ATTR Amyloidosis trials

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Brief background on ATTR amyloidosis

Amyloidosis is a disorder of protein folding, where normally soluble proteins misfold and form abnormal, insoluble amyloid fibrils, which deposit in the tissues and accumulate to damage the structure and function of tissues and organs.

Transthyretin (TTR) is a normal blood protein which transports thyroid hormones and retinol (vitamin A), hence its name ‘trans-thy-retin’.  All TTR in the blood is produced in the liver; TTR is also produced in the brain and eye but does not reach the blood from there.  In ATTR amyloidosis, the amyloid deposits in the organs contain amyloid fibrils formed from misfolded TTR protein.

Hereditary ATTR amyloidosis is caused by a mutation in the gene for TTR, inherited from one parent.  The disease therefore runs in families, though the timing, development and severity of the disease can vary greatly.

In acquired (non-hereditary) ATTR amyloidosis, the amyloid is formed by the normal, so‑called ‘wild-type’ protein.  This disease is not hereditary.  It is known as wild-type ATTR (ATTRwt) amyloidosis (formerly called senile systemic amyloidosis (SSA)).

The clinical presentation and effects of ATTR amyloidosis vary widely depending on which organs are mostly affected.

Hereditary ATTR amyloidosis – ‘variant’ ATTR amyloid deposits

People with mutations in the TTR gene produce abnormal, amyloidogenic, ‘variant’ TTR throughout their lives.  The genetic mutations in ‘variant’ TTR destabilise the TTR protein and greatly promote its inherent amyloid forming potential.  Amyloid deposits start to form and then build up until they cause clinical disease, mainly affecting the nerves and/or heart, and sometimes the kidneys, eyes and synovial tissues (tendons and ligaments).  Symptoms may appear at any time from early adult life onwards.  This condition runs in families.

Hereditary ATTR amyloidosis was traditionally referred to as familial amyloid polyneuropathy (FAP) when disease mainly affected the nerves or familial amyloid cardiomyopathy (FAC) when disease mainly affected the heart.  However it is now understood that in clinical practice there is significant overlap in disease manifestations not only between patients with different mutations but also among those with the same mutation.  Most TTR mutations can cause amyloid deposits in both the nerves and the heart.  The International Society of Amyloidosis has therefore recommended the use of the term hereditary ATTR amyloidosis to describe disease caused by ATTR amyloid deposits in all patients with TTR gene mutations.

Hereditary ATTR amyloidosis is the most commonly recognised form of hereditary systemic amyloidosis but it is nevertheless a very rare disease.  More than 150 amyloidogenic variants (mutations) of TTR have been observed and different mutations may cause different disease manifestations.

Despite being extremely rare in most parts of the world, hereditary ATTR amyloidosis is common in some very localised parts of Portugal, Sweden and Japan.  It may also be common, but under-diagnosed in several other regions including Spain, France, Brazil, Argentina, Cyprus, Bulgaria and Ireland.

Hereditary ATTR amyloidosis is sometimes seen in people living in the UK, with ancestors from these regions.

Wild-type ATTR amyloidosis – non hereditary

Normal, ‘wild type’ TTR may also be amyloidogenic Microscopic deposits of ‘wild-type’ ATTR amyloid are very common in the elderly, and have been found in 1 in 4 autopsies of people aged over 80.  Until recently it was thought that these ‘wild type’ ATTR amyloid deposits hardly ever caused disease.  However, new imaging techniques have shown that in fact, disease caused by ‘wild type’ ATTR deposits may be far commoner than anyone thought.  This disease was formerly known as senile systemic amyloidosis, or senile cardiac amyloidosis.  Amyloid deposits consisting of ‘wild type’ TTR mainly affect the heart but may also cause carpal tunnel syndrome, backpain from lumbar canal stenosis, and bleeding from the bladder in some people.  Wild -type ATTR amyloidosis is not hereditary (it does not run in families).  Most patients with this condition are men aged over 70 but it can also present as young as 50 years.

Drugs for ATTR amyloidosis

Two new drugs (patisiran and inotersen) have recently been granted a license for treatment of hereditary ATTR amyloidosis with neuropathy (i.e., with nerve involvement). They are both undergoing evaluation by NICE/NHS England with respect to funding in the UK.  Other disease-modifying drugs are in varying stages of development and licensing.

The TRANSCEND study

The full name of this study is: TRansthyretin Amyloidosis: Neuropathy, Senility, Cardiomyopathy, Evaluation, Natural history and Diagnosis.

The goal of TRANSCEND is to achieve a ‘real world’ picture of ATTR amyloidosis in the UK by close monitoring of all patients with ATTR amyloidosis regardless of age or disease severity.

The TRANSCEND study will include patients seen at the NAC with all types of ATTR amyloidosis.

ATTR amyloidosis: filling in the gaps in our knowledge

Hereditary ATTR amyloidosis:

The FAP World Transplant Registry (FAP WTR) was established in 1995, in order to compile data on survival of patients who undergo liver transplantation for hereditary ATTR amyloidosis (previously known as FAP) and to determine the optimal time for liver transplantation.  Most patients worldwide who have undergone liver transplantation for hereditary ATTR amyloidosis carry a single TTR mutation, Val30Met, which is rare in the UK. There is a relative lack of data on the natural history of hereditary ATTR amyloidosis in association with the other disease-causing TTR gene mutations.

We now know that liver transplantation does not prevent continued build-up of ATTR amyloid in the heart.  There is a need for careful cardiac follow up of patients who have undergone liver transplantation for hereditary ATTR amyloidosis, to enhance our understanding of this process.

Wild-type ATTR amyloidosis and amyloid cardiomyopathy

Newly available cardiac imaging techniques (cardiac magnetic resonance imaging and DPD scintigraphy) have resulted in greatly increased diagnoses of cardiac ATTR amyloidosis.  There has been a 40 fold increase in the number of referrals of patients to the NAC with wild-type ATTR amyloidosis over the past decade.

ATTR amyloidosis may be a relatively common cause of heart failure in the elderly.  There is a need to follow these patients systematically in order to learn about the natural history of this emerging condition, and to increase awareness of the condition throughout the UK.

Quality of life (QOL)

At present there are no standard, accepted measures of QOL for ATTR amyloidosis.  TRANSCEND aims to establish and validate such measures, by following QOL throughout the disease course.  QOL measures will also be important when assessing the effects of new drugs for ATTR amyloidosis.

New treatments

There are a number of drugs for ATTR amyloidosis currently in various stages of development.  In order to arrange future clinical trials of these drugs, and to assess their effects, there is an urgent need for increased understanding of the natural course of both cardiac and nervous system disease caused by amyloid.

What the study involves for patients

Patients will undergo all the standard assessments that are usually performed at the NAC.  There are no additional tests performed on patients (it is an observational study); the important difference is that we will systematically and carefully record all data in a special database for analysis.

These include:

  1. Baseline assessment: evaluation of the medical history, neurological and cardiac assessment, physical examination, blood tests, specialised cardiac imaging tests, functional tests and QOL assessment.
  2. Ongoing assessments include recording hospital admissions and changes in drug dosages. A member of the NAC study team will conduct a telephone consultation with any patient who has been admitted to their local hospital.
  3. Annual review at the NAC including weight, blood tests, specialised cardiac imaging (echocardiography and cardiac MRI scan), functional tests such as 6 minute walking distance and performance status assessment, neuropathy scoring (where relevant), and QOL assessment.

All of these assessments are routinely undertaken at NAC as part of standard clinical care.

Who can take part in the trial

All patients diagnosed with ATTR amyloidosis assessed at the NAC are eligible for the trial if they are capable of providing written, informed consent.

Study aims

The TRANSCEND study aims to do for ATTR amyloidosis what the ALchemy study has done for AL amyloidosis.

The ALchemy study, which has been running since 2009, follows all patients diagnosed with systemic AL amyloidosis at the NAC.  The data gathered has contributed greatly to our knowledge and understanding of the full spectrum of this disease in the UK.  Some of our standard clinical management protocols have been adjusted in the light of the information gathered in this study.

The TRANSCEND study aims to achieve similar goals for ATTR amyloidosis by following all patients diagnosed with this condition at the NAC.  It is a prospective study, which means that patients will be followed from the time of diagnosis.  It is observational, meaning that there are no additional interventions for patients and the goal is systematic and careful data collection.

As discussed above, there have not previously been large scale trials following patients with all types of ATTR amyloidosis.  Our understanding of the condition is rapidly evolving, with a significant recent increase in the frequency with which wild type ATTR amyloidosis is diagnosed.  The only way we can fill in the gaps in our knowledge of this condition is by carefully following large numbers of patients over time.

The study itself will not involve any alterations in standard clinical practice.  However, it is likely that understanding gained from this study may eventually influence and improve clinical management of patients.

Timing

The TRANSCEND study is due to open in 2019

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