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Our Pipeline

Developing a first in class, once daily breakthrough treatment for cough hypersensitivity disorders.

Orvepitant: A Targeted Approach to Chronic Cough in IPF

NeRRe Therapeutics is advancing orvepitant, a highly selective and potent neurokinin-1 (NK1) receptor antagonist, as a first-in-class treatment for chronic cough associated with idiopathic pulmonary fibrosis (IPF)—a rare and terminal lung disease with no approved therapies for its most burdensome symptom: persistent, treatment-resistant cough.

Clinical Development

Orvepitant is currently in Phase 2 clinical development for chronic cough in IPF. The ongoing study is a randomized, double-blind, placebo-controlled, two-period cross-over trial (ClinicalTrials.gov ID: NCT05185089).

Our earlier Phase 2b VOLCANO-2 trial in refractory or unexplained chronic cough (RUCC) provided strong clinical proof of concept. Patients receiving orvepitant 30 mg once daily reported statistically significant and clinically meaningful improvements in patient-reported outcomes related to cough burden.

These results support further development in IPF, where cough burden is even more severe and consistent, and the need for effective treatments is acute.

Why Orvepitant?

  • Mechanism of Action: Orvepitant blocks the NK1 receptor, which is activated by Substance P, a key neurotransmitter involved in cough hypersensitivity.

  • CNS Penetration: At the preferred clinical dose, orvepitant fully occupies brain NK1 receptors for 24 hours.

  • Convenient Dosing: Orvepitant is delivered as a once-daily oral tablet, with a favorable pharmacokinetic and safety profile.

  • Extensive Safety Data: Evaluated in over 900 healthy subjects and patients, orvepitant has demonstrated good tolerability across multiple studies.

Focus: Chronic Cough in Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible lung disease marked by scarring (fibrosis) that impairs breathing. It primarily affects older adults and has a median survival of just 2–5 years following diagnosis—worse than many cancers.

Cough is a dominant and disabling symptom in IPF, severely affecting quality of life. It can lead to:

  • Sleep disruption
  • Chest pain and fatigue
  • Urinary incontinence
  • Rib fractures or fainting in extreme cases

 

Worse, cough may not just reflect disease—it may drive it, through repeated mechanical stress and potential stimulation of profibrotic pathways.

IPF Cough = Cough Hypersensitivity Syndrome

Emerging research shows that IPF-related cough is driven by heightened cough reflex sensitivity:

  • Patients with IPF show exaggerated responses to capsaicin (a cough-inducing agent) and mechanical stimulation.
  • Substance P triggers cough in IPF patients, but not in healthy individuals—indicating upregulation of NK1 receptor pathways, which orvepitant is designed to block.

 

This positions orvepitant as a rational, targeted treatment for chronic cough in IPF—addressing the underlying neurogenic mechanism rather than simply suppressing symptoms.

Orvepitant’s development is grounded in an evolving body of clinical and translational research. Key references include:

  1. Orphanet ORPHA:2032

  2. Meltzer & Noble, 2008

  3. Key AL et al., 2010

  4. FDA Chronic Cough Patient-Focused Drug Development Report, 2015

  5. Morice AH et al., 2007

  6. Ryerson CJ et al., 2011

  7. Sato R et al., 2019

  8. van Manen MJG et al., 2016

  9. Doherty MJ et al., 2000

  10. Hope-Gill B et al., 2003

  11. Jones RM et al., 2011