Improving lives through innovation Nyrada Inc (ASX:NYR) ABRN 625 401 818 Annual report For the year ended 30 June 2022
NYRADA INC (ASX:NYR) 2 Nyrada Overview Nyrada is developing novel, high value small molecule drugs: Key drivers of future value Key milestones in the next 18 months Results of preclinical stroke model study CholesterolLowering Program preclinical safety, pharmacology and toxicology studies Brain-Injury Program preclinical safety, pharmacology, and toxicology studies Commencement of CholesterolLowering Phase I Study Commencement of Brain-Injury Phase I Study TBI efficacy study withWalter Reed Army Institute of Research and UNSWSydney Safety confirmed in Phase I CholesterolLowering Study Efficacy signal in joint Nyrada/ WRAIR/ UNSW TBI Study Brain Injury Program Phase I Study confirms safety New patents secured to expand IP protection Drug Candidate Indication Aim Target Market NYX-PCSK9i Oral PCSK9 inhibitor Cholesterol-Lowering Best-in-class small molecule drug to disrupt and broaden the class in cardiovascular management, offering the convenience of a pill >18Mpatients (US)1 NYR-BI02 TRPC 3/6/7 blocker Brain Injury First-in-class treatment to prevent secondary brain injury and reduce disability following moderate-severe TBI, concussion, or stroke ~5.5Mpatients/ year (globally)2
ANNUAL REPORT FY22 3 Corporate Directory Board of Directors John Moore Peter Marks (resigned 1 August 2022) Rüdiger Weseloh Marcus Frampton Christopher Cox Ian Dixon Gisela Mautner (appointed 1 August 2022) Company Secretary David Franks Registered office in Australia and principal place of business Suite 2, Level 3 828 Pacific Highway Gordon, NSW 2072 Australia Tel: +61 2 9498 3390 Registered office in place of incorporation 1209 Orange Street Wilmington, Delaware 19801 United States of America Share/CDI Registry Automic Pty Ltd Level 5, 126 Phillip Street Sydney, NSW 2000 Australia Auditor William Buck Audit (Vic) Pty Ltd Level 20, 181 William Street Melbourne, VIC 3000 Australia Stock exchange listing Nyrada Inc. instruments registered for trade on the Australian Securities Exchange are CHESS Depositary Interests (CDIs). One CDI is equivalent to one Share, being Class A Common Stock. ASX Code NYR Website www.nyrada.com Email firstname.lastname@example.org
NYRADA INC (ASX:NYR) 4 Contents Chairman’s Letter 5 CEO Report 8 Directors’ Report 12 Auditor’s Independence Declaration 33 Independent Auditor’s Report 34 Consolidated Statement of Profit or Loss and Other Comprehensive Income 38 Consolidated Statement of Financial Position 39 Consolidated Statement of Changes in Equity 40 Consolidated Statement of Cash Flows 41 Notes to the Financial Statements 42 Directors’ Declaration 57 Shareholder Information 58 References 61
ANNUAL REPORT FY22 5 Chairman’s Letter Dear Fellow Shareholders, I am pleased to present Nyrada’s Annual Report for the financial year ended 30 June 2022, during which we saw notable progress in both of our drug development programs. Our vision is to improve lives and offer hope through innovation. This is reflected in the objectives of both our Cholesterol-Lowering and Brain Injury drug development programs, which target diseases with substantial market size and unmet patient need. The team has invested significant effort over the year as Nyrada evolves from a preclinical drug discovery company to a pharmaceutical company approaching the clinic. We are currently focused on completing the required preclinical studies before entering first-in-human trials. Considerable progress was made in both our programs. In addition to lowering cholesterol levels in a mouse model of hyperlipidemia, a candidate from Nyrada’s PCSK9 inhibitor family of compounds was shown to attenuate the early stages of atherosclerosis in a novel human tissue-engineered blood vessel model of the disease, developed by researchers at Duke University. Our oral drug candidate has the potential to provide a valuable alternative to expensive and inconvenient injectable PCSK9 inhibitor drugs. Nyrada is also developing a first-in-class neuroprotectant drug to prevent secondary brain injury. This is the injury that occurs in the hours and days following the primary injury, leading to increased disability and reduced quality of life. Each year, globally, more than 60 million people suffer a concussion or moderate to severe traumatic brain injury (TBI)3, yet no FDA-approved treatment for secondary brain injury exists. For stroke the need is similar, with only limited treatment options available. Nyrada’s NYR-BI02 drug candidate offers the potential to reduce the secondary injury, and therefore reduce patient mortality and disability and improve quality of life. Recently, the team revealed NYR-BI02 targets three Transient Receptor Potential Canonical (TRPC) ion channel subtypes, making it a versatile, potent blocker of the channel. This creates significant potential for future studies in a range of other neurological diseases, along with diseases of the kidneys, heart, lung, and muscle. As part of our existing collaboration with the Walter Reed Army Institute of Research, Nyrada will initially test the efficacy of its NYR-BI02 molecule as a TRPC 3/6/7 channel blocker in a model of TBI. The efficacy study will also involve injury volume assessments using a specialised MRI technique developed at UNSW Sydney. The last twelve months have been a challenging period for global equity markets, as central banks continue to lift interest rates to slow rising inflation amidst ongoing economic uncertainty, impacting investor sentiment across a variety of sectors, including biotech, life sciences and healthcare. Our key focus remains on creating value for our shareholders. We have actively taken steps during the year to raise awareness of our technologies with investors and potential partners via our participation in industry and investment conferences, helped by the easing of COVID-related travel restrictions. “High LDL-cholesterol is a significant risk factor for cardiovascular disease and is most prevalent in older adults. The World Health Organization estimates that by 2030, 1 in 6 people will be aged 60 years or over, accounting for ~1.4 billion people globally. A large study found that of an estimated 27 million US adults taking statins, 70% were not able to reach a safe target cholesterol level. Nyrada’s oral PCSK9 inhibitor drug has the potential to be a next generation alternative to expensive and inconvenient PCSK9 injectable drugs.”
