ATTR Amyloidosis trials

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, back pain 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 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.

Another drug, 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.

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 ongoing at the NAC.

The Eidos AG10-301 study (ATTRIBUTE-CM)

AG10 is a new selective TTR stabilizer drug being developed to treat ATTR amyloidosis. Destabilization, misfolding and aggregation of TTR leads to ATTR amyloid tissue deposits. Several small molecules have been shown to bind to and stabilize TTR, potentially preventing the initiating event in ATTR amyloidogenesis. AG10 is a highly selective, potent TTR stabilizer hoped to halt or slow ATTR disease progression.

The trial

This is a phase 3 randomised international study of the efficacy and safety of AG-10 in patients with symptomatic ATTR amyloidosis affecting the heart. The study will include patients with hereditary ATTR amyloidosis and patients with wild type ATTR amyloidosis.

What the study involves for patients

Eligible patients will be randomised in a 2:1 ratio to receive AG10 or matching placebo twice a day. Treatment will continue for a duration of about 32 months, including up to 35 days for screening, 30 months for treatment and up to 1 month for follow up.

At the end of 12 months of treatment, treatment efficacy will be assessed using the 6 minute walk test and standardised questionnaires to evaluate health-related quality of life.

At the end of 30 months treatment efficacy will be further assessed by analysis of all-cause mortality and frequency of hospitalisation related to cardiac causes.

All patients completing the trial may be eligible for participation in an open label extension study of long term AG10 treatment.

Who can take part in the trial

Patients diagnosed with either hereditary ATTR amyloidosis or wild type ATTR amyloidosis affecting the heart are eligible to take part in the trial.

They must have a history of symptomatic heart failure, raised NT-proBNP level, increased left ventricle wall thickness and must have completed over 150 m on two consecutive 6 minute walk tests.

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

Outcomes

The primary outcomes assessed will be:

  • 6 minute walk test:

Change from baseline to Month 12 of treatment in the total distance walked in 6 minutes

  • Total number of deaths due to all causes and frequency of cardiovascular-related hospitalization over 30 months.

Other outcomes assessed will include:

  • Scores on standardised health –related quality of life questionnaires (Kansas City Cardiomyopathy Questionnaire (KCCQ)) at month 12 and month 30
  • Incidence of adverse events related to treatment
  • Pharmacodynamics assessments of TTR stabilisation at various time points
  • Effect of AG10 on cardiac biomarkers
  • AG10 activity across various TTR mutations

Timing

This study has completed recruitment and is ongoing at the NAC.  The NAC is the top recruiter globally.

The HELIOS-A study (ATTRIBUTE-CM)

Vutrisiran (ALN-TTRSC02) is a second generation RNA inhibitor TTR lowering drug, administered by subcutaneous injection.  This trial will compare vutrisiran with patisiran, a first generation RNA inhibitor TTR lowering drug, which is administered by intravenous infusion.

The trial

This is a phase 3, randomized, open-label study to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02) in patients with hereditary transthyretin amyloidosis (hATTR amyloidosis).

What the study involves for patients

Participants will receive vutrisiran or the reference comparator patisiran during the Treatment Period.  The Treatment Period is followed by a Treatment Extension Period during which all participants in the patisiran group will switch to vutrisiran.

Who can take part in the trial

Patients diagnosed with hereditary ATTR amyloidosis with neuropathy may take part.

Patients may not take part in the study if they have undergone liver transplantation or are likely to undergo liver transplantation, if they have significant liver function abnormalities, have received prior TTR lowering treatment or have other known cases of neuropathy.

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

Outcomes

The primary outcomes assessed will be:

  • Change from baseline to Month 9 of treatment in the Modified Neurologic Impairment Score +7 (mNIS+7)
  • Change from baseline to Month 9 of treatment in the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score

Other outcomes assessed will include:

  • Change from Baseline in the timed 10-meter walk test at Months 9 and 18
  • Change from Baseline in the Modified Body Mass Index (mBMI) at Months 9 and 18
  • Change from Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Months 9 and 18
  • Percentage Reduction in Serum Transthyretin (TTR) Levels at Months 9 and 18
  • Frequency of All-Cause Deaths and/or All-Cause Hospitalizations Up to Month 18
  • Frequency of All-Cause Deaths and/or All-Cause Hospitalizations in Participants with Cardiac Involvement Up to Month 18

Timing

This study has completed recruitment and is ongoing at the NAC.  Overall 164 participants from around the world have been enrolled.

