Nyrada Inc. announced encouraging efficacy results from its in vivo study of NYX-PCSK9i in a specialised mouse model, called APOE*3-Leiden.CETP. The results support the selection of NYX-PCSK9i as the preferred compound for preclinical studies at an internationally recognised Contract Research Organisation, ahead of a Phase 1 first-in-human study. Results from an in vivo efficacy study in a specialised mouse model showed NYX-PCSK9i reduced total cholesterol by 46% as a monotherapy, and 65% when dosed in combination with the statin drug Lipitor over the study period. This compares to the reduction achieved using Lipitor alone of 27%. Since it was approved in 1997, Lipitor has been the best-selling drug worldwide generating lifetime sales of US$164 billion.1 It was also the most prescribed drug in Australia in 2020. In this study, a dose of 50mg/kg was administered and evaluated over 35 days (5 weeks) with no adverse effects identified. Pleasingly, NYX-PCSK9i was well-tolerated with no significant changes in food intake, body weight, or liver function observed. Whilst the NYX-PCSK9i in vivo study was of shorter duration, the results compare favourably to a historical study of Praluent (alirocumab), an injectable PCSK9 monoclonal antibody. In the 2014 study by Kühnast and colleagues3 alirocumab was shown to reduce cholesterol by 37-46% (moderate-optimal dose) in APOE*3-Leiden.CETP mice when injected weekly for 18 weeks. In the same study, Praluent decreased cholesterol by 58% when dosed in combination with Lipitor. This compares with the 65% reduction in total cholesterol achieved dosing with NYX-PCSK9i using the same statin in this study. Earlier medicinal chemistry work revealed analogues NYX-PCSK9i-211 and NYX-PCSK9i-212 as two compounds more potent than NYX-PCSK9i, which led to their inclusion as additional arms of the study. NYX-PCSK9i-211 showed a 39% reduction by 14 days, however the compound was not well-tolerated. Notwithstanding, NYX-PCSK9i- 211 has the characteristics of a strong second-generation compound. The Company is undertaking further medicinal chemistry work in a targeted approach to improve the tolerability of the compound. Nyrada has several promising compounds in its portfolio and continues to develop these through its medicinal chemistry program that runs in tandem with its primary preclinical studies. NYX-PCSK9-212 showed a modest reduction in total cholesterol but did not reach statistical significance. Follow-up exploratory analysis of the in vivo study will be reported in July, detailing further study parameters. In addition, safety pharmacology and toxicology studies of NYX-PCSK9i will commence in H2 2021 in preparation for a Phase I first-in-human study, which is set to commence mid-2022. Nyrada selected a specialised mouse model called the APOE*3-Leiden.CETP mouse model that has been specifically generated to possess human-like characteristics concerning cholesterol metabolism and cardiovascular health. The model expresses three human genes to specifically model the human hyperlipidemia condition and is very well regarded in the cardiovascular field, having been used for over 170 drug intervention studies by the pharmaceutical industry over the last 15 years. When the body has too much LDL (bad) cholesterol, it can accumulate on artery walls, restricting blood flow which can lead to heart attack and stroke. LDL cholesterol is cleared from circulation by binding to LDL receptors (LDLR) on the surface of liver cells. PCSK9 is a naturally produced protein that plays a counter role in this regulation process. It does this by degrading the LDLR, lowering the number of receptors available to remove LDL cholesterol. This leads to increased levels of LDL cholesterol in the bloodstream. Inhibition of PCSK9 function causes a beneficial increase in LDLR on the surface of cells, improving the body's ability to clear LDL cholesterol from the bloodstream.