̽��ֱ�� of Cambridge - GlaxoSmithKline (GSK)

Scientists launch a pre-emptive strike on deadly post-transplant infection

ta385 — Tue, 23 Feb 2021 12:45:00 +0000

Around 80% of the UK population is currently infected with human cytomegalovirus (HCMV) and in developing countries this can be as high as 95%. ̽��ֱ��virus can remain dormant in our white blood cells for decades and, if it reactivates in a healthy individual, does not usually cause symptoms. But, for people who are immunocompromised, HCMV reactivation can be devastating.

HCMV reactivation has been identified in COVID-19 patients, though scientists do not yet understand the relationship between the two viruses. Reactivation or re-infection in transplant recipients can lead to severe illness, including organ rejection and, in some cases, death.

More than 200,000 kidney, lung and stem cell transplants take place globally every year and HCMV reactivation occurs in more than half of these cases. For reasons scientists don’t yet fully understand, immunosuppressants appear to encourage the virus to reactivate as well as compromising the patient’s ability to fight it. There remains no effective vaccine against HCMV and anti-viral therapies often prove ineffective or detrimental.

Now, a team from the ̽��ֱ�� of Cambridge’s School of Clinical Medicine has identified a drug type and treatment strategy that could dramatically reduce these devastating reactivation events. ̽��ֱ��study, published in the journal PNAS, describes how scientists exposed HCMV-infected blood samples to a wide-range of ‘epigenetic inhibitors’ – drugs widely used in cancer treatment – hoping to prompt the latent virus to produce proteins or targetable antigen that are visible to our immune system.

They discovered that a particular group of these drugs, ‘bromodomain inhibitors’, successfully reactivated the virus by forcing it to convert its hidden genetic instructions into protein. This then enabled T-cells in the blood samples to target and kill these previously undetectable infected cells.

̽��ֱ��study is the first to identify the involvement of human host bromodomain (BRD) proteins in the regulation of HCMV latency and reactivation but also proposes a novel ‘shock and kill’ treatment strategy to protect transplant patients.

Lead author Dr Ian Groves said: “We’re looking to purge the patient’s viral reservoir before they go into the operating theatre and before they start taking immunosuppressants, when they would become extremely vulnerable to the virus reactivating. In other words, we’re proposing a pre-emptive strike.

“Prior to transplantation, many patients will have a relatively healthy immune system, so when the virus puts its head above the parapet, its cover is blown, and the immune system will see it and kill the cells it’s been hiding in. Ideally, donors would also be treated to avoid re-infecting recipients.”

There are similar drugs in Phase 1–3 clinical trials around the world for other intended uses, mainly in the treatment of cancers but also Type 2 diabetes-related cardiovascular disease.

Dr Groves said: “This would be the first type of treatment to reduce HCMV infection levels pre-transplant in order to lower the chances of virus reactivation during immune suppression after transplantation. Our findings could lead to thousands of lives being saved every year.”

“In addition to the terrible human suffering this virus causes, treating its effects adds enormously to the high costs already incurred by transplantation. It’s a really serious issue for health services in wealthy nations and a desperate one in developing countries. Our findings offer an opportunity to transform this horrible situation.”

̽��ֱ��study builds on over 25 years of extensive research into the molecular biology of HCMV and its immune evasion tactics (funded by the Medical Research Council). ̽��ֱ��researchers hope their study could eventually help doctors fight HCMV on other fronts, including in maternity and neo-natal care. HCMV affects at least 1% of all live births in developed countries, and many more in developing countries. These children can be left with brain damage and hearing loss, but congenital infection during pregnancy can also lead to miscarriage.

Reference

I. J. Groves et al., ‘Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention’. PNAS (2021). DOI: 10.1073/pnas.2023025118

A potential new treatment to protect immunosuppressed patients from human cytomegalovirus (HCMV) has been discovered by scientists at the ̽��ֱ�� of Cambridge. Their study shows that certain epigenetic inhibitors expose and help to destroy dormant HCMV infections, which often reactivate to cause serious illness and death in these vulnerable groups. Subject to clinical trials, their proposed ‘shock and kill’ treatment strategy offers hope to transplant patients across the world.

Our findings could lead to thousands of lives being saved every year

Ian Groves

Sasin Tipchai via Pixabay

Surgeons at work in an operating theatre

Funding

This research was supported by GlaxoSmithKline and the Medical Research Council.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Cambridge COVID-19 Testing Centre passes 2 million tests milestone

cjb250 — Thu, 24 Dec 2020 11:31:04 +0000

̽��ֱ��facility was set up in a collaboration between the ̽��ֱ�� of Cambridge and two major pharmaceutical partners, AstraZeneca and GSK. Soon after its launch, the facility was brought into the Government’s national diagnostic lab network, the largest in British history.

