< PreviousM&A ROUND-UP 10 Pharma Business International www.pbiforum.net the Federal Trade Commission (FTC) to divest the US rights to brazikumab and zenpep to AstraZeneca and Nestlé respectively. The latter will also be acquiring Viokace, another pancreatic enzyme preparation, as part of the same transaction. As of writing, the consent decree remains subject to further review and approval by the FTC, but both companies anticipate the deal closing in May. Provided there’s no more hurdles or unforeseen setbacks, we’ll be covering the deal’s close in our next issue. In early March, Thermo Fisher Scientific, a biotechnology product development company based in Massachusetts, announced its intention to acquire disease test kit maker Qiangen for $11.5 billion. The addition of Qiagen, a German company providing life science and molecular diagnostics solutions, expands Thermo Fisher Scientific’s speciality diagnostics portfolio of molecular diagnostics capabilities such as infectious disease testing. It also expands its commercial and geographic reach, expanding customer access. Speaking when the deal was first announced, Marc N. Casper, Chairman, President and CEO of Thermo Fisher Scientific, said: “This acquisition provides us with the opportunity to leverage our industry-leading capabilities and R&D expertise to accelerate innovation and address emerging healthcare needs. For shareholders, we expect the transaction to be immediately accretive and to generate significant cost and revenue synergies.” Of course, there’s still shareholder backing and regulatory hurdles to clear and, at present, the transaction is forecast to close in the first half of 2021. The third and final multi-million-dollar deal explored this issue was also first announced in early March with Gilead strengthening its immuno-oncology position. The biotech is acquiring fellow © Shutterstock /Michael ViPharma Business International 11 www.pbiforum.net M&A ROUND-UP Californian company Forty Seven in a $4.9 billion deal that significantly strengthens its immuno-oncology R&D portfolio. The acquisition provides it will access to Forty Seven’s investigational lead product candidate – magrolimab – which has the potential to be a first-in- class therapy. Magrolimab is a monoclonal antibody in clinical development for the treatment of several cancers for which new, transformative medicines are urgently needed, including myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and diffuse large B-cell lymphoma. The investigational therapy targets CD47, a “do not eat me” signal that allows cancer cells to avoid destruction thereby permitting the patient’s own innate immune system to engulf and eradicate those cancer cells. Forty Seven presented promising results of a Phase 1b study of magrolimab in patients with MDS and AML at the American Society of Haematology meeting in December 2019 and it’s clearly got Gilead’s senior team excited. “This agreement builds on Gilead’s presence in immuno-oncology and adds significant potential to our clinical pipeline,” said Daniel O’Day, Chairman and CEO of Gilead Sciences. “Magrolimab complements our existing work in haematology, adding a non-cell therapy program that complements Kite’s pipeline of cell therapies for haematological cancers. With a profile that lends itself to combination therapies, magrolimab could potentially have transformative benefits for a range of tumour types.” The deal, which was unanimously approved by both company’s boards of directors, is expected to close during the second quarter of the year, so be sure to check in with our next issue for all the closing details. © Shutterstock /Sundry PhotographyHIV AND AIDS EXPOSÉ 12 Pharma Business International www.pbiforum.net Over the last three decades, major advances in awareness and treatments have made HIV a manageable condition instead of a death sentence. The past year has seen great steps taken forward for simplifying HIV treatment, as well as new approaches and medicines enter the spotlight. With 38 million people currently living with HIV, 1.7 million new infections a year, and a United Nations initiative aiming to end AIDS by 2030, there is still work to be done. The HIV space saw positive news in 2019 after researchers from University of Nebraska Medical Centre and the Lewis Kats School of Medicine at Temple University eliminated the HIV virus from the genomes of mice for the first time. The findings, in Nature Communications, present an important stride towards the development of a potential cure for human HIV infection. The study combined long-acting slow-effective release (LASER) ART, which targets viral sanctuaries and maintains HIV replication at low levels for extended periods of time with modified antiretroviral drugs, with gene editing via CRISPR-Cas9 technology, to see if LASER ART could suppress HIV replication long enough for CRISPR-Cas9 