Preclinical target validation for non-addictive therapeutics development for pain

ABSTRACT

Introduction

The Helping to End Addiction Long-term^SM Initiative supports a wide range of programs to develop new or improved prevention and opioid addiction treatment strategies. An essential component of this effort is to accelerate development of non-opioid pain therapeutics. In all fields of medicine, therapeutics development is an arduous process and late-stage translational efforts such as clinical trials to validate targets are particularly complex and costly. While there are plentiful novel targets for pain treatment, successful clinical validation is rare. It is therefore crucial to develop processes whereby therapeutic targets can be reasonably ‘de-risked’ prior to substantial late-stage validation efforts. Such rigorous validation of novel therapeutic targets in the preclinical space will give potential private sector partners the confidence to pursue clinical validation of promising therapeutic concepts and compounds.

Areas covered

In 2020, the National Institutes of Health (NIH) held the Target Validation for Non-Addictive Therapeutics Development for Pain workshop to gather insights from key opinion leaders in academia, industry, and venture-financing.

Expert opinion

The result was a roadmap for pain target validation focusing on three modalities: 1) human evidence; 2) assay development in vitro; 3) assay development in vivo.

KEYWORDS:

• Target validation
• pain therapeutics
• human evidence
• in vitro assays
• in vivo assays

Article highlights

• Accelerating development of non-opioid treatments for pain is an essential component of the HEAL Initiative^SM

• Validating targets is proposed in three steps: Human evidence and in vitro and in vivo models

• Demonstrating proof of target engagement and proof of mechanism is of great priority for investment in discovery efforts

• Building confidence for initial validation starts from human condition and should include biomarkers

• Collecting rigorous data and statistically assessed experimental design are essential at every step of target validation

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank everyone who helped organize the Target Validation for Non-Addictive Therapeutics Development for Pain workshop. Special thanks go to Maria Charlier at the National Institute for Neurological Disorders and Stroke. The authors also express their gratitude to the following people who served as discussants at the workshop: Ralf Baron, Thomas Christoph, Ci Chu, Franziska Denk, Luda Diatchenko, Greg Dussor, Marc Ferrer, Rachel Groth, Martin Koltzenburg, Owen McManus, Paul Miller, Frank Porreca, Theodore Price, Andrew Rice, Max Salick, Jordi Serra, Myung Kyun Shin, Cheryl Stucky, Camilla Svensson, Mark Urban, Mark Varney, Clifford Woolf.

Declaration of interest

NT Dhruv, J Driscoll, M Gill, S Iyegar, WJ Koroshetz, P Laeng, DC Lo, ML Oshinsky, GS Sittampalam, SA Woller, and AP Tamiz are employees of the National Institutes of Health (NIH). This report does not represent the official view of the NIH or any part of the US Federal Government. No official support or endorsement of this article by the NIH is intended or should be inferred.

R Hargreaves is an employee of Bristol Myers Squibb.

K Akinsanya is an employee of Schrödinger.

SK Ajit is an employee of Drexel University College of Medicine.

P Farina is an employee of Canaan Partners.

N Gavva is an employee of Takeda Pharmaceuticals.

A Houghton is an employee of Merck & Co Inc.

S Iyengar is a past employee and shareholder of Eli Lilly and Company.

C Jones is an employee of Vanderbilt University.

A Kavelaars is a past employee of MD Anderson Center.

A Kaykas is an employee of Insitro.

JM Laird is an employee and shareholder of Eli Lilly and Company.

J Luthman is an employee and shareholder of Lundbeck.

G Munro is an employee of Hoba Therapeutics.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.