NEWSLETTER 27 January 2018

Transcription

1 NEWSLETTER 27 January 2018

2 I am calling this our inaugural newsletter, but it is not so much a newsletter as a welcome on board and a brief introduction to the company you now part-own. Nyrada has been underway effectively for the past 3 months as control and operation of its 3 drug assets transitioned from Noxopharm and Altnia. Being in transition still meant that the R&D programs continued, but at something short of full pace with limited personnel and funding. With the transitioning now complete and subscription funds about to be released, Nyrada is able to start the process of getting into full swing. Company Snapshot We are a drug discovery and drug development company. There is no notion at this stage of doing anything more than bringing new drugs into the clinic, establishing their therapeutic potential, and then finding someone else to take the drug through the final steps of the regulatory process and bringing it to market. The 80:20 rule classically applies to drug development: getting an experimental drug to the point of being 80% confident of its final success represents about 20% of that drug s final cost of development. Nyrada does not need to be taking on the final 80% of the cost of that exercise, even if that process represents just 20% of the total development time. Passing a drug onto someone else might vary between a trade sale of a particular asset, or a license, or a partnership, or something else more creative. Irrespective of the nature of the deal, at this stage our horizon is Phase 2 clinical stage development. We also will be focusing on drug development in areas of high community demand. And with high community need comes high pharmaceutical industry interest. The 4 therapeutic indications we currently are exploring, happen to be areas of considerable interest for big pharmaceutical companies. Large acquisitions are taking place, and we will be looking to position individual Nyrada assets to that end. We are a US company. It s not difficult to guess why.. the US capital markets are where we expect to get greater attention and better value for the stock. It is the home of wealthy foundations and significant government funding, with our 3 therapeutic indications the targets of substantial funding activity. The strategy is to conduct our business largely in Australia for the next 2 years, with a growing foothold in the US, eventually leading to the Company s HQ being relocated to the US in early In the Company s 2 formative years, it makes sense to not have to duplicate the administrative, pre-clinical and clinical resources within Noxopharm.

3 We aim to list. The aim is to provide liquidity for our shareholders, as well as having ready access to capital markets for fund-raising. The timing is as soon as possible, but obviously will be dependent on a number of factors, some of which are under our control, and others that are not. The current plan is to seek a listing on the ASX under the CHESS Depositary Interest (CDI) facility. This is a process requiring the issue of a full prospectus and having a minimum of 300 shareholders. A NASDAQ listing is an obvious objective as well, but our current strategy is to pursue an ASX listing first. We intend to be focused. Given the high-risk, binary nature of drug development, diversity is a sensible de-risking strategy in this high-stakes game. But diversity also carries the risk of distracting people and of diluting effort and scarce resources. That is why Noxopharm carved out Nyrada in the first place. Nyrada is deliberately de-risked. It starts life pursuing 3 broad therapeutic indications: 2 of them are neurological in nature, and 1 non-neurological. Each one of these programs is too early in development to be playing favourites because at this early stage each one has got roughly equal proof-of-concept and equal likelihood of making it to market. So, each is being given equal resources. But, right now, the starting intention is to focus eventually on neurological drug development, and to add as much value as we can to our non-neurological asset over the next 2 years before looking to pass it on to pharma companies that specialises in the field of cardiovascular health. The one predictable aspect of drug development is its unpredictability, and we intend that Nyrada will be sufficiently advised and smart enough to recognise opportunity and to make the right calls on its scientific and commercial strategies. A neurosciences company. That is how we envisage Nyrada. Of course, that vision will always be open to change as we stay alert to opportunity and circumstances, but it is our starting vision. Neurodegenerative disease is one of medicine s great unexplored frontiers with an enormous call for medicines across a wide spectrum of diseases and conditions. But this is a call that remains largely unanswered. For example, no drug is approved for the treatment of loss of hearing, or for the underlying disease processes in Alzheimer s, or Huntingdon s, or Parkinson s, or ALS (motor neurone disease), or multiple sclerosis, or direct injuries to the nervous system such as stroke, trauma and drug side-effects. Under any other circumstances, such need would have been met with a wave of companies entering the field. But the human nervous system presents a raft of challenges not found in other systems, most of which have presented insurmountable barriers up to now. Those barriers have led to significant constraints on companies in the neurosciences field, typically restricting them to focus on treating the symptoms of disease, rather than addressing the underlying disease processes and seeking to stop their progression.

4 Nyrada has a vision of being able to block the progressive nature of many common neurodegenerative diseases and disorders, rather than just their symptoms. That vision has its basis in two proprietary drug technologies that address two key underlying pathologies common to most neurodegenerative diseases: excitotoxicity and inflammation. NYX-104 is our lead drug in the field of excitotoxicity, and NYX-205 in the field of neuroinflammation. Management Board of Directors Scientific Advisory Panel Chair: Prof. Gary Housley Dr Graham Kelly CEO James Bonner V-P. R&D Mark Waring Senior V-P. US Operations R&D team Board The Board currently stands at 3: Dr Graham Kelly (Executive Chairman and CEO), Mr Peter Marks (Non-Executive Director) and Mr Josiah Austin (Non-Executive Director). Josiah is a US citizen and resident and is an Independent Director. Another 2 directors are to be appointed.

5 Scientific Advisory Board The Scientific Advisory Board will provide general guidance to the Board of Directors on scientific and commercial strategies, and to advise the executive and scientific teams on the conduct of the various R&D programs. The Advisory Board is chaired by Scientia Professor Gary Housley, who holds the UNSW Sydney Chair of Physiology, and is Director of the Translational Neurosciences Facility at UNSW. Professor Housley is to be joined by 4 other eminent scientists, 2 others in the field of neuroscience and 2 in the field of blood lipid metabolism. These scientists have been identified and approached, and currently are in the process of having their appointments confirmed. CEO The appointment of Graham Kelly as CEO is an interim step only and is a part-time position. The intention is for Graham to see the Company through its formative stages and to have identified and appointed a full-time CEO by the time the Company is ready to relocate its headquarters to the US. Graham s appointment is expected to be for no more than 24 months. Executive James Bonnar has joined the Company as Vice-President, Research & Development. James has had a distinguished career in neurological drug development in the biotechnology sector. In addition to overseeing all R&D in Nyrada, James will take personal control of the NYX-104 (neuroprotectant) drug program, an area in which he has considerable experience. Mr Mark Waring is Senior Vice-President, US Operations. Mark is based in the US and will anchor the Company s activities there for the next 2 years ahead of the Company s relocation to New York. R&D Team Dr Benny Evison is Director, Anti-Inflammatory Drug Program. Benny has been with Nyrada for 9 months and is responsible for bringing all 3 drug programs to their current position. In the short-term, Benny will focus on the NYX-205 drug program. A Director, Cardiovascular Drug Program currently is being sought. An additional 2 scientists are to be appointed by March to complete the R&D team at this stage. Further appointments will be made as the R&D programs expand. Ancillary resources For the foreseeable future, most other corporate and research resources will be supplied by Noxopharm under a general services agreement. Over time as the need arises, Nyrada will switch to in-house resources. General office management, HR, chemistry, drug manufacture, regulatory affairs and clinical trial management, all will be provided by Noxopharm on a contractual basis.

6 The science Now to the business end of the Company. Three drugs and multiple indications. It s a full book of work. And it s important and potentially ground-breaking work. NYX-104 Excitotoxicity. The extraordinary self-destruct phenomenon, seemingly peculiar to the nervous system, that continues to damage and kill nerve cells, for days and weeks following an acute injury. A phenomenon that means greater damage, and therefore delayed recovery, after physical injury to the central nervous system (brain and spinal cord) from events such as stroke, concussion, severe epileptic seizure, physical trauma and loud noise. A phenomenon that manifests in permanent disability after stroke, or early onset dementia in professional sportspeople, or hearing impairment in service men and women. A common phenomenon in our community in urgent need of an effective therapy. Our aim is to develop NYX-104 as a first-in-class neuroprotectant to meet this need. Where we are up to R We have achieved the key first step in any drug development program in having identified a potential drug candidate. Professor Gary Housley s team at UNSW have made significant progress recently in groundbreaking research that has led to a better understanding of the biochemical processes underlying excitotoxicity. A key protein and signalling pathway have been identified and a patent lodged by UNSW, with the first grant of this patent recently achieved. NYX-104 is a small molecule drug selected initially for its ability in the laboratory to block the excitotoxicity pathway described by Professor Housley s team. When given to mice bearing a brain injury mimicing human stroke, NYX-104 blocked the extent of post-injury brain death (excitotoxicity) by 60%. This is key proof-of-principle data that gives the Company confidence that it has a potential major new therapeutic on its hands.

7 Using the Noxopharm LIPROSE drug delivery system, NYX-104 was delivered rectally to the mice, leading to the formation of a pro-drug form of NYX-104 that crosses the blood-brain barrier of the mice, reaching brain tissue in relatively high, therapeutic levels. For the scientifically-minded, NYX-104 is a kinase inhibitor, which is a drug that inhibits the ability of kinases, enzymes that activate (phosphorylate) proteins. In the case of NYX-104, we believe it is inhibiting the proteins identified by Professor Housley that are involved in the mobilisation of calcium in neurons. It is this mobilisation of calcium in response to injury that is a major factor in the cascade of neuronal cell death that occurs with strokes and brain injuries. What we need to do now Before we can even think about starting human studies, we need to do the following basic studies: a) We believe that NYX-104 is our final molecule. But we need to be certain. This means testing in the laboratory more compounds closely related to NYX-104 to see if we can find a more powerful compound. b) Develop both intravenous and suppository dosage forms of NYX-104 for acute and chronic administration respectively. c) Test the final drug in a large animal model of brain injury. d) Determine the extent of off-target activity of the drug and its safety in animals. Steps (b), (c) and (d) are proceeding with NYX-104 on the basis that a more powerful molecule is unlikely to be found. Step (a) is current; should a better (or equally potent) lead molecule emerge, then it will be developed in parallel with NYX-104 to provide a competitive selection process. The intellectual property pertaining to the chemical composition of the NYX-104 family of compounds and target action are part of the Nyrada patent portfolio. This is not going to be a quick route into the clinic. The Company is facing several years of study to prove that the drug is sufficiently likely to provide a therapeutic benefit in humans and likely to be without significant safety issues. But each step we take brings us closer to the clinic and increases the value of this asset. And we won t be on this journey alone. We are going to seek collaborations with highprofile clinical research groups around the world in order to expedite entry into the clinic across a number of different clinical indications. NYX-205 NYX-205 is an anti-inflammatory drug. More specifically a drug that inhibits the formation of one of the key contributors to inflammation. a hormone known as thromboxane.

8 After decades of flying under the scientific radar, thromboxane has emerged in recent years as a putative key player in the inflammatory processes associated with many neurodegenerative diseases. The challenge with this discovery is that there are remarkably few drugs that specifically inhibit the production of thromboxane, coupled with a complete absence of any such drugs able to cross the blood-brain barrier to inhibit thromboxane production in the brain. Our aim is to develop NYX-205 as the first specific inhibitor of thromboxane production, with the additional key feature of being able to cross the blood-brain and blood-nerve barriers to treat inflammation of the central nervous system (brain and spinal cord) and peripheral nerves. Neuro-Inflammation. Inflammation is the body s response to injury, designed to kick-start the repair process. Once the injury subsides and the repair process is complete, the inflammatory process then retreats and the tissue returns to normal function. But where the underlying injury or disease process persists, then the inflammation also persists and eventually becomes chronic. Chronic inflammation then becomes a disease in itself on top of the original injury or disease, typically causing loss of function in its own right. Inflammation of nervous tissue (neuro-inflammation) follows anything that injures nerve cells. This can be as varied as physical trauma, deprivation of oxygen, chemical poisons, genetic malfunction and viruses. And while inflammation in any tissue is a complex interplay between numerous hormones and chemicals, thromboxane has emerged in recent years as a likely key player in neuro-inflammation, marking it, therefore, as a key drug target. NYX-205 blocks the production of thromboxane by inhibiting the function of the enzyme responsible for its manufacture, thromboxane synthase. NYX-205 specifically inhibits thromboxane synthase without affecting the production of the other key component of inflammation, the prostacyclins, which are the target of the great majority of antiinflammatory drugs used in humans. Thromboxane was long thought to be a relatively minor player in the inflammatory process being produced by blood platelets, with major functions being to clump platelets and to cause blood vessels to contract. We now know that it is produced by a wide variety of tissues and to play broad and integral roles in inflammatory and immune responses to tissue injury. Recent experiments in a mouse model of Alzheimer s Disease found that blocking thromboxane activity in the brain put a very considerable brake on the development of structural changes in the mouse s brain associated with dementia. Where we are up to R NYX-205 is confirmed as a potent inhibitor of thromboxane synthase. It is our confirmed lead candidate drug, meaning we are able to proceed with the standard preclinical development process leading up to human studies.

