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BARCELONA—A negative phase III clinical trial of 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, according to post hoc analyses of the trial’s data presented at the Clinical Trials in Alzheimer’s Disease conference.
The subanalyses of the SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took 225 mg of gantenerumab had some cognitive benefit. Patients who had the highest plasma concentrations of the drug particularly benefited.
Biomarker results also were positive for patients who received a high dose of treatment. Amyloid PET imaging showed significantly greater plaque reduction in the brains of participants with the highest gantenerumab exposure. CSF tests found that the antibody significantly decreased the level of phosphorylated tau. This result is the first evidence that targeting amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major contributor to cognitive decline in Alzheimer’s disease, said Tania Nikolcheva, MD, PhD, of Roche in Basel, Switzerland.
“We demonstrated that gantenerumab shows a consistent effect on the intended target, as well as on downstream biomarkers,” said Dr. Nikolcheva. “These [effects] 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 two-year interim analysis found that neither the 105-mg nor 225-mg dose conferred a significant cognitive benefit, relative to placebo. The drug is still being investigated, however, in another Roche-sponsored trial of patients with mild Alzheimer’s disease called MARGUERITE ROAD.
In addition, researchers are examining gantenerumab as part of the Dominantly Inherited Alzheimer Network Trial (DIAN-TU). This study is comparing gantenerumab with another antiamyloid antibody, solanezumab, and with placebo. DIAN-TU may provide data that support the amyloid-cascade hypothesis, and investigators are enrolling people who are cognitively normal at baseline but are highly likely to develop early-onset Alzheimer’s disease because they carry a mutation in the presenilin or amyloid precursor protein gene. Researchers seek to determine whether the drugs will prevent or delay the onset of cognitive symptoms by preventing or slowing the formation of amyloid plaques.
Roche did not release any clinical or biomarker data when it ended SCARLET ROAD. During the 2015 Alzheimer’s Association International Conference, the company disclosed that researchers had found no significant differences after two years of treatment between placebo and either drug dose in the primary cognitive end point, the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SOB). The investigators also did not find differences between treatment arms in any secondary end points, which included the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-Cog 13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).
Rate of Disease Progression Affected Efficacy
The data did contain signs, however, that the 225-mg dose of gantenerumab was somewhat effective in the subgroup of patients who were predicted to have more rapidly progressing disease, said Robert Lasser, MD, Group Medical Director, Neurodegenerative Disorders, for Roche. The benefit was obscured in the overall analysis because patient progression rates varied highly, he said. About one-third of patients progressed rapidly, one-third progressed slowly, and one-third did not progress at all during the two-year period examined in the interim analysis.
Although the dropout rates were similar in the three treatment arms, data presented at the Clinical Trials in Alzheimer’s Disease conference 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-Cog 13 than did those who remained in the study. Dropping out probably reflected their desire to abandon an ineffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Juergen Dukart, PhD, Head of Clinical Imaging at 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, said Dr. Dukart.
Drug Exposure Influenced Outcomes
The interim analysis of 315 participants that prompted the trial’s termination did not include data on the 190 participants who had dropped out by two years. But outcomes presented at the Clinical Trials in Alzheimer’s Disease conference did include data on those participants, and significant treatment differences appeared, especially when drug exposure levels were examined. Of patients with rapid progression, those with higher plasma gantenerumab concentrations had less clinical decline than did patients with lower drug exposure or patients taking placebo, said Sylvie Retout, PhD, of Roche. Among patients with rapid progression, the ADAS-Cog 13 score increased 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 patients with rapid progression were seen on MMSE scores, but not on CDR-SOB scores.
Results were different among patients who progressed slowly, said Dr. Retout. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the two-year treatment period was probably limiting the detection of a drug effect,” she said.
Finding the Right Trial Population
Variability in progression, dropout rates, and potentially skewed clinical outcomes are difficult challenges for trials of drugs to treat Alzheimer’s disease, said Dr. Lasser. “This is likely to continue to surprise us if we still have 25% to 30% [of participants] 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 allows the recruitment of a population with pure Alzheimer’s disease, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging helps to predict conversion from mild cognitive impairment to dementia, it is less useful as a tool for predicting progression. Taking baseline CSF tau levels into account did not improve the prediction of progression, said Dr. Lasser. 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-SOB and FAQ. Patients with rapid progression showed significantly more impairment on both of these scales at baseline than did patients with slow progression.
“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” said Dr. Lasser. “At baseline, the most meaningful difference was not the MMSE, but the CDR-SOB. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”
—Michele G. Sullivan
BARCELONA—A negative phase III clinical trial of 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, according to post hoc analyses of the trial’s data presented at the Clinical Trials in Alzheimer’s Disease conference.
The subanalyses of the SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took 225 mg of gantenerumab had some cognitive benefit. Patients who had the highest plasma concentrations of the drug particularly benefited.
Biomarker results also were positive for patients who received a high dose of treatment. Amyloid PET imaging showed significantly greater plaque reduction in the brains of participants with the highest gantenerumab exposure. CSF tests found that the antibody significantly decreased the level of phosphorylated tau. This result is the first evidence that targeting amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major contributor to cognitive decline in Alzheimer’s disease, said Tania Nikolcheva, MD, PhD, of Roche in Basel, Switzerland.
“We demonstrated that gantenerumab shows a consistent effect on the intended target, as well as on downstream biomarkers,” said Dr. Nikolcheva. “These [effects] 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 two-year interim analysis found that neither the 105-mg nor 225-mg dose conferred a significant cognitive benefit, relative to placebo. The drug is still being investigated, however, in another Roche-sponsored trial of patients with mild Alzheimer’s disease called MARGUERITE ROAD.
In addition, researchers are examining gantenerumab as part of the Dominantly Inherited Alzheimer Network Trial (DIAN-TU). This study is comparing gantenerumab with another antiamyloid antibody, solanezumab, and with placebo. DIAN-TU may provide data that support the amyloid-cascade hypothesis, and investigators are enrolling people who are cognitively normal at baseline but are highly likely to develop early-onset Alzheimer’s disease because they carry a mutation in the presenilin or amyloid precursor protein gene. Researchers seek to determine whether the drugs will prevent or delay the onset of cognitive symptoms by preventing or slowing the formation of amyloid plaques.
Roche did not release any clinical or biomarker data when it ended SCARLET ROAD. During the 2015 Alzheimer’s Association International Conference, the company disclosed that researchers had found no significant differences after two years of treatment between placebo and either drug dose in the primary cognitive end point, the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SOB). The investigators also did not find differences between treatment arms in any secondary end points, which included the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-Cog 13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).
Rate of Disease Progression Affected Efficacy
The data did contain signs, however, that the 225-mg dose of gantenerumab was somewhat effective in the subgroup of patients who were predicted to have more rapidly progressing disease, said Robert Lasser, MD, Group Medical Director, Neurodegenerative Disorders, for Roche. The benefit was obscured in the overall analysis because patient progression rates varied highly, he said. About one-third of patients progressed rapidly, one-third progressed slowly, and one-third did not progress at all during the two-year period examined in the interim analysis.
Although the dropout rates were similar in the three treatment arms, data presented at the Clinical Trials in Alzheimer’s Disease conference 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-Cog 13 than did those who remained in the study. Dropping out probably reflected their desire to abandon an ineffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Juergen Dukart, PhD, Head of Clinical Imaging at 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, said Dr. Dukart.
Drug Exposure Influenced Outcomes
The interim analysis of 315 participants that prompted the trial’s termination did not include data on the 190 participants who had dropped out by two years. But outcomes presented at the Clinical Trials in Alzheimer’s Disease conference did include data on those participants, and significant treatment differences appeared, especially when drug exposure levels were examined. Of patients with rapid progression, those with higher plasma gantenerumab concentrations had less clinical decline than did patients with lower drug exposure or patients taking placebo, said Sylvie Retout, PhD, of Roche. Among patients with rapid progression, the ADAS-Cog 13 score increased 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 patients with rapid progression were seen on MMSE scores, but not on CDR-SOB scores.
Results were different among patients who progressed slowly, said Dr. Retout. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the two-year treatment period was probably limiting the detection of a drug effect,” she said.
Finding the Right Trial Population
Variability in progression, dropout rates, and potentially skewed clinical outcomes are difficult challenges for trials of drugs to treat Alzheimer’s disease, said Dr. Lasser. “This is likely to continue to surprise us if we still have 25% to 30% [of participants] 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 allows the recruitment of a population with pure Alzheimer’s disease, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging helps to predict conversion from mild cognitive impairment to dementia, it is less useful as a tool for predicting progression. Taking baseline CSF tau levels into account did not improve the prediction of progression, said Dr. Lasser. 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-SOB and FAQ. Patients with rapid progression showed significantly more impairment on both of these scales at baseline than did patients with slow progression.
“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” said Dr. Lasser. “At baseline, the most meaningful difference was not the MMSE, but the CDR-SOB. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”
—Michele G. Sullivan
BARCELONA—A negative phase III clinical trial of 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, according to post hoc analyses of the trial’s data presented at the Clinical Trials in Alzheimer’s Disease conference.
The subanalyses of the SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took 225 mg of gantenerumab had some cognitive benefit. Patients who had the highest plasma concentrations of the drug particularly benefited.
Biomarker results also were positive for patients who received a high dose of treatment. Amyloid PET imaging showed significantly greater plaque reduction in the brains of participants with the highest gantenerumab exposure. CSF tests found that the antibody significantly decreased the level of phosphorylated tau. This result is the first evidence that targeting amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major contributor to cognitive decline in Alzheimer’s disease, said Tania Nikolcheva, MD, PhD, of Roche in Basel, Switzerland.
“We demonstrated that gantenerumab shows a consistent effect on the intended target, as well as on downstream biomarkers,” said Dr. Nikolcheva. “These [effects] 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 two-year interim analysis found that neither the 105-mg nor 225-mg dose conferred a significant cognitive benefit, relative to placebo. The drug is still being investigated, however, in another Roche-sponsored trial of patients with mild Alzheimer’s disease called MARGUERITE ROAD.
In addition, researchers are examining gantenerumab as part of the Dominantly Inherited Alzheimer Network Trial (DIAN-TU). This study is comparing gantenerumab with another antiamyloid antibody, solanezumab, and with placebo. DIAN-TU may provide data that support the amyloid-cascade hypothesis, and investigators are enrolling people who are cognitively normal at baseline but are highly likely to develop early-onset Alzheimer’s disease because they carry a mutation in the presenilin or amyloid precursor protein gene. Researchers seek to determine whether the drugs will prevent or delay the onset of cognitive symptoms by preventing or slowing the formation of amyloid plaques.
Roche did not release any clinical or biomarker data when it ended SCARLET ROAD. During the 2015 Alzheimer’s Association International Conference, the company disclosed that researchers had found no significant differences after two years of treatment between placebo and either drug dose in the primary cognitive end point, the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SOB). The investigators also did not find differences between treatment arms in any secondary end points, which included the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-Cog 13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).
Rate of Disease Progression Affected Efficacy
The data did contain signs, however, that the 225-mg dose of gantenerumab was somewhat effective in the subgroup of patients who were predicted to have more rapidly progressing disease, said Robert Lasser, MD, Group Medical Director, Neurodegenerative Disorders, for Roche. The benefit was obscured in the overall analysis because patient progression rates varied highly, he said. About one-third of patients progressed rapidly, one-third progressed slowly, and one-third did not progress at all during the two-year period examined in the interim analysis.
Although the dropout rates were similar in the three treatment arms, data presented at the Clinical Trials in Alzheimer’s Disease conference 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-Cog 13 than did those who remained in the study. Dropping out probably reflected their desire to abandon an ineffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Juergen Dukart, PhD, Head of Clinical Imaging at 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, said Dr. Dukart.
Drug Exposure Influenced Outcomes
The interim analysis of 315 participants that prompted the trial’s termination did not include data on the 190 participants who had dropped out by two years. But outcomes presented at the Clinical Trials in Alzheimer’s Disease conference did include data on those participants, and significant treatment differences appeared, especially when drug exposure levels were examined. Of patients with rapid progression, those with higher plasma gantenerumab concentrations had less clinical decline than did patients with lower drug exposure or patients taking placebo, said Sylvie Retout, PhD, of Roche. Among patients with rapid progression, the ADAS-Cog 13 score increased 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 patients with rapid progression were seen on MMSE scores, but not on CDR-SOB scores.
Results were different among patients who progressed slowly, said Dr. Retout. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the two-year treatment period was probably limiting the detection of a drug effect,” she said.
Finding the Right Trial Population
Variability in progression, dropout rates, and potentially skewed clinical outcomes are difficult challenges for trials of drugs to treat Alzheimer’s disease, said Dr. Lasser. “This is likely to continue to surprise us if we still have 25% to 30% [of participants] 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 allows the recruitment of a population with pure Alzheimer’s disease, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging helps to predict conversion from mild cognitive impairment to dementia, it is less useful as a tool for predicting progression. Taking baseline CSF tau levels into account did not improve the prediction of progression, said Dr. Lasser. 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-SOB and FAQ. Patients with rapid progression showed significantly more impairment on both of these scales at baseline than did patients with slow progression.
“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” said Dr. Lasser. “At baseline, the most meaningful difference was not the MMSE, but the CDR-SOB. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”
—Michele G. Sullivan