̽��ֱ�� of Cambridge - Ian Wilkinson

Thousands of pregnancies tracked in UK’s biggest study on pre-eclampsia

Anonymous — Wed, 19 Jul 2023 10:16:45 +0000

̽��ֱ��POPPY study (Preconception to pOst-partum study of cardiometabolic health in Primigravid PregnancY) is funded by Wellcome and is being led by a team from Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH) and the ̽��ֱ�� of Cambridge. ̽��ֱ��study is also being carried out in Glasgow and up to four other research centres in London.

In the first large scale study of its kind in the UK, women are being monitored before, during and after their first pregnancy to see what factors might be influencing the health of their placenta and their long-term cardiovascular risk. It’s hoped that by understanding this risk, the health of women who develop placental complications can also be improved over their lifetime.

Placental complications affect around 1 in 10 pregnancies and includes:

pre-eclampsia (high blood pressure with kidney/liver/brain involvement)
gestational hypertension (high blood pressure in pregnancy)
fetal growth restriction (baby being small).

These conditions can lead to serious complications for both mother and baby if not monitored or treated.

High blood pressure (hypertension), diabetes, autoimmune conditions, age and being obese before pregnancy are just some of the factors likely to increase the risk of pre-eclampsia and placental dysfunction, but it’s unclear exactly why and whether there are other causes.

In addition, women who experience placental complications are twice as likely to develop heart disease and diabetes later in life, compared with women who have a healthy pregnancy.

It’s not clear however whether placental complications cause heart disease and diabetes directly, or whether these conditions happen in women who already have some underlying and/or unknown health issues before pregnancy.

Women thought to be at high risk of developing pre-eclampsia are advised to take a 75 to 150mg daily dose of aspirin from the twelfth week of pregnancy until birth to reduce the risk of developing this condition. If a woman develops pre-eclampsia, the only way to cure it is to deliver the baby, normally at around 37 to 38 weeks of pregnancy, although this can be earlier in more severe cases.

Dr Bernadette Jenner is a medical registrar in obstetric medicine and clinical pharmacology at Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH) and is leading the POPPY study in Cambridge. She said:

“This study is going to be monitoring thousands of women from before they become pregnant for the first time and will track them through to birth and beyond to try and discover why some develop placental conditions and others don’t. We also hope to find out whether or not these conditions trigger longer-term health issues such as heart disease and diabetes.”

“We have a significant lack of understanding when it comes to placental conditions, especially when you consider how common they are, and the serious impact they can have on women and babies, which at times is life-threatening. To prevent pre-eclampsia and other placental conditions we need to know what really causes them and why. We have some big gaps in our knowledge and this study hopes to find answers.”

Professor Ian Wilkinson is leading the POPPY study and is a clinical pharmacologist and Professor of Therapeutics at the ̽��ֱ�� of Cambridge. He said:

“ ̽��ֱ��POPPY study is a world first and will help us to better understand why common complications of pregnancy adversely affect women’s long term cardiovascular health. This is the key to reducing this risk and may also allow us to prevent pregnancy complications before they occur.”

"Unfortunately, many women who suffer from pre-eclampsia, or one of the other placental complications, are not aware of the potential long term risks, and very few of them are actively followed up after birth - despite recommendations by NICE.”

“Therefore, whilst we await the findings of the POPPY study it is important that women who have experienced one of these complications are seen by a medical professional in the months after delivery to ensure that their blood pressure and other cardiovascular risk factors are checked and treated if necessary."

̽��ֱ��POPPY study is now open at Addenbrooke’s Hospital in Cambridge. Two more sites will be open soon at Glasgow Royal Infirmary NHS and Imperial College Healthcare NHS Trust, with further sites in London to start in the coming months.

Participants must be planning their first pregnancy and live in Glasgow, Cambridge or London where the study is taking place. Participation will involve monitoring alongside regular pregnancy checks and tests.

Find out how you can take part on the POPPY Study website.

Adapted from a press release by CUH

Up to 3,500 first time mums are due to take part in a study led by Cambridge researchers to understand why some will develop pre-eclampsia and placental complications during pregnancy and whether it effects their long-term health.

We have a significant lack of understanding when it comes to placental conditions, especially when you consider how common they are, and the serious impact they can have on women and babies, which at times is life-threatening

Bernadette Jenner

POPPY study | Dr Bernadette Jenner

Suhyeon Choi

Pregnant person holding her stomach

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 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.

Yes

Licence type:

Public Domain

Training a new breed of clinical triallist

skbf2 — Thu, 03 Feb 2022 11:48:27 +0000

Cambridge's Experimental Medicine Initiative, working with AstraZeneca and GSK, is training specialists who can work out at an earlier stage of clinical trials if a treatment is likely to succeed.

National trial launched to test re-purposing existing drugs to treat COVID-19 patients

cjb250 — Wed, 20 May 2020 10:59:02 +0000

A new trial to prevent organ failure and death in COVID-19 patients has been launched, led by clinicians and scientists in Cambridge and London.

