A number of new drugs for TTR amyloidosis are in various stages of development. Some of these drugs are not yet available, but they offer hope for the future.
Diflunisal
This belongs to a class of drugs called ‘non-steroidal anti-inflammatories'(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. The first study report was recently published, with an encouraging result, 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 2 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.
Tafamidis
Tafamidis was developed as a specific drug for hereditary ATTR amyloidosis affecting the nerves. It is bound by TTR in the blood. This binding is thought to stabilise the TTR and makes it less amyloidogenic. Tafamidis has been studied in a trial involving 91 patients with early neuropathy. Neuropathy progression was slightly slower in patients who received the drug than in those who did not. However, many of the participants had very early, often barely clinically significant disease at baseline. Given the major clinical unmet need, tafamidis has recently been approved in Europe, but only for polyneuropathy caused by ATTR amyloid. Unfortunately the evidence that tafamidis has an effect on polyneuropathy is not strong, and it has not been approved by the FDA in the USA. It is also not available in the NHS. The drug has not been tested in cardiac TTR amyloidosis and has not received approval for this indication.
Other therapies that are currently in early stages of development and clinical trials include:
Genetic based therapies
small interfering RNA
antisense oligonucleotides
These two approaches aim to “switch off” the gene for TTR in the liver cells, so that TTR (both mutant and wild-type) is simply not produced. Recent clinical trials of these drugs in patients with hereditary ATTR amyloidosis and symptomatic neuropathy had very encouraging results.
A drug called patisiran belongs to the small interfering RNA drug class. The APOLLO trial was a phase 3 study which enrolled 225 patients with hereditary ATTR amyloidosis and randomised them to receive either patisiran or placebo by intravenous injection every 3 weeks for 18 months. Patients who received patisiran did significantly better than those who received placebo, in terms of neuropathy symptoms, quality of life, daily activities and disability. According to standardised neuropathy scores, neuropathy symptoms actually improved with patisiran. Patisiran was safe and well tolerated.
Another drug called inotersen belongs to the antisense oligonucleotide drug class. The NEURO-TTR trial was 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 functions. 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. Media coverage of the effects of these drugs, based on a press release from the National Amyloidosis Centre in September 2018, can be viewed here and here.
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 drug trials.
The NAC 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 details of ongoing trials at the NAC see here.
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Research
New drugs for ATTR amyloidosis
Diflunisal
This belongs to a class of drugs called ‘non-steroidal anti-inflammatories'(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. The first study report was recently published, with an encouraging result, 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 2 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:
Diflunisal use for ATTR amyloidosis is an ‘off-label’ indication, and only amyloidosis specialists should prescribe it.
Tafamidis
Tafamidis was developed as a specific drug for hereditary ATTR amyloidosis affecting the nerves. It is bound by TTR in the blood. This binding is thought to stabilise the TTR and makes it less amyloidogenic. Tafamidis has been studied in a trial involving 91 patients with early neuropathy. Neuropathy progression was slightly slower in patients who received the drug than in those who did not. However, many of the participants had very early, often barely clinically significant disease at baseline. Given the major clinical unmet need, tafamidis has recently been approved in Europe, but only for polyneuropathy caused by ATTR amyloid. Unfortunately the evidence that tafamidis has an effect on polyneuropathy is not strong, and it has not been approved by the FDA in the USA. It is also not available in the NHS. The drug has not been tested in cardiac TTR amyloidosis and has not received approval for this indication.
Other therapies that are currently in early stages of development and clinical trials include:
Genetic based therapies
These two approaches aim to “switch off” the gene for TTR in the liver cells, so that TTR (both mutant and wild-type) is simply not produced. Recent clinical trials of these drugs in patients with hereditary ATTR amyloidosis and symptomatic neuropathy had very encouraging results.
A drug called patisiran belongs to the small interfering RNA drug class. The APOLLO trial was a phase 3 study which enrolled 225 patients with hereditary ATTR amyloidosis and randomised them to receive either patisiran or placebo by intravenous injection every 3 weeks for 18 months. Patients who received patisiran did significantly better than those who received placebo, in terms of neuropathy symptoms, quality of life, daily activities and disability. According to standardised neuropathy scores, neuropathy symptoms actually improved with patisiran. Patisiran was safe and well tolerated.
Another drug called inotersen belongs to the antisense oligonucleotide drug class. The NEURO-TTR trial was 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 functions. 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. Media coverage of the effects of these drugs, based on a press release from the National Amyloidosis Centre in September 2018, can be viewed here and here.
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 drug trials.
The NAC 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 details of ongoing trials at the NAC see here.