Abbott s TRPV1 Antagonist Program

Transcription

1 Abbott s TRPV1 Antagonist Program Connie R. Faltynek, Ph.D. Sr. Director, Neuroscience and Pain Discovery American Pain Society Annual Meeting Basic Science Dinner Symposium May 9, 2008

2 Early History of Analgesics Major Modern Analgesics have their Origin in Plant Extracts Two major classes of analgesics in current clinical use: opioids, such as morphine non-steroidal anti-inflammatory agents, such as aspirin Both have been used to treat pain for centuries, initially as plant extracts, and more recently as synthesized pure compounds. morphine from poppies aspirin from willow bark 2 GDS_

3 Overview of TRPV1 (VR1) Member of the transient receptor potential (TRP) superfamily First described as the receptor for capsaicin, the hot ingredient in chili peppers Activated during an inflammatory response and contributes to pain associated with inflammation Detects painful stimuli in multiple pain states preclinically TRPV1 antagonists efficacious in several preclinical pain models Data from TRPV1 knockout mice support the role for TRPV1 in pain transmission 3 GDS_

4 TRPV1: Targeting Key Points (Spinal, Supraspinal, Peripheral) in Pain Transmission TRPV1 TRPV1 TRPV1 4 GDS_

5 TRPV1: Polymodal Integrator of Multiple Pain Stimuli NGF GDNF PGE 2 Bradykinin Activation NADA Acid Heat Anandamide Na +, Ca +2 CGRP Substance P Pain Neurotransmitters TRPV1 Sensitization Phosphorylation of TRPV1 Na +, Ca +2 Action Potential Firing 5 GDS_

6 TRPV1 Receptor Antagonist: ABT-102 Positive attributes of ABT-102 Potent and selective for TRPV1 Block activation of both recombinant human and native rat TRPV1 Block activation by multiple stimuli Good CNS penetration Potent and highly efficacious in animal models of osteoarthritis pain, inflammatory pain, and bone cancer pain Chronic dosing with low doses increases efficacy Greater therapeutic index than morphine in preclinical studies 6 GDS_

7 ABT-102: In Vitro Activity and Potency ABT-102 blocks: activation of both human and rat TRPV1 activation by multiple stimuli, including capsaicin, lipids, acidic ph and heat calcium flux, inward current, and release of major pain neurotransmitter (CGRP) Receptor Assay Stimulus ABT-102 IC 50 Recombinant human TRPV1 Ca 2+ flux Ca 2+ flux Capsaicin NADA (natural lipid activator) 4 nm 2 nm Ca 2+ flux Acidic ph 1 nm Native rat TRPV1 Ca 2+ flux Inward current Capsaicin Capsaicin NT 7 nm NT: Not tested 7 GDS_

8 Efficacy and Potency in Model of OA Pain ABT-102 exhibits full efficacy in the OA pain model, similarly to celecoxib and tramadol. Side effects limit efficacy of morphine to 40% in this model. CFmax/kg Body Weight * ** ** ** Naive (N) Vehicle (V) ABT N V A ABT-102 (µmol/kg p.o.) ABT-102 also potent and fully efficacious in carrageenan model of inflammatory pain, similarly to celecoxib and morphine. 8 GDS_

9 ABT-102 is Efficacious in Spontaneous and Evoked Bone Cancer Pain ABT-102 Spontaneous Pain Movement-Evoked Pain Palpation-Evoked Pain Flinching Guarding Open Field Rotorod Flinching Guarding Acute 30 µmol/kg 65% # 70% 85% 95% 74% 65% # % effect NS: not significant Spontaneous pain is a major unmet medical need in metastatic bone cancer. Current agents are ineffective. ABT-102 is effective on both spontaneous and evoked pain. Chronic dosing increases efficacy in bone cancer pain model without appreciable increase in plasma concentrations. Collaboration with Dr. Patrick Mantyh 9 GDS_

10 Preclinical Side Effect Analysis of ABT-102 Major preclinical side effect is self-limiting elevation in body temperature. ABT-102 lacks the opiate side effects of sedation and constipation. ABT-102 exhibits no significant cardiovascular or CNS side effects up to 30 times the efficacious plasma level. 10 GDS_

11 Summary TRPV1 is a promising new molecular target for novel agents to manage pain. Preclinical studies support robust efficacy in multiple pain models with limited side effects. Major preclinical side effect is self-limiting elevation in body temperature with most compounds. Multiple companies have advanced TRPV1 compounds into the clinic. GSK reported efficacy in experimental pain model. Neurogen/Merck reported positive data in dental pain. Data from clinical trials with TRPV1 antagonists in chronic pain such as osteoarthritis is eagerly awaited. 11 GDS_

12 References Identification of (R)-1-(5-tert-Butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea (ABT-102) as a Potent TRPV1 Antagonist for Pain Management (2008) Gomtsyan A, Bayburt EK, Schmidt RG, Surowy CS, Honore P, Marsh KC, Hannick SM, McDonald HA, Wetter JM, Sullivan JP, Jarvis MF, Faltynek CR, Lee C-H J. Med. Chem.51: ABT-102 ((R)-1-(5-tert-Butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea) Blocks Polymodal Activation of TRPV1 Receptors in Vitro and Heat-Evoked Firing of Spinal Dorsal Horn Neurons in Vivo. Surowy CS, Neelands TR, Bianchi BR, McGaraughty S, El-Kouhen R, Han P, Chu K, McDonald HA, Vos M, Niforatos W, Bayburt EK, Lee C-H, Gomtsyan A, Honore P, Sullivan JP, Jarvis MF, Faltynek CR (submitted for publication) Repeated Dosing of ABT-102, a Potent and Selective TRPV1 Antagonist, Enhances TRPV1-Mediated Analgesic Activity in Rodents, but Attenuates Antagonist- Induced Hyperthermia. Honore P, Chandran P, Hernandez G, Gauvin DM, Mikusa JP, Zhong C, Ghilardi JR, Sevcik MA, Fryer RM, Segreti JA, Banfor PN, Marsh K, Neelands T, Bayburt E, Daanen JF, Gomtsyan A, Lee C-H, Kort ME, Reilly RM, Surowy CS, Kym PR, Mantyh PW, Sullivan JP, Jarvis MF, Faltynek CR (submitted for publication) 12 GDS_