̽��ֱ�� ̽��ֱ�� has been able to share its world-leading research expertise with the innovation and robotics know-how from its two pharmaceutical partners to create a new, high-throughput centre. ̽��ֱ��facility is based at the Anne McLaren Building on the Cambridge Biomedical Campus.

Hundreds of volunteers were recruited and trained from across the three organisations to get the Centre up and running, including researchers from the ̽��ֱ��. Each volunteer stepped forward at a time of national crisis with their own reasons for wanting to contribute to the COVID-19 testing programme.

Innovative robotics and automation were installed and an entire supply chain was sourced and implemented to ensure the testing facility was both resilient and highly effective. All of this was done in just five weeks, an operation which would usually take six months.

Since it began operating, the facility has processed more than 2 million tests.

“This is a tremendous achievement and testament to the hard work of the team involved in setting up and running this facility,” said Professor Andy Neely, Pro-Vice-Chancellor for Enterprise and Business Relations at the ̽��ֱ�� of Cambridge. “I would like to thank everyone who has played a part in making the Centre a huge success and enabling it to play an important role in helping keep Cambridgeshire and the UK safe.”

̽��ֱ��Cambridge COVID-19 Testing Centre, set up in April in response to the urgent need to boost the UK’s testing capabilities, has processed two million tests.

This is a tremendous achievement and testament to the hard work of the team involved in setting up and running this facility

Andy Neely

Volunteer in the testing centre

Yes

Unexpected experiences: Meet the volunteers behind the masks at the Cambridge Testing Centre

zs332 — Mon, 05 Oct 2020 08:00:36 +0000

They juggled their jobs and sacrificed sleep to volunteer at the Cambridge Testing Centre, a collaboration between the ̽��ֱ��, AstraZeneca and GSK to support the national effort to boost COVID-19 testing. They say they were simply fulfilling their duty as scientists. Meet the volunteers behind the masks.

Cambridge Heart and Lung Research Institute receives major funding boost

cjb250 — Wed, 10 Jul 2019 15:10:21 +0000

̽��ֱ��Institute will draw together the highest concentration of heart and lung researchers from academia, healthcare and industry in Europe. It has set an ambitious five-year target to demonstrate proof-of-concept for at least ten new drugs or diagnostic approaches in heart and lung diseases.

̽��ֱ��HLRI will be situated next to Royal Papworth Hospital, which was officially opened by HM the Queen on 9 July, and forms part of the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States of America. It will be home to over 380 scientists and state-of-the-art laboratories in genomics, population sciences, research into cellular mechanisms of disease and translational science. It will also include a special ten bed facility where the first-in-patient studies of new treatments can be conducted.

“This is an incredibly exciting project bringing together world-renowned expertise in cardiovascular and respiratory science at Cambridge ̽��ֱ�� and clinical excellence at Royal Papworth Hospital,” says Professor Nick Morrell from the ̽��ֱ�� of Cambridge, Interim Director of the institute and a non-Executive Director of Royal Papworth Hospital.

“Heart and lung diseases affect many millions of people of people worldwide and the numbers are growing. Institutes such as ours, focussed on these big health challenges, are urgently needed. ̽��ֱ��discoveries made by our researchers will deliver major benefits to the public through improvements in public health, new approaches to diagnosing and treating disease, and new medicines.”

Professor John Wallwork, Chairman of Royal Papworth Hospital, said: “ ̽��ֱ��Heart and Lung Research Institute will mean new treatments will be created, tested and delivered to tackle the biggest causes of premature death in the world all on one site. This will be a huge step forward and demonstrates one of the reasons Royal Papworth Hospital moved to the Cambridge Biomedical Campus – to collaborate with the best researchers in the world to help to save lives. ̽��ֱ��importance of this building cannot be underestimated and I can’t wait to see how it will transform healthcare in the years to come.”

Image: Cambridge Heart and Lung Research Institute (artist's impression)

̽��ֱ��award is one of 11 announced from flagship capital investment scheme the UK Research Partnership Investment Fund, totalling over £670m of new investment into UK research and innovation. It complements £10 million of funding committed to the institute by the British Heart Foundation (BHF). Further funding will be provided by the ̽��ֱ�� and Royal Papworth Hospital, and the Wolfson Foundation.

̽��ֱ��BHF award, which contributes to the capital cost of the building, is one of the charity’s largest ever strategic award. ̽��ֱ��charity has also committed an additional £6m in funding for the BHF Cambridge Centre for Cardiovascular Research Excellence, which will be housed in the institute.

