Grünenthal Moves NOP Agonist into Phase II After Positive Phase I Results

Grünenthal has completed a Phase I clinical trial of its proprietary nociceptin receptor (NOP) agonist, marking an important step in the development of a potential first-in-class non-opioid therapy for acute and chronic pain. The investigational compound demonstrated a favorable safety and tolerability profile in 113 healthy volunteers and is scheduled to enter a Phase II clinical trial later this year.

The upcoming Phase II study will enroll approximately 400 patients in the United States undergoing bunionectomy, a widely accepted postoperative pain model used by regulatory authorities to evaluate analgesic efficacy and safety. Trial results are expected during the second half of 2027.

Novel Non-Opioid Mechanism Targets the NOP Receptor

Unlike conventional opioid analgesics, Grünenthal’s investigational therapy selectively activates the nociceptin/orphanin FQ peptide (NOP) receptor, a G protein-coupled receptor involved in pain modulation. Although structurally related to classical opioid receptors, the NOP receptor has minimal affinity for opioid peptides or morphine-like compounds, offering the potential to deliver effective analgesia through a distinct biological pathway.

Preclinical research has suggested that selective NOP agonists can provide potent pain relief without the abuse liability commonly associated with opioid therapies. If confirmed in later-stage studies, the compound could represent a new therapeutic class for patients requiring effective pain management while reducing risks linked to traditional opioids.

The need for safer analgesics remains substantial as healthcare systems continue to balance effective pain control with concerns surrounding opioid dependence, respiratory depression, constipation, and sedation.

Phase I Trial Supports Advancement into Mid-Stage Development

The completed Phase I trial evaluated the safety and tolerability of the investigational NOP agonist in 113 healthy participants. The study found the compound to be safe and well tolerated across evaluated dose levels, with no dose-dependent pattern of adverse events.

Investigators reported no opioid-like adverse events, including somnolence, constipation, or respiratory depression. The study also identified no findings suggesting abuse liability, reinforcing the therapeutic rationale for advancing the candidate into patient studies.

The Phase II trial will assess the compound in patients undergoing bunionectomy, a standardized surgical pain model frequently used to establish proof of concept for acute pain therapies before expanding into broader clinical indications.

Company Highlights Clinical Potential

Commenting on the program’s progress, Chief Scientific Officer Dr. Uli Brödl said the successful Phase I study strengthens confidence in advancing the compound into patient trials. He noted that selective activation of the nociceptin receptor offers an opportunity to introduce a new mechanism for pain treatment while providing patients with an alternative to conventional opioid therapies.

Regulatory Path

Grünenthal expects to initiate the Phase II bunionectomy trial later in 2026. The study will provide the first assessment of the compound’s analgesic efficacy in patients and will help determine its potential for broader development in both acute and chronic pain indications.

Positive Phase II findings could position the investigational NOP agonist as one of the leading first-in-class non-opioid analgesic candidates advancing through clinical development, addressing a longstanding need for effective pain therapies with an improved safety profile.

Reference

Completion of NOP Phase I trial | Grünenthal