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Aducanumab continues to rack up positive numbers in phase 1b open-label extension
BOSTON – The antiamyloid antibody aducanumab continued its slide around the bases this week, revealing more positive imaging and cognitive data at 36 months into the phase 1b PRIME trial.
Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study improved the most on two measures of cognition, the Mini Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–sum of boxes (CDR-sb). On the pathology side, at least some of the 10-mg/kg patients dropped below the threshold of PET amyloid positivity by 24 months and stayed at that low level up to 36 months, Samantha Budd Haeberlein, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
The 36-month data support the continued development of aducanumab, she said. The antibody is now being tested in two phase 3 studies, ENGAGE and EMERGE.
“The aducanumab data reported at CTAD is good news for safety and good news for the signals we need to see in the phase 3 trials,” Maria Carillo, PhD, chief science officer of the Alzheimer’s Association said when asked to comment on the latest data. “These are hopeful signs, but – based on what we’ve learned from past Alzheimer’s studies – we need to wait for the phase 3 trial results.”
Aducanumab 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 Biogen. 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 purely PET-proven amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. This was followed by a 2-year open-label extension period. Patients who were randomized to placebo or 1 mg/kg were switched to aducanumab 3 mg/kg or to a 3- to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3, 6 or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group.
Dr. Haeberlein presented only the fixed-dose data; the titration group data will be presented later in the conference.
PRIME’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase 1b study, are exploratory. This is important to remember, Dr. Haeberlein said. She also stressed that the numbers in each dosing group are quite small. Of the original cohort, 117 entered the extension study and just 50 made it to 166 weeks, at which time 10-16 patients were in each of the dosage cohorts.
At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan. The 6-mg/kg group approached the threshold, but did not fall below it. The 1- and 3-mg/kg groups declined similarly to each other, although not as dramatically as the higher-dose group.
Everyone in the trial declined on both cognitive measures, the MMSE and CDR-sb. However, the decline was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who took 10 mg/kg. The average decline from baseline on the CDR-sb was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-sb were:
- 5.28 points in those who switched from placebo to 3 mg/kg.
- 6.11 points in those who switched from 1 mg/kg to 3 mg/kg.
- 3.86 points in the 3-mg/kg treatment group.
- 4.49 points in the 6-mg/kg treatment group.
Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were:
- 7.98 points in those who switched from placebo to 3 mg/kg.
- 6.35 points in those who switched from 1 mg/kg to 3 mg/kg.
- 4.83 points in the 3-mg/kg treatment group.
- 8.97 points in the 6 mg/kg treatment group.
During the presentation, Dr. Haeberlein said these differences were not statistically significant. In an interview, she said, “In this extension trial, we aren’t talking about statistical significance. We are beyond that.”
The incidence of ARIA (Amyloid-Related Imaging Abnormalities), however, did not follow this dose-dependent pattern. All eight cases of ARIA-E (the edematous form) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg or in the 1-mg/kg group that titrated up to 3 mg/kg. All cases occurred early in the extension phase, with no new cases during the last year, and all but one occurred in APOE4 allele carriers.
Hemorrhagic ARIA was more sporadic, occurring in two placebo switchers, five taking 3 mg/kg, two taking 6 mg/kg, and one patient taking the highest 10 mg/kg dose. Again, these cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously.
In all of PRIME, 46 patients have experienced ARIA, with 6 experiencing more than one episode.
The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died – one taking 6 mg/kg and one taking 10 mg/kg. Neither death was related to the study medication.
[email protected]
On Twitter @alz_gal
BOSTON – The antiamyloid antibody aducanumab continued its slide around the bases this week, revealing more positive imaging and cognitive data at 36 months into the phase 1b PRIME trial.
Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study improved the most on two measures of cognition, the Mini Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–sum of boxes (CDR-sb). On the pathology side, at least some of the 10-mg/kg patients dropped below the threshold of PET amyloid positivity by 24 months and stayed at that low level up to 36 months, Samantha Budd Haeberlein, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
The 36-month data support the continued development of aducanumab, she said. The antibody is now being tested in two phase 3 studies, ENGAGE and EMERGE.