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, said: “Through this funding we will help create a fantastic centre that will have a key role in driving forward our ambitious programme of heart and circulatory research. By bringing together world-leading scientists it will enable exciting opportunities for collaboration between researchers from different disciplines. And it will also accelerate the transformation of discoveries in the laboratory to treatments available at patients’ bedside.

“This grant is one of the largest the BHF has ever made and we have only been able to make this investment because of the incredible generosity of the public.”

̽��ֱ��Cystic Fibrosis Trust has also committed to raise up to £5 million to fund the Cystic Fibrosis Innovation Hub, which launched last year and will transfer to the new building once it has been completed. Both AstraZeneca and GlaxoSmithKline will also embed integrated research hubs in the Institute to maximise translational impact.

Work on the HLRI will begin almost immediately, with ground-breaking taking place in November 2019 and construction starting in early 2020.

Without further medical advances, an estimated one in four people in the UK will die from heart or circulatory disease, while one in five will die from lung disease. Combined, cardiovascular and respiratory diseases cost over £840 billion worldwide every year.

Chris Skidmore, Minister for Universities, Science, Research and Innovation, announced on 10 July 2019 a £30 million award to the ̽��ֱ�� of Cambridge to support the new Cambridge Heart and Lung Research Institute (HLRI).

This is an incredibly exciting project bringing together world-renowned expertise in cardiovascular and respiratory science at Cambridge ̽��ֱ�� and clinical excellence at the Royal Papworth Hospital

Nick Morrell

Cambridge Heart and Lung Research Institute (artist's impression)

Yes

Milner Therapeutics Institute: a drug discovery ecosystem

lw355 — Wed, 28 Jun 2017 14:30:05 +0000

Professor Tony Kouzarides is the founding Director of the Milner Therapeutics Institute, which is due to open in 2018 on the Cambridge Biomedical Campus. ̽��ֱ��ecosystem he sees thriving within its walls is one in which academic researchers (“experts in the biology of diseases”) work closely with pharmaceutical companies (“who know what’s needed to get the drug to clinic”) to find new medicines. Put simply, he says, the Institute will be “a pipeline for drug discovery within an academic setting.”

While the labs are being fitted out with robotics for customised drug screening, gene-editing facilities to rewrite DNA and bioinformatics support to help scientists deal with huge datasets, the partnerships between industry and academia are already under way.

In June 2015, a research agreement was signed between the ̽��ֱ�� of Cambridge, the Wellcome Trust Sanger Institute and the Babraham Institute with three pharmaceutical companies – AstraZeneca (AZ), Astex and GSK. Since then, Pfizer, Shionogi and Elysium Pharmaceuticals have joined the Milner Therapeutics Consortium, the outreach programme of the Institute.

With this one agreement, doors opened. Dr Kathryn Chapman, Executive Manager of the Milner Therapeutics Institute, explains: “Forming the Consortium means there’s now a free exchange of potential drug molecules between pharma and academia. This sounds straightforward but, before the agreement, this could take a year because of confidentiality and material transfer contracts. Now it takes two to three weeks. It lowers barriers of engagement, it speeds up research and it can involve hundreds of molecules in one go.”

One consequence is drugs that have already been approved for use in certain diseases are now being tested for use in other diseases – a practice called repositioning or repurposing.

“An academic might have developed a brain disease model using an organoid – a mini organ in a Petri dish,” explains Kouzarides. “We can use this to test drugs that have been licensed for use in other diseases such as arthritis or cancer.”

It also means that novel therapeutic agents across the entire portfolio of drugs being developed by each of the companies can be screened at an early stage in biological assays, to see whether any are worth progressing along the drug development pipeline.

For example, one of the Consortium’s first collaborative projects is a partnership between AZ and Professor Carlos Caldas at the Cancer Research UK Cambridge Institute.

Breast cancer consists of several different genomic subtypes, which makes effective treatment challenging and prognosis variable. Some subtypes respond well to particular drugs or drug combinations whereas others are resistant. Caldas has pioneered the development of a biobank of patient-derived breast cancer cells and tissues that have greater predictive power for clinical outcome than other preclinical models (such as cancer cell lines).Carlos and AZ are now working together to test how different subtypes of breast cancer respond to different AZ compounds and compound combinations, as well as looking at potential drug-resistance mechanisms.

From 2018, the Consortium will form a major part of the Milner Therapeutics Institute, which has been made possible through a £5m donation from Dr Jonathan Milner, a former member of Kouzarides’ research group and entrepreneur. Milner and Kouzarides are two of the founders of leading Cambridge biotechnology company Abcam.

