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, a new study suggests.
Currently, the only drug approved to treat ATTR is tafamidis, which improves survival and reduces hospitalizations, but does not reverse disease symptoms, the authors noted.
NI006 is a recombinant human anti-ATTR antibody given by infusion that was developed to trigger removal of ATTR by the body’s phagocytic immune cells.
Use of the drug was not associated with serious drug-related adverse events, though mild and moderate adverse events did occur.
Median N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin T levels also seemed to be reduced over the study period.
Given the success of the antibody in this initial 40-patient trial, a larger phase-3 placebo-controlled trial is planned and expected to launch in the second half of 2023, said lead author Pablo Garcia-Pavia, MD, of Hospital Universitario Puerta de Hierro and the Spanish National Cardiovascular Research Institute, Madrid.
However, “The design of appropriate phase-3 trials to demonstrate efficacy of drugs for ATTR-CM is becoming more complicated and challenging,” he said.
“Increased awareness of the disease and advances in cardiac imaging techniques have led to recognition of a larger number of patients with ATTR-CM who have a different clinical profile and a different prognosis than the patients who were diagnosed in previous years and were enrolled in the initial trials of stabilizers,” Dr. Garcia-Pavia added.
“Moreover, the availability of tafamidis, and hopefully soon other medications to treat ATTR-CM has complicated the design of new clinical trials because of the heterogenicity of treatments that patients might receive,” he said. “Therefore, it is critical to plan the design very well.”
Dr. Garcia-Pavia presented the findings on NI006 at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions. The study was published simultaneously in the New England Journal of Medicine.
No serious adverse events
For the phase-1, double-blind, multicenter study, the investigators randomly assigned (2:1 ratio) 40 patients (median age, 72 years; 98% men) with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive IV infusions of either NI006, at one of six doses ranging from 0.3 mg/kg to 60 mg/kg of body weight, or placebo every 4 weeks for 4 months.
After the four infusions, participants were enrolled in an open-label extension phase in which they received eight NI006 infusions with stepwise increases in the dose.
Participants had a confirmed diagnosis of ATTR-CM; left ventricular wall thickness of at least 14 mm; left ventricular ejection fraction of at least 40%; New York Heart Association class I, II, or III; estimated glomerular filtration rate of more than 30 mL/min per 1.73 m2; and an NT-proBNP level of 600 to 6,000 pg/mL.
Most (36) were receiving tafamidis, with a median treatment duration of 7 months; other ATTR-specific drugs were not permitted. Patients randomly assigned to receive NI006 seemed to have more advanced disease compared with those assigned to placebo.
Adherence to the trial protocol was high: Thirty-four patients received the four scheduled infusions during the ascending-dose phase, and 34 of 35 patients who completed this phase subsequently enrolled in the open-label extension.
No apparent drug-related serious adverse events were reported. However, during the ascending-dose phase, 38 patients had at least one adverse event, most of which were mild or moderate; of the 191 total events, 124 were grade 1 and 60 were grade 2 (most commonly heart failure and arrhythmias). Three patients had cytokine release syndrome; all three completed treatment through the extension phase.
Musculoskeletal events increased with ascending doses of NI006, which led two patients to withdraw from the trial.
At doses of at least 10 mg/kg, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac MRI, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over 12 months.
Because NI006 stimulates the patient’s own immune system to eliminate cardiac amyloid fibrils, one session chair at the meeting wondered whether NI006 represented the “rise of immunology in cardiology,” and whether biologics might follow.
Another questioned how removing amyloid might affect cardiac function. The echocardiographic findings gathered so far don’t indicate dysfunction, “but this is a small trial, and we need more data,” Dr. Garcia-Pavia said.
Tempered excitement
In a comment, Ronald Witteles, MD, professor of cardiovascular medicine, Stanford (Calif.) University, and founder/codirector of the Stanford Amyloid Center, said that “antibody-based amyloid removal strategies are not currently clinically available and represent a fundamentally different mechanism to treat the disease from what we currently have.
“While the data are encouraging and will generate excitement for later-phase studies, we’re talking about small numbers of patients and nothing definitive should be drawn from this data,” said Dr. Witteles, deputy editor of JACC: CardioOncology.
“The biggest caveat is that similar approaches of antibody removal of amyloid deposits for other forms of amyloidosis — most notably AL amyloidosis (amyloid light chain or primary amyloidosis) – have failed in late-phase trials. Although there is reason to believe that ATTR amyloidosis may be more amenable to improvements with amyloid fibril removal than AL amyloidosis, the unimpressive results in other forms of amyloidosis still do temper the excitement to a degree.”
Like Dr. Garcia-Pavia, Dr. Witteles said, “Ultimately, we are going to need to see a phase 3 clinical trial which shows that NI006 – on top of standard-of-care treatment – improves hard outcomes in the disease. As treatment options likely expand in the coming years, that is likely to be a harder and harder bar to reach.”
Furthermore, although the safety profile was favorable overall, it “wasn’t entirely clean,” given cytokine release syndrome in three patients, a lowering of platelet counts in a couple of patients, and musculoskeletal side effects that triggered two to withdraw from the study. “Unless that changes,” he said, “that will be a barrier for some patients.”
Overall, he noted, “With the vast majority of patients being able to be diagnosed noninvasively, and with treatment options now available, we have seen a true explosion in the number of patients being diagnosed.
“But we also know that the large majority ... are still not getting diagnosed or are having huge delays in diagnosis. As such, the biggest thing we can do for patients with the disease is to continue to educate people about it,” Dr. Witteles concluded.
The study was funded by Neurimmune. Dr. Garcia-Pavia disclosed ties to Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio, General Electric, Intellia, Ionis Pharmaceuticals, Neurimmune, Novo Nordisk, and Pfizer. Dr. Witteles reported ties to Alexion, Alnylam, AstraZeneca, BridgeBio, Intellia, Ionis, Janssen, Novo Nordisk, and Pfizer.
A version of this article first appeared on Medscape.com.
, a new study suggests.
Currently, the only drug approved to treat ATTR is tafamidis, which improves survival and reduces hospitalizations, but does not reverse disease symptoms, the authors noted.
NI006 is a recombinant human anti-ATTR antibody given by infusion that was developed to trigger removal of ATTR by the body’s phagocytic immune cells.
Use of the drug was not associated with serious drug-related adverse events, though mild and moderate adverse events did occur.
Median N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin T levels also seemed to be reduced over the study period.
Given the success of the antibody in this initial 40-patient trial, a larger phase-3 placebo-controlled trial is planned and expected to launch in the second half of 2023, said lead author Pablo Garcia-Pavia, MD, of Hospital Universitario Puerta de Hierro and the Spanish National Cardiovascular Research Institute, Madrid.
However, “The design of appropriate phase-3 trials to demonstrate efficacy of drugs for ATTR-CM is becoming more complicated and challenging,” he said.
“Increased awareness of the disease and advances in cardiac imaging techniques have led to recognition of a larger number of patients with ATTR-CM who have a different clinical profile and a different prognosis than the patients who were diagnosed in previous years and were enrolled in the initial trials of stabilizers,” Dr. Garcia-Pavia added.
“Moreover, the availability of tafamidis, and hopefully soon other medications to treat ATTR-CM has complicated the design of new clinical trials because of the heterogenicity of treatments that patients might receive,” he said. “Therefore, it is critical to plan the design very well.”
Dr. Garcia-Pavia presented the findings on NI006 at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions. The study was published simultaneously in the New England Journal of Medicine.
No serious adverse events
For the phase-1, double-blind, multicenter study, the investigators randomly assigned (2:1 ratio) 40 patients (median age, 72 years; 98% men) with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive IV infusions of either NI006, at one of six doses ranging from 0.3 mg/kg to 60 mg/kg of body weight, or placebo every 4 weeks for 4 months.
After the four infusions, participants were enrolled in an open-label extension phase in which they received eight NI006 infusions with stepwise increases in the dose.
Participants had a confirmed diagnosis of ATTR-CM; left ventricular wall thickness of at least 14 mm; left ventricular ejection fraction of at least 40%; New York Heart Association class I, II, or III; estimated glomerular filtration rate of more than 30 mL/min per 1.73 m2; and an NT-proBNP level of 600 to 6,000 pg/mL.
Most (36) were receiving tafamidis, with a median treatment duration of 7 months; other ATTR-specific drugs were not permitted. Patients randomly assigned to receive NI006 seemed to have more advanced disease compared with those assigned to placebo.
Adherence to the trial protocol was high: Thirty-four patients received the four scheduled infusions during the ascending-dose phase, and 34 of 35 patients who completed this phase subsequently enrolled in the open-label extension.
No apparent drug-related serious adverse events were reported. However, during the ascending-dose phase, 38 patients had at least one adverse event, most of which were mild or moderate; of the 191 total events, 124 were grade 1 and 60 were grade 2 (most commonly heart failure and arrhythmias). Three patients had cytokine release syndrome; all three completed treatment through the extension phase.
Musculoskeletal events increased with ascending doses of NI006, which led two patients to withdraw from the trial.
At doses of at least 10 mg/kg, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac MRI, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over 12 months.
Because NI006 stimulates the patient’s own immune system to eliminate cardiac amyloid fibrils, one session chair at the meeting wondered whether NI006 represented the “rise of immunology in cardiology,” and whether biologics might follow.
Another questioned how removing amyloid might affect cardiac function. The echocardiographic findings gathered so far don’t indicate dysfunction, “but this is a small trial, and we need more data,” Dr. Garcia-Pavia said.
Tempered excitement
In a comment, Ronald Witteles, MD, professor of cardiovascular medicine, Stanford (Calif.) University, and founder/codirector of the Stanford Amyloid Center, said that “antibody-based amyloid removal strategies are not currently clinically available and represent a fundamentally different mechanism to treat the disease from what we currently have.
“While the data are encouraging and will generate excitement for later-phase studies, we’re talking about small numbers of patients and nothing definitive should be drawn from this data,” said Dr. Witteles, deputy editor of JACC: CardioOncology.
“The biggest caveat is that similar approaches of antibody removal of amyloid deposits for other forms of amyloidosis — most notably AL amyloidosis (amyloid light chain or primary amyloidosis) – have failed in late-phase trials. Although there is reason to believe that ATTR amyloidosis may be more amenable to improvements with amyloid fibril removal than AL amyloidosis, the unimpressive results in other forms of amyloidosis still do temper the excitement to a degree.”
Like Dr. Garcia-Pavia, Dr. Witteles said, “Ultimately, we are going to need to see a phase 3 clinical trial which shows that NI006 – on top of standard-of-care treatment – improves hard outcomes in the disease. As treatment options likely expand in the coming years, that is likely to be a harder and harder bar to reach.”
Furthermore, although the safety profile was favorable overall, it “wasn’t entirely clean,” given cytokine release syndrome in three patients, a lowering of platelet counts in a couple of patients, and musculoskeletal side effects that triggered two to withdraw from the study. “Unless that changes,” he said, “that will be a barrier for some patients.”
Overall, he noted, “With the vast majority of patients being able to be diagnosed noninvasively, and with treatment options now available, we have seen a true explosion in the number of patients being diagnosed.
“But we also know that the large majority ... are still not getting diagnosed or are having huge delays in diagnosis. As such, the biggest thing we can do for patients with the disease is to continue to educate people about it,” Dr. Witteles concluded.
The study was funded by Neurimmune. Dr. Garcia-Pavia disclosed ties to Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio, General Electric, Intellia, Ionis Pharmaceuticals, Neurimmune, Novo Nordisk, and Pfizer. Dr. Witteles reported ties to Alexion, Alnylam, AstraZeneca, BridgeBio, Intellia, Ionis, Janssen, Novo Nordisk, and Pfizer.
A version of this article first appeared on Medscape.com.
, a new study suggests.
Currently, the only drug approved to treat ATTR is tafamidis, which improves survival and reduces hospitalizations, but does not reverse disease symptoms, the authors noted.
NI006 is a recombinant human anti-ATTR antibody given by infusion that was developed to trigger removal of ATTR by the body’s phagocytic immune cells.
Use of the drug was not associated with serious drug-related adverse events, though mild and moderate adverse events did occur.
Median N-terminal pro–B-type natriuretic peptide (NT-proBNP) and troponin T levels also seemed to be reduced over the study period.
Given the success of the antibody in this initial 40-patient trial, a larger phase-3 placebo-controlled trial is planned and expected to launch in the second half of 2023, said lead author Pablo Garcia-Pavia, MD, of Hospital Universitario Puerta de Hierro and the Spanish National Cardiovascular Research Institute, Madrid.
However, “The design of appropriate phase-3 trials to demonstrate efficacy of drugs for ATTR-CM is becoming more complicated and challenging,” he said.
“Increased awareness of the disease and advances in cardiac imaging techniques have led to recognition of a larger number of patients with ATTR-CM who have a different clinical profile and a different prognosis than the patients who were diagnosed in previous years and were enrolled in the initial trials of stabilizers,” Dr. Garcia-Pavia added.
“Moreover, the availability of tafamidis, and hopefully soon other medications to treat ATTR-CM has complicated the design of new clinical trials because of the heterogenicity of treatments that patients might receive,” he said. “Therefore, it is critical to plan the design very well.”
Dr. Garcia-Pavia presented the findings on NI006 at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2023 sessions. The study was published simultaneously in the New England Journal of Medicine.
No serious adverse events
For the phase-1, double-blind, multicenter study, the investigators randomly assigned (2:1 ratio) 40 patients (median age, 72 years; 98% men) with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive IV infusions of either NI006, at one of six doses ranging from 0.3 mg/kg to 60 mg/kg of body weight, or placebo every 4 weeks for 4 months.
After the four infusions, participants were enrolled in an open-label extension phase in which they received eight NI006 infusions with stepwise increases in the dose.
Participants had a confirmed diagnosis of ATTR-CM; left ventricular wall thickness of at least 14 mm; left ventricular ejection fraction of at least 40%; New York Heart Association class I, II, or III; estimated glomerular filtration rate of more than 30 mL/min per 1.73 m2; and an NT-proBNP level of 600 to 6,000 pg/mL.
Most (36) were receiving tafamidis, with a median treatment duration of 7 months; other ATTR-specific drugs were not permitted. Patients randomly assigned to receive NI006 seemed to have more advanced disease compared with those assigned to placebo.
Adherence to the trial protocol was high: Thirty-four patients received the four scheduled infusions during the ascending-dose phase, and 34 of 35 patients who completed this phase subsequently enrolled in the open-label extension.
No apparent drug-related serious adverse events were reported. However, during the ascending-dose phase, 38 patients had at least one adverse event, most of which were mild or moderate; of the 191 total events, 124 were grade 1 and 60 were grade 2 (most commonly heart failure and arrhythmias). Three patients had cytokine release syndrome; all three completed treatment through the extension phase.
Musculoskeletal events increased with ascending doses of NI006, which led two patients to withdraw from the trial.
At doses of at least 10 mg/kg, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac MRI, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over 12 months.
Because NI006 stimulates the patient’s own immune system to eliminate cardiac amyloid fibrils, one session chair at the meeting wondered whether NI006 represented the “rise of immunology in cardiology,” and whether biologics might follow.
Another questioned how removing amyloid might affect cardiac function. The echocardiographic findings gathered so far don’t indicate dysfunction, “but this is a small trial, and we need more data,” Dr. Garcia-Pavia said.
Tempered excitement
In a comment, Ronald Witteles, MD, professor of cardiovascular medicine, Stanford (Calif.) University, and founder/codirector of the Stanford Amyloid Center, said that “antibody-based amyloid removal strategies are not currently clinically available and represent a fundamentally different mechanism to treat the disease from what we currently have.
“While the data are encouraging and will generate excitement for later-phase studies, we’re talking about small numbers of patients and nothing definitive should be drawn from this data,” said Dr. Witteles, deputy editor of JACC: CardioOncology.
“The biggest caveat is that similar approaches of antibody removal of amyloid deposits for other forms of amyloidosis — most notably AL amyloidosis (amyloid light chain or primary amyloidosis) – have failed in late-phase trials. Although there is reason to believe that ATTR amyloidosis may be more amenable to improvements with amyloid fibril removal than AL amyloidosis, the unimpressive results in other forms of amyloidosis still do temper the excitement to a degree.”
Like Dr. Garcia-Pavia, Dr. Witteles said, “Ultimately, we are going to need to see a phase 3 clinical trial which shows that NI006 – on top of standard-of-care treatment – improves hard outcomes in the disease. As treatment options likely expand in the coming years, that is likely to be a harder and harder bar to reach.”
Furthermore, although the safety profile was favorable overall, it “wasn’t entirely clean,” given cytokine release syndrome in three patients, a lowering of platelet counts in a couple of patients, and musculoskeletal side effects that triggered two to withdraw from the study. “Unless that changes,” he said, “that will be a barrier for some patients.”
Overall, he noted, “With the vast majority of patients being able to be diagnosed noninvasively, and with treatment options now available, we have seen a true explosion in the number of patients being diagnosed.
“But we also know that the large majority ... are still not getting diagnosed or are having huge delays in diagnosis. As such, the biggest thing we can do for patients with the disease is to continue to educate people about it,” Dr. Witteles concluded.
The study was funded by Neurimmune. Dr. Garcia-Pavia disclosed ties to Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio, General Electric, Intellia, Ionis Pharmaceuticals, Neurimmune, Novo Nordisk, and Pfizer. Dr. Witteles reported ties to Alexion, Alnylam, AstraZeneca, BridgeBio, Intellia, Ionis, Janssen, Novo Nordisk, and Pfizer.
A version of this article first appeared on Medscape.com.
FROM ESC HEART FAILURE 2023