< PreviousM&A ROUND-UP 10 Pharma Business International www.pbiforum.net The merger agreement, which has been unanimously approved by the boards of Alexion and Portola, will see a subsidiary of Alexion will commence a tender offer to acquire all of the outstanding shares of Portola’s common stock at a price of $18 per share in cash. Following successful completion of the tender offer, Alexion will acquire all remaining shares not tendered in the offer at the same price of $18 per share through a merger. The transaction is expected to close in the third quarter of 2020. Though there was only the one million- dollar-plus deal this issue, there are a couple of other deals of note to discuss. With the aim of expanding its presence in the US and strengthening its oncology portfolio, Italian pharma and diagnostics company, Menarini Group, is acquiring Stemline Therapeutics, a New York biopharma focussed on novel oncology therapeutics, for $677 million. As per the agreement, a wholly owned subsidiary of the Menarini Group will commence a tender offer for all outstanding shares of Stemline. With the support of Menarini’s infrastructure, Stemline will continue its efforts to develop additional applications of ELZONRIS to serve the unmet needs of patients suffering from difficult to treat diseases and cancers. The deal provides Menarini access to Stemline’s ELZONRIS, a novel targeted therapy directed to the interleukin-3 (IL-3) receptor-α (CD123). It was approved as a treatment of blastic plasmacytoid dendritic cell neoplasm in paediatric patients two years and older by the FDA in December 2018. Following its strong US launch, Stemline will benefit from Menarini’s experience in bringing products to markets in Europe and emerging markets as it prepares for a successful international launch upon receipt of regulatory approval in ex-US territories. “Stemline is an excellent fit for Menarini, enabling us to expand our presence in the US with an established biopharmaceutical company focused on 08-11.qxp_Layout 1 09/06/2020 11:06 Page 3Pharma Business International 11 www.pbiforum.net M&A ROUND-UP © Shutterstock /Andrey_Popov developing oncology therapeutics,” said Elcin Barker Ergun, CEO of Menarini Group. “Through this acquisition, we will continue to strengthen our portfolio and pipeline of oncology assets and deliver novel therapies around the world.” Lastly this issue, Danish company Onifarm aims to evolve into a “much more traditional manufacturing pharmaceutical company” after a portfolio of select over the counter and prescription pharma products sold in Europe from Takeda for €615 million. The acquisition, the largest in its history, allows Orifarm to future-proof its business by strengthening the company’s core business areas: parallel imported pharmaceuticals, over the-counter pharmaceuticals, and prescription generic pharmaceuticals. It will reinforce Orifarm’s position in its key markets and expand its geographic reach to new markets, strengthening its position for the long-term. The future sales and production of over-the-counter and prescription pharmaceuticals will become equally important, the company said. The products acquired from Takeda are a well-known and recognised portfolio across their key geographies, with significant brand recognition amongst pharmacists and consumers. It includes approximately 110 pharmaceuticals and dietary supplements, including well- known brands like Pamol, Kodimagnyl, and Zymelin. CEO Erik Sanberg said the deal is “a gigantic transaction for Orifarm and a gamechanger for Orifarm as a company.” He added: “We will grow to a greater extent into a much more traditional manufacturing pharmaceutical company, and with the acquisition of both the line of products and two further manufacturing sites, we will be able to control a larger part of our value chain.” That’s it for our M&A round-up this month. As the global crisis continues, market activity will likely continue to cool. However, we’ll cover all the major deals in our next issue. Watch this space. 08-11.qxp_Layout 1 09/06/2020 11:06 Page 4TUBERCULOSIS EXPOSÉ 12 Pharma Business International www.pbiforum.net Once treated with sunlight and fresh air in sanatoriums, TB treatment saw great change with the development of effective chemotherapy in the 1940s. Though breakthroughs in the TB space have since been slow, innovation is picking up pace. T uberculosis (TB) kills 1.5 million people annually, more than any other infectious disease. Approximately a third of the world’s population are infected with Mycobacterium tuberculosis (Mtb) and in 2018 an estimated ten million people developed the bacterial infection. Though mortality rates have been declining since 2000, the outbreak of antibiotic-resistant strains of the TB bacterium, with the infection the cause of up to a third of all deaths associated with antimicrobial resistance, is placing increasing pressure on TB research, especially the search for new vaccines, treatment options and better diagnostics. While five years ago world leaders committed to ending the TB epidemic by 2030, and at a 2018 meeting pledged to increase response to TB and double funding by 2022, COVID-19 has created new concern, in slowing the fight against TB and disrupting programs across method of administration holds potential to improve BCG’s effectiveness. Researchers from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases and the University of Pittsburgh School of Medicine indicates that switching administration from intradermal to intravenous increases BCG’s ability to protect rhesus macaques from infection post-exposure to Mtb. These findings will support further investigation of intravenous BCG administration in clinical trials in order to establish if this enhances its effectiveness in adults and teenagers. In the study, animals received the vaccine via intradermal, intravenous or aerosol routes and scientists assessed immune response in blood and fluid from the lungs for twenty- four weeks after vaccination. Intravenous BCG vaccination resulted in the most T cells in the 14 Á the globe. Modelling analysis has revealed that instances of TB could grow by eleven per cent between 2020 and 2025 with a three-month lockdown and a protracted ten- month restoration. This sees up to an additional 6.3 million cases of TB expected by 2025, mirroring levels last seen in 2013 and 2016, and 1.4 million additional deaths in this period, with cases going undiagnosed and untreated as lockdowns remain in effect. Efforts to end TB are expected to be set back by five to eight years due to the pandemic. This new challenge comes at a time when there is still just one licensed TB vaccine, BCG. Developed a century ago, it is delivered to infants with a needle under the skin. Though the vaccine is efficacious at protecting infants and young children against severe forms of TB, it is ineffective against pulmonary disease in adolescents and adults, and in reducing transmission. However, a new Tackling tuberculosis 12-15.qxp_Layout 1 09/06/2020 11:07 Page 1Pharma Business International 13 www.pbiforum.net TUBERCULOSIS EXPOSÉ © Shutterstock /Kateryna Kon 12-15.qxp_Layout 1 09/06/2020 11:07 Page 214 Pharma Business International www.pbiforum.net lungs and blood. Six months after vaccination, vaccinated and unvaccinated rhesus macaques were exposed to a virulent strain of Mtb, with bacteria introduced directly into the lungs. Infection and disease development were then tracked for over three months. Nine out of ten of those subject to intravenous BCG vaccination were highly protected, six had no detectable signs of infection, and three had low counts of Mtb action in lung tissue. Those vaccinated by the other methods and unvaccinated displayed greater infection. This step forward in TB vaccine research however is far from clinical practice with obstacles such as the method having a higher infection risk, the difficulty of administering vaccines intravenously and the need for better understanding of safety when injecting the live bacterium directly into the blood stream, in play. Presently, a completely new vaccine is considered essential for preventing adult TB and containing the spread of multi- drug resistant TB (MDR-TB). Hope has been renewed for this in the past couple of years with the vaccine candidate M72/AS01E, which was found to be significantly protective against TB in a Phase IIb trial conducted in Kenya, South Africa and Zambia in individuals with evidence of latent tuberculosis infection, with the point estimate of vaccine efficacy fifty-four per cent over two years of follow-up. At the start of 2020, GlaxoSmithKline licensed the vaccine to the Bill & Melinda Gates Medical Research Institute, to accelerate its development for low-income countries. Strides are also being made in drug treatments, to meet the need for new, safe, and more effective drug regimens that work faster and can respond to MDR-TB and extensively drug resistant tuberculosis (XDR-TB). The US Food and Drug Administration (FDA) last year approved a combination regimen containing pretomanid, a new drug, for the treatment of XDR-TB. This is the third new drug developed for TB in half a century (pretomanid, bedaquiline and delamanid are the only three anti-TB drugs approved for use by the FDA in over forty years). The safety and effectiveness of pretomanid, taken orally in combination with bedaquiline and linezolid, was demonstrated in a study of 109 patients with XDR-TB, treatment intolerant or non-responsive multidrug- © Shutterstock /ESB Professional 12-15.qxp_Layout 1 09/06/2020 11:07 Page 3Pharma Business International 15 www.pbiforum.net TUBERCULOSIS EXPOSÉ resistant pulmonary TB. Of the 107 patients who were evaluated six months after the end of therapy, ninety-five were successes, which exceeded historical success rates for treatment of XDR-TB. Médecins Sans Frontières and Interactive Research and Development, meanwhile, started a clinical trial in Pakistan in October, to find better, shorter treatments against MDR-TB. The phase III randomised controlled trial is comparing five new treatment regimens against MDR-TB which contain bedaquiline and delamanid, in combination with other oral TB drugs. A parallel trial will assess a sixth treatment combination and two different treatment durations to be used against forms of MDR-TB which are also resistant to fluoroquinolones, a group of antibiotics used as second-line drugs in TB treatment. Uncovering these shorter treatments is vital for TB regimens, where poor adherence is common, boosting the spread of TB, causing relapse for patients, and further developing drug resistant TB. Standard treatments for TB involve a six-month regimen with the combined administration of three or four antibiotics for drug-susceptible TB, and a longer, up to two-year, duration for drug- resistant TB. Research is fortunately now delivering shorter, safe TB drug treatments, indicating for example that latent TB infection can be treated with four months of rifampicin, or a combination of rifapentine and isoniazid for a month. In addressing TB, and to advance progress towards global elimination goals, innovative partnerships are needed to facilitate development of new drugs and treatment regimens. Spurring the development of new therapies, a team of public and private organisations, alongside a 200-million-euro budget, is aiming to transform how therapies are developed for TB. Launched in January, ERA4TB is an international consortium accelerating the development of comprehensive treatments. Partners will share their expertise, knowledge, and resources to rapidly progress new candidate drugs into clinical trials. ERA4TB is looking to “change the paradigm of tuberculosis treatment development by abandoning the sequential approach for a parallel pathway,” allowing the simultaneous investigation of over a dozen drug candidates. Another new collaboration is PAN-TB. Looking to speed up the development of novel drug regimens for any form of TB that are ready for phase 3 development, it aims to create transformative treatment regimens that have little to no drug resistance, are shorter in duration, simpler to use, and better tolerated in comparison to existing options. The PAN- TB collaboration will identify and assess the potential of investigational pan-TB regimens, through phase 2 clinical efficacy studies. Collaborative pre-clinical research activities have begun. While the presence of just one licensed vaccine and the small number of new drugs in the TB space is discouraging as the world looks to eradicate the bacterial infection, multiple trials for vaccines and new drug regimens are ongoing, and changes are being made to treatment guidelines. Other difficulties certainly remain and are gradually being addressed, including the need for early detection with systematic screening of high risk groups, increasing the availability of fast diagnostic tests, developing better diagnostic tools, establishing more preventative care options, and enhancing drug affordability to make treatments more available. Looking ahead, the next few years will mark major transformation in TB treatment. 