Clinical Trials on Alzheimer's Disease (CTAD)

SAN DIEGO – Ladostigil, a drug that combines molecular characteristics of rivastigmine and rasagiline, was associated with some modest memory improvement and – perhaps more interestingly – a signal of brain volume preservation in a phase IIb study of patients with mild cognitive impairment.

Both whole brain and hippocampal volume after 3 years were about 1% higher in the trial’s active group than in the placebo group.

The volumetric data are potentially of more interest than the cognitive results, which didn’t meet the study’s primary endpoint of delaying or preventing conversion from mild cognitive impairment (MCI) to Alzheimer’s disease, Lon Schneider, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

“The whole brain and hippocampal volume started to separate after 1 year and maximized at 2 years,” said Dr. Schneider of the University of Southern California, Los Angeles. “With hippocampal volume, we lose the significance of the effect by year 3, but when we continue on to the end there is a nominal significance in whole brain volume favoring the drug.”

He said the trial was plagued by a 35% dropout rate, probably because of perceived ineffectiveness of the drug. “Those numbers got in the way of looking at this outcome, particularly with 12 drops between years 2 and 3.”

Nevertheless, the drug will continue along its developmental pathway. The Israeli company developing it, Avraham Pharma, is seeking a larger pharmaceutical company with which to partner, according to its website.

Ladostigil pieces together molecular structures from both the monoamine oxidase-B inhibitor rasagiline and the anticholinesterase inhibitor rivastigmine (Exelon).

Avraham suggests that ladostigil could modify Alzheimer’s by neuroprotection, immune modulation, and reducing oxidative stress that leads the release of proinflammatory cytokines and microglial activation.

In 2012, the drug failed a phase II trial focusing on cognition in patients with Alzheimer’s. Afterward, Avraham lowered the dose from 80 mg to 20 mg and launched the current trial, with a refocus on MCI conversion.

It comprised 210 patients with MCI. The mean age was 71 years; mean Mini-Mental State Examination score was 28. About one-third were carriers of the high-risk apolipoprotein E4 allele. Patients were randomized to placebo or 20 mg ladostigil daily for 36 months. Brain MRI was performed at baseline and every 6 months throughout the trial.

The study failed to meet its primary endpoint of MCI conversion to Alzheimer’s. Fourteen patients in the active group and 20 in the placebo group progressed to Alzheimer’s. In year 3, there was a separation of curves with 4 vs. 10 patients progressing to Alzheimer’s, but overall the endpoint was not statistically significant (P = .16).

The two groups began to separate in the decline of brain volume around 1 year into the trial. For hippocampal volume, the difference was statistically significant only at 24 months. By 36 months, volume in the active and placebo groups overlapped slightly with a P value of .31.

The changes in whole-brain volume were somewhat more pronounced. The declining slopes in whole-brain volume began to separate at 12 months. At both 24 and 36 months, the differences were statistically significant (P = .033 and .036, respectively), with curves continuing to diverge at the study’s end.

Adverse events occurred in about 80% of patients (82% with active treatment vs. 79% with placebo); about 25% of both arms experienced serious adverse events.

Common adverse events were atrial fibrillation (8% vs. 3%), chest pain (5% vs. 3%), and benign prostatic hyperplasia (6% vs. 3%). Other events included dizziness, arthralgia, depression, and confusion.

None of the 35% who dropped out of the trial did so for an adverse event, Dr. Schneider noted.

The Neuropsychological Test Battery (NTB) and the Rey Auditory Verbal Learning Test (RAVLT) were secondary measures of behavior and cognition. Both showed positive trends for ladostigil, but neither was statistically significant.

Dr. Schneider has disclosed financial relationships with numerous pharmaceutical companies, but has no financial ties with Avraham.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – Ladostigil, a drug that combines molecular characteristics of rivastigmine and rasagiline, was associated with some modest memory improvement and – perhaps more interestingly – a signal of brain volume preservation in a phase IIb study of patients with mild cognitive impairment.

Both whole brain and hippocampal volume after 3 years were about 1% higher in the trial’s active group than in the placebo group.

The volumetric data are potentially of more interest than the cognitive results, which didn’t meet the study’s primary endpoint of delaying or preventing conversion from mild cognitive impairment (MCI) to Alzheimer’s disease, Lon Schneider, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

“The whole brain and hippocampal volume started to separate after 1 year and maximized at 2 years,” said Dr. Schneider of the University of Southern California, Los Angeles. “With hippocampal volume, we lose the significance of the effect by year 3, but when we continue on to the end there is a nominal significance in whole brain volume favoring the drug.”

He said the trial was plagued by a 35% dropout rate, probably because of perceived ineffectiveness of the drug. “Those numbers got in the way of looking at this outcome, particularly with 12 drops between years 2 and 3.”

Nevertheless, the drug will continue along its developmental pathway. The Israeli company developing it, Avraham Pharma, is seeking a larger pharmaceutical company with which to partner, according to its website.

Ladostigil pieces together molecular structures from both the monoamine oxidase-B inhibitor rasagiline and the anticholinesterase inhibitor rivastigmine (Exelon).

Avraham suggests that ladostigil could modify Alzheimer’s by neuroprotection, immune modulation, and reducing oxidative stress that leads the release of proinflammatory cytokines and microglial activation.

In 2012, the drug failed a phase II trial focusing on cognition in patients with Alzheimer’s. Afterward, Avraham lowered the dose from 80 mg to 20 mg and launched the current trial, with a refocus on MCI conversion.

It comprised 210 patients with MCI. The mean age was 71 years; mean Mini-Mental State Examination score was 28. About one-third were carriers of the high-risk apolipoprotein E4 allele. Patients were randomized to placebo or 20 mg ladostigil daily for 36 months. Brain MRI was performed at baseline and every 6 months throughout the trial.

The study failed to meet its primary endpoint of MCI conversion to Alzheimer’s. Fourteen patients in the active group and 20 in the placebo group progressed to Alzheimer’s. In year 3, there was a separation of curves with 4 vs. 10 patients progressing to Alzheimer’s, but overall the endpoint was not statistically significant (P = .16).

The two groups began to separate in the decline of brain volume around 1 year into the trial. For hippocampal volume, the difference was statistically significant only at 24 months. By 36 months, volume in the active and placebo groups overlapped slightly with a P value of .31.

The changes in whole-brain volume were somewhat more pronounced. The declining slopes in whole-brain volume began to separate at 12 months. At both 24 and 36 months, the differences were statistically significant (P = .033 and .036, respectively), with curves continuing to diverge at the study’s end.

Adverse events occurred in about 80% of patients (82% with active treatment vs. 79% with placebo); about 25% of both arms experienced serious adverse events.

Common adverse events were atrial fibrillation (8% vs. 3%), chest pain (5% vs. 3%), and benign prostatic hyperplasia (6% vs. 3%). Other events included dizziness, arthralgia, depression, and confusion.

None of the 35% who dropped out of the trial did so for an adverse event, Dr. Schneider noted.

The Neuropsychological Test Battery (NTB) and the Rey Auditory Verbal Learning Test (RAVLT) were secondary measures of behavior and cognition. Both showed positive trends for ladostigil, but neither was statistically significant.

Dr. Schneider has disclosed financial relationships with numerous pharmaceutical companies, but has no financial ties with Avraham.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – Ladostigil, a drug that combines molecular characteristics of rivastigmine and rasagiline, was associated with some modest memory improvement and – perhaps more interestingly – a signal of brain volume preservation in a phase IIb study of patients with mild cognitive impairment.

Both whole brain and hippocampal volume after 3 years were about 1% higher in the trial’s active group than in the placebo group.

The volumetric data are potentially of more interest than the cognitive results, which didn’t meet the study’s primary endpoint of delaying or preventing conversion from mild cognitive impairment (MCI) to Alzheimer’s disease, Lon Schneider, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

“The whole brain and hippocampal volume started to separate after 1 year and maximized at 2 years,” said Dr. Schneider of the University of Southern California, Los Angeles. “With hippocampal volume, we lose the significance of the effect by year 3, but when we continue on to the end there is a nominal significance in whole brain volume favoring the drug.”

He said the trial was plagued by a 35% dropout rate, probably because of perceived ineffectiveness of the drug. “Those numbers got in the way of looking at this outcome, particularly with 12 drops between years 2 and 3.”

Nevertheless, the drug will continue along its developmental pathway. The Israeli company developing it, Avraham Pharma, is seeking a larger pharmaceutical company with which to partner, according to its website.

Ladostigil pieces together molecular structures from both the monoamine oxidase-B inhibitor rasagiline and the anticholinesterase inhibitor rivastigmine (Exelon).

Avraham suggests that ladostigil could modify Alzheimer’s by neuroprotection, immune modulation, and reducing oxidative stress that leads the release of proinflammatory cytokines and microglial activation.

In 2012, the drug failed a phase II trial focusing on cognition in patients with Alzheimer’s. Afterward, Avraham lowered the dose from 80 mg to 20 mg and launched the current trial, with a refocus on MCI conversion.

It comprised 210 patients with MCI. The mean age was 71 years; mean Mini-Mental State Examination score was 28. About one-third were carriers of the high-risk apolipoprotein E4 allele. Patients were randomized to placebo or 20 mg ladostigil daily for 36 months. Brain MRI was performed at baseline and every 6 months throughout the trial.

