< PreviousANTIDEPRESSANTS 20 Pharma Business International www.pbiforum.net be some traction left to this serendipitous discovery. Antidepressant Sertraline found to inhibit cancer growth In another case of serendipity, studies by KU Leuven have demonstrated that the commonly used antidepressant Sertraline can help inhibit the growth of cancer cells by acting on a metabolic addiction to amino acids, which cancer cells use to grow. “This mechanism is an interesting target because cancer cells are so dependent on it,” said Kim De Keersmaecker, PhD, head of the Laboratory for Disease Mechanisms in Cancer (LDMC). “Healthy cells use this mechanism to a lesser extent and also take up serine and glycine from food. This is not sufficient for cancer cells, however, meaning they start producing more. If we can halt this production, we will be able to fight the cancer without affecting healthy cells.” If this research (currently conducted on mice) proves true, it could be a great help in the fight against certain cancers, allowing for earlier preventative and mitigative treatment to be rolled out and ease the strain on already packed cancer treatment schedules. That the treatment could be so readily affordable would also mean a lot for hospitals and patients alike. “Now that we’ve been able to identify this mechanism for breast cancer, we can start examining other types of cancer that are also addicted to serine and glycerine synthesis,” said Professor De Keersmaecker. “This is for example the case in T-cell leukemia, but also in certain types of brain, lung and skin cancer. The more tumors we can identify that are sensitive to sertraline, the better 18-21.qxp_Layout 1 07/12/2020 10:52 Page 3Pharma Business International 21 www.pbiforum.net ANTIDEPRESSANTS the prospects are for helping patients in the future … These are, of course, results of experimental research, not clinical studies, but we can be optimistic about the potential.” Drug-free antidepressants? Technology and apps have brought about much change in the pharmaceutical industry, but one company – Flow Neuroscience – are taking that even further with a medically approved, drug- free, at home treatment for depression involving a high-tech stimulation headset and an app therapy program. People with depression often have a lower neural activity in the left part of the brain region that controls emotional expression and certain cognitive skills. The Flow headset uses transcranial direct current stimulation (tDCS), a mild electrical signal, to stimulate and rebalance neural activity in this frontal area of the brain. To maximise recovery during the brain stimulation process, users engage with a virtual therapist app which is based on the latest psychology and neuroscience research. The virtual therapist helps users to understand, treat and prevent depression across four areas proven to improve symptoms: sleep, nutrition, fitness and meditation. Randomised controlled trials published in the New England Journal of Medicine and the British Journal of Psychiatry showed that tDCS brain stimulation, of the type used in the Flow headset, had a similar impact to antidepressants but with fewer and less-severe side effects. In the largest study to date twenty-three per cent of patients completely overcame their depression, while forty-one per cent found that at least half of their symptoms disappeared after six weeks. © Shutterstock /Chinnapong 18-21.qxp_Layout 1 07/12/2020 10:52 Page 4AI IN DRUG DEVELOPMENT 22 Pharma Business International www.pbiforum.net © Shutterstock /any_keen 22-25.qxp_Layout 1 07/12/2020 10:53 Page 1Pharma Business International 23 www.pbiforum.net AI IN DRUG DEVELOPMENT The best estimates put the time it takes for new drugs to make it from the lab to market between ten and fifteen years. Not only can AI be used to drastically shorten this process, but also reduce the £1.5 billion price tag that comes with it. As if there was any doubt that artificial intelligence (AI) is transforming the industry, all ten of the world’s biggest pharmaceutical companies are all involved at one stage or another with AI, whether that’s via direct collaboration, or funding via a venture capital arm. While big data and machine learning can be utilised right across the pharmaceutical and healthcare sectors, it’s in drug discovery where some of the most important research is taking place. The cost of discovering and developing new drugs has been climbing over the years, especially as greater regulatory scrutiny and ongoing healthcare pricing issues means that new treatments can be kept from reaching patients. Here AI can help by 24 Á The future of drug development? drug development? 