Impact case study database

Prior to 2013, knowledge and awareness of ATTR amyloidosis were poor and cardiologists diagnosed few patients. Researchers at UCL’s NAC have created a diagnostic clinical pathway that eliminates the need for invasive, costly and risky heart biopsies, allowing safe and effective diagnosis. Their methods have been incorporated into best practice clinical guidelines and now thousands of patients have been correctly diagnosed, worldwide. These UCL-led innovations and collaborations with pharmaceutical companies have expedited development of new medicines to treat ATTR amyloidosis, which are transforming thousands of lives.

Advances in NHS treatment services and benefits to patients

Diagnostic methods developed at UCL have revolutionized management of ATTR amyloidosis. The possibility of amyloidosis as a rare cause of heart failure was seldom pursued since it required a highly specialised cardiac biopsy and there was no treatment. Now, the diagnosis of ATTR amyloidosis is readily confirmed with ^99mTc-DPD scintigraphy; staging of disease severity achieved simply using routinely performed blood tests; and cardiac MRI is used in addition to characterise and serially quantify the amyloid burden. MRI can thus track the course of disease, its response to emerging treatments and inform clinical trials.

NHS implementation of these technologies has dramatically increased diagnosis of ATTR amyloidosis, and as a consequence, cardiac biopsies are now only performed in complex cases. In 2013-14, UCL’s NAC central records show that 38 UK patients were diagnosed using cardiac biopsies. Since the development of the new non-invasive UCL methods (published in 2016) the numbers of patients diagnosed has steadily increased and in 2019-20, 500 patients were diagnosed without the use of cardiac biopsies ( S1). Diagnosis by ^99mTc-DPD scintigraphy is currently saving the NHS approximately GBP450,000 per year (NHS tariffs – ^99mTc-DPD scintigraphy GBP200; cardiac biopsy – GBP1,100).

Scintigraphy for ATTR is now performed widely in Europe, Australia and the US. Curium Pharma UK Ltd, which distributes ^99mTc-DPD radiotracer in the UK, supplied 41 NHS hospitals with ^99mTc-DPD kits in 2020, compared to only 7 hospitals in 2015; sufficient to scan several thousand patients ( S2).

Cardiac MRI (CMR) innovations, developed and validated at UCL are now provided in more than 60 NHS hospitals and allow the underlying quantity of amyloid to be measured for the first time. Changes in amyloid load and other CMR parameters measured over time are now frequently used as efficacy endpoint measures in industry sponsored trials ( S3). In 2016, NHS Highly Specialised Services commissioned a dedicated GBP3,000,000 CMR facility at UCL’s NAC, which has served more than 4500 patients. Central NHS funding of GBP8,000,000 per year ensures access of all amyloidosis patients to these advances in clinical care.

Identifying ATTR amyloidosis in the wider heart disease population

Cardiologists are increasingly using ^99mTc-DPD scintigraphy in several common cardiac disease populations in which amyloid deposition may be a contributor or even the primary cause of symptoms. These include the 450,000 UK patients with heart failure with preserved ejection fraction (HFpEF), of whom up to 10% may have cardiac amyloid that could be treated. Scintigraphy has also shown co-existing ATTR amyloidosis in more than 10% of patients undergoing surgery for aortic valve stenosis (approximately 5000 patients per year in England), which previously was missed in most cases ( S4); this allows additional risk assessment before surgery, and consideration of specific amyloid therapy. Crucially, it has been possible to confirm that patients with co-existing ATTR amyloidosis greatly benefit from valve surgery.

Updated clinical guidelines for management of ATTR amyloidosis

The UCL diagnostic methods are now included in UK, European and US guidelines for the clinical management of ATTR amyloidosis ( S5). Guidelines developed by the Amyloid Research Consortium and specialist medical societies provide best practices for diagnosis and characterisation of ATTR amyloidosis, facilitating rapid and accurate identification without need for cardiac biopsy. They state, “Myocardial scintigraphy with bone avid tracers …. has high sensitivity and specificity for ATTR-CM…. Ease of access, simplicity of imaging, relatively low cost and specificity are some of the advantages of myocardial scintigraphy compared with…. [other methods]” ( S5).

Role of UCL diagnostic pathway in developing new treatments

Scintigraphy, CMR and staging methods developed at UCL have been adopted in at least 8 major clinical trials of novel therapies ( S6), involving approximately 2500 patients. President and CMO of Eidos Therapeutics Inc. said, “We enrolled the vast majority of participants in our study based on the UCL NAC algorithm, providing an efficiency in recruitment that we believe is unprecedented... This algorithm has been widely and enthusiastically adopted at major centers throughout the United States and the rest of the developed world and is making an incredible contribution to increasing the numbers of patients being accurately diagnosed earlier in the course of their disease (if at all), which significantly improves their survival” ( S7).

According to Pfizer, who licenced a treatment (tafamidis) for ATTR cardiomyopathy in the US in May 2019, the number of patients diagnosed increased from approximately 2,000 to more than 17,500 patients since the UCL scintigraphy method was introduced; 7,500 US patients are now being treated with Pfizer’s tafamidis, generating Q3 sales in 2020 of USD351,000,000. Pfizer’s tafamidis franchise has now been estimated to exceed USD2.5 billion in 2020 ( S8).

The UCL NAC team’s expertise in amyloidosis has, together with its large, well characterised patient population and the new diagnostic tools, underpinned an ongoing collaboration with Alnylam Pharmaceuticals Inc. For over a decade, Professor Hawkins has acted as a consultant to Alnylam to support development of a revolutionary gene silencing RNA interference (RNAi) therapy (patisiran) for ATTR amyloidosis ( S9). NAC is a core laboratory for international clinical trials and the UCL team’s expertise has contributed to approvals of the new therapies at the European Medicines Agency and in NICE evaluations, leading to approval for use of gene silencing medicines within the NHS. President of R&D at Alnylam said: “Our longstanding work with NAC represents an exemplar of healthcare collaboration that has underpinned a landmark innovation in pharmacology and medical practice” ( S10).

Treatment with patisiran can reverse clinical symptoms within a year and it is approved for use in the UK, EU and US ( S11). This remarkable success has heralded a new era in medicine.

Alnylam achieved Q3 product sales in 2020 for patisiran of USD82,500,000, with more than 1,150 patients being treated worldwide. British hand surgeon Carlos Heras-Palou, founder and chairperson of the UK’s ATTR Amyloidosis Patients’ Association (UKATPA), who was treated with patisiran described the gene silencing therapy as "ground-breaking….like the proverbial silver bullet. The treatment has saved my career, and my life". All eligible patients in the UK with hereditary ATTR amyloidosis now gain access to the gene silencing therapy via UCL’s NAC, courtesy of the NHS. In 2020, 151 patients in the UK were successfully treated with patisiran.