User login
BARCELONA – A failed phase III clinical trial for the investigational antiamyloid antibody gantenerumab in patients with Alzheimer’s disease may have had better results with a higher dose aimed at a more targeted population, new post hoc analyses of the trial’s data suggest.
The subanalyses of the now-defunct SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took gantenerumab 225 mg received some cognitive benefit, especially in those who had the highest plasma concentrations.
Biomarker results also shifted toward the positive, according to data presented at the Clinical Trials in Alzheimer’s Disease conference. Amyloid PET imaging showed significantly greater plaque reduction in the brains of those with the highest gantenerumab exposure. Cerebrospinal fluid tests found that the antibody significantly decreased the level of phosphorylated tau. This, said Dr. Tania Nikolcheva, is the first evidence that attacking amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major player in Alzheimer’s cognitive decline.
“We demonstrated that gantenerumab shows a consistent effect on the intended target as well as on downstream biomarkers,” said Dr. Nikolcheva of Hoffman-LaRoche, which is developing the drug. “These seem to be exposure- and dose-dependent, which supports following this trial with tests of higher dosages.”
In December 2014, Roche’s SCARLET ROAD study was halted after a 2-year interim analysis found that neither the 105 mg nor 225 mg dose conferred a significant cognitive benefit relative to placebo. But the antibody’s story is still unfolding: The drug is still being investigated in another Roche-sponsored trial of patients with mild disease called MARGUERITE ROAD.
Gantenerumab’s most highly anticipated test, however, will be in the Dominantly Inherited Alzheimer Network Trial(DIAN-TU). This study is comparing gantenerumab to another antiamyloid antibody, solanezumab, and to placebo. A crucial investigation with the potential of proving the amyloid cascade hypothesis, DIAN-TU is enrolling people who are cognitively normal at baseline but are virtually guaranteed to develop early-onset Alzheimer’s because they carry a mutation in the presenilin or amyloid precursor protein gene. The hope is that the drugs will prevent or at least delay the onset of cognitive symptoms by preventing or slowing amyloid plaque formation.
Roche didn’t release any clinical or biomarker data when it ended SCARLET ROAD a year ago. During the Alzheimer’s Association International Conference (AAIC) in July, the company disclosed that there were no significant differences after 2 years of treatment between placebo and either drug dose in the primary cognitive endpoint, the Clinical Dementia Rating–sum of boxes (CDR-sb), or in any secondary endpoints: the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-cog13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).
Rate of disease progression proved important
However, there were signs that the 225-mg dose of gantenerumab was at least somewhat effective in the subgroup of patients who seemed destined to have more rapidly progressing disease, Roche’s Dr. Robert Lasser said at AAIC. The benefit was obscured in the overall analysis, he said, because patient progression rates varied so highly – about a third progressed rapidly, a third slowly, and a third didn’t progress at all over the 2-year period examined in the interim analysis.
While the dropout rates were similar in the three treatment arms, data presented at CTAD showed that patients in the placebo group who dropped out were progressing four times faster on the MMSE and three times faster on the ADAS-cog13 than did those who remained in the study. Dropping out probably reflected their desire to abandon a noneffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Dr. Juergen Dukart of Roche.
Conversely, patients with rapidly progressing disease in the active groups may have responded well to the treatment, making them more likely to stay in the trial. The disproportionate retention combined with variable progression could have masked the real treatment effect, he said.
Drug exposure in rapidly progressing disease
The trial-ending interim analysis of 315 subjects didn’t include data on the 190 who had dropped out by 2 years. But outcomes presented at CTAD did include data on those subjects, and significant treatment differences appeared, especially in light of drug exposure levels. Of the fast progressers, those with higher plasma gantenerumab concentrations had less clinical decline than did those with lower drug exposure or those taking placebo, said Dr. Sylvie Retout of Roche. Among fast progressers, the ADAS-cog13 increased (indicating worsening) by 6 points in the placebo group; by 5 points in the low-exposure group; by 4 points in the medium-exposure group; and by 2 points in the high-exposure group. Similar exposure trends among fast progressers were seen on MMSE scores, but not on CDR-sb scores.
The story was different among patients who progressed slowly, Dr. Retout said. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the 2-year treatment period was probably limiting the detection of a drug effect,” she said.