“The aducanumab data reported at CTAD is good news for safety and good news for the signals we need to see in the phase 3 trials,” Maria Carillo, PhD, chief science officer of the Alzheimer’s Association said when asked to comment on the latest data. “These are hopeful signs, but – based on what we’ve learned from past Alzheimer’s studies – we need to wait for the phase 3 trial results.”
Aducanumab 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 Biogen. 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 purely PET-proven amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. This was followed by a 2-year open-label extension period. Patients who were randomized to placebo or 1 mg/kg were switched to aducanumab 3 mg/kg or to a 3- to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3, 6 or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group.
Dr. Haeberlein presented only the fixed-dose data; the titration group data will be presented later in the conference.
PRIME’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase 1b study, are exploratory. This is important to remember, Dr. Haeberlein said. She also stressed that the numbers in each dosing group are quite small. Of the original cohort, 117 entered the extension study and just 50 made it to 166 weeks, at which time 10-16 patients were in each of the dosage cohorts.
At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan. The 6-mg/kg group approached the threshold, but did not fall below it. The 1- and 3-mg/kg groups declined similarly to each other, although not as dramatically as the higher-dose group.
Everyone in the trial declined on both cognitive measures, the MMSE and CDR-sb. However, the decline was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who took 10 mg/kg. The average decline from baseline on the CDR-sb was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-sb were:
- 5.28 points in those who switched from placebo to 3 mg/kg.
- 6.11 points in those who switched from 1 mg/kg to 3 mg/kg.
- 3.86 points in the 3-mg/kg treatment group.
- 4.49 points in the 6-mg/kg treatment group.
Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were:
- 7.98 points in those who switched from placebo to 3 mg/kg.
- 6.35 points in those who switched from 1 mg/kg to 3 mg/kg.
- 4.83 points in the 3-mg/kg treatment group.
- 8.97 points in the 6 mg/kg treatment group.
During the presentation, Dr. Haeberlein said these differences were not statistically significant. In an interview, she said, “In this extension trial, we aren’t talking about statistical significance. We are beyond that.”
The incidence of ARIA (Amyloid-Related Imaging Abnormalities), however, did not follow this dose-dependent pattern. All eight cases of ARIA-E (the edematous form) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg or in the 1-mg/kg group that titrated up to 3 mg/kg. All cases occurred early in the extension phase, with no new cases during the last year, and all but one occurred in APOE4 allele carriers.
Hemorrhagic ARIA was more sporadic, occurring in two placebo switchers, five taking 3 mg/kg, two taking 6 mg/kg, and one patient taking the highest 10 mg/kg dose. Again, these cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously.
In all of PRIME, 46 patients have experienced ARIA, with 6 experiencing more than one episode.
The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died – one taking 6 mg/kg and one taking 10 mg/kg. Neither death was related to the study medication.
[email protected]
On Twitter @alz_gal
BOSTON – The antiamyloid antibody aducanumab continued its slide around the bases this week, revealing more positive imaging and cognitive data at 36 months into the phase 1b PRIME trial.
Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study improved the most on two measures of cognition, the Mini Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–sum of boxes (CDR-sb). On the pathology side, at least some of the 10-mg/kg patients dropped below the threshold of PET amyloid positivity by 24 months and stayed at that low level up to 36 months, Samantha Budd Haeberlein, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
The 36-month data support the continued development of aducanumab, she said. The antibody is now being tested in two phase 3 studies, ENGAGE and EMERGE.
“The aducanumab data reported at CTAD is good news for safety and good news for the signals we need to see in the phase 3 trials,” Maria Carillo, PhD, chief science officer of the Alzheimer’s Association said when asked to comment on the latest data. “These are hopeful signs, but – based on what we’ve learned from past Alzheimer’s studies – we need to wait for the phase 3 trial results.”
