NOVEMBER 2020 # 70
Upfront In My View NextGen Sitting Down With Reducing the carbon The scavengers’ guide Pharma vs diabetes: Will Downie, CEO footprint of clinical trials to precious metal catalysts progress so far of Vectura Group, UK
08 13 46 – 49 50 – 51
Making Medicine… Anywhere
How can biologics be made on-demand in deep space environments?
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Cobra Biologics is part of the Cognate BioServices family Beyond the Storm What happens after COVID-19? Editorial
ack in 2017, we explored what healthcare and pharma might look like in 100 years’ time (1); the experts I spoke with were intrigued by the Bpremise, but were quick to point out that it’s hard to predict what will happen in five years’ time – and so virtually impossible to imagine a world in 2100 (although they still tried!). As 2020 has proven, even six months can seem like a very long time. The term “COVID-19” didn’t exist in November 2019, but by mid-March it was a household name, with most of us living in lockdown, trying to come to terms with how quickly a black swan event can transform our lives. Right now, I don’t know what 2021 will look like, but I do know that a single revolutionary medicine or vaccine could significantly transform the COVID-19 outlook. And the whole research and development community is working hard to bring us that breakthrough sooner rather than later. But what lies beyond COVID-19? There are many diseases that could benefit from all the collaborative effort and funding being poured into COVID-19. What if the world could rally around malaria or tuberculosis in the same way? Vaccines and treatments already exist for TB, References but it still killed 1.4 million people in 2019 (2). Experts 1. The Medicine Maker, “November 2017 Issue have also expressed concerns about the pandemic’s impact of The Medicine Maker” (2017). Available on the treatment of other infectious diseases (3); once the at https://themedicinemaker.com/ COVID-19 storm passes, it’s likely we’ll need a thorough issues/1017 reassessment of global healthcare priorities. 2. WHO, “Tuberculosis” (2020). Available at Where else can the wider pharma industry develop https://bit.ly/3mZQ6NE. partnerships to bring about drastic improvements? 3. Nature, “How to stop COVID-19 fuelling a Manufacturing seems like one area that could benefit; most resurgence of AIDS, malaria and vendors work alongside pharma partners, but few vendors tuberculosis,” (2020). Available at https:// work together – or with partners outside the industry – to go.nature.com/3exUqAJ. develop truly revolutionary tools. And yet, working together seems like the fastest way toward disruptive change. On that note, our cover feature looks at one provocative (and, if successful, disruptive) direction: the ability to synthesize biologic medicines in any location – even on Mars. Sound far-fetched? On page 18, scientists explain how it is possible, perhaps offering us a glimpse of what could lie on the post-pandemic horizon.
Stephanie Sutton Editor
www.themedicinemaker.com Contents
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38 In My View
12 Nik Kotecha asks if your business is prepared for Brexit
03 Editorial Upfront 13 Three experts present the Beyond the Storm, scavengers guide to precious by Stephanie Sutton 06 The latest news, views, and metal catalysts research – including an off- the-shelf CAR T therapy, the 14 Manufacturers should adjust On The Cover Cover carbon footprint of clinical their patient-support programs trials, and the pain-relieving post-pandemic, says Corey Ford How are researchers tackling properties of spider venom the issue of makingng medicines in 16 Medicine Makers explain how deep space? their personal and professional lives have changed in the Pandemic Diaries ISSUE 70 - NOVEMBER 2020
Feel free to contact any one of us: [email protected] Content Team Editor - Stephanie Sutton Charlotte Barker (Associate Content Director) Kirstie Anderson (Commercial Editor) James Strachan (Deputy Editor) Maryam Mahdi (Associate Editor) Commercial Team Associate Publisher - Helen Conygham Helen Johnson (Business Development Manager) Stacy Gaines (Business Development Manager, North America) Design Team Head of Design - Marc Bird Hannah Ennis (Senior Designer) Charlotte Brittain (Designer)
Digital Team Digital Team Lead - David Roberts Peter Bartley (Digital Producer Web/Email) Abygail Bradley (Digital Producer Web/App) Audience Team Audience Growth Strategy Manager – Brice Agamemnon CRM & Compliance CRM & Compliance Manager - Tracey Nicholls 30 Hayley Atiz (CRM Assistant) Commercial Support Team Internal Systems Manager - Jody Fryett Dan Marr (Campaign Reporting Analyst) Commercial Services Commercial Service and Social Media Manager- Matt Everett Kevin O’Donnell (Marketing Executive) Feature NextGen Alice Daniels-Wright (Video Project Manager) Jess Lines (Video and Project Support Coordinator) 18 Making Medicine… Anywhere 46 Diabetes: Finding a Panacea Lindsey Vickers (Sales Support Project Manager) Researchers explain how How far has pharma come in Jennifer Bradley (Sales Support Coordinator) biologic medicines could be reducing the global incidence of Marketing Team Marketing Manager - Katy Pearson made on demand in deep space diabetes? And what more can Jo Baylay (Marketing Executive) for astronauts – and if we can companies do? Accounts Team Kerri Benson (Accounts Assistant) make them in space, we can Emily Scragg (Accounts Apprentice) make them anywhere Human Resources Human Resource Manager - Tara Higby 30 Preparing for the Reports Management Team Chief Executive Officer - Andy Davies Next Pandemic Chief Operating Officer- Tracey Peers How can we transfer lessons on 28 Mapping Out MAM Senior Vice President (North America) - Fedra Pavlou pandemic preparedness from flu Financial Director - Phil Dale Commercial Director - Richard Hodson to COVID-19? Russell Basser 35 Advanced Therapies Content Director - Rich Whitworth from Seqirus gives his view – VIA Capsule System Change of address [email protected] Hayley Atiz, The Medicine Maker, Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, UK 42 Fighting Viruses with General enquiries Enhanced ADCC www.texerepublishing.com | [email protected] Profession +44 (0) 1565 745 200 | [email protected] Distribution: The Medicine Maker (ISSN 2055-8201), is published monthly by Texere Publishing Limited, Booths Park 1, Chelford Road, Knutsford, Cheshire, WA16 8GS, 38 From Big Pharma to New UK. Single copy sales £15 (plus postage, cost available on request [email protected]). Non-qualified annual Green Horizons: Lessons Sitting Down With subscription cost is £110 plus postage Learned with Ross Burn Reprints & Permissions – [email protected] The copyright in the materials contained in this publication and the Ross Burn presents the story 50 Will Downie, CEO of Vectura typographical arrangement of this publication belongs to Texere Publishing Limited. No person may copy, modify, transmit, distribute, display, behind his career, including setting Group, UK reproduce, publish, licence or create works from any part of this material or typographical arrangement, or otherwise use it, for any public or commercial up a company on process chemistry use without the prior written consent of Texere Publishing Limited. The names, publication titles, logos, images and presentation style appearing and his views on industry 4.0 in this publication which identify Texere Publishing Limited and/or its products and services, including but without limitation Texere and The Medicine Maker are proprietary marks of Texere Publishing Limited. Nothing contained in this publication shall be deemed to confer on any person any licence or right on the part of Texere Publishing Limited with respect to any such name, title, logo, image or style. 6 Upfront Upfront
Research Trends Informing Innovation Consent
Are seriously ill patients vulnerable to overestimating the benefits and underestimating the risks of gene editing studies?
As genomic editing trials become more common, it is crucial to ensure patients have full knowledge of the risks and benefits of experimental treatments. To discover what patients wanted (and needed) to know about genome editing public – exceeding the expectations a totally curative-type effect. I think we to make informed decisions about trial of physicians. are not confident yet,” they said. They participation, researchers at the US However, there were some also pointed out that patients need to National Human Genome Research misconceptions about genome editing know that a gene therapy may only Institute spoke with patients, parents, procedures, as the transcripts showed. be “curative” if done at birth. “If you and physicians in the sickle cell disease “I think it was when she talked about wait until you have already suffered a (SCD) community (1). the embryo and changing the DNA of stroke, renal disease, whatever other – The team concluded that information the embryo,” one patient said. “In my and organ damage does occur, even if about criteria for participation and mind, that’s what I saw – a pregnant you have gene therapy, this is not going quality-of-life post-procedure are lady sitting on the table and they were to reverse the damage that has already important aspects of being informed. digging in her belly button to get DNA occurred. In that sense, it is not really And though physicians expressed from the embryo that’s inside her and a cure the way I think patients think it concerns about patient knowledge, then changing it.” is a cure.” adults with SCD and parents of The Fort Lauderdale Physician Group children with SCD demonstrated was also concerned that current levels of Reference greater understanding of the genetic uncertainty are not being expressed in 1. S Desine et al., “The Meaning of Informed concepts tested (genetic, chromosome, conversations about CRISPR genome Consent: Genome Editing Clinical Trials for susceptibility, mutation, variation, editing for SCD. “It may make things Sickle Cell Disease,” AJOB Empir Bioeth, 11, heredity, and sporadic) than the general better. It is also possible that it will have 4 (2020).
INFOGRAPHIC In progression Top drivers influencing the toward decision to use CMOs/CDMOs: Trends in ATMP commercial production, Available companies plan workforce Uncertainty 7% Manufacturing on pursuing: of clinical results 9% Cell and gene industry leaders look to automation Limited as process development and Schedule existing 12% GMP optimization challenges loom manufacturing In-house manufacturing 23% capacity CMO/CDMOs 20% 54% Capital Combination of both 57% cost 18% Upfront 7
ADVANCED MEDICINE IN BRIEF
A $4-billion acquisition, a key finding geriatric age. The scientists for sarcopenia drug development, and hope that their findings will algorithmic efficiency… What’s new in help “harness the potential Allogeneic advanced medicine? of stem cells for regenerative medicine in sarcopenia.” Advance • Bayer is paying US$2 billion • Techniques to culture and upfront and up to US$2 billion in control cells have improved a A step closer to an off-the- success-based milestone payments lot over the years, but finding shelf CAR T cell therapy to acquire gene therapy developer the perfect conditions to keep AskBio. AskBio has a pipeline undifferentiated cells alive and Two-out-of-four patients in a 300 million- of gene therapies, including prevent them from acquiring a cell cohort, and one-out-of-three in a 100- programs for Parkinson’s, different cellular state remains cell cohort, achieved a complete response congestive heart failure, and tricky. Now, researchers in following treatment with CRISPR Pompe disease in early human Singapore and Australia have Therapeutics’ allogeneic CAR T cell trials. “Instead of going to Wall developed a computational therapy CTX110 (1). Street and every quarter trying biology algorithm called The B-cell malignancy treatment was safe to make milestones, we have one EpiMogrify, which predicts at the 300-million dose level and below. The financial partner with which we’re factors that maintain cell state only patient who received a 600 million-cell trying to bring this technology in vitro and identifies factors dose, after initially achieving a complete to fruition,” said Sheila Mikhail, that induce cell conversion. response, was hospitalized with febrile AskBio CEO. The team reported a significant neutropenia and later died after reactivation • Losing muscle mass is a increase in the efficiency of of HHV-6 and HHV-6 encephalitis. significant problem for older astrocyte and cardiomyocyte CTX110 is derived from healthy donor T people and is partly due to differentiation using cells, which are modified using CRISPR/ a loss of the regenerative EpiMogrify-predicted factors Cas 9 to i) insert a CAR construct, which functions of satellite cells. for conversion conditions. binds to cancer cells and activates T cells Now, a team of researchers and ii) knock out the T cell receptor and mainly based in Spain Want to stay up to date with all the MHC1, which reduces the risk of graft have found a subgroup of advanced medicine news each week? versus host disease and rejection. satellite cells that, due to Subscribe – for free – to The Cell + FoxO activation, maintain Gene Curator: Reference their regenerative capacity www.texerenewsletters.com/ 1. CRISPR Therapeutics (2020). Available at: over time, declining only at covid19newsletter https://bit.ly/2TxT5Ag
Near-term technology advancements expected to have the Biggest challenges in progressing most impact on the manufacturing process: toward commercial manufacturing:
Process automation 72% Process development & optimization 77% Closed-cell processing systems 68% Capital resources 49% Switching from adherent to suspension cell culture 38% Navigating regulations 43% Robotic filling 24% Equipment selection 42% Supply chain logistics 39% Isolators 19% Integrating process & facility automation solutions 32%
Others 9% Workforce resources 18% Source CRB, “Cell and Gene Therapy”(2020). Available at: https://bit.ly/31YzD4q
0 10203040506070 0 10203040506070 8 Upfront
Poisoning Pain
Investigating the pain- relieving properties of spider venom
Offering an alternative to conventional analgesics, newly published research suggests that two compounds derived from the venom of the Venezuelan Pinkfoot Goliath tarantula could be useful in managing pain associated with irritable bowel syndrome (IBS) (1). IBS affects up to 11 percent of the world’s population (1). Symptoms include constipation and/or diarrhea, and abdominal pain, which can be gastrointestinal tract and the nerves sodium channel ion expressed in pain- severe. NSAIDs and opioids have been that send pain signals from the gut to sensing neurons.” tested as pain management solutions, but the brain.” The researchers also found that the have proved ineffective for most patients. The team chose to investigate tarantula spider venom-derived compounds “Historically, treatments for IBS have venoms based on earlier studies that were capable of inhibiting calcium focused on trying to normalize the effects indicated their potential for blocking channel pain targets, including Cav3.2. of the condition on gastrointestinal specific ion channels involved in visceral According to Lewis, this combination motility, but this has had little effect pain. “We screened a broad range of “was particularly useful in reversing on visceral (internal organ) pain” says spider venoms using high-throughput IBS pain.” Next, the team hopes to Stuart Brierley, a professor at Flinders sodium channel assays,” says Richard optimize the structure of the compounds University, Australia, and the project’s Lewis, a professor from The University to improve their activity at pain targets co-lead, adding: “Furthermore, opioids of Queensland’s Institute for Molecular and reduce side effects. cause constipation, which poses Bioscience and co-lead on the project. significant problems for patients who “Our study identified two novel peptides Reference already suffer from it. These types in the venom of the Venezuelan Pinkfoot 1. FC Cardoso et al., Pain [Online ahead of of drugs also fail to target both the Goliath tarantula that block Nav1.7 – a print] (2020). DOI:10.1097/j.
company’s carbon footprint is linked to so refurbishing is a feasible solution for both Green Trials their eCOA projects – and over three- short-term studies and replacing a device quarters of this comes from the production during the course of a study. Small changes in clinical of smartphones and tablets required for “Faced with the threat of climate change, trials could benefit the clinical sites. It’s clear that reducing the every company and each individual has environment number of devices manufactured could a key role to play in reducing the global make a big difference. carbon footprint,” Kayentis CEO, How can companies lower the carbon The company suggests that an online Guillaume Juge, said in a statement. footprints of clinical trials? Kayentis – platform could be used to directly enter which provides electronic clinical outcome patient data, rather than stockpiling spare assessment (eCOA) solutions – has given devices on each site. It also recommends that the matter some thought. According companies consider refurbished devices. to their estimates, 70 percent of the The lifespan of a device is around four years, Upfront 9
IMAGE OF THE MONTH Mass Spec Meets Machine Learning
Can machine learning offer mass spectrometry a boost for drug discovery?