to free cells of viral DNA. Using mice engineered to produce human T cells susceptible to HIV infection, infection was established, and mice were treated with LASER ART and subsequently CRISPR-Cas9. At the end of the treatment period, mice were examined for viral load. HIV DNA was completely removed in a third of HIV-infected mice. Drs Howard Gendelman and Kamel Khalili, senior investigators on the study, said: “The big message of this work is that it takes both CRISPR-Cas9 and virus suppression through a method such as LASER ART, administered together, to produce a cure for HIV infection. We now have a clear path to move ahead to trials in non-human primates and possibly clinical trials in human patients.” Hope for the future was further renewed recently after news broke that a London man had become the second person to be “cured” of HIV - or more accurately in long term viral remission. As of March 2020 he had remained free of the virus for over 30 months after stopping antiretroviral therapy, with no detectable active virus in blood, tissues, sperm, gut, lymph nodes or cerebrospinal fluid, according to a paper published in Lancet HIV. In the London man’s case, who was tentatively said to be cured last year, the “cure” came as a result of a stem cell transplant for advanced Hodgkin’s lymphoma from a donor with a CCR5 mutation that makes it practically impossible for a carrier to be infected with HIV. Currently ninety-nine of Adam Castillejo’s stem cells are said to be donor derived. The concept of stem cell transplants as a treatment for HIV however is not feasible. Used in this instance to treat cancer, rather than HIV, the therapy is aggressive, high risk and a last resort that relies on Homing in on HIV Pharma Business International considers some of the recent advances in HIV treatment, its simplification, and the fight to find a vaccine. 14 Á 12-15.qxp_Layout 1 08/04/2020 11:01 Page 1Pharma Business International 13 www.pbiforum.net HIV AND AIDS EXPOSÉ © Shutterstock /Alim YakubovHIV AND AIDS EXPOSÉ 14 Pharma Business International www.pbiforum.net finding a donor with the rare CCR5 mutation, and who is a blood match for the patient. While the idea of a cure is on the minds of many, a wealth of novel strategies are in development to offer simpler alternatives for HIV prevention and treatment. For example, while people not infected with HIV are able to take the pre-exposure prophylaxis drug (PrEP) to avoid contracting it, a potentially simpler option has been highlighted with hopes of reaching the many who start PrEP but do not continue with it, or undermine its effectiveness with intermittent use. At the International AIDS Conference in Mexico City, Merck & Co showcased an implant. The slow release implant of an experimental long-lasting antiretroviral drug to provide protection from HIV for a year or longer was used in a study of just 12, meaning further testing of safety and effectiveness in large scale studies is required. In the Merck study, testing two doses, implants with compound MK- 8591/islatravir, which inhibits an enzyme HIV requires for replication, were placed under the skin of people not infected with HIV for 12 weeks. Then, after a further four weeks, MK-8591 levels were measured in the blood of participants. Those who were given a higher dose maintained such high levels of the compound that it would be able to prevent infection for over a year. Widening HIV treatment options to transform care and convenience, an injection antiretroviral treatment strategy has been successful in clinical trials. Cabenuva, a combination of cabotegravir, from ViiV Healthcare, and rilpivirine, from Janssen, is injected into the buttocks once a month. The treatment option could be useful for those who dislike pills, don’t want to be seen taking them due to social pressures or tend to forget them, and has been stated by most participants in clinical trials as preferred over oral daily regimens. The results of two phase III trials examining the efficacy and safety of the treatment amongst over 1,100 participants across 16 countries suggested the monthly shot of antiretroviral drugs works as well as daily pills. Following these results, Health Canada approved the long-acting injectable treatment in March, its first approval in the world. ViiV Healthcare has also revealed positive 48-week data from a phase III study showing that a two- monthly regimen of long-acting injectable cabotegravir and rilpivirine has similar efficacy to the once-monthly dosing. This could allow people living with HIV, who take daily medication, to reduce treatment dosing days from 365 to six annually. Getting caught in the headlines, on a less positive note, is the failure of an HIV vaccine in South Africa. HVTN 702 had been thought one of the most promising potential treatments. With 5,407 sexually active men and women without HIV between 18 and 35 years old enrolled in a study, who lived in HIV prevalent communities, volunteers were assigned the vaccine or a placebo. Participants were instructed to be safe with condoms, contraception, PrEP and HIV prevention counselling. 