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The RNA interference therapy suppresses transthyretin production and reduces neuropathy impairment, compared with placebo.
LOS ANGELES—Patisiran, an investigational RNA interference therapy that suppresses the production of transthyretin (TTR) protein, significantly improves polyneuropathy in patients with hereditary TTR-mediated (hATTR) amyloidosis, according to phase III trial results described at the 70th Annual Meeting of the American Academy of Neurology. 
After 18 months of treatment with patisiran, patients’ scores on a measure of neuropathy impairment had improved from baseline, whereas scores progressively worsened among patients who received placebo.
“The results are amazing,” said principal investigator David Adams, MD, PhD, Head of the Department of Neurology at Centre Hospitalier Universitaire Bicêtre in Paris. “The hope is to stop the progression of the disease and eventually to reverse it.”
Patients Often Present With Polyneuropathy
Formerly known as familial amyloidotic polyneuropathy, hATTR amyloidosis is a rare, multisystemic, progressive, life-threatening disease caused by mutations in the TTR gene. The mutations may cause misfolded TTR protein to accumulate as amyloid fibrils in the nerves, heart, and gastrointestinal tract. There are more than 120 known TTR mutations, and people with the most common mutation, Val30Met, often present with polyneuropathy. Patients with hATTR amyloidosis also may present with cardiomyopathy or a mixed phenotype. The median age of disease onset is 39.
In addition, hATTR amyloidosis may cause CNS symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg, neuropathic pain, altered sensitivity, muscle weakness, and impaired balance). Current treatment options include liver transplantation.
Researchers are studying whether small interfering RNAs that bind to TTR messenger RNA and prevent production of TTR protein may benefit patients with hATTR amyloidosis. Alnylam Pharmaceuticals, based in Cambridge, Massachusetts, is developing patisiran, a lipid nanoparticle formulation of small interfering RNA designed to knock down the production of mutant and wild-type TTR protein in the liver. Phase I and II trials found that patisiran was generally well tolerated and resulted in dose-dependent suppression of TTR production.
The APOLLO Trial
To evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy, Dr. Adams and colleagues conducted the phase III, randomized, double-blind, placebo-controlled APOLLO study. Eligible patients were between ages 18 and 85 with hATTR amyloidosis, investigator-estimated survival of at least two years, a Neuropathy Impairment Score (NIS) of between 5 and 130, and a Polyneuropathy Disability score of IIIb or less. The investigators randomized patients 2:1 to receive IV patisiran 0.3 mg/kg or placebo every three weeks. To reduce the likelihood of infusion-related reactions, patients received premedication with dexamethasone, oral acetaminophen, an H2 blocker, and an H1 blocker at least 60 minutes before each study drug infusion.
The primary end point was change from baseline on the modified NIS+7, a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function, at 18 months. Secondary end points included the effect of patisiran on Norfolk Quality of Life–Diabetic Neuropathy score, nutritional status (as evaluated by modified BMI), motor function (as measured by NIS-weakness and the timed 10-meter walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 [COMPASS-31]). Exploratory measures include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden.
Assessing Change From Baseline
The researchers enrolled 225 patients from 44 sites in 19 countries between December 2013 and January 2016. Patients’ mean age was 61, and patients had been diagnosed with hATTR amyloidosis for an average of about 2.5 years. In all, 148 patients were randomized to receive patisiran, and 77 were randomized to receive placebo. Study completion rates were 71.4% in the placebo group and 93.2% in the patisiran group.
At 18 months, mean serum TTR knockdown from baseline was 84.3% among patients who received patisiran, compared with 4.8% among patients who received placebo.
At nine months, least squares mean change from baseline in modified NIS+7 was –2.04 points in the patisiran group, versus 13.95 points in the placebo group.