Researchers from Purdue University believe that combining machine learning and tandem mass spectrometry could improve drug discovery. Interpreting mass spectra for drug discovery can be challenging and time-consuming, so the team developed a decision tree model trained on 36 known ion-molecule reactions with 2-methoxypropene (MOP), a neutral reagent used to differentiate between isomeric Breaking New Ground drug metabolites. In the paper, the researchers explain that the model Construction begins for the Medicines Manufacturing Innovation Centre in “uses the graph-based connectivity of Renfrewshire, Scotland, UK. The center stems from a collaboration between the UK’s CPI, analytes’ functional groups as input the University of Strathclyde and founding industry partners, AstraZeneca and GSK. to predict whether the protonated analyte will undergo a diagnostic Would you like your photo featured in Image of the Month? reaction with MOP (1).” The model Send it to [email protected] can characterize complex mixtures and identify chemical reactions and drug metabolites by predicting how compounds will interact with MOP in a tandem mass spectrometer. QUOTE of the month One flaw of machine learning methodologies is that they can be difficult for humans to interpret, so the Purdue team has developed “International mail and express consignment are major conduits for chemical reactivity flowcharts that drug smugglers. This has become more challenging for law can help users understand the mass enforcement as volumes have skyrocketed, and because of e-commerce spectra for structural information. and rapid shipping logistics.” Reference US Customs and Border Protection Acting Commissioner 1. J Fine et al., Chemical Science (2020). Mark A. Morgan on the agency’s collaboration with the FDA to prevent illegal drug imports. https://bit.ly/3kKSyHc 10 Upfront
The EMA already had a policy in place The COVID-19 to publish clinical data supporting marketing authorization; however, this Curator was suspended at the end of 2018 due to the agency’s relocation from London to Your roundup of the key Amsterdam. It remains suspended due scientific studies and industry to various pressures and human resource announcements emerging constraints, but the agency says it will from the pandemic strive to publish data for COVID-19 medicines. The clinical data is available at Our weekly newsletter collates the https://clinicaldata.ema.europa.eu. most impactful scientific news to come out of COVID-19 and delivers Regeneron has been told to modify its trial it straight to your inbox. Subscribe: for REGN-COV2 (a “cocktail” of two Nanoparticle vaccine. Scientists at https://www.texerenewsletters.com/ monoclonal antibodies) by the independent the University of Washington School covid19newsletter data monitoring committee. Specifically, of Medicine in Seattle have designed Here, we roundup a selection of some the company has been advised to put a an “ultrapotent” nanoparticle vaccine of the latest and greatest research studies hold on enrolling patients requiring high- against COVID-19. The vaccine’s and company announcements about flow oxygen or mechanical ventilation molecular structure roughly mimics COVID-19 from October 2020. because of a safety signal and “unfavorable that of a virus – and the team risk/benefit profile.” Enrollment of other claim it can produce ten times Industry news patients will continue. more neutralizing antibodies in mice than the leading COVID-19 The FDA has approved remdesivir CureVac has reported interim data from vaccine candidates – at a much (Veklury) for hospitalized COVID-19 its ongoing phase I dose-escalation study lower vaccine dose. The vaccine patients (adults and pediatric patients over of CVnCoV, an mRNA-based vaccine is described as a “self-assembling the age of 12 – and weighing at least 40 that encodes the prefusion stabilized full- protein nanoparticle that displays kg). The approval is based on three clinical length spike protein of SARS-CoV-2. 60 copies of the SARS-CoV-2 Spike trials – one of which was conducted by the The vaccine has been well-tolerated protein’s receptor-binding domain in National Institute of Allergy and Infectious across all tested doses (2-12μg) and a highly immunogenic array”. Diseases. According to the WHO’s induces strong binding and neutralizing AC Wells at al., “Elicitation of potent Solidarity trial, however, remdesivir does antibody responses, as well as indication neutralizing antibody responses by not reduce mortality or reduce recovery of T cell activation. Phase IIb/III studies designed protein nanoparticle vaccines time for COVID-19. The same trial also are expected to begin by the end of 2020. for SARS-CoV-2,” CELL (2020). found that hydroxychloroquine, lopinavir- DOI: 10.1016/j.cell.2020.10.043. ritonavir, and interferon beta 1a all had Early research little or no effect in COVID-19 patients. The trial involved more than 11,000 adults Jelly investigations. Autopsies of deceased in 30 countries. COVID-19 patients show a clear liquid Other avenues jelly in the lung alveoli. Researchers The EMA is implementing extra say this jelly consists of hyaluronan, Defining efficacy. A review article transparency measures for COVID-19 a polysaccharide that binds to water. explores challenges in assessing efficacy medicines by publishing clinical Existing drugs, including cortisone, can of SARS-CoV-2 vaccine candidates and data that supports the authorization reduce production of hyaluronan and may suggests routinely applying standardized, of remdesivir and information on reduce the amount of jelly in the lungs. quantifiable endpoints across trials. COVID-19 treatments and vaccines U Hellman et al., “Presence of hyaluronan SH Hodgson et al., “What defines an that have received scientific advice or in lung alveoli in severe Covid-19 - an efficacious COVID-19 vaccine? A review of informal guidance from the agency’s opening for new treatment options?” the challenges assessing the clinical efficacy of Pandemic Task Force (COVID-ETF). Journal of Biological Chemistry, (2020). vaccines against SARS-CoV-2,” Upfront 11
Convalescent crisis. The PLACID trial CoV-2: a community study of 365,000 in India, involving 464 patients, shows adults” [Online ahead of print] (2020). that convalescent plasma is ineffective in preventing progression to severe Different strokes. A publicly available genetic COVID-19 or all-cause mortality. analysis tool has detected and categorized A Agarwal et al., “Convalescent plasma regional SARS-CoV-2 variations, showing in the management of moderate covid-19 transmission routes and revealing mutation- in adults in India: open label phase II resistant areas of the genome. multicentre randomised controlled trial Z Zhao et al., “Genetic grouping of (PLACID Trial),” BMJ, 371 (2020). DOI: SARS-CoV-2 coronavirus sequences 10.1136/bmj.m3939 using informative subtype markers for pandemic spread visualization,” PLOS Cautious hope. Tocilizumab may reduce Computational Biology (2020). DOI: The Lancet (2020). DOI: 10.1016/S1473- mortality of critically ill COVID-19 10.1371/journal.pcbi.1008269 3099(20)30773-8 patients by counteracting inflammatory cytokine release syndrome; researchers No signs. A recent study of 36,061 UK Knowledge gap. Analysis of COVID-19 urge caution over findings. residents showed that 76.5 percent of publications has shown that basic S Gupta et al., “Association Between those testing positive for COVID-19 were microbiological research on SARS-CoV-2 Early Treatment With Tocilizumab and asymptomatic; 86 percent lacked COVID- is lacking. Though perhaps understandable Mortality Among Critically Ill Patients 19-specific symptoms. during a pandemic, this relative lack of lab- With COVID-19,” JAMA Internal I Petersen, A Phillips, “Three Quarters based studies is unique when compared Medicine [Online ahead of print] (2020). of People with SARS-CoV-2 Infection with research into other coronaviruses. are Asymptomatic: Analysis of English A Doanvo et al., “Machine Learning Maps Feel the G. Vaccines modeled on the Household Survey Data,” Clinical Research Needs in COVID19 Literature,” D-strain of SARS-CoV-2 are still effective Epidemiology (2020). DOI: 10.2147/ Patterns, 1 (2020). against the now globally dominant CLEP.S276825 G-strain and so vaccine-matching each Triple weakness. By studying host-virus season should not be required, according Small, but mighty. “Mini-lungs” that protein interactions in SARS-CoV, to the authors of a study. mimic alveoli damage caused by SARS- SARS-CoV-2, and MERS-CoV, an AJ McAuley, “Experimental and in silico CoV-2 show how, 60 hours after infection, international consortium of almost 200 evidence suggests vaccines are unlikely to alveolar cells start to disintegrate and researchers has identified key molecular be affected by D614G mutation in SARS- damage lung tissue. mechanisms for all three viruses as well as CoV-2 spike protein,” NPJ Vaccines (2020). H Katsura et al., “Human Lung Stem potential drugs that could be repurposed. Cell-Based Alveolospheres Provide Insights DE Gordon at al., “Comparative host- Understanding COVID-19 into SARS-CoV-2-Mediated Interferon coronavirus protein interaction networks Responses and Pneumocyte Dysfunction,” reveal pan-viral disease mechanisms,” Science Immunity indecision. Studies seem Cell Stem Cell, [Online ahead of print] (2020). DOI: 10.1126/science.abe9403 divided on the longevity of antibody- (2020). DOI: 10.1016/j.stem.2020.10.005 based immunity to COVID-19, with T cell therapy. T cells from recovered some new studies revealing that robust Sweet (pre)disposition. Diabetic patients COVID-19 patients and multiplied neutralizing antibodies persist for may be more vulnerable to SARS-CoV-2 in the lab have been found to maintain months even as others show significant through primed kidney cells. Moreover, the ability to target proteins essential to drops in population antibody positivity. higher ACE2 receptor levels found in both SARS-CoV-2 function. P Figueredo-Campos et al., European diabetes and kidney disease may trigger MD Keller et al., “SARS-CoV-2 specific Journal of Immunology (2020). DOI: severe COVID-19. T-cells Are Rapidly Expanded for 10.1002/eji.202048970; A Wajnberg R Menon et al., “SARS-CoV-2 receptor Therapeutic Use and Target Conserved et al., Science (2020). DOI: 10.1126/ networks in diabetic and COVID-19– Regions of Membrane Protein,” Blood science.abd7728; H Ward et al., “Declining associated kidney disease,” (2020). DOI: (2020). DOI: 2020008488 prevalence of antibody positivity to SARS- 10.1016/j.kint.2020.09.015
www.themedicinemaker.com 12 In My View In My View Experts from across the world share a single Brexit Trading strongly held opinion Unknowns or key idea.
Is your business prepared for Brexit? Here’s my advice.
By Nik Kotecha, Chief Executive of Morningside Pharmaceuticals Ltd, Department for International Trade (DIT) Export Champion and a CBI Regional Councillor, UK
As the famous quote goes, there are known knowns, known unknowns, and also unknown unknowns. And that very much applies to the current Brexit negotiations between the UK and the EU. We know there are red lines on both our supply chain. There is no import in good stead when it comes to trading sides, but the overall outcomes are still duty on “finished” pharmaceutical packs, not only with the EU, but also with the unknown. What is clear to me and my but we are concerned about disruption rest of the world. company is that businesses must prepare to our supply chains and the time taken For importing, businesses will have for every eventuality – and start right to get products to destinations through to make customs declarations when now (if they have not done so already). customs. We’re also checking tariffs importing goods from the EU. Be aware Post-Brexit EU trade deal negotiations that may be payable under the new UK that from January 1, 2021, the rules for are continuing, but the UK will come Global Tariff that will apply to goods importing some types of goods will to the end of the Transition Period on imported from around the world, unless change. You should also make sure you December 31, 2020. there’s a trade agreement in place. have secured an EORI number starting But the first question for UK One of the most important actions with “GB,” checked the rate of tax and businesses: Where should we start? The we’ve taken is to apply to be an duty, and looked at ways to speed up the best source of information, if you are Authorized Economic Operator (AEO), importing process. just beginning the process, is gov.uk/ which is an international standard All export shipments to the EU will also transition where you can find the latest accreditation given by HMRC, which require a customs declaration, and you will government guidance on preparing for shows that our supply chain is safe and need to be aware of licensing requirements the end of the transition period. For secure. It also ensures that the holder and rules for the goods you export. For most pharma businesses, the guidance may be able to benefit from arrangements example, the rule for pharmaceuticals on importing and exporting goods under Mutual Recognition Agreements, entering the EU is that any product being with the EU is particularly important. which are agreed with third country If you can’t find the answers you need, customs authorities. To achieve this, a you can also make use of an enquiry business must submit an application to service run by the Department for UK Revenue & Customs, which is then “But the first International Trade. followed by an audit and inspection of My company manufactures and the security and supply chain. To help question for UK supplies generic medicines to both the prepare for the audit, we conducted a UK and international markets. We are gap analysis to further improve our businesses: where actively making plans to mitigate any processes, which were fully reviewed in disruption to our import and export line with the criteria. We believe that the should we start? ” activities from the EU, particularly with AEO (c) and (s) standards will keep us In My View 13
used in the EU, and going to an end Dover, UK, and Calais, France. we are able to continue to supply our patient there, must be batch released by a In the event of a no-deal Brexit, we patients in the UK, as well as exporting Qualified Person within the EU. have built contingency plans to release medicines to patients who need them Pharmaceuticals manufacturers and batches for our patients in the EU “on time” – especially as the risks of a suppliers are proactively taking action through a site in the Republic of Ireland. second COVID-19 wave this winter are to ensure there is no disruption to the Having an EU base will also enable us all too apparent. supply of medicines. You may wish to comply with EU regulations around My advice to businesses is to look at to look at what action your logistics pharmacovigilance and the licensing all of your known knowns and unknown partners are taking. For example, some of medicines in the EU from an EU knowns, and start preparing for the haulage providers are taking part in territory. Another high priority for us unknown unknowns – or, put another Alternative Routing, which is worth is to work with the UK Department way, every eventuality. Only then will exploring and may help avoid delays at for Health & Social Care to ensure you be as prepared as you can be.
There’s no doubt that catalysis has played a variety of platinum group metal (PGM) Precious Metal a significant role in the global chemical catalysts to facilitate the production of industry over the past few decades – APIs and regulatory starting materials. Catalysts: recognized by numerous recent Nobel But doing so presents challenges, such Prizes in Chemistry: Knowles, Noyori, as rising metal costs and the need to The Scavengers’ and Sharpless’ work for asymmetric remove metal impurities. This latter catalysis (2001), Schrock, Grubbs, and challenge can be addressed by selecting Guide Chauvin’s work on alkene metathesis the most efficient catalyst and limiting (2005), and Suzuki, Heck, and Negishi’s catalyst loading as much as possible. Platinum group (and other work on the development of cross- After loading has been optimized, precious) metal catalysts are coupling chemistry (2010). attention turns to the removal of routinely used to synthesize In pharma, under constant pressure elemental impurities through various APIs – but they are inherently to reduce time to market for successful purification steps. expensive, so why not recover drugs, process chemistry teams must PGM catalysts are expensive – as and recycle? find the most cost-effective and scalable you’d expect with precious metals – synthetic route as quickly as possible. and subject to price fluctuations (PGMs At the same time, driven by the pursuit are traded on the public market). of increasingly difficult therapeutic And so, we believe it makes sense to targets, discovery teams are probing consider a closed-loop approach to the molecules that contain synthetically catalyst lifecycle that makes the most challenging motifs, such as macrocycles, of scavenging. The possibilities for spirocycles, and multiple stereocenters. scavenging are diverse – from simple To address the challenges presented charcoal slurry and filtration to more by more complex structures, process complex solutions, such as functionalized development chemists have embraced resins and silicas. The key is efficiency. new methodologies, many of which Once a closed loop is implemented, the By Philip Wheeler, Business involve precious metal catalysis. For majority of the metal price is paid only Development Manager, Umicore Precious example, the development of macrocyclic once; recovered metal can be applied Metals Chemistry, California (USA). protease inhibitors to treat hepatitis C as credit toward future purchases of Dirk Rickert, Sales Manager, and infections led to the refinement and the finished catalyst. Moreover, as the Thorsten Rieke, Head of Marketing, adoption of ruthenium-catalyzed ring- recovered metal will be stored in metal Market Intelligence & Business Research, closing metathesis macrocyclization at weight rather than currency, it will be Umicore Precious Metals Refining, the industrial scale (1). insulated from market fluctuations. Hanau, Germany Pharmaceutical manufacturers employ Implementing a recycling approach
www.themedicinemaker.com 14 In My View
between a refiner and manufacturer variety of sensitive analytical instruments are vital to ensure the recycling plan and techniques. “The possibilities for is practical and effective. When Pharmaceutical companies are typically choosing the right refining partner for a not able to sample and assay in-house, so scavenging are process, you should, of course, consider you will be reliant on your refining partner. maximum recovery and fast processing And that’s why transparency – and trust – diverse – from turnarounds, but you should also think are so important. about transparency, communication, The application of catalysis within the simple charcoal and overall support – just as you would pharmaceutical industry is rapidly evolving. with any outsourcing partner. With the availability of novel laboratory slurry and The refiner will need to obtain a tools for characterization, new approaches representative sample of the overall spent to synthesis and advanced computational filtration to more catalyst and to understand how much capabilities, we have unparalleled potential of the PGM content in the catalyst for making significant advances in modern complex solutions.” is recoverable. Here, direct sampling development. But as the industry continues techniques (without incineration) usually to design innovative processes, let’s not provide more accurate insights into a broad overlook the opportunities for precious requires chemists to work closely with range of solid and liquid spent industrial metal recovery. engineers, smelters, and supply chain catalysts. When sampling is completed, experts to appropriately plan, design refiners must accurately and reliably Reference and implement the recovery solution. measure the precious metal content of the 1. A Horváth et al., J. Org. Chem., 84, 4932 Collaboration and transparency materials being reclaimed, using a wide (2019).