Aducanumab 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 Biogen. 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 purely PET-proven amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. This was followed by a 2-year open-label extension period. Patients who were randomized to placebo or 1 mg/kg were switched to aducanumab 3 mg/kg or to a 3- to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3, 6 or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group.
Dr. Haeberlein presented only the fixed-dose data; the titration group data will be presented later in the conference.
PRIME’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase 1b study, are exploratory. This is important to remember, Dr. Haeberlein said. She also stressed that the numbers in each dosing group are quite small. Of the original cohort, 117 entered the extension study and just 50 made it to 166 weeks, at which time 10-16 patients were in each of the dosage cohorts.
At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan. The 6-mg/kg group approached the threshold, but did not fall below it. The 1- and 3-mg/kg groups declined similarly to each other, although not as dramatically as the higher-dose group.
Everyone in the trial declined on both cognitive measures, the MMSE and CDR-sb. However, the decline was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who took 10 mg/kg. The average decline from baseline on the CDR-sb was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-sb were:
- 5.28 points in those who switched from placebo to 3 mg/kg.
- 6.11 points in those who switched from 1 mg/kg to 3 mg/kg.
- 3.86 points in the 3-mg/kg treatment group.
- 4.49 points in the 6-mg/kg treatment group.
Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were:
- 7.98 points in those who switched from placebo to 3 mg/kg.
- 6.35 points in those who switched from 1 mg/kg to 3 mg/kg.
- 4.83 points in the 3-mg/kg treatment group.
- 8.97 points in the 6 mg/kg treatment group.
During the presentation, Dr. Haeberlein said these differences were not statistically significant. In an interview, she said, “In this extension trial, we aren’t talking about statistical significance. We are beyond that.”
The incidence of ARIA (Amyloid-Related Imaging Abnormalities), however, did not follow this dose-dependent pattern. All eight cases of ARIA-E (the edematous form) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg or in the 1-mg/kg group that titrated up to 3 mg/kg. All cases occurred early in the extension phase, with no new cases during the last year, and all but one occurred in APOE4 allele carriers.
Hemorrhagic ARIA was more sporadic, occurring in two placebo switchers, five taking 3 mg/kg, two taking 6 mg/kg, and one patient taking the highest 10 mg/kg dose. Again, these cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously.
In all of PRIME, 46 patients have experienced ARIA, with 6 experiencing more than one episode.
The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died – one taking 6 mg/kg and one taking 10 mg/kg. Neither death was related to the study medication.
[email protected]
On Twitter @alz_gal
EXPERT ANALYSIS FROM CTAD
Key clinical point:
Major finding: At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan.
Data source: 3-year extension phase data from the phase 1B PRIME trial.
Disclosures: The PRIME trial is sponsored by Biogen. The presenter is an employee of the company.
Analysis of failed Alzheimer’s trials gives two antiamyloid antibodies new momentum
BOSTON – Despite years of frustrating failures, Alzheimer’s researchers keep punching away at beta-amyloid brain plaques, now apparently with a highly focused one-two of “more drug, given sooner.”
Solanezumab and gantenerumab – both of which failed in earlier phase 3 studies – will be pushed forward now at much higher doses, the Alzheimer’s disease research community learned at the opening session of the Clinical Trials on Alzheimer’s Disease conference.
Both drugs are antiamyloid antibodies. In their prior trials, both effectively cleared amyloid plaques, but neither significantly improved cognition in patients with mild-moderate disease. This has been a common theme of every antiamyloid study: Although these drugs stimulate different mechanisms of plaque removal, none has ever significantly improved thinking or memory.
In discussing these failures, the Alzheimer’s research community has collectively wondered whether the doses were high enough. Drug companies have erred on the side of caution in large part because antiamyloid antibodies can cause a syndrome called ARIA (Amyloid-Related Imaging Abnormalities), an inflammatory response of brain edema or microhemorrhages. Concern over this side effect has moderated as researchers accumulate more adverse event data. Most cases are asymptomatic and resolve spontaneously. New open-label extension data from the Scarlet Road and Marguerite Road trials of gantenerumab, plus a new titration model by Roche, have also increased confidence that patients will tolerate the antibody at subcutaneous doses of up to 1,200 mg.
The other fear that plagues researchers is therapeutic timing. It’s increasingly apparent that plaque eradication does not rescue cognition. As heart disease must be attacked before cardiac damage occurs, it seems likely that Alzheimer’s disease must be attacked before amyloid and its attendant protein, tau, wreak havoc in the hippocampus and neocortex.
After reevaluating the high-profile solanezumab and gantenerumab failures, researchers now hope that higher doses delivered much earlier in the disease process might be effective, not at restoring lost cognition, but at preventing cognitive decline in the first place.
“One of the greatest advances in this field over the past 10 years is the recognition that Alzheimer’s disease is a continuum that likely begins well before the stage we recognize as dementia, and even before the stages of mild cognitive impairment [MCI] and prodromal Alzheimer’s,” said Dr. Sperling of Brigham and Women’s Hospital, Boston. “Treating in the presymptomatic phase may be the best opportunity to bend this curve back toward the trajectory of normal aging.”
But amyloid is only part of the Alzheimer’s disease story. Tau is a key player and, some say, the prime antagonist, since it is the main driver of memory and thought decline. Tau is present deep in the brains of most cognitively aging normal people, but something about amyloid deposition spurs its devastating spread into the neocortex. Preventing amyloid accumulation may prevent dementia, not just by keeping amyloid at bay, but by preventing it from igniting the spread of tau.
Dr. Sperling cited unpublished data showing very subtle cognitive decline in cognitively normal patients who have both amyloid and tau in the brain. Although the scores stayed within normal, subjects with both declined over 2 years on specific measures of memory and were more likely to progress to MCI.
“This is very striking to me and made me a little worried about the critical window of intervention,” she said. “What is also striking is that, even though we restricted the eligibility criteria of A4 to those with normal memory and normal cognition, we do see that tau positivity at baseline is associated with lower baseline performance. Again we have this suggestion that amyloid is associated with tau and tau is associated with poor memory even in normal people.”
Although hard to swallow, digesting solanezumab’s failure in the series of EXPEDITION studies has now refined the A4 protocol. “To be honest, I didn’t sleep for months following the release of EXPEDITION 3 data, because I was really concerned about how it should guide us about changes to A4. We think solanezumab has an increased chance of success here [compared with EXPEDITION] because we’re employing it 10-15 years earlier in the disease. But we also want to maximize its chances.”
Thus, she said, investigators and Eli Lilly have now decided to quadruple the dose in A4. Subjects will titrate from 600 mg to 800 mg for 2 months and then go up to 1,600 mg every 4 weeks. A safety cohort of 200 patients will be monitored for any adverse events, with a particular eye out for hemorrhagic or edematous ARIA. “We are also extending the double-blind phase to 240 weeks, which allows everyone to dose-escalate and increases our power to detect small effect sizes,” she said.
Right now, recruitment stands at 1,151; Dr. Sperling expects the full 1,200-subject cohort to be randomized by the end of 2017.
Gantenerumab is also experiencing a rebirth after a deep dive into open-label extension data from both the Scarlet Road and Marguerite Road studies, Dr. Klein said. Patients in these studies were randomized to either 105 or 225 mg of the antibody. While there were no significant cognitive benefits, there were trends toward improvement with the higher dose, as well as dose-dependent plaque clearance. This encouraged researchers to look at higher doses in 52-week open-label extensions of each study.
Dr. Klein presented new imaging data for these studies. Between both, 40 patients were maintained for 6-9 months on the highest doses (900-1,200 mg). Of these, 17 had almost total clearance of their amyloid burden. Their scans, Dr. Klein said, read as traces of amyloid or as amyloid negative. The effect was consistent regardless of the amount of amyloid at baseline.