The study failed to meet its primary endpoint of MCI conversion to Alzheimer’s. Fourteen patients in the active group and 20 in the placebo group progressed to Alzheimer’s. In year 3, there was a separation of curves with 4 vs. 10 patients progressing to Alzheimer’s, but overall the endpoint was not statistically significant (P = .16).

The two groups began to separate in the decline of brain volume around 1 year into the trial. For hippocampal volume, the difference was statistically significant only at 24 months. By 36 months, volume in the active and placebo groups overlapped slightly with a P value of .31.

The changes in whole-brain volume were somewhat more pronounced. The declining slopes in whole-brain volume began to separate at 12 months. At both 24 and 36 months, the differences were statistically significant (P = .033 and .036, respectively), with curves continuing to diverge at the study’s end.

Adverse events occurred in about 80% of patients (82% with active treatment vs. 79% with placebo); about 25% of both arms experienced serious adverse events.

Common adverse events were atrial fibrillation (8% vs. 3%), chest pain (5% vs. 3%), and benign prostatic hyperplasia (6% vs. 3%). Other events included dizziness, arthralgia, depression, and confusion.

None of the 35% who dropped out of the trial did so for an adverse event, Dr. Schneider noted.

The Neuropsychological Test Battery (NTB) and the Rey Auditory Verbal Learning Test (RAVLT) were secondary measures of behavior and cognition. Both showed positive trends for ladostigil, but neither was statistically significant.

Dr. Schneider has disclosed financial relationships with numerous pharmaceutical companies, but has no financial ties with Avraham.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – The antiamyloid antibody aducanumab significantly reduced amyloid brain plaques in Alzheimer’s disease patients who entered a second year of therapy in an open-label extension trial.

Plaque volume declined in a time- and dose-dependent manner, with a bit of movement even among patients who crossed over to the lowest 1-mg/kg dose after a year of taking placebo in the phase Ib PRIME study, Samantha Haeberlein, PhD, reported at the Clinical Trials on Alzheimer’s Disease conference.

The linear declines in plaque burden were dramatic enough to draw a collective gasp of appreciation from the packed auditorium. But the cognitive and functional data of aducanumab (Biogen), while deemed encouraging, were not as striking. The Clinical Dementia Rating Scale-sum of boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) showed dose-dependent slowing of decline, but the drug’s effect approached statistical significance only among those who finished 2 years on 10 mg/kg aducanumab infused every 4 weeks. This group experienced relative stability of MMSE scores, which dropped only about 1 point from baseline, and also showed the greatest decline in amyloid plaque volume.

Biogen deemed this result on the MMSE, which represented a 3.27-point separation from the 1-mg/kg dose group, as “nominally significant,” with a P value noted as “less than .05.”

However, the finding must be viewed with extreme caution, said Dr. Haeberlein, Biogen’s vice president of clinical development. There were only 15 subjects in this group, and the study was not primarily intended to examine cognition.

“I must emphasize once again that these are exploratory data and these sample sizes are very small for these types of assessments,” she said. “Nonetheless, we find them informative.”

MMSE changes in the other dosing groups of 1, 3, and 6 mg/kg were not statistically significant at the end of the study. There were not any significant findings on the CDR-SB measure.

Alzheimer’s Association reaction

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, was cautiously optimistic.

Full 12-month results

Biogen presented two aducanumab abstracts at the meeting, both describing its 12-month phase Ib PRIME study and its 12-month, open-label extension study. The drug is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to the company. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.

PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a pure amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. PRIME’s primary outcomes were safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase Ib study, were exploratory.

They must also be interpreted in light of the very small numbers, about 30 patients in each dosing group at baseline. In addition, just 69 patients finished the entire 24-month dosing period, leaving only 15-23 patients in each group by the end of the study.

Vissia Viglietta, MD, Biogen’s senior medical director of clinical development, presented the 12-month data. At 52 weeks, all dosing groups, even the 1 mg/kg, saw statistically significant reductions in amyloid plaque, compared with placebo. These changes were dose-dependent; the 10-mg/kg group had the largest reduction, with a P value of less than .001.

There also were dose-dependent changes in the CDR-SB and MMSE, and some of these reached statistical significance.

On the CDR-SB, patients taking placebo declined by an average of 1.89 points. Declines in the 1-, 3-, and 6-mg/kg groups were not significant relative to placebo. However, the 10-mg/kg arm experienced a significant separation from placebo, declining an average of 0.63 points (P less than .05).

The story was similar for the MMSE. Patients taking placebo declined by 2.45 points. The decline was 2.2 points in the 1-mg/kg group; 0.75 in the 3-mg/kg group; and 0.55 in the 10-mg/kg group. The only statistically significant results relative to placebo occurred with the 10-mg/kg group (P less than .05).

The 6-mg/kg group didn’t fit this pattern though, losing an average of 2 points. Biogen has been unable to explain this, but some researchers suggest such an outlying result isn’t surprising, given the small numbers in each group and the exploratory nature of the cognitive analysis.

Amyloid-related imaging abnormalities (ARIA), an inflammatory reaction thought to be related to the removal of amyloid plaque, were the most common adverse event (n = 27). Most of these (22) were in apolipoprotein E4 allele carriers.

Two patients in the placebo arm died, as well as one in the 10-mg/kg arm, but it was not considered related to the study drug. There were no significant changes in hematology, chemistry, urinalysis, electrocardiogram, or vital signs.

Open-label extension results

Dr. Haeberlein focused on the subsequent 12-month, open-label extension trial, which enrolled 117 of the randomized cohort. In this study, patients who had been taking placebo were switched to either 3- or 6-mg/kg aducanumab. Patients who had taken 1 mg/kg were switched to 3 mg/kg. By the end, the remaining patients had taken the antibody for 2 years.

By 24 months, all the dosing groups showed a continued, linear reduction of amyloid plaques. Even those who switched from placebo to 3 mg/kg started to experience plaque reduction, although of a lesser magnitude than with the higher doses.

While still expressing caution, Dr. Haeberlein framed the CDR-SB results as very positive. The placebo and 1-mg/kg switchers continued to progress, but for those who continued on the 3-, 6-, and 10-mg/kg doses, “we saw a saw a numerical slowing of disease progression at both 18 and 24 months.”

However, none of the changes in CDR-SB scores reached statistical significance.

The numbers were somewhat more encouraging in the MMSE analysis. The 3- and 10-mg/kg groups began to separate at 12 months. By 24 months, the 10-mg/kg group had lost about 1 point on the MMSE while there were declines of about 2 points in the 3-mg/kg group and about 3 points in the 1-mg/kg group. Again, the 6-mg/kg group was an outlier, losing about 5 points.

“We already observed that this group behaved differently at 12 months on this endpoint, and we saw that particular cohort continued to follow that trend,” Dr. Haeberlein said.

There were 16 cases of ARIA in the extension trial. Eight were ARIA accompanied by vascular edema (ARIA-E) and these all occurred in the placebo and 1-mg/kg switchers. Three patients discontinued due to ARIA-E.

The remaining eight cases of ARIA were accompanied by microhemorrhage (ARIA-H); these were distributed among all of the dosage groups.

One patient with ARIA-E experienced a seizure and transient loss of pulse. Dr. Haeberlein didn’t elaborate on the possible cause of this event. Two additional patients died, with neither death judged related to the study medication.

The safety data, combined with the reduction of amyloid plaque and hints of cognitive and functional benefit, are enough to continue developing aducanumab, Dr. Haeberlein said. Biogen is recruiting 2,700 subjects with mild cognitive impairment or mild Alzheimer’s for identical phase III studies dubbed ENGAGE and EMERGE.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – The antiamyloid antibody aducanumab significantly reduced amyloid brain plaques in Alzheimer’s disease patients who entered a second year of therapy in an open-label extension trial.

Plaque volume declined in a time- and dose-dependent manner, with a bit of movement even among patients who crossed over to the lowest 1-mg/kg dose after a year of taking placebo in the phase Ib PRIME study, Samantha Haeberlein, PhD, reported at the Clinical Trials on Alzheimer’s Disease conference.

The linear declines in plaque burden were dramatic enough to draw a collective gasp of appreciation from the packed auditorium. But the cognitive and functional data of aducanumab (Biogen), while deemed encouraging, were not as striking. The Clinical Dementia Rating Scale-sum of boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) showed dose-dependent slowing of decline, but the drug’s effect approached statistical significance only among those who finished 2 years on 10 mg/kg aducanumab infused every 4 weeks. This group experienced relative stability of MMSE scores, which dropped only about 1 point from baseline, and also showed the greatest decline in amyloid plaque volume.

Biogen deemed this result on the MMSE, which represented a 3.27-point separation from the 1-mg/kg dose group, as “nominally significant,” with a P value noted as “less than .05.”

However, the finding must be viewed with extreme caution, said Dr. Haeberlein, Biogen’s vice president of clinical development. There were only 15 subjects in this group, and the study was not primarily intended to examine cognition.

“I must emphasize once again that these are exploratory data and these sample sizes are very small for these types of assessments,” she said. “Nonetheless, we find them informative.”