22-25.qxp_Layout 1 07/12/2020 10:53 Page 2AI IN DRUG DEVELOPMENT 24 Pharma Business International www.pbiforum.net dealing with the massive amounts of data involved in new drug development. The overwhelming amount of health records, genetics profiles, preclinical studies and clinical trial data can all be correlated and examined en masse, and patterns found. During development stages, new data is coming in daily and with AI all of this can be added to and compared with a huge pre-existing pool of data, providing a thorough foundation to build on. Issues and inconsistencies can be identified early and gaps in research found as well as conveying where research has been clustered and allowing researchers to see where better to focus their efforts. With machine learning, data isn’t only correlated, and patterns extrapolated, but outcomes can be generated, providing pathways for drug discovery. A research team simply couldn’t do this on their own but, guided by these same researchers, AI can use all the facts generated from this massive data pool to create hypotheses that can then be tested and speed up the development process. With a shorter development process, there’s less cost involved, meaning that potential new treatments can move to clinical study faster, offering a lifeline for patients. Last year, Hong Kong start-up Insilico Medicine developed a new AI system that dramatically accelerates the drug discovery process from years to days. In the industry’s first successful experimental validation of AI for drug discovery in cells and animals, the company successfully created a series of entirely new molecules capable of combatting disorders like fibrosis. Traditionally, drug discover begins with the testing of thousands of small molecules to get just a few lead-like molecules. Only one in ten of these pass clinical trials in human patients making it a protracted, costly and inefficient 22-25.qxp_Layout 1 07/12/2020 10:53 Page 3Pharma Business International 25 www.pbiforum.net AI IN DRUG DEVELOPMENT © Shutterstock /everything possible process. But with Insilico’s AI, it was able to ideate and generate novel molecules from start to finish in just twenty-one days. Powered by generative chemistry utilising modern AI techniques, the company’s GENTRL can rapidly generate molecular structures with specified properties in a technique similar to that used by DeepMind (the AI company acquired by Google in 2014) to outcompete human GO players. The start-up has made the source code open source to make it more broadly accessible to the public and allow other companies and research teams to leverage the technology. This year, just a few months after Insilico’s breakthrough, a clinical trial began in Japan exploring the first drug candidate discovered using AI. DSP- 1181 is being progressed as a long- acting and potent serotonin 5-HT1A receptor agonist for obsessive- compulsive disorder as an initial indication. It was jointly created by combining Sumitomo Dainippon Pharma’s science and know-how in monoamine GPCR drug discovery, with University of Dundee spin-out Exscientia’s Centaur Chemist AI platform for drug discovery. With this AI-powered process, it required less than twelve months to complete the exploratory research phase, less than a quarter of the time of the typical average of 4.5 years using conventional research techniques. Although artificial intelligence is still in its infancy where drug discovery is concerned, the breakthroughs have already been profound. From dramatically shortening development times, to reducing costs, the technology is helping to change the way in which new drugs are discovered, developed and brought to market. 22-25.qxp_Layout 1 07/12/2020 10:53 Page 4REPURPOSING THERAPIES 26 Pharma Business International www.pbiforum.net Interest in oncological drug repurposing is driven by a range of concerns: productivity issues in current drug development; the need to address existing unmet patient needs; and the economic impact of existing and projected cancer incidence on health systems in both advanced and developing countries. A recent analysis has shown that the number of new drugs approved per billion US dollars spent on research and development has halved every nine years since 1950, falling around eighty-fold in inflation-adjusted terms. Indeed, some observers have described the situation as a ‘productivity crisis,’ and there has been much discussion as to the causes of, and possible solutions to, this crisis. The crisis is particularly acute in oncology, where the success rate for new drugs from Phase I trial to US Food and Drug Administration (FDA) approval in the period 2003 to 2011 was around 6.7 per cent, a figure that is about half the rate for non-oncological drugs. The mean development time for antineoplastic drugs, from the time of the first filing of investigational new drug application to the granting of NDA/BLA approval, is estimated to be 8.3 years. This apparent slowdown of new oncology drugs emerging from product pipelines into clinical use is occurring against a twin backdrop, one of increased cancer incidence across the globe, and the other of existing significant therapeutic challenge in many types of malignant disease. The global distribution of cancer incidence is also changing, and this change is projected to continue. Projecting historic