or infusion, but data suggests a recent Looking After rebound. Additionally, the government’s stimulus packages provided short-term Patients – Post- relief from an economic standpoint, and some employers also allowed newly laid Pandemic off workers to maintain health insurance on a short-term basis. However, the Manufacturers must consider unemployment assistance afforded in the adjusting their patient federal stimulus ran out in July, and the support programs to reach outlook for a fourth stimulus remains the increasing number uncertain. of individuals struggling Without a clear end in sight for the financially in the wake of straight weeks. GDP has seen the most pandemic, the economic impact – and COVID-19 significant drop on record. Initially, the thus the demand for financial assistance pharmaceutical industry braced for a surge to help support patients accessing their By Corey Ford, Director, Reimbursement of patients in need of financial assistance prescriptions – could still surge in the & Policy Insights, Xcenda following a loss of employer-sponsored future. As such, manufacturers should health insurance. Though that expected proactively prepare for an increase in Among its many challenges, the surge in demand failed to materialize at financial need from uninsured, and COVID-19 pandemic has led the outset of the pandemic, it could be even underinsured patients, and explore to extraordinary economic upheaval. lurking on the horizon. Some patients ways to enhance patient access in the Specifically, the unemployment rate in in specialized therapeutic areas may have challenging months ahead. the US has reached levels unseen since been initially concerned about going to To prepare for the various scenarios the Great Depression, with jobless a healthcare facility or physician clinic that could play out in these rapidly claims exceeding one million for 20 to receive treatment via an injection changing times, manufacturers should In My View 15
conduct a series of financial exposure patient support programs. FRS teams analyses that project patient demand offer robust tools and resources to help and financial exposure for assistance “Manufacturers risk providers manage patient access and programs. Exposure models project reimbursement hurdles, which have the financial needs of various patient losing these patients become increasingly important given populations based on current and nearly 50 percent of provider offices emerging trends in the greater healthcare if their previous at the time of writing have furloughed landscape. Some manufacturers have staff (2). In addition to raising awareness this capability in-house, but there are therapy regimen is for the programs themselves, FRS a limited number of external patient- teams also ensure providers remain support partners uniquely positioned no longer effective up-to-date on any adjustments or to model the impact of developments changes to manufacturers’ programs, within the broader landscape on patient following a lapse in so they can make the most appropriate and copay assistance programs via an recommendations to patients. exposure analysis. These patient-support treatment.” To accommodate the shelter in partners model various contingencies place and social distancing policies and scenarios to determine how implemented at the outset of the manufacturers should prepare, and to documentation to apply for PAP support. pandemic, interactions between FRS identify whether additional resources are Manufacturers should also consider teams and providers have largely needed to meet that demand. further enhancing their provider portals. transitioned to a virtual support model, Such financial analysis is particularly Before the pandemic, patients may leveraging a mix of web-based and phone important for specialty areas that require have applied for financial assistance engagement. Given the accessibility of high-touch products and treatments, such via a patient support program in the virtual platforms, this trend may continue as oncology, immunology, and multiple physician’s office. Today, with fewer to some degree even after the intense sclerosis. If these patients discontinue patients making in-person visits to period of social distancing ends, but more their treatment regimens, they are at high their providers, manufacturers should provider education, in whatever form, will risk of becoming more gravely ill and may consider establishing a provider portal continue to greatly benefit patients. face greater financial challenges in the that is accessible through the support As the long-term impact of the future as a result of a worsening condition. program website. The portals allow COVID-19 pandemic continues At the same time, manufacturers risk providers and their office staff to enroll to unfold in the months ahead, losing these patients if their previous patients into support programs and manufacturers have a responsibility therapy regimen is no longer effective review status updates for select patients. to respond to the changing needs of following a lapse in treatment. Regardless of the changes that their patient populations. Actively Pharmaceutical manufacturers manufacturers may implement to their preparing for an uptick in uninsured generally use patient support programs programs, it’s imperative to educate patients, anticipating a shifting demand to help them manage affordability providers and their office staff that such for patient and financial support, and access obstacles. In our current programs exist. Recent studies have and evolving interaction strategies environment, it is critical to reassess shown that only 40 percent of healthcare with healthcare providers should patient needs and adapt accordingly. providers are “very aware” of manufacturer- help companies successfully position Manufacturers must consider how to sponsored patient programs, and less than themselves to maintain patient access adjust their current patient support one in five patients are aware of the support and ensure affordability of therapy. programs to appropriately reach a wider services available to them (1). With the swath of patients and effectively address pandemic reducing in-person interactions References the new and unique challenges facing with doctors, this gap in education is at 1. Accenture, “Pharma’s Growing Opportunity in the industry. This type of adjustment risk of widening. Patient Services.” 2020. Available at: https:// in the age of COVID-19 may include Field reimbursement specialist (FRS) accntu.re/37IPnfG. expanding the typical income eligibility teams, who assist providers in navigating 2. MGMA, “COVID-19 Financial Impact on criteria required for a patient assistance complex challenges, play a critical role Medical Practices.” 2020. Available at: program (PAP) or minimizing the in driving awareness for manufacturers’ https://bit.ly/3jrz0pP.
www.themedicinemaker.com 16 In My View
This pandemic has had an unprecedented manufacturing capacities. The Pandemic impact on our communities. Our families For me, the crisis is shining a light on have lost friends and loved ones, and we’ve why organizations such as the Coalition Diaries faced disruption in every aspect of our lives. for Epidemic Preparedness Innovations Navigating successfully through challenging (CEPI) are vital in today’s vaccine industry We ask medicine makers times has given me a unique insight into our landscape. It also highlights the value of around the world to tell us teams and shown how strong we are when disruptive vaccine technologies, such as how their professional and we support one another. mRNA and viral vectors; I am incredibly personal lives have changed I’d say the pharmaceutical industry’s interested in seeing how these potential over the course of the response to the pandemic has been game-changers perform in clinical trials. COVID-19 crisis exceptional. I believe global collaboration Despite the underlying competitive is vital in the treatment and cure of spirit among biopharma companies to be COVID-19. New relationships and the first to create a vaccine, I believe this ways of working have been forged with pandemic demonstrates the importance business customers within the industry of collaboration among different industry and my hope is that the work we do here members. Many of the front runners for at West will go some way to helping with a SARS-CoV-2 vaccine candidate come the development and delivery of new from diverse teams that are benefitting treatments and vaccines for COVID-19. from pulling together complementary areas of expertise. And this includes small biotechs or universities that have By Don O’Callaghan, Vice President developed promising candidates working European Operations at West alongside established vaccine developers, Pharmaceutical Services with a well-rounded history of managing clinical trials and regulatory knowledge. COVID-19 is a unique and challenging These companies, in turn, are collaborating time marked by the need for unprecedented with contract manufacturing organizations, leadership and navigational skills for all of life science suppliers, and funding us. As a leader, I truly never expected to be organizations. The real challenge is the in a situation where I was forced to activate By Amélie Boulais, Vaccine Platform speed with which vaccine developers are the company’s Regional Pandemic team Marketing Manager at Sartorius trying to create COVID-19 vaccines: 12– – it’s something you plan for but hope to 18 months instead of 10 years. And that is avoid. But I have been hugely inspired by At the conferences I attended in the past, where great teamwork is proving vital. our teams at West and everyone’s ability a topic that came up frequently was, “Are From this pandemic, we are learning to stay focused during these difficult we ready for a pandemic?” The answer now that we must set up protocols to facilitate times. Our employees have demonstrated is obvious: no. We were not ready enough. communication between vaccine enormous strength of character and have As a supplier to the biopharma and developers, vaccine manufacturers, and been working at a steadfast pace to rally and vaccine industry, Sartorius has witnessed regulatory bodies. We must facilitate the deliver to the cause. I feel my colleagues the impact of COVID-19 on our sector dissemination of the right information and I shoulder an enormous burden to first-hand, and we are seeing reallocation at the right time to the right people. respond to the global need brought about of biopharmaceutical pipeline priorities We also need to retrospectively analyze by COVID-19. We are committed to in record time. On the one hand, we are which parts of existing processes failed supporting solutions, including both the working with scientific teams globally to (if they were in place) and strengthen development of much needed treatments provide technology to help them develop industry associations, such as the CEPI, and vaccines, and ensuring supply of the their SARS-CoV-2 vaccine candidates as well as non-profit organizations, and critical components and devices needed at unprecedented speed. On the flip- expert groups working on pandemic for the healthcare industry. side, many companies are slowing down preparedness. We need to fund them From the outset, my top priority has been – development as their clinical trials are properly and give them more power, as it and will continue to be – the health and safety put on hold. And that means readjusting will help us all be better equipped to deal of West’s team members and their families. priorities, product roadmaps, and with any future pandemics. Through our leading solid form science Solid state services FDSDELOLWLHVZHRȄHUWKHSKDUPDFHXWLFDOLQGXVWU\ one of the broadest and most reliable services to enhance drug WRHQKDQFHGUXJGLVFRYHU\DQGGHYHORSPHQW enabling better products and a faster route to discovery and PDUNHW/HYHUDJLQJRXUVWDWHRIWKHDUWIDFLOLW\ we provide a full range of solid state research development capabilities including developing optimal SRO\PRUSKVVDOWIRUPVFU\VWDOPRUSKRORJ\ and controlled particles.
7RÀQGRXWPRUHVHDUFKVROLGIRUPDWPDWWKH\FRP RUHPDLOSKDUPD#PDWWKH\FRP Making Medicine… ANYWHERE
NASA ultimately wants to send humans to Mars – and those humans will need medicines. How can these be manufactured in space? And if we can manufacture medicines in space, how might the lessons learned translate for patients on Earth?
By Stephanie Sutton Feature 19
A GGrueling differentlyffe duringu spaceflight. With the now-known link between ENVIRONMENT thehe gut andd the brain, and the link between the state of the microbiomem m and mental health, there are many interlinked and By Phil Williams complexx iissues that need to be researched and understood when it comess tto long-term spaceflight. And issues around mental health The altereded envenvironmentironment o fof spac spaceflightefli causesch changesan inman many willl oonlyn be compounded by the obvious pressures of confinement, biologicalbiio processes that have evolvedvo to functionfun in ththee 1G, socialoci isolation, stress, and changes in circadian rhythm. radiation-free,ation-free, tetemperate,mperate, ssalinealine enenvironmentviro of EEarth.art The All of these issues, and more, come to the fore when considering immediate change tto ththe bbodyd is caused by thee environmentenvi of a mission to Mars. Such a mission, described by NASA’s Design microgravity,microgravity, wherewhere astronauts are inin constant freefallfre as theyy orbitorb Reference Architecture 5.0, on which Andrew Weir wrote the the globe.lobe ThThisis environment causes causes re redistributiondi of fluidsuids in the book ‘The Martian,’ would be around three years with a crew body, in particular the blood, which is no longerer pupulledlle towards of six. It has been estimated that the chance of serious illness or thethe feetf and away from the head. Thee bodydy ccompensatesom for this death in an activity such as spaceflight is 0.06 per-man-per-year. unnaturalral popoolingoling in tthehe uupperpper halhalff of the body by then reducing The chance of such an incident in one of six crew in their three- the volume of the blood. These changes in fluid distribution and year mission to Mars is 67 percent. There is a 20 percent chance blood volume all cause immediate changes to pharmacokinetics/ that half the crew will suffer. We must find a way to treat these pharmacodynamics (PK/PD). Studies on the SpaceLab (the explorers if such a mission is to take place. They cannot take every laboratory that flew in the bay of the Space Shuttle), for example, medicine with them on the journey. have shown that the rate of absorption (measured in saliva) of Bringing things closer to home, the often dramatic and largely paracetamol and scopolamine/dexedrine from tablets were double unpredictable rapid changes to PK/PD on spaceflight could after one day of space flight, and almost halved after two. Longer produce real and current problems in the area of space tourism. For term changes caused by microgravity include muscle atrophy, paracetamol, a doubling of the rate of absorption and maximum insulin receptor desensitization (astronauts can be clinically diabetic plasma concentration after a few hours of flight is not a huge after 30 days of spaceflight), retinopathy, and decalcification of problem. But if the astronaut took a drug with a narrow therapeutic bone (and the consequent deposition of calcium elsewhere, often window, then such a change could be fatal. Until now, astronauts as kidney stones). are selected based on their physical and mental fitness (and on the It has also been shown that stem cells change in microgravity. payroll of national governments). But with the advent of space They tend to remain undifferentiated in flight, but they differentiate tourism, where the financial drivers and considerations differ, the on return to Earth along one lineage far quicker than normal. considerations of medication become greater. Who will license? Bacteria are also shown to behave differently. Whether due to Who will authorize? Who will prescribe? Who will provide the changes in the mechanics of membranes evident in parabolic medical information for space medication? This area – although flight or cell surface receptor recruitment or other factors, bacteria not covered in this feature – is something that my colleague, Li have been shown to be more resistant to antibiotics and, for other Shean Toh, at the University of Nottingham, is developing. reasons, antibiotics are also less effective. With changes to bacteria, there are also changes to the gut Phil Williams is Professor of Biophysics, Director of Research microbiome. Enzyme activity has been shown to be affected, and Knowledge Exchange, School of Pharmacy, at the meaning that food and medicines are absorbed and processed University of Nottingham, UK
www.themedicinemaker.com 20 FeatureFe
T h e required to escape the Earth’s gravity. Saving mass and volume ASTROPHARMACYC is critical, so astronauts must carefully consider what they take Concept with them. In terms of an astronaut’s health, there are significant medical tests and a quarantine period before someone is allowed A system for making medicines on demandde n to go into space. Health should not be a problem on short-term missions and astronauts are closely monitored. If there was a LynnLyy J.. Rothschildschild is a senior rresearch scscientistist at NANASA’ss problem, the astronaut could return to Earth, or a medication Amesmes RResearchesearch CenterCe with a keen iinterestnt in evolutionarylut ry could potentially be sent up. biology,biol gy, but more recently she hhasas bbeeneene invoinvolvedl in creatingtin But what about long-term missions? There are plans for a an “astropha“astropharmacy”pharmacy” systemsystem that can produceprodu biologiciol drdrugs long-term human presence on the moon and, eventually, to send on ddemandemand (1).(1). Her work combines ppre-programedogra cecells in humans to Mars. With current technology, it would take around spore form,m, genetic engineering, and a smalsmall volumeume system six months to reach Mars and the astronauts would have to stay a adaptedapted from standard laboratory protocprotocols. year and a half for the planets to realign to minimize the journey time home. For such a long trip, you cannot possibly WHEREWH DID THE pack every potentially useful medicine. It ASTROPHARMACYROPHARMACY would take up too much mass – and most CONCEPT COME medicines also have a limited shelf life, FROM? which would render them useless “You part way through the journey. Around 15 years ago, our Center cannot When NASA put out a call Director at the time asked me for projects for making drugs to start a program on synthetic possibly on demand, we decided to biology, with the idea that it pack every focus on biologics – and we could potentially be a game- potentially now have funding from the changing technology for NASA Innovative Concepts space exploration. useful medicine. Program. Biologics are I met Phil Williams, a professor It would take extremely expensive and have of pharmacy at the University of up too much a very short shelf life, even Nottingham, when he came to visit with refrigeration. However, a postdoc student at NASAASA Ames.Ames. mass.” manyma of the medical problems He was very interested in the workwork thatthat astronauts could potentially we did, and we came upp with the idea faceface couldco probably be effectively of “astropharmacy” – combiningmbining my workwork treatedtreated wiwith biologics. with the pharmacy field too sosolvelve tthehe cchallengehallenge of of From the point of view of delivering pharmaceuticall care in space. a bioengineer, protein-based drugsdr are easy to make. If the WHAT ARE DNAD has the right coding THE UNIQUEE mmechanism then it should be CONSIDERATIONST IONS possiblepo to get the organisms FOR SPACEFLIGHT,LIGHT, to synthesize the right protein. PARTICULARLYR LY Initially,In we’ve been working IN TERMS OFF on non-glycosylated biologics, MEDICINES?? butbu in principle we should alsoal be able to figure out ways It is extremely expensiveve to llaunchaunch toto glycosylateg the proteins, and a spacecraft. A large partpart of the toto engineere cells with different spacecraft is jettisoned inn thethe fifirstrst metabolicme pathways so that few minutes after take-off bbecauseecause we can make other things too of the sheer amount off ffueluel besidesbe protein-based drugs. Feature 21
In collaboration with Phill Williams, we are using the common soil bacterium Bacillus subtilis to secrete the protein- based drugs. Importantly, B. subtilis forms extremely resistant spores that can be dried and stored at room temperature – in fact, B. subtilis spores were able to survive exposure to a space environment for nearly six years on the LDEF mission. I’m actually working with these spores on another mission, PowerCell on Eu:CROPIS – and they are working beautifully! B. subtilis is already used as a platform for external bioengineering, so a lot of the relevant lab tools already exist. pump. Essentially, we just need to program the bacteria, put them in It will, spore form, and then they can be sent into space – potentially however, on punch outs on a piece of paper, though we are exploring depend on other approaches too. Once reconstituted, they can be used the size of to produce the protein. We are also working on approaches a crew. If we to purification. need to make medicines for WHAT TYPE OF a crew of five or EQUIPMENT WOULD ten, then a dedicated ASTRONAUTS NEED TO TAKE pump would probably INTO SPACE TO PRODUCE be necessary, but most likely MEDICINES ON DEMAND? medicines will only be required for one or two individuals. If medicine To answer this question, I’ll direct you to students who worked is needed for something chronic, then we envisage that an on the International Genetically Engineered Machine (IGEM) astronaut could set up a production day once every three competition (2). I’ve been working on the astropharmacy months or so to create a backlog. Other medicines can just system with a team of students from Brown University be made on demand. and Stanford University – and last year we also had some wonderful students from Princeton University. One of the WHAT IMPLICATIONS DOES Browns students is also working with me for his Masters – THE ASTROPHARMACY HAVE and, incidentally, he is specifically interested in taking the FOR PATIENTS ON EARTH? technologies into the pharmaceutical industry. Currently we also have an undergraduate from Yale working on the I really believe that a lot of what we do at NASA and in the manufacturing technologies. space industry ultimately has applications for Earth. Pharma The students are working on technologies and approaches companies focus on producing a large number of doses with a for diagnostics, drug production and drug purification – and high profit. With our system, we have the opposite situation in have come up with technologies for a synthesis system, drug that we can only produce very few doses – but this is exactly expression chamber, and a purification platform. I’ve been very what is needed for some medicines, such as orphan drugs. firm with them that the technology needs to be as small and We’ve had pharma companies approach us before about our as simple as possible! Astronauts will want an easy system – work because they are specifically interested in orphan drugs preferably something that works at the press of a button. Right and making personalized medicines on demand. now, we have a lab system that requires an external pump and various other components, but I am pushing for us to use References microfluidic systems. I can’t give too much away on this at the 1. NASA, “An Astropharmacy,” (2020). Available at https://go.nasa. moment… come back to me in a year! But I will say that we are gov/3lp1TUS. aiming for something the size of a wallet that doesn’t require an 2. IGEM, “Astropharmacy,” (2019). Available at https://bit.ly/3iCOeI8.