MMSE changes in the other dosing groups of 1, 3, and 6 mg/kg were not statistically significant at the end of the study. There were not any significant findings on the CDR-SB measure.

Alzheimer’s Association reaction

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, was cautiously optimistic.

Full 12-month results

Biogen presented two aducanumab abstracts at the meeting, both describing its 12-month phase Ib PRIME study and its 12-month, open-label extension study. The drug is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to the company. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.

PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a pure amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. PRIME’s primary outcomes were safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase Ib study, were exploratory.

They must also be interpreted in light of the very small numbers, about 30 patients in each dosing group at baseline. In addition, just 69 patients finished the entire 24-month dosing period, leaving only 15-23 patients in each group by the end of the study.

Vissia Viglietta, MD, Biogen’s senior medical director of clinical development, presented the 12-month data. At 52 weeks, all dosing groups, even the 1 mg/kg, saw statistically significant reductions in amyloid plaque, compared with placebo. These changes were dose-dependent; the 10-mg/kg group had the largest reduction, with a P value of less than .001.

There also were dose-dependent changes in the CDR-SB and MMSE, and some of these reached statistical significance.

On the CDR-SB, patients taking placebo declined by an average of 1.89 points. Declines in the 1-, 3-, and 6-mg/kg groups were not significant relative to placebo. However, the 10-mg/kg arm experienced a significant separation from placebo, declining an average of 0.63 points (P less than .05).

The story was similar for the MMSE. Patients taking placebo declined by 2.45 points. The decline was 2.2 points in the 1-mg/kg group; 0.75 in the 3-mg/kg group; and 0.55 in the 10-mg/kg group. The only statistically significant results relative to placebo occurred with the 10-mg/kg group (P less than .05).

The 6-mg/kg group didn’t fit this pattern though, losing an average of 2 points. Biogen has been unable to explain this, but some researchers suggest such an outlying result isn’t surprising, given the small numbers in each group and the exploratory nature of the cognitive analysis.

Amyloid-related imaging abnormalities (ARIA), an inflammatory reaction thought to be related to the removal of amyloid plaque, were the most common adverse event (n = 27). Most of these (22) were in apolipoprotein E4 allele carriers.

Two patients in the placebo arm died, as well as one in the 10-mg/kg arm, but it was not considered related to the study drug. There were no significant changes in hematology, chemistry, urinalysis, electrocardiogram, or vital signs.

Open-label extension results

Dr. Haeberlein focused on the subsequent 12-month, open-label extension trial, which enrolled 117 of the randomized cohort. In this study, patients who had been taking placebo were switched to either 3- or 6-mg/kg aducanumab. Patients who had taken 1 mg/kg were switched to 3 mg/kg. By the end, the remaining patients had taken the antibody for 2 years.

By 24 months, all the dosing groups showed a continued, linear reduction of amyloid plaques. Even those who switched from placebo to 3 mg/kg started to experience plaque reduction, although of a lesser magnitude than with the higher doses.

While still expressing caution, Dr. Haeberlein framed the CDR-SB results as very positive. The placebo and 1-mg/kg switchers continued to progress, but for those who continued on the 3-, 6-, and 10-mg/kg doses, “we saw a saw a numerical slowing of disease progression at both 18 and 24 months.”

However, none of the changes in CDR-SB scores reached statistical significance.

The numbers were somewhat more encouraging in the MMSE analysis. The 3- and 10-mg/kg groups began to separate at 12 months. By 24 months, the 10-mg/kg group had lost about 1 point on the MMSE while there were declines of about 2 points in the 3-mg/kg group and about 3 points in the 1-mg/kg group. Again, the 6-mg/kg group was an outlier, losing about 5 points.

“We already observed that this group behaved differently at 12 months on this endpoint, and we saw that particular cohort continued to follow that trend,” Dr. Haeberlein said.

There were 16 cases of ARIA in the extension trial. Eight were ARIA accompanied by vascular edema (ARIA-E) and these all occurred in the placebo and 1-mg/kg switchers. Three patients discontinued due to ARIA-E.

The remaining eight cases of ARIA were accompanied by microhemorrhage (ARIA-H); these were distributed among all of the dosage groups.

One patient with ARIA-E experienced a seizure and transient loss of pulse. Dr. Haeberlein didn’t elaborate on the possible cause of this event. Two additional patients died, with neither death judged related to the study medication.

The safety data, combined with the reduction of amyloid plaque and hints of cognitive and functional benefit, are enough to continue developing aducanumab, Dr. Haeberlein said. Biogen is recruiting 2,700 subjects with mild cognitive impairment or mild Alzheimer’s for identical phase III studies dubbed ENGAGE and EMERGE.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – The antiamyloid antibody aducanumab significantly reduced amyloid brain plaques in Alzheimer’s disease patients who entered a second year of therapy in an open-label extension trial.

Plaque volume declined in a time- and dose-dependent manner, with a bit of movement even among patients who crossed over to the lowest 1-mg/kg dose after a year of taking placebo in the phase Ib PRIME study, Samantha Haeberlein, PhD, reported at the Clinical Trials on Alzheimer’s Disease conference.

The linear declines in plaque burden were dramatic enough to draw a collective gasp of appreciation from the packed auditorium. But the cognitive and functional data of aducanumab (Biogen), while deemed encouraging, were not as striking. The Clinical Dementia Rating Scale-sum of boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) showed dose-dependent slowing of decline, but the drug’s effect approached statistical significance only among those who finished 2 years on 10 mg/kg aducanumab infused every 4 weeks. This group experienced relative stability of MMSE scores, which dropped only about 1 point from baseline, and also showed the greatest decline in amyloid plaque volume.

Biogen deemed this result on the MMSE, which represented a 3.27-point separation from the 1-mg/kg dose group, as “nominally significant,” with a P value noted as “less than .05.”

However, the finding must be viewed with extreme caution, said Dr. Haeberlein, Biogen’s vice president of clinical development. There were only 15 subjects in this group, and the study was not primarily intended to examine cognition.

“I must emphasize once again that these are exploratory data and these sample sizes are very small for these types of assessments,” she said. “Nonetheless, we find them informative.”

MMSE changes in the other dosing groups of 1, 3, and 6 mg/kg were not statistically significant at the end of the study. There were not any significant findings on the CDR-SB measure.

Alzheimer’s Association reaction

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, was cautiously optimistic.

Full 12-month results

Biogen presented two aducanumab abstracts at the meeting, both describing its 12-month phase Ib PRIME study and its 12-month, open-label extension study. The drug is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to the company. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.

PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a pure amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. PRIME’s primary outcomes were safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase Ib study, were exploratory.

They must also be interpreted in light of the very small numbers, about 30 patients in each dosing group at baseline. In addition, just 69 patients finished the entire 24-month dosing period, leaving only 15-23 patients in each group by the end of the study.

Vissia Viglietta, MD, Biogen’s senior medical director of clinical development, presented the 12-month data. At 52 weeks, all dosing groups, even the 1 mg/kg, saw statistically significant reductions in amyloid plaque, compared with placebo. These changes were dose-dependent; the 10-mg/kg group had the largest reduction, with a P value of less than .001.

There also were dose-dependent changes in the CDR-SB and MMSE, and some of these reached statistical significance.

On the CDR-SB, patients taking placebo declined by an average of 1.89 points. Declines in the 1-, 3-, and 6-mg/kg groups were not significant relative to placebo. However, the 10-mg/kg arm experienced a significant separation from placebo, declining an average of 0.63 points (P less than .05).

The story was similar for the MMSE. Patients taking placebo declined by 2.45 points. The decline was 2.2 points in the 1-mg/kg group; 0.75 in the 3-mg/kg group; and 0.55 in the 10-mg/kg group. The only statistically significant results relative to placebo occurred with the 10-mg/kg group (P less than .05).

The 6-mg/kg group didn’t fit this pattern though, losing an average of 2 points. Biogen has been unable to explain this, but some researchers suggest such an outlying result isn’t surprising, given the small numbers in each group and the exploratory nature of the cognitive analysis.

Amyloid-related imaging abnormalities (ARIA), an inflammatory reaction thought to be related to the removal of amyloid plaque, were the most common adverse event (n = 27). Most of these (22) were in apolipoprotein E4 allele carriers.

Two patients in the placebo arm died, as well as one in the 10-mg/kg arm, but it was not considered related to the study drug. There were no significant changes in hematology, chemistry, urinalysis, electrocardiogram, or vital signs.

Open-label extension results

Dr. Haeberlein focused on the subsequent 12-month, open-label extension trial, which enrolled 117 of the randomized cohort. In this study, patients who had been taking placebo were switched to either 3- or 6-mg/kg aducanumab. Patients who had taken 1 mg/kg were switched to 3 mg/kg. By the end, the remaining patients had taken the antibody for 2 years.

By 24 months, all the dosing groups showed a continued, linear reduction of amyloid plaques. Even those who switched from placebo to 3 mg/kg started to experience plaque reduction, although of a lesser magnitude than with the higher doses.

While still expressing caution, Dr. Haeberlein framed the CDR-SB results as very positive. The placebo and 1-mg/kg switchers continued to progress, but for those who continued on the 3-, 6-, and 10-mg/kg doses, “we saw a saw a numerical slowing of disease progression at both 18 and 24 months.”

However, none of the changes in CDR-SB scores reached statistical significance.

The numbers were somewhat more encouraging in the MMSE analysis. The 3- and 10-mg/kg groups began to separate at 12 months. By 24 months, the 10-mg/kg group had lost about 1 point on the MMSE while there were declines of about 2 points in the 3-mg/kg group and about 3 points in the 1-mg/kg group. Again, the 6-mg/kg group was an outlier, losing about 5 points.

“We already observed that this group behaved differently at 12 months on this endpoint, and we saw that particular cohort continued to follow that trend,” Dr. Haeberlein said.

There were 16 cases of ARIA in the extension trial. Eight were ARIA accompanied by vascular edema (ARIA-E) and these all occurred in the placebo and 1-mg/kg switchers. Three patients discontinued due to ARIA-E.

The remaining eight cases of ARIA were accompanied by microhemorrhage (ARIA-H); these were distributed among all of the dosage groups.

One patient with ARIA-E experienced a seizure and transient loss of pulse. Dr. Haeberlein didn’t elaborate on the possible cause of this event. Two additional patients died, with neither death judged related to the study medication.

The safety data, combined with the reduction of amyloid plaque and hints of cognitive and functional benefit, are enough to continue developing aducanumab, Dr. Haeberlein said. Biogen is recruiting 2,700 subjects with mild cognitive impairment or mild Alzheimer’s for identical phase III studies dubbed ENGAGE and EMERGE.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.

Patients with mild to moderate Alzheimer’s who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on either the Mini-Mental State Examination (MMSE) or the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test – an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.

Agnieszka Letowska/Thinkstock

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.

Patients with mild to moderate Alzheimer’s who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on either the Mini-Mental State Examination (MMSE) or the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test – an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.

Agnieszka Letowska/Thinkstock

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – A novel Alzheimer’s disease drug candidate appeared to stabilize cognition and function over 57 weeks in a small, early-phase, open-label trial.

Patients with mild to moderate Alzheimer’s who took ANAVEX 2-73, an agonist of the sigma-1 receptor, experienced virtually no decline on either the Mini-Mental State Examination (MMSE) or the Alzheimer’s Disease Cooperative Study–activities of daily living (ADCS-ADL) functional scale. These findings correlated with significant improvements in the P300 evoked potential test – an electrophysiologic measure sometimes used to approximate synaptic connectivity and cortical processing speed.

Agnieszka Letowska/Thinkstock

msullivan@frontlinemedcom.com

On Twitter @alz_gal

SAN DIEGO – An anti-tau compound that has stirred scientific controversy for 8 years will continue along its developmental pathway at a much lower dose, despite yet another study that has Alzheimer’s researchers scratching their heads.

The drug, dubbed LMTM, is a derivative of the dye methylene blue. Its most recent phase III study, reported at the Clinical Trials on Alzheimer’s Disease conference, found that 100 mg twice a day conferred no cognitive or functional benefit upon patients with mild AD, compared with a control dose of 4 mg.

Michele G. Sullivan/Frontline Medical News

Some significant differences, however, did emerge in two prespecified subanalyses of the 4-mg control group. Patients who took the low dose, intended to be a placebo comparator, did better than those on the high dose – but only if they were not taking any standard symptomatic AD medications.

Based on these findings, TauRx, which is developing LMTM, will abandon the 100-mg dose and refocus on the 4-mg dose, said Claude Wischik, MD, chairman and chief executive officer of the Singapore-based company.

“I think it looks effective and there’s no advantage to going to a higher dose,” Dr. Wischik said in an interview. “The 100-mg dose doesn’t offer anything above the 4-mg dose, and we saw more dropouts in the higher-dose group. We will go forward with a new trial using 4 mg.”

The new commitment to 4 mg turns LMTM’s prior development trajectory on its head, as nothing lower than 75 mg has been investigated in a phase III study. The 4-mg control dose was used as a placebo stand-in, since LMTM colors urine blue or green. The low dose was considered biologically inactive and used to maintain the study blind.

Dr. Wischik has been investigating LMTM as a tau anti-aggregant for 10 years, first publicly reporting clinical data in 2008. LMTM has never posted significant cognitive or functional benefits in any primary analysis. Instead, it has moved forward based on a series of subanalyses that showed significant or near-significant benefits in smaller, meticulously constructed subgroups – conclusions that critics have called questionable at best. The most recent of these examined the drug’s effect in patients with mild to moderate disease and was presented last July at the Alzheimer’s Association’s International Conference (AAIC).

That study also didn’t meet its primary endpoints in the overall cohort of 891 patients, but TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who were not taking memantine or cholinesterase inhibitors.

Among these patients, those taking 75 mg twice daily declined 6 points less on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) than those taking 4 mg. Those taking 125 mg twice daily declined 6 points less than the 4-mg group. On the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), patients taking 75 mg twice daily scored 6.5 points higher than did the placebo group, indicating better function, and those taking 125 mg twice daily scored 7 points higher than did the placebo group.
 

At AAIC, researchers suggested that the monotherapy groups could have had a less aggressive disease course, or might not have had Alzheimer’s disease at all. Others complained about the unorthodox grouping of control patients in the subgroup analysis.

It was after digesting these data that TauRx investigators changed the statistical analysis of the current study, then in its final months, from a randomized trial to a cohort analysis. This was done before data lockdown, but it was still a dramatic shift from the original study design.

“The primary analysis was changed to essentially analyze this as a cohort study,” said Lon Schneider, MD, who presented the results at CTAD. “The comparisons of interest were patients taking 100 mg twice a day who were not on [symptomatic treatment], compared to the original control group of 4 mg. The other comparison was the 4-mg group not on cholinesterase inhibitors to the 4-mg group that was on them.”

The 18-month trial randomized 800 patients with mild AD to 100 mg LMTM twice daily or to 4 mg twice daily. Patients were drawn from two global regions: Canada and the United States, and eastern Europe and Australia.

The study group was a typical one, with a mean age of 70 years and a mean Mini Mental State Exam score of 22. The mean ADAS-cog score was 17. Most (80%) were taking a cholinesterase inhibitor, memantine, or both; 20% were naive to these medications.

Primary endpoints were the ADAS-cog11, ADCS-ADL, and left ventricular volume. Secondary outcomes included the Mini Mental State Exam and Neuropsychiatric Index.

In the primary analysis as the trial was created and conducted, LMTM 100 mg/twice daily did not confer any benefit, compared with the control 4-mg dose. The decline curves were virtually superimposable in the ADAS-cog score, ADCS-ADL score, and in loss of left ventricular volume. 
This same nonsignificant pattern occurred in all the secondary endpoints, which Dr. Schneider did not show.

The cohort analyses stratified patients according to whether they were taking any cholinesterase inhibitor or memantine, or both, at baseline. That was where some differences did emerge.

The first compared the entire 4-mg cohort to the subset of patients taking 100 mg as monotherapy (absent any symptomatic medications). Both the 100-mg and 4-mg groups declined linearly on all measures, but compared to the 4 mg group the 100 mg group experienced about a 3-point benefit on both the ADAS-cog and ADS-ADL measures.* The 100-mg group also experienced significantly more dropouts (45% vs. 23%), with 16% of those being due to adverse events.

The second analysis compared the two 4-mg groups: those taking LMTM as monotherapy and those taking it in combination with standard AD medications. Again, both groups declined, but that decline was attenuated in the monotherapy group, with a 4-point advantage in the ADAS-cog and nearly a 5-point advantage in the ADS-ADL. The 3-cc ventricular volume advantage was seen as well.

Again, Dr. Schneider said, these results were recapitulated in the secondary endpoints, which he did not show.

The trial seems to upend TauRx’s earlier firm contention that the previously tested higher doses slow cognitive and functional decline – a view Dr. Wischik clung to after the July data were released. Dr. Schneider attempted to address this by suggesting that “the 4-mg dose may not have been as inactive as the developer thought.”

However, he noted, another possibility is that the patients who took the 4-mg dose but not the symptomatic drugs “may have had a more benign course of disease, compared to those taking cholinesterase inhibitors and memantine.”

This new study has now aroused the same criticism levied last summer. Maria Carrillo, PhD, chief scientific officer of the Alzheimer’s Association, was blunt in her assessment.

“The results of post hoc analyses, even when preplanned, are not valid and could be spurious,” she said. “They may mean nothing. As a field, we have been lured into rabbit holes in the past due to post hoc analyses and wasted too much time and way too much money. Of course, companies can do what they want as next steps in trials if they have the financial backing to do so.”

Dr. Wischik, however, said both the July data and the new data clearly justify taking the 4-mg dose forward in a randomized, placebo-controlled study.

“It’s really very exciting that we got exactly the same results now as we did in the post-hoc analysis [of the July data],” he said in an interview. “We predicted these results based on what we saw, we changed the statistical analysis, and we got the predicted results. This has nothing to do with data scouring.”

The question of whether the monotherapy patients are fundamentally different from those taking standard AD drugs is a valid one, he admitted. “We can’t avoid that criticism until we do another study where people who are not on any AD treatment are randomized.”

Dr. Wischik was then asked whether it would be difficult to recruit an entire cohort of patients with mild Alzheimer’s who are willing to forego approved symptomatic medications while in such a study. He did not think that would be problematic.