12-15.qxp_Layout 1 09/06/2020 11:07 Page 4FINDING A CURE FOR CORONAVIRUS 16 Pharma Business International www.pbiforum.net Curing Coronavirus © Shutterstock /Lightspring 16-19.qxp_Layout 1 09/06/2020 11:08 Page 1Pharma Business International 17 www.pbiforum.net FINDING A CURE FOR CORONAVIRUS C oronavirus continues to be at the tip of everyone’s tongue as pharmaceutical companies, researchers and governments push to accelerate the development of potential cures and treatments. The search for a vaccine is a priority for many, with over one hundred COVID-19 vaccines under development across the globe, according to WHO, and ten candidates in clinical trials (at the time of writing). Amongst the newer technologies being evaluated for the development of a COVID-19 vaccine is messenger RNA (mRNA) based vaccine technology. According to GlobalData, eighteen candidates are in development. The use of these vaccines has been praised for the speed of their production. Where conventional vaccines require lengthy and arduous production of viruses or viral proteins and are subject to limited production capacity, RNA vaccines introduce an mRNA sequence encoding the disease-specific antigen to trigger the immune system. Stimulating the body to produce viral proteins itself, mRNA vaccines bypass aspects of the manufacturing process to be easier and quicker to produce and scale up than traditional vaccines, essential in the current pandemic. While there are no licensed mRNA vaccines, the pandemic has presented a chance to showcase their potential. In April BioNTech and Pfizer initiated phase 1/2 clinical studies for its BNT162 RNA vaccine program in Germany, which will also be conducted in China and the US, and Moderna’s mRNA-1273 is expected to enter a phase 2 study imminently, phase 3 trials in July, and has been fast- tracked by the FDA. The latter vaccine, using mRNA to push the body to produce a key protein from the Coronavirus and stimulate an immune response, entered into clinical trials only sixty-six days after SARS-CoV-2 was sequenced, and in May Moderna released the first data from a human trial. The vaccine triggered an immune response against Coronavirus in the blood of healthy volunteers, caused minimal severe and no lasting health issues and has prevented viral replication in the lungs of mice. Looking away from mRNA vaccines, University of Oxford’s ChAdOx1 nCoV- 19, a recombinant viral vector vaccine, is a frontrunner. Being developed by the Jenner Institute and Oxford Vaccine Group, phase 1 human trials began in Vaccine developers have advanced ten COVID-19 vaccine candidates into clinical trials: * Moderna and NIAID’s mRNA vaccine mRNA-1273 is in phase 2 * BioNTech and Pfizer’s mRNA vaccine BNT162 is in phase 1/2 * Inovio Pharmaceuticals DNA vaccine INO-4800 is in phase 1 * University of Oxford and AstraZeneca’s recombinant viral vector vaccine ChAdOx1 nCoV-19 (now known as AZD1222) is in phase 2b/3 * CanSino Biologics’ adenovirus vaccine Ad5-nCoV is in phase 2 * Wuhan Institute of Biological Products and Sinopharm’s unnamed inactivated virus vaccine is in phase 1/2 * Beijing Institute of Biological Products and Sinopharm’s unnamed inactivated virus vaccine is in phase 1/2 * Sinovac’s inactivated virus vaccine PiCoVacc is in phase 1/2 * Institute of Medical Biology and Chinese Academy of Medical Sciences’ unnamed inactivated virus vaccine is in phase 1 * Novavax’s protein subunit vaccine NVX-CoV2373 is in phase 1/2 With the number of reported COVID-19 cases well past six million, pharmaceutical companies and researchers are working rapidly to develop vaccines and uncover effective treatments. 18 Á 16-19.qxp_Layout 1 09/06/2020 11:08 Page 218 Pharma Business International www.pbiforum.net April, with British Health Minister Matt Hancock pledging £20 million to the vaccine. In this instance genetic material used to make proteins from the COVID- 19 virus found on the surface of SARS- CoV-2 (called Spike glycoprotein (S)), will be placed into another modified virus, which is injected into humans with the hope of creating an immune response to the Spike protein that will help stop the virus entering human cells. AstraZeneca and the University of Oxford have announced an agreement for the global development and distribution of the vaccine, to ensure it is available as early as possible, should the vaccine work. The researchers have said late-stage trials could be reached by the middle of 2020. Of course vaccines aren’t the only focus for researchers. With no specific treatments for COVID-19, trials are ongoing to help tackle Coronavirus and its symptoms. Primarily, research and advances focus on repurposing existing drugs to facilitate the quick roll-out of treatments, but there are three main pathways being considered - using antivirals, using drugs to calm the immune system, and using antibodies. Gilead Sciences’ antiviral drug remdesivir, administered via daily infusion, has perhaps received the most attention. In May, a preliminary data analysis, from a randomised controlled trial involving 1063 patients which began in February, unveiled that hospitalised patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients who received placebo. Results indicate that patients who received remdesivir had a thirty-one per cent faster time to recovery than those who received placebo. In May, Veklury (remdesivir) was approved in Japan as a treatment for COVID-19 under an exceptional approval pathway, closely following the Emergency Use Authorisation of remdesivir in the US. Malaria drugs are also being investigated, with the spotlight on hydroxychloroquine, which is also a treatment used for rheumatoid arthritis © Shutterstock /solarseven 16-19.qxp_Layout 1 09/06/2020 11:08 Page 3Pharma Business International 19 www.pbiforum.net FINDING A CURE FOR CORONAVIRUS for its help in regulating the immune system. With many of the complications of COVID-19 thought to be linked to the body’s immune response to the virus, the drugs’ ability to inhibit the immune system could be key to limiting this. Hydroxychloroquine has been shown to inhibit Coronavirus in lab tests, though a recent trial from the University of Minnesota showed no significant effect. Concern arose over hydroxychloroquine’s safety in May when WHO halted its global trials of the drug, after a study found it may increase mortality. However, in June, it was announced that trials of the drug would resume after the study in question was reviewed, while additional trials have found the drug to have no serious side effects. The international Solidarity Trial, launched in March by WHO, featuring hydroxychloroquine, is one of many studies comparing multiple treatment options, trialling remdesivir, lopinavir/ritonavir, lopinavir/ritonavir with interferon beta-1a, and hydroxychloroquine. The blood of COVID-19 survivors is also being assessed as a treatment, wherein blood plasma is given to patients struggling to develop their own antibodies to improve recovery. Small tests in China have found patients who are severely ill could benefit from these transfusions. The safety of convalescent plasma transfusions however still needs to be confirmed by robust clinical trials. A number of further antibody treatments are being developed, with mice being genetically engineered to mirror the human immune system and exposed to the virus so that blockage antibodies can be recovered. In addition synthetic antibodies are being explored through isolating the antibody producing white blood cells from recovered patients’ blood, copying DNA and reproducing it. The antibodies found to be most effective against COVID-19 would be pinpointed and mass manufactured. Meanwhile, the first antibody drug developed to treat COVID-19 specifically, LY-CoV555, is now being studied amongst patients in the US, administered via IV, and is hoped to offer temporary protection for weeks or months. AI is also being utilised to generate, screen and optimise antibodies, some of which are already known to have targeted the Coronavirus involved in the 2003 SARS outbreak. Though antibody research in labs takes years it can take just a week for algorithms to identify antibodies capable of fighting the virus, expediting treatment discovery. Across COVID-19 treatment research AI has become a vital tool, scanning through libraries of drugs, drug fragments and studies to highlight potential treatments, with companies like BenevolentAI finding through machine learning and its database of all existing approved drugs within three days that baricitinib, a drug used to treat rheumatoid arthritis, could be an effective COVID-19 treatment. Eli Lilley has since begun the clinical trial of the drug, with anti-inflammatory effects that could control the body’s reaction to Coronavirus. Concurrently researchers such as those at Northwestern University are using AI to predict which COVID-19 studies are most likely to be replicable, and scientists at Atomwise are using AI screening technology to predict the binding of millions of small molecules to a protein of interest identified as a potential target for COVID-19, narrowing down to a few hundred predicted hit molecules. 16-19.qxp_Layout 1 09/06/2020 11:08 Page 4Next >