NYRADA INC (ASX:NYR) 6 Nyrada is fortunate to be in a strong position with respect to broader supply chain and inflationary pressures. In part, this is due to pre-arranged pricing secured for preclinical studies, as well as proactive measures taken by the Company to hedge our exposure to the US Dollar. The ongoing global impacts of COVID-19 have, however, had a modest impact on our drug manufacture and timelines. As a result, the anticipated Phase I first-in-human studies for the Cholesterol-Lowering program are now expected to commence in the first half of CY2023. As Nyrada evolves, so too do the skills and expertise requirements of our Board. In recognition of the importance of adding skills that align with our growth strategy as we progress to clinical development, we were delighted to welcome Dr. Gisela Mautner as Non-Executive Director. Gisela brings more than 20 years of extensive leadership experience in global pharmaceutical organisations across multiple therapeutic areas. Her experience overseeing drug development at some of the world’s leading pharmaceutical companies will be invaluable as Nyrada’s programs advance towards the clinic. Peter Marks also retired from the Board after supporting the Company through its IPO and first years as a public company. I would like to extend the Board’s thanks to Mr Marks for his valuable contribution to Nyrada during his term as Non-Executive Director. His deep capital markets knowledge and networks have been invaluable in supporting the early growth of the Company. We remain confident in our strategy and in the long-term potential of both drug programs. Indeed, the markets for Cholesterol-Lowering and Brain Injury are growing due to the increasing incidence, as well as expanding awareness of the need for better treatment options. Nyrada’s small molecule drugs present significant treatment advantages that differentiate them from existing options currently available in the market. I wish to acknowledge the ongoing support of our Scientific Advisory Board, which has a strong track record in finding and realising the value of biotech companies. Their counsel and input have been integral to the success of our programs to date. On behalf of the Board, I’d also like to thank our shareholders for their support of Nyrada and extend our gratitude to the operational team for their perseverance throughout the year. Our highly dedicated management team continues to lead Nyrada from strength to strength, working hard to advance our programs to the clinic. Looking ahead, Nyrada is entering an exciting phase as it approaches first-in-human trials for both of its programs, and we are optimistic of the path ahead. We look forward to keeping you updated on progress over the next year. Yours sincerely, John Moore Non-Executive Chairman Nyrada Inc.
“Globally, we continue to see growing interest in the development of oral PCSK9 inhibitors, which clinicians consider to be an optimal approach to LDL-cholesterol lowering as an adjunct to statin treatment.”
NYRADA INC (ASX:NYR) 8 CEO Report Dear Fellow Shareholders, I am pleased to share our results and operating review for FY2022. The major operational challenge during the past 12 months has been the COVID-19 pandemic which has continued to disrupt global supply chains and logistics. While Nyrada’s drug manufacturing timelines were temporarily impacted by COVID-related lockdowns in Shanghai, China, delays were minimised because of the exceptional efforts of employees at the Contract Manufacturing Organisation (CMO) engaged by Nyrada, who worked tirelessly to recover time lost during the lockdown. Notwithstanding, we have continued to deliver promising preclinical results in both our Cholesterol-Lowering and Brain Injury Programs. In the Cholesterol-Lowering program, exploratory analysis conducted as part of a successful in vivo cholesterol efficacy study of drug candidate NYX-PCSK9i, delivered encouraging results that further support its mechanism of action in lowering cholesterol. Furthermore, in a novel human tissue-engineered model of atherosclerosis developed by researchers at Duke University, an optimised analogue of NYX-PCSK9i was shown to block the early phases of atherosclerosis, which is the chronic inflammatory response to elevated LDL-cholesterol leading to a build-up of plaque in the inner lining of the arteries. This analogue also exhibited superior pharmacokinetic parameters (improved absorption and distribution) in the study and accordingly, will be evaluated in Nyrada’s Phase I study in the first half of CY2023. The results of the atherosclerotic study are an exciting development in understanding the broader applications for PCSK9 inhibitors beyond lowering LDL-cholesterol, particularly as atherosclerotic plaque build-up is a major cause of cardiovascular disease. Additionally, there continues to be encouraging industry interest globally in the development of oral PCSK9 inhibitors, which clinicians consider to be an optimal approach to LDL-cholesterol lowering as an adjunct to statin treatment. Moreover, Nyrada’s lead brain injury drug candidate, NYR-BI02, a TRPC channel blocker, showed excellent oral bioavailability in an exploratory study, demonstrating it could potentially be administered as an oral treatment for concussion, in addition to intravenous dosing for severe traumatic brain injury (TBI) and stroke. The convenience of an oral dose 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 recovery outcomes. Given the significant interest in this area, these results open the door for the Company to potentially develop NYR-BI02 as an oral treatment for concussion as an additional program. Collectively, these results speak to the quality of the assets that the Nyrada team is developing, and their potential to positively impact patient lives as both programs advance towards the clinic. We are also encouraged by recent published preclinical research that highlights emerging opportunities in chronic heart and kidney disease indications for an orally bioavailable drug targeting TRPC 3/6/7 channels. Nyrada is reviewing these opportunities and considering next steps. “With the incidence of TBI increasing globally, this remains a large market with a significant unmet clinical need. Through our relationships with the world-class leading research teams at the Walter Reed Army Institute of Research (WRAIR) and UNSW Sydney (UNSW), Nyrada is in a unique position to develop the first drug to treat both TBI and stroke, with the potential to make a tangible difference in the quality of life of people affected by these injuries.”
