The NeRRe portfolio has the potential to tackle a range of disorders with high unmet need, starting with the primary indication of focus – Refractory or Unexplained Chronic Cough (RUCC).
The lead compound orvepitant, a potent and highly selective neurokinin-1 receptor antagonist (NK-1RA)¹, has just completed a Phase 2b dose range finding multinational trial – “VOLCANO-2”, to assess the benefit in patients with RUCC. In VOLCANO-2 Patients reported that orvepitant is effective and reduces the severity of chronic cough in a way that is clinically meaningful (and statistically significant). Orvepitant has the potential to be a first-in-class, once-daily oral therapy, bringing significant benefits to sufferers of this incapacitating condition for which there are currently no approved medicines.
RUCC and rationale for efficacy with a NK-1RA
Excessive coughing is the leading reason for ambulatory care visits by patients in the United States. Patients with chronic cough (lasting longer than 8-weeks) experience impaired quality-of-life with significant physical, social and psychological consequences. In most patients there is an underlying cause for the cough and treatment results in resolution or improvement of the cough. However, in many individuals there is no identifiable cause of their cough and it is refractory to intervention. This condition is called RUCC and it is a difficult symptom for physicians to manage as there are no approved treatments for patients desperate for relief. There remains a substantial need for new and effective therapies.²
Coughing can be both voluntarily induced and involuntarily initiated (cough-reflex) by activation of vagal afferent sensory nerves in the airways and lungs, and motor efferent nerves to stimulate respiratory muscles to cause coughing. Patients with RUCC have an exaggerated sensitivity of their cough neural circuitry, resulting in cough being triggered by innocuous or/and low-level stimuli. This hypersensitivity may be in the sensory neural pathways that innervate the airways and lungs or/and centrally in the brainstem ‘cough centre’ and/or higher central pathways. Symptoms include a persistent irritating sensation in the chest or throat creating an urge-to-cough that often precedes the typical uncontrollable coughing paroxysms. These abnormal sensations and triggers have recently been recognised as a disorder of cough neural function, and termed “cough hypersensitivity syndrome” (CHS).³
CHS has considerable parallels with the mechanisms of heightened neural sensitisation that underlies neuropathic pain4 which features hyperalgesia and allodynia, and chronic itch4,5 with alloknesis and hyperknesis.
Substance P (SP) is the preferred agonist peptide ligand of the (NK)-1R and is upregulated in chronic inflammatory conditions. There is a strong rationale supported by preclinical data that SP by activating the NK-1R sensitises cough synapses in the brainstem ‘Cough Centre’ and in the higher ‘voluntary control’ brain centres. This suggests that centrally acting NK-1 antagonists could be a safe and effective treatment for the neural hypersensitivity driving the excessive coughing experienced by RUCC patients, without the limitations of other centrally acting agents such as opioids, gabapentin and amitriptyline.
This hypothesis was initially proven in the clinic in a pilot study with NeRRe’s lead NK-1 antagonist orvepitant in RUCC patients at the world-leading clinical chronic cough research centre in Manchester UK, led by Prof Jaclyn Smith.6 This study (VOLCANO-1) was an open label assessment of the efficacy and safety of orvepitant in patients with RUCC. Compared to baseline, there were statistically significant and clinically relevant reductions in measures of cough frequency and severity. This initial clinical evidence shows that blockade of the NK-1R with orvepitant has the potential to be a novel and effective treatment for cough symptoms in the RUCC patient population.
This potential was comprehensively assessed in a fully powered, randomised, double-blind, placebo-controlled Phase 2b trial in RUCC patients called VOLCANO-2 (CT.gov identifier: NCT02993822). The results of this dose range finding study demonstrate that 30 mg of orvepitant given once-daily is effective and resulted in statistically significant and clinically relevant improvements in all Patient Reported Outcomes/ Quality-of-Life endpoints in the full analysis set.7 The cough frequency endpoint missed significance in the full analysis set due to high data variability in lower frequency cough subjects. It is the variability in this lower cougher sub-population which makes the signal difficult to detect overall. However, in a pre-defined sub-group of higher frequency coughers, the cough frequency signal was less variable, allowing a clear separation of the 30 mg once-daily dose arm from placebo. There was a statistically significant difference (p=0.009) in responder rates between the 30 mg once-daily dose arm (70%) and placebo (44%). The company will present the VOLCANO-2 data at the forthcoming European Respiratory Society (ERS) meeting in Madrid8 and discuss these positive Phase 2b results and the proposed Phase 3 pivotal programme for orvepitant with regulators in Q4 2019.
Of additional interest is that positive randomised controlled clinical trial data in another chronic cough condition ‘Cough in Lung Cancer’ has been achieved with NK-1R antagonism therapy9, giving promise for broader utility of orvepitant to provide relief to patients in related cough indications to RUCC.
NeRRe Therapeutics is led by an experienced management team. The company is backed by international life sciences investors: Advent Life Sciences, Fountain Healthcare Partners, Forbion Capital Partners and OrbiMed, all of whom took part in a £23m Series B fundraising in 2017. The company was founded in 2012 as a spin out from GSK, which transferred its NK antagonist portfolio, including clinical data, toxicity, safety and formulation packages, and all associated intellectual property to NeRRe. The company has built on this package, generating exciting new preclinical and clinical data to support the progression of its portfolio and creating further value with novel intellectual property.
A unique NK-1,3RA called NT-814 was demerged from NeRRe Therapeutics into KaNDy Therapeutics in September 2017, in order to allow NeRRe to focus on developing the NK-1RA pipeline.
NeRRe is based at the state-of-the-art Stevenage Bioscience Catalyst (www.stevenagecatalyst.com), the UK’s first open innovation bioscience campus.
1 Di Fabio R, Trower M et al. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. Bioorg Med Chem. 2013 Nov 1;21(21):6264-73.
2 Gibson PG, Vertigan AE. Management of chronic refractory cough. BMJ 2015 Dec 14; 351:h5590.
3 Chung (2011) Chronic ‘cough hypersensitivity syndrome’: a more precise label for chronic cough. Pulm Pharmacol Ther. 2011 Jun;24(3):267-71.
4 Ji (2015) Neuroimmune interactions in itch: Do chronic itch, chronic pain, and chronic cough share similar mechanisms? Pulm Pharmacol Ther. 2015 Dec;35:81-6.
5 Ständer & Yosipovitch (2019) Substance P and neurokinin 1 receptor are new targets for the treatment of chronic pruritus. Br J Dermatol. 2019 Apr 23.
6 Smith J, Trower M et al. The Neurokinin-1 Receptor Antagonist Orvepitant is a Novel Antitussive Therapy for Chronic Refractory Cough: Results from a Phase 2 Pilot Study (VOLCANO-1). Chest. 2019 Aug 14. pii: S0012-3692(19)31451-5.
7 NeRRe Therapeutics Press Release dated 7th June 2019.
8 Smith J, Ballantyne E, Kerr M, McGarvey L, Morice A, Sher M, Trower M, Pawsey S. The neurokinin-1 receptor antagonist orvepitant improves chronic cough symptoms: results from a Phase 2b trial. ERS Abstract PA600.
9 Harle A, Smith J et al. A placebo-controlled trial of aprepitant for cough in lung cancer. J. Clin. Oncol. 2015 33:29_suppl, 2-2.
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