“One of the main aims of the Institute will be to develop multiple disease models to understand how drugs could work on the real disease,” explains Kouzarides. “We plan to focus on some of the most challenging diseases to start with – cancer, neurodegeneration and inflammation – but we are disease agnostic. If we have a method of testing for efficacy and a library of molecules to test, then we’ll test!”

Kouzarides’ enthusiasm for making sure the ‘Petri-dish-to-pill’ pipeline works comes from his own positive experience of a collaboration with GSK that has resulted in a leukaemia drug now being used in the clinic to treat patients.

It came about through serendipity. “GSK was developing a molecule called I-BET against an epigenetic protein. I was a consultant on the project and became aware that the molecule could be effective against mixed lineage leukaemia (MLL), the most common type of leukaemia in children under two years old. We had the cell assays and disease models in Cambridge, and we asked to test the drug. It worked and it’s now in the clinic.

“I started to wonder why this pharma–academia collaboration doesn’t happen more often. People have been talking about the translational gap between fundamental research and the clinic for years, and it’s still there. While serendipity is good – and many amazing medical innovations have come out of chance encounters – we can’t trust only to chance.

“ ̽��ֱ��world needs new medicines to be developed. It’s time-consuming and costly, and that’s why we need an ecosystem that will nurture and speed up the success.”

̽��ֱ��Milner Institute will be within the Capella building at the Cambridge Biomedical Campus, alongside the relocated Wellcome Trust/MRC Cambridge Stem Cell Institute, the Cambridge Institute of Therapeutic Immunology and Infectious Disease, and ̽��ֱ��Cambridge Centre for Haematopoiesis and Haematological Malignancies.

Tony Kouzarides is passionate about ecosystems: well-balanced communities that flourish on mutual and dynamic interactions. But the ecosystems that excite him are not made up of plants, animals and environments. They’re made up of experts.

̽��ֱ��world needs new medicines to be developed. It’s time-consuming and costly, and that’s why we need an ecosystem that will nurture and speed up the success.

Tony Kouzarides

David Anderson

Neurons

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Drugs: how to pick a winner in clinical trials

lw355 — Mon, 26 Jun 2017 11:00:12 +0000

“Did not meet primary endpoint.”

Prosaic words, but they can mean a billion dollar failure has just happened.

̽��ֱ��average cost of taking a scientific discovery all the way through to a drug on a shelf is enormous – last year it was estimated at $2.6 billion by the Tufts Center for the Study of Drug Development.

One reason the figure is so high is because it also includes the cost of failure. Recent years have seen some very high-profile failures of drug candidates that either did not meet the ‘primary endpoint’ (they didn’t work) or had their trials halted owing to serious side effects.

“It’s only natural that some drugs will fail in clinical trials – the process exists to ensure that treatments are safe and effective for patients,” says Professor Ian Wilkinson, Director of the Cambridge Clinical Trials Unit (CCTU) on the Cambridge Biomedical Campus. “But what’s unexpected is the high number of drugs that fail in phase III. You’d think that by this stage the molecule would be a sufficiently good candidate to make it through.”

He explains that failures in phases I and II – when the drug is tested for safety and dosage in healthy volunteers and patients – are inevitable. However, a great many molecules don’t make it through phase III, the stage at which the drug’s effectiveness is tested in large numbers of patients before regulatory approval is given. In fact only 10–20% of drugs that enter phase I are ultimately licensed.

“ ̽��ֱ��problem with failing at phase III is it’s very expensive – a single drug trial can cost around $500m.”

He continues: “There’s a human impact for the thousands of patients who enrolled on the trial. For patients with cancer, it’s sometimes their last available treatment option,” says Wilkinson. “It’s also really unhelpful economically. Pharma companies have less money to put back into R&D, and it becomes even harder to fund drug development.”

This is why Wilkinson, along with a team of clinicians, scientists and pharmaceutical collaborators, together with statisticians at the Medical Research Council Biostatistics Unit, has been taking a hard look at the early phases of clinical trials. Their aim is to ask what can be done to get an early indication that a potential drug will make it to market.

“Traditionally, clinical trials have been organised to test safety first and efficacy last,” he explains. “It’s a cautious step-by-step approach adopted to ensure that pharma companies can satisfy regulators that the drug is safe.

“For many drugs this has worked well. But we are in a landscape where drug targets are more challenging – think for instance of conditions like psychiatric disorders and dementia. Leaving questions of whether a drug is effective to the final stages is now too risky and expensive.”

On any one day, the CCTU (one of the UK units accredited by the National Institute for Health Research) might be coordinating up to 20 trials in various phases for potential treatments for cancer, stroke, infections, dementia, heart attack, and so on.

