• The primary challenge in non-opioid, non-addictive analgesic early development is demonstrating proof of concept (POC):

  • Selecting the most appropriate, targeted indication (including use of master protocols)

  • Demonstrating target engagement and identifying reliable biomarkers

  • Integrating clinical PK/PD analyses

  • Refining inclusion/exclusion criteria to enhance signal detection and reduce placebo effects

• Lilly ‘Master protocol’ to identify the most sensitive pain type for the individual in non-opioid, non-addictive analgesic in POC studies

  • Traditionally using a single pain type, for chronic neuropathic pain, classically diabetic peripheral neuropathic (DPN) pain and post-herpetic neuropathic pain (PHN)

  • The master protocol allows a single new analgesic to be tested in 3-4 different chronic pain types (including DPN, chemotherapy-induce peripheral neuropathic pain, CIPN, low back pain, typically painful lumbosacral radiculopathy, PLSR)

  • Sharing the common placebo arm

• Mechanisms or rationale merit, but not necessarily transferring to adjacent pain indications (partially observed for Vertex´s Nav1.8) 

• Nav1.8 exclusively express in the sensory nervous system, especially nociceptive afferents and dorsal root ganglia. 

• In a Phase II proof of concept studies show efficacy small fiber neuropathy, but failed in low back and leg pain (mainly chronic neuropathic pain). 

• Strong target validation that does not translate into proper trial level efficacy (Nav1.7)

• Genetic gain-of-function and lose-of-function validate Nav1.7

• Lack of effect size or dose-limited toxicity (safety issue). 

• Clinical efficacy shown but with unacceptable on-target safety liability that is discovered late either clinical (eg NGF mAbs) development

  • Optimize animal models and long-term studies to predict the on-target, ie pharmacology-related safety liability

  • Increased use of in vitro human tissue models in toxicology, ex vivo human tissues, hIPSC and human organoids. 

• Additional challenges include high requirements for safety, tolerability, and consistent efficacy

  • Focusing on clinically validated or strongly biologically supported targets

  • Designing optimized titration and dosing regimens

  • Implementing strategies to minimize placebo response – Exclude strong placebo response participates

• Evolving FDA and regulatory landscape

  • Potential acceptance of a single pivotal Phase III study in certain cases

  • Seeking analgesia could be a reward-seeking behavior. Most CNS-acting drugs, particularly non-addictive drugs will be subject to abuse potential clinical studies after Phase II completion

So in a nutshell, we are preparing efficacy trials and considering the following options: 

• POC – Pros: small, rapid, and Cons: statistical significance and power

• Master protocol. Pros – evidence-based indication selection; Cons – under power, cost, speed

• Phase II clinical trials, Pros – Classic, efficacy with power, optimal dose finding; Cons – cost, and speed

• Adaptive Phase II/III protocol. Pros: Rapid progression from Phase II to Phase III, allowing Phase II patients to continue into the Phase III trial. Cons: Regulatory acceptance may be challenging, and the design carries higher risk and requires greater upfront capital.