www.themedicinemaker.com 22 Feature
Down to EARTH pharmaceutical market is worth well over US$1 trillion… and the vast majority of cold chain Aiming for technologies that can makem e medicinesd e products (60 percent) are transported by air. in space or on Mars can also help us withth problemso m If we can get rid of centralized manufacturing closer to home, such as challenges wwithh coldd chaini and make medicines for individuals where and and getting medicines to remotee locationsl at when they need it, there will be huge advantages in terms of cost and the environment – as well as WithW Phil Williams for patients, who will get the medicine they need tailored to them. The excitementxcitement of wworkingorking on projectscts thatt will enablele human My group has done a lot of work with cell-free explorationexploration of MMars is huge. I dondon’t thinknk we’ll seese people synthesis. From our work on in vitro evolution, we landingng on Mars during my lifelifetime, but ththe greatesteate driver for began exploring the use of synthetic biology to make me is knowing that if we can maintain and restoreestor the health of proteins. Here, we take the machinery that a cell uses explorersrers on Mars, then we can do it anywherenywh – in to make proteins out of the cell and put it in a a hospital, on a nuclear submarine, in the test tube. With a DNA synthesizer, it is Antarctic,arctic, or in a remote communitycomm in possible to make DNA strands of any South America. Making a medicine on “An sequence. We can give the DNA site and on demand, using resources that encodes a particular protein to that can be sourced locally – and on-demand the cell machinery – which then ideally that are waste products approach produces the desired protein. from something else – would to drug Our cell-free protein synthesis solve issues with cold chain. manufacturing method uses the machinery Cold chain supply accounts could completely from an extremophile for roughly one percent of the change how we (Deinococcus radiodurans), total pharmaceutical market. make medicine – combined with microfluidics Although one percent isn’t and novel protein storage and much, the numbers add up and realize the reconstitution ideas. The project fast when you consider that the ultimate goal of is funded by the UK’s Engineering telepharmacy.” and Physical Sciences Research Council (EPSRC), through their Adventurous Manufacturing program. Once the protein is produced, it has to be formulated into a deliverable therapeutic. To do this, we are working with 3D printing experts. Some of my colleagues at the University of Nottingham – Clive Roberts’ group – are pioneers in additive manufacturing and in particular of pharmaceutical formulations. We are considering a variety of ways in which 3D printing can be used for formulation of the on-demand-manufactured drug, such inhaled drug delivery or dissolvable microneedles. An on-demand approach to drug manufacturing could completely change how we make medicine – and realize the ultimate goal of telepharmacy, where a pharmacist or medical practitioner can transmit a particular drug and its formulation over any distance. Once the technology is in place to synthesize and formulate the drug on demand, all that is required is a set of instructions that tell the system how to make the drug (the DNA codes) and formulate the Feature 23
ExtraterrestrialE x t r a t e r r e t ri RISK
What biosecurity risks do exo-microorganisms pose? Neil resulting protein into Gow, Deputy Vice-Chancellor for Research and Impact, an appropriate dosage and a professor of microbiology at the University of Exeter, form (the printer instructions), UK, and Mihai Netea, a professor at Radboud University with the correct release profile. We’re talking Medical Center, the Netherlands, mulled the idea while about a digital file that could be sent across continents… or walking on the beach at a scientific meeting in the across the solar system. Caribbean – and devised two potential studies on how to Theoretically, we could separate the drug discovery process address the risks. The first of those studies was published from manufacturing and distribution. It would be possible for earlier this year (1): “A Weakened Immune Response to a drug discovery company to release a drug without having Synthetic Exo-Peptides Predicts a Potential Biosecurity to go through the process of manufacturing and transporting Risk in the Retrieval of Exo-Microorganisms.” it. They would just release the software or instructions for the Discussing the work at an astrobiology conference in drug, which could be downloaded across the globe to make Seattle in 2019, Katja Schaefer, lead author on the study, the medicine. We’re not at that point yet, of course. discussed the field of exo-immunobiology ( originally Biologics are considered the future of most medicines – and introduced by Netea) – where the human immune system are the ones with the most demanding cold chain requirements encounters either a completely alien microorganism, – but there will also always be demand for small molecules or Earth organisms that have been adapted to space too. We’re also looking at how to make small molecules the environments. How would the immune system react? way nature does by using cell-free synthesis to make enzymes And would it even recognize the organisms to elicit an that can convert one material to another. It’s all early work immune response? and baby steps but, ultimately, we envision a system that can Exo-microorganisms are not just a risk for those make protein therapeutics, and also proteins that can be used exploring space – they could be brought back to Earth to make more molecules. during sample retrieval from exoplanets or moons, for example. Schaefer, Gow, Netea, and their co- SPORES FOR SPACE authors believe that exo-microorganisms with distinct proteomes may present immunological challenges. Their The project with Lynn at NASA and others builds on the study tested the mammalian immune response towards cell-free synthesis method and uses spores, which have been protein antigens containing two amino acids: isovaline shown to survive the environment of space outside of the ISS, and Ŷ-aminoisobutyric acid. Both are extremely rare in to house the cell machinery. The idea is to create a system that earth organisms, but have been identified in abundance allows astronauts to create biopharmaceuticals on demand. in chondrite meteorites. We are using a number of protein-based therapeutics as “My background actually lies in fungal pathogens, exemplars – a thrombolytic (stroke is a risk factor of space but when I started working with Neil Gow, he told me flight), a hormone for osteoporosis prevention (decalcification about his provocative ideas involving amino acids on
www.themedicinemaker.com 24 Feature
meteorites – and it was interesting! We decided that I of bone), a toll-like receptor 5 agonists (radiation protection), would start it as a side project to my main work,” says and G-CSF (for neutropenia). Schaefer. “Other papers have discussed the characterization Once you leave Earth, there is no ionosphere for protection and of amino acids from meteorites, but to find out how they’d the conditions are extreme. Solar radiation is very damaging, and affect the immune response, a peptide was needed. I didn’t there are also extremes of hot and cold. With Lynn, we discovered have an immunological background, so we brought in that spores are a very robust container for cell machinery and are other collaborators. Once we had the peptide, we isolated resistant to the damage of space. Spores housed on the outside of immune cells from mice and measured the effectw hen the International Space Station for around three years were still they were exposed to the peptide.” able to regenerate and produce proteins. Nature never ceases The result? The peptide was recognized by the immune to amaze me – and this is also why a lot of work has looked system, which led to an immunological response, but T cell at extremophiles that have evolved in extreme environments, activation and proliferation were both significantly reduced such as hypothermal vents, the Antarctic, or the bottom of compared with exposure to common peptides on Earth. the ocean. Now, we are combining spores with microfluidics What does this mean for humans? It’s very difficult to as a way to handle and reconstitute them effectively. For the say, but peptides or organisms made up of different amino platform, you’ll be able to push a button to reconstitute the acids to those on Earth could pose an immunological risk. spores and then they will start protein production. “There are many other questions that we can also explore, As well as ensuring the spores can survive in space, we also such as why the immune response was low, what enzymes need to consider the technology that will be used to make and processes are involved, and whether it is possible for the platform. It must be a self-contained unit, so that if the mammalian immune system to produce antibodies in something goes wrong it doesn’t cause a cascade failure that response to the peptides,” says Schaefer. affects the spacecraft. It must also be robust, and capable of The risk could also be greater for astronauts. Conditions self-monitoring and correcting errors. The people that are in space can also change how the immune system works. using it aren’t going to be pharmacists or biochemists, after all. Astronauts are exposed to very extreme environmental And then we need to consider the purity of the protein stresses, including microgravity, radiation, and poor therapeutic that is produced. When it comes to consistent quality nutrition – which can result in a weakened immune and purity for biopharmaceuticals, even big pharma companies response, including reduced cytokine release and can struggle. Something that is in our favor though is that we reduced T cell function (2). “This is already in effect are only making relatively small amounts of material, which without exposure to a pathogen – and also remains in makes purification much easier. When purifying a large batch effect for sometime time af after the astronauts have returned of product, at times it can be like looking for a particular needle too Earth,” explains Schaefer. “It wowould be interesting in a pile of different but ever-so-similarly looking needles. We to do experimentseriments with the immune cells of returning are still working on purification methods but, ultimately, we astronautstronauts to see how the immune responseonse changes hope to incorporate an automated quality control function into whenw exposedexposedosed to these rare amino acids. We also want the system. We are very interested in antibody fragments and to loolookk at how the properties of terrestrialtria microbescrob nanobodies because they can be produced using the cell-free couldcoc d be alteredalterrede by growing on exo-substrates.exo-sub es. I’m also system. We would express the protein we want, and also the interestederests d iinn the fact thathat different ssugarss hav have beenen foundd antibody for that protein, with the latter being used to separate on metmeteoriteseo – anand,d, rrecently, a peptidepeptide. Thisis i is a ibrvibrant out the protein. Both protein and nanobody would have to be area of research.” folded correctly and functional for the separation to work, and in this way only correctly folded and functional biologics References would be outputted from our system. It is early stage, but we 1. K Schaefer et al., Microorganisms, 8 (2020). are making progress. 2. MG Netea et al., PLOS Pathogens (2020). A BOLD NEW FIELD
Our astropharmacy field is growing and every corner we turn opens up many new directions. It’s a very exciting field to be workingwork in. We currently have seven PhD students working on a vvarietyar of projects, including: Feature
• On-site, on-demand manufacture. Linked to the EPSRC project mentioned earlier, this project is studying “In my view, patients after a few days. This various extremophiles astropharmacy project is researching the as potential sources is a new way biochemical processes that of environmental- regulate receptor activity, tolerant cell-free t o t e a c h and looking at potential protein synthesis. people to solve pharmaceutical therapies and • Drug delivery from problems.” engineering solutions prevent halophiles. Exploring or restore activity. the particular and unique • CubeSAT design. Ultimately, properties of halophiles, research into how to make and whether we can reverse medicines and treat people in space engineer novel drug delivery needs to be done in the environment vectors based on their membranes. of spaceflight. Here, we are developing a • Cold plasma food processing. The nutritional flexible platform for astropharmacy experiments, requirements and ability to absorb nutrients of an astronaut based on a CubeSAT design. We hope to fly the first changes in time. We are exploring the use of processing Astropharmacy CubeSat in February 2021. technology as methodology to modify the physical and nutritional content of food for personalized care. The enthusiasm of the students is inspiring – and by • Bacterial/immune system crosstalk. It is known that focusing on the extreme problem of supporting life on Mars, both bacteria and the cells of the immune system change I believe that we will, as a consequence, come up with many in microgravity. We are studying any interlink between new solutions and approaches that can also benefit patients the behavior of these two systems to research potential on Earth. In my view, astropharmacy is a new way to teach new methods to control infection and moderate disease. people to solve problems. It’s not about solving the particular • Insulin receptor dynamics and restorative treatment. problem, but translating problems to new environments. Insulin receptors in muscle shutdown in spaceflight Because when you look at a problem from a new angle or in a after a month. The same happens to immobile new environment, you can often find new insight.
www.themedicinemaker.com Credit: NASA/Kevin Depew Credit:
On Earth, bacterial cultures are often grown in incubators and require mixing of the liquid to promote gas exchange (aeration), which is optimal for many of the organisms used as biotechnology platforms today. However, efficient mixing in current space-based bioreactors may be limited. Joe made a connection between the fluid dynamics technology that Amir was developing and the Bringing biological principles he learned in my class, and came up with BIOREACTORS the idea of using the RSD as a bioreactor to more efficiently to Space aerate and grow microorganisms such as E.coli in space. These microorganisms could be used to help astronauts produce protein- Is it possible to design a bioreactor thatt can based medicines that may be necessary during long-term space function in microgravity? exploration. Currently, inhabited space missions are limited to low Earth orbit (LEO) on the International Space Station. With Richard Bonocora, senior lecturer Basic human necessities, including pharmaceuticals, food, and at Rensselaer Polytechnic Institute water, are provided by frequent resupply missions. The need for pharmaceutical production becomes important as the missions OneOne daday,y, a stustudent, Joe Adam,am, whowho hadhad previouslyvio beenbe inn mym become more adventurous and spacecraft travel past LEO to the class,s ccamee to ask if I still had the bbacteriaia wew hadad workedke on Moon, Mars, and beyond. I was intrigued – and thus began my that expexpressedpressedressed green flfluorescentuorescentuoresce protein protein. henWhen I saidd y yes, he interest in the field of space microbiology. askedked if I would like to send them intinto space. As with other bioreactors, the RSD will require a motor and a He wasas working on a project wwith Amirmir HHirsa, a pprofessor of harness to secure it during space flight, but since surface tension Aerospace Engineering at Renssaeler, iinvolvingg theth ring-sheared is doing all the heavy lifting regarding the liquid, there is no drop (RSD).RSD). The RSD was devedeveloped oto st studyud the flow within additional container weight. Furthermore, problems of biofilm liquids without the constraints of solid walls,wa something that can formation and the resulting biofouling that have been observed on only happenppen in the absence of gravity. grav In microgravity, free liquid previous space missions are substantially mitigated as only contact naturally takes on a spherical shape and it is this property of liquids rings touch the culture. that the RSD exploits. The edges of two cylinders (contact rings) My collaboration with the team began a few years ago. touch the drop and use surface tension to hold the drop in place. Since then, the RSD has been installed on the International One ring then rotates while the other is stationary, producing flow Space Station (2019) and is being used to study the formation and mixing throughout its volume throughugh the action of surface of protein clusters like those found in brain tissue in shear viscosity – all without the needeed for a solid container. neurodegenerativeneur diseases (1). We recently reported on how we used a ground-based analogue of the RSD called the knife-edge surface viscometer (KEV) to evaluate the feasibility of growing microorganisms in microgravity and the RSD (2). The RSD only works in microgravity, which makes it difficult to test on Earth! However, tests with the KEV, which also uses surface shear viscosity to produce mixing, show that it is a viable method of growing E. coli. In addition, recombinant protein expression was comparable to using standard growth methods. We’re now planning to do tests to see if the RSD can successfully hold drops with living bacterial cultures during Comprehensive short bursts of microgravity on a parabolic flight (also known as the Vomit Comet) (3). I’m positive that we will see some good results! support for I am now working on optimizing microorganisms for space, by selecting or engineering the new organism(s) for producing your injectables biologics in space with improved functions such as growth rate and protein production. At the moment, we are focusing on improving resistance to radiation. As missions extend deeper into space, exposure to galactic and solar radiation will increase. For over 40 years, Vetter has been a trusted partner Astronauts will need adequate shielding to protect them from such in injectables manufacturing for pharmaceutical exposure. Microorganisms used to produce biologics will also need and biotech companies around the world. Our deep shielding. However, we are interested in reducing the amount of expertise enables us to integrate with your team physical shielding needed by microorganism biofactories. There to design and implement a personalized plan for are microorganisms that have extreme resistance to radiation. We success in a shifting global marketplace. are investigating how to harness these abilities and put them to Our strategic partnership includes: use with more biotechnologically amenable species to create a “cellular shield” that protects the contents of the cell, namely Customized clinical and commercial manufacturing the desired biologic. services for your product throughout its lifecycle In essence, this will transfer the shielding burden from the spacecraft to the cellular factory and will allow more shielding Deep and comprehensive technical, analytical, mass to be devoted to the astronaut cabin. I liken this to the and regulatory subject matter expertise difference between the insulation needed in a family’s home as compared to that needed for their garage. Garages are always Proven manufacturing processes that are flexible, cold or hot, but you don’t have to live in them! efficient, and scalable I am fortunate to be working at Rensselaer with so many bright students like Joe who have so many great ideas. I am also Filling and packaging capabilities that utilize the fortunate that Rensselaer has an extremely supportive collaborative latest technology to meet international market environment. Fluid dynamics and engineering expertise lies with demands Amir, Joe and Shreyash Gulati (another member of our team who provided critical analysis to our KEV work). My role lies on the microbiology side. I believe collaborations like ours that combine different disciplines are what’s important to drive science forward.
