Nyrada Inc - Annual Report 2021

NYRADA INC (ASX:NYR) 16 Advancing a first-ever oral cholesterol-lowering drug towards first-in-human trials Our Cholesterol-Lowering Program delivered a series of positive results in FY21 which led to Nyrada selecting NYX-PCSK9i, an optimised oral PCSK9 inhibitor, to take forward into safety pharmacology and toxicology studies, before entering a Phase I first-in-human study in mid-2022. In July 2020, Nyrada achieved a significant scientific milestone in its efforts to replace expensive inconvenient, and ongoing injections with the first-ever oral PCSK9 inhibitor pill. NYX-PCSK9i demonstrated equivalency to the two FDA-approved injectable PCSK9 monoclonal antibody drugs, Repatha® (Amgen) and Praluent® (Sanofi/Regeneron), in healthy human white blood cells. These results opened the potential for NYX-PCSK9i to be used alone, or in combination with a statin. Very encouraging preliminary in vivo efficacy results were reported in December 2020, where NYX-PCSK9i demonstrated a 57% reduction in total cholesterol. These results marked an important step towards creating an effective, convenient, and cost-competitive single-pill treatment option for the 70% of US patients unable to reach their target LDL (“bad”) cholesterol level despite taking a statin, which would replace ongoing expensive injections. 1 This proof-of-concept study was conducted in a specialised mouse model of hypercholesterolemia which is known to be highly predictive of human cholesterol metabolism and cardiovascular health outcomes. The NYX-PCSK9i results compared favourably with historical in vivo studies of the statin, Lipitor® (atorvastatin, Pfizer), the best-selling drug of all time, and Praluent®, in the magnitude of total cholesterol reduction. In January 2021, additional results from an exploratory arm in Nyrada’s in vivo cholesterol efficacy study built on the 57% reduction in total cholesterol, confirming LDL cholesterol levels were lowered in a dose- dependent manner by NYX-PCSK9i. Importantly, no adverse effects were observed and NYX-PCSK9i was well-tolerated. Further medicinal chemistry work revealed two additional candidates (called NYX-PCSK9i-211 and NYX-PCSK9i-212) which had improved potency in vitro compared to NYX-PCSK9i. In May 2021, Nyrada commenced a new in vivo efficacy study in the same specialised mouse model, evaluating NYX-PCSK9i in combination with a statin, alongside the two new drug candidates to determine if NYX-PCSK9i enhances the efficacy of a statin drug when co-administered. This proof-of-concept study showed encouraging efficacy with NYX-PCSK9i reducing total cholesterol by 65% when given in combination with the statin Lipitor®, and 46% when given as a monotherapy. This compares to the 27% reduction achieved using Lipitor® alone. Nyrada’s results, reported in June 2021, compare favourably to a similar 2014 study which found total cholesterol was reduced by the injectable PCSK9 monoclonal antibody, Praluent®, by 58% when given in combination with Lipitor®, and by 37% - 46% when given as a monotherapy. 2 The study also demonstrated one of the new candidates NYX-PCSK9i-211, had compelling efficacy at the 14-day mark, however it presented with tolerability issues. Nyrada is undertaking further medicinal chemistry work in a targeted approach to improve the tolerability of the compound. Results from a follow- up exploratory analysis of the study were reported in Q1 FY22. Based on the strong results reported throughout the year, Nyrada has selected NYX-PCSK9i as the preferred compound to take forward into safety pharmacology and toxicology studies at an internationally recognised Contract Research Organisation, before commencing a Phase I first-in-human study in mid-2022. 1 Wong ND et al. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011-2012. J Clin Lipidol. 2016 Sep-Oct;10(5):1109-18. 2 Kühnast S et al. Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res. 2014 Oct;55(10): 2103–2112