ANNUAL REPORT FY22 9 Cholesterol-Lowering Program The World Health Organization (WHO) estimates that by 2030, 1 in 6 people will be aged 60 years or over, accounting for ~1.4 billion people globally.4 High cholesterol, specifically LDL or “bad” cholesterol, is a known significant risk factor for developing cardiovascular disease and is most prevalent between the ages of 55-64 in Australia, and 40-59 in the US.5 A large US study6 estimated that more than 62 million Americans have risk factors associated with cardiovascular disease, and are therefore eligible for cholesterol-lowering treatment. From this population, approximately 27 million take a statin drug, the current first line treatment for high LDL-cholesterol. Of those taking a statin, more than 18 million, or close to 70% are unable to achieve their safe target cholesterol level. As the world’s population continues to age, patient need for new, more effective, and convenient cholesterol-lowering drugs will only increase. We have shown through preclinical studies that Nyrada’s small molecule PCSK9 inhibitor is able to significantly lower LDL-cholesterol levels, while also increasing the number of LDL receptors which are responsible for removing cholesterol from the bloodstream. The drug Nyrada is developing is intended to be taken as a once-per-day pill, alone or in combination with a statin, overcoming the inconvenience of expensive injectable PCSK9 inhibitors. Small molecule drugs also have a lower manufacturing cost than biologics, which includes PCSK9 inhibitors. The program is entering an exciting period as safety, pharmacology, and toxicology studies get underway in the second half of this year, ahead of a Phase I first-in-human study expected to commence in the first half of next year, to be run in Australia. The primary objective of the Phase I study is to evaluate Nyrada’s drug candidate for safety and tolerability. However, a secondary endpoint will assess blood cholesterol levels in cohorts treated for 14 days with Nyrada’s drug candidate as a preliminary indication of the drug’s efficacy in humans. I am delighted that Nyrada’s intellectual property portfolio also continues to grow with the granting of patents for our PCSK9 inhibitor compounds in the US and Europe, providing composition of matter protection through to 2038. Brain Injury Program Nyrada’s Brain Injury Program made significant progress during the year. We revealed the biological target for the program as a class of proteins known as the “Canonical” Transient Receptor Potential, or TRPC ion channels. After a brain injury, these channels remain “open”, allowing calcium to accumulate in neuronal cells to toxic levels, leading to cell death.7 Nyrada’s brain injury drug candidate, NYR-BI02, is a potent blocker of three subtypes of the TRPC channel – TRPC 3/6/7, which are widely expressed in the brain. By targeting these channels, our brain injury drug candidate can inhibit the entry of calcium into cells and thereby reduce secondary brain injury. NYR-BI02 also readily crosses the intact blood-brain-barrier, indicating it can reach therapeutic levels in an injured brain. There is still no FDA-approved drug to treat TBI and only limited treatment options for stroke. To the Company’s knowledge, there is also no other small molecule brain injury drug in development that targets TRPC ion channels. A recent report8 estimated that annually, ~55.9 million people globally experience a mild TBI, with 5.48 million experiencing a severe TBI. More than 55 million people, or 0.7% of the world’s population are thought to be living with the effects of medically treated TBI. In the US, 4.8 million people are evaluated in emergency departments for TBI each year, with TBI being diagnosed in approximately 2% of total emergency department visits, hospitalisations, and deaths.9 This is not just a civilian issue, with 1 in 5 US military service members reporting experiencing a TBI during active duty. With the incidence of TBI increasing globally, this remains a large market with a significant unmet clinical need. Through our relationships with the world-class leading research teams at the Walter Reed Army Institute of Research (WRAIR) and UNSW Sydney (UNSW), Nyrada is in a unique position to develop the first drug to treat both TBI and stroke, with the potential to make a tangible difference in the quality of life of people affected by these injuries.
