Invion's INV102 demonstrates modest increase in smoking cessation but significant potential for harm reduction - opportunities to improve quit rate through biomarker guided Phase 3 selection

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• Invion has reported that INV102 increases the rate of smoking cessation from 11% to 19% over 10-12wks
  
• 155 smokers with chronic cough who had previously attempted to quit but relapsed due to their cough were randomized to INV102 or placebo
• The proportion of patients benefiting from a >70% reduction in cigarettes smoked was nearly doubled from 36% to 61%
• INV102 also reduced sputum MUC5AC and ERK1, epithelial biomarkers of mucous metaplasia (ie abnormal build up of mucous).  Chronic cough is thought to be due to mucous secretion
• Further data analysis will attempt to correlate biomarker and smoking cessation data.  This will be used to strengthen Invion's IP position and also guide Phase 3 patient inclusion
• An End of Phase 2 meeting with the FDA has been requested for early 2016 to discuss Phase 3 development.
• INV102 is thought to inhibit the beta arrestin pathway, mucous metaplasia and hence mucus production.  This contributes to "smokers cough" which is a common cause of relapse to smoking

Comments: INV102 is an inverse beta adrenoceptor agonist which is already marketed as Corgard (nadolol) for CV indications.  Nguyen et al (2008) previously reported that nadolol reduces airway inflammation supporting a possible role in asthma and COPD, future indications for INV102.  Despite the relatively poor efficacy in terms of smoking cessation (eg Chantix/Champix supports abstinence rates of 42% in COPD patients [Tashkin]), we find the present study of considerable interest for multiple reasons.  1.  The identification of biomarker reduction offers opportunities to amplify efficacy.  The fact that this may also improve the IP position is an added bonus; 2. The present study did not include the adjunctive use of current smoking cessation products.  Since INV102 has a completely different MOA to current NRTs, the combination of nicotine replacement and INV102 could produce much higher quit rates; 3. The study enrolled patients with chronic cough including those with COPD.  This group is at increased risk of smoking related acceleration of smoking related disease, moreover they are also associated with reduced smoking abstinence using NRT; 4. The rate of smoking reduction appears dramatic (perhaps disproportionately so given the low quit rate).  This may offer significant harm reduction opportunities and hence opportunities for approval especially in the EU; 5. Opportunities for harm reduction may be further enhanced given that nadolol is an anti-hypertensive which may be of CV benefit in long-term smokers.  Moreover there is evidence that ERK1 blockade may both prevent the development of lung cancer and also increase sensitivity to chemotherapies in diagnosed cancers, with the former further offering opportunities for harm reduction.  Invion will be developing INV102 as a treatment of COPD. The possibility of reducing signs and symptoms of COPD alongside reduced smoking, the cause of COPD is highly attractive