A drug known as a "gene silencer" has shown promise in reducing hospitalisation and deaths from a devastating condition known as transthyretin (ATTR) cardiac amyloidosis, according to a new study led by UCL researchers.
The study, presented at the European Society of Cardiology (ESC) congress, with results simultaneously published in The New England Journal of Medicine, found that a drug called vutrisiran reduced the risk of death and recurring cardiovascular events - such as hospitalisation - by 28% over three and a half years and by 33% in patients not already taking another drug, tafamidis, which also delays disease progression.
The drug is one of four currently being trialled that show promise in transforming the treatment of ATTR amyloidosis, a disease that until recently had limited treatment options.
The results of all four drug trials, led by Professor Julian Gillmore and Professor Marianna Fontana (both UCL Division of Medicine), have been published in the New England Journal of Medicine within the last three years. Early results of one of these treatments, a novel gene-editing therapy based on CRISPR/Cas9, indicate it may stop disease progression.
In addition, the UCL team showed last year for the first time that the condition could be reversed, reporting on three men who spontaneously recovered from the disease. At the time the team said the discovery raised the bar for what might be possible with treatments.
The latest results were from a clinical trial called HELIOS-B, involving 655 patients from 87 sites across 26 countries randomly assigned either a placebo or vutrisiran, an injection given every three months.
ATTR cardiac amyloidosis occurs when a protein in the bloodstream called transthyretin (TTR) misfolds and accumulates in the heart tissue as amyloid, making the heart stiff and less able to pump blood. If left untreated, it is almost invariably fatal within four to six years. It can either be hereditary or occur with age.
Previously, ATTR amyloidosis was considered rare. In recent years in the UK, however, the number of people being diagnosed has increased dramatically, partly due to improvements in imaging pioneered at the UCL Centre for Amyloidosis.
Vutrisiran, sold under the brand name Amvuttra, blocks the expression of a gene by binding to messenger RNA (mRNA), thereby reducing the production of the disease-causing TTR protein.
Lead author Professor Marianna Fontana (UCL Division of Medicine and Royal Free Hospital), said: "ATTR is a progressive, fatal disease in which misfolded transthyretin protein accumulates as amyloid deposits in various parts of the body, often damaging the heart.
"We investigated whether a novel RNA interference (RNAi) therapeutic, vutrisiran, which targets transthyretin production, could improve clinical outcomes in patients with ATTR-CM and the results were very promising.
"Vutrisiran was highly effective and well tolerated in this contemporary population representative of patients that we see in our clinics, with consistent benefits regardless of background tafamidis therapy.
"Our findings indicate that vutrisiran has the potential to become the new standard of care.
"This trial is also important as it is the first to show the benefit of gene silencers in any type of cardiomyopathy."
Participants had heart failure symptoms and 40% were already taking another drug, tafamidis.
The researchers found that quality of life improved for patients taking vutrisiran compared to placebo and there were benefits in terms of disease progression, as measured by several clinical markers.
Risk of death was reduced by 36% over 42 months and by 35% among patients who were only receiving vutrisiran.
Professor Bryan Williams, chief scientific and medical officer at the British Heart Foundation, based at the UCL Institute of Cardiovascular Science, described the study as unlocking the benefits of gene silencing.
"Transthyretin amyloidosis causes progressive heart failure, which can be devastating for patients and their families, and is difficult to treat," he said.
"This study reveals the promising effects of a new kind of treatment, with vutrisiran significantly reducing the number of deaths, and improving the quality of life of those with this condition.
"This study unlocks the benefits of gene silencing as a potential way to treat cardiomyopathies, bringing us another step closer to a new treatment option for those living with the condition. We look forward to further studies to better understand the benefits of this drug in a wider, more diverse patient group."
Pushkal Garg, chief medical officer at vutrisiran manufacturer Alnylam, said: "While the results have not yet been reviewed by a regulatory authority, the data we have shared today suggest that vutrisiran has the potential to become a new standard of care treatment for ATTR-CM, a progressive and ultimately fatal disease with limited treatment options."
A separate study published last week in JAMA Cardiology, led by Dr Luis Lopes (UCL Institute of Cardiovascular Science) alongside Queen Mary University of London, found that one in 1,000 people in the UK had potentially harmful genetic variants that may be associated with ATTR amyloidosis, a higher than expected proportion.