Many of the trials are now designed with what Wilkinson calls “added value” built in at very early stages to give indications of whether the drug might work. This could include a biomarker that shows a drug for cirrhosis is reaching the liver, or a drug for heart disease is lowering cholesterol. “These are read-outs. They don’t show the drug works for the disease, but if the results are negative then there’s no point in progressing to later stages.”

̽��ֱ��trials are also run ‘adaptively’. “We look at data for each person as it comes in… once we have enough information to guide us, we make a decision that might change the trial. It’s a quite different approach to the traditional rigidity of trials. It maximises the value of information a trial can yield.”

In recent years, pharmaceutical companies like GSK and AstraZeneca (AZ) have championed the need for rigorous trial design to weed out likely failures earlier in the process.

GSK has its only trials unit in the UK in the same building as the CCTU. There, GSK researchers work alongside Cambridge clinicians and scientists on first-in-man studies. A more targeted approach to testing medicines in patients is a key component of a Strategic Partnership between GSK, the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), which has the long-term ambition of jointly delivering new medicines to patients in the next five to ten years.

A few years ago, AZ analysed its drug pipeline before embarking on a major revision of its R&D strategy to increase the chance of successful transition to phase III and beyond. One area AZ identified as being crucial to success is to identify a causal relationship between target and disease. This might seem obvious but so-called mistaken causation has led to late failures right across the drugs industry. ̽��ֱ��usual cause is confounding – where a factor that does not itself cause a disease is associated with factors that do increase disease risk.

Professor John Danesh and colleagues at the Department of Public Health and Primary Care have pioneered a new way of finding evidence for causality before a patient is ever involved. Called ‘Mendelian randomisation’, it’s akin to a trial carried out by nature itself.

“Misinterpreting correlation as causation is a big problem,” explains Dr James Peters, who works with Danesh. “An increase in a protein biomarker in patients with atherosclerosis might suggest it’s important in the disease, but it’s not a valid drug target unless it plays a causal role. ̽��ֱ��conventional way to test this is to block the protein with a drug in a clinical trial, which is expensive, time-consuming and not always ethical.

“In phase III trials, the randomisation of participants helps to average out all differences apart from whether they are receiving the drug. Instead, we take advantage of the natural randomisation of genetic variants that occurs during reproduction.”

Some genetic variants can increase or decrease certain proteins that have been linked to a disease. If these variants can be identified – by computationally analysing enormous genetic datasets – then researchers can compare groups of people to see whether having the variant also increases the risk of a disease.

̽��ֱ��team has used this method to look retrospectively at why two phase III trials for a potential cardiovascular drug failed. “ ̽��ֱ��genetic evidence showed that the drug target was not valid,” says Peters. “We would have advised against taking this drug to a clinical trial.”

But it’s not just about predicting failures, Danesh’s team is picking winners. Evidence for the role of an inflammatory protein in atherosclerosis has now resulted in a clinical trial to see if an arthritis drug can be repurposed for atherosclerosis.

̽��ֱ��researchers are helping industrial collaborators to prioritise potential drug targets and predict side effects. They also hope to expand their capabilities to test large numbers of variants for different potential targets in an automated fashion – a high-throughput approach to therapeutic target prioritisation.

Meanwhile, Wilkinson is planning ahead to avoid a different type of limitation: expertise. “There is a lack of individuals trained to design and deliver innovative clinical trials, and this is now impacting on drug development,” he explains.

Last year, an Experimental Medicine Training Initiative was launched to train medics how to run innovative clinical trials. Wilkinson is its Director and it’s supported by the ̽��ֱ�� in partnership with CUH, Cambridge Biomedical Research Centre, and AZ/MedImmune and GSK.

“We all believe that the failure rate for drug candidates making it through phase III is unacceptably high,” he says. “Less than one in a thousand molecules discovered in the lab make it through to being a drug. We want to be sure that we can answer the billion dollar question of which are most likely to be winners.”

Read more about research on future therapeutics in Research Horizons magazine.

When a drug fails late on in clinical trials it’s a major setback for launching new medicines. It can cost millions, even billions, of research and development funds. Now, an ‘adaptive’ approach to clinical trials and a genetic tool for predicting success are increasing the odds of picking a winner.

We all believe that the failure rate for drug candidates making it through phase III is unacceptably high. We want to be sure that we can answer the billion dollar question of which are most likely to be winners.

Ian Wilkinson

Gatis Gribusts

Medication

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Apollo's mission to drive therapeutic innovation

lw355 — Tue, 20 Jun 2017 10:50:20 +0000

Over the past year, a four-strong team has had over a hundred meetings with scientists at three UK universities. By the end of this year, they will probably have had another hundred.