demographic trends and changes in cancer incidence, by 2030 cancer incidence in the low to medium human development index (HDI) countries will represent fifty-two per cent of the global total, or 10.6 million cases. This increasing incidence of cancer, associated to a large degree with aging populations in developed countries and with changes in diet, levels of physical activity, and other lifestyle factors in developing countries, will increase economic pressures on health systems in both developed and developing economies. In tandem, and despite Finding a new purpose Repurposing existing therapies for oncology could help to circumvent many of the time and financial costs involved in developing new treatments, as the innovative ReDO project is discovering. 28 Á 26-29.qxp_Layout 1 07/12/2020 10:54 Page 1Pharma Business International 27 www.pbiforum.net REPURPOSING THERAPIES 26-29.qxp_Layout 1 07/12/2020 10:54 Page 2REPURPOSING THERAPIES 28 Pharma Business International www.pbiforum.net successes in some areas, new treatments are needed for refractory disease where there are effective first-line therapies, and effective first-line treatments in some forms of cancer for which current treatment options are limited, such as lung, pancreatic, ovarian, and liver cancers, sarcomas, and other rare malignancies. In particular, there are few effective treatments for the vast majority of metastatic solid tumours, a class of disease that has remained intractable despite notable successes in haematological diseases such as chronic myeloid leukaemia (CML) and some lymphomas. Therefore, the Repurposing Drugs in Oncology (ReDO) Project seeks to repurpose well-known and well- characterised non-cancer drugs for new uses in oncology. High throughput drug screening, in silico modelling, and other techniques are identifying an ever increasing number of compounds—both novel and existing—with some level of anti-cancer activity. There is no shortage of drug candidates for repurposing, in fact the opposite problem exists, and there are too many candidate drugs with some potential activity that warrants some degree of investigation. However, there are candidate drugs for which there is often a higher degree of evidence—in vitro and/or in vivo studies, in silico modelling, isolated case reports, or early phase clinical trials. Often, the evidence is dispersed, unsummarised, or otherwise obscured. If we are to make progress with drug repurposing and bring these drugs to the clinic, then a number of steps have to be taken: 1. Candidate drugs have to be filtered and assessed and the most promising identified for further clinical investigation. 2. The data for these most promising drugs need to be reviewed, summarised, and brought to the attention of clinical investigators and the broader oncological community. 26-29.qxp_Layout 1 07/12/2020 10:54 Page 3Pharma Business International 29 www.pbiforum.net REPURPOSING THERAPIES © Shutterstock /V iacheslav Lopatin 3. Identification and documentation on how these drugs can be combined with existing therapies, or with other repurposed drugs, for specific cancer indications must be developed. 4. Work must take place with investigators to develop clinical trials to provide positive or negative evidence of efficacy. 5. Where necessary, we must suggest areas where further pre-clinical work is necessary to shed further light on mechanisms of action, evidence of synergy for combinations, or seek other additional data to help prioritise those agents, or combinations with a high probability of clinical efficacy. The ReDO project aims to undertake these steps and to work with clinicians to make these trials a reality. A key output from this project, therefore, will be a series of papers that focus on specific drug candidates, and which will make the case for specific clinical trials by reviewing and summarising existing data, and formulating sample combinations and protocols for the treatment of various cancer types. Much current work on drug repurposing in oncology focuses on single agents or on specific cancer types. In contrast, ReDO will focus on a wide range of agents and across many different cancer indications, examining evidence not just for efficacy as single agents, but seeking evidence for drug combinations in those indications. These combinations may include multiple repurposed drugs working in concert, as well as existing therapeutics. In addition, the scope of the project extends beyond the purely clinical, and encompasses the wider social and political issues that impact the success, or otherwise, of repurposing. It’s a brave new world ahead for repurposing existing durgs against oncology, overcoming many of the persisting issues involved with developing new therapies. The Repurposing Drugs in Oncology (ReDO) Project report was written by Pan Pantziarka as primary author. Contributing authors: Gauthier Bouche, Lydie Meheus, Vidula Sukhatme, and Vikas P. Sukhatme. © Shutterstock /Numstocker 26-29.qxp_Layout 1 07/12/2020 10:54 Page 4Next >