A Novel Approach to Treat Serious and Chronic Neurologically Mediated Conditions
Our novel oral formulation of the small molecule drug nalbuphine is unlocking new market opportunities and the potential to significantly improve the quality of life of patients suffering from the serious symptoms associated with chronic neurologically mediated conditions for which there are few, if any, treatment options.
Haduvio™ (nalbuphine ER), an investigational therapy, has a dual mechanism of action by acting as both an antagonist (blocker) to the body’s mu opioid receptor and as an agonist (activator) to the kappa opioid receptor. The kappa and mu opioid receptors are known to be critical mediators of the urges to scratch and cough, as well as of certain movement disorders. Nalbuphine’s mechanism of action may also mitigate the risk of abuse associated with mu opioid agonists because it blocks the mu opioid receptor.
The History
of Nalbuphine
In its injectable formulation, nalbuphine has a long history of efficacy and safety. It’s been approved for more than 20 years in the U.S. and EU for relief of moderate to severe pain in the hospital setting and is currently the only opioid that is not classified as a controlled substance in those geographies.
The founders of Trevi were previously involved in the formulation and development of the oral, extended release version of nalbuphine that extended the plasma half-life from ~2 hours to 9 hours, enabling twice-daily oral dosing and opening up its potential use in patients with a variety of serious symptoms caused by chronic neurologically mediated conditions.
We are currently developing the investigational therapy Haduvio™ for the treatment of chronic pruritus, chronic cough in patients with idiopathic pulmonary fibrosis (IPF) and levodopa-induced dyskinesia (LID) in patients with Parkinson’s disease. These conditions share a common pathophysiology that is mediated through opioid receptors in the central and peripheral nervous systems. Due to nalbuphine’s mechanism of action as a modulator of opioid receptors, we believe it has the opportunity to be effective in treating each of these conditions.
We have completed clinical trials in two distinct and serious pruritic conditions: pruritus associated with prurigo nodularis, and uremic pruritus. In these trials, we treated more than 400 patients with different doses of Haduvio™, generating positive results in these two difficult-to-treat pruritic conditions, and an expected long-term safety profile up to one year on therapy.
Prurigo Nodularis (PN)
A chronic, intensely pruritic dermatological condition characterized by the presence of pruriginous lesions such as papules, nodules or plaques, which may be associated with excoriations and ulcerations.
We conducted a Phase 2 clinical trial in 63 patients with moderate to severe PN. A post hoc analysis of 50 patients completing 10 weeks of treatment with Haduvio™ 162 mg twice daily showed a statistically significant mean reduction in itch intensity compared to placebo.
Uremic Pruritus (UP)
We conducted a Phase 2b/3 study enrolling 373 patients with moderate to severe UP. Patients receiving 108 mg of Haduvio™ twice daily showed a statistically significant mean reduction in itch intensity compared to placebo.
Due to its dual mechanism, we believe Haduvio™ is well suited to address pruritus and other dermatologic, metabolic, hematologic and neuropathic conditions that represent large markets with significant unmet medical needs.
For more on our global Haduvio™ clinical development programs, please visit our Pipeline page.
What is pruritus?
Chronic pruritus is itching that lasts longer than six weeks. It causes a number of physical and psychological issues that substantially impact patients’ daily well‑being.
The urge to scratch can be unbearable, and the act of scratching can remove layers of skin and break the skin barrier leading to bleeding and scarring and greatly increasing the risk of infection. Chronic pruritus is a hallmark of many dermatologic and systemic diseases and is the predominant reason that patients with these diseases experience so much discomfort.
A report published in the Journal of the American Academy of Dermatology estimated that up to 26% of the worldwide population will suffer from chronic pruritus at some point in their lives. According to the Global Pruritus Therapeutic Market Research Report issued in 2020, the market for pruritus therapeutics was $12.9 billion in 2020 and is expected to grow to $19.9 billion in 2026.
There are no drugs approved in the United States or Europe for the treatment of moderate to severe pruritus.
scientific and clinical
posters & publications
Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase
Weisshaar E. et al., Journal of The European Academy of Dermatology and Venereology (2021)
Prevalence, Incidence, and Presence of Comorbidities in Patients with Prurigo and Pruritus in Germany: A Population-Based Claims Data Analysis
Augustin et al., Journal of The European Academy of Dermatology and Venereology (2021)
The Role of Kappa- and Mu- Opioid Receptors in Pruritus
as presented at Maui Derm for Dermatologists 2021
Modulation of the Mu and Kappa Opioid Axis for Treatment of Chronic Pruritus
as presented at Maui Derm for Dermatologists 2021
Prevalence of prurigo nodularis in the United States of America: A retrospective database analysis
Ständer et al., The American Academy of Dermatology (JAAD) International (2020)
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus
as presented at the 2020 Fall Clinical Dermatology Conference
Efficacy and Safety of Oral Nalbuphine Extended Release in Prurigo Nodularis: Results of a Phase 2, Randomized, Controlled Trial with an Open-Label Extension Phase
as presented at the 2020 Fall Clinical Dermatology Conference
Prevalence of Prurigo Nodularis in Poland
Reich and Ryczek, Acta Dermato Venereologica (2020)
Prevalence of Prurigo Nodularis in the United States: Findings of a Retrospective Database Analysis
as presented at the 2020 AAD Annual Meeting
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus
Mathur et al., American Journal of Nephrology (2017)
ER Tablets in Hemodialysis Patients with Severe Uremic Pruritus: Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial
as presented at the National Kidney Foundation Spring 2016 Meeting.
Long-Term Effects of Nalbuphine ER Tablets in Hemodialysis Patients with Uremic Pruritus: A Multicenter Open-Label Trial
as presented at the National Kidney Foundation Spring 2016 Meeting.
Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus
Hawi, et al, BMC Nephrology (2015)
Pharmacokinetics of nalbuphine hydrochloride proof-of-concept study with pharmacokinetics demonstrating anti-pruritic activity of oral nalbuphine in hemodialysis patients with uremic pruritus
as presented at the 2014 Meeting of the Society for Investigative Dermatology.
Pharmacokinetics of Nalbuphine Hydrochloride Extended Release Tablets in Hemodialysis and Healthy Subjects following Multiple Escalating Oral Doses
as presented at the 2014 Meeting of the American College of Pharmacology.
Exploring Clinical and Pharmacological Effects of Nalbuphine HCl Oral Tablets in Hemodialysis Subjects with Pruritus
as presented at American Society of Nephrology’s 2014 Kidney Week.
Nalbuphine attenuates itch in the substance P-induced mouse model
as presented at 7th World Congress on Itch (2013).