̽��ֱ��team is garnering the most comprehensive sense of what’s happening at the bench across three UK universities – Cambridge, Imperial College London and ̽��ֱ�� College London (UCL) – that anyone has ever amassed. Their job is to identify research that has the greatest potential of making it all the way through to becoming a new medicine, and then to help this happen. This is Apollo Therapeutics.

Dr Richard Butt, who heads up the team, explains the drive behind their meetings: “We live in an age of rapidly escalating biomedical innovation – an age where the development of new medicines should be at an all-time high. But the number of new drugs being developed is largely static.”

In drug discovery, the period between getting promising results in an academic lab and receiving real interest from an investor or pharmaceutical company has been called the ‘Valley of Death’ – and not without good reason. Discovering and developing potential new medicines requires not just money but also expertise and the rapid delivery of industrial-type science. Most drug candidates succumb along the way, long before it’s possible to know whether they might have fulfilled an unmet medical need.

In January 2016, the tech transfer offices (TTOs) of Cambridge, Imperial College and UCL joined forces with three global pharmaceutical companies – AstraZeneca (AZ), GSK and Johnson & Johnson – to create a £40m collaboration called Apollo Therapeutics. Their aim is to streamline the academia-to-industry pipeline by “finding the best translatable science, funding it fast and running the right development programme to make it attractive to industry,” says Butt.

In effect, Apollo aims to maximise the chance that a potential drug will be developed from emerging basic science by investing in a state-of-the-art drug discovery programme that a pharma company will find attractive to license.

“ ̽��ֱ��Apollo approach is wholly new and revolutionary,” says Dr Iain Thomas, Head of Life Sciences of Cambridge Enterprise (Cambridge’s TTO). “You could say that Apollo is building reassurance. ̽��ֱ��hardest part of our job at Cambridge Enterprise is selling really good technology to pharma. It relates to the psychology of buying – people don’t buy complicated stuff with lots of risk without a lot of analysis. Reassurance comes from being engaged with an opportunity for a long time.”

Engagement and partnership are at the heart of the Apollo model. First, Butt’s team speaks to the academics and TTOs of the universities to identify exciting prospects, before taking some of the ideas to the wider team of investors (each of the three companies and the TTOs). “As scientists, we will always be very happy to spend time engaging in discussions with any academic about their work. As drug discoverers, we’ve been very picky about what to take forward,” he says. “We filter very aggressively to maximise the chance of success.”

Once a project is selected for investment, Apollo and the academics work together to develop the discovery to a stage that will be attractive to a company to license and take further.

This work might take place in the academic’s laboratory, or in one of the pharma companies, or in a contract company. It might also take place at the Milner Therapeutics Institute – research laboratories that will open on the Cambridge Biomedical Campus in 2018 dedicated to fostering close collaborative interactions between academia and industry.

“ ̽��ֱ��key is bringing together the skill sets, philosophies and expertise of those who discover with those who know what to do with that discovery,” says Dr Ian Tomlinson, Chair of Apollo. “We are all motivated by the goal of finding new medicines for patients.”

Tomlinson adds: “ ̽��ֱ��conventional pipeline works like this: an academic does some great science, takes it as far as they are able to within the confines of the lab and then, if they want to take it further, either forms a spin-out or licenses to pharma. This still has its place, but it takes time and is costly. If Richard’s team brings the investment team an idea that looks good, Apollo can fund it and be working with the academic in a matter of weeks.”

Between them, Butt and his three colleagues have over 60 years of experience of the pharma industry. “We’ve been at the sharp end of drug discovery and failure,” he says. “We saw the boom of the late 80s/early 90s of drug approvals. And then genomics, high-throughput screening and a seeming wealth of targets led to the mindset of ‘we can scale this success’ – if we run three times more projects we’ll be three times more successful’. ̽��ֱ��basic biology almost ceased to matter. Projects were run that shouldn’t have been. R&D costs escalated but the output of new drugs flat-lined or even declined.

“Apollo is led by the science we see. ̽��ֱ��academic fully understands the biology and mechanisms of the disease target, and we understand the milestones that need to be overcome to become a medicine – drug discovery, formulation, toxicology, clinical trial design, regulators, business models.”

Already his team has identified eight projects across the three universities to receive Apollo funding. ̽��ֱ��first to be backed came out of a 20-year search by Dr Ravi Mahadeva at Cambridge’s Department of Medicine for a small molecule drug to treat Alpha-1 trypsin deficiency (AATD). AAT is a protein that normally protects the lungs. In AATD, a single genetic mutation causes it to aggregate in the liver and the resulting effects on the liver and lungs are disabling and ultimately fatal. There is currently no effective long-term treatment for the disease.

