NYRADA INC (ASX:NYR) 18 Developing a drug to block secondary brain damage following traumatic brain injury or a stroke Our Brain Injury Program continued to make significant progress during the year. Further optimisation to improve the overall drug-like properties of Nyrada’s previous brain injury drug candidate NYR-BI01, led to the development of NYR-BI02 and its selection as our preferred drug candidate to take into the clinic. NYR-BI02 has a superior pharmacokinetic profile to NYR-BI01 and has improved stability and solubility. We also revealed the biological target for the Brain Injury Program as a class of proteins known as “Canonical” Transient Receptor Potential, or TRPC ion channels. These channels are present on the surface of brain cells and allow calcium to enter the cell. Calcium is critical to cell survival, however excess calcium triggers cell death pathways. Following an injury in the brain, the mechanisms that keep calcium levels in-check fail as they rely on energy, which quickly depletes. After a brain injury such as a stroke, accident impact or concussion, the TRPC channels remain constantly activated, allowing sustained calcium entry into the cells leading to cell death. Nyrada’s brain injury drug candidate NYR-BI02 is a potent blocker of three subtypes of the channel – TRPC3, TRPC6 and TRPC7, which are present in high levels in brain tissue. By targeting these channels, Nyrada’s brain injury drug candidate blocks the sustained entry of calcium into the cells reducing secondary brain injury. NYR-BI02 is also able to cross the blood-brain-barrier, indicating it can reach therapeutic levels in an injured brain. There are currently no FDA-approved small molecule blockers of TRPC 3/6/7 ion channels. Possible New Oral Treatment for Concussion In March 2022, exploratory pharmacokinetic studies undertaken as part of Nyrada’s medicinal chemistry program revealed excellent oral bioavailability of NYR-BI02, indicating it has the potential to be administered orally to patients who suffer a concussion. The convenience of an oral dosage form that can be administered in the field immediately after a concussion injury, without having to wait for hospitalisation, has the potential to significantly improve patient outcomes. While Nyrada remains focused on developing a drug to treat moderate to severe TBI and stroke which would be administered intravenously, given the potential to positively impact patient outcomes and market interest in this area, Nyrada may pursue NYR-BI02’s development as an oral treatment for concussion as an additional program. Testing Nyrada’s Brain Injury Drug Candidate in Stroke The efficacy of Nyrada’s brain injury drug candidate will be evaluated in a well-established preclinical model of stroke. The model is called the Photothrombotic Model of Ischemia, where localised clot formation is achieved in a specific brain region, leading to a stroke. This model was previously used by Nyrada to test the efficacy of its first-generation molecule, which showed a promising efficacy signal. This work in stroke is outside of the studies being undertaken as part of Nyrada’s collaboration with WRAIR and UNSW. WRAIR’s focus remains solely on developing a drug to mitigate the impact of TBI on military service members. A key advantage of the drug that Nyrada is developing is it can be administered to stroke and TBI patients in the same manner, by way of intravenous dosing over a 3-day period, which is matched to patient emergency hospital admission. It is anticipated the results of the preclinical stroke model study will be available in Q4 CY2022. TBI Efficacy Study Nyrada will initially test the efficacy of its NYR-BI02 molecule as a TRPC 3/6/7 channel blocker in a model of TBI through its collaboration with WRAIR. The efficacy study will employ the penetrating traumatic brain injury (PTBI) model which has been developed by the WRAIR team to emulate penetrating head wounds on the battlefield. The study will involve dosing animals with a vehicle or NYRBI02 in a blinded fashion and assessing the injury volume using a specialised MRI technique at UNSW. The study will include assessment of blood biomarkers that are commonly used in the clinical setting for diagnosis and prognosis purposes in TBI and stroke patients. The efficacy study will also incorporate assessment techniques commonly used in animal brain injury models. This multifaceted study is dependent on the contribution of substantial resources from WRAIR, which has seen some of its project timelines impacted by the ongoing COVID-19 pandemic. This study is expected to start in CY2023 once the necessary additional resources from WRAIR can be directed towards this project. Delays to the start of the TBI efficacy study will not impact the commencement of the Phase I first-in-human study, as these studies can be run in tandem.