“These are very encouraging biomarker data,” he said. “We are going into our new phase 3 studies, Graduate I and II, very optimistic.”
Little information is available about these studies. According to a press release, they will target patients with prodromal-mild disease at the higher doses. Emails to Roche and its German partner, MorphoSys, were not returned by press time. But from Dr. Klein’s comments, it seems clear that gantenerumab has not reached the end of its road.
Dr. Sperling disclosed relationships with numerous pharmaceutical companies. Dr. Klein is an employee of Roche.
[email protected]
On Twitter @alz_gal
BOSTON – Despite years of frustrating failures, Alzheimer’s researchers keep punching away at beta-amyloid brain plaques, now apparently with a highly focused one-two of “more drug, given sooner.”
Solanezumab and gantenerumab – both of which failed in earlier phase 3 studies – will be pushed forward now at much higher doses, the Alzheimer’s disease research community learned at the opening session of the Clinical Trials on Alzheimer’s Disease conference.
Both drugs are antiamyloid antibodies. In their prior trials, both effectively cleared amyloid plaques, but neither significantly improved cognition in patients with mild-moderate disease. This has been a common theme of every antiamyloid study: Although these drugs stimulate different mechanisms of plaque removal, none has ever significantly improved thinking or memory.
In discussing these failures, the Alzheimer’s research community has collectively wondered whether the doses were high enough. Drug companies have erred on the side of caution in large part because antiamyloid antibodies can cause a syndrome called ARIA (Amyloid-Related Imaging Abnormalities), an inflammatory response of brain edema or microhemorrhages. Concern over this side effect has moderated as researchers accumulate more adverse event data. Most cases are asymptomatic and resolve spontaneously. New open-label extension data from the Scarlet Road and Marguerite Road trials of gantenerumab, plus a new titration model by Roche, have also increased confidence that patients will tolerate the antibody at subcutaneous doses of up to 1,200 mg.
The other fear that plagues researchers is therapeutic timing. It’s increasingly apparent that plaque eradication does not rescue cognition. As heart disease must be attacked before cardiac damage occurs, it seems likely that Alzheimer’s disease must be attacked before amyloid and its attendant protein, tau, wreak havoc in the hippocampus and neocortex.
After reevaluating the high-profile solanezumab and gantenerumab failures, researchers now hope that higher doses delivered much earlier in the disease process might be effective, not at restoring lost cognition, but at preventing cognitive decline in the first place.
“One of the greatest advances in this field over the past 10 years is the recognition that Alzheimer’s disease is a continuum that likely begins well before the stage we recognize as dementia, and even before the stages of mild cognitive impairment [MCI] and prodromal Alzheimer’s,” said Dr. Sperling of Brigham and Women’s Hospital, Boston. “Treating in the presymptomatic phase may be the best opportunity to bend this curve back toward the trajectory of normal aging.”
But amyloid is only part of the Alzheimer’s disease story. Tau is a key player and, some say, the prime antagonist, since it is the main driver of memory and thought decline. Tau is present deep in the brains of most cognitively aging normal people, but something about amyloid deposition spurs its devastating spread into the neocortex. Preventing amyloid accumulation may prevent dementia, not just by keeping amyloid at bay, but by preventing it from igniting the spread of tau.
Dr. Sperling cited unpublished data showing very subtle cognitive decline in cognitively normal patients who have both amyloid and tau in the brain. Although the scores stayed within normal, subjects with both declined over 2 years on specific measures of memory and were more likely to progress to MCI.
“This is very striking to me and made me a little worried about the critical window of intervention,” she said. “What is also striking is that, even though we restricted the eligibility criteria of A4 to those with normal memory and normal cognition, we do see that tau positivity at baseline is associated with lower baseline performance. Again we have this suggestion that amyloid is associated with tau and tau is associated with poor memory even in normal people.”