“Twenty percent of our cohort was already in that slot,” he said. “This practice pattern is determined somewhat by geography and somewhat by the type of clinician treating the patient. People also go on the drugs and then come off for various reasons. But even in the U.S., only 55% of Alzheimer’s patients are taking them.”

Dr. Wischik didn’t mention the problem of finding an appropriate placebo for such a study. If indeed the 4-mg dose is biologically active, such a placebo would have to be demonstrably inert, as well as provide the appropriate urine color to keep the blinding unbroken.

“That’s a challenge,” Dr. Schneider said.

Dr. Schneider was a coinvestigator on the LMTM phase III program. He has disclosed financial relationships with numerous pharmaceutical companies.

Correction, 12/12/16: An earlier version of this article misstated the results of this study.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

SAN DIEGO – An anti-tau compound that has stirred scientific controversy for 8 years will continue along its developmental pathway at a much lower dose, despite yet another study that has Alzheimer’s researchers scratching their heads.

The drug, dubbed LMTM, is a derivative of the dye methylene blue. Its most recent phase III study, reported at the Clinical Trials on Alzheimer’s Disease conference, found that 100 mg twice a day conferred no cognitive or functional benefit upon patients with mild AD, compared with a control dose of 4 mg.

Michele G. Sullivan/Frontline Medical News

Some significant differences, however, did emerge in two prespecified subanalyses of the 4-mg control group. Patients who took the low dose, intended to be a placebo comparator, did better than those on the high dose – but only if they were not taking any standard symptomatic AD medications.

Based on these findings, TauRx, which is developing LMTM, will abandon the 100-mg dose and refocus on the 4-mg dose, said Claude Wischik, MD, chairman and chief executive officer of the Singapore-based company.

“I think it looks effective and there’s no advantage to going to a higher dose,” Dr. Wischik said in an interview. “The 100-mg dose doesn’t offer anything above the 4-mg dose, and we saw more dropouts in the higher-dose group. We will go forward with a new trial using 4 mg.”

The new commitment to 4 mg turns LMTM’s prior development trajectory on its head, as nothing lower than 75 mg has been investigated in a phase III study. The 4-mg control dose was used as a placebo stand-in, since LMTM colors urine blue or green. The low dose was considered biologically inactive and used to maintain the study blind.

Dr. Wischik has been investigating LMTM as a tau anti-aggregant for 10 years, first publicly reporting clinical data in 2008. LMTM has never posted significant cognitive or functional benefits in any primary analysis. Instead, it has moved forward based on a series of subanalyses that showed significant or near-significant benefits in smaller, meticulously constructed subgroups – conclusions that critics have called questionable at best. The most recent of these examined the drug’s effect in patients with mild to moderate disease and was presented last July at the Alzheimer’s Association’s International Conference (AAIC).

That study also didn’t meet its primary endpoints in the overall cohort of 891 patients, but TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who were not taking memantine or cholinesterase inhibitors.

Among these patients, those taking 75 mg twice daily declined 6 points less on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) than those taking 4 mg. Those taking 125 mg twice daily declined 6 points less than the 4-mg group. On the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), patients taking 75 mg twice daily scored 6.5 points higher than did the placebo group, indicating better function, and those taking 125 mg twice daily scored 7 points higher than did the placebo group.
 

At AAIC, researchers suggested that the monotherapy groups could have had a less aggressive disease course, or might not have had Alzheimer’s disease at all. Others complained about the unorthodox grouping of control patients in the subgroup analysis.

It was after digesting these data that TauRx investigators changed the statistical analysis of the current study, then in its final months, from a randomized trial to a cohort analysis. This was done before data lockdown, but it was still a dramatic shift from the original study design.

“The primary analysis was changed to essentially analyze this as a cohort study,” said Lon Schneider, MD, who presented the results at CTAD. “The comparisons of interest were patients taking 100 mg twice a day who were not on [symptomatic treatment], compared to the original control group of 4 mg. The other comparison was the 4-mg group not on cholinesterase inhibitors to the 4-mg group that was on them.”

The 18-month trial randomized 800 patients with mild AD to 100 mg LMTM twice daily or to 4 mg twice daily. Patients were drawn from two global regions: Canada and the United States, and eastern Europe and Australia.

The study group was a typical one, with a mean age of 70 years and a mean Mini Mental State Exam score of 22. The mean ADAS-cog score was 17. Most (80%) were taking a cholinesterase inhibitor, memantine, or both; 20% were naive to these medications.

Primary endpoints were the ADAS-cog11, ADCS-ADL, and left ventricular volume. Secondary outcomes included the Mini Mental State Exam and Neuropsychiatric Index.

In the primary analysis as the trial was created and conducted, LMTM 100 mg/twice daily did not confer any benefit, compared with the control 4-mg dose. The decline curves were virtually superimposable in the ADAS-cog score, ADCS-ADL score, and in loss of left ventricular volume. 
This same nonsignificant pattern occurred in all the secondary endpoints, which Dr. Schneider did not show.

The cohort analyses stratified patients according to whether they were taking any cholinesterase inhibitor or memantine, or both, at baseline. That was where some differences did emerge.

The first compared the entire 4-mg cohort to the subset of patients taking 100 mg as monotherapy (absent any symptomatic medications). Both the 100-mg and 4-mg groups declined linearly on all measures, but compared to the 4 mg group the 100 mg group experienced about a 3-point benefit on both the ADAS-cog and ADS-ADL measures.* The 100-mg group also experienced significantly more dropouts (45% vs. 23%), with 16% of those being due to adverse events.

The second analysis compared the two 4-mg groups: those taking LMTM as monotherapy and those taking it in combination with standard AD medications. Again, both groups declined, but that decline was attenuated in the monotherapy group, with a 4-point advantage in the ADAS-cog and nearly a 5-point advantage in the ADS-ADL. The 3-cc ventricular volume advantage was seen as well.

Again, Dr. Schneider said, these results were recapitulated in the secondary endpoints, which he did not show.

The trial seems to upend TauRx’s earlier firm contention that the previously tested higher doses slow cognitive and functional decline – a view Dr. Wischik clung to after the July data were released. Dr. Schneider attempted to address this by suggesting that “the 4-mg dose may not have been as inactive as the developer thought.”

However, he noted, another possibility is that the patients who took the 4-mg dose but not the symptomatic drugs “may have had a more benign course of disease, compared to those taking cholinesterase inhibitors and memantine.”

This new study has now aroused the same criticism levied last summer. Maria Carrillo, PhD, chief scientific officer of the Alzheimer’s Association, was blunt in her assessment.

“The results of post hoc analyses, even when preplanned, are not valid and could be spurious,” she said. “They may mean nothing. As a field, we have been lured into rabbit holes in the past due to post hoc analyses and wasted too much time and way too much money. Of course, companies can do what they want as next steps in trials if they have the financial backing to do so.”

Dr. Wischik, however, said both the July data and the new data clearly justify taking the 4-mg dose forward in a randomized, placebo-controlled study.

“It’s really very exciting that we got exactly the same results now as we did in the post-hoc analysis [of the July data],” he said in an interview. “We predicted these results based on what we saw, we changed the statistical analysis, and we got the predicted results. This has nothing to do with data scouring.”

The question of whether the monotherapy patients are fundamentally different from those taking standard AD drugs is a valid one, he admitted. “We can’t avoid that criticism until we do another study where people who are not on any AD treatment are randomized.”

Dr. Wischik was then asked whether it would be difficult to recruit an entire cohort of patients with mild Alzheimer’s who are willing to forego approved symptomatic medications while in such a study. He did not think that would be problematic.

“Twenty percent of our cohort was already in that slot,” he said. “This practice pattern is determined somewhat by geography and somewhat by the type of clinician treating the patient. People also go on the drugs and then come off for various reasons. But even in the U.S., only 55% of Alzheimer’s patients are taking them.”

Dr. Wischik didn’t mention the problem of finding an appropriate placebo for such a study. If indeed the 4-mg dose is biologically active, such a placebo would have to be demonstrably inert, as well as provide the appropriate urine color to keep the blinding unbroken.

“That’s a challenge,” Dr. Schneider said.

Dr. Schneider was a coinvestigator on the LMTM phase III program. He has disclosed financial relationships with numerous pharmaceutical companies.

Correction, 12/12/16: An earlier version of this article misstated the results of this study.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

SAN DIEGO – An anti-tau compound that has stirred scientific controversy for 8 years will continue along its developmental pathway at a much lower dose, despite yet another study that has Alzheimer’s researchers scratching their heads.

The drug, dubbed LMTM, is a derivative of the dye methylene blue. Its most recent phase III study, reported at the Clinical Trials on Alzheimer’s Disease conference, found that 100 mg twice a day conferred no cognitive or functional benefit upon patients with mild AD, compared with a control dose of 4 mg.

Michele G. Sullivan/Frontline Medical News

Some significant differences, however, did emerge in two prespecified subanalyses of the 4-mg control group. Patients who took the low dose, intended to be a placebo comparator, did better than those on the high dose – but only if they were not taking any standard symptomatic AD medications.

Based on these findings, TauRx, which is developing LMTM, will abandon the 100-mg dose and refocus on the 4-mg dose, said Claude Wischik, MD, chairman and chief executive officer of the Singapore-based company.

“I think it looks effective and there’s no advantage to going to a higher dose,” Dr. Wischik said in an interview. “The 100-mg dose doesn’t offer anything above the 4-mg dose, and we saw more dropouts in the higher-dose group. We will go forward with a new trial using 4 mg.”

The new commitment to 4 mg turns LMTM’s prior development trajectory on its head, as nothing lower than 75 mg has been investigated in a phase III study. The 4-mg control dose was used as a placebo stand-in, since LMTM colors urine blue or green. The low dose was considered biologically inactive and used to maintain the study blind.

Dr. Wischik has been investigating LMTM as a tau anti-aggregant for 10 years, first publicly reporting clinical data in 2008. LMTM has never posted significant cognitive or functional benefits in any primary analysis. Instead, it has moved forward based on a series of subanalyses that showed significant or near-significant benefits in smaller, meticulously constructed subgroups – conclusions that critics have called questionable at best. The most recent of these examined the drug’s effect in patients with mild to moderate disease and was presented last July at the Alzheimer’s Association’s International Conference (AAIC).

That study also didn’t meet its primary endpoints in the overall cohort of 891 patients, but TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who were not taking memantine or cholinesterase inhibitors.

Among these patients, those taking 75 mg twice daily declined 6 points less on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) than those taking 4 mg. Those taking 125 mg twice daily declined 6 points less than the 4-mg group. On the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), patients taking 75 mg twice daily scored 6.5 points higher than did the placebo group, indicating better function, and those taking 125 mg twice daily scored 7 points higher than did the placebo group.
 

At AAIC, researchers suggested that the monotherapy groups could have had a less aggressive disease course, or might not have had Alzheimer’s disease at all. Others complained about the unorthodox grouping of control patients in the subgroup analysis.

It was after digesting these data that TauRx investigators changed the statistical analysis of the current study, then in its final months, from a randomized trial to a cohort analysis. This was done before data lockdown, but it was still a dramatic shift from the original study design.

“The primary analysis was changed to essentially analyze this as a cohort study,” said Lon Schneider, MD, who presented the results at CTAD. “The comparisons of interest were patients taking 100 mg twice a day who were not on [symptomatic treatment], compared to the original control group of 4 mg. The other comparison was the 4-mg group not on cholinesterase inhibitors to the 4-mg group that was on them.”

The 18-month trial randomized 800 patients with mild AD to 100 mg LMTM twice daily or to 4 mg twice daily. Patients were drawn from two global regions: Canada and the United States, and eastern Europe and Australia.

The study group was a typical one, with a mean age of 70 years and a mean Mini Mental State Exam score of 22. The mean ADAS-cog score was 17. Most (80%) were taking a cholinesterase inhibitor, memantine, or both; 20% were naive to these medications.

Primary endpoints were the ADAS-cog11, ADCS-ADL, and left ventricular volume. Secondary outcomes included the Mini Mental State Exam and Neuropsychiatric Index.

In the primary analysis as the trial was created and conducted, LMTM 100 mg/twice daily did not confer any benefit, compared with the control 4-mg dose. The decline curves were virtually superimposable in the ADAS-cog score, ADCS-ADL score, and in loss of left ventricular volume. 
This same nonsignificant pattern occurred in all the secondary endpoints, which Dr. Schneider did not show.

The cohort analyses stratified patients according to whether they were taking any cholinesterase inhibitor or memantine, or both, at baseline. That was where some differences did emerge.

The first compared the entire 4-mg cohort to the subset of patients taking 100 mg as monotherapy (absent any symptomatic medications). Both the 100-mg and 4-mg groups declined linearly on all measures, but compared to the 4 mg group the 100 mg group experienced about a 3-point benefit on both the ADAS-cog and ADS-ADL measures.* The 100-mg group also experienced significantly more dropouts (45% vs. 23%), with 16% of those being due to adverse events.

The second analysis compared the two 4-mg groups: those taking LMTM as monotherapy and those taking it in combination with standard AD medications. Again, both groups declined, but that decline was attenuated in the monotherapy group, with a 4-point advantage in the ADAS-cog and nearly a 5-point advantage in the ADS-ADL. The 3-cc ventricular volume advantage was seen as well.

Again, Dr. Schneider said, these results were recapitulated in the secondary endpoints, which he did not show.

The trial seems to upend TauRx’s earlier firm contention that the previously tested higher doses slow cognitive and functional decline – a view Dr. Wischik clung to after the July data were released. Dr. Schneider attempted to address this by suggesting that “the 4-mg dose may not have been as inactive as the developer thought.”

However, he noted, another possibility is that the patients who took the 4-mg dose but not the symptomatic drugs “may have had a more benign course of disease, compared to those taking cholinesterase inhibitors and memantine.”

This new study has now aroused the same criticism levied last summer. Maria Carrillo, PhD, chief scientific officer of the Alzheimer’s Association, was blunt in her assessment.

“The results of post hoc analyses, even when preplanned, are not valid and could be spurious,” she said. “They may mean nothing. As a field, we have been lured into rabbit holes in the past due to post hoc analyses and wasted too much time and way too much money. Of course, companies can do what they want as next steps in trials if they have the financial backing to do so.”

Dr. Wischik, however, said both the July data and the new data clearly justify taking the 4-mg dose forward in a randomized, placebo-controlled study.

“It’s really very exciting that we got exactly the same results now as we did in the post-hoc analysis [of the July data],” he said in an interview. “We predicted these results based on what we saw, we changed the statistical analysis, and we got the predicted results. This has nothing to do with data scouring.”

The question of whether the monotherapy patients are fundamentally different from those taking standard AD drugs is a valid one, he admitted. “We can’t avoid that criticism until we do another study where people who are not on any AD treatment are randomized.”

Dr. Wischik was then asked whether it would be difficult to recruit an entire cohort of patients with mild Alzheimer’s who are willing to forego approved symptomatic medications while in such a study. He did not think that would be problematic.

“Twenty percent of our cohort was already in that slot,” he said. “This practice pattern is determined somewhat by geography and somewhat by the type of clinician treating the patient. People also go on the drugs and then come off for various reasons. But even in the U.S., only 55% of Alzheimer’s patients are taking them.”

Dr. Wischik didn’t mention the problem of finding an appropriate placebo for such a study. If indeed the 4-mg dose is biologically active, such a placebo would have to be demonstrably inert, as well as provide the appropriate urine color to keep the blinding unbroken.

“That’s a challenge,” Dr. Schneider said.

Dr. Schneider was a coinvestigator on the LMTM phase III program. He has disclosed financial relationships with numerous pharmaceutical companies.

Correction, 12/12/16: An earlier version of this article misstated the results of this study.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

SAN DIEGO – Solanezumab may have not have slowed the relentless march of Alzheimer’s disease (AD), but it was a valuable proving ground of the amyloid hypothesis, experts said during a wide-ranging discussion of Lilly’s failed EXPEDITION 3 trial.

Lilly representatives and EXPEDITION investigators released the study’s full results at the Clinical Trials in Alzheimer ’s disease meeting. While solanezumab failed to post significant results in its primary cognitive endpoint, it did achieve significance on several secondary endpoints – findings that should be read as tremendously encouraging rather than a defeat, according to Paul Aisen, MD, director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

“We have here a negative study that confirms a beneficial treatment,” said Dr. Aisen, who was also an EXPEDITION 3 investigator. “We have a treatment that engages its target, binds to soluble amyloid, and, by virtue of that mechanism, is slowing cognitive and functional decline,” not only in EXPEDITION 3, but in its predecessors EXPEDITION and EXPEDITION 2.

“This is not a refutation of the amyloid hypothesis but a confirmation of it.”

Nevertheless, the trial must be read as a failed one, he admitted. There was no statistically significant separation between solanezumab and placebo on the ADAS-Cog14, a combined assessment of cognition and function that was the study’s primary endpoint. The active group experienced 11% less cognitive decline than did the placebo group, but the p-value remained tantalizingly below the level of significance, at 0.095.

“But what if solanezumab had hit at 0.05 instead of 0.095?” Dr. Aisen asked. “In fact, it would still be a small effect size,” which would have thrown into question the drug’s clinical utility. “Going into this, we thought we might see a 30% slowing of decline on the ADAS-Cog, and it was disappointing to only get 11%. But that is also what we saw on the key secondaries. Overall the effect size looks to be about 12%-13%, and that’s just too small.”

EXPEDITION 3 was the last of a triad of solanezumab studies, all of which posted intriguing signals of cognitive and functional benefit in patients with mild-moderate AD. It was based on subgroup analyses of EXPEDITION 1 and 2, both of which failed to meet their primary endpoints. But when researchers pooled the mild patients from both studies, they found that solanezumab was associated with a 34% slowing of cognitive decline on the ADAS-Cog14. This translated to a clinical change of less than 2 points on the scale, however.

Lilly very carefully drafted EXPEDITION 3 to come as close to recreating those findings as possible but still stumbled over results that were numerically positive for the antibody but not statistically significant or clinically meaningful.

Lawrence S. Honig, MD, professor of neurology at Columbia University Medical Center, N.Y., and principal investigator of the EXPEDITION 3 study, presented the study’s full results to a packed audience on Dec. 8.

The study comprised about 2,000 patients with imaging-confirmed amyloid brain plaques and mild-moderate AD. They were randomized to placebo or monthly injections of 400 mg solanezumab for 80 weeks. The global study was conducted in 11 countries and 210 study sites.

Dr. Honig detailed the key secondary endpoints of cognition and function, and also revealed biomarker data.

While the ADAS-Cog failed to meet statistical significance, changes in the Mini Mental State Exam score did, with a 13% slowing of decline compared to placebo (P = .014). There was also a significant 5% difference in the Clinical Dementia Rating scale-sum of boxes test (P = .004).

Outcomes were mixed in measures of function. The Alzheimer’s Disease Cooperative Study activities of daily living (ADCS-ADL) and its related measure, the ADCS-ADL inventory instrumental items, posted significant results with 15% and 14% differences, respectively, relative to placebo (P = .009 and .019, respectively).

But results on the Functional Activities Questionnaire, an informant measure of more complex activities, were not significant, with only a 7% separation from placebo and a P value of .140.

Biomarkers trended the right way, Dr. Honig noted. Solanezumab did what it was supposed to: bind soluble amyloid beta. This resulted in a 500- to 800-fold increase in the protein in plasma relative to placebo. There were no changes in amyloid brain plaques as measured by PET imaging, but this was no surprise, Dr. Aisen said, since the antibody doesn’t recognize fibrillar amyloid.

“What we expect to see with biomarkers differs based on the epitope targeted. Solanezumab ignores plaques. It targets the middle of the peptide, binding to soluble AB. Now how that helps AD is something of a debate, but it is important tor recognize that it does not attack plaques. Instead, by tying up monomeric AB, it may change the dynamic exchange of various species of amyloid around plaques; the toxicity of amyloid is thought to reside as much in oligomeric species as in the fibrillar deposits. I see this [plasma AB increase] as confirming that it’s tying up monomeric amyloid species and that the result is a slowing of disease progression. I believe it is supportive of the amyloid hypothesis.”

Solanezumab had no significant effect on tau, either in cerebrospinal fluid or imaging, nor did it change the progression of ventricular enlargement, a marker of whole brain atrophy.

The antibody was quite safe, with 17% of patient reporting an adverse event, compared to 19% of placebo patients. There were 9 deaths in the solanezumab arm and 16 in the placebo arm; about 4% of each group discontinued treatment because of an adverse event.

Although the data discussion was framed in the most hopeful light possible, no one on the panel attempted to massage it into a more clinically positive form. On a webcast in late November, Eric Siemers, MD, senior medical director of the Alzheimer’s Disease Global Development Team at Eli Lilly, said the company was disappointed but would not bring solanezumab forward for approval for mild or moderate AD patients. He echoed that sentiment during the panel discussion.

“We didn’t expect this to be a cure for this disease, but we did hope it would be the first drug to slow its progress. So yes, we are very disappointed.”

He and Dr. Aisen confirmed, however, that two other trials using solanezumab in a different population will go forward uninterrupted. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4 study) is investigating its effect in cognitively health elders with Alzheimer’s risk factors, and the Dominantly Inherited Alzheimer’s Network (DIAN) study of patients with autosomal dominant mutations in Alzheimer’s genes.

There was also brief discussion of dosing. Some audience members suggested that a higher dose than EXPEDITION’s 400 mg might have bumped up efficacy, and asked if Lilly would reconsider the dosing schedule in the A4 and DIAN studies.

“There has been a lot of discussion around that,” said Dr. Siemers. “But it’s not as easy and straightforward as you think.”

Nevertheless, Dr. Aisen is excited about solanezumab’s potential in these trials that target the disease at its earliest phase, even before cognitive symptoms develop. “I expect all antiamyloid treatments would work better when neurodegeneration is not extensive. Any of the antiamyloid antibodies would theoretically be more effective at a preclinical stage of AD than even in the mild dementia stage.”

Maria Carrillo, PhD, chief science officer of the Alzheimer’s Association, said that EXPEDITION 3 is far from a path to nowhere. Instead, she urged the research community, patients, and families to double down on their commitment to tackling the disease.

“These results stress the urgency for pushing forward harder. This is not a time to slow down. It’s a time to ramp up our efforts. This is not the time to sit back and say, ‘The amyloid hypothesis has been the wrong pathway and we need to drop it.’ But we also need to pursue other pathways, to broaden our approach and to broaden the armamentarium our clinicians will need to combat this disease.”

“This is not a win, true. But it gets us a little closer to one.”
 

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

SAN DIEGO – Solanezumab may have not have slowed the relentless march of Alzheimer’s disease (AD), but it was a valuable proving ground of the amyloid hypothesis, experts said during a wide-ranging discussion of Lilly’s failed EXPEDITION 3 trial.

Lilly representatives and EXPEDITION investigators released the study’s full results at the Clinical Trials in Alzheimer ’s disease meeting. While solanezumab failed to post significant results in its primary cognitive endpoint, it did achieve significance on several secondary endpoints – findings that should be read as tremendously encouraging rather than a defeat, according to Paul Aisen, MD, director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

“We have here a negative study that confirms a beneficial treatment,” said Dr. Aisen, who was also an EXPEDITION 3 investigator. “We have a treatment that engages its target, binds to soluble amyloid, and, by virtue of that mechanism, is slowing cognitive and functional decline,” not only in EXPEDITION 3, but in its predecessors EXPEDITION and EXPEDITION 2.

“This is not a refutation of the amyloid hypothesis but a confirmation of it.”

Nevertheless, the trial must be read as a failed one, he admitted. There was no statistically significant separation between solanezumab and placebo on the ADAS-Cog14, a combined assessment of cognition and function that was the study’s primary endpoint. The active group experienced 11% less cognitive decline than did the placebo group, but the p-value remained tantalizingly below the level of significance, at 0.095.

“But what if solanezumab had hit at 0.05 instead of 0.095?” Dr. Aisen asked. “In fact, it would still be a small effect size,” which would have thrown into question the drug’s clinical utility. “Going into this, we thought we might see a 30% slowing of decline on the ADAS-Cog, and it was disappointing to only get 11%. But that is also what we saw on the key secondaries. Overall the effect size looks to be about 12%-13%, and that’s just too small.”

EXPEDITION 3 was the last of a triad of solanezumab studies, all of which posted intriguing signals of cognitive and functional benefit in patients with mild-moderate AD. It was based on subgroup analyses of EXPEDITION 1 and 2, both of which failed to meet their primary endpoints. But when researchers pooled the mild patients from both studies, they found that solanezumab was associated with a 34% slowing of cognitive decline on the ADAS-Cog14. This translated to a clinical change of less than 2 points on the scale, however.

Lilly very carefully drafted EXPEDITION 3 to come as close to recreating those findings as possible but still stumbled over results that were numerically positive for the antibody but not statistically significant or clinically meaningful.

Lawrence S. Honig, MD, professor of neurology at Columbia University Medical Center, N.Y., and principal investigator of the EXPEDITION 3 study, presented the study’s full results to a packed audience on Dec. 8.

The study comprised about 2,000 patients with imaging-confirmed amyloid brain plaques and mild-moderate AD. They were randomized to placebo or monthly injections of 400 mg solanezumab for 80 weeks. The global study was conducted in 11 countries and 210 study sites.

Dr. Honig detailed the key secondary endpoints of cognition and function, and also revealed biomarker data.

While the ADAS-Cog failed to meet statistical significance, changes in the Mini Mental State Exam score did, with a 13% slowing of decline compared to placebo (P = .014). There was also a significant 5% difference in the Clinical Dementia Rating scale-sum of boxes test (P = .004).

Outcomes were mixed in measures of function. The Alzheimer’s Disease Cooperative Study activities of daily living (ADCS-ADL) and its related measure, the ADCS-ADL inventory instrumental items, posted significant results with 15% and 14% differences, respectively, relative to placebo (P = .009 and .019, respectively).

But results on the Functional Activities Questionnaire, an informant measure of more complex activities, were not significant, with only a 7% separation from placebo and a P value of .140.

Biomarkers trended the right way, Dr. Honig noted. Solanezumab did what it was supposed to: bind soluble amyloid beta. This resulted in a 500- to 800-fold increase in the protein in plasma relative to placebo. There were no changes in amyloid brain plaques as measured by PET imaging, but this was no surprise, Dr. Aisen said, since the antibody doesn’t recognize fibrillar amyloid.

“What we expect to see with biomarkers differs based on the epitope targeted. Solanezumab ignores plaques. It targets the middle of the peptide, binding to soluble AB. Now how that helps AD is something of a debate, but it is important tor recognize that it does not attack plaques. Instead, by tying up monomeric AB, it may change the dynamic exchange of various species of amyloid around plaques; the toxicity of amyloid is thought to reside as much in oligomeric species as in the fibrillar deposits. I see this [plasma AB increase] as confirming that it’s tying up monomeric amyloid species and that the result is a slowing of disease progression. I believe it is supportive of the amyloid hypothesis.”

Solanezumab had no significant effect on tau, either in cerebrospinal fluid or imaging, nor did it change the progression of ventricular enlargement, a marker of whole brain atrophy.

The antibody was quite safe, with 17% of patient reporting an adverse event, compared to 19% of placebo patients. There were 9 deaths in the solanezumab arm and 16 in the placebo arm; about 4% of each group discontinued treatment because of an adverse event.