9 What we are doing now While neuro-inflammation in diseases such as Alzheimer s, Parkinson s, Huntingdon s and amyotrophic lateral sclerosis (ALS, or motor neurone disease) are the obvious long-term therapeutic targets for NYX-205, clinical trials in those indications will be challenging. The Company has adopted a strategy of first proving the clinical benefit of NYX-205 in more readily accessible clinical models, which in their own right still represent major commercial opportunities. The clinical target we are pursuing is peripheral neuropathy, or loss of function of the nerves supplying the hands and feet. The loss of function follows loss of their myelin (insulating) sheath as a result of chronic inflammation. It is a common side-effect of certain common cancer chemotherapies in both adults and children, as well as a common outcome in patients with Type 1 diabetes. The barrier that prevents most drugs from reaching the brain, is the same barrier that prevents drugs being able to reach peripheral nerves (the so-called blood-nerve barrier). Providing evidence of clinical benefit in peripheral neuropathy, while of significant community benefit in its own right, should provide the rationale for extending studies of NYX- 205 use into central nervous system indications. Nyrada currently is conducting studies in collaboration with a research group at UNSW (Sydney) using a mouse model of cisplatin-induced peripheral neuropathy. Those studies are intended to provide the necessary proof-of-principle evidence of NYX-205 therapeutic benefit required to justify clinical studies in cancer patients experiencing side-effects of peripheral neuropathy. NYX-330 This is the Company s single non-neurological drug program. NYX-330 is under development as a treatment for hypercholesterolemia, or elevated blood levels of LDL (low density lipoprotein) cholesterol where it presents a risk factor for cardiovascular disease. After almost 3 decades of relying on the so-called statin drugs to lower LDL levels, the therapeutic target has shifted from blocking the production of LDL cholesterol, to increasing the rate at which LDL cholesterol is removed from the body. Driving this shift is the roughly one-third of patients dosed with statin drugs who need to stop treatment because of unwanted side-effects and the roughly one-third in whom the treatment fails to deliver the targeted clinical effect. The new target is the protein, PCSK9, a plasma protein that regulates the clearance of LDL cholesterol from the bloodstream. The more PCSK9 protein that a person has in their

10 bloodstream, the less able that person is to clear the LDL cholesterol from the blood and the higher LDL cholesterol levels rise. The following diagram shows the dynamics of removal of LDL cholesterol from the blood. The surface of liver cells (hepatocytes) express a protein (LDL-receptor, or LDLR) that attaches to the LDL cholesterol particles as the blood passes through the liver. This forms a 2-party complex (cholesterol particle + LDLR) that moves inside the liver cell where the LDL cholesterol particle s broken down. The LDLR then recycles to the surface of the liver cell to repeat the action. If PCSK9 is present, it interferes in this dynamic by binding to the LDLR-cholesterol complex, forming a 3-party complex that once inside the liver cell, leads to the complete degradation of all 3 components, including the LDLR. Without the ability to recycle the LDLRs, the outcome is a net loss of LDLRs and a resulting decreased capacity of the liver to remove LDL cholesterol from the blood. NYX-330 is a small molecule that has been designed to block the ability of the plasma protein, PCSK9, to bind to the LDL receptor-ldl cholesterol particle complex. NYX-330 is being developed as an oral, well-tolerated medication that either will augment the efficacy of statins in those individuals unsatisfied with the statin benefit, or to replace statins in patients unable to tolerate statins. Where we are up to R NYX-330 is confirmed in the laboratory as blocking binding between PCSK9 and LDLR, and in mice as having an appropriate pharmacokinetic profile in terms of blood levels and drug half-life and being well tolerated after short-term dosing.

11 What we are doing now a) We believe that NYX-330 is our final molecule. But as with NYX-104, we need to be certain. This means testing in the laboratory chemical variations of NYX-330 to see if we can find a more powerful compound. b) Develop an oral dosage form that optimises the bio-availability (rate of absorption) of NYX-330. c) Determine the extent of off-target (potentially unwanted activity) by both laboratory tests and animal safety studies. Investor relations The Nyrada shareholder base currently stands at just under 30 entities. Being an unlisted company carries certain advantages in terms of communication, although we still are a public company and a subsidiary of Noxopharm, a listed company, and that brings certain restrictions and obligations. I intend to keep you regularly updated on progress with both our R&D and corporate activities. Where we see any news as market sensitive, then we likely will release it as a Noxopharm ASX announcement. My address is graham.kelly@nyrada.com. My telephone contact is Don t hesitate to contact me with any questions. GRAHAM KELLY Executive Chairman and CEO *Declaration: Professor Housley is a shareholder of Nyrada.