“Ravi came to us with an idea and some early compounds,” says Butt. “Quite simply, it wouldn’t have been picked up by a drug company based on the package that he had. We knew we could design a work package to generate more potent, more selective and more drug-like compounds, and create a package of data that pharma would find attractive.”

For Professor Randall Johnson, Apollo funds have meant that his research in Cambridge’s Department of Physiology, Development and Neuroscience has continued seamlessly through to a drug development programme without the stop-start of waiting for funding, licensing or forming a spin-out. “Randall was one of the first Cambridge academics I saw,” says Butt. “He was excited because he was about to publish a key publication on his genuinely novel work highly relevant to the emerging immune-oncology field. Before Randall’s Nature paper was published, we were already working on a project plan and made the commitment to collaborate on the project.

“Because we are embedded in the ̽��ֱ�� and work closely with Cambridge Enterprise, we have fully confidential access to talk to any academic at any of the three universities. When we worked in pharma, it could take months simply to sit around a table and talk about science and look at data with academics.”

Further down the line, potential therapeutics developed from any of the Apollo-funded programmes will first be offered for licensing to AZ, GSK and Johnson & Johnson, and then more widely; the capital gain of any licensing agreements will be divided between the three universities and the three pharma investors. And the interaction with the companies is not just transactional. Each of them is also committing time, resources and expertise to help the projects that are approved for collaboration.

“ ̽��ֱ��cost to license from us will be much lower than the sum cost to have done all that research internally,” says Tomlinson. “At a time when all the pharmas are cutting their costs and doing less R&D, this provides a different model that will be cost-effective to add potential drugs to their pipelines.

“There are very few totally new drugs every year. To get one of those, you’ve got to cast the net very wide and do everything you can to make the most of the opportunities.

“Apollo has the advantage of not being pigeonholed into working only on one disease or therapy area or limited by drug modality, as we would be if we were a pharma company. As a result, we don’t have to consider a ‘strategic fit’ – we’re simply following the best translatable science that should result in a higher success in getting new medicines to patients.”

Inset image: Read more about research on future therapeutics in Research Horizons magazine.

̽��ֱ��stirrings of a revolution are starting to ripple through hundreds of laboratories. It’s a revolution that aims to result in new medicines – faster and with fewer failures – and it’s being led by three UK universities and three global pharmaceutical companies.

̽��ֱ��key is bringing together the skill sets, philosophies and expertise of those who discover with those who know what to do with that discovery.

Ian Tomlinson, Apollo Therapeutics

Taema

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Take your medicine: how research into supply chains will help you take care of yourself

lw355 — Wed, 14 Jun 2017 15:20:27 +0000

“Like many people of my age, I have to take pills morning and night. I’m pretty good at taking them in the evenings, mainly because my wife makes me! But, left to my own devices in the mornings, I only remember to take them perhaps one day out of four,” says Dr Jag Srai.

“Wouldn’t it be fantastic if smartphones could remind patients, capture use and track activity, blood pressure, sugar level, and so on? And if, at the same time, their GP could see this data and call them in if there’s a problem?”

He explains that upwards of 30% of prescribed drugs are not taken by patients and, in the case of respiratory drugs, where application is more intricate, 70% are not taken as directed. ̽��ֱ��numbers vary depending on the type of condition being treated but they are disarmingly high across the board. This has consequences, and not only for the patient. ̽��ֱ��cost to the taxpayer of drugs that are not being used is considerable and reduces the pot of money available for patient care.

“In a world of scarce resources this in itself seems incredibly wasteful. But there are other reasons to be concerned,” adds Srai, who is Head of the Institute for Manufacturing (IfM)’s Centre for International Manufacturing. “Around 50% of patients taking antibiotics don’t complete the course. ̽��ֱ��consequences of this are potentially catastrophic as infections become increasingly resistant to drug treatment. And drugs contain active ingredients which, when disposed of inappropriately, end up as contaminants in our water supply.”

Tackling the thorny problem of patient compliance is just one aspect of the pharmaceutical industry that Srai and his team at the IfM are looking to revolutionise. They are working with other universities and major UK pharmaceutical companies AstraZeneca and GSK to make improvements across the whole supply chain, from how a pill is made to the moment it’s swallowed by the patient.

Advances in genetics and biochemistry are helping us move towards a much more tailored approach to medicine, focused on more targeted or niche patient populations, and ultimately the development of bespoke treatments to meet individual patient needs. ̽��ֱ��implications for how the pharmaceutical industry manufactures its medicines and gets them to the patient are clearly immense.