NYRADA INC (ASX:NYR) 10 As part of its active intellectual property protection program, Nyrada has filed a provisional patent covering a library of molecules, including NYR-BI02, that block these TRPC channels. It is anticipated that the patent will have coverage in the US, Australia, and Europe. Outside of our collaboration with WRAIR, we are also evaluating the efficacy of our brain injury drug candidate in a well-established preclinical stroke model, the Photothrombotic Model of Ischemia, with results expected in the fourth quarter. This model was previously used by Nyrada to test the efficacy of its first-generation molecule, which showed a promising efficacy signal. Nyrada will initially test the efficacy of its NYR-BI02 molecule as a TRPC 3/6/7 channel blocker in a model of TBI via our existing collaboration with WRAIR. The efficacy study will use the penetrating traumatic brain injury (PTBI) model which has been developed by the WRAIR team to emulate penetrating head wounds on the battlefield. The complex nature of this study requires WRAIR to contribute considerable resources to enable its completion. Like many large research organisations globally, the ongoing COVID-19 pandemic has had an impact on some project timelines. The progression of this study is largely driven by availability of the necessary resources at WRAIR, and we expect this study to commence in the new year. 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 at the same time. The required safety, pharmacology and toxicology studies that will evaluate the safety and tolerability of Nyrada’s lead brain injury drug candidate remain on track to commence during the current quarter. With drug manufacture now complete, formulation development work is in progress to ensure a suitable dose form for intravenous administration. This will not affect the in vitro safety and toxicology studies but is necessary for the start of the in-vivo safety and toxicology studies. While continued pressure on the availability of GLP study slots at CROs due to the limited resources available during COVID-19 has made booking study slots difficult, we are in regular dialogue with the CROs to ensure these studies are progressed expeditiously. Data from these studies will determine the safe starting dose for the Phase I first-in-human study which is now expected to start in the first half of CY2023. The Phase I study will be run in Australia and will evaluate the safety and tolerability of NYR-BI02. The Phase I study will support the development of Nyrada’s drug in both TBI and stroke indications, significantly expanding the commercial opportunities potentially available to the Company. I am proud of what Nyrada has achieved this year. Our success is testament to the significant time and effort invested by our talented team. Nyrada’s transition to a clinical drug development company over the coming 6-12 months is a turning point. The team and I wish to thank you for your ongoing support and look forward to sharing news of our progress as the preclinical studies unfold and our programs advance towards the clinic. Yours Sincerely, James Bonnar CEO Nyrada Inc
“Each year, globally, more than 60 million people suffer a concussion or moderate to severe traumatic brain injury (TBI), yet no FDA-approved treatment for secondary brain injury exists. For stroke the need is similar, with only limited treatment options available. Nyrada’s NYR-BI02 drug candidate offers the potential to reduce the secondary injury, and therefore reduce patient mortality and disability and improve quality of life. ”
NYRADA INC (ASX:NYR) 12 Directors’ Report The Directors present their report, together with the financial statements, on the Consolidated Entity (referred to hereafter as the 'Consolidated Entity') consisting of Nyrada Inc. (referred to hereafter as the 'Company' or 'Parent entity') and the entities it controlled at the end of, or during, the year ended 30 June 2022. Directors The following persons were directors of Nyrada Inc. during the whole of the financial year and up to the date of this report, unless otherwise stated: John Moore Non-Executive Chairman Peter Marks Non-Executive Director (resigned 1 August 2022) Rüdiger Weseloh Non-Executive Director Marcus Frampton Non-Executive Director Christopher Cox Non-Executive Director Ian Dixon Non-Executive Director Gisela Mautner Non-Executive Director (appointed 1 August 2022) John Moore Non-Executive Chairman, joined the Board in June 2019 John Moore currently serves as Chairman of Trialogics, a clinical trial informatics business, Chairman of Scientific Industries (SCND-OTCQB), a producer of laboratory instruments for the life sciences industry and Chairman of Cormetech, a manufacturer of environmental catalysts. John was CEO of Acorn Energy from 2006 to 2015, during which time the CoaLogix business was acquired for US$11 million and sold for US$101 million, and the Comverge business listed in the US before its sale to Constellation Energy. In 2002 he was a Partner and CEO of Edson Moore Healthcare Ventures and acquired for US$148 million a portfolio of sixteen drug delivery investments from Elan Pharmaceuticals. He is a graduate of Rutgers University, US. Interest in shares and options 358,423 shares and 3,600,000 unlisted options Special responsibilities Chair of the Board. Member of Audit & Risk Committee Member of Remuneration & Nomination Committee Directorship held in other listed entities (last 3 years) Noxopharm Limited (ASX:NOX) – resigned 16 July 2019
