< PreviousM&A ROUND-UP 10 Pharma Business International www.pbiforum.net Takeda and Shire In early January, Japan’s Takeda cleared all the necessary regulatory hurdles and secured strong shareholder backing to complete its $62 billion acquisition of US biotechnology company Shire. The deal was originally announced back in May 2018 and provides Takeda with a significantly expanded geographical footprint and, crucially, positions it amongst the top ten pharmaceutical companies in the world. Lily acquires Loxo Oncology It was a busy start to the year with Indiana’s Eli Lilly making its largest transaction to date in January with the $8 billion acquisition of US biopharma Loxo Oncology. The intention was to broaden its own cancer treatment effort and provides a pipeline of targeted medicines focussed on cancers that are unique dependent on simple gene abnormalities that can be detected by genomic testing. The deal completed in early February. GE bids BioPharma business bon voyage Back in February, Boston-based conglomerate, GE, revealed it was selling the BioPharma portion of its Life Sciences business to Washington DC’s Danaher Corporation for $21.4 billion in a bid to strengthen its balance sheet. In September, Danaher initiated a stock sale to fund the acquisition. Although the deal had originally been scheduled to close in the fourth quarter of 2019, in October, Danaher signed an agreement sell its label-free biomolecular characterisation chromatography hardware and resins, and microcarriers and particle validation standards businesses to Sartorius for $750 million as part of the process to gaining regulatory approval for its BioPharma acquisition. The company said it expects to close the transaction in the first quarter of 2020, though there are still regulatory approvals needed. Roche swoops for Spark Therapeutics In February, Switzerland’s Roche made a significant move to expand its presence in the gene therapy field with the $4.2 billion acquisition of Philadelphia start-up Spark Therapeutics. It was an advantageous move, providing Roche with proven expertise across the entire gene therapy value chain. However, in June the Federal Trade Commission required additional information and documentary material to support its review. At the same time, the UK Competition and Markets Authority (CMA) opened an investigation to obtain further information in relation to the deal and, in October, the CMA confirmed it was launching an investigation to ascertain whether the deal will result in a “substantial lessening” of competition. As of writing, this investigation is still pending, though a decision is planned for mid-December, putting the deadline back yet again. Best of the rest Outside of the BMS/Celgene merger, here are some of the biggest deals that have taken place in the pharmaceutical industry this year. 08-11.qxp_Layout 1 02/12/2019 10:19 Page 3Pharma Business International 11 www.pbiforum.net M&A ROUND-UP AbbVie and Allergan In June, Chicago-based biopharma AbbVie announced that it was acquiring Ireland’s Allergan for $63 billion. As well as offering scale and profitability, the deal also provides AbbVie with new growth platforms and leadership positions to diversify and expand its revenue base. Crucially, it will result in significant cash flow generation. In 2018, for example, the combined companies generated $19 billion in operating cash flow. The deal secured shareholder backing in October, clearing the way to completion in early 2020 (see next issue’s round-up for more). Pfizer buys Array BioPharma June also saw Pfizer enhance its presence in oncology with the $11.4 billion acquisition of Boulder-based biopharma, Array BioPharma. The deal completed in July with Array bringing a portfolio that includes the approved combined use of Braftovi (encorafenib) and Mektovi (binimetinib) for the treatment of BRAFV600E or BRAFV600K mutant unresectable or metastatic melanoma. Novartis acquires The Medicines Company As we were putting this issue together, Novartis announced that it was acquiring New Jersey-based biopharmaceutical company, The Medicines Company, for $9.7 billion. The deal adds the “potentially transformational” investigational cholesterol-lowering therapy inclisiran to its pipeline. Regulatory submissions are expected for the therapy in the US is still pending as of writing with a European submission slated for the first quarter of 2020 when the deal is expected to close. © Shutterstock /eamesBot 08-11.qxp_Layout 1 02/12/2019 10:19 Page 4DEPRESSION EXPOSÉ 12 Pharma Business International www.pbiforum.net W ith some 300 million people suffering from the various forms of depression globally, it is the world’s predominate mental health problem and the leading cause of disability worldwide. Though the illness can, and does, occur independently, it often co-occurs with other mental health problems such as anxiety. Studies have shown that issues surrounding depression tend to begin early in life with half of all metal health problems established by the age of fourteen. There also appears to be some natural gender bias. Here in England, twenty-four per cent of women are diagnosed with one form of depression or another in their lifetime, compared to thirteen per cent of men. Quite why the illness appears to affect women more than men isn’t entirely understood, though the general male reluctance to seek help is a contributing factor, as is the occurrence of post-partum depression in women. What can be ascertained from anecdotal evidence and statistics is that although women are more likely to be affected by depression, men are much more likely to take their own lives. It’s clear from the figures that depression is becoming more prevalent. Although experts admit that this is undoubtedly down to people being more willing to admit and report mental health problems thanks to changing attitudes, a rise in awareness and an easing of social stigmas, it’s also clear that modern life is taking its toll. At present, we have to contend with a constant barrage of political issues, economic uncertainty, global conflicts, and the dysmorphia inducing echo chamber of social media. Coupled with longer work hours and stagnant wages, it’s really no wonder that depression is on the rise. Yet this line of thinking comes dangerously close to the assumption that depression is a choice or synonymous with sadness. While environmental factors can, of course, play a role in the onset of depression, it’s just as likely to be caused by genetics, biochemistry and personality. The way in which depression is discussed is changing, especially in the workplace, with employers getting to grips with mental illness and taking appropriate training courses to tool themselves with the knowledge needed to deal with and support staff suffering from mental health issues. 2019, in particular, has been an important year for mental illness, especially depression, with the US Food and Drug Administration this year approving the first and only medicine specially approved for treating post-partum depression. The prevalence of treatments for depression continues to grow alongside the illness itself, with antidepressant A light in the dark For this month’s cover feature, Pharma Business International explores what’s happening in the depression pipeline, exploring new treatment options, delivery systems and breakthroughs. 14 Á 12-15.qxp_Layout 1 02/12/2019 10:21 Page 1Pharma Business International 13 www.pbiforum.net DEPRESSION EXPOSÉ © Shutterstock /asiandelight 12-15.qxp_Layout 1 02/12/2019 10:21 Page 2DEPRESSION EXPOSÉ 14 Pharma Business International www.pbiforum.net prescriptions almost doubling in ten years – rising from thirty-six million in 2008, to seventy-one million in 2018. Usage is very obviously on the up as more people seek help, but these figures convey how prescription patterns have changed over the years, with doctors much more likely to keep people on drugs for longer. Although evidence suggests that this is a more effective way of treating patients, different kinds of treatment options, delivery systems and formulations are coming to the fray. For some people, mental health issues such as depression can be managed with the use of cognitive behavioural therapy (CBT) independent of any prescription drugs. For others, it’s a combination of both approaches, yet there’s no one approach that works in all cases of depression. More than the fact that there are different types of depression – from major depressive order (MDD) to seasonal depression – is that every individual is different. It’s therefore important that there is a variety of treatment methods available to meet patient needs. For an individual with MDD expressing suicidal intent, a course of antidepressants that can take four to six weeks to become effective isn’t sufficient. Orally isn’t the only way in which antidepressants can be administered, with more nasally administered options becoming available to patients which, according to studies, can deliver results much quicker than tablets. Esketamine is used as a general anaesthetic and for treatment-resistant depression. A few months ago, Johnson & Johnson company Janssen reported positive data from two Phase 3 clinical studies evaluating the efficacy and safety of esketamine nasal spray in adults with MDD who have active suicide ideation with intend. Both studies met their primary efficacy endpoints of demonstrating a reduction in depression symptoms within twenty-four hours after first dose. Coupled with comprehensive standard of care, the treatment demonstrated a clinically meaningful and statistically significant superiority over placebo plus comprehensive standard of care. As we’ve already