Treatment of all types of amyloidosis is currently based on the following principles:
- Reducing the supply of amyloid forming precursor proteins.
- Supporting the function of organs containing amyloid.
When amyloid precursor protein supply is controlled:
- existing amyloid deposits often regress (become smaller)
- new amyloid deposits stop appearing
- organ function is often preserved and may also recover
Reducing variant TTR supply
Genetic based therapies
Two recently developed genetic therapies, patisiran and inotersen, aim to ‘switch off’ the TTR gene in the liver cells, so that TTR (both mutant and wild-type) is simply not produced. Patisiran belongs to the small interfering RNA drug class and inotersen belongs to the antisense oligonucleotide drug class. In clinical trials in patients with hereditary ATTR amyloidosis both these drugs improved neuropathy symptoms, quality of life, daily activities and disability.
Patisiran has been shown to reverse neuropathy in a majority of patients who participated in a phase 3 study called the APOLLO trial. This trial enrolled 225 patients with hereditary ATTR amyloidosis and randomised them to receive either patisiran or placebo by intravenous injection every three weeks for 18 months. Patients who received patisiran fared significantly better than those who received placebo, in terms of neuropathy symptoms, quality of life, daily activities and disability. According to standardised scores, neuropathy symptoms improved with patisiran. Patisiran was safe and well tolerated.
Inotersen was studied in the NEURO-TTR trial, a phase 3 study which enrolled 172 patients with hereditary ATTR amyloidosis and randomised them to receive either inotersen or placebo for 15 months. Patients who received inotersen did significantly better than those who received placebo, in terms of neuropathy symptoms, quality of life, daily activities and disability. A few patients receiving inotersen experienced drops in platelet counts and abnormal kidney function. Once this was observed, all patients receiving inotersen were monitored with regular blood tests.
Patisiran and inotersen have been approved by the European Medicines Agency and the U.S. Food and Drug Administration (FDA) for treating neuropathy caused by hereditary ATTR amyloidosis.
On 22 May 2019 NICE published guidance recommending inotersen for treating stage 1 and stage 2 polyneuropathy in adults with hereditary transthyretin amyloidosis.
On 14 August 2019 NICE published guidance recommending patisiran for treating hereditary transthyretin amyloidosis in adults with stage 1 and stage 2 polyneuropathy.
Both inotersen and patisiran have now been approved by NHS England for this indication.
So far trials have only assessed the impact of these drugs on nerve damage caused by ATTR amyloidosis. Effects on cardiac ATTR amyloidosis have not been formally assessed and patients with wild-type ATTR amyloidosis were not included in the completed drug trials.
Some of the ongoing clinical trials of patisiran, and of other, newer genetic therapies include patients with both hereditary and wild type cardiac ATTR amyloidosis.
Tafamidis was developed as a specific drug for ATTR amyloidosis. It is bound by TTR in the blood. This binding is thought to stabilise the TTR and makes it less amyloidogenic. The pivotal trial of tafamidis included 441 patients, some of whom had wild-type ATTR amyloidosis while others had hereditary ATTR amyloidosis. Patients who received the active drug had better outcomes than those who received placebo, including fewer hospitalisations for heart disease, a 30% reduction in death over a period of 2.5 years, reduced decline in functional capacity and improved quality of life. Tafamidis is approved in Europe for treatment of hereditary ATTR amyloidosis patients with stage 1 symptomatic polyneuropathy to delay neurological impairment and before liver transplantation, but it is not currently available within the NHS. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved tafamidis for cardiomyopathy caused by ATTR amyloidosis although it is not approved in the US for ATTR polyneuropathy. It will need to be evaluated by NICE before it can become available within the NHS.
This drug belongs to a class of drugs called ‘non-steroidal anti-inflammatory drugs’ (NSAIDs). These drugs are in common use as pain killers, for conditions such as arthritis. Diflunisal is bound by TTR in the blood. This binding is presumed to make the TTR less amyloidogenic. Trials are currently underway to assess the effect of diflunisal on the progression of neuropathy and cardiomyopathy in patients with hereditary ATTR amyloidosis. Results from the first study report were encouraging, but the numbers of patients involved was small and the extent of benefit was modest. The trial involved 130 patients with hereditary ATTR amyloidosis affecting the nerves, 64 of whom received diflunisal for two years while 66 received placebo (dummy pills). The rate of progression of neuropathy was slower in the patients who received diflunisal than in those who did not. Results of trials of diflunisal in cardiac ATTR amyloidosis are not yet available. It is important to note that NSAIDs such as diflunisal may have serious side effects, which may be especially dangerous in patients who are already unwell with amyloidosis. These side effects include:
bleeding from the stomach and gut.
worsening of kidney function.
worsening of heart failure.
Diflunisal use for ATTR amyloidosis is an ‘off-label’ indication, and only amyloidosis specialists should prescribe it.
The National Amyloidosis Centre (NAC) at the Royal Free Hospital, London, can now offer patients with ATTR amyloidosis, subject to various eligibility criteria demanded by the pharmaceutical companies, various opportunities for treatment with the new drugs or for participation in clinical trials. for information on ongoing trials at the NAC, see here.
All the TTR in the blood, which forms the amyloid deposits everywhere except in the eye and the blood vessels around the brain, is made in the liver. In the past, liver transplantation was a treatment option for some patients with hereditary ATTR amyloidosis, although almost exclusively younger patients with the Val30Met mutation. Since the advent of the new drugs, liver transplantation is rarely recommended in the UK.
Supporting amyloidotic organ function
In all types of amyloidosis it is important that treatment should support the function of organs containing amyloid. In ATTR amyloidosis this may include: