First Clinical Translation of the Anti-Nociceptive/Anti-Hyperalgesic Efficacy of a T-Type Calcium Channel Modulator (Z944) – Using Laser Evoked Potentials and VAS in UV-B and Capsaicin Irritated Skin in Healthy Humans

K. D. Schaffler Germany,Head, HPR-Human Pharmacodynamic Res., Munich; M. S. Lee, Res. & Translational Med., Zalicus Pharmaceuticals Ltd., Cambridge, MA, USA; M. Versavel, Zalicus Pharmaceuticals

The IASP congress took place October 6 – 11, 2014 – in Buenos Aires.

Please download HPR poster here.

Positive results of Z944 Phase 1B Clinical Study in Pain

Efficacy Signals in Inflammatory and Neuropathic Pain Observed

Second U.S. Patent Issues for Z944 Providing Exclusivity to 2029

Munich, Germany – June 17th, 2014 – HPR Dr. Schaffler GmbH, a contract research organization, which conducts Phase 1 clinical trials in the field of CNS pain research, announced positive results of a Phase 1b clinical study for its customer Zalicus (Z944). Research object is a novel oral T-type calcium channel modulator in development for the treatment of pain. The Phase 1b study is an experimental clinical model utilizing Laser-Evoked-Potentials (LEP) to provide both objective and subjective assessments of the activity of Z944 in induced pain states. Based on these results, Zalicus is planning to advance a modified-release formulation of Z944 into Phase 2 clinical development in an appropriate pain indication in 2014. In addition, a second United States patent for Z944 (U.S. Patent number 8,569,344) covering methods of treating pain was issued on October 29, 2013, providing additional patent protection for Z944 in the United States until at least 2029.

“This is the first T-type calcium channel modulator to demonstrate clinical translation in pain, and these results are indicative of Z944’s potential activity in modulating pain signaling. We look forward to further evaluating a modified release formulation of Z944 in a relevant clinical pain syndrome in 2014,” commented Mark H.N. Corrigan, MD, President and CEO of Zalicus.

This exploratory, double-blind placebo-controlled, randomized cross-over, Phase 1b clinical study enrolled 16 healthy volunteers and was conducted in a single center in Germany.
The primary objective of the study was to compare the analgesic/anti-hyperalgesic properties of three different single doses of Z944 in a model of inflammatory pain and in a model of chronic neuropathic pain as compared with placebo.
Highlights of the results of the Z944 Phase 1b LEP study results include:
Statistically significant and meaningful reductions at each of the three doses compared to placebo of overall peak-to-peak (PtP) amplitude of LEPs in models of both inflammatory (p≤0.0002) and neuropathic (p<0.05) pain. Consistent trends in reduction of subjective pain scores compared to placebo using a visual analog scale in both pain models. Meaningful trends in effects based on dose and concentration, providing important insights into the potential therapeutic window and effective plasma concentrations of Z944. Z944 was generally well tolerated with dose dependent CNS side effects and no serious adverse events.
In this study, hypersensitivity to laser thermal stimulation was induced by UV light exposure as a model of inflammatory pain and by topical capsaicin as a model of neuropathic pain. Electrical voltage fluctuations evoked by laser thermal stimulation were quantified with vertex-Electroencephalography(EEG) in addition to a subject-reported pain score. Many currently approved and emerging pain drugs have been evaluated using the LEP model, providing the ability to benchmark the efficacy of Z944 against other therapies.

About Z944 and T-type Calcium Channels

Z944 is a novel, oral, state-dependent, selective T-type calcium channel modulator that has demonstrated efficacy in multiple preclinical inflammatory pain models and in a Phase 1b experimental model of pain. T-type calcium channels have been recognized as key targets for therapeutic intervention in a broad range of cell functions and have been implicated in pain signaling. Zalicus is planning to advance a modified release formulation of Z944 through further clinical development.

Please download press release for clinical study on Z944.

Abstract

AIMS: Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG Peak-to-Peak (PtP) amplitude were used to determine acute antinociceptive/ antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared to active controls and placebo in normal and UV(B)-inflamed skin of healthy humans.
METHODS: This was a randomized, placebo- and active-controlled, double-blind, intra-individual-crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg, and placebo. Painful stimuli were induced by CO(2)-laser on normal and UV(B)-inflamed skin. LEPs and visual analog scale (VAS-Pain) ratings were taken at baseline and hourly up to 8 hours post-dose from both skin types.
RESULTS: Compared to placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UV(B)-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8-hour period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8-hour period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared to placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4, and 9.4 ng/mL for the 0.5, 2, and 6 mg doses, respectively. There were no clinically significant safety findings.
CONCLUSIONS: TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation.

Link to full paper here.

Eef Hoeben, Johan W. Smit, David Upmalis, Sarah Rusch, Klaus Schaffler, Peter Reitmeir, Bernhard Mangold    http://dx.doi.org/10.1016/j.pain.2012.04.018

in PAIN 153 (2012) 1648–1656 (full paper here:)

Abstract: The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10 mg/morphine 20 mg, 3.00 and 1.63 respectively for oxycodone 15 mg/morphine 30 mg, and 1.12 and 1.25 respectively for oxycodone 20 mg/morphine 40 mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40 mg) and of oxycodone at all doses (10, 15, 20 mg) was considered to be clinically relevant based on a difference from placebo of >2.5 micV.
For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points <.001 at all doses). Hyperalgesia developed over time vs baseline due to acute exposure to UVB irradiation and to topical/occlusive 1% capsaicin solution. For both compounds, the principal onset of analgesic/antihyperalgesic drug effects was around 0.5 hours with an average peak at about 1 to 2 hours and the effect lasting for more than 3 hours (morphine 20 and 30 mg) or 6 hours (morphine 40 mg and oxycodone all doses).
In conclusion, the study demonstrated a solid outcome of a mixed objective/subjective human experimental algesimetric model to approach dose-response relationships and analgesic/anti-hyperalgesic effects of 2 opioids.

https://www.youtube.com/watch?feature=player_embedded&v=XxqTiHlgJAE

We (Andrea Edginton and Klaus Schaffler) had a poster presentation – (in cooperation between School of Pharmacy, University of Waterloo, Ontario, Canada and HPR Munich) at the 2012 ASCPT/ American Society for Clinical Pharmacology and Therapeutics Annual Meeting, March 12-17, 2012, National Harbor, Maryland, US with the following title (please contact us, for sending a poster PDF-file – if convenient – or have a look here Final Edginton Pain ASCPT 2012 (5)):

Title: “PAIN PERCEPTION AND PROCESSING IN A MEDICATED STATE:
A PILOT STUDY IN AN ELDERLY COHORT”

(regarding anti-nociceptive properties of APAP on normal and UVB skin in elderlies)