Does Solanezumab Modify Alzheimer's Disease Progression?

WASHINGTON, DC—Solanezumab, an antiamyloid monoclonal antibody, may have a disease-modifying effect on Alzheimer’s disease, according to a delayed-start analysis presented at the 2015 Alzheimer’s Association International Conference. The analysis, which uses a new statistical methodology, was presented by Paul Aisen, MD, Director of the Alz­heimer’s Therapeutic Research Institute at the University of Southern California in San Diego.

Hong Liu-Seifert, PhD, a study research advisor at Eli Lilly and Company, and colleagues developed the methodology to assess the possibly disease-modifying effects of solanezumab. The analysis was published online July 25 in Alzheimer’s & Dementia: Translational Research & Clinical Interventions.

“Agents such as antiamyloid drugs and antibodies may alter the underlying neurobiology of [Alzheimer’s disease], presumably an important distinction from symptomatic drugs that target neurotransmitters,” said Dr. Aisen. Such therapies could modify the disease in a way “that accrues benefit with time, so that the earlier you start, the greater the benefit. If you start therapy later, you don’t catch up.”

To assess the effect of solanezumab in patients with mild Alzheimer’s disease dementia, investigators analyzed data from two completed phase III trials, EXPEDITION and EXPEDITION2, and an ongoing open-label extension, EXPEDITION-EXT. The 18-month placebo-controlled trials were identically designed studies that included patients with mild to moderate Alzheimer’s disease. While the primary analyses of the trials were negative, secondary analyses showed signs of efficacy in the mild subgroups. Patients with mild disease who received solanezumab appeared to experience less cognitive decline than those who received placebo.

In the delayed-start analysis, researchers compared a total of 1,322 patients with mild Alzheimer’s disease from the completed phase III trials—659 patients who initially received solanezumab and 663 patients who initially received placebo and then received solanezumab 18 months later in the open-label extension. Of the 1,024 patients who completed the placebo-controlled period, 975 (95.2%) entered the open-label extension, and 286 delayed-start patients (58.2%) and 295 early-start patients (61%) completed two years in the study. Researchers applied a noninferiority test framework to determine if the delayed-start patients caught up with the early-start patients.

On the 14-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog ₁₄ ), the pre-specified analysis indicates that the groups remain significantly different, that the treatment effect is maintained out to 108 weeks and 132 weeks and that treatment difference remains significant,” Dr. Aisen said. “With time—so now this goes out to three-and-a-half years—patients drop out and significance is lost, but I emphasize that the curves continue to look parallel. If this were a symptomatic benefit, those two curves would merge. This suggests a disease-modifying effect instead of a symptomatic effect.”

The results “suggest that for the ADAS-Cog ₁₄ and ADCS-iADL [Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory instrumental items] scales, the benefit observed at the end of the placebo-controlled portion of the study persisted during much of the delayed-start period, supporting initiation of treatment as early as possible,” the researchers said. The 1.8-point treatment difference on the ADAS-Cog ₁₄ observed in pooled data from EXPEDITION and EXPEDITION2 at 80 weeks represents a 34% reduction in cognitive decline and the effect was sustained through 132 weeks, as evidenced by the delayed-start analysis.”

Results on the MMSE and CDR-SB scales were not statistically significant, which warrants some caution in drawing firm conclusions, the researchers said. The safety and efficacy of solanezumab treatment will continue to be evaluated in the ongoing EXPEDITION3 study in patients with mild Alzheimer’s disease.

“We are particularly excited about these data because this is the first time the delayed-start methodology has been implemented for an Alzheimer’s disease clinical trial,” said Dr. Liu-Seifert. “This new analytical method enabled us to assess if solanezumab had an effect that is consistent with slowing progression of disease by modifying the underlying disease progression, which, up until now, has not been studied. These results support the trial design and delayed-start analysis plan of EXPEDITION3, which is expected to have the last patient visit in October 2016.”

—Jake Remaly

WASHINGTON, DC—Solanezumab, an antiamyloid monoclonal antibody, may have a disease-modifying effect on Alzheimer’s disease, according to a delayed-start analysis presented at the 2015 Alzheimer’s Association International Conference. The analysis, which uses a new statistical methodology, was presented by Paul Aisen, MD, Director of the Alz­heimer’s Therapeutic Research Institute at the University of Southern California in San Diego.

Hong Liu-Seifert, PhD, a study research advisor at Eli Lilly and Company, and colleagues developed the methodology to assess the possibly disease-modifying effects of solanezumab. The analysis was published online July 25 in Alzheimer’s & Dementia: Translational Research & Clinical Interventions.

“Agents such as antiamyloid drugs and antibodies may alter the underlying neurobiology of [Alzheimer’s disease], presumably an important distinction from symptomatic drugs that target neurotransmitters,” said Dr. Aisen. Such therapies could modify the disease in a way “that accrues benefit with time, so that the earlier you start, the greater the benefit. If you start therapy later, you don’t catch up.”

To assess the effect of solanezumab in patients with mild Alzheimer’s disease dementia, investigators analyzed data from two completed phase III trials, EXPEDITION and EXPEDITION2, and an ongoing open-label extension, EXPEDITION-EXT. The 18-month placebo-controlled trials were identically designed studies that included patients with mild to moderate Alzheimer’s disease. While the primary analyses of the trials were negative, secondary analyses showed signs of efficacy in the mild subgroups. Patients with mild disease who received solanezumab appeared to experience less cognitive decline than those who received placebo.

In the delayed-start analysis, researchers compared a total of 1,322 patients with mild Alzheimer’s disease from the completed phase III trials—659 patients who initially received solanezumab and 663 patients who initially received placebo and then received solanezumab 18 months later in the open-label extension. Of the 1,024 patients who completed the placebo-controlled period, 975 (95.2%) entered the open-label extension, and 286 delayed-start patients (58.2%) and 295 early-start patients (61%) completed two years in the study. Researchers applied a noninferiority test framework to determine if the delayed-start patients caught up with the early-start patients.

On the 14-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog ₁₄ ), the pre-specified analysis indicates that the groups remain significantly different, that the treatment effect is maintained out to 108 weeks and 132 weeks and that treatment difference remains significant,” Dr. Aisen said. “With time—so now this goes out to three-and-a-half years—patients drop out and significance is lost, but I emphasize that the curves continue to look parallel. If this were a symptomatic benefit, those two curves would merge. This suggests a disease-modifying effect instead of a symptomatic effect.”

The results “suggest that for the ADAS-Cog ₁₄ and ADCS-iADL [Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory instrumental items] scales, the benefit observed at the end of the placebo-controlled portion of the study persisted during much of the delayed-start period, supporting initiation of treatment as early as possible,” the researchers said. The 1.8-point treatment difference on the ADAS-Cog ₁₄ observed in pooled data from EXPEDITION and EXPEDITION2 at 80 weeks represents a 34% reduction in cognitive decline and the effect was sustained through 132 weeks, as evidenced by the delayed-start analysis.”

Results on the MMSE and CDR-SB scales were not statistically significant, which warrants some caution in drawing firm conclusions, the researchers said. The safety and efficacy of solanezumab treatment will continue to be evaluated in the ongoing EXPEDITION3 study in patients with mild Alzheimer’s disease.

“We are particularly excited about these data because this is the first time the delayed-start methodology has been implemented for an Alzheimer’s disease clinical trial,” said Dr. Liu-Seifert. “This new analytical method enabled us to assess if solanezumab had an effect that is consistent with slowing progression of disease by modifying the underlying disease progression, which, up until now, has not been studied. These results support the trial design and delayed-start analysis plan of EXPEDITION3, which is expected to have the last patient visit in October 2016.”

—Jake Remaly

WASHINGTON, DC—Solanezumab, an antiamyloid monoclonal antibody, may have a disease-modifying effect on Alzheimer’s disease, according to a delayed-start analysis presented at the 2015 Alzheimer’s Association International Conference. The analysis, which uses a new statistical methodology, was presented by Paul Aisen, MD, Director of the Alz­heimer’s Therapeutic Research Institute at the University of Southern California in San Diego.

Hong Liu-Seifert, PhD, a study research advisor at Eli Lilly and Company, and colleagues developed the methodology to assess the possibly disease-modifying effects of solanezumab. The analysis was published online July 25 in Alzheimer’s & Dementia: Translational Research & Clinical Interventions.

“Agents such as antiamyloid drugs and antibodies may alter the underlying neurobiology of [Alzheimer’s disease], presumably an important distinction from symptomatic drugs that target neurotransmitters,” said Dr. Aisen. Such therapies could modify the disease in a way “that accrues benefit with time, so that the earlier you start, the greater the benefit. If you start therapy later, you don’t catch up.”

To assess the effect of solanezumab in patients with mild Alzheimer’s disease dementia, investigators analyzed data from two completed phase III trials, EXPEDITION and EXPEDITION2, and an ongoing open-label extension, EXPEDITION-EXT. The 18-month placebo-controlled trials were identically designed studies that included patients with mild to moderate Alzheimer’s disease. While the primary analyses of the trials were negative, secondary analyses showed signs of efficacy in the mild subgroups. Patients with mild disease who received solanezumab appeared to experience less cognitive decline than those who received placebo.

In the delayed-start analysis, researchers compared a total of 1,322 patients with mild Alzheimer’s disease from the completed phase III trials—659 patients who initially received solanezumab and 663 patients who initially received placebo and then received solanezumab 18 months later in the open-label extension. Of the 1,024 patients who completed the placebo-controlled period, 975 (95.2%) entered the open-label extension, and 286 delayed-start patients (58.2%) and 295 early-start patients (61%) completed two years in the study. Researchers applied a noninferiority test framework to determine if the delayed-start patients caught up with the early-start patients.

On the 14-item Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog ₁₄ ), the pre-specified analysis indicates that the groups remain significantly different, that the treatment effect is maintained out to 108 weeks and 132 weeks and that treatment difference remains significant,” Dr. Aisen said. “With time—so now this goes out to three-and-a-half years—patients drop out and significance is lost, but I emphasize that the curves continue to look parallel. If this were a symptomatic benefit, those two curves would merge. This suggests a disease-modifying effect instead of a symptomatic effect.”

The results “suggest that for the ADAS-Cog ₁₄ and ADCS-iADL [Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory instrumental items] scales, the benefit observed at the end of the placebo-controlled portion of the study persisted during much of the delayed-start period, supporting initiation of treatment as early as possible,” the researchers said. The 1.8-point treatment difference on the ADAS-Cog ₁₄ observed in pooled data from EXPEDITION and EXPEDITION2 at 80 weeks represents a 34% reduction in cognitive decline and the effect was sustained through 132 weeks, as evidenced by the delayed-start analysis.”

Results on the MMSE and CDR-SB scales were not statistically significant, which warrants some caution in drawing firm conclusions, the researchers said. The safety and efficacy of solanezumab treatment will continue to be evaluated in the ongoing EXPEDITION3 study in patients with mild Alzheimer’s disease.

“We are particularly excited about these data because this is the first time the delayed-start methodology has been implemented for an Alzheimer’s disease clinical trial,” said Dr. Liu-Seifert. “This new analytical method enabled us to assess if solanezumab had an effect that is consistent with slowing progression of disease by modifying the underlying disease progression, which, up until now, has not been studied. These results support the trial design and delayed-start analysis plan of EXPEDITION3, which is expected to have the last patient visit in October 2016.”

—Jake Remaly