Although the data discussion was framed in the most hopeful light possible, no one on the panel attempted to massage it into a more clinically positive form. On a webcast in late November, Eric Siemers, MD, senior medical director of the Alzheimer’s Disease Global Development Team at Eli Lilly, said the company was disappointed but would not bring solanezumab forward for approval for mild or moderate AD patients. He echoed that sentiment during the panel discussion.

“We didn’t expect this to be a cure for this disease, but we did hope it would be the first drug to slow its progress. So yes, we are very disappointed.”

He and Dr. Aisen confirmed, however, that two other trials using solanezumab in a different population will go forward uninterrupted. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4 study) is investigating its effect in cognitively health elders with Alzheimer’s risk factors, and the Dominantly Inherited Alzheimer’s Network (DIAN) study of patients with autosomal dominant mutations in Alzheimer’s genes.

There was also brief discussion of dosing. Some audience members suggested that a higher dose than EXPEDITION’s 400 mg might have bumped up efficacy, and asked if Lilly would reconsider the dosing schedule in the A4 and DIAN studies.

“There has been a lot of discussion around that,” said Dr. Siemers. “But it’s not as easy and straightforward as you think.”

Nevertheless, Dr. Aisen is excited about solanezumab’s potential in these trials that target the disease at its earliest phase, even before cognitive symptoms develop. “I expect all antiamyloid treatments would work better when neurodegeneration is not extensive. Any of the antiamyloid antibodies would theoretically be more effective at a preclinical stage of AD than even in the mild dementia stage.”

Maria Carrillo, PhD, chief science officer of the Alzheimer’s Association, said that EXPEDITION 3 is far from a path to nowhere. Instead, she urged the research community, patients, and families to double down on their commitment to tackling the disease.

“These results stress the urgency for pushing forward harder. This is not a time to slow down. It’s a time to ramp up our efforts. This is not the time to sit back and say, ‘The amyloid hypothesis has been the wrong pathway and we need to drop it.’ But we also need to pursue other pathways, to broaden our approach and to broaden the armamentarium our clinicians will need to combat this disease.”

“This is not a win, true. But it gets us a little closer to one.”
 

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

SAN DIEGO – Solanezumab may have not have slowed the relentless march of Alzheimer’s disease (AD), but it was a valuable proving ground of the amyloid hypothesis, experts said during a wide-ranging discussion of Lilly’s failed EXPEDITION 3 trial.

Lilly representatives and EXPEDITION investigators released the study’s full results at the Clinical Trials in Alzheimer ’s disease meeting. While solanezumab failed to post significant results in its primary cognitive endpoint, it did achieve significance on several secondary endpoints – findings that should be read as tremendously encouraging rather than a defeat, according to Paul Aisen, MD, director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

“We have here a negative study that confirms a beneficial treatment,” said Dr. Aisen, who was also an EXPEDITION 3 investigator. “We have a treatment that engages its target, binds to soluble amyloid, and, by virtue of that mechanism, is slowing cognitive and functional decline,” not only in EXPEDITION 3, but in its predecessors EXPEDITION and EXPEDITION 2.

“This is not a refutation of the amyloid hypothesis but a confirmation of it.”

Nevertheless, the trial must be read as a failed one, he admitted. There was no statistically significant separation between solanezumab and placebo on the ADAS-Cog14, a combined assessment of cognition and function that was the study’s primary endpoint. The active group experienced 11% less cognitive decline than did the placebo group, but the p-value remained tantalizingly below the level of significance, at 0.095.

“But what if solanezumab had hit at 0.05 instead of 0.095?” Dr. Aisen asked. “In fact, it would still be a small effect size,” which would have thrown into question the drug’s clinical utility. “Going into this, we thought we might see a 30% slowing of decline on the ADAS-Cog, and it was disappointing to only get 11%. But that is also what we saw on the key secondaries. Overall the effect size looks to be about 12%-13%, and that’s just too small.”

EXPEDITION 3 was the last of a triad of solanezumab studies, all of which posted intriguing signals of cognitive and functional benefit in patients with mild-moderate AD. It was based on subgroup analyses of EXPEDITION 1 and 2, both of which failed to meet their primary endpoints. But when researchers pooled the mild patients from both studies, they found that solanezumab was associated with a 34% slowing of cognitive decline on the ADAS-Cog14. This translated to a clinical change of less than 2 points on the scale, however.

Lilly very carefully drafted EXPEDITION 3 to come as close to recreating those findings as possible but still stumbled over results that were numerically positive for the antibody but not statistically significant or clinically meaningful.

Lawrence S. Honig, MD, professor of neurology at Columbia University Medical Center, N.Y., and principal investigator of the EXPEDITION 3 study, presented the study’s full results to a packed audience on Dec. 8.

The study comprised about 2,000 patients with imaging-confirmed amyloid brain plaques and mild-moderate AD. They were randomized to placebo or monthly injections of 400 mg solanezumab for 80 weeks. The global study was conducted in 11 countries and 210 study sites.

Dr. Honig detailed the key secondary endpoints of cognition and function, and also revealed biomarker data.

While the ADAS-Cog failed to meet statistical significance, changes in the Mini Mental State Exam score did, with a 13% slowing of decline compared to placebo (P = .014). There was also a significant 5% difference in the Clinical Dementia Rating scale-sum of boxes test (P = .004).

Outcomes were mixed in measures of function. The Alzheimer’s Disease Cooperative Study activities of daily living (ADCS-ADL) and its related measure, the ADCS-ADL inventory instrumental items, posted significant results with 15% and 14% differences, respectively, relative to placebo (P = .009 and .019, respectively).

But results on the Functional Activities Questionnaire, an informant measure of more complex activities, were not significant, with only a 7% separation from placebo and a P value of .140.

Biomarkers trended the right way, Dr. Honig noted. Solanezumab did what it was supposed to: bind soluble amyloid beta. This resulted in a 500- to 800-fold increase in the protein in plasma relative to placebo. There were no changes in amyloid brain plaques as measured by PET imaging, but this was no surprise, Dr. Aisen said, since the antibody doesn’t recognize fibrillar amyloid.

“What we expect to see with biomarkers differs based on the epitope targeted. Solanezumab ignores plaques. It targets the middle of the peptide, binding to soluble AB. Now how that helps AD is something of a debate, but it is important tor recognize that it does not attack plaques. Instead, by tying up monomeric AB, it may change the dynamic exchange of various species of amyloid around plaques; the toxicity of amyloid is thought to reside as much in oligomeric species as in the fibrillar deposits. I see this [plasma AB increase] as confirming that it’s tying up monomeric amyloid species and that the result is a slowing of disease progression. I believe it is supportive of the amyloid hypothesis.”

Solanezumab had no significant effect on tau, either in cerebrospinal fluid or imaging, nor did it change the progression of ventricular enlargement, a marker of whole brain atrophy.

The antibody was quite safe, with 17% of patient reporting an adverse event, compared to 19% of placebo patients. There were 9 deaths in the solanezumab arm and 16 in the placebo arm; about 4% of each group discontinued treatment because of an adverse event.

Although the data discussion was framed in the most hopeful light possible, no one on the panel attempted to massage it into a more clinically positive form. On a webcast in late November, Eric Siemers, MD, senior medical director of the Alzheimer’s Disease Global Development Team at Eli Lilly, said the company was disappointed but would not bring solanezumab forward for approval for mild or moderate AD patients. He echoed that sentiment during the panel discussion.

“We didn’t expect this to be a cure for this disease, but we did hope it would be the first drug to slow its progress. So yes, we are very disappointed.”

He and Dr. Aisen confirmed, however, that two other trials using solanezumab in a different population will go forward uninterrupted. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4 study) is investigating its effect in cognitively health elders with Alzheimer’s risk factors, and the Dominantly Inherited Alzheimer’s Network (DIAN) study of patients with autosomal dominant mutations in Alzheimer’s genes.

There was also brief discussion of dosing. Some audience members suggested that a higher dose than EXPEDITION’s 400 mg might have bumped up efficacy, and asked if Lilly would reconsider the dosing schedule in the A4 and DIAN studies.

“There has been a lot of discussion around that,” said Dr. Siemers. “But it’s not as easy and straightforward as you think.”

Nevertheless, Dr. Aisen is excited about solanezumab’s potential in these trials that target the disease at its earliest phase, even before cognitive symptoms develop. “I expect all antiamyloid treatments would work better when neurodegeneration is not extensive. Any of the antiamyloid antibodies would theoretically be more effective at a preclinical stage of AD than even in the mild dementia stage.”

Maria Carrillo, PhD, chief science officer of the Alzheimer’s Association, said that EXPEDITION 3 is far from a path to nowhere. Instead, she urged the research community, patients, and families to double down on their commitment to tackling the disease.

“These results stress the urgency for pushing forward harder. This is not a time to slow down. It’s a time to ramp up our efforts. This is not the time to sit back and say, ‘The amyloid hypothesis has been the wrong pathway and we need to drop it.’ But we also need to pursue other pathways, to broaden our approach and to broaden the armamentarium our clinicians will need to combat this disease.”

“This is not a win, true. But it gets us a little closer to one.”
 

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal