The NeRRe portfolio has the potential to tackle a range of disorders with high unmet need, starting with the primary indication of focus – chronic refractory cough (CRC).
The lead compound orvepitant, a potent and highly selective NK-1RA, is in a Phase 2b multinational trial to assess its benefit in patients with chronic refractory cough. It 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.
CRC 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 CRC 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 therapies1.
It is hypothesized that CRC results from hypersensitivity of peripheral airway sensory afferent neurons and neurons centrally in the brainstem which, together, control the cough reflex. The neuronal hypersensitivity results in coughing in response to otherwise trivial stimuli, or in the absence of any obvious initiating event.
Substance P (SP) is an agonist ligand of the (NK)-1R. An increasing body of evidence shows that the SP/NK-1R system plays a key role in induction and maintenance of cough reflex hypersensitivity. The first clinical evidence that a centrally acting NK-1RA could be effective in chronic cough was from a pilot study with aprepitant (EMEND®) in patients with cough associated with lung cancer2. In this randomised, double-blind, placebo-controlled, crossover trial in lung cancer patients with bothersome cough, there were statistically significant improvement in cough frequency (the primary efficacy endpoint), cough severity and quality-of-life. A pilot study with orvepitant in CRC patients has been undertaken by NeRRe at the world-leading clinical chronic cough research centre in Manchester UK, led by Prof Jaclyn Smith. This study (VOLCANO-1) was an open label assessment of the efficacy and safety of orvepitant in patients with CRC. Compared to baseline, there were statistically significant and clinically relevant reductions in measures of cough frequency and severity3. 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 CRC patient population. This potential is currently being assessed in a fully powered, randomised, double-blind, placebo-controlled Phase 2b trial in CRC patients called VOLCANO-2 (CT.gov identifier: NCT02993822).
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.
2 Harle M, Blackhall F, Molassiotis A, et al. Neurokinin-1 receptor antagonism for the treatment of cough in lung cancer. ERS Congress 2016, Abstract PA5060.
3 Jaclyn A. Smith AS, Allman D, Badri H, Miller R, Morris J, Satia I, Wood A, Trower M. The Neurokinin-1 Receptor Antagonist Orvepitant Is a Novel Anti-Tussive Therapy for Chronic Refractory Cough: Results from a Phase 2 Study (VOLCANO-1). Am J Respir Crit Care Med 2017;195:A2672