touched on, currently available orally-administered antidepressants are effective in patients, but their onset of effect can take a month or more, offering limited benefit to those in urgent need. However, with an onset of effect of around twenty-four hours, this treatment could offer a literal lifeline to patients. It was approved in the US back in March and, in October, Janssen submitted a marketing authorisation application to the European Medicines Agency seeking approval in Europe, a decision which is still pending as of writing. Attitudes and understanding of depression have evolved alongside the rise of digital technologies, the latter of which offer a novel therapeutic approach to patients. Over the last few years, there’s been an increase in the development and application of digital therapeutics with success reported with ADHD in children, but there’s plenty of scope for depression and anxiety. Click Therapeutics is a New York company developing and commercialising software as prescription medical treatments. Earlier this year, the company teamed up with the American subsidiary of Japanese pharmaceutical company Otsuka to develop and commercialise a prescription digital therapeutic to treat MDD (of which 6.7 per cent of US adults suffer from). The idea is that digital therapeutics naturally align with psychiatry and have the potential to transform mental health. That all sounds great on paper, but what about in practice? According to Click, the companies aim to bring to market a new offering that, they claim, will provide a novel treatment for MDD. At present, the treatment is in efficacy trials, along with Click’s smoking cessation digital therapeutic. As well as exploring the digital avenue, other areas of treating depression are emerging. Researchers at the University of Buffalo in New York have found that the plant compound resveratrol – which is found in the skin of grapes and berries – displays anti-stress effects which could open the door for new treatments of depression and anxiety. While research has previously identified resveratrol to have antidepressant effects, the compound’s relationship to phosphodiesterase 4 – an enzyme influenced by the stress hormone corticosterone – was unknown. Simply put, corticosterone regulates the body’s response to stress. Too much stress can lead to excessive amounts of the hormone circulating in the brain and, ultimately, the development of depression or other mental disorders. Unsurprisingly, these unknown physiological relationships make drug therapy complex, with current antidepressants focussing on serotonin or noradrenaline function in the brain. But only one third of patients with depression enter full remission in response to these medications. Breakthroughs such as these are therefore vital to enabling new treatments that can benefit patients and help to manage and mitigate depression. Our understanding of depression has come a long way since it was referred to as “melancholia” and thought of as one of the four temperaments matching the four humours, but we still have a long way ahead with depression believed to play a role in half of all suicides worldwide. New delivery systems could mean that patients receive the benefits of antidepressants in a fraction of the time, while innovative new approaches are creating a whole new treatment option. Coupled with clinical breakthroughs and it’s clear the treatment pipeline for depression is a healthy one and minimising the role depression plays in society should remain a key goal for the pharmaceutical industry going forward. © Janssen 12-15.qxp_Layout 1 02/12/2019 10:21 Page 3Pharma Business International 15 www.pbiforum.net DEPRESSION EXPOSÉ © Shutterstock /LILAWA.COM 12-15.qxp_Layout 1 02/12/2019 10:21 Page 4PRECISION MEDICINE 16 Pharma Business International www.pbiforum.net Targeted treatments Breakthroughs over the last few decades have paved the way for precision medicine, but there is still much more research needed before this approach becomes the norm. 16-19.qxp_Layout 1 02/12/2019 10:23 Page 1Pharma Business International 17 www.pbiforum.net PRECISION MEDICINE © Shutterstock /vitstudio 18 Á F or centuries, medical treatments have frequently favoured a one-size-fits-all approach. This can perhaps be most pertinently seen in cancer care where patients typically receive the same treatment as others who have the same type and stage of cancer. Yet different people respond differently to treatments and, until relatively recently, the reasons for this were unknown. Following decades of research, scientists now understand that patient’s tumours have genetic changes that cause cancer to grow and change and, critically for the emerging approach of precision medicine, changes that occur in one person’s cancer may not manifest in another person who has the same type of cancer. Precision