< PreviousANTIBIOTICS EXPOSÉ 20 Pharma Business International www.pbiforum.net are being taken to change this. The UK, for instance, is to pilot a subscription payment model to encourage antibiotic development for resistant infections where pharma companies would receive an upfront payment for medicines based on their worth to the NHS, instead of based on volume of antibiotics sold. At the end of 2019, British researchers from the Centre for Ecology & Hydrology, Oxford Martin School and Liverpool School of Tropical Medicine argued that the development of new antibiotics should be brought into the public sector to repair the “broken antibiotic pipeline” and tackle rising AMR. They pinpointed a two-stage approach involving a short- term expansion of incentives for the private sector, to maximise the impact of existing commercial research, followed by the establishment of a global, publicly funded antibiotic research and development institute. In a paper in Lancet Infectious Diseases, the researchers show how a co-ordinated international research effort, with long term funding and staff, could overcome some of the key issues with current public-private partnerships, such as ensuring that development is prioritised according to need rather than profit potential, centralising funding, and ensuring that new antibiotic patents are in public hands. An historic problem for antibiotics and AMR has been over-prescription - with misuse of antibiotics a leading cause of AMR. Data from the US Centre for Disease Control shows that approximately thirty per cent of antibiotic prescriptions in the US are unnecessary. Antibiotics are often used to treat illnesses like coughs, sore throats and earache that are less serious and can resolve themselves. In overprescribing antibiotics, the harmful bacteria living within patients can become resistant, leading to antibiotics not working when truly required. People are also being prescribed unnecessarily long courses of antibiotics, increasing risk of antibiotic resistant infections. In the UK, NICE © Shutterstock /Vlad IspasPharma Business International 21 www.pbiforum.net ANTIBIOTICS EXPOSÉ © Shutterstock /Fahroni guidance on the matter is not always followed as well as it should be, as shown in a recent study covering 2013- 2015. The study found for example that people, on average, were taking antibiotics for bronchitis for two days longer than guidelines state. Positive steps have been taken to address this with the aforementioned ESPAUR report indicating a seventeen per cent drop in antibiotic prescriptions written and dispensed in general practice since 2014, and the UK government publishing a five-year action plan in 2019, outlining how it will tackle AMR. This includes reducing antibiotic use by fifteen per cent and reducing the number of resistant infections by ten per cent by 2025. Better diagnostic tests are also required to ensure antibiotics are used only as needed. For instance, the Global Antibiotic Research and Development Partnership (GARDP) has highlighted issues in distinguishing gonorrhoea and chlamydia. Due to the similarity of symptoms and frequent absence of conclusive diagnosis, two drugs tend to be prescribed to combat both infections. However, in doing this, we are only adding to the development of drug resistant gonorrhoea. With more accurate diagnostic tests new antibiotics will be able to be used more carefully, to keep them effective for longer. Resistance has developed to all antimicrobial treatments introduced for infections by Neisseria gonorrhoea and more strains have become resistant to the last line of antibiotics available. Super gonorrhoea has joined the AMR battle. One fund looking to improve diagnosis is The Longitude Prize - a £10 million prize fund, with an £8 million pay-out. It will reward a team of researchers who develop “a point–of–care diagnostic test that will conserve antibiotics for future generations and revolutionise the delivery of global healthcare.” The prize is to remain open to at least 31 December 2020 or until a winner is chosen. A variety of tests and technologies are in the pipeline to improve diagnosis and help avoid antibiotic misuse. One research consortium has developed a breath analysis test which can indicate whether patents with respiratory infections should be treated with antibiotics. The ‘BreathSpec’ device helps distinguish between bacterial and viral infections to prevent the overprescribing of antibiotics. Further developments in the antibiotics field have seen researchers from the Chinese Academy of Sciences develop bandages that change colour to identify drug sensitive and resistant bacteria in wounds and release antibiotics, researchers at the National Physical Laboratory engineer an artificial virus to fight antibiotic resistance, scientists at the University of Birmingham create a new probiotic drink to take on antibiotic resistant bacteria and researchers at McGill University and Institut national de la recherche scientifique (INRS) in Montreal find that pathogenic bacteria treated with molecules derived from cranberries become more sensitive to lower doses of antibiotics. Meanwhile, there has also been a return to researching use of bacteriophages. Of course, new treatments will not be able to tackle AMR alone, as over time bacteria will learn to resist these too. Thus we also need to innovate diagnostics, vaccines and prevention control to see real change.BLOCKCHAIN 22 Pharma Business International www.pbiforum.net Hailed as a technical advancement that can push the pharmaceutical industry further than ever, several companies and countries are already investing – but blockchain isn’t without its disadvantages. 