The HELIOS-B study (ATTRIBUTE-CM)

Vutrisiran (ALN-TTRSC02) is a second generation RNA inhibitor TTR lowering drug, administered by subcutaneous injection.  This trial will compare vutrisiran with placebo in patients with ATTR amyloidosis with cardiomyopathy.

The trial

This is a phase 3, randomised, double-blind, placebo-controlled international study is to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02) in patients with ATTR amyloidosis with cardiomyopathy.

What the study involves for patients

Participants will receive vutrisiran or placebo every 3 months over a period of 30-36 months.

Who can take part in the trial

Patients diagnosed with either hereditary (hATTR) ATTR amyloidosis with cardiomyopathy, or wild-type (wtATTR) ATTR amyloidosis with cardiomyopathy, may take part.  Participants must have a medical history of heart failure.

Patients may not take part in the study if they have AL amyloidosis, severe heart failure, significant polyneuropathy disability, estimated glomerular filtration rate (eGFR) below 30ml/min/1.73m2, have received prior TTR lowering treatment or have other non-ATTR cardiomyopathy.

Recruitment of about 600 participants is planned.

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

Outcomes

The primary outcome assessed will be:

  • Composite endpoint of all-cause mortality and recurrent cardiovascular (CV) events.

Other outcomes assessed will include:

  • Change from Baseline in the 6-minute walk test at Month 30
  • Change from Baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) at Month 30
  • Change from Baseline in Mean Left Ventricular (LV) Wall Thickness by Echocardiographic Assessment at Month 30
  • Change from Baseline in Global Longitudinal Strain by Echocardiographic Assessment at Month 30
  • Composite Endpoint of All-Cause Mortality and Recurrent All-cause Hospitalizations and Urgent HF Visits
  • All-cause Mortality
  • Rate of Recurrent CV Events (CV Hospitalizations and Urgent HF Visits)
  • Change from Baseline in N-terminal prohormone B-type Natriuretic Peptide (NTproBNP) at Month 30

Timing

This study is open for recruitment at the NAC.

Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant

Patisiran is an RNA inhibitor TTR lowering drug, belonging to the small interfering RNA drug class.  It is administered by intravenous infusion.  Patisiran has been shown to reverse neuropathy in patients with hereditary ATTR amyloidosis and neuropathy, and is approved by the regulatory authorities for this indication. This study will evaluate the efficacy and safety of patisiran in participants with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) with disease progression after liver transplant.

What the study involves for patients

The study aims to enrol 20 participants to receive patisiran by intravenous infusion over a 12 months period.

Who can take part in the trial

Patients who received a liver transplant for treatment of hereditary ATTR amyloidosis at least 12 months before the study started, and who have an increase in polyneuropathy (PND) score after transplant may take part.  Participants must have received stable immunosuppression treatment with prednisone for at least 3 months prior to the starting the study.

Patients may not take part in the study if they have previously received patisiran or inotersen, have clinically significant liver function test abnormalities, portal hypertension with ascites, severe renal failure, leptomeningeal amyloidosis or very poor performance status.

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

Outcomes

The primary outcomes assessed will be:

  • Average of Month 6 and Month 12 Percentage Reduction from Baseline in Serum Transthyretin (TTR)

Other outcomes assessed will include:

  • Change from baseline to Month 12 of treatment in the Modified Neurologic Impairment Score +7 (mNIS+7)
  • Change from baseline to Month 12 of treatment in the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score
  • Change from Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 12
  • Change from Baseline in the Composite Autonomic Symptom Score (COMPASS-31) at Month 12
  • Change from baseline in the Modified Body Mass Index (mBMI) at Month 12
  • Percentage of Participants With Adverse Events

Timing

This study is  open for recruitment at the NAC.

APOLLO-B: A Study to Evaluate Patisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)

Patisiran is an RNA inhibitor TTR lowering drug, belonging to the small interfering RNA drug class.  It is administered by intravenous infusion.  Patisiran has been shown to reverse neuropathy in patients with hereditary ATTR amyloidosis and neuropathy, and is approved by the regulatory authorities for this indication.

This is a phase 3 randomised, double blind, placebo-controlled multicentre study to evaluate the efficacy and safety of patisiran in patients with ATTR amyloidosis with cardiomyopathy

What the study involves for patients

The study aims to enrol about 300 patients with ATTR amyloidosis (hereditary or wild type). There will be an initial screening period of up to 45 days, a 12 month double blind, placebo controlled period (during which half the patients will receive patisiran and half will receive placebo, via intravenous infusion every 3 weeks), a 12 month open-label extension period (during which all patients will receive patisiran) and a 28 day follow up period.

The efficacy of patisiran treatment versus placebo will be assessed by evaluating change from baseline in 6 minute walk test and in a standardized cardiomyopathy symptom questionnaire at various time points.

Who can take part in the trial

Patients with ATTR amyloidosis affecting the heart (cardiomyopathy) may take part in the study. They must be aged 18-85, and may have either hereditary or wild type ATTR amyloidosis. It is expected that about 80% of participants will have wild type, and 20% will have hereditary ATTR amyloidosis. They must either be tafamidis naïve ( taken tafamidis for less than 30 days and none within 6 months before starting the study) or currently taking tafamidis with disease progression.

Patients may not take part in the study if they have severe heart failure or severe disability due to neuropathy.

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

Outcomes

The primary outcomes assessed will be:

  • Change from baseline in 6 minute walk test at month 12

Other outcomes assessed will include:

  • Change from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary(KCCQ-OS) score at Month 12
  • Composite endpoint of all-cause mortality, frequency of cardiovascular (CV)-related hospitalizations and change from baseline in 6-MWT over the 12-month double-blind period.
  • Composite endpoint of all-cause mortality and frequency of all-cause hospitalizations over the 12-month double-blind period.

Timing

This study is open for recruitment at the NAC.

CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of AKCEA-TTR-LRx in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)

AKCEA-TTR-LRx is an RNA inhibitor TTR lowering drug, belonging to the antisense oligonucleotide drug class.  This type of drug inhibits the production of the TTR protein.  It is administered by subcutaneous injection.

The trial

This is a phase 3 global, double-blind, randomised study to evaluate the efficacy and safety of AKCEA-TTR-LRx compared to placebo in patients with ATTR cardiomyopathy (ATTR-CM).

What the study involves for patients

Participants will receive AKCEA-TTR-LRx or placebo by subcutaneous injection every 4 weeks for 120 weeks.  All participants will also receive vitamin A supplements.

Who can take part in the trial

Patients diagnosed with ATTR cardiomyopathy may take part.

Patients may not take part in the study if they have cardiomyopathy not primarily caused by ATTR-CM, AL amyloidosis, prior liver or heart transplant, current or previous treatment with another RNA inhibitor drug.

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

Recruitment of about 750 participants is planned

Outcomes

The primary outcomes assessed will be:

  • Composite Outcome of Cardiovascular (CV) Mortality and frequency of CV clinical events at Week 120
  • Change From Baseline on the 6-Minute Walk Test at Week 61

Other outcomes assessed will include:

  • Change From Baseline in the 6MWT Distance at Week 120
  • Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Week 120
  • Rate of CV Mortality at Week 120
  • Rate of CV Clinical Events at Week 120
  • Rate of All-Cause Mortality at Week 120

Timing

This study is open for recruitment at the NAC.

NEURO-TTRansform: A Study to Evaluate the Efficacy and Safety of AKCEA-TTR-LRx in Participants With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

AKCEA-TTR-LRx and Inotersen are RNA inhibitor TTR lowering drugs, belonging to the antisense oligonucleotide drug class.  This type of drug inhibits the production of the TTR protein.

Inotersen has been shown to reverse neuropathy in patients with hereditary Transthyretin-Mediated Amyloid Polyneuropathy (hATTR-PN), and is approved by the regulatory authorities for this indication.  AKCEA-TTR-LRx is an investigational medicine.

AKCEA-TTR-LRx and inotersen are administered by subcutaneous injection.

The trial

This is a phase 3 global, open-label, randomised study to evaluate the efficacy and safety of AKCEA-TTR-LRx in patients with hereditary transthyretin-mediated amyloid polyneuropathy (hATTR-PN), as compared to inotersen.

What the study involves for patients

Participants will receive subcutaneous injections of either AKCEA-TTR-LRx every 4 weeks or inotersen once a week.  All participants will also receive vitamin A supplements.  The study will last for 65 weeks. Participants receiving inotersen will be crossed over to AKCEA-TTR-LRx at week 37 after completing the week 35 assessments.

Who can take part in the trial

Patients diagnosed with symptomatic hereditary transthyretin-mediated polyneuropathy may take part.

Patients may not take part in the study if they have neuropathy due to other causes, prior liver transplant, current or previous treatment with another RNA inhibitor drug.

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

Recruitment of about 140 participants is planned

Outcomes

The primary outcomes assessed will be:

  • Change from baseline in mNIS+7 (neurological impairment score) at Week 66
  • Change from baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
  • Percent change from baseline in serum TTR concentration at Week 66
  • Percent change from baseline in serum transthyretin (TTR) concentration at Week 35
  • Change from baseline in modified neuropathy impairment score plus 7 (mNIS+7) at Week 35

Other outcomes assessed will include:

  • Change from baseline in Norfolk QOL-DN at Week 35
  • Change from baseline in Neuropathy Symptom and Change (NSC) score at Weeks 35 and 66
  • Change from baseline in the Physical Component Summary (PCS) score of the 36-Item Short Form Survey (SF-36) at Week 65
  • Change from baseline in Polyneuropathy Disability (PND) score at Week 65
  • Change from baseline in modified body mass index (mBMI) at Week 65

Timing

This study is open for recruitment at the NAC.

Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN)

NTLA-2001 is an experimental therapy that could potentially be the first curative treatment for ATTR amyloidosis.

CRISPR/cas9 technology is a novel gene editing tool that allows scientists to alter genes very precisely and efficiently.  The protein Cas9 (or CRISPR- associated) is an enzyme that functions like a pair of molecular scissors, so that specific sections of the DNA can be removed, altered or added.

NTLA-2001 is the first CRISPR therapy to be administered systemically (intravenously) to edit genes inside the body.  Almost all the TTR in the body is made in the liver.  NTLA-2001 uses a lipid nanoparticle delivery system to deliver the gene editing CRISPR protein to the liver.  The goal is to permanently delete the gene for TTR in a single course of treatment.  If this process happens in enough cells, it may lead to a potentially significant decrease in TTR protein production and thus, an impact on disease.

Preclinical data has shown promising results, and this trial is the first time the therapy has been administered to humans.

The trial

This is a phase 1, first in human (FIH), open-label trial to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of NTLA-2001 in patients with hereditary ATTR amyloidosis with polyneuropathy.

What the study involves for patients

In part 1 of the study, participants will receive a single dose of NTLA-2001 and then be followed for up to 24 months.  In part 2, participants will receive the optimal biologically active dose (OBD) identified in part 1 as a single dose and then be followed for up to 24 months.

Who can take part in the trial

Patients diagnosed with hereditary ATTR amyloidosis polyneuropathy may take part.

Patients may not take part in the study if they have non-ATTR amyloidosis, leptomeningeal TTR amyloidosis, or have used a different TTR directed therapy for ATTR amyloidosis within a certain previous timeframe.

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

Recruitment of 38 participants is planned

Outcomes

The primary outcomes assessed will include pharmacokinetic and pharmacodynamic parameters reflecting efficacy of the therapy and adverse events:

Other outcomes assessed will include clinical assessments of polyneuropathy-related symptoms

Timing

This study is open for recruitment at the NAC.