TACTIC, as the trial is known, will test whether re-purposing existing drugs, which target the body’s own immune response, can prevent people suffering severe organ failure or death. ̽��ֱ��trial is part of the coordinated national approach by the UK Government to support the early phase development of potential new treatments for COVID-19.

For the majority of people with COVID-19, the infection causes only mild symptoms, including a fever and cough. However, around 15% of patients develop severe disease, including serious damage to the lungs and multiple organ failure, and about two percent die.

̽��ֱ��serious symptoms appear to be mostly caused by the body’s own immune system responding to the presence of infected cells and ‘over-reacting’, destroying healthy cells as well as virus-infected ones.

Two drugs will initially be tested through TACTIC on patients at a network of hospitals across the UK, including Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), Guy’s and St Thomas’ NHS Foundation Trust, and King’s College Hospital.

̽��ֱ��first patient was recruited onto the study at Addenbrooke’s Hospital in Cambridge on Friday 8 May.

̽��ֱ��two drugs, Ravulizumab and Baricitinib, have been carefully selected by a consortium of doctors and scientists with expertise in treating immune-response diseases. They are both thought to have a high chance of reducing the sometimes fatal over-reaction of the immune system seen in very sick patients with COVID-19.

This study is one of a number of COVID-19 studies that have been given urgent public health research status by the Department of Health and Social Care. It is supported by the National Institute for Health Research (NIHR) Biomedical Research Centres at Cambridge and Guy’s and St Thomas’ and UK Research and Innovation; the drug manufacturers , Lilly and Alexion, have each supplied the drug for up to 469 subjects as well as contributing up to £200,000 in running costs for the project.

If the trial demonstrates that a drug is effective, it will be quickly moved into NHS care pathways, to treat the patients with severe COVID-19 related disease. Similarly, if the trial reveals that a drug is not effective, it can be quickly removed so that other options can be tested.

UK Research and Innovation Chief Executive, Professor Sir Mark Walport, said: “By supporting the rapid progress of these re-purposed drugs into early clinical trials we will test whether they can prevent the development of severe COVID-19 symptoms. Trialling drugs that have the potential to suppress the severe inflammation caused by an over-reaction of the immune system is an important part of tackling the COVID pandemic.”

Dr Frances Hall, Consultant Rheumatologist, CUH, and TACTIC Chief Investigator, said: “It is striking that the severe COVID-19-related disease is associated with the person’s own immune system causing most of the damage. It seems that, while most people’s immune system attacks the virus appropriately, in those who become really sick, the immune response appears to overreact.

“We have selected the first two drugs for the TACTIC study based on their ability to ‘dial-down’, or block, two distinct types of response, each of which appear important in the immune response which causes damage to lungs and other organs in COVID-19-related disease. Baricitinib acts through the network of cytokines (soluble immune system signals running between cells); it reduces the upscaling of the cytokine response which leads to the “cytokine storm” evident in severe COVID-19-related disease. On the other hand Ravulizumab inhibits the activation of a trigger in a “tag-team” of molecules, called the complement cascade, which serves to rapidly ramp up inflammation and cell killing.”

̽��ֱ��two drugs are used routinely as treatments – Baricitinib in severe rheumatoid arthritis and Ravulizumab in blood diseases where complement activation destroys red blood cells. Dr Hall says there is good reason to believe that either or both of these strategies could help prevent severe organ failure and even death in patients with COVID-19.

Professor Ian Wilkinson, Director of the Cambridge Clinical Trials Unit, and Professor of Therapeutics at the ̽��ֱ�� of Cambridge, said: "This is a time of huge national effort in the fight against COVID-19 and I am delighted that Cambridge is playing a key role in this. TACTIC will test the effectiveness of a number of existing and new drugs in patients admitted to hospital, in a similar way to the RECOVERY trial, but with a strong focus on modulating the immune response and collecting high quality data that can be used by our partner pharmaceutical companies to seek the necessary approvals for widespread international use.”

Dr James Galloway, Senior Lecturer in Rheumatology at King’s College London, and a Co-Investigator on the TACTIC trial, said: “By testing existing drugs that we think have the best chance of working against COVID-19, we hope that we can find proven ways to treat the disease. Identifying the high risk patients taking part in this research will be key, and we’re incredibly grateful to the patients who have been so willing to take part, and their families.”

Dr Hall is a Fellow in Medical and Veterinary Science at Sidney Sussex College. Professor Wilkinson is a Fellow in Clinical Medicine at Trinity Hall.

Adapted from a press release from Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust

A new trial to prevent organ failure and death in COVID-19 patients has been launched led by clinicians and scientists in Cambridge and London.

This is a time of huge national effort in the fight against COVID-19 and I am delighted that Cambridge is playing a key role

Ian Wilkinson

Matryx

Coronavirus

̽��ֱ��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.

Yes

Licence type:

Public Domain

Strategic partner: AstraZeneca

skbf2 — Mon, 11 Nov 2019 16:20:03 +0000

Scientists at AstraZeneca, a global biopharmaceutical company, have been working with Cambridge ̽��ֱ�� for more than two decades. What are the secrets of their success?

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

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

Yes

Licence type:

Attribution-Noncommerical