22-24.qxp_Layout 1 10/02/2020 13:05 Page 1Pharma Business International 23 www.pbiforum.net BLOCKCHAIN Knowledge is power. The adage has never been truer than in the pharma industry, where secrets are jealously guarded and research can be worth billions. In such an industry, it’s easy to see both the potential for blockchain, and the problems it might face. On a purely ideological level, blockchain could see development and information sharing on an unprecedented level, expanding medical science for decades. It is not an ideological world we live in, however, and profit will always underpin such collaboration. In those terms, blockchain can be a risk, another flashpoint where things might go wrong. It’s still possible for pharma to utilise blockchain within its own sphere, however, with benefits noted for improving the supply line and avoiding problems. One of the biggest reasons it hasn’t already become standard in the industry is the high up-front costs, which will hopefully lower once the technology and the expertise behind it become more commonplace. This is a trend seen before in automation and robotics equipment, which was initially too expensive to be viable but is now common in most pharma manufacturing facilities. The key benefit of blockchain technology is thought to be the ability to execute numerous transactions without a third party. Pharma companies are able to manage business without central authority, involvement or control. On the other hand, this can become a problem where transparency is involved, and with recent media unrest having painted pharma in a negative light (many big businesses, in fact) the onus of convincing the public that there are no ill- goings-on seems to lay with the business. In recent news, new blockchain 24 Á © Shutterstock /Production PerigBLOCKCHAIN 24 Pharma Business International www.pbiforum.net partnerships have been coming to light. A new consortium was formed this February following a compliance with the DSCSA. After a trial period in 2019, the companies IBM, Walmart, Merck and KPMG have formed a blockchain alliance called the Pharmaceutical Utility Network (PhUN). In its announcement, IBM stated that “PhUN takes an open-source platform first approach – a similar concept to the Apple App Store – to empower stakeholders to comply with regulations and use them as the basis for innovation.” They are not the only ones experimenting in such things. The United Arab Emirates recently launched a blockchain platform for storing healthcare and pharmaceutical data. Along with storing data, the app will work like a registry of healthcare professionals in the UAE, allowing users to search for health facilities, medical personnel and more. Available more as business to consumer than business to business, the app is also expected to help promote medical tourism to the UAE by making people readily able to see the kind of expertise available in the region. One report, by PreScouter, claimed that while blockchain could add $3 billion of value to life sciences companies by 2025, adoption of it is being held back by the mindset of leadership in the sector. The results in the survey stated that seventy per cent of life sciences leaders intend to set up a network within the year, but that there are still challenges to face when it comes to adoption – and that the changing mindset of private, public and political leadership for adopting blockchain technology is the single greatest hurdle in its development. The biggest issues naturally come at those areas of highest risk of loss – namely in patient privacy but also noticeably in IP protection. With intellectual property being profit at the end of the day, it’s easy to see why a system that might contain all that information in one place might not be desirable. Still, with blockchain having the potential to drastically reduce waste and increase efficiency, and with so many companies piloting and investing in it, those thoughts are going to have to change soon. Those that fail to read the writing on the wall may suffer for it. © Shutterstock /Venomous VectorPharma Business International 25 www.pbiforum.net EXPLORING ANTIBODIES Drugs based on monoclonal antibodies (mAbs) are a cornerstone in medicine today. mAbs are a type of targeted therapy, designed to interact, for example, with specific cancer cell targets, and are also used in immunotherapy, to improve immune system response, for instance, to attack cancer cells more effectively. Made up of one single type of antibody, mAbs can be made in large amounts for clinical use and bind to specific antigens on the cancer cell surface, which has seen them become a mainstay in immuno- oncological therapies. Thanks to their specificity, therapeutic antibodies have become a primary class of new drugs. The market for therapeutic antibody drugs has witnessed major growth, with antibodies amongst the best-selling drugs in the pharmaceutical market, with the global therapeutic mAb market expected to generate revenue of $300 billion by 2025, after being valued at $115.2 billion in 2018. The discovery of antibodies with therapeutic potential is high on agenda for biopharma companies. Antibody research, development and treatments are booming, addressing a variety of conditions. Recent positive developments for antibodies include the opening of the first human trial of a mAb to prevent malaria in January. The Phase 1 clinical trial testing the safety and effectiveness of a mAb against malaria began enrolling healthy volunteers at the National Institutes of Health Clinical Centre in Maryland. This is the first trial to test mAb CIS43LS in humans. It will see most volunteers exposed to malaria parasite-carrying mosquitoes under controlled conditions after receiving mAb CIS43LS. According to the National Institute of Allergy and Infectious Diseases, if found to be effective and safe, the mAb could be used preventatively by tourists, medical workers and military personnel who travel to areas where malaria is commonly found. At the end of 2019, meanwhile, a new preclinical study, from neurogeneticists at the University of Florida (with Johns Hopkins University and investigators at Biogen and Neurimmune), indicated that antibody therapy could offer a potential treatment path for slowing the disease process and extending the survival of people with amyotrophic lateral sclerosis (ALS). The research highlights that Antibodies and ADCs In exploring antibodies scientists have made significant progress in developing new treatments for diseases and delivery methods. 26 Á © Shutterstock /Kateryna KonEXPLORING ANTIBODIES 26 Pharma Business International www.pbiforum.net targeting a mutant protein in the brain with an antibody derived from humans can decrease neuroinflammation and neurodegeneration, as well as lengthen survival in the common genetic form of ALS and frontotemporal dementia. The mouse-model study published in Neuron presents a new option for treatment, targeting a pathological protein produced by a mutant C9orf72 gene. A further interesting development came last October, when news broke that an antibody that protects mice against a vast range of flu strains had been discovered. The study from Scripps Research, Washington University School of Medicine and Icahn School of Medicine, published in Science, highlights a new approach for treating severe flu cases. The antibody central to the study binds to neuraminidase, a protein essential for the flu virus to replicate in the body which sits on the surface of the virus. The researchers say their antibody discovery could be key in designing a universal vaccine, protecting against all influenza strains. After mice were given a lethal dose of influenza virus, the antibody 1G01 protected against twelve strains tested, including all three groups of human flu virus alongside avian and other nonhuman strains. Mice survived even if given the antibody seventy-two hours after infection. This suggests an application in intensive care situations where it is too late to treat with Tamiflu, which must be administered within twenty-four hours of symptoms. The researchers found that the antibodies provide broad protection because they target the conserved residues in the active site of the neuraminidase protein (a site that stays the same across many flu strains due to its importance in allowing replication), inserting a single loop without contacting surrounding hypervariable regions. Work has begun on developing new treatments and vaccines for influenza based on antibody 1G01. Additionally, in November, research was published in Nature Communications, showing that University of Sheffield scientists, working with Kymab Ltd, had identified a novel antibody with the potential to become a new treatment for pulmonary arterial hypertension (PAH). The research indicated that treatment with a specific antibody can reverse the process behind the development of PAH. It is now to be considered for clinical development. A pivotal area of research and development for antibodies and the pharmaceutical industry is antibody-drug conjugates (ADCs), which have been proven particularly effective against solid tumours. Consisting of an antibody linked to a biologically active cytotoxic agent, ADCs combine the targeting abilities of mAbs with the cancer killing capacity of cytotoxic drugs. Favourably, ADCs are able to discriminate between healthy and diseased tissue. Despite 25-27.qxp_Layout 1 10/02/2020 13:06 Page 2Pharma Business International 27 www.pbiforum.net EXPLORING ANTIBODIES limited approvals, ADCs continue to be tested in the biotechnology industry, to fight cancer mainly. 