BLU-5937 is a potent, highly selective, orally bioavailable small molecule antagonist of the P2X3 receptor, a clinically validated target for chronic cough. BLU-5937 has the potential to be a best-in-class therapeutic for chronic cough patients who do not respond to current therapies.

BLU-5937 has shown a significant reduction in cough and no effect on taste perception in two separate preclinical models. In a guinea pig cough model, BLU-5937 has shown comparable efficacy to the current leading P2X3 antagonist in development, Merck & Co’s Gefapixant (also named AF-219 or MK-7264). In a rat taste model, BLU-5937 did not change taste perception; however, consistent with clinical trial data previously presented by Merck & Co, Gefapixant led to significant change in taste perception (alteration or loss). Refer to Preclinical Study Results section below for details.

The Company has completed all preclinical studies on BLU-5937 needed to submit a Clinical Trial Application (“CTA”), including 28-day toxicology animal studies, which demonstrated an excellent safety profile. The Company expects to submit the CTA to Health Canada in the second quarter of 2018 to initiate a Phase 1 clinical study on humans in the third quarter of 2018.

Phase 1 Study Design

The main objectives of the Phase 1 clinical study will be to assess the safety, tolerability (including taste perception) and pharmacokinetic profile of BLU-5937 in healthy subjects. This will be a randomized, double-blind, placebo-controlled, single- and multiple-dose escalating study of orally administered BLU-5937 in healthy adult subjects.

Subject to final regulatory approval, the study will be designed as follows:

Part 1: A single-ascending dose (“SAD”) study will be conducted in approximately 60 healthy subjects. Subjects will be enrolled into approximately 6 cohorts of 10 subjects (8 BLU-5937: 2 placebo).

Part 2: A multiple-ascending dose (“MAD”) study will be conducted in approximately 30 healthy subjects. Subjects will be enrolled into approximately 3 cohorts of 10 subjects (8 BLU-5937: 2 placebo). Each subject will receive daily oral administrations of the assigned treatment for 7 consecutive days. The dose regimen for the MAD study will be established based on the SAD study results.

Results of the Phase 1 clinical study are expected in the fourth quarter of 2018. These results will help define BLU-5937’s expected product profile, including: safety, tolerability (including taste perception) and dosing regimen.

Preclinical Study Results

BLU-5937’s Reduction in Cough Frequency Comparable to the Leading P2X3 Antagonist, Gefapixant

The anti-tussive effect of BLU-5937 was compared to that of Gefapixant in a guinea pig cough model.  Treatments (control, BLU-5937 (0.3, 3 and 30 mg/kg) or Gefapixant (0.3, 3 or 30 mg/kg)) were administered orally in seven groups of 6 animals 2 hours prior to tussive agent exposure (citric acid and histamine) and the number of coughs were counted for a period of 15 minutes. Both treatments showed comparable dose-dependent reduction in cough frequency as compared to the control. The reduction in cough was statistically significant at 3 mg/kg (39% vs. control) and 30 mg/kg (52% vs. control) with BLU-5937, and at 30 mg/kg (45% vs. control) with Gefapixant.

BLU-5937’s Duration of Effect also Comparable to Gefapixant

Using the same guinea pig cough model, a time course study was conducted to assess the duration of the anti-tussive effect of BLU-5937 and Gefapixant following the administration of a single oral 30 mg/kg dose. In this study, animals in groups of 6 were exposed to tussive agents (citric acid and histamine) at various times after the administration of the study drugs (2, 4, 6, 8 and 12 hours post-dose for BLU-5937 and 2 and 8 hours post-dose for Gefapixant) and the number of coughs were measured for 15 minutes. The reduction in cough frequency compared to control was shown to be statistically significant at 2, 4 and 6 hours post-dose with BLU-5937, and at 2 hours post-dose with Gefapixant. The anti-tussive effect was no longer significant at 8 hours post-dose for both agents. These results indicate that BLU-5937 and Gefapexiant have comparable duration of effect.

BLU-5937 Shows No Effect on Taste Perception, Leading P2X3 Antagonist Gefapixant Shows Significant Effect on Taste Perception in the Rat Taste Model

A rat taste model was used to compare BLU-5937’s effect on taste function with that of Gefapixant. Animals were water-fasted overnight and presented with one bottle of water and one bottle of (bitter-tasting) quinine at the time corresponding to the maximum plasma concentration of study drugs; and the volume of liquid consumed from each bottle was measured for 15 minutes. Treatments (control, BLU-5937 (10 or 20 mg/kg) or Gefapixant (10 or 20 mg/kg)) were administered intraperitoneally in two groups of 10 rats. Animals treated with BLU-5937 did not drink more quinine than the control animals, while those treated with Gefapixant drank significantly (approximately 5 times) more quinine than the control at the two doses tested. These results indicate that Gefapixant had an effect on taste perception, while BLU-5937 did not.

Disease and Market

Chronic cough is associated with significant adverse social, psychosocial and physical effects on quality of life. Chronic cough, defined as a cough that lasts more than eight weeks, is estimated to affect approximately 10% of adults in the U.S. While an underlying etiology may contribute to cough in some of these patients, including gastro-oesophageal reflux, asthma, or allergic rhinitis, an underlying condition cannot be identified in 10%-20% of chronic cough patients (unexplained chronic cough). A portion of patients with an underlying condition as well as the large majority of unexplained chronic cough patients are not well controlled by current therapies.

In June 2017, the Company commissioned Torreya Insights LLC to conduct a market assessment through an evaluation of chronic cough epidemiology and pricing estimates. Based on primary and secondary research, the report concludes that, in the United States alone, more than 26 million adults suffer from chronic cough and more than 2.6 million of these patients have chronic cough lasting for more than a year. The number of treatment-refractory chronic cough patients expands to 11.7 million when taking into account those patients with a cough duration between eight weeks and one year. The market assessment also sought to better understand the pricing and reimbursement landscape for a condition that has no recently-approved therapies, and therefore no direct comparables. Based on interviews with Key Opinion Leaders, prescribing physicians and payers, the consensus is that new chronic cough treatments, such as BLU-5937, will be priced similarly to therapies for chronic constipation, asthma and partial onset seizures. These analogs represent non-lethal chronic conditions that have a significant impact on quality of life and address a large patient population in competitive markets that also include generic and over-the-counter products. The monthly price for these analogs varies between US $300 and $600.

On April 4, 2018, the European Patent Office (“EPO”) granted patent No. 2951177 with claims covering the composition of matter of BLU-5937 and related imidazopyridine compounds in addition to pharmaceutical compositions comprising BLU-5937 and uses thereof. BLU-5937 has now obtained patent protection in three of the four major pharmaceutical markets, with equivalent patents issued in 2017 by the U.S. Patent and Trademark Office and the Chinese Patent Office with similar broad claims. The patents have an expiration date of 2034, excluding any potential patent term extension. Patent applications with similarly broad claims are currently pending in Japan and other industrialized nations.

Pathophysiology of Chronic Cough

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