Clinical Medicine Research (UoA1)

New discovery

Atypical Haemolytic Uraemic Syndrome (aHUS) is a rare kidney disease. Kidney transplantation does not correct the underlying genetic defect, so it has a high mortality rate.

We worked alongside Newcastle Upon Tyne Hospitals NHS Foundation Trust on this research. We discovered that aHUS resulted from mutations in genes responsible for the complement pathway. This is a major part of the immune response.

Eculizumab is an inhibitor of the complement pathway. Further work found it was an effective treatment. We could identify patients who responded to it through genetic testing. Newcastle research underpinned national NICE recommendation of eculizumab.

Successful treatments

NHS England awarded a contract to the Newcastle-based National aHUS Service. They coordinated aHUS treatment, performing genetic testing to identify patients who will respond.

Out of 969 patients referrals, around 280 have received eculizumab without adverse effect. The treatment either prevented end-stage renal failure or allowed curative renal transplantation.

There have been zero aHUS-related deaths.

Investigating Lynch syndrome

We characterise Lynch syndrome (LS) by an increased likelihood of early-life colorectal cancer. The research also looked at other malignancies. 

Patients have an 80% lifetime likelihood of developing cancer. Frequent colonoscopy and removal of polyps is of limited effectiveness in this high risk population.

Capp2

The Colorectal Adenoma/carcinoma Prevention Progamme (Capp2) is a Newcastle-led clinical trial. It investigated the protective effect of 600mg daily aspirin dosing over a two-year period. 

A 10-year follow-up study saw 861 patients confirm the protective effect of daily aspirin. Findings showed much lower number of colorectal cancers in patients taking aspirin, compared with placebo.

These findings led to changes in UK, European, Australian and US guidelines for the prevention of colorectal cancers.

Limbal stem cell deficiency (LSCD) is a sight-threatening rare disease. It is often caused by chemical burns through accident or attacks. LSCD also causes the failure of corneal transplants used to try to reverse the damage.  Newcastle-led research improved upon existing treatments.

We helped to create the first animal-free:

• autologous cultivated limbal epithelial stem cell transplantation for unilateral cases
• autologous oral mucosa epithelium for bilateral cases.

The technology has treated all patients referred to the service from all over the UK. 

90% of the corneal transplants remain successful 12 months post-surgery. This improves patient quality of life and independence. 

Identifying patients with improved outcomes

Medulloblastoma accounts for approximately 10% of all childhood cancer deaths. With aggressive treatment ~70% of children with medulloblastoma can expect to be free of disease 5 years later.

But it was not clear how to identify the patients with improved outcomes.  

Newcastle research identified and/or validated four distinct molecular subgroups:

• WNT
• SHH
• Group 3
• Group 4

Molecular subgroup recognition

The four subgroups stratified patients into excellent prognosis or poor prognosis groups.  They are now recognised in the field as the ‘standard-of-care’ for medulloblastoma.

Additionally, the WNT biomarker is guiding patient stratification in three international clinical trials. This allows children to have reduced radiotherapy treatments. 

Newcastle also hosts the National Reference Centre for Medulloblastoma Diagnostics. This provides advanced molecular diagnostics for UK medulloblastoma patients. 

Better vision during endoscopies

Colorectal cancer (CRC) kills 16,000 people in the UK each year.  It is the second most common cause of cancer death.

Since CRC arises from adenomas, detecting these early is key to reducing CRC deaths. Adenoma detection rate during endoscopy varies, because of folds within the colon that limit the view. 

In collaboration with the manufacturer, Newcastle research investigated the effectiveness of Endocuff Vision. This simple, inexpensive device fits securely to the end of an endoscope to improve vision during endoscopy. 

The results showed an absolute increase in adenoma detection rate of 10.8%, one of the largest increases in detection of any approach ever seen. 

NICE fast-tracked Endocuff Vision into practice in the UK and the number of units supplied increased from 1,500 to 69,000 in two years. 

Industry recognition

The success of its use in the UK drove the expansion of the device’s ownership and distribution rights. These are now held by the world’s leading endoscopy company Olympus, whose Endoscopic Solutions Division is worth over £3 billion. 

As testament to its clinical value, the device has received multiple awards and commendations. 

The device has won:

• a UK Industry Award for collaboration and an Academic Health Science Networks collaboration/innovation award
• The British Healthcare Trades Award for Best Innovation Developed in Collaboration with the NHS 

The research also formed the basis of the Royal College of Physicians’ Excellence in Patient Care Research Award in May 2020.

Exploring new cancer treatments

Rucaparib is a first-in-class poly adenosine diphosphate-ribose polymerase (PARP) inhibitor. Research into this treatment was a Newcastle-led development.

Since 2014, many Newcastle-led research projects and industry clinical trials have investigated rucaparib.

They wanted to be successful in treating cancers driven by somatic BRCA and similar mutations. Some of these will result in homologous repair deficiency.

Winning approval

Rucaparib has received approval from:

• The US Food and Drug Administration (FDA)
• European Medicines Agency
• National Institute for Health and Care Excellence

The approval covers germline and somatic ovarian, fallopian tube and peritoneal cancer. Further clinical testing led to FDA approval for germline and somatic prostate cancer.

More than 9,000 patients received cancer treatment in further clinical trials using rucaparib. Increased rucaparib use has also led to increased revenue to Newcastle's Clovis Oncology and company growth.

Remission hope for T2D

In the UK, type 2 diabetes (T2D) affects over 4.2 million people. The healthcare cost for this exceeds £23 billion.

Newcastle research has showed that remission of T2D was possible within 10 years of diagnosis using a specific low calorie diet.

The diet reduces weight in patients. This allows the liver, pancreas and insulin secretion to return to normal in approximately half of participants.

Research expansion

This paradigm-shifting research informed the 2016 WHO Global Report on Diabetes and the 2019 NHS Long Term Plan.

In 2020, an NHS pilot scaling up Newcastle clinical trial techniques began. Over the next 2 years, the pilot will see 5,000 patients enrolled. The current number is over 500 patients enrolled.

A similar low calorie diet intervention was rolled out across Scotland in 2018. These intervention initiatives offer hope to millions of patients that their T2D is reversible.

Newcastle leading on DMD research

Duchenne muscular dystrophy (DMD) has no cure. Though 10% of patients carry a stop codon mutation in the dystrophin gene that is potentially treatable.

Newcastle University was instrumental in creating the first large international multicentre study in DMD.

A double-blind placebo control study involved ataluren in 174 patients at 37 sites across 11 countries. Findings showed a positive change in the six-minute walking distance of patients taking 40 mg/kg/day doses versus placebo.

Regulator approval

This data was the basis for the European Medicines Agency (EMA) granting ataluren conditional marketing authorisation in 2014. NICE approval came in 2016 through a Management Access Agreement.

Patients now receive ataluren as part of regular clinical practice. This is recorded as part of the STRIDE registry, which the University manages.