-fold greater than morphine, that lack respiratory depression, physical dependence, reward behavior and have minimal constipation. 

Gavril Pasternak, MD, Ph.D., Anne Burnett Tandy Chair in Neurology, Laboratory Head, Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center

11:10 New Frontiers in Migraine Therapy – LBR-101 and Monoclonal Antibodies Anti CGRP
In this presentation, Dr. Bigal will discuss the following:

• Migraine: the scope of the health problem
• Relevance of CGRP in migraine
• Small molecules vs antibodies in migraine therapy
• What is the unmet need that antibodies can address in migraine
• LBR-101 development status and clinical data to date

Marcelo E. Bigal, MD, Ph.D., Chief Medical Officer, Labrys Biologics, Inc.

11:45 Targeting Glial Activation for Treating Chronic Pain and Improving Opioid Efficacy: The Promise of XT-101
Research spanning 20 years into the mechanisms of neuropathic pain has defined a new therapeutic target: glial cell activation. In neuropathic pain, glial cells become activated, causing them to release substances that pathologically amplify pain. This new understanding has provided an explanation for the clinical experience that opioids  often have  pain-promoting side effects. Opioid administration causes glial activation, which paradoxically opposes the pain-modulating effect of opioids.

Reversal of the pro-inflammatory activation of glia would thus not only reverse neuropathic pain in general but should also enhance the clinical efficacy of morphine and other opioids.
 
Xalud Therapeutics is developing XT-101, a single administration therapeutic designed to reverse glial activation. XT-101 is an intrathecal therapy that drives the production of the anti-inflammatory cytokine interleukin-10 (IL-10) at the spinal cord. This presentation will describe evidence demonstrating a critical role of glial activation in creating and maintaining pathological pain states, such as neuropathic pain and data to support the potential of XT-101 in reversing this state.

Linda Watkins, Ph.D., Distinguished Professor, Department of Psychology & Neuroscience and Center for Neuroscience, University of Colorado, Co-Chair, Advisory Board, Xalud Therapeutics, Inc.

12:20 Luncheon

1:25 Targeting Voltage-gated Sodium Channels Involved in Pain: Recent Developments
Voltage-gated sodium channels are key determinants regulating action potential generation and propagation in nociceptive neurons. Changes in sodium channel function can have profound effects on neuronal excitability and pain signaling. Multiple sodium channels have been implicated as playing important roles in pain pathways, including Nav1.7, Nav1.8 and Nav1.9. However, recent evidence suggests that unusual resurgent sodium currents, as well as Nav1.6 may be important in certain pain syndromes. These recent findings and strategies for targeting resurgent sodium currents, beta subunits and sodium channel voltage-sensors will be discussed.

Ted Cummins, Ph.D., Associate Professor and Interim Chair, Department of Pharmacology and Toxicology, Indiana University School of Medicine

2:00 Recognition of the Bladder as a Pelvic Pain Generator and New Medical Therapies that Successfully Manage it
Dr. Parsons will discuss the mechanism  that causes the bladder to generate pain, how common is is (up to one in 4 women), to recognize and diagnose the bladder as the source of pelvic pain and new successful methods to manage it including intravesical alkalinized lidocaine-heparin (URG101) for the symptoms of pelvic pain and urgency of bladder origin.

C. Lowell Parsons, MD, Professor of Surgery/Urology, School of Medicine, UC San Diego

2:35 Extended Question & Answer Session

3:30 End of Conference