2019 saw US officials approve three ADCs, representing the most approved in a single year, which included a breast cancer drug, a bladder cancer drug, and a lymphoma drug. The selective mAb can target tumour associated antigens, allowing the delivery of chemotherapeutic agents. After binding, the ADC is internalised and cytotoxic agents released through lysosomal degradation. Unlike with chemotherapy, antibody conjugates are designed to deliver treatment only to the cells that need it, to target and kill tumour cells while reprieving healthy tissue. Though the idea of ADCs delivering a cytotoxic drug directly to tumour cells while minimising damage to normal cells is praised as an advancement in precision medicine, it has been challenging to see through the concept in the clinic. Failures in ADC development have primarily come in pairing the right antibody with the right cancer killing substance, with some being too harming and others weak. Managing toxicity can be difficult. Additionally with a plethora of combinations of their three components - mAbs, linker molecules and payloads - ADC manufacturing is complex, and often sees need for outsourcing and collaboration. Progress for ADCs however has come with consideration of more exquisite targeting, such as using bispecific ADCs, alongside improvements in linker technologies, which join an antibody to cancer killing cytotoxins and are important for ADC stability. Linker molecules have been refined to ensure that toxins are only released when a drug is absorbed by a cancer cell, improving upon early ADCs where some fell apart in the bloodstream, damaging healthy tissues. A new generation of more efficient linker molecules has come on the scene, seeing a revival in ADC investment. ADC research is expanding outside its main focus of cancer too, with researchers like those at AbbVie looking to use ADC technology for immune- mediated diseases, for targeted immunology treatments, where the antibody could deliver a steroid inside an immune cell and have it still work property. The discriminatory ability of ADCs here would help negate how steroids currently impact healthy cells, being unable to distinguish normal and pathogenic cells. Conjugates are also being developed for treating inflammation, diabetes, Alzheimer’s and Parkinson’s, amongst other diseases. Achieving success with ADCs will require further development and sound project management. Strong hope for ADCs is clear, however, with the ADC market set to be worth more than $15 billion by 2030, according to analysis by Roots Analysis. © Shutterstock /ustas7777777Q&A - INFLUENZA VACCINE 28 Pharma Business International www.pbiforum.net AUDENZ, the first ever, adjuvanted, cell-based pandemic influenza vaccine to protect against influenza A (H5N1), has been approved by the US FDA. Can you tell us more about what this means for patients and healthcare providers? AUDENZ™ (Influenza A (H5N1) Monovalent Vaccine, Adjuvanted), combines two leading-edge technologies—MF59®adjuvant and cell- based antigen manufacturing—setting the stage for new industry best practices to meet the public health challenge of an influenza pandemic. AUDENZ provides active immunization against the influenza A (H5N1) virus strain and it is approved in the U.S. to help protect individuals six months of age and older in the event of an A (H5N1) influenza pandemic. AUDENZ is created with MF59® adjuvant that reduces the amount of antigen required to produce an immune response, which increases the number of doses of vaccine developed so that a large number of people can be protected as quickly as possible. How is the regulatory filing of AUDENZ progressing in Europe and elsewhere? While we do not have immediate plans to license AUDENZ in other countries, Seqirus is committed to partnering with key stakeholders to develop adequate and effective pandemic preparedness plans that can help protect communities and mitigate the negative economic impact of an influenza pandemic. The recent coronavirus outbreak has shown serious shortcomings in global pandemic preparedness. What improvements can be made? The risk of a pandemic is ever-present, but it is difficult to predict so it is critical to be prepared. The negative impact of an influenza pandemic in individual countries can be mitigated by local pandemic readiness plans. Seqirus is committed to partnering with key stakeholders to develop adequate and effective pandemic preparedness plans that can help protect communities and mitigate the negative economic impact of an influenza pandemic. Scale and speed are critical during a pandemic. As a result of our multi-year public-private partnership with the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services, Seqirus is prepared to manufacture cell-based vaccines on a pandemic scale. How can healthcare providers and patients be better prepared for influenza outbreaks? According to the World Health Organization (WHO), the most effective way to prevent influenza is to get an annual flu shot. It is also critical that the public understands the overall importance and benefits of influenza vaccination. If seasonal vaccination rates are high across a population, there will likely be a comparable uptake in pandemic vaccination. At the time of a pandemic outbreak, manufacturing switches from producing seasonal vaccines to matched pandemic vaccines. Our capacity to produce seasonal vaccines allows us to seamlessly switch in a timely manner to pandemic vaccine production. Q&A Interview with Russell Basser Pharma Business International spoke with Russell Basser, Chief Scientist and Senior Vice President of Research and Development at Seqirus, a global-based leader in influenza prevention and pandemic response. Q&A Interview with Russell Basser Pharma Business International spoke with Russell Basser, Chief Scientist and Senior Vice President of Research and Development at Seqirus, a global-based leader in influenza prevention and pandemic response. 28-29.qxp_Layout 1 11/02/2020 09:04 Page 1Pharma Business International 29 www.pbiforum.net Q&A - INFLUENZA VACCINE 28-29.qxp_Layout 1 11/02/2020 09:04 Page 2Next >