Alzheimer's Drug Pulled From Phase III for Lack of Efficacy

Another potential Alzheimer’s disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer’s drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

“Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism,” he said in an interview. “IDENTITY had a lot going for it. This was a tough one to swallow.”

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

“This is disappointing news for the millions of Alzheimer’s patients and their families worldwide who anxiously await a successful treatment for this devastating illness,” Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up “will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued.”

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. “I would be very cautious on interpreting these data until the full analysis has unfolded.”

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. “They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy.” Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer’s plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

“In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18),” Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

“By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease,” he said. “The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?”

It may be time, he said, to think of Alzheimer’s as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. “Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage.”

Dr. Sabbagh said he wondered if some of the Alzheimer’s drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. “My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop.”

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. “A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different.”

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

Another potential Alzheimer’s disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer’s drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

“Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism,” he said in an interview. “IDENTITY had a lot going for it. This was a tough one to swallow.”

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

“This is disappointing news for the millions of Alzheimer’s patients and their families worldwide who anxiously await a successful treatment for this devastating illness,” Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up “will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued.”

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. “I would be very cautious on interpreting these data until the full analysis has unfolded.”

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. “They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy.” Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer’s plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

“In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18),” Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

“By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease,” he said. “The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?”

It may be time, he said, to think of Alzheimer’s as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. “Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage.”

Dr. Sabbagh said he wondered if some of the Alzheimer’s drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. “My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop.”

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. “A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different.”

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.

Another potential Alzheimer’s disease drug failed after Eli Lilly and Co. pulled the plug Aug. 17 on its phase III study of semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques.

This latest in a long string of Alzheimer’s drug flops carried an especially harsh sting, said Dr. Marwan Sabbagh, an investigator in the IDENTITY (Interrupting Alzheimer’s Dementia by Evaluating Treatment of Amyloid Pathology) and IDENTITY-2 trials.

“Unlike some of the previous failed phase III studies, IDENTITY was a well-designed, well-powered study of a drug with a very specific mechanism,” he said in an interview. “IDENTITY had a lot going for it. This was a tough one to swallow.”

The company announced its decision to halt semagacestat development after a planned interim analysis of both trials showed that patients who took the study drug did not experience cognitive improvement and, in fact, showed a significant worsening of cognition and the ability to perform activities of daily living, compared with those taking placebo.

In a press statement, the company also noted that semagacestat was associated with an increased risk of skin cancer. No data were available as to the risk ratio, crude incidence rate, or type of cancers observed.

“This is disappointing news for the millions of Alzheimer’s patients and their families worldwide who anxiously await a successful treatment for this devastating illness,” Jan M. Lundberg, Ph.D., president of Lilly Research Laboratories, said in a statement.

IDENTITY and IDENTITY-2 randomized more than 2,600 patients with mild to moderate Alzheimer’s disease to either placebo or 140-mg semagacestat for 24 months. Although the trials have been halted, Lilly will continue to follow patients and analyze safety and efficacy data from both studies for at least another 6 months. The statement noted that the extended follow-up “will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued.”

Dr. Sabbagh, the clinical and research medical director of the Banner Sun Health Research Institute in Sun City, Ariz., said it is still too early to understand why those who took the study drug fared worse than the placebo group, or how it may have affected skin cancer risk. “I would be very cautious on interpreting these data until the full analysis has unfolded.”

Semagacestat made a somewhat unusual leap from phase II to phase III research, Dr. Sabbagh said. “They had some very promising data going into phase III, but it was a very different approach. Their 14-week, phase II study [in 51 patients] met the safety end points, but did not look at [cognitive] efficacy.” Instead, he said, Lilly moved the drug forward on the basis of significantly reduced beta-amyloid levels in blood plasma.

The drug does not decrease the existing Alzheimer’s plaque burden. Instead, its aim is to prevent new plaques. It decreases the amount of plaque-forming beta-amyloid protein by changing the point at which gamma secretase cleaves the amyloid precursor protein. The resulting shorter peptide lengths do not aggregate into brain plaques like those with 40 and 42 amino acids—amyloid beta40 (Abeta40), and Abeta42.

In the phase II study, patients who took 100-mg semagacestat daily had a 58% reduction of Abeta40 in the plasma; those who took 140 mg daily had a 65% reduction. However, there were no significant reductions in CSF Abeta40 levels (Arch. Neurol. 2008;65:1031-8).

Although the drug was generally well tolerated, the phase II researchers, led by Dr. Adam Fleischer of University of California, San Diego, expressed some concern about safety. All gamma secretase inhibitors interfere with Notch signaling. The Notch protein is important in programmed cell death; blocking it particularly affects organ systems with high cell turnover, such as the gut and immune system. In the phase II trial, there were more – but not significantly more – gastrointestinal side effects in the active group (27% vs. 13%). One small-bowel obstruction was considered possibly drug related.

“In addition, when combining reports of somnolence, fatigue, lethargy, and asthenia from different organ classes, we found that 40% of treatment subjects noted one or more of these symptoms, whereas only 13% in the placebo group had these symptoms (P = .18),” Dr. Fleischer and his colleagues reported.

Although the drug mobilized Abeta40 in phase II, the changes did not translate into clinical benefit during phase III, Dr. Sabbagh said. But that finding may mean that semagacestat’s failure is a case of poor timing rather than poor efficacy.

“By the time you have Alzheimer’s symptoms, you already have a critical mass of amyloid plaque, and this stays relatively constant as you progress through the disease,” he said. “The question is, will any antiamyloid drug have a meaningful effect if it’s given after the plaques have already developed?”

It may be time, he said, to think of Alzheimer’s as a biphasic disorder, with different drugs for each phase. Initially, amyloid plaques appear in the disease, followed by tau neurofibrillatory tangling and its associated neurotoxicity. “Maybe our amyloid-based therapies should be used in the presymptomatic phase, before the plaques build to that critical level. Other drugs might be more useful in the symptomatic stage.”

Dr. Sabbagh said he wondered if some of the Alzheimer’s drugs that have been abandoned after failing their phase III studies might be more successful if used earlier in the disease course. “My fear is that a drug will be shelved when in fact it might be a good choice in a presymptomatic scenario, when amyloid plaques are just beginning to develop.”

With the enormous leaps now being made in amyloid imaging, researchers are pushing back the diagnostic timeline, identifying patients at the very onset of mild cognitive impairment – and perhaps even before any memory complaints appear. “A drug like semagacestat would be interesting to study in patients at that stage. Don’t chuck the product altogether; back it up into an earlier phase and see if the results are any different.”

Lilly sponsored the studies. Dr. Sabbagh reported no financial ties with the company.