At 18 months, least squares mean change from baseline in modified NIS+7 was –6.03 points among patients who received patisiran, compared with 27.96 points among patients who received placebo. The difference between groups was statistically significant. The proportion of patients with improvement in modified NIS+7 was 56.1% in the patisiran group and 3.9% in the placebo group (odds ratio, 39.9).
“Regardless of the state of the disease and the severity of the NIS at baseline, you have the same effect,” Dr. Adams said.
The positive treatment effect also was observed in patients with various TTR genotypes and in patients with cardiac involvement.
All secondary end points favored treatment with patisiran, indicating “significant improvement in quality of life, reduction in disease symptoms and disability, and improvement in nutritional status, strength, and ambulation seen with patisiran, relative to placebo,” Dr. Adams said. In the subpopulation with cardiac involvement, patisiran significantly improved cardiac end points such as mean left ventricular wall thickness and global longitudinal strain.
In a post hoc analysis, patisiran resulted in a 50% reduction in a composite rate of all-cause hospitalization and mortality and an approximately 45% reduction in a composite rate of cardiac hospitalization and all-cause mortality.
Therapy Is Under FDA Review
There were 13 deaths in the trial. None of the deaths were due to the study drug, and the rate of deaths was higher in the placebo group than in the patisiran group (7.8% vs 4.7%). The majority of adverse events were mild or moderate and included peripheral edema (29.7% of patients in the patisiran group vs 22.1% of patients in the placebo group) and infusion-related reactions (18.9% of patients in the patisiran group vs 9.1% of patients in the placebo group). Infusion-related reaction led one patient to discontinue the trial. There were no severe, life-threatening, or serious infusion-related reactions.
Adverse events that were reported more often in the placebo group than in the patisiran group included fall (28.6% vs 16.9%), urinary tract infection (18.2% vs 12.8%), nausea (20.8% vs 14.9%), muscular weakness (14.3% vs 3.4%), anemia (10.4% vs 2%), and syncope (10.4% vs 2%).
The researchers observed no safety signals regarding cataracts, hyperglycemia, infection, osteopenia or osteoporosis, liver function tests, hematology, or renal dysfunction related to patisiran. Safety in the cardiac subpopulation was comparable to that in the overall study population.
Patients who completed the APOLLO study were eligible for patisiran treatment in an open-label extension study, and 99% of eligible patients enrolled in this extension. Patisiran is under review by the FDA as a breakthrough therapy for hATTR amyloidosis. The FDA plans to complete its review by August 11, 2018.
—Jake Remaly
Suggested Reading
Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.
Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829.
Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.
Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.
The RNA interference therapy suppresses transthyretin production and reduces neuropathy impairment, compared with placebo.
The RNA interference therapy suppresses transthyretin production and reduces neuropathy impairment, compared with placebo.
LOS ANGELES—Patisiran, an investigational RNA interference therapy that suppresses the production of transthyretin (TTR) protein, significantly improves polyneuropathy in patients with hereditary TTR-mediated (hATTR) amyloidosis, according to phase III trial results described at the 70th Annual Meeting of the American Academy of Neurology.
After 18 months of treatment with patisiran, patients’ scores on a measure of neuropathy impairment had improved from baseline, whereas scores progressively worsened among patients who received placebo.
“The results are amazing,” said principal investigator David Adams, MD, PhD, Head of the Department of Neurology at Centre Hospitalier Universitaire Bicêtre in Paris. “The hope is to stop the progression of the disease and eventually to reverse it.”
Patients Often Present With Polyneuropathy
Formerly known as familial amyloidotic polyneuropathy, hATTR amyloidosis is a rare, multisystemic, progressive, life-threatening disease caused by mutations in the TTR gene. The mutations may cause misfolded TTR protein to accumulate as amyloid fibrils in the nerves, heart, and gastrointestinal tract. There are more than 120 known TTR mutations, and people with the most common mutation, Val30Met, often present with polyneuropathy. Patients with hATTR amyloidosis also may present with cardiomyopathy or a mixed phenotype. The median age of disease onset is 39.
In addition, hATTR amyloidosis may cause CNS symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg, neuropathic pain, altered sensitivity, muscle weakness, and impaired balance). Current treatment options include liver transplantation.
Researchers are studying whether small interfering RNAs that bind to TTR messenger RNA and prevent production of TTR protein may benefit patients with hATTR amyloidosis. Alnylam Pharmaceuticals, based in Cambridge, Massachusetts, is developing patisiran, a lipid nanoparticle formulation of small interfering RNA designed to knock down the production of mutant and wild-type TTR protein in the liver. Phase I and II trials found that patisiran was generally well tolerated and resulted in dose-dependent suppression of TTR production.
The APOLLO Trial
To evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy, Dr. Adams and colleagues conducted the phase III, randomized, double-blind, placebo-controlled APOLLO study. Eligible patients were between ages 18 and 85 with hATTR amyloidosis, investigator-estimated survival of at least two years, a Neuropathy Impairment Score (NIS) of between 5 and 130, and a Polyneuropathy Disability score of IIIb or less. The investigators randomized patients 2:1 to receive IV patisiran 0.3 mg/kg or placebo every three weeks. To reduce the likelihood of infusion-related reactions, patients received premedication with dexamethasone, oral acetaminophen, an H2 blocker, and an H1 blocker at least 60 minutes before each study drug infusion.
The primary end point was change from baseline on the modified NIS+7, a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function, at 18 months. Secondary end points included the effect of patisiran on Norfolk Quality of Life–Diabetic Neuropathy score, nutritional status (as evaluated by modified BMI), motor function (as measured by NIS-weakness and the timed 10-meter walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 [COMPASS-31]). Exploratory measures include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden.
Assessing Change From Baseline
The researchers enrolled 225 patients from 44 sites in 19 countries between December 2013 and January 2016. Patients’ mean age was 61, and patients had been diagnosed with hATTR amyloidosis for an average of about 2.5 years. In all, 148 patients were randomized to receive patisiran, and 77 were randomized to receive placebo. Study completion rates were 71.4% in the placebo group and 93.2% in the patisiran group.
At 18 months, mean serum TTR knockdown from baseline was 84.3% among patients who received patisiran, compared with 4.8% among patients who received placebo.
At nine months, least squares mean change from baseline in modified NIS+7 was –2.04 points in the patisiran group, versus 13.95 points in the placebo group.
At 18 months, least squares mean change from baseline in modified NIS+7 was –6.03 points among patients who received patisiran, compared with 27.96 points among patients who received placebo. The difference between groups was statistically significant. The proportion of patients with improvement in modified NIS+7 was 56.1% in the patisiran group and 3.9% in the placebo group (odds ratio, 39.9).
“Regardless of the state of the disease and the severity of the NIS at baseline, you have the same effect,” Dr. Adams said.
The positive treatment effect also was observed in patients with various TTR genotypes and in patients with cardiac involvement.
All secondary end points favored treatment with patisiran, indicating “significant improvement in quality of life, reduction in disease symptoms and disability, and improvement in nutritional status, strength, and ambulation seen with patisiran, relative to placebo,” Dr. Adams said. In the subpopulation with cardiac involvement, patisiran significantly improved cardiac end points such as mean left ventricular wall thickness and global longitudinal strain.
In a post hoc analysis, patisiran resulted in a 50% reduction in a composite rate of all-cause hospitalization and mortality and an approximately 45% reduction in a composite rate of cardiac hospitalization and all-cause mortality.
Therapy Is Under FDA Review
There were 13 deaths in the trial. None of the deaths were due to the study drug, and the rate of deaths was higher in the placebo group than in the patisiran group (7.8% vs 4.7%). The majority of adverse events were mild or moderate and included peripheral edema (29.7% of patients in the patisiran group vs 22.1% of patients in the placebo group) and infusion-related reactions (18.9% of patients in the patisiran group vs 9.1% of patients in the placebo group). Infusion-related reaction led one patient to discontinue the trial. There were no severe, life-threatening, or serious infusion-related reactions.
Adverse events that were reported more often in the placebo group than in the patisiran group included fall (28.6% vs 16.9%), urinary tract infection (18.2% vs 12.8%), nausea (20.8% vs 14.9%), muscular weakness (14.3% vs 3.4%), anemia (10.4% vs 2%), and syncope (10.4% vs 2%).
The researchers observed no safety signals regarding cataracts, hyperglycemia, infection, osteopenia or osteoporosis, liver function tests, hematology, or renal dysfunction related to patisiran. Safety in the cardiac subpopulation was comparable to that in the overall study population.
Patients who completed the APOLLO study were eligible for patisiran treatment in an open-label extension study, and 99% of eligible patients enrolled in this extension. Patisiran is under review by the FDA as a breakthrough therapy for hATTR amyloidosis. The FDA plans to complete its review by August 11, 2018.
—Jake Remaly
Suggested Reading
Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.
Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829.
Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.
Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.
LOS ANGELES—Patisiran, an investigational RNA interference therapy that suppresses the production of transthyretin (TTR) protein, significantly improves polyneuropathy in patients with hereditary TTR-mediated (hATTR) amyloidosis, according to phase III trial results described at the 70th Annual Meeting of the American Academy of Neurology.
After 18 months of treatment with patisiran, patients’ scores on a measure of neuropathy impairment had improved from baseline, whereas scores progressively worsened among patients who received placebo.
“The results are amazing,” said principal investigator David Adams, MD, PhD, Head of the Department of Neurology at Centre Hospitalier Universitaire Bicêtre in Paris. “The hope is to stop the progression of the disease and eventually to reverse it.”
Patients Often Present With Polyneuropathy
Formerly known as familial amyloidotic polyneuropathy, hATTR amyloidosis is a rare, multisystemic, progressive, life-threatening disease caused by mutations in the TTR gene. The mutations may cause misfolded TTR protein to accumulate as amyloid fibrils in the nerves, heart, and gastrointestinal tract. There are more than 120 known TTR mutations, and people with the most common mutation, Val30Met, often present with polyneuropathy. Patients with hATTR amyloidosis also may present with cardiomyopathy or a mixed phenotype. The median age of disease onset is 39.
In addition, hATTR amyloidosis may cause CNS symptoms (eg, progressive dementia, headache, ataxia, and seizures), autonomic neuropathy (eg, orthostatic hypotension, urinary retention, and sexual dysfunction), and peripheral sensorimotor neuropathy (eg, neuropathic pain, altered sensitivity, muscle weakness, and impaired balance). Current treatment options include liver transplantation.
Researchers are studying whether small interfering RNAs that bind to TTR messenger RNA and prevent production of TTR protein may benefit patients with hATTR amyloidosis. Alnylam Pharmaceuticals, based in Cambridge, Massachusetts, is developing patisiran, a lipid nanoparticle formulation of small interfering RNA designed to knock down the production of mutant and wild-type TTR protein in the liver. Phase I and II trials found that patisiran was generally well tolerated and resulted in dose-dependent suppression of TTR production.
The APOLLO Trial
To evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy, Dr. Adams and colleagues conducted the phase III, randomized, double-blind, placebo-controlled APOLLO study. Eligible patients were between ages 18 and 85 with hATTR amyloidosis, investigator-estimated survival of at least two years, a Neuropathy Impairment Score (NIS) of between 5 and 130, and a Polyneuropathy Disability score of IIIb or less. The investigators randomized patients 2:1 to receive IV patisiran 0.3 mg/kg or placebo every three weeks. To reduce the likelihood of infusion-related reactions, patients received premedication with dexamethasone, oral acetaminophen, an H2 blocker, and an H1 blocker at least 60 minutes before each study drug infusion.
The primary end point was change from baseline on the modified NIS+7, a composite measure of motor strength, sensation, reflexes, nerve conduction, and autonomic function, at 18 months. Secondary end points included the effect of patisiran on Norfolk Quality of Life–Diabetic Neuropathy score, nutritional status (as evaluated by modified BMI), motor function (as measured by NIS-weakness and the timed 10-meter walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 [COMPASS-31]). Exploratory measures include assessment of cardiac function and pathologic evaluation to assess nerve fiber innervation and amyloid burden.
Assessing Change From Baseline
The researchers enrolled 225 patients from 44 sites in 19 countries between December 2013 and January 2016. Patients’ mean age was 61, and patients had been diagnosed with hATTR amyloidosis for an average of about 2.5 years. In all, 148 patients were randomized to receive patisiran, and 77 were randomized to receive placebo. Study completion rates were 71.4% in the placebo group and 93.2% in the patisiran group.
At 18 months, mean serum TTR knockdown from baseline was 84.3% among patients who received patisiran, compared with 4.8% among patients who received placebo.
At nine months, least squares mean change from baseline in modified NIS+7 was –2.04 points in the patisiran group, versus 13.95 points in the placebo group.
At 18 months, least squares mean change from baseline in modified NIS+7 was –6.03 points among patients who received patisiran, compared with 27.96 points among patients who received placebo. The difference between groups was statistically significant. The proportion of patients with improvement in modified NIS+7 was 56.1% in the patisiran group and 3.9% in the placebo group (odds ratio, 39.9).
“Regardless of the state of the disease and the severity of the NIS at baseline, you have the same effect,” Dr. Adams said.
The positive treatment effect also was observed in patients with various TTR genotypes and in patients with cardiac involvement.
All secondary end points favored treatment with patisiran, indicating “significant improvement in quality of life, reduction in disease symptoms and disability, and improvement in nutritional status, strength, and ambulation seen with patisiran, relative to placebo,” Dr. Adams said. In the subpopulation with cardiac involvement, patisiran significantly improved cardiac end points such as mean left ventricular wall thickness and global longitudinal strain.
In a post hoc analysis, patisiran resulted in a 50% reduction in a composite rate of all-cause hospitalization and mortality and an approximately 45% reduction in a composite rate of cardiac hospitalization and all-cause mortality.
Therapy Is Under FDA Review
There were 13 deaths in the trial. None of the deaths were due to the study drug, and the rate of deaths was higher in the placebo group than in the patisiran group (7.8% vs 4.7%). The majority of adverse events were mild or moderate and included peripheral edema (29.7% of patients in the patisiran group vs 22.1% of patients in the placebo group) and infusion-related reactions (18.9% of patients in the patisiran group vs 9.1% of patients in the placebo group). Infusion-related reaction led one patient to discontinue the trial. There were no severe, life-threatening, or serious infusion-related reactions.
Adverse events that were reported more often in the placebo group than in the patisiran group included fall (28.6% vs 16.9%), urinary tract infection (18.2% vs 12.8%), nausea (20.8% vs 14.9%), muscular weakness (14.3% vs 3.4%), anemia (10.4% vs 2%), and syncope (10.4% vs 2%).
The researchers observed no safety signals regarding cataracts, hyperglycemia, infection, osteopenia or osteoporosis, liver function tests, hematology, or renal dysfunction related to patisiran. Safety in the cardiac subpopulation was comparable to that in the overall study population.
Patients who completed the APOLLO study were eligible for patisiran treatment in an open-label extension study, and 99% of eligible patients enrolled in this extension. Patisiran is under review by the FDA as a breakthrough therapy for hATTR amyloidosis. The FDA plans to complete its review by August 11, 2018.
—Jake Remaly
Suggested Reading
Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.
Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369(9):819-829.
Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.
Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015;10:109.