Phase II Findings in AD Drug Trial 'Not All Bad'

CHICAