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.  Normal TTR can form amyloid fibrils in elderly people and there are many genetically variant types of TTR, which form amyloid much more aggressively and at an earlier age.  There are three distinct different types of ATTR amyloidosis:

  1. Familial amyloid polyneuropathy (FAP) (hereditary – runs in families)
  2. Inherited amyloid cardiomyopathy (hereditary – runs in families)
  3. Senile systemic amyloidosis or wild type ATTR amyloidosis (not hereditary – does not run in families)

Hereditary ATTR amyloidosis – ‘variant’ ATTR amyloid deposits

People with mutations in the TTR gene produce abnormal, amyloidogenic, ‘variantTTR throughout their lives.  The genetic mutations in ‘variantTTR destabilise the TTR protein and greatly promote its inherent amyloid forming potential.

Amyloid deposits consisting of abnormal ‘variantTTR may cause:

  1. Familial amyloid polyneuropathy (FAP) is by far the most common form of hereditary amyloidosis.  This disease affects the nervous system, often also the heart and sometimes the kidneys, eyes and other organs.  Disease symptoms usually appear between the third and seventh decade, although they may start as early as age 20 or as late as age 80.  It is very rare, and the commonest type, associated with the Val30Met mutation, is thought to affect about 10,000 people in the whole world.  In the UK, FAP is most common in people of Irish ancestry, carrying the so-called Thr60Ala mutation. FAP is inherited by autosomal dominant inheritance, meaning that each child of a person with FAP has a 50% chance of inheriting the abnormal gene .  Liver transplantation was introduced as ‘surgical gene therapy’ for FAP in 1991, in a collaboration between Swedish colleagues and our team.  Replacement of the patient’s own liver, producing the amyloidogenic variant of TTR, with a normal liver producing only normal TTR was intended to halt amyloid formation.  More than 2000 patients with FAP, most of whom carry the Val30Met mutation, have undergone liver transplantation, and it can lead to prolonged survival, especially in patients who receive their transplant early in the course of disease.  However, since normal TTR is also itself amyloidogenic, the disease often progresses in many liver transplant recipients.
  2. Familial amyloid cardiomyopathy (FAC) (heart disease), presenting in young adults is an extremely rare hereditary condition in which genetically variant TTR amyloid principally or exclusively affects the heart.  However amyloid cardiomyopathy in elderly black people, most commonly men over age 60, of West African ancestry, is caused by a particular TTR variant (Val122Ile) which is present in a significant proportion of individuals of this genetic background.  Because the genetic variant is so common, it is known as a polymorphism rather than a mutation.  Other organs are not affected and there is very rarely a family history due to the late age of onset and the fact that not all carriers of the affected gene actually get the disease.  This condition has only been recognised in recent years, was previously rarely diagnosed and is probably much more common than formerly realised.

Normal, ‘wild type’ TTR may also be amyloidogenic, causing senile systemic amyloidosis (wild type ATTR amyloidosis):

Non-hereditary ATTR amyloidosis – ‘wild-type’ ATTR amyloid deposits

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 called senile systemic amyloidosis, or senile cardiac amyloidosis until 2014.  It was decided at the XIV International Symposium on Amyloidosis in 2014 that this condition should in future be referred to as wild-type transthyretin amyloidosis or wild-type ATTR amyloidosisAmyloid deposits consisting of ‘wild type’ TTR mainly affect the heart but may also cause carpal tunnel syndrome in some people.  Senile systemic amyloidosis (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 before age 60.

Drugs for ATTR amyloidosis

There are no available drug therapies for ATTR amyloidosis in the UK.  However, several drugs are in varying stages of development and licensing.  See below for details of ongoing studies and studies about to begin at the NAC.

The TRANSCEND trial

The full name of this trial 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.

ATTR amyloidosis is caused by amyloid deposits made up of a protein called transthyretin (TTR). There are three distinct different types of ATTR amyloidosis:

  1. Familial amyloid polyneuropathy (FAP) (hereditary – runs in families)
  2. Inherited amyloid cardiomyopathy (hereditary – runs in families)
  3. Senile systemic amyloidosis (not hereditary – does not run in families)

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

ATTR amyloidosis: filling in the gaps in our knowledge

FAP:

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 FAP and to determine the optimal time for liver transplantation.  Most patients who have undergone liver transplantation carry the Val30Met mutation.

However, there is a lack of data on the natural history of non Val30Met associated FAP, as most of these patients have not undergone liver transplantation and have not previously been consistently followed in large numbers.

Liver transplantation for FAP does not prevent continued build-up of ATTR amyloid in the heart.  Sometimes the ‘wild type’ TTR produced by the transplanted normal liver may deposit ‘on top of’ the ‘variant’ ATTR template already present in the heart.  There is a need for careful cardiac follow up of patients who have undergone liver transplantation for FAP, to enhance our understanding of this process.

Senile systemic amyloidosis and amyloid cardiomyopathy

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

ATTR amyloidosis may be a 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.

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 be useful for 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 disease.

What the trial involves for patients

Patients will undergo all the standard assessments that are usually performed at the NAC.  The only difference is that we will 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 and QOL assessment.
  2. On-going assessments including posting a monthly Clinical Progress Form to the NAC, detailing any changes in the medical condition, patient’s weight or treatment.  If there are marked changes then a member of the NAC study team will conduct a telephone consultation with the patient.
  3. Six monthly review at the NAC including weight, blood tests, echocardiography and functional tests such as 6 minute walking distance and performance status assessment.
  4. Twelve monthly review including additional assessments such as neuropathy scoring, specialised cardiac imaging, QOL assessment and patient satisfaction survey.

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 also observational, meaning that the goal is 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 senile cardiac 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 possible that understanding gained from this study may eventually influence clinical management of patients.

Timing

The TRANSCEND study is due to open in 2015 at the NAC but many of the assessments are already being routinely carried out.

Efficacy and Safety of IONIS-TTR Rx in Familial Amyloid Polyneuropathy

IONIS TTR Rx

IONIS TTR Rx is one of a class of drugs called antisense oligonucleotides which act by a type of gene therapy known as ‘gene silencing’.  The drug is not intended to repair the faulty TTR gene, rather to ‘silence’ its effects by interfering with TTR production in the liver cells.

All proteins in the body are produced in cells by a process called ‘gene expression,’ using the information present in the genetic code.  This process can be likened to the building of a house.  The DNA making up the genes in the nucleus of each cell are like the architect’s blueprints.  Other molecules in the nucleus of the cell, known as messenger RNA (mRNA) and transfer RNA (tRNA) act like the various builders, electricians, plumbers, etc, who need to read and follow the blueprints and communicate effectively together to ensure that the end product is a success.

In the early steps of protein production, the information contained in the DNA in the cell’s nucleus is conveyed out of the nucleus by messenger RNA.  The messenger RNA contains the instructions for protein structure which are then translated from the language of genetic code into the language of amino acids, the building blocks of proteins.

Gene expression inside a cell, showing mechanism of action of ISIS TTR Rx.

Gene expression inside a cell, showing mechanism of action of ISIS TTR Rx.

The IONIS TTR Rx molecule is made up of a short string of nucleotides (the building blocks of the genetic code in DNA and RNA) designed to bind tightly to TTR messenger RNA.  When this binding occurs, the TTR messenger RNA is broken down by an enzyme in the cell, preventing the translation step in protein building and thus blocking the production of both ‘variantTTR and normal ‘wild type’ TTR protein.

It is hoped that decreasing the amount of TTR protein in the blood will reduce the formation of ATTR amyloid deposits, slowing or halting disease progression.  After liver transplantation, wild type TTR from the new liver may continue to deposit as amyloid fibrils.  However, because IONIS TTR Rx is hoped to reduce the production of both variant and wild type TTR, if successful, this approach may be more effective than liver transplantation in halting amyloid deposit progression.

The trial

The purpose of the trial is to determine whether IONIS TTR Rx can slow or stop the nerve damage caused by ATTR deposits in patients with FAP.  This study will enrol FAP patients with early stage neuropathy.  Patients will receive either IONIS TTR Rx or placebo for 65 weeks.  This is a randomised controlled double blind phase 3 trial.  Phase 1 trials in small numbers of people have already established that the drug is safe in humans, have determined an appropriate dosage range, and identified side effects.  Phase 3 trials involve a large number of patients.  The trial is multicentre meaning that patients all around the world are taking part in this trial.

What the trial involves for patients

In order to see whether IONIS TTR Rx helps patients with FAP, each patient taking part in the trial will be randomly assigned to one of 2 groups:

  • intervention group – these patients will receive 300 mg of the IONIS TTR Rx drug by subcutaneous injection 3 times on alternate days in the first week, then once weekly for 64 weeks.
  • control group – these patients will receive placebo (dummy injection) by subcutaneous injection 3 times on alternate days in the first week, then once weekly for 64 weeks.

This is a double blind trial.  This means that the doctors and nurses running the trial at the NAC, and the patients participating will not know which patients are receiving IONIS TTR Rx and which are receiving placebo.

Who can take part in the trial

Patients with stage 1 and stage 2 FAP, aged between 18 to 75 years who can walk unaided or with no more than one stick/cane are eligible to take part.

Patients who have undergone liver transplantation or have other serious diseases are not eligible to take part. For a full list of exclusion criteria, see the www.clinicaltrials.gov website.

Outcomes

This trial is only designed to assess the effects of IONIS TTR Rx on neuropathy caused by FAP, not on heart disease.

The main (primary) outcome measures will be change in baseline score in two standardised measures for assessing the severity of neuropathy:

  1. The modified Neuropathy Impairment Score.
  2. The Norfolk Quality of Life Diabetic Neuropathy questionnaire (this was developed for patients with diabetic neuropathy and is applicable to FAP even though FAP has got nothing at all to do with diabetes).

All patients will undergo neuropathy assessment at the start of the trial, so that there will be a baseline score for comparison.

Measurement of the change from baseline in the TTR levels in the blood will be a secondary measure.

Timing

The trial started recruiting participants in other centres at the end of 2012. Recruitment at the NAC is ongoing.

ALN-TTRSC in ATTR cardiac amyloidosis

ALN-TTRSC

ALN-TTRSC belongs to a class of drugs called small interfering RNA (siRNA) drugs which act by a type of gene therapy known as ‘gene silencing’.  The drug is not intended to repair the faulty TTR gene, rather to ‘silence’ its effects by interfering with TTR production in the liver cells.

All proteins in the body are produced in cells by a process called ‘gene expression,’ using the information present in the genetic code.  This process can be likened to the building of a house.  The DNA making up the genes in the nucleus of each cell are like the architect’s blueprints.  Other molecules in the nucleus of the cell, known as messenger RNA (mRNA) and transfer RNA (tRNA) act like the various builders, electricians, plumbers etc who need to read and follow the blueprints and communicate effectively together to ensure that the end product is a success.

In the early steps of protein production, the information contained in the DNA in the cell’s nucleus is conveyed out of the nucleus by messenger RNA.  The messenger RNA contains the instructions for protein structure which are then translated from the language of genetic code into the language of amino acids, the building blocks of proteins.

Gene expression inside a cell and mechanism of action of ALN-TTRSC.

Gene expression inside a cell and mechanism of action of ALN-TTRSC.

The ALN-TTRSC molecule is made up of a short string of nucleotides (the building blocks of the genetic code in DNA and RNA) designed to bind tightly to TTR messenger RNA.  When this binding occurs, the TTR messenger RNA is broken down by an enzyme in the cell, preventing the translation step in protein building and thus blocking the production of both ‘variantTTR and normal ‘wild type’ TTR protein.

It is hoped that decreasing the amount of TTR protein in the blood will reduce the formation of ATTR amyloid deposits, slowing or halting disease progression.  After liver transplantation, wild type TTR from the new liver may continue to deposit as amyloid fibrils.  However, because ALN-TTRSC is hoped to reduce the production of both variant and wild type TTR, if successful, this approach may be more effective than liver transplantation in halting amyloid deposit progression.

The trial

This is a multi-centre, open-label, multi-dose phase 2 trial.

Phase 2 trials are performed at a relatively early stage in drug development, and the trial aims to recruit only 12 patients.

The trial is multicentre meaning that patients and researchers from different sites (in the UK and the US) are taking part.

The trial is open-label, meaning that all patients and researchers know the drug and the dose being give.  It is not placebo controlled, meaning that none of the participants will receive a dummy (placebo) injection.

What the trial involves for patients

Each patient taking part in the trial will receive 10 subcutaneous injections of ALN-TTRSC on an outpatient basis.  In the first week there will be 5 daily doses on days 0, 1, 2, 3 and 4.  After that there will be 5 weekly doses.

There will be clinic visits for screening up to 28 days before drug administration, and more visits for follow up to 90 days after starting participation in the trial.

Who can take part in the trial

Patients with biopsy proven TTR cardiac amyloidosis, aged between 18 to 80 years who are clinically stable are eligible to take part.

For a full list of exclusion criteria, see the www.clinicaltrials.gov  website.

Objectives

The purpose of the trial is to evaluate the safety and tolerability of multiple doses of ALN-TTRSC in patients with TTR cardiac amyloidosis.

The trial does not aim to assess the effects of ALN-TTRSC on the patients’ clinical condition.  If this trial finds that ALN-TTRSC is safe and well tolerated, then future, larger phase 3 trials may evaluate the clinical efficacy of this drug.

Timing

Recruitment at the NAC started in December 2013 and is ongoing.

 

 

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