ANNUAL REPORT FY22 13 Peter Marks Non-Executive Director, joined the Board in August 2017, resigned 1 August 2022 Peter has over 35 years' experience in corporate advisory and investment banking. Over the course of his long career, he has specialised in capital raisings, IPOs, cross border, M&A transactions, corporate underwriting and venture capital transactions for companies in Australia, the United States and Israel. He has been involved in a broad range of transactions with a special focus on the life sciences, biotechnology, medical technology and high-tech segments. Peter has served as both an Executive and Non-Executive Director of a number of different entities which have been listed on the ASX, NASDAQ, and AIM markets. Peter is currently a Director of Alterity Therapeutics Limited (ASX:ATH and NASDAQ:ATHE), NonExecutive Director of Noxopharm Limited (ASX: NOX) and Non-Executive Director of Iris Metals Limited (ASX:IR1). Peter holds an MBA from the University of Edinburgh, Scotland, a Bachelor of Economics, a Bachelor of Laws, and a Graduate Diploma in Commercial Law. Interest in shares and options 250,000 shares and 2,600,000 unlisted options Special responsibilities Member of Audit & Risk Committee Directorship held in other listed entities (last 3 years) Alterity Therapeutics Limited (ASX: ATH) - current Noxopharm Limited (ASX:NOX) - current Elsight Limited (ASX:ELS) - current Iris Metals Limited (ASX:IR1) – current Fluence Corporation Limited (ASX:FLC) - resigned 31 March 2020 Christopher Cox Non-Executive Director, joined the Board in November 2019 Christopher Cox is a Co-Founder and has been a Managing Partner of Population Health Partners since April 2020. He is also a Senior Vice President of Population Health Investment Co. Inc (Nasdaq: PHIC). Additionally, Chris is a retired Partner of Cadwalader, Wickersham & Taft LLP (New York) a position he held from January 2012. He remains a Senior Attorney of the firm. Previously the Chairman of Cadwalader’s Corporate Department and a member of its Management Committee, Chris advises clients on a wide array of corporate and financial matters, including mergers and acquisitions and restructurings, spin-offs, joint ventures, IP monetisation’s and other complex financing transactions. From February 2016 to March 2019, Chris was seconded to The Medicines Company, a global biopharmaceutical company, where he served as Executive Vice President and Chief Corporate Development Officer and was responsible for business development and strategy. Before January 2012, Chris was a partner at Cahill Gordon & Reindel LLP in New York. Chris also serves as the Chief Executive Officer of Symphony Capital Holdings, LLC, a private investment holding company with interests in biotechnology, network security and entertainment. Chris received both his undergraduate degree and J.D. from the University of Missouri, where he was also a member of the Missouri Law Review. Interest in shares and options 1,425,000 shares and 1,800,000 unlisted options Special responsibilities Chair of Remuneration & Nomination Committee Directorship held in other listed entities (last 3 years) N/A
NYRADA INC (ASX:NYR) 14 Marcus Frampton Non-Executive Director, joined the Board in June 2019 Marcus Frampton currently serves as the Chief Investment Officer of the Alaska Permanent Fund Corporation (APFC), the US$77 billion sovereign wealth fund for the State of Alaska. Marcus manages the investment team at APFC and leads all investment decisions related to APFC’s investment portfolio within the guidelines established by APFC’s Board of Trustees. Before joining the APFC in 2012, Marcus held positions ranging from Investment Banking Analyst & Associate at Lehman Brothers (2002-2005), to private equity investing at PCG Capital Partners (2005-2010), and acted as an executive of a private equity-backed portfolio company at LPL Financial (2010-2012). In addition to his duties at the APFC, Marcus is also a shareholder and sits on the board of directors of Scientific Industries, Inc., a leading manufacturer of laboratory equipment and the owner of intellectual property related to bioprocessing systems. Marcus graduated from UCLA with a Bachelor’s degree in BusinessEconomics and a Minor in Accounting. Interest in shares and options 245,075 shares and 1,800,000 unlisted options Special responsibilities Chair of Audit & Risk Committee Directorship held in other listed entities (last 3 years) N/A Rüdiger Weseloh Ph.D. Non-Executive Director, joined the Board in June 2019 Rüdiger Weseloh is a Senior Director of Business Development at Merck KGaA, Darmstadt, Germany, where over a period of 15 years he has led more than 80 transactions for its pharmaceutical division, completing deals across the drug development value chain in the fields of Oncology, Rheumatology, Neurodegenerative diseases, and Fertility. Before Merck KgaA, Rüdiger spent 5 years as a Biotech/Pharma Equity Analyst, at Gontard & Metallbank AG, Frankfurt, and Sal. Oppenheim, Cologne/Frankfurt, as well as 3 years as a Postdoc at the Max-Planck-Institute for Experimental Medicine in Goettingen. He has a university diploma in Biochemistry from the University of Hannover and a PhD in Molecular Neurobiology, obtained at the Center for Molecular Neurobiology in Hamburg. Rüdiger also served 5 years on the Supervisory Board of Cytotools AG, Freiburg, Germany. Interest in shares and options 100,000 shares and 1,800,000 unlisted options Special responsibilities N/A Directorship held in other listed entities (last 3 years) Cytotools AG (FRA:T50) - resigned in September 2021
ANNUAL REPORT FY22 15 Ian Dixon Ph.D. Non-Executive Director, joined the Board in September 2020. Dr Dixon has a PhD in biomedical engineering from Monash University, an MBA from Swinburne University and professional engineering qualifications. He is also a co-inventor of Nyrada’s patented drug NYX-330 to treat hypercholesterolemia and atherosclerosis. Dr Dixon brings to the Board an extensive technical and entrepreneurial background in founding, building and running technology-based companies, in recognising the potential commercial value of early-stage drug development, and in understanding the challenges involved in drug development. In 2011, Dr Dixon co-founded Cynata Inc, now a subsidiary of ASX-listed Cynata Therapeutics Ltd (ASX-CYP), a company progressing the commercialisation what has become the Cymerus stem cell therapy to treat various medical conditions including osteoarthritis, ARDS and critical limb ischemia. Also a founder director of genetic medicines company Exopharm Ltd (ASX-EX1) in 2013 and during the last three years Dr Dixon has served as a director of the following listed companies: Medigard Ltd (ASX-MGZ); Noxopharm Ltd:(ASX-NOX). Interest in shares and options 10,114,033 shares, 5,999,400 Performance Shares and 1,800,000 unlisted options Special responsibilities Member of Remuneration & Nomination Committee Directorship held in other listed entities (last 3 years) Exopharm Limited (ASX:EX1) -current Noxopharm Limited (ASX:NOX) - resigned on 31 August 2020 Gisela Mautner Non-executive Director, joined the Board 1 August 2022 Gisela is an international business leader with significant experience developing and launching new pharmaceutical products, and delivering successful corporate strategies in highly competitive global markets. She also has over thirty years’ experience in medical and scientific research, most recently as the Chief Medical Officer of Noxopharm Ltd (ASX-NOX). Gisela has held senior positions with Amgen, Bayer, Siemens Medical Solutions and Merck/MSD generating successful commercial and scientific outcomes. She is currently the Past-President of the Australian Pharmaceutical Physicians Association (APPA), a Fellow of the Australasian College of Physician Executives and a Member of the Australian Institute of Company Directors and the CEO Institute. Gisela holds an MD from the Technical University of Munich, a PhD from the Ludwig Maximilian University, an MPH from Harvard University and an MBA from Northwestern University Chicago. Interest in shares and options N/A Special responsibilities N/A Directorship held in other listed entities (last 3 years) Noxopharm Limited (ASX:NOX) - current Company Secretary - David Franks David is a Chartered Accountant, Fellow of the Financial Services Institute of Australia, Fellow of the Governance Institute of Australia, Justice of the Peace, Registered Tax Agent and holds a Bachelor of Economics (Finance and Accounting) from Macquarie University. With over 25 years in finance and governance (including company secretarial and corporate finance), David has been CFO, company secretary and director for numerous ASX listed and unlisted public and private companies, in a range of industries covering energy retailing, software as a service, transport, financial services, oil and gas / mineral exploration, technology, automotive, software development, wholesale distributions, retail, biotechnology and healthcare. He has acted in these capacities for Top 200 to small-cap companies listed on ASX, including for companies with OTC listings. David is also the Company Secretary of Noxopharm. David is also a Non-Executive Director of Jcurve Solutions Limited (ASX:JCS) and a Director, Principal and shareholder of Automic Group Pty Ltd, a service provider to the Company.
NYRADA INC (ASX:NYR) 16 Principal activities Nyrada is a preclinical stage, drug discovery and development company, specialising in novel small molecule drugs to treat cardiovascular and neurological diseases. The Company’s two lead programs are focused on Cholesterol-Lowering and Brain Injury, each targeting market sectors of significant size and unmet clinical need. These programs are developing an oral, small molecule Cholesterol-Lowering drug, and a drug to reduce secondary brain damage following a stroke or traumatic brain injury (TBI). Nyrada is a Company incorporated in the state of Delaware, US and is listed on the Australian Securities Exchange (ASX:NYR). Significant changes in the state of affairs There were no significant changes in the state of affairs of the Consolidated Entity during the financial year. Financial results The loss for the Consolidated Entity after providing for income tax amounted to $3,959,661 (30 June 2021: $3,539,253). The year ended 30 June 2022 operating results included the following: • Research and Development Tax Incentive refund of $1,048,333 relating to the accrued FY2022 refund (2021: $2,286,022 relating to the FY2020/2021 refund of $1,309,650 and received FY2019/2020 refund of $976,372). • Research and development costs of $1,835,072 (FY2021: $2,175,050); • Corporate and administration expenses of $699,653 (FY2021: $895,839); • Share based payment expense of $966,951 (FY2021: $1,111,622); • Professional services expense of $338,841 (FY2021: $509,842); and • Employee benefits expense of $1,000,030 (FY2021: $929,931) The cash position as at 30 June 2022 was $10,816,039 (30 June 2021: $13,750,743). Review of operations During the 2022 financial year, Nyrada continued to advance its two lead drug development programs: • Cholesterol-Lowering Program: an oral PCSK9 inhibitor drug for the treatment of high blood LDL-cholesterol levels in patients at risk of cardiovascular disease, where statin drugs are poorly tolerated (monotherapy) or ineffective (single pill combination treatment). • Brain Injury Program: a neuroprotectant drug to reduce the impact of secondary brain injury in patients following a stroke or TBI, such as can occur following a motor vehicle accident, fall, or sporting injury. Strong results from both of these programs over the course of the year positions the Company well for the clinical studies ahead. Breaking new ground in the development of a once-per-day, oral cholesterol-lowering drug Nyrada’s oral PCSK9 inhibitor drug creates the potential for a next generation alternative to expensive and inconvenient PCSK9 injectable drugs. During FY2022, Nyrada’s Cholesterol-Lowering Program continued to deliver impressive preclinical results. In August 2021, exploratory analysis results from an in vivo cholesterol efficacy study showed NYX-PCSK9i significantly increased plasma PCSK9 levels, supporting the mechanism of action of Nyrada’s compound in lowering cholesterol. The 35-day study used a specialised mouse model genetically modified to better reflect the way in which humans metabolise cholesterol. NYX-PCSK9i was dosed at 50mg/kg as a monotherapy and in combination with the statin drug Lipitor® (atorvastatin, Pfizer) with no adverse effects identified. Treatment with NYX-PCSK9i also significantly increased the number of LDL receptors responsible for removing cholesterol from the bloodstream, with further analysis revealing Nyrada’s compound enhances cholesterol clearance from the body.
ANNUAL REPORT FY22 17 Testing Nyrada’s PCSK9 Inhibitor in a Model of Atherosclerosis On 19 July 2022, results from a study run by researchers at Duke University Pratt School of Engineering (Duke), using select candidates from Nyrada’s PCSK9 inhibitor family of compounds were presented at the North American Vascular Biology Organisation (NAVBO) 2022 Vasculata conference in North Carolina. The study aimed to determine if PCSK9 inhibitors attenuate inflammation in vascular cells in the early phases of atherosclerosis. In a human tissue-engineered blood vessel model of atherosclerosis, developed in the lab of Professor George Truskey, Nyrada’s PCSK9 inhibitor blocked the early stages of atherosclerotic plaque progression, including preventing monocyte adhesion and suppression of inflammatory cytokines, which are key mediators of the disease process. An optimised version of NYX-PCSK9i with superior pharmacokinetic parameters (improved absorption and distribution) was evaluated in this study. Accordingly, this compound will be assessed in Nyrada’s Phase I study in the first half of CY2023. It is the first time the model has been used to characterise the role of PCSK9 in the early phases of atherosclerosis and the potential for small molecule inhibitors of PCSK9 to block this process. The researchers at Duke intend to publish the findings of this study in a peer-reviewed paper. Preclinical Safety and Toxicity Studies During the second half of FY2022, an escalation in the number of COVID cases in Shanghai, China led to widespread lockdowns, which delayed the scale-up manufacture of Nyrada’s drug candidate, as employees of the contract manufacturing organisation (CMO) engaged by Nyrada were not able to access laboratory worksites. Drug manufacture was quick to recommence upon Shanghai’s reopening, with the CMO deploying additional personnel and resources to recover lost time. Impacted by the lockdowns, the required preclinical safety, pharmacology, and toxicology studies are expected to commence in H2 CY2022. These studies will evaluate the safety and tolerability of Nyrada’s drug and will be run at Inotiv, a US based contract research organisation (CRO). Data from these studies will determine the safe starting dose for the Phase I first-in-human study. Phase I Study The primary objective of the Phase I study is to evaluate Nyrada’s drug candidate for safety and tolerability. The study will be a double-blind, randomised, dose escalation design evaluating the safety, tolerability, and pharmacokinetics of Nyrada’s leading drug candidate in approximately 56 healthy volunteers aged 18 to 50 years. A secondary endpoint will assess blood cholesterol levels in cohorts treated for 14 days with Nyrada’s drug candidate as a preliminary indication of the drug’s efficacy in humans. Favourable results from the Phase I study will position Nyrada well for a possible Phase II clinical trial, which would provide a comprehensive assessment of the efficacy of Nyrada’s drug candidate in the target population, patients with a high cholesterol. As a result of scale-up drug manufacturing delays caused by COVID-related lockdowns in Shanghai, the Phase I first-in human study is expected to commence during the first half of CY2023. Objectives • Evaluate safety, tolerability, and pharmacokinetics of NYX-PCSK9i • Measure changes in LDL-cholesterol Design (subject to ethics approval) • Double-blind, randomized, placebo-controlled, dose escalation study • Single ascending oral dose (Cohorts 1-5) • Once daily oral dose over 14-day treatment period (Cohorts 6, 7) • Pharmacokinetic and pathology samples will be collected at selected time points over the trial period for all subjects Participants • 56 healthy volunteers (18 to 50 years) • 7 cohorts (6 active: 2 placebo per cohort) Location & Duration • Study will be conducted at a clinical trial center in Australia • The dosing period will vary between 1 – 14 days Cohorts 1-5 Cohorts 6-7 Day 1 Day 2 Day 14 Data analysis Single ascending oral dose Once daily oral dose
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.
ANNUAL REPORT FY22 19 Preclinical Safety and Toxicity Studies Safety, pharmacology, and toxicology studies are anticipated to begin in Q3 CY2022. These studies will evaluate the safety and tolerability of Nyrada’s lead brain injury drug candidate in research models. Data from these studies will determine the safe starting dose for the Phase I first-in-human study. Manufacture of the batch of drug to be used in the preclinical and clinical studies has been completed and is now undergoing formulation development to deliver a dose form suitable for intravenous administration. The necessary formulation development work is being undertaken at a leading US based CRO from mid-September and is expected to take between 2 - 6 weeks to complete. This formulation work does not impact on the timing of cell-based in vitro safety and toxicology studies, which are due to commence in Q3 CY2022. However, this formulation work must be completed prior to the commencement of the in vivo safety and toxicology studies to ensure optimal drug delivery. The ongoing COVID-19 pandemic has led to an industry wide constraint on resources and complicated logistics, resulting in a lack of availability of GLP study slots, making scheduling preclinical work with CROs challenging. The Company is in regular contact with the CRO to ensure these studies are expedited. Phase I Study Pending completion of the FDA mandated preclinical safety and toxicology studies and ethics committee approval of the trial protocol, recruitment, and dosing of the first participant is expected to commence in H1 CY2023. The Phase I study will be run in Australia and will evaluate the safety and tolerability of NYR-BI02. The trial participants will be split into 5 groups of 8, with 6 receiving the drug and 2 receiving a placebo. Blood samples will be drawn several times throughout the study period and analysed for drug levels. Participants will be monitored for clinical signs throughout the study duration. The study will support the development of Nyrada’s drug in both TBI and stroke indications, significantly expanding the commercial opportunities available to the Company. Objectives • To assess the safety, tolerability, and pharmacokinetics of NYR-BI02 Design (subject to ethics approval) • Randomized, double-blind placebo –controlled, dose escalation design • 5 cohorts; 8 participants each cohort; 6:2 active and placebo treatments • 3 cohorts will be single ascending doses • 2 cohorts will be given continuous infusion doses Participants • Male and female healthy volunteers • 18 – 50 years age Cohort number Dose administered 1 Low dose single bolus 2 Medium dose single bolus 3 High dose 4 Low dose continuous infusion (72 hrs) 5 High dose continuous infusion (72 hrs) Location & Duration • Study will be conducted at a clinical trial center in Australia • The study duration will vary between 1 – 4 days Cohorts 1-3 Cohorts 4-5 Day 1 Day 2 Day 10 Continuous infusion Day 7 Day 3 Bolus delivery Safety assessment Safety assessment
NYRADA INC (ASX:NYR) 20 Intellectual Property Cholesterol-Lowering Program Nyrada’s medicinal chemistry program continued to generate further promising PCSK9 inhibitor analogues, which enabled the Company to file a Patent Cooperation Treaty (PCT) application for new generation PCSK9 inhibitor compounds in December 2021. A PCT application makes it possible to seek protection for an invention simultaneously in a large number of countries by filing a single “international” patent application, instead of filing several separate national or regional applications. This application builds on the patent granted by the US Patent and Trademark Office, as announced on 30 July 2021. In July 2022, the European Patent Office granted a composition of matter patent for the Company’s novel compounds inhibiting PCSK9, providing protection for Nyrada’s intellectual property relating to its PCSK9 inhibitor technology until 16 March 2038. Nyrada now has patent protection for the compounds in both the US and European Union. Brain Injury Program In May 2022, Nyrada filed a provisional patent covering a library of molecules, including NYR-BI02, that block TRPC ion channels. It is anticipated that the patent will have coverage firstly in Australia, followed by Europe and US. Board Changes In August 2022, Dr. Gisela Mautner was appointed to the Board as a non-executive director. Dr. Mautner is a medical doctor and brings over 20 years pharmaceutical industry experience encompassing all aspects of drug development, from clinical research through to product commercialisation. She is a seasoned senior leader, having held positions at MSD (Merck), Bayer and Amgen, where she successfully launched several new drugs in different therapeutic areas, including in cardiovascular diseases. In addition, Peter Marks retired from his role as a non-executive director on the Board to pursue a range of other interests, having supported Nyrada through its IPO and key first years as a listed company. COVID-19 Pandemic Nyrada retained the remote working model we adopted early on in the COVID-19 pandemic, while maintaining access to a shared office for regular in personmeetings. Greater flexibility in how and where our employees choose to work continues to benefit team morale, as well as enhance productivity while also keeping office overhead costs low. It also means little to no disruption to the Company’s operations when health authorities issue work from home recommendations during an increase in COVID-19 case numbers. Other In January 2022, Nyrada received an A$1.3 million cash rebate (“R&D rebate”) from the Australian Federal Government’s Research & Development (R&D) tax incentive program. The R&D rebate relates to expenditure incurred on eligible R&D activities conducted during the 2021 financial year, in respect of Nyrada’s preclinical work for its Cholesterol-Lowering and Brain Injury drug development programs. The amount received will partially fund the progression of these two programs to Phase I clinical trials and the working capital requirements of Nyrada Inc. Financial Position 2022 $ 2021 $ Cash and cash equivalents 10,816,039 13,750,743 Net assets / total equity 11,498,916 14,491,626 Contributed equity 25,320,332 25,320,332 Accumulated losses (19,515,280) (15,555,619) The Directors believe the Consolidated Entity is in a strong and stable financial position to expand its current operations.