References INTERPHEX JAPAN 2020 1. NASA, “NASA, Industry Partner for Space-based Study of Potential Alzheimer’s Key,” (2019). Available at https://go.nasa.gov/2I0SNPQ. Get in Contact with us! 2. JA Adam et al., “Growth of microorganisms in an interfacially driven space bioreactor analog,” npj Microgravity, 6 (2020). 3. NASA Flight Opportunities, “Adapting the ring-sheared drop (RSD) technology as a bioreactor,” (2020). Available at https://go.nasa.gov/36Kj7YM.
www.vetter-pharma.com Answers that work
Vetter_VDS_Print Ad_Medicine Maker_Oct_Nov2020.indd 1 08.10.20 12:34 28 Sponsored Feature
identification tools will Mapping become redundant, says 7GMIRXM½G (MVIGXSV (E 6IR Out MAM ±1%1GSR½VQWXLIEQMRSEGMH WIUYIRGI¯ERHMWJEVQSVIWTIGM½GXLER Amgen has brought the Multi- ELISA assays.” And while chromatographic Attribute Method (MAM) into the methods may detect charge variants, details of the MAM approach, mainstream, but what’s next for only MAM elucidates the molecular basis operation and performance, including this analytical workflow – and for of the variations. “It doesn’t just alert us robustness, failure rates, and the standard biopharmaceutical QC? XSETITXMHIQSHM½GEXMSRMXHI½RIWXLI criteria for “passing” a product with TVIGMWIWMXISJXLIQSHM½GEXMSR²RSXIW VIKEVHXS'5%W%RHWLIMWGSR½HIRXSJ (E6IRMW7GMIRXM½G(MVIGXSV.IXXI;]T]GLMW 6IR'SRWIUYIRXP]1%1EPPS[WHIXEMPIH meeting the expectations of the regulatory )\IGYXMZI(MVIGXSV%XXVMFYXI7GMIRGIWERH assessment of the relevance of such events bodies. “Eventually in the coming years, I 8MRK7SRKMW7IRMSV7GMIRXMWXEPPEX%QKIR XSHVYKWEJIX]ERHIJ½GEG] expect MAM will be globally accepted as a 8LSYWERH3EOW'EPMJSVRME97% replacement for conventional QC assays.” Growing regulatory endorsement 6IRIQTLEWM^IWXLEX1%1EPVIEH]½XW In the biologics industry, it sometimes Amgen’s quality focus inevitably led the very well with current regulatory thinking. seems like the only constant is change. team to concentrate on monitoring and ±-X½XWI\EGXP][MXLMRXLI5F(TEVEHMKQ² Consider how the cumbersome, laborious control of critical quality attributes (CQAs) Furthermore, he emphasizes, MAM has mass spectrometers of the 1980s have in biologics manufacture. “It’s all part of the WEXMW½IHEPPRIGIWWEV]-',KYMHIPMRIW¯JSV evolved into sophisticated protein analysis quality by design (QbD) approach,” says I\EQTPIXLIGYVVIRX-',5 6 KYMHERGI tools. Today’s instruments, says Ting Song, a 6IR±1%1EPPS[WYWXSJYPP]YRHIVWXERH – that pertains to analytical methods used Senior Scientist at Amgen, can even analyze the product and to control its quality in a cGMP environment. And that’s why he binding of a drug to its target. Amgen now attributes throughout the development expects to see continued uptake of MAM has taken mass spectrometry into the and manufacturing process.” This, he says, in the industry, and increasing acceptance cGMP environment – so what changes MW[L]1%1[MPPLEZI[MHIVERKMRKFIRI½XW by regulators worldwide. should we expect next? to the pharmaceutical industry – and it also “We have ambitious goals,” says Wypych. explains the increasing support for MAM “But look how far we’ve come in the The new normal from the regulators. PEWX½ZI]IEVWERHGSRWMHIVXLIKVS[MRK If you want a hint on what’s next for Wypych notes agencies’ enthusiasm momentum for MAM uptake – more and MAM, think about how quickly SDS- as well, especially after some adopted more companies are adopting MAM in their PAGE clipping assays were replaced by and gained experience with the method QC functions.” But a key requirement, she electrophoresis. “Electrophoresis will for themselves. But this didn’t happen by WE]WMWXSQEOI1%1WYJ½GMIRXP]VSFYWX in turn be displaced by MAM – not just chance – Amgen engaged major regulators and affordable for adoption by all, including CE-SDS but also capillary IEF,” states early in the MAM development process. contract testing labs and import testing labs. Executive Director of Attribute Sciences ±%X½VWX%QKIR[EWEPSRIZSMGIFYX The latter point, she says, is important for Jette Wypych. “MAM is not intended to be over the years we have slowly convinced countries that require import testing, for complementary to existing assays – it is a the industry of the merit of MAM,” says I\EQTPI6YWWME7SYXL/SVIEERH'LMRE replacement.” She lists QC techniques likely Wypych. And in 2017, Amgen – along to be less prominent in the future: certain [MXL.YWX&MSXLIVETIYXMGW1IVGO4½^IV Upgraded technical capabilities chromatographic methods for assessing Biogen, and Genentech – published a paper In an environment as dynamic as the amino acid modifications, establishing that MAM was ready for QC biologics industry, should we also expect glycan mapping techniques, application (1). “That was hugely uplifting!” MAM to evolve? Certainly, the Amgen ion exchange chromatography, Nevertheless, there’s still some way to team is always thinking bigger and better, hydrophobic interaction go before agencies worldwide converge ERHGSRXMRYIWXSVI½RI1%1JSVZEVMSYW chromatography, and standalone on MAM as a routine QC tool. What will ETTPMGEXMSRW6IRTSMRXWSYXXLIIRSVQSYW peptide mapping methods with it take to win over those regulators who potential of this young technology, and UV detection. still have questions? Wypych thinks outlines two broad areas of interest that he Similarly, antibody-based the answer lies in providing full and his colleagues are currently addressing. 7SJX[EVIXLEXMW What should I • user-friendly (easy to use, automated data processing look for when and reporting) 8LI½VWXMWEYXSQEXIHWEQTPITVITEVEXMSR • allowing easy method transfer – an area of interest to many companies adopting MAM? across instrumentsments and sites besides Amgen. Ting Song notes that • robust and allows for reproducible automation in both sample preparation and -RWXVYQIRXEXMSRGETEFPISJTVSZMHMRK result generation data analysis would support the evolution of HEXEJSVEXXVMFYXIUYERXMXEXMSRERHRI[ • '*64EVXGSQTPMERGIVIEH] MAM into a real-time release and stability TIEOHIXIGXMSR • capable of assuring data integrity testing tool, compressing the testing cycle • high resolution (a measure for the and security (e.g., secure back-ups) and helping manufacturers get drugs to width of a mass spectrometric patients in shorter time-frames. peak – the higher the resolution, 7]WXIQWXLEXEVI -RWYTTSVXSJXLMWIRHIEZSVWE]W6IR the narrower the peak and the • accessible for contract labs %QKIRLEWQEHIWMKRM½GERXMRZIWXQIRXW higher the chances to distinguish and for countries that must aimed at extending their capabilities in ions that are very close in their repeat manufacturer’s release automated data analysis: “The idea is that detected mass to charge ratio methodology (i.e., easy to operators will simply put a sample into one [Q^] in a mass spectrum use, affordable) end of the system and collect processed • high mass accuracy (a measure data at the other end – the intervening steps of how close a detected mass to :IRHSVWXLEX of sample preparation, sample analysis, and the theoretical mass of an ion • commit to long term support on data analysis will all be automated.” is, provided as mass deviation in instrument and software %GGSVHMRKXS6IREHZERGIWMRXLMWEVIE parts-per-million [ppm]) • offer complete solutions pre- will likely need further close collaboration • reproducible isotope distribution evaluated and optimized for user with instrumentation vendors. “We’ve JSVTITXMHIGSR½VQEXMSR?VIUYMVIW expertise level already asked them to consider how we reproducible measurements of • respond rapidly to service might collaborate to develop systems with ion intensities with high mass requests (minimize downtime) higher levels of automation.” In addition, accuracy and high resolution]) • provide software training WE]W6IREWTIGXWSJHEXEEREP]WMWVIUYMVI • with highly reproducible • are open to collaborate on improvement. “The methods used for chromatographic separation system/software optimization integration of peaks haven’t changed for decades – the time is ripe for application of EVXM½GMEPMRXIPPMKIRGITS[IVIHHEXEEREP]WMW XLMWGSYPHVIZSPYXMSRM^IXLI½IPHERHVITPEGI human analysts.” biopharmaceutical pioneer such as Amgen. positive change in many regulators’ view of The second area of interest for Amgen is %W6IRI\TPEMRW%QKIR´WWGMIRGIFEWIH MAM, and we will continue to address any miniaturization. “Manufacturers will have to culture and embedded values of agility and concerns as they are presented.” Amgen’s develop small-footprint mass spectrometers adaptability – present since its genesis – efforts have contributed to a sea-change in XLEXEVIWYJ½GMIRXP]GSQTEGXERHQSFMPIXS have remained with the company as it has MAM uptake and enhanced the reputation FIQSZIHEVSYRHXLIQERYJEGXYVMRK¾SSV grown into a major industry player. “Our as the developer of this novel technology. EWSTIVEXSVWVIUYMVI²WE]W6IR-REHHMXMSR values, together with our strategic focus In other words, when quality is an intrinsic he believes that a range of software on quality, explain why we continually seek component of your core values, competitive companies – not just the major vendors to develop better products and thereby advantage tends to follow. – will want to leverage the opportunities better serve patients,” he says. to develop solutions that support MAM But there is another factor at play, 8S½RHSYXQSVIZMWMXLXXTW in the QC environment. “This will result according to Wypych: “To make a difference XLIQIHMGMRIQEOIVGSQEQKIRQEQ in growth in the currently limited number you have to be a risk-taker – while strongly of vendors that can serve the compliance committing to ensure compliance.” Reference WSJX[EVI½IPH² Amgen’s desire to provide patients with 66SKIVWIXEP±%ZMI[SRXLIMQTSVXERGISJ the best possible options also informs the ³QYPXMEXXVMFYXIQIXLSH´JSVQIEWYVMRKTYVMX] A virtuous circle company’s proactive engagement with SJFMSTLEVQEGIYXMGEPWERHMQTVSZMRKSZIVEPP If any company can upend the bioprocessing regulators. “That won’t change,” says GSRXVSPWXVEXIK]²%%%47.SYVREP environment, it’s likely to be an archetypal Wypych. “We’ve already facilitated a big 41-(
www.thermofisher.com/learnMAMwww.thermofisher.com/learnMAM Credit: NIAD Feature 31
Ever since the “bird flu” outbreaks of the mid-2000s, public health experts have been concerned about an influenza pandemic to rival the 1918 Spanish Flu. Now, blindsided by a less expected beast, can we transfer lessons on pandemic preparedness from flu to COVID-19? We caught up with Russell Basser, Head of R&D at flu vaccine manufacturer Seqirus to find out more about the past, present, and future of vaccine production – and how COVID-19 changes the outlook.
Your company has an interesting origin story… where we make our cell-based vaccines today. Novartis/Chiron Commonwealth Serum Laboratories – as it used to be known – also pioneered the use of an adjuvant called MA59 to boost was set up by the Australian government in 1916 as a public utility. immune responses to influenza vaccine. At that time, it was hard for Australia to get access to modern The 2000s also saw the advent of the live attenuated flu virus, medicines because they were developed and manufactured administered via a nasal spray (Flumist). Developed by Aviron such vast distances away. The first big challenge for the newly (later Wyeth, then Medimmune and now AstraZeneca) this formed CSL was the 1918–1920 Spanish Flu. The company was frozen vaccine, also produced in eggs, has had something of a successful in producing what was referred to as a vaccine, but was chequered history. Initial trials showed it to be highly effective, actually an antiserum from patients with pneumococcal infection. but logistical challenges hampered uptake. Later, post- CSL went on to produce insulin, penicillin, and vaccines for polio, marketing data showed that it was not always as protective as diphtheria, tetanus, and whooping cough. hoped, leading to it being dropped from vaccination programs The first true vaccines for flu were actually developed in the in some countries. US in the 1940s, based on the pioneering work of Australian The next big innovation came in the 2010s from Sanofi – Nobel prize winner Macfarlane Burnet, who discovered that a recombinant protein vaccine (Flublok). Insect cells were flu could replicate in embryonated chicken eggs. In the late genetically engineered to produce the most important surface 1950s, CSL brought flu vaccination technology to Australia. antigen of the flu virus – hemagglutinin. The result is similar to cell culture-based production – faster manufacture and no How have manufacturing technologies for flu risk of “egg adaptation.” vaccines evolved since then? Back in the early 2000s, everybody thought flu vaccination In the early days, the virus was grown in eggs, killed, and was a “dead” area with little hope of innovation. The changes injected whole, but this caused some significant side effects. we’ve seen over the past 20 years disprove that – showing that Soon, methods were developed to split the virus using chemical even long-established processes in pharma can be improved upon. detergents and to purify it to leave only the viral proteins that give maximum immunity and minimum side effects. Even What are the most important lessons the industry today, up to 90 percent of the world’s flu vaccine supply consists has learned from manufacturing flu vaccines over of highly purified, inactivated viruses grown in eggs. the years? However, egg-based production has some important Around 2005, my boss took a call from the head of CBER, disadvantages – it’s slow, wasteful, and carries a risk of “egg the vaccine division of the FDA. They had just had to close adaptation” (see sidebar The Egg (and the Chicken) on page down a major flu vaccine production facility due to quality 33). In a bid to develop a faster, more efficient process, Chiron concerns, which meant there was only one factory licensed to developed a vaccine grown in mammalian cells (dog kidney make the flu vaccine for the US market – a precarious position! cells) in the early-2000s. The vaccine was launched in Europe, How did it come to this? The answer holds an important lesson but it failed to find commercial success when pitted against – not just for flu vaccines, but for medicines more generally. In well-established and inexpensive egg-based vaccines. essence, flu vaccines had become so uneconomical to produce The emergence of H5N1 (bird flu) in the mid-2000s brought that manufacturers had pulled out. Those that remained flu vaccine production into the spotlight. Concerned at the slow struggled financially and started to slip behind in the quality turnaround of traditional egg-based manufacturing methods, standards demanded by regulatory agencies. When we, as a US government agencies showed renewed interest in cell- society, do not value important existing products and focus all based alternatives. With government backing, Chiron (which our attention on new medicines, we leave ourselves vulnerable. by this time had been taken over and was, then, Novartis When H5N1 (bird flu) emerged in the mid-2000s, causing Vaccines) brought the technology from Europe to America, a number of infections in close contact and a mortality rate building a new factory in North Carolina – the same factory that suggested it had the potential to cause a pandemic to
www.themedicinemaker.com 32 Feature
MEET RUSSELL BASSER then, governments have been investing more heavily in flu preparedness, in the hopes of being ready for the next pandemic.