medicine is a process wherein medical treatments are tailored to the individual characteristic of each patient, taking into account individual variability in the genes, environment and lifestyle of each person. In practice, this would allow doctors and researchers to predict more accurately which treatments and prevention strategies for a particular disease will work in which groups of people. The key is understanding how variations in our genes influence our health and that means understanding and mapping our genes themselves. It would have been unthinkable even twenty years ago that in 2019 we would be able to sequence the human genome in a day. Back in 2001, a human genome cost a massive $100 million to sequence but, by 2014, a new machine was able to sequence sixteen human genomes in three days at a cost of about $1,000. Now, single human genomes can be sequence in around a day, meaning that patients could obtain their entire genome sequence for the same cost as an MRI scan and provide them with an invaluable resource that will continue to inform their medical decisions for the rest of their lives. With this resource at our disposal, researchers can identify why some genetic variances protect us from disease and others make us more susceptible and treat accordingly. 16-19.qxp_Layout 1 02/12/2019 10:23 Page 2PRECISION MEDICINE 18 Pharma Business International www.pbiforum.net As we’ve already mentioned, our knowledge of the genetic variances and changes have come along in leaps and bounds, but scientists still haven’t discovered every change. Once changes have been discovered, however, the next step is to look for drugs that can target these changes and then test those with people in clinical trials. Oncology is an area where precision medicine stands to have the biggest impact and so exciting and innovative research efforts have clustered in this field. An important step forward has been recently reported by researchers from the Faculty of Medicine and the Institute for Molecular Medicine (FIMM) at the University of Helsinki in Finland. Researchers have developed a computational model that, they say, enables accurate identification of essential genes in cancer cells for development of anti-cancer drugs, paving the way for precision medicine in drug design. The activation of certain genes leads to cancer cells growing fast and so targeted therapies aim at inhibiting the genes that are activated only in cancer cells and thus minimising side effects to normal cells. High-throughput genetic screening has been established for evaluating the importance of individual genes for the survival of cancer cells. Such an approach allows the researchers to determine the so-called gene essentiality scores for nearly all genes across a large variety of cancer cell lines. However, challenges with replicability of the estimated gene essentiality have hindered its use for drug target discovery. “shRNA and CRISPR-Cas9 are the two common techniques used to perform high-throughput genetic screening. Despite improved quality control, the 16-19.qxp_Layout 1 02/12/2019 10:23 Page 3Pharma Business International 19 www.pbiforum.net PRECISION MEDICINE gene essentiality scores from these two techniques differ from each other on the same cancer cell lines,” says Wenyu Wang, first author of the study. In order to harmonise genetic screening data, the researchers proposed a novel computational method called Combined Essentiality Scoring (CES) that predicts cancer essential genes using the information from shRNA and CRISPR-Cas9 screens plus molecular features of cancer cells. The team demonstrated that CES could detect essential genes with higher accuracy than the existing computational methods. Moreover, the team showed that two predicted essential genes were indeed correlated with poor prognosis separately for breast cancer and leukaemia patients, suggesting their potential as drug targets. “Improving gene essentiality scoring is just a beginning,” says assistant professor Jing Tang, corresponding author of the study. “Our next aim is to predict drug-target interactions by integrating drug sensitivity and gene essentiality profiles. Given the ever- increasing volumes of functional screening datasets, we hope to extend our knowledge of drug target profiles that will eventually benefit drug discovery in personalised medicine.” Doctors, researchers and healthcare providers have all spoken to the treatment possibilities offered by precision medicine. By all accounts it will transform the way in which we think about therapies and how patients themselves are treated. Yet this is a burgeoning field, with plenty more research still needed, and treatments needing to clear clinical trials and regulatory hurdles before the transformation can take place. © Shutterstock /Gio.tto 16-19.qxp_Layout 1 02/12/2019 10:23 Page 4Next >