Although hard to swallow, digesting solanezumab’s failure in the series of EXPEDITION studies has now refined the A4 protocol. “To be honest, I didn’t sleep for months following the release of EXPEDITION 3 data, because I was really concerned about how it should guide us about changes to A4. We think solanezumab has an increased chance of success here [compared with EXPEDITION] because we’re employing it 10-15 years earlier in the disease. But we also want to maximize its chances.”
Thus, she said, investigators and Eli Lilly have now decided to quadruple the dose in A4. Subjects will titrate from 600 mg to 800 mg for 2 months and then go up to 1,600 mg every 4 weeks. A safety cohort of 200 patients will be monitored for any adverse events, with a particular eye out for hemorrhagic or edematous ARIA. “We are also extending the double-blind phase to 240 weeks, which allows everyone to dose-escalate and increases our power to detect small effect sizes,” she said.
Right now, recruitment stands at 1,151; Dr. Sperling expects the full 1,200-subject cohort to be randomized by the end of 2017.
Gantenerumab is also experiencing a rebirth after a deep dive into open-label extension data from both the Scarlet Road and Marguerite Road studies, Dr. Klein said. Patients in these studies were randomized to either 105 or 225 mg of the antibody. While there were no significant cognitive benefits, there were trends toward improvement with the higher dose, as well as dose-dependent plaque clearance. This encouraged researchers to look at higher doses in 52-week open-label extensions of each study.
Dr. Klein presented new imaging data for these studies. Between both, 40 patients were maintained for 6-9 months on the highest doses (900-1,200 mg). Of these, 17 had almost total clearance of their amyloid burden. Their scans, Dr. Klein said, read as traces of amyloid or as amyloid negative. The effect was consistent regardless of the amount of amyloid at baseline.
“These are very encouraging biomarker data,” he said. “We are going into our new phase 3 studies, Graduate I and II, very optimistic.”
Little information is available about these studies. According to a press release, they will target patients with prodromal-mild disease at the higher doses. Emails to Roche and its German partner, MorphoSys, were not returned by press time. But from Dr. Klein’s comments, it seems clear that gantenerumab has not reached the end of its road.
Dr. Sperling disclosed relationships with numerous pharmaceutical companies. Dr. Klein is an employee of Roche.
[email protected]
On Twitter @alz_gal
BOSTON – Despite years of frustrating failures, Alzheimer’s researchers keep punching away at beta-amyloid brain plaques, now apparently with a highly focused one-two of “more drug, given sooner.”
Solanezumab and gantenerumab – both of which failed in earlier phase 3 studies – will be pushed forward now at much higher doses, the Alzheimer’s disease research community learned at the opening session of the Clinical Trials on Alzheimer’s Disease conference.
Both drugs are antiamyloid antibodies. In their prior trials, both effectively cleared amyloid plaques, but neither significantly improved cognition in patients with mild-moderate disease. This has been a common theme of every antiamyloid study: Although these drugs stimulate different mechanisms of plaque removal, none has ever significantly improved thinking or memory.
In discussing these failures, the Alzheimer’s research community has collectively wondered whether the doses were high enough. Drug companies have erred on the side of caution in large part because antiamyloid antibodies can cause a syndrome called ARIA (Amyloid-Related Imaging Abnormalities), an inflammatory response of brain edema or microhemorrhages. Concern over this side effect has moderated as researchers accumulate more adverse event data. Most cases are asymptomatic and resolve spontaneously. New open-label extension data from the Scarlet Road and Marguerite Road trials of gantenerumab, plus a new titration model by Roche, have also increased confidence that patients will tolerate the antibody at subcutaneous doses of up to 1,200 mg.
The other fear that plagues researchers is therapeutic timing. It’s increasingly apparent that plaque eradication does not rescue cognition. As heart disease must be attacked before cardiac damage occurs, it seems likely that Alzheimer’s disease must be attacked before amyloid and its attendant protein, tau, wreak havoc in the hippocampus and neocortex.
After reevaluating the high-profile solanezumab and gantenerumab failures, researchers now hope that higher doses delivered much earlier in the disease process might be effective, not at restoring lost cognition, but at preventing cognitive decline in the first place.
“One of the greatest advances in this field over the past 10 years is the recognition that Alzheimer’s disease is a continuum that likely begins well before the stage we recognize as dementia, and even before the stages of mild cognitive impairment [MCI] and prodromal Alzheimer’s,” said Dr. Sperling of Brigham and Women’s Hospital, Boston. “Treating in the presymptomatic phase may be the best opportunity to bend this curve back toward the trajectory of normal aging.”
But amyloid is only part of the Alzheimer’s disease story. Tau is a key player and, some say, the prime antagonist, since it is the main driver of memory and thought decline. Tau is present deep in the brains of most cognitively aging normal people, but something about amyloid deposition spurs its devastating spread into the neocortex. Preventing amyloid accumulation may prevent dementia, not just by keeping amyloid at bay, but by preventing it from igniting the spread of tau.
Dr. Sperling cited unpublished data showing very subtle cognitive decline in cognitively normal patients who have both amyloid and tau in the brain. Although the scores stayed within normal, subjects with both declined over 2 years on specific measures of memory and were more likely to progress to MCI.
“This is very striking to me and made me a little worried about the critical window of intervention,” she said. “What is also striking is that, even though we restricted the eligibility criteria of A4 to those with normal memory and normal cognition, we do see that tau positivity at baseline is associated with lower baseline performance. Again we have this suggestion that amyloid is associated with tau and tau is associated with poor memory even in normal people.”
Although hard to swallow, digesting solanezumab’s failure in the series of EXPEDITION studies has now refined the A4 protocol. “To be honest, I didn’t sleep for months following the release of EXPEDITION 3 data, because I was really concerned about how it should guide us about changes to A4. We think solanezumab has an increased chance of success here [compared with EXPEDITION] because we’re employing it 10-15 years earlier in the disease. But we also want to maximize its chances.”
Thus, she said, investigators and Eli Lilly have now decided to quadruple the dose in A4. Subjects will titrate from 600 mg to 800 mg for 2 months and then go up to 1,600 mg every 4 weeks. A safety cohort of 200 patients will be monitored for any adverse events, with a particular eye out for hemorrhagic or edematous ARIA. “We are also extending the double-blind phase to 240 weeks, which allows everyone to dose-escalate and increases our power to detect small effect sizes,” she said.
Right now, recruitment stands at 1,151; Dr. Sperling expects the full 1,200-subject cohort to be randomized by the end of 2017.
Gantenerumab is also experiencing a rebirth after a deep dive into open-label extension data from both the Scarlet Road and Marguerite Road studies, Dr. Klein said. Patients in these studies were randomized to either 105 or 225 mg of the antibody. While there were no significant cognitive benefits, there were trends toward improvement with the higher dose, as well as dose-dependent plaque clearance. This encouraged researchers to look at higher doses in 52-week open-label extensions of each study.
Dr. Klein presented new imaging data for these studies. Between both, 40 patients were maintained for 6-9 months on the highest doses (900-1,200 mg). Of these, 17 had almost total clearance of their amyloid burden. Their scans, Dr. Klein said, read as traces of amyloid or as amyloid negative. The effect was consistent regardless of the amount of amyloid at baseline.
“These are very encouraging biomarker data,” he said. “We are going into our new phase 3 studies, Graduate I and II, very optimistic.”
Little information is available about these studies. According to a press release, they will target patients with prodromal-mild disease at the higher doses. Emails to Roche and its German partner, MorphoSys, were not returned by press time. But from Dr. Klein’s comments, it seems clear that gantenerumab has not reached the end of its road.
Dr. Sperling disclosed relationships with numerous pharmaceutical companies. Dr. Klein is an employee of Roche.
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