What lessons about pandemic preparedness can we take from COVID-19? We think of our seasonal flu vaccine campaigns as practice runs for a pandemic. We’re very aware that companies like ours are an important line of defence for communities. COVID-19 is, naturally, the overwhelming focus right now, but new flu viruses remain a risk, and there are lessons we can take from COVID-19. One lesson is that days and weeks are very important, and ideally we should be prepared to take action quickly. In many countries, governments were initially slow to take decisive action; the delay has cost many lives. I started off working at our parent company CSL almostt Another lesson is how important it is to “know your enemy.” 20 years ago. When the FDA requested that we bring our SARS-CoV-2 is a new virus but is essentially similar to the influenza vaccine from Australia to the US to combat vaccine viruses that cause SARS and MERS, for which vaccines were shortages in the mid-2000s, my group led the clinical and already in development before COVID-19 came along. That regulatory project. The year 2009 saw the emergence of swine prior knowledge has enabled rapid development of vaccines for flu, and my group was responsible for supporting the Australian SARS-CoV-2; we already had a good idea of how the virus government in their response to the virus. operates and had an existing target (the “S protein”) that could I found flu a fascinating area and later took on the role of head be rapidly developed into a potential vaccine. of R&D for the newly formed Seqirus – a semi-independentt If a new flu virus threatens to take hold, I believe we are business under the CSL umbrella, focusing solely on flu in a much better position to respond than we have been to vaccines. My role encompasses everything from basic research COVID-19, with manufacturing and supply chains already in through to manufacturing development, clinical, regulatory, place around the world. Taking preparedness a step further, drug safety, and medical affairs. Seqirus has already registered a vaccine for H5N1 and gained regulatory approval in the US. If a pandemic were to emerge, we could start manufacturing a vaccine as soon as the genetic rival Spanish Flu, the world was less prepared than it could code of the strain responsible was sequenced. We believe we have been. Fortunately, H5N1 has yet to develop the ability to could have a vaccine available in as little as three months. We transmit between people but remains a threatening presence are already in talks with governments about developing similar in bird populations. “pre-pandemic” vaccines for other avian flu viruses, such as A less severe pandemic emerged in 2009 in the form of H7N9 and H5N6, in case they make the switch to human- H1N1 swine flu, that swept across the globe, causing fatalities human transmission. Over time, we hope to build up a portfolio amongst children and pregnant women in particular. Since of these vaccines, ready to roll out if we ever need them. You can’t be truly prepared until you have tackled something many times. Being prepared “on paper” is a bit like visualizing running fast or kicking a ball into a goal – it helps, but true “There is a saying expertise comes with action. I will remain somewhat cautious in the flu world about new vaccine platforms until they are truly tested in the field. that when you’ve Despite your caution, what developments in seen one flu season, vaccines are you excited about? you’ve seen… Going back to pandemic preparedness, I believe some of the one flu season. new technology platforms being developed in the vaccine space are another way in which we can become more responsive to Every season is new threats. For example, mRNA and vector-based vaccines different.” could allow very rapid vaccine development. However, these THE EGG (AND THE CHICKEN) MostM flu vaccines are produced in the yolks of fertilized hen’s eggs. It’s a well-established, inexpensive method, but is it still fit for purpose in the 21st Century?
ToT produce flu vaccines, the WHO has a highly sophisticated platforms have not been widely used to date and we need more surveillance program, with many different labs from around information on safety and efficacy at a population level and the world submitting samples of flu virus from patients in over time to confidently rely on these approaches. their area. Based on this information, the WHO makes a Vector-based vaccines, like the SARS-CoV-2 vaccine under twice-yearly recommendation on which strains to include development by AstraZeneca and the University of Oxford, in the vaccine for the forthcoming flu season – once for the are very interesting but, as the vector itself will generate an northern hemisphere and once for the southern hemisphere. immune response, they may not be effective if administered The chosen strains are then grown in just a few labs more than once or twice. worldwidew – including Seqirus in Australia, NIBSC in mRNA vaccines, which get the body itself to produce viral the UK, and the NIH in America. Eggs are not the natural proteins, also have amazing potential. We have an mRNA habitat for the flu virus; it must adapt and mutate slightly program at Seqirus and we’ve found that it is possible to generate to grow successfully in this alien environment. For egg- a new vaccine in a matter of weeks. We’ve also seen very strong based production, the labs mix the chosen flu strains with responses, even better than many currently commercialized a virus that’s known to grow well in eggs and select the technologies. However, there is much to learn about mRNA mutated virus that represents the best compromise between vaccines – they seem to cause quite marked reaction at the site similarity to the “wild” virus and the ability to grow in eggs. of injection, as well as fever when administered at high doses. TheseTh final strains are then distributed to the flu vaccine This latter property indicates that care will need to be taken manufacturers to produce the flu vaccine for that year. when administering such a vaccine to young children, who can There is growing evidence that, in certain flu strains, the be especially sensitive to such an effect. Another challenge is mutations that allow the virus to grow in eggs can affect the that mRNA vaccines are very unstable and have to be frozen. hemagglutinin proteins critical for the efficacy of the vaccine. This has been manageable during the development phase, but Hemagglutinin is the protein responsible for binding to will add considerable complexity and cost in distribution to and entering host cells – but the cells in the egg are not the the general population, which will provide logistical problems same as human cells, so the protein must alter slightly to be COVID-19 has brought these new platforms onto the fast- able to reproduce in eggs: “egg adaptation.” And so, when track with almost unlimited money and resources, which could the immune system encounters the wild-type protein, it have a positive impact on the field for years to come – and only partially recognizes it. In years when the dominant flu that’s fantastic. But it’s also important to remember that there strain is affected by egg adaptation, egg-based vaccines may is still a lot of work to do. As soon as a vaccine shows some be significantly less effective. There are also other challenges success in clinical trials, the press and community at large has associated with egg-based vaccine manufacture. Production expectations that this will make the virus disappear and allow is slow (six months), relies on a massive supply of eggs (up to life to return to normal almost instantly. However, population three eggs per dose), and it generates a lot of waste. vaccination programs will take time; the first generation of Alternatives are available – a vaccine grown in mammalian vaccines are unlikely to be perfect and we will continue to cells (from Seqirus) and a recombinant vaccine (from Sanofi learn about their pros and cons along the way. Pasteur). There is evidence that these egg-free vaccines offer enhanced protection (1), with larger studies underway (2). Is Seqirus involved in SARS-CoV-2 vaccine efforts? TheyTh are also faster than egg-based methods, offering the We are partnering with the non-profit Coalition for Epidemic hope of a rapid response to any new pandemic strain. Preparedness Innovations (CEPI) and The University of Other companies are looking into a variety of Queensland (UQ ) to help develop their protein subunit approaches, from growing virus-like particles in plants vaccine. They are using their molecular clamp platform, to mRNA vaccines that cause the body’s own cells to designed specifically for rapid response vaccine development. produce flu proteins (3). We have provided the MF59 adjuvant, an important additional element that stimulates the body’s immune response to the S References protein. The UQ vaccine is currently undergoing phase I trials, 1. LM Dunkle et al., “Efficacy of Recombinant Influenza Vaccine in Adults 50 Years and we’ll take responsibility for further development after this of Age or Older,” The New England Journal of Medicine, 376, 2427-2436 (2017). study is finished (and assuming it is safe and immunogenic). 2.2 ClinicalTrials.gov, “A Pragmatic Assessment of Influenza Vaccine Effectiveness We have also been contracted to produce the AstraZeneca in the DoD (PAIVED),” (2018). Available at https://bit.ly/37qofBL. vector-based vaccine for the Australian Government. 3. Nature, “Accelerating flu protection,” (2019). Available at https:// go.nature.com/3dJKq7b.
www.themedicinemaker.comwww.themedicinemaker.com 34 Feature Credit: Navy Medicine from Washington, DC, USA
But your main focus remains flu? a single vaccine that confers lifelong immunity to all strains of That’s right. Seqirus has been an extraordinarily successful industrial flu. But, as one of my mentors told me, the less you know about experiment! We took unprofitable parts of two companies and something, the more exciting it is. Knowing what I do about the flu created a successful entity, focusing solely on the then-unfashionable virus, I doubt we’ll see a universal vaccine within my working life. area of flu vaccines. The secret of our success has been to keep It’s easy to believe fantastic advances like the recombinant that focus narrow and deep on the single disease area. Flu is more HPV vaccines – which require only one dose to provide lifelong difficult than most other vaccines, so our laser focus is essential. immunity – are possible for all viruses. But flu is a different There is a saying in the flu world that when you’ve seen proposition as there are four separate viruses, all mutating rapidly. one flu season, you’ve seen… one flu season. Every season is Before we can even begin to think about a universal vaccine, we different. This is one aspect that distinguishes flu from all other need to know a lot more about how the virus behaves in the body vaccine fields – we’re constantly chasing a mutating virus, but and find strategies to trick the immune system into generating a never quite catching up to it. Even with all the advances in stronger and more long-lived response. medicine, flu remains a challenge. Sometimes the vaccine is To that end, we participate in a public–private partnership very effective, and sometimes the virus drifts after the vaccine group, the Human Vaccine Project, which is mapping the strains are chosen and efficacy drops off dramatically. intricacies of the human immune system down to individual The deep expertise we’ve developed in flu has allowed us molecules. The aim is to better understand how the body to innovate; in particular, developing the MF59 adjuvant responds to infection and vaccination to see if we can uncover and the cell culture platform I mentioned earlier. Now, we’re some secrets that might help us generate better vaccines. The combining the two advances. We’ve already done this for our exploration is fascinating, exciting and extremely complicated pre-pandemic vaccines, and we hope to soon apply the same – the more we know, the more we realize we don’t know! combination to create the very best annual vaccine possible For me, flu is one of the most fascinating spaces to be in. It with current technology. It’s an exciting direction! combines immunology, virology, public health, and geopolitics. And that means it is constantly changing – and constantly challenging. Do you think we’ll ever see a universal flu vaccine? The press was very hot on this around five years ago and I still Russell Basser is Senior Vice President, Research & Development get asked about the potential. It is certainly a wonderful prospect: at Seqirus, Australia SponsoredSpS onsored FeaturFeaturee 35
“VIA Capsule DuringDurin testing the VIA Capsule system AdvancedAdvanced allowsallows ttherapiesherapies to traveledtraveled far and wide – over 80,000 km bebe delivered safely and securely across EEurope, Asia, and North America. TherapiesTherapies – VIA withoutwithout liliquidquid nitrogen,nitrogen, avoavoidingiding A key ppartnera for the VIA Capsule logistics thethe associatedassociated compcomplexity,lexity, rrisks,isks, anandd processprocess is World Courier, which has Capsule™Capsule™ System inefficiencies,”inefficiencies,” says Bill Shingleton, hubs aacrossc the globe. World Courier AlliancesAlliances Manager at Cytiva. “It can be performedperform its own testing and validation ConfidentlyConfidentlyy sshiphip anandd monitor used for shipping cellular products from ofof VIA CCapsule to ensure that it meets the precious samples saamamplples without manufacturingmanufacturing centers to clinics, and also qualityquality tthey seek in shipping systems. liquid nitrogen for shipping cell therapy starting material.” The graphic below shows how VIA % QENSV FIRI½X SJ XLI :-% 'ETWYPI 'ETWYPI[EWYWIHMRE9/PSKMWXMGWXVMEP Cell and gene therapies have the system is that it tracks where the product with the Advanced Therapy Treatment potential to change lives and even cure is at any time. It also monitors the Centres (ATTC network) and Orbsen diseases. It is critical that these products temperature and the angle of the system Therapeutics to transport a stromal cell maintain their quality during transport, throughout the journey, providing real- MQQYRSXLIVET]36&')08LIVIWYPX# even when there are delays. With all time alerts if thresholds are exceeded. Viability of cells shipped using VIA Capsule of this in mind, cryobiologists at Cytiva “The status can be monitored using was similar to the viability of cells retained developed a liquid nitrogen-free system Chronicle™ web-based software, at the original site. to ship cryopreserved products in a which can be accessed from different GSRXVSPPIHERHGSR½HIRX[E]0MUYMH devices, including tablets and phones. *MRHSYXQSVIMRXLI[IFMREVEZEMPEFPI nitrogen requires specialized handling Clinical staff at the receiving sites can EX LXXTW XLIQIHMGMRIQEOIVGSQ – and many of the facilities that will also have oversight of when the drug will [IFMREVEHZERGIHPSKMWXMGWJSVEHZERGIH ultimately treat patients with advanced arrive so that they can prepare patients XLIVETMIWIZMHIRGIYWMRKZMEGETWYPIXQ therapies are not set up for this. accordingly,” says Shingleton. GV]SKIRMGW]WXIQ
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38-41 From Big Pharma to New Green Horizons: Lessons Learned with Ross Burn Analytical chemist Ross Burn took on a range of new scientific, financial, business development, and leadership responsibilities when he co-founded CatSci in 2010. He shares his lessons learned along the way. 38 Profession
going down the forensic side, you could Fortunately, the UK government at From Big say pharma chose me! that time ran a three-day crash course in business skills that taught you the essentials Pharma to New A big pharma company allows you to as a business owner. And AstraZeneca develop into a top-class scientist were kind enough to allow us to take some Green Horizons: After my PhD, I was fortunate to get my time during our final months to educate first role at AstraZeneca. After having spent ourselves. They did that for anyone looking Lessons Learned several years at Pfizer during my PhD and to change careers as part of their winding then at AstraZeneca as a process chemist, down process. with Ross Burn I realized that large pharmaceutical companies know how to develop top class A 40-second elevator pitch is worth With just a three-day crash scientists. Not only are you working with more than a 100-page business plan course in business finance cutting edge equipment, but you’re learning I realized early the importance of having under his belt, analytical from experienced professionals who are a good value proposition – and that’s what chemist Ross Burn co-founded brilliant at following the science towards really got us going. My advice to anyone CatSci in 2010. Here, he talks answers to complex practical problems. looking to set up a business is, don’t about surviving and thriving Big pharma gets a lot of bad press, but expect it to be something like Dragon’s as a new company focused on my experience was that they empowered Den! Ensure you thoroughly carry out process chemistry, alongside us to be the best scientists we could be. your market research, validate that your more recent moves into You can see why many are happy to spend product provides a value-add or a solution industry 4.0 and collaborations their entire careers within a large pharma to a current problem or need, and make sure in the contract research space. company, but that wasn’t my path… your product or service is market ready at launch. There are startup networks and Let your profession choose you You need thick skin to build new accelerators available that function as Having an interest in chemistry and being relationships from scratch sounding boards for testing your hypotheses someone who enjoys solving problems In 2010, AstraZeneca decided to reduce and prepare yourself for many years of hard meant that analytical chemistry was its R&D footprint and shut down several graft to build a sustainable business. a great fit for my MSc. That’s what I sites in the UK. But they wanted to retain And as a new business you will need studied at Strathclyde University – along what we were doing well in the Bristol lab: funding – cash is king, as they say. with forensics. This was back in 1998- catalysis screening. So, four colleagues Traversing the entrepreneurial valley of 2003 before forensic chemistry hit the and I decided to set up an independent death from startup to breakeven isn’t easy. mainstream with CSI! Even then, some lab and service AstraZeneca’s portfolio people had this idea that they’d be helping until they were able to recreate the facility to solve crimes or giving evidence as an in Macclesfield. expert witness in court, but the day-to- Although for a period of time we were day job of a forensic scientist tends to be carrying on the work we were doing as “Without a big quite routine. AstraZeneca employees, I noticed some I was always more inclined towards significant changes when trying to find pharma name, the analytical side – I especially enjoyed new contracts. Without a big pharma separation science and investigative name, building new relationships from building new analysis. And that led me to study for a scratch wasn’t easy and we had to grow PhD, funded by Pfizer, based on analyzing thick skin to handle rejection. I also relationships from the human proteome and trying to find took on the financial responsibilities of new biomarkers of disease. There, I the company from the start, in addition scratch wasn’t easy; was exposed to the workings of drug to working on the science, business development within a large pharmaceutical development, and leadership. Finding the we had to grow company and began to appreciate the role right work/life balance was tough while analytical science plays in bettering human we honed our entrepreneurial skills and thick skin.” health. So, while I couldn’t see myself fought to create a sustainable business. We’re a bootstrap business, which means We decided to focus on sales and dollars in the ecosystem waiting to help that we are owned by the co-founders and marketing from the beginning and a business start and scale up – you just we don’t have any capital partners that assemble the best team we could. The goal need the right business and team to make inject cash into our business. The upshot was to get beyond the breakeven point as it happen. is that we started the business with bucket quickly as possible and to plan our funding I wouldn’t recommend spending weeks loads of sweat equity, and still to this day needs from there. There are a number of writing a 100-page business plan in the reinvest as much of our profits as possible great schemes available in most countries early stages. Instead, make sure to refine to fuel our business to grow. We also take (in the UK, one can take advantage of the your sales and marketing strategy so on significant risk accelerating growth Entrepreneur Investment Scheme) that that you can clearly explain your value by leveraging additional bank debts into allow companies to raise external finance proposition – one that will resonate with the business. quickly. Remember, there’s trillions of stakeholders – in 10 slides or so. Having a
www.themedicinemaker.com 40 Profession
40-second elevator pitch to grab people’s molecule medicines. Since we made the We passionately believe that attention is vital. change, we’ve grown an average 50 percent companies need to be thinking about the year-on-year. environmental impact of their processes Don’t be afraid to re-evaluate when early. We see a lot of emerging companies things don’t go to plan Consider the environmental impact early developing new chemical entities. Often, We were lucky enough to have our first or risk trouble down the road they aren’t looking to commercialize the client, AstraZeneca, in the bag at launch Another key decision we made was to process themselves so environmental and we managed to win business quite focus on green chemistry. I believe we concerns aren’t near the top of their quickly. But that turned out to be a false should do our best, as a company and an priorities. But companies must be aware dawn. Many of our initial customers industry, to reduce our carbon footprint that, even if you’re making kilos of API, were intrigued to see how we were using and minimize the use of finite materials. the process mass intensity could be huge AstraZeneca’s honed methodology, which Many processes use platinum group – especially if you have a high number of we owned, to solve catalysis problems. metals that predominantly come from steps. We try to explain that companies They wanted to see what sorts of processes just two countries: South Africa and need to be thinking about the process AstraZeneca was using and perhaps didn’t Russia. Our approach is to use iron or at the candidate selection stage because intend on giving us repeat business. base metal catalysis, which are far more you don’t want an inefficient process with In the end, we decided to shift our abundant. The environmental case is clear considerable environmental impact down business model from catalysis screening but there’s also an economic argument. the road. to pharmaceutical process research and Such rare materials will continue to Fortunately, the industry as a whole is development. Many of our initial projects increase in price and you are limited becoming more environmentally conscious. were in other sectors such as chemicals and in terms of building redundancy into The big pharma companies all have green agro. We decided to use catalysis as a tool your supply chains – something people metrics to which they try to aspire – in to solve problems in the pharma industry are increasingly concerned about due turn, that’s putting pressure on CMOs and and go back to what we were always good to COVID-19, Brexit and global trade CDMOs, as well as the smaller companies, at: developing chemical processes for small negotiations. to follow suit. Over the next 5–10 years, Profession 41
I believe most companies will have good was tough when working remotely. We’re also seeing a trend away from the green metrics in their objectives. In terms of our clients, they fell into two traditional contract research organization camps. In camp one, they knew how to towards “innovation partners.” Much of the Never underestimate the importance of proceed. They had their own milestones innovation in the industry is coming from staff wellbeing to hit and they decided to proceed as the smaller, emerging pharma companies Of course, we, along with everyone else, normal. In camp two, companies were and the supplier “CROs”, with pharma are having to adapt to the new challenges more inclined to hold off on making companies outsourcing more and more – associated with COVID-19. We were decisions on repeat business until they potentially to the extent that a candidate allocated key worker status and were open had a better idea of when lockdown may be outsourced all the way through to throughout lockdown and we never had was going to end. This delayed decision the clinic. But many companies are thinking any confirmed cases of COVID-19 within making did give us some concern, but too bilaterally with their collaborations. For the company. We couldn’t operate quite now we’re back to business as usual. example, they might have an outsourcing as effectively as usual but we managed to manager that has conversations with parts deliver on the projects we had booked. Digital technologies are coming, but of the value chain, but the niche CROs and Like everyone else, we had to accelerate collaboration is also key to innovation CDMOs never work together. We believe our digital strategy by probably 5 years, When we talk about the (digital) future, we can disrupt that thinking and work with managers and leaders working from we’re talking about CatSci 4.0. Phase more collaboratively. We’re now forming home and interacting digitally with their 1 was the initial founding, phase 2 partnerships with other niche organizations colleagues. But we were already quite was the switch to process research and in the UK and overseas to bring new familiar with tools like Teams and Zoom development, and phase 3 involved innovation to the industry. In fact, we recently because we have an international sales team. bringing in a new senior management announced new partnerships with three The impact on the business wasn’t as team. Now we’re planning on further UK companies across the pharmaceutical severe as other industries and companies. embracing industry 4.0 concepts: using supply chain – M2M Pharmaceuticals, The real challenge for us was the in-silico tools for chemistry, using bots New Path Molecular and Upperton Pharma wellbeing of staff. People react differently for automated back end processes in Solutions. This collaboration will ensure that to an existential threat like a pandemic the business, intelligent automation customers can access specialised capabilities and many were anxious. Finding ways of for parallel synthesis, and integrating and expertise throughout the journey from making sure that everyone felt supported artificial intelligence across the business. molecule to medicine. – with so much negativity in the press and The idea is to free up the minds of the people worried about their loved ones – chemists to solve the difficult problems. Ross T. Burn is CEO at CatSci Ltd
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antibodiesantib directly prevent viral infection. ERXMFSHMIW[MXL-K+ERH-K+MRXIVEGXMRK+MRXIVVEGXMRK Fighting BindingB of a virus-antibody complex to an QSWXIJ½GMIRXP]8LMWMRXIVEGXMSRMWGVMXMGEPP]R MWGVMXMGEG PP] Fc receptor on a phagocyte can trigger dependent on the glycan at the N297297 site iinn Viruses with phagocytosis, resulting in destruction of XLI',VIKMSR 6IQSZEPSJXLIIRXMVIIRXMVI the virus (see Figure 1). Binding to the Fc N-glycan structure reduces the binding ofof Enhanced ADCC receptors on immune effector cells, such as Fc to Fcɶ6WERHVIHYGIWSVIPMQMREXIWXLI QSRSG]XIWRIYXVSTLMPWISWMRSTLMPWERH2/ associated effector functions. Conversely, With evidence mounting for cells, trigger the release of cytotoxic factors eliminating only the fucose residue from the importance of antibody- (for example, antiviral interferons), creating the core glycan structure creates an dependent cellular cytotoxicity a microenvironment that is hostile to virus afucosyl mAb and strengthens the binding in controlling viral infections, replication. Various research groups (4–8) of a mAb to Fcɶ6---EVIGITXSVWIRLERGMRK mAbs engineered to enhance LEZIHIQSRWXVEXIHXLEXFVSEHP]WTIGM½G %('' ¯ 8LIWXVIRKXLSJ*G*Gɶ6 the effect are primed for success neutralizing mAbs targeting highly conser ved interactions can also be modulated by regions of haemagglutinin (a glycoprotein mutating the Fc region (19). %RHVI[.6EGLIV4L(6 ((MVIGXSV JSYRHSRXLIWYVJEGISJMR¾YIR^EZMVYWIW This mechanism also has support from ¯-47XVEXIK]EX0SR^E and integral to their infectivity) require (IWLIRK/SRKERHGSPPIEKYIW[LS Fc-mediated effector functions, especially WLS[IH XLEX ER ERXM,-: EJYGSW]P Antibodies form an important feature of %(''XSTVSXIGXEKEMRWXMR¾YIR^EZMVYW FMWTIGM½GERXMFSH]LEHEKVIEXIVEFMPMX] the host adaptive immune response to challenge in vivo. Therefore, enhancing the XSOMPP,-:MRJIGXIHGIPPWXLVSYKL viral pathogens. Passive administration of potency of ADCC could be an effective ADCC than the fucosylated form (20). antibodies obtained from convalescent [E]SJGSQFEXMRKMR¾YIR^EZMVYWMRJIGXMSR Another study found that enhanced patient plasma is a well-established concept ADCC may be important in controlling ADCC was a potential mechanism for (1), for example, as part of the treatment other viral infections too. For example, protection against Ebola virus infection, regimen following exposure to rabies virus. VIWIEVGLIVWLEZIWYGGIWWJYPP]XVIEXIH,-: with afucosylated mAbs having up-to an Building upon this concept, a number of [MXLFVSEHP]WTIGM½GQ%FWMRERMQEP approximately 11-fold lower ED50 than recombinant mAbs have been developed models (9–11). They attributed this success fucosylated mAbs (21). over the last 25 years for treating viral to both the neutralization function of the The growing evidence for the infections (2). At the time of writing, there ERXM,-:Q%FWEW[IPPEWXLIMVEFMPMX] importance of ADCC in controlling viral are six antibody therapeutics approved to activate ADCC – which removes infections suggests that mAbs engineered for the treatment of viral infections. Two infected cells. ADCC is also considered to enhance ADCC (for example, through of these antiviral antibody therapies are a potentially important mechanism for TVSHYGXMSR MR ',3 *98 ORSGOSYX cocktails of at least two mAbs. As of early protective immunity in herpes simplex virus variants of the host cell line (such as November 2020, there are sixteen mAbs in infections (12). It has also been shown that Lonza’s POTELLIGENT® ',3/7:®) clinical trials for the treatment of COVID-19 serum antibodies against hepatitis C virus will become an important element of XLEXXEVKIXXLI7%67'S:7TVSXIMR )TVSXIMRGERQIHMEXI%('' successfully treating viral infections. 8LVII SJ XLIWI Q%FW EVI *GQSHM½IH Taken as a whole, there is growing evidence 6IGIRXWXYHMIW TSMRXXS[EVHW to reduce the likelihood of antibody- XLEX%(''MWEWMKRM½GERXGSQTSRIRXSJ the potential importance of strategies dependent enhancement of virus infection, the adaptive immune response to virus that target effector function pathways. to extend half-life, or to enhance binding to infection, highlighting the importance of Schäfer and colleagues (22) report that immune-activating receptors. strategies that induce and enhance ADCC intact Fc effector function is required for 6IWIEVGLIVWEVIEP[E]WPSSOMRKJSVRI[ in vaccine development. TVSXIGXMSRJVSQ7%67'S:MRJIGXMSR ways to improve effectiveness of antibody 'LEOVEFSVX]ERHGSPPIEKYIW VITSVX therapy – often by engineering cells to Enhancing ADCC lower Fc fucosylation in antibodies to the enhance certain immune mechanisms. One ,S[QMKLXVIWIEVGLIVWKSEFSYXIRLERGMRK VIGITXSVFMRHMRKHSQEMRSJXLI7%67 such promising mechanism is antibody- %(''# 8LI TVMRGMTEP VIGITXSV JSV 2/ 'S:WTMOITVSXIMRMREHYPXW[MXL4'6 dependent cellular cytotoxicity (ADCC). GIPPQIHMEXIH%(''MWXLIPS[EJ½RMX]*G HMEKRSWIH'3:-( GSQTEVIHXS7%67 Following the initial virus challenge, gamma receptor, Fcɶ6---E '(E *Gɶ6W CoV-2-seropositive children and relative there are a number of processes – such as bind to a region in the hinge and proximal XSEHYPXW[MXLW]QTXSQEXMGMR¾YIR^E neutralization and agglutination – by which ', VIKMSR [MXLMR XLI *G JVEKQIRX SJ virus infections. This suggests strategiesrategies *MKYVI%RXMFSH]QSHIWSJEGXMSR'IPPP]WMWXLVSYKLEGXMZEXMSRSJGSQTPIQIRXHITIRHIRXG]XSXS\MGMX] '(' MRXIVEGXMSR[MXL*GVIGITXSVWSRIJJIGXSV GIPPWXSIRKEKIERXMFSH]HITIRHIRXGIPPYPEVG]XSXS\MGMX] %('' WMKREPMRKJSVMRKIWXMSRSJETEXLSKIRSVXEVKIXGIPPF]ETLEKSG]XI
that target Fcɶ6---ETEXL[E]WQE]LEZI virus infection are already cocktails of at (.(M0MPPSIXEP2EX1IH XLIVETIYXMGFIRI½XW8LIIRLERGIH%('' least two mAbs. Such antibody cocktails ;,IIXEP4VSG2EXP%GEH7GM97% activity of reduced fucose antibodies could simultaneously target non-overlapping 4)0ISRIXEP4VSG2EXP%GEH7GM97% contribute to viral clearance through epitopes minimizing the likelihood that (')OMIVXIXEP7GMIRGI killing and removal of infected cells. the virus becomes resistant to treatment. 21%FYLEVJIMP11=EWIIRERH*1%PWLI]EF As overactive ADCC function may 8LI½IPHLEWGSQIEPSRK[E]WMRGIXLI %'7-RJIGX(MW exacerbate symptoms in some cases, it ETTVSZEPSJXLI½VWXXLIVETIYXMGQ%FMR .'EVVMPPS&'PSXIXERH.&PERGS*VSRX will be important to carefully dose mAbs the 1980s. Today, we may be witnessing, -QQYRSP with high levels of effector function. as Alicia Chenoweth and colleagues ;70IIERH7./IRX'YVVIRXSTMRMSRMR,-:ERH 6IGSQFMRERX PS[ JYGSWI SV EJYGSW]P (24) have alluded to, the “next-gen” of %-(7 Q%FWTVSHYGIHYWMRK',3GIPPW[SYPH antibody therapies, with researchers 7+}VERHIVIXEP:MVYWIW form an important element of a strategy XEOMRKRI[½RHMRKWJVSQMQQYRSPSK] .2EXXIVQERRIXEP.,ITEXSP to produce mAbs with high-level ADCC and using them to tweak and improve 00SRKERH87LIR.'PMR'IPP-QQYRSP effector function. existing treatments. These next-gen ,0MYIXEP&MSXIGLRSP4VSK The adaptive immune response to biologics may unlock the full potential of 607LMIPHWIXEP.&MSP'LIQ . P'LIQ virus infection is complex, involving the antibody immune therapiespies – brbringinginging nnewew =7 =7EOEIIXEP7GMIRXM½G6ITSVXW EOEIIXEP7GMIRXM½G6ITSVXW production of a broad repertoire of and exciting treatmentss to patients with 87 87LMROE[EIXEP.&MSP'LIQ LMROE[EIIXEP .. &MSP'P LIQ antibodies that interact with a range of Fc- HMJ½GYPXSVMQTSWWMFPIXSXVIEXHMWIEWIWSXVIEXHMWIEWIW <;ERK11EXLMIYERH6.&VI^WOM4VSXIMR<;ERKK11 11EXLMIYERH6. &VI^WOM4VSXIMR and other receptors. As such, potent Fc- ' 'IPP IPP engineered or glycan-engineered mAbs 6IJIVIRGIW (/ (/SRKIXEP%-(7 0SRHSR)RKPERH SRKKIXEP%-(-(7 0SRHHSHSR)RKPEERH with enhanced ADCC activity may form %,I]1MGVSFMSPSK]WTIGXVYQ YQ 0> 0>IMXPMRIXEP4VSG2EXP%GEH7GM97% IMXPMMRIXEP4V4VSG2EXP%%GEH7GM997% par t of an antibody cocktail that mimics the +7EPE^EVIXEP24.:EGGMRIW W %7GLmJIVIXEPFMS6\MZ %7GLmmJIVIXEPFMS6\MZ nuanced in vivo response to virus infection – 0(I*VERGIWGS2EX&MSXIGLRSP RSP 7' 7'LEOVEFSVX]IXEPQIH6\MZ LEOOVEFV SVX]IXEPQIH6\MZZ anda a number of mAb-therapies for treatingreating (.(M0MPPSIXEP.'PMR-RZIWX (.(M0MPPSIXEP.'PMR-RZIWX %1'LI %1'LIRS[IXLIXEP-QQYRSP'IPP&MSP RS[S[IXL IX EP-QQYRSP'IPP &MSPSP
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46-49 Diabetes: Finding a Panacea As the number of diabetic patients grows, pharmaceutical stakeholders are working to curb the problem. But what approaches will have the greatest impact? 46 NextGen
Diabetes: Finding a Panacea
What is pharma doing to reduce the global incidence of diabetes?
By Maryam Mahdi
In 2013, world leaders came together to develop an action plan to address the global rise in noncommunicable diseases (1). Among the goals was to prevent further increases in the number of cases of diabetes mellitus (types 1 and 2). But adequately addressing the current epidemiological situation is a challenge; over 400 million people worldwide live with diabetes (5-10 percent of individuals live with type 1) and estimates suggest that the number will continue to rise (2,3). The high disease burden has placed significant stress on countries’ economic and healthcare infrastructure. According to Kiran Mazumdar-Shaw, Founder and Executive Chairperson of Biocon, ensuring proper disease management is crucial to curbing this global healthcare problem. “Diabetes is “Insulin has been used as a life-saving often described as a disease of halves – treatment for close to 100 years,” says “Addressing the only half of the people living with it get Stephan Kissler, Associate Professor of diagnosed; only half this group receive Medicine at Harvard Medical School. current treatment; and, among this group, only “Though the types of insulin preparations half are compliant with their medication,” available have continuously improved, as epidemiological she says. “Although early insulinization have methods of administering them – is regarded as an efficient aid to improve with smaller needles, insulin pens, and situation is a long-term control and the quality of automated pumps available today – we patient lives, this method of treatment still don’t have a treatment to prevent or challenge; over 400 fails to address certain problems.” Needle cure diabetes.” anxiety and issues related to cold chain This leaves the door for innovation million people supply, particularly in rural areas of wide open. But before new options developing countries, may delay the can be developed, Mazumdar-Shaw worldwide live onset of treatment, she adds – problems believes that the pharmaceutical exacerbated by the stunted growth of the industry can do more to improve access with diabetes.” treatment pipeline. to existing treatments. The price of cost. It is an untenable situation because, debt or cutting back on medication,” good health despite being universally available for she continues. So, with these difficult nearly a century, insulin is yet to be decisions to make, what can the industry In recent years, debates about the price universally accessible.” do to better support patients? of insulin have swirled around industry Insulin-dependent diabetes patients For Biocon, the answer lies in creating spheres. Though a necessary treatment have to contend with a large price solutions for emerging and developing for all type 1 and some type 2 diabetic differential between recombinant human markets. “Using our proprietary patients, the cost of the drug has (rh-) insulin formulations that tend to platform technology that relies on continued to rise. In the US, for example, be more affordable and pricier insulin Pichia pastoris – a yeast species – we can a single vial of insulin can cost US$250, analog formulations. Insulin analogs manufacture cost-effective rh-insulin preventing the most vulnerable from are genetically engineered to produce and insulin analogs,” says Mazumdar- accessing it (8). “The lack of equitable either long-acting or rapid-acting forms Shaw. This proprietary technology offers access to affordable insulin remains a key of the drug. They differ from rh-insulin an efficient and optimized process for impediment to successful treatment and in that more changes are made to their manufacturing insulin. results in comorbid complications and amino acids to allow for their faster or And though companies are proving premature deaths,” Mazumdar-Shaw prolonged action in the body. that they are committed to positively says. “Not only are people with diabetes “The increasing use of insulin analogs impacting patient lives, there is still in low- and middle-income countries compared with rh-insulin in the recent more that can be done to ensure struggling to manage their condition, past – especially in the developed therapies are affordable and accessible. but even those in developed markets are world – has meant that many are Time will be the determining factor in forced to ration insulin due to its high forced to choose between going into seeing real change.
The immunotherapy approach of cancer care and I am really excited other recent results, has been a source According to Kissler, researchers have to see it starting to come to the fore of inspiration for Walker, whose work spent decades trying to understand in autoimmunity,” she says. “There on abatacept – an immunosuppressive type 1 diabetes and devise effective are, understandably, more barriers to drug – could help treat the condition. therapies. “In recent years, the field testing new therapies in people with In 2014, she found that T follicular has recognized that, instead of solely type 1 diabetes, who are often young helper cells were partly responsible targeting the immune system that and otherwise healthy, than in people for the destruction of the pancreatic causes the destruction of insulin- with advanced cancer. However, recent beta cells that produce insulin. Now, producing cells, an alternative approach studies show that T cell-directed in a project funded by Diabetes UK might be to protect these cells from immunotherapy could delay the and AstraZeneca, Walker is exploring the immune system instead. This is a development of the condition by two the role of abatacept in reducing T relatively new strategy that holds much years.” Last year, the EMA awarded follicular helper cell numbers and promise,” he says. Priority Medicines designation to thereby protecting insulin-producing For Lucy Walker, Professor of teplizumab – a drug that binds to the cells. So far, the drug – currently used Immune Regulation at University proinflammatory T cell co-receptor to treat rheumatoid arthritis – has been College London, immunotherapy may CD3, preventing it from killing shown to help some people with type 1 hold the key to tackling type 1 diabetes. insulin-producing cells. It also received diabetes, but not others, but the study Leading a team of researchers, she a breakthrough designation from the must be expanded for its full potential has begun to investigate how existing FDA. The drug was shown to slow to be realized. immunosuppressive therapies can be the onset of type 1 diabetes in at-risk Walker’s work is just one example of applied to the disease. “Immunotherapy patients by two to three years (4). The the innovative research taking place to has completely changed the landscape potential of this therapy, coupled with help people living with diabetes; many
www.themedicinemaker.com 48 NextGen
It’s Complicated
Addressing the cardiovascular risks associated with type 2 diabetes
Though many diabetes patients comply with treatment, others struggle – and, left unchecked, the disease can lead to several comorbid conditions. Stephen Gough, Chief Medical Officer at Novo Nordisk, discusses the impact of one such complication – cardiovascular disease – on type 2 diabetic patients and how the pharma industry is trying to help. the artery walls). The study also showed What steps need to be taken for the How has the treatment of diabetes evolved? that only 20 percent of people with type future of diabetes management? The pharmaceutical industry has come a 2 diabetes and atherosclerotic CVD are Recent clinical guidelines from long way in its ability to address diabetes. At receiving a glucose-lowering treatment with professional bodies, such as the Novo Nordisk, for example, we developed proven cardiovascular benefits. American College of Cardiologists and our first insulin products in 1923 and These data show that people with type the American Diabetes Association continue to produce treatments for both type 2 diabetes need to be more aware of their emphasize the importance of an 1 and type 2 diabetes today. Metformin, risk factors, and that physicians need to integrated, multidisciplinary approach DPP-4, SGLT-2 inhibitors, and recent not only actively screen for them, but also to treating diabetes – in particular, innovations like GLP-1 RAs are especially prescribe blood glucose-lowering therapies bringing together endocrinologists effective in blood glucose-lowering in with proven cardiovascular benefit if patient and cardiologists – to reduce the comparison to previous treatments, but outcomes are to be improved. cardiovascular risks and other potential there are still issues for pharma to address. complications of this disease. For example, we need to innovate on the What are you doing to help? For us, partnerships with policymakers drug delivery front. Injectable therapies, We developed an oral form of semaglutide and with organizations in the public- though useful, aren’t suitable for everyone. – a GLP-1 RA – that works by boosting private space is integral. Two examples of Exploring new options will help us better insulin levels and stabilizing blood sugars. initiatives we’re involved in are Changing support patients. Previously, the GLP-1 Ras were only Diabetes and Cities Changing Diabetes. available as injectables and, despite the Through the former, we work alongside What challenges do patients face? efficacy in reducing hyperglycemia, body patients, lawmakers, and healthcare Diabetes is associated with many other weight, and cardiovascular risk, only 5-10 professionals to address diabetes risk conditions – including cardiovascular percent of people with type 2 diabetes are factors in urban areas, ensuring that disease, the leading cause of death and treated with a GLP-1 RAs. people with diabetes are diagnosed earlier disability in type 2 diabetes patients. We Our oral formulation was approved by and that they have access to adequate care. recently conducted a study, CAPTURE, the FDA in 2019, but our GLP-1 RA Through the latter, we collaborate and to address a gap in the knowledge of the portfolio isn’t limited to this one option. form cross-sector links with businesses global prevalence of cardiovascular disease, Injectables are still a vital part of the and organizations to build cities that help as well as its risk and management in people diabetes management landscape, so we us all live healthier lives. with type 2 diabetes (1). Nearly 10,000 also manufacture a once-weekly injection participants took part in the global study. of semaglutide, which also helps combat Reference We found that one in three people with type the symptoms of type 2 diabetes. We’re also 1. Novo Nordisk, “World’s largest study of 2 diabetes have established cardiovascular working on a once-weekly insulin injection, cardiovascular disease in type 2 diabetes shows disease (CVD), and 90 percent of those icodec. It’s important to expand the variety need for improved knowledge and disease had atherosclerotic CVD (a build-up of of available treatments to suit the broad and management” (2020). Available at: https://bit. fat, cholesterol, and other substances in varied needs of people with diabetes. ly/34FgEO1. others are working on new treatments. “We went on to search for a small interventions are currently used across Researchers at Texas A&M University’s molecule that could inhibit renalase a variety of disease indications to help College of Medicine, for example, have function to mimic the protection we patients manage the conditions they live reported on an immunotherapy that observed in cells whose RNLS gene with. She says, “Digital therapeutics will was shown to reduce inflammation and we had inactivated with a mutation,” emerge as part of the new standard of halt immune attacks on beta cells (5). Kissler says. “This search yielded the care for diabetes. By pairing insulin with The Type 1 Diabetes UK drug pargyline, which was developed as a digital solution we hope to improve Immunotherapy Consortium is also a treatment for hypertension. Although treatment outcomes thus lowering the conducting several trials to investigate it is no longer being made, the patent chances of patients developing co- the potential of immunotherapies. has long since expired, which should morbidities, which will reduce costs to This includes the USTEKID Phase II make it inexpensive to produce.” The healthcare systems in the long term.” trial, which is investigating whether team now plan to test the drug in newly The biggest question of all, however, ustekinumab – a drug first produced diagnosed diabetic patients but, because is: will a cure for diabetes be found in by Janssen to treat psoriasis – will this drug and others like it are not our lifetimes? Kissler is optimistic. “It’s be effective in preventing pancreatic specifically designed to treat diabetes, definitely possible. We all look forward damage (6). questions arise as to the challenges to working on this with optimism, Other research teams are approaching associated with their use. knowing that there may be failures and the problem by using currently “Because the drug was originally challenges ahead, but hoping that we available small molecules to their designed for a different purpose – in can help cure all forms of diabetes as advantage. “Repurposing an old drug this case, the treatment of hypertension well as their complications.” that is off-patent has the benefit of – one has to make sure that the original potentially making a very cheap drug effect of the drug does not pose a safety References available to patients,” Kissler says. issue for the new application of the 1. WHO, “Global Action Plan for the “Because a repurposed drug does not drug,” Kissler says. Prevention and Control of NCDs 2013- have to undergo lengthy preclinical 2020” (2013). Available at https://bit. development and the many stages of In the years to come ly/2IZ6Eqm. toxicity and safety testing, its cost can Whether companies and researchers are 2. Diabetes UK, “Facts and Figures” (2020). remain low.” pursuing new drugs or repurposing old Available at https://bit.ly/34vKdBm. Though scientists have developed ones, funding is still vital. Walker says that 3. WR Rowley, “Diabetes 2030: Insights from methods of creating insulin-producing sustained funding – particularly for those Yesterday, Today, and Future Trends,” Popul cells by resetting the pluripotency of in academic environments – is crucial to Health Manag, 20, 6 (2017). blood and skin cells – allowing them making headway in diabetes research. 4. JDRF, “New Findings from Groundbreaking to be converted into pancreatic beta “High-quality research takes time Study Shows Extended Delay in Onset of cells – the risk of their destruction by and, therefore, requires consistent Type 1 Diabetes” (2020). Available at the immune system still remains. With funding to help move it forward,” she https://bit.ly/34tWjv1. this in mind, Kissler and his colleague says. “I have been lucky to have received 5. M Haque et al., “Stem cell–derived Peng Yi at the Joslin Diabetes Center long-term support, enabling me to tissue-associated regulatory T cells suppress are investigating how a drug first build a sustainable program of work. the activity of pathogenic cells in autoimmune developed in the 1950s could prevent Ultimately, there is a human capital that diabetes,” JCI Insight, 4,7 (2019). the autoimmune killing of beta cells. goes into making research findings and 6. T1D Immunotherapy Consortium, Using a genetic screening approach, it would be hugely satisfying to take “USTEKID Study” (2020). Available at the researchers discovered an enzyme, this project to the point where people https://bit.ly/3kBZBSB. renalase, that had previously been can benefit.” 7. EP Cai et al., “Genome-scale in vivo associated with the risk of type 1 Although new therapeutic solutions CRISPR screen identifies RNLS as a target diabetes, but whose function in will help inform the future landscape of for beta cell protection in type 1 diabetes,” Nat disease was unknown. They found diabetes management, Mazumdar-Shaw Metab, 2, 934 (2020). that the enzyme modifies beta cells’ believes that digital therapeutics will 8. Singlecare, “Insulin prices: How much does ability to withstand cellular stress and also help “achieve optimal outcomes for insulin cost?” (2020). Available at https://bit. autoimmune killing (7). diabetic patients.” These software-driven ly/3kHYCjy.
www.themedicinemaker.com Getting the Job (Done)
Sitting Down With… Will Downie, CEO of Vectura Group, UK Sitting Down With 51
Why business and not science? worked with great companies during my we set up a coronavirus management team After graduating with a degree in career – and many opportunities have come that helped us get organized. We kept biochemistry, I wasn’t sure if a life in the my way. Like the opportunity with Vectura. very close to our teams across all sites and lab was for me. There were far better people From the outside I saw a company with adopted a family-orientated approach to around who were much more talented deep scientific expertise and a rich heritage working through every challenge. in terms of scientific prowess. I saw a job in inhalation drug development that could advert for a medical sales rep and thought, unlock significant potential if it redirected What projects are you excited about? why not try that? I was living in Edinburgh its efforts into the CDMO industry. The Previously, the company was developing at the time. I travelled to London and at CDMO market today is a very attractive its own pipeline and working with quite a the end of the interview, they asked if I had space to be in, especially if you are a narrow corridor of clients in the respiratory any questions. I naively and brazenly said, company with great technology, world- area. Now that we’ve pivoted to becoming “Only one question to be honest. Have I got class innovation and excellent scientists. a CDMO, we’ve opened the aperture of the job?” After all, I didn’t like the idea of That’s exactly what Vectura is. I’ve been the business and diversified our customers traveling home 400 miles without knowing here eleven months now and I love it. base – we’re developing products for a whole the answer! They sent me back into the range of indications, including asthma, reception area while they had a discussion, How did you find the transition to the COPD, cystic fibrosis, pulmonary arterial and ten minutes later they called me back in CEO role? hypertension, lung fibrosis, and COVID-19. and offered me a job! I had the option to have Previously, I was part of Catalent’s executive One project that I am particularly excited territory in either the Highlands of Scotland team. I joined in 2009 and the company about is our work with Monash University or Essex. In my mind, the Highlands were went through a huge transformation while in Melbourne, Australia. We are working cold and rainy, and I didn’t know anything I was there – and has been very successful. on Oxytocin, which is a standard of care about Essex, so I said Essex. I moved from Catalent is now a very mature company for women during pregnancy to avoid Scotland to London – and I loved it. and considered one of the top three players postpartum haemorrhage. In the developed in the space. My role at Catalent was very world, women receive the standard of care What lessons did you learn early in commercially-focussed, whereas now I am via injection, but in the developing world your career? working for a much smaller company in a it is challenging because the formulation There is an unwritten rule when you are more generalist role. When you make the requires cold chain supply and refrigeration, a medical sales rep: you visit doctors in transition to CEO, especially in a public which is clearly a major challenge in hot the morning and you won’t be able to see company, you need to work with a much climates. The number of women who die them at any other time. But nobody ever broader set of stakeholders, from investors, of postpartum haemorrhage is shocking in told me that so I would go see them in the to shareholders, a board of directors and, developing countries. We are working on afternoons and evenings – and it turned of course, all employees in all functions. the development of a dry powder inhaler out that I saw more doctors than any of I must say, I am enjoying the diversity of version of oxytocin that will not require my competitor reps! I really enjoyed the the role and working with our great team. refrigeration, and may potentially have faster job and I think it worked out because I onset of action. It could have a profound didn’t have preconceptions and I didn’t set And what about the challenges of being impact on women in developing countries. myself boundaries. I think that mindset is a new CEO when the pandemic started? very important in any job. Don’t be limited It felt like the switch for the pandemic What is your top advice for other scientists by artificial boundaries. And if you work was flipped overnight! We’d all heard who want to move into commercial roles? hard, good things will happen. about the emerging virus but the situation It’s your career, so you have to take escalated rapidly. There was no playbook ownership and find a way to make things From medical sales rep to company to refer to and we huddled together as a happen. Look for new opportunities to try CEO… Was it planned? leadership team to establish our priorities out – ways to expand your experience, such My career has never been planned! But for the business, with our most important as a secondment position, or a new project, my rules along the way have always been focus being the safety and well-being of or an entirely new role. And don’t be afraid the same: work hard, try your best, be our employees. We quickly put in place the about the transition from science to the honest, treat people well, learn as much measures and operating rhythm we needed commercial world. If you have the right as you can, and don’t be afraid of making to keep the company safe, maintain our attitude, work hard, and treat people the mistakes and taking risks. quality standards and look after the needs way you expect to be treated, then good I’ve been very fortunate in that I’ve of our customers. From the very beginning, things tend to happen.
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