September 27, 2017
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
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
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.
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
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
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
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.
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 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
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
September 28, 2017
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
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
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
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.
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
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.