Most pharmaceutical manufacturing still takes place in huge factory complexes, where large volumes of chemicals are processed in a series of ‘batch-processing’ steps, and often a dozen or more are required to produce the final oral dose tablet. Developing new drugs is an expensive business and so big pharma companies hope for a ‘blockbuster’ drug – a medicine that could be used to treat a very common condition, such as asthma or high blood pressure, and which can be manufactured in large quantities.

But, says Srai, the manufacture of these blockbuster drugs is becoming a thing of the past. ̽��ֱ��batch process is costly, inefficient and makes less sense when producing medicines in small volumes.

New ‘continuous’ manufacturing processes mean that drugs can be made in a more flow-through model, requiring fewer steps in the manufacturing process, and in volumes better aligned with market demand. In the case of small volume manufacture, this technology breakthrough can support the move towards more personalised medicine.

“Combine this with the way in which digital technologies are transforming supply chains – through flexible production and automation, using sensors to track location, quality and authenticity, and big data analytics on consumption patterns – and it’s clear that the pharmaceutical industry is on the cusp of a huge change,” adds Srai.

Recognising this, and to make sure they harness the value these advances in science and technology can deliver, pharmaceutical companies are working together in a number of ‘pre-competitive forums’.

̽��ֱ��IfM team is playing a key part in two major related UK initiatives: the Continuous Manufacturing and Crystallisation (CMAC) Future Manufacturing Research Hub based at Strathclyde ̽��ֱ��, funded by £10m from the Engineering and Physical Sciences Research Council and a further £31m from industry; and REMEDIES, a £23m UK pharmaceutical supply-chain sector project, jointly funded by government and industry.

CMAC is focused on the move to continuous manufacturing and REMEDIES on developing new clinical and commercial supply chains. Srai’s team is leading the work on mapping the existing supply chains for different types of treatment, and modelling what the future might look like.

“We can envisage a future in which for some medicines, production is no longer a highly centralised large-scale batch operation but one where manufacturing is more about continuous processing, more distributed in nature, smaller scale and closer to the point of consumption.”

Asked how local this can become, Srai adds: “In some instances we are already able to ‘print’ tablet medicines on demand, and we are now exploring whether this might take place at more local production/distribution sites, or at the local pharmacy or even in our own homes. Of course, some critical hurdles still need to be overcome, not least in terms of assuring product quality at multiple sites and establishing appropriate regulatory regimes.

“New technologies are also opening up other possibilities in the way that patients receive healthcare. Wearable and smartphone apps could be feeding diagnostic and health information to our doctors – be they human or (with the advances in artificial intelligence) robot – who would assess our symptoms remotely. We may change our consultation habits completely and only go to the doctor for very specific types of treatment. Indeed, in the UK today, trials suggest some 30% of GP visits are unnecessary.”

As part of the REMEDIES project, the IfM team has been exploring the possibilities presented by technologies that are available now such as Quick Response (QR) codes that can be scanned by mobile apps on our smart phones – and how they can help ensure that patients are taking their medicine.

“A relatively easy thing to do with packaging is to use it as an information source for patients. For example, packs of pills come with a small leaflet that hardly anybody reads. If we want to help patients adhere to their treatment regimes, can we support them by giving them this plus more useful information in a more accessible electronic format?”

̽��ֱ��REMEDIES team is working on a mobile phone app that will allow patients to read the instructions on their phone (in a font size and language of their choice) or listen to some explanatory audio or watch a video. “This is simple, readily available technology that could have a significant impact on compliance,” says Srai.

̽��ֱ��potential for exploiting data to deliver bespoke healthcare in the future is enormous. With smart packaging, smartphones and wearable devices, information can become increasingly dynamic and interactive. Indicators such as time, location – even mood – can affect whether and how drugs are taken; and data such as blood pressure and pulse can show the effect they have on the patient.

“As in the world of e-commerce, we are at the early stages of understanding how this consumer and patient data can inform the supply chain,” says Srai. “But we can now contemplate scenarios in certain therapeutic areas, in which each dose a patient takes is fully optimised for the here and now, and manufactured continuously, or even printed on demand.”

And if the patient forgets to take it, they will, if they choose, be reminded to do so by a very insistent app.

Inset image: Read more about research on future therapeutics in Research Horizons magazine.

Researchers are working with pharmaceutical companies to make improvements across the whole supply chain, from how a pill is made to the moment it is swallowed by the patient.

We are already able to ‘print’ tablet medicines on demand, and we are now exploring whether this might take place at more local sites, or at the local pharmacy or even in our own homes.

Jag Srai

Kate Russell

Keep taking the tablets

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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