Extension study of Patisiran in patients with FAP
Research type
Research Study
Full title
A Multicenter, Open-Label, Extension Study to Evaluate the Long-term Safety and Efficacy of Patisiran in Patients with Familial Amyloidotic Polyneuropathy Who Have Completed a Prior Clinical Study with Patisiran
IRAS ID
201116
Contact name
Julian Gillmore
Contact email
Sponsor organisation
Alnylam Pharmaceuticals, Inc.
Eudract number
2014-003877-40
Duration of Study in the UK
5 years, 0 months, 0 days
Research summary
Transthyretin mediated amyloidosis (ATTR) is an inherited disease caused by a mutation in the transthyretin (TTR) gene. Transthyretin is a protein secreted predominantly by cells within the liver. Mutations in this protein cause it to form insoluble fibrous deposits in tissues. The particular TTR mutation and sites of the deposit are what determine which body systems the disease affects.
ATTR is a progressive disease associated with severe morbidity (life expectancy 5 to 15 years). There are over 100 reported TTR mutations which are associated with 2 clinical syndromes: familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC). “Patisiran” is being developed by Alnylam for the treatment of ATTR patients with symptomatic FAP.
Patisiran comprises a small interfering ribonucleic acid which is specific for TTR, and formulated in a hepatotropic lipid nanoparticle (LNP) for intravenous (IV) administration. Following LNP mediated delivery to the liver, patisiran targets TTR mRNA for degradation, resulting in the potent and sustained reduction of mutant and WT TTR protein via the RNAi mechanism. Since circulating TTR is almost exclusively synthesized in the liver, the IV administration of patisiran is postulated to reduce the level of precursors that lead to amyloid fibril deposition, resulting in clinical benefit to patients with FAP. Experience, suggest that lowering the circulating amyloidogenic protein by at least 50% is required to impact the clinical course of the disease, with reductions beyond 50% providing further improvement in outcomes.
This is an extension study for patients who have FAP with a documented TTR mutation and that have completed a prior clinical study with patisiran. The study will collect information about how patients with FAP respond to long-term treatment with patisiran (whether their FAP improves and any side effects). Approximately 230 patients (males and females aged 18 and 85 years) will be recruited in the study.Summary of Results:
OVERVIEW
ALN-TTR02-006 (Study 006) studied a medicine called patisiran (pah-TEE-si-ran) in people with hereditary trans thyretin-mediated amyloidosis (hATTR amyloidosis) who had already finished one of 2 earlier studies. The earlier studies, called “parent” studies, were Study 003 and Study 004. This document is a summary of Study 006 and its results. Scientific summaries of this research will also be available.
What is hATTR Amyloidosis?
hATTR amyloidosis is a rare, hereditary disease, which means it runs in families.
hATTR amyloidosis is caused by problems with a protein in the body called transthyretin (TTR):
• TTR is made mostly in the liver and carries vitamin A and other substances around the body.
• In people with hATTR amyloidosis, some small fibres of TTR clump together to make deposits called “amyloid”.
• Amyloid can build up in the nerves, heart, and other parts of the body, preventing them from functioning normally. This causes the symptoms of hATTR amyloidosis.
• Amyloid build-up in the nerves can cause “neuropathy” due to damage in the nerves. This leads to symptoms such as pain, weakness, tingling, numbness in the hands and feet, loss of balance, and difficulty walking.
• Amyloid build-up in the heart can cause the muscle to become thick and stiff, a condition called “cardiomyopathy”. This leads to symptoms such as tiredness and weakness, shortness of breath, irregular heartbeats, and swelling in the legs and ankles.
• People with hATTR amyloidosis often have diarrhoea or constipation as well.About Patisiran
Patisiran works by lowering the amount of TTR protein that the liver makes.
• This means there is less TTR protein in the blood that can form amyloid.
• This may help to reduce the symptoms of hATTR amyloidosisWHY WAS THIS RESEARCH NEEDED?
Patisiran was one of the first medicines approved for hATTR amyloidosis with polyneuropathy. This study was done to understand if continued treatment with patisiran is safe and effective in people with neuropathy symptoms of hATTR amyloidosis. Specifically, did patisiran:
• Decrease levels of TTR in the blood?
• Help nerve function, quality of life, and functional physical abilities?
• Cause any medical problems?WHO TOOK PART IN THE STUDY?
Men and women with neuropathy symptoms of hATTR amyloidosis who had already finished a parent study could take part in this study.
The study enrolled 211 participants at 43 clinical centres in 19 countries in North America, South America, Europe, and Asia. 25 participants came from parent Study 003, and 186 came from parent Study 004. In this study:
• Participants were between 26 to 84 years old • 74% of participants were men and 26% were women • 79% of participants were White • 18% were Asian • Less than 5% of participants were Black or African American or identified their race as Other or having more than one race.
WHAT HAPPENED DURING THE STUDY?
In parent Study 003, all participants were given patisiran for 24 months. In parent Study 004, some participants were given patisiran while others were given placebo for 18 months. A placebo looks like a medication but does not contain any active medicine.
In this study, Study 006, all participants were given patisiran. The goal of this study was to see how participants responded to patisiran over a longer period of time.
- Before starting the study, people who agreed to take part were checked by the study doctors to be sure they could join.
- During the study, participants received patisiran every 3 weeks for up to 5 years. The amount of patisiran each participant received was based on his or her body weight.
- Throughout the study, blood samples were collected to measure TTR levels.
- Study doctors examined participants for their neuropathy symptoms and participants answered questions about their disease every year.
- The study doctors continued checking the participants’ overall health and asked them how they were feeling throughout the study.
HOW WAS PATISIRAN GIVEN?
Everyone in this study was given patisiran. Patisiran was given as a drip into a vein, also called an intravenous (IV) infusion, once every 3 weeks. Reactions to IV infusions can happen during treatment with patisiran. These reactions, often referred to as infusion related reactions, may include reddening of the skin, back pain, nausea, stomach pain, shortness of breath, and headache. Before each IV infusion, participants were given medicines to help lower the chance of a reaction.WHAT WERE THE RESULTS OF THE STUDY?
Did patisiran decrease TTR in the blood?
At the beginning of this study, also called “baseline”, participants who were previously given placebo in parent Study 004 had higher TTR levels in their blood than those who were given patisiran. After a year in this study, participants who were previously given placebo saw an average drop of 88% in their blood’s TTR levels, and these levels stayed low for the rest of the study. Participants who were previously given patisiran maintained low TTR in their blood during the study.Did patisiran help nerve function?
Researchers used the Neuropathy Impairment Score (called NIS) to measure nerve function, which is another way of saying how well nerves send messages between your brain and your body. The NIS is scored from 0 (no loss of nerve function) to 244 points (the most loss of nerve function). Higher scores mean more severe disease. At baseline, participants who were previously given placebo in parent Study 004 had more severe disease than participants who were previously given patisiran. Study doctors found that, over 5 years, NIS scores were stable in participants who were given patisiran in the parent studies meaning that their disease was not getting any worse during the study. Similarly, participants who were given placebo in the parent Study 004 but then were given patisiran in this study found that their NIS scores did not continue to worsen but remained stable, showing that they benefited from patisiran.Did patisiran help quality of life?
Researchers used the Norfolk QOL-DN questionnaire to measure participants’ quality of life. They asked participants about the severity of their neuropathy symptoms, how often they experienced them, and what impact they felt the symptoms had on their daily lives. The Norfolk QOL-DN is scored from -4 (no effect on quality of life) to 136 (severe effect on quality of life). The questionnaire asks about:
- physical sensations like pain, tingling, numbness, or weakness in legs and feet
- sleep, like if pain keeps you awake
- daily activities, like getting ready in the morning
- social life, like if nerve problems limit spending time with family and friends
- mood and wellness, like nerve issues limiting your ability to work or have hobbies
Study doctors found that, over 5 years, changes in scores were stable in participants who were given patisiran in the parent studies meaning their quality of life was not getting any worse during the study. Similarly, participants who were given placebo in the parent Study 004 but then were given patisiran in this study found that their quality of life did not continue to worsen but remained stable, showing that they benefited from patisiran.
Did patisiran help other measures of overall health?
Study doctors also looked at other health measures in participants. They checked:
• how much the disease was affecting their daily life • how fast they could walk • their nutrition • any nerve issues that were reported • their grip strength • their heart health Study doctors found that, over 5 years, other measures of overall health were stable in participants who were given patisiran in the parent studies. Participants who were given placebo in parent Study 004 but then were given patisiran in this study found that their disease did not continue to worsen, showing that they benefited from patisiran. Lower scores on an assessment of disability called the Rasch-Built Overall Disability Scale, or R-ODS, mean more severe disability. At baseline, participants who were previously on placebo in parent Study 004 had more severe disability than participants who were previously on patisiran. Study doctors found that, over 5 years, changes in R-ODS were stable in all participants, meaning their disability was not getting any worse during the study.
What medical problems did the participants have during the study?
Doctors record any medical problems (called “adverse events”) that a participant has during a study. Participants can have adverse events that are either related or not related to the study medication; this is decided by the study doctor.
• Adverse events can be caused by another disease, by another medication, or by chance. Sometimes the cause is unknown.
• An adverse event is considered “serious” when it is life-threatening, causes lasting problems, requires hospital care, or the doctor thinks it is medically important.
How many participants had an adverse event?
All 211 participants had at least 1 adverse event in this study. The most common adverse event was diarrhoea. Most of the adverse events that the study doctors thought were caused by patisiran were reactions to the IV infusion.
22% of participants stopped receiving patisiran because of an adverse event and 1% stopped receiving patisiran because of an adverse event that was thought to be related to patisiran (an event of abdominal discomfort and a reaction to the IV infusion).
Most Common Adverse Events (Those Reported by at Least 15% of Participants)
- Diarrhoea
- Peripheral odema (swelling in legs, feet, or hands)
- Urinary tract infection
- Fall
- Nasopharyngitis (common cold or head cold)
- Pain in extremity/limbs
- Nausea
- Cough
- Infusion related reactions
- DizzinessHow many participants had serious adverse events?
During this 5-year study, 19% of participants died from their hATTR amyloidosis, which is often fatal, or other medical problems. A larger percentage (39%) of participants who were given placebo in the parent Study 004 and therefore had more severe disease at baseline died compared to those who were given patisiran (4% in Study 003 and 15% in Study 004).
63% of participants had at least 1 serious adverse event during the study. Of these participants, 2% had serious adverse events that were thought to be related to patisiran. The serious adverse events reported in more than 1% of participants were:
• cellulitis (skin infection)
• urinary tract infection
• pneumonia
• atrial fibrillation
• irregular heartbeat
• atrioventricular block complete (total block of the heart’s signals) • cerebrovascular accident (stroke) • syncope (fainting) • cardiac failure • cardiac amyloidosis (amyloid disease relating to the heart) • cardiac arrest • hip fractureHOW HAS THE STUDY HELPED PARTICIPANTS AND RESEARCHERS?
ALN-TTR02-006 helped researchers learn about the long-term use of patisiran in people with hATTR amyloidosis with polyneuropathy. The results showed that after treatment with patisiran, participants’ disease did not worsen over time. Additionally, no new safety concerns were found with patisiran when given over a longer period of time. The effects of patisiran seen in ALN-TTR02-006 were similar to those seen in previous studies of patisiran. Other clinical studies with patisiran are ongoing at the time of this summary.REC name
South Central - Hampshire B Research Ethics Committee
REC reference
16/SC/0451
Date of REC Opinion
11 Oct 2016
REC opinion
Further Information Favourable Opinion