Finding the right trial population
The problem of progression variability, dropout rates, and potentially skewed clinical outcomes is a tough nut for Alzheimer’s drug trials, Dr. Lasser said at the CTAD conference.
“This is likely to continue to surprise us if we still have this 25%-30% in our trials who don’t decline over the course of treatment. There really aren’t any big differences at baseline that stand out so that you could create the inclusion criteria to minimize this population of patients.”
Amyloid imaging, which does at least allow recruitment of a pure Alzheimer’s cohort, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging is a great tool for predicting conversion to dementia from mild cognitive impairment, it’s not terribly useful as a tool for predicting progression.
Factoring baseline cerebrospinal fluid tau levels into the equation didn’t improve prediction, Dr. Lasser noted. Apolipoprotein E (APOE) allele status was similarly unhelpful.
“We didn’t find very much difference among the allele groups; there was no consistent pattern, and the between-group differences were small. So we’re beginning to hypothesize that while APOE is an excellent risk marker before cognitive decline develops, once it does start, allele status may not be as crucial in determining the patient’s eventual outcome.”
The only hints of progression speed at baseline were in the two functional measures of CDR-sb and FAQ. Fast progressers showed significantly more impairment on both of these at baseline than did slow progressers.
“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” Dr. Lasser said. “At baseline, the most meaningful difference was not the MMSE, but the CDR-sb. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”
On Twitter @Alz_Gal
BARCELONA – A failed phase III clinical trial for the investigational antiamyloid antibody gantenerumab in patients with Alzheimer’s disease may have had better results with a higher dose aimed at a more targeted population, new post hoc analyses of the trial’s data suggest.
The subanalyses of the now-defunct SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took gantenerumab 225 mg received some cognitive benefit, especially in those who had the highest plasma concentrations.
Biomarker results also shifted toward the positive, according to data presented at the Clinical Trials in Alzheimer’s Disease conference. Amyloid PET imaging showed significantly greater plaque reduction in the brains of those with the highest gantenerumab exposure. Cerebrospinal fluid tests found that the antibody significantly decreased the level of phosphorylated tau. This, said Dr. Tania Nikolcheva, is the first evidence that attacking amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major player in Alzheimer’s cognitive decline.
“We demonstrated that gantenerumab shows a consistent effect on the intended target as well as on downstream biomarkers,” said Dr. Nikolcheva of Hoffman-LaRoche, which is developing the drug. “These seem to be exposure- and dose-dependent, which supports following this trial with tests of higher dosages.”
In December 2014, Roche’s SCARLET ROAD study was halted after a 2-year interim analysis found that neither the 105 mg nor 225 mg dose conferred a significant cognitive benefit relative to placebo. But the antibody’s story is still unfolding: The drug is still being investigated in another Roche-sponsored trial of patients with mild disease called MARGUERITE ROAD.
Gantenerumab’s most highly anticipated test, however, will be in the Dominantly Inherited Alzheimer Network Trial(DIAN-TU). This study is comparing gantenerumab to another antiamyloid antibody, solanezumab, and to placebo. A crucial investigation with the potential of proving the amyloid cascade hypothesis, DIAN-TU is enrolling people who are cognitively normal at baseline but are virtually guaranteed to develop early-onset Alzheimer’s because they carry a mutation in the presenilin or amyloid precursor protein gene. The hope is that the drugs will prevent or at least delay the onset of cognitive symptoms by preventing or slowing amyloid plaque formation.
Roche didn’t release any clinical or biomarker data when it ended SCARLET ROAD a year ago. During the Alzheimer’s Association International Conference (AAIC) in July, the company disclosed that there were no significant differences after 2 years of treatment between placebo and either drug dose in the primary cognitive endpoint, the Clinical Dementia Rating–sum of boxes (CDR-sb), or in any secondary endpoints: the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-cog13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).
Rate of disease progression proved important
However, there were signs that the 225-mg dose of gantenerumab was at least somewhat effective in the subgroup of patients who seemed destined to have more rapidly progressing disease, Roche’s Dr. Robert Lasser said at AAIC. The benefit was obscured in the overall analysis, he said, because patient progression rates varied so highly – about a third progressed rapidly, a third slowly, and a third didn’t progress at all over the 2-year period examined in the interim analysis.
While the dropout rates were similar in the three treatment arms, data presented at CTAD showed that patients in the placebo group who dropped out were progressing four times faster on the MMSE and three times faster on the ADAS-cog13 than did those who remained in the study. Dropping out probably reflected their desire to abandon a noneffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Dr. Juergen Dukart of Roche.
Conversely, patients with rapidly progressing disease in the active groups may have responded well to the treatment, making them more likely to stay in the trial. The disproportionate retention combined with variable progression could have masked the real treatment effect, he said.
Drug exposure in rapidly progressing disease
The trial-ending interim analysis of 315 subjects didn’t include data on the 190 who had dropped out by 2 years. But outcomes presented at CTAD did include data on those subjects, and significant treatment differences appeared, especially in light of drug exposure levels. Of the fast progressers, those with higher plasma gantenerumab concentrations had less clinical decline than did those with lower drug exposure or those taking placebo, said Dr. Sylvie Retout of Roche. Among fast progressers, the ADAS-cog13 increased (indicating worsening) by 6 points in the placebo group; by 5 points in the low-exposure group; by 4 points in the medium-exposure group; and by 2 points in the high-exposure group. Similar exposure trends among fast progressers were seen on MMSE scores, but not on CDR-sb scores.
The story was different among patients who progressed slowly, Dr. Retout said. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the 2-year treatment period was probably limiting the detection of a drug effect,” she said.
Finding the right trial population
The problem of progression variability, dropout rates, and potentially skewed clinical outcomes is a tough nut for Alzheimer’s drug trials, Dr. Lasser said at the CTAD conference.
“This is likely to continue to surprise us if we still have this 25%-30% in our trials who don’t decline over the course of treatment. There really aren’t any big differences at baseline that stand out so that you could create the inclusion criteria to minimize this population of patients.”
Amyloid imaging, which does at least allow recruitment of a pure Alzheimer’s cohort, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging is a great tool for predicting conversion to dementia from mild cognitive impairment, it’s not terribly useful as a tool for predicting progression.
Factoring baseline cerebrospinal fluid tau levels into the equation didn’t improve prediction, Dr. Lasser noted. Apolipoprotein E (APOE) allele status was similarly unhelpful.
“We didn’t find very much difference among the allele groups; there was no consistent pattern, and the between-group differences were small. So we’re beginning to hypothesize that while APOE is an excellent risk marker before cognitive decline develops, once it does start, allele status may not be as crucial in determining the patient’s eventual outcome.”
The only hints of progression speed at baseline were in the two functional measures of CDR-sb and FAQ. Fast progressers showed significantly more impairment on both of these at baseline than did slow progressers.
“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” Dr. Lasser said. “At baseline, the most meaningful difference was not the MMSE, but the CDR-sb. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”
On Twitter @Alz_Gal
BARCELONA – A failed phase III clinical trial for the investigational antiamyloid antibody gantenerumab in patients with Alzheimer’s disease may have had better results with a higher dose aimed at a more targeted population, new post hoc analyses of the trial’s data suggest.
The subanalyses of the now-defunct SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took gantenerumab 225 mg received some cognitive benefit, especially in those who had the highest plasma concentrations.
Biomarker results also shifted toward the positive, according to data presented at the Clinical Trials in Alzheimer’s Disease conference. Amyloid PET imaging showed significantly greater plaque reduction in the brains of those with the highest gantenerumab exposure. Cerebrospinal fluid tests found that the antibody significantly decreased the level of phosphorylated tau. This, said Dr. Tania Nikolcheva, is the first evidence that attacking amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major player in Alzheimer’s cognitive decline.
“We demonstrated that gantenerumab shows a consistent effect on the intended target as well as on downstream biomarkers,” said Dr. Nikolcheva of Hoffman-LaRoche, which is developing the drug. “These seem to be exposure- and dose-dependent, which supports following this trial with tests of higher dosages.”
In December 2014, Roche’s SCARLET ROAD study was halted after a 2-year interim analysis found that neither the 105 mg nor 225 mg dose conferred a significant cognitive benefit relative to placebo. But the antibody’s story is still unfolding: The drug is still being investigated in another Roche-sponsored trial of patients with mild disease called MARGUERITE ROAD.
Gantenerumab’s most highly anticipated test, however, will be in the Dominantly Inherited Alzheimer Network Trial(DIAN-TU). This study is comparing gantenerumab to another antiamyloid antibody, solanezumab, and to placebo. A crucial investigation with the potential of proving the amyloid cascade hypothesis, DIAN-TU is enrolling people who are cognitively normal at baseline but are virtually guaranteed to develop early-onset Alzheimer’s because they carry a mutation in the presenilin or amyloid precursor protein gene. The hope is that the drugs will prevent or at least delay the onset of cognitive symptoms by preventing or slowing amyloid plaque formation.
Roche didn’t release any clinical or biomarker data when it ended SCARLET ROAD a year ago. During the Alzheimer’s Association International Conference (AAIC) in July, the company disclosed that there were no significant differences after 2 years of treatment between placebo and either drug dose in the primary cognitive endpoint, the Clinical Dementia Rating–sum of boxes (CDR-sb), or in any secondary endpoints: the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-cog13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).
Rate of disease progression proved important
However, there were signs that the 225-mg dose of gantenerumab was at least somewhat effective in the subgroup of patients who seemed destined to have more rapidly progressing disease, Roche’s Dr. Robert Lasser said at AAIC. The benefit was obscured in the overall analysis, he said, because patient progression rates varied so highly – about a third progressed rapidly, a third slowly, and a third didn’t progress at all over the 2-year period examined in the interim analysis.
While the dropout rates were similar in the three treatment arms, data presented at CTAD showed that patients in the placebo group who dropped out were progressing four times faster on the MMSE and three times faster on the ADAS-cog13 than did those who remained in the study. Dropping out probably reflected their desire to abandon a noneffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Dr. Juergen Dukart of Roche.
Conversely, patients with rapidly progressing disease in the active groups may have responded well to the treatment, making them more likely to stay in the trial. The disproportionate retention combined with variable progression could have masked the real treatment effect, he said.
Drug exposure in rapidly progressing disease
The trial-ending interim analysis of 315 subjects didn’t include data on the 190 who had dropped out by 2 years. But outcomes presented at CTAD did include data on those subjects, and significant treatment differences appeared, especially in light of drug exposure levels. Of the fast progressers, those with higher plasma gantenerumab concentrations had less clinical decline than did those with lower drug exposure or those taking placebo, said Dr. Sylvie Retout of Roche. Among fast progressers, the ADAS-cog13 increased (indicating worsening) by 6 points in the placebo group; by 5 points in the low-exposure group; by 4 points in the medium-exposure group; and by 2 points in the high-exposure group. Similar exposure trends among fast progressers were seen on MMSE scores, but not on CDR-sb scores.
The story was different among patients who progressed slowly, Dr. Retout said. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the 2-year treatment period was probably limiting the detection of a drug effect,” she said.
Finding the right trial population
The problem of progression variability, dropout rates, and potentially skewed clinical outcomes is a tough nut for Alzheimer’s drug trials, Dr. Lasser said at the CTAD conference.
“This is likely to continue to surprise us if we still have this 25%-30% in our trials who don’t decline over the course of treatment. There really aren’t any big differences at baseline that stand out so that you could create the inclusion criteria to minimize this population of patients.”
Amyloid imaging, which does at least allow recruitment of a pure Alzheimer’s cohort, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging is a great tool for predicting conversion to dementia from mild cognitive impairment, it’s not terribly useful as a tool for predicting progression.
Factoring baseline cerebrospinal fluid tau levels into the equation didn’t improve prediction, Dr. Lasser noted. Apolipoprotein E (APOE) allele status was similarly unhelpful.
“We didn’t find very much difference among the allele groups; there was no consistent pattern, and the between-group differences were small. So we’re beginning to hypothesize that while APOE is an excellent risk marker before cognitive decline develops, once it does start, allele status may not be as crucial in determining the patient’s eventual outcome.”
The only hints of progression speed at baseline were in the two functional measures of CDR-sb and FAQ. Fast progressers showed significantly more impairment on both of these at baseline than did slow progressers.
“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” Dr. Lasser said. “At baseline, the most meaningful difference was not the MMSE, but the CDR-sb. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”
On Twitter @Alz_Gal
AT CTAD