129 volunteers who received the vaccine however became infected with HIV after two years alongside 123 of those who received the placebo. Subsequently the trial was cut short in January. This has not slowed down the pipeline for an HIV vaccine however, with other trials currently underway, with the HIV Vaccine Trials Network testing HVTN 705 and HVTN 706. The former is being trialled in South Africa, Malawi, Mozambique, Zambia and Zimbabwe and the latter in Europe and the Americas. Both vaccines are designed to generate immune reactions against various strains of HIV. Another strategy in development involves broadly neutralising antibodies (bNAbs). Organised by the HIV Vaccine Trials Network, antibody mediated prevention is under trial in eleven countries, and gives antibodies directly to participants with IV infusions. bNAbs, which can prevent the infection of new cells, are being given in the hope that they will protect participants from getting HIV. However, to remain effective in practice they would need regular re-administration. If able to show how bNAbs can protect against HIV infection in people, researchers will be pushed forward to create vaccines that help humans generate these naturally. At the 2020 Conference on Retroviruses and Opportunistic Infections in March, it was revealed that a vaccine had been concocted that induced human cells to create bNAbs to HIV. 12-15.qxp_Layout 1 08/04/2020 11:01 Page 3Pharma Business International 15 www.pbiforum.net © Shutterstock /ktsdesignCLINICAL TRIALS 16 Pharma Business International www.pbiforum.net © Shutterstock /New AfricaPharma Business International 17 www.pbiforum.net CLINICAL TRIALS Race for treatment We explore the clinical trials currently taking place to test vaccine candidates for COVID-19. D espite the rapid, unprecedented response from researchers and the global pharmaceutical sector in the wake of the COVID-19 pandemic, GlobalData says that it will probably take at least a year for a vaccine to be approved and made available to patients – an issue compounded by the fact that the virus has already mutated into two strains. However, as the virus changes slowly, it’s poorly equipped to evade the immune system, and animal models have already shown that vaccines against the related coronaviruses that cause SARS and MERS are similarly effective for this new strain, called Sars-CoV-2. As evidence by this issue’s coronavirus focussed news pages (4-6), there are a slew of potential vaccine candidates currently in development running the gamut from those derived from plasma, with others utilising antibodies and, crucially, those repurposing existing medicines for other viruses to potentially treat COVID-19. ‘The efforts to finance and coordinate COVID-19 vaccine development is being spearheaded by Norwegian non-profit, the Coalition for Epidemic Preparedness Innovations (CEPI). To date, CEPI has initiated eight COVID-19 vaccine development projects with Curevac, Inovio Pharmaceuticals, Moderna, Novavax, The University of Hong Kong, The University of Oxford, The University of Queensland and a consortium led by Institut Pasteur to develop vaccine candidates. But for any of these candidates to serve patients, they must first be clinically tested. Even in pressing, unprecedented circumstances such as these, the process toward and during clinical testing is protracted, with three hurdles required to clear before any medicine can be made widely available to patients. And that’s assuming approval is granted by regulators. At present, a table put together by the World Health Organisation (WHO) lists a total of fifty-two vaccine candidates that could soon go into clinical testing. That’s on top of those promising few that have already entered early trials and begun testing. A solid foundation was already in place for researchers to build on, facilitating a speedy response to develop a vaccine. This included recent efforts from Chinese researchers who, in early January, shared the genetic sequence of Sars-CoV-2, thus allowing researchers around the world to grow the live virus to study. However, this groundwork stretches further back, to earlier outbreaks of coronavirus. As we’ve already touched on, this new strain shares a similarity with the pre-existing strains, Severe Acute Respiratory Syndrome (SARS) which broke out in China in 2002-04, and Middle East Respiratory Syndrome (MERS), which originated in Saudi Arabia back in 2012. As in both cases, research and development began on vaccines that were ultimately shelved when the outbreaks were contained. Because of these earlier outbreaks, there already existed a foundation of investment and understanding in how to develop vaccines for other coronaviruses, says Richard Hatchett, CEO of CEPI. 18 ÁCLINICAL TRIALS 18 Pharma Business International www.pbiforum.net Perhaps the most promising example of this approach sees Novavax, a Maryland- based late-stage biotechnology company developing next-generation vaccines for serious infectious diseases, repurpose these medicines for Sars-CoV-2. The vaccine maker has produced – and is currently assessing – multiple nanoparticle vaccine candidates in animal models prior to identifying an optimal candidate for human testing. The company said it expects to utilise its proprietary Matrix- M adjuvant with its vaccine candidate to enhance immune responses. In March, CEPI awarded Novavax with an initial $4 million, supporting its efforts and accelerating the development of a COVID-19 vaccine to prepare for Phase 1 clinical testing. Further funding is currently being discussed to address costs through these trials. With the clinical trial slated to start in late spring, it represents one of the most pressing and promising potential treatments for COVID-19, but it isn’t the only one at the forefront of the response. Moderna, a biotech from Cambridge, Massachusetts that has yet to bring a product to market, continues to build on work on the MERS virus conducted at the US National institute of Allergy and Infectious Diseases. In mid-March, an American woman became the first person outside of China to receive an experimental vaccine powered by messenger RNA (mRNA) technology against COVID-19. Along with China’s CanSino Biologics, Moderna is the first to launch small clinical trials of vaccines against the virus. The aim – to find out firstly if they are safe and if they can trigger immune responses. Funded by The National Institute of Allergy and Infectious Diseases (NIAID) – part of the National Institutes of Health – the Phase 1 open-label clinical trial is taking place at the Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle. It will enrol forty-five healthy adult volunteers ages eighteen to fifty-five years over approximately six weeks. The study is evaluating different doses of the experimental vaccine for safety and its ability to induce an immune response in participants. This is the first of multiple steps in the clinical trial process for evaluating the potential benefit of the vaccine. The vaccine – called mRNA-1273 – was developed by NIAID scientists and Moderna, with CEPI having supported the manufacture of the vaccine candidate for the trial. Though these trials are the first, there are others. Researchers at the University of 16-19.qxp_Layout 1 08/04/2020 11:13 Page 3Pharma Business International 19 www.pbiforum.net CLINICAL TRIALS Oxford in the UK, for example, have recently commenced enrolment of healthy volunteers for a clinical trial of the COVID-19 vaccine candidate called ChAdOx1 nCoV-19. The vaccine is based on an adenovirus vaccine vector and the SARS-CoV-2 spike protein. As of writing, it is currently in production at the university’s Clinical Biomanufacturing Facility. The trial is designed to enrol up to 510 participants aged eighteen to fifty-five and is being conducted by the university’s Jenner Institute and Oxford Vaccine Group. The study will assess the vaccine candidate’s safety and ability to induce an immune response against the novel coronavirus and ChAdOx1 nCoV-19 will be compared to a control injection. The University said that the vaccine will undergo additional preclinical tests and will be manufactured in large quantities before entering the trial. Elsewhere, Regeneron and Sanofi have started a clinical program evaluating Kevzara (sarilumab) in patients hospitalised with severe COVID-19 infection. Kevzara is a fully-human monoclonal antibody (mAB) that inhibits the interleukin-6 (IL-6) pathway by binding and blocking the IL-6 receptor. IL-6 may play a role in driving the overactive inflammatory response in the lungs of patients who are severely or critically ill with COVID-19. This is supported by preliminary data from a single-arm study in China using another IL-6 receptor antibody. If, as GlobalData predicts, a vaccine for COVID-19 is still a year from a commercial launch, the clinical tests we’ve covered – and those candidates still in development move closer to Phase 1 testing – will be crucial steppingstones towards tackling the pandemic. In March, CEPI awarded Novavax with an initial $4 million, supporting its efforts and accelerating the development of a COVID-19 vaccine to prepare for Phase 1 clinical testing. Further funding is currently being discussed to address costs through these trials. With the clinical trial slated to start in late spring, it represents one of the most pressing and promising potential treatments for COVID-19, but it isn’t the only one at the forefront of the response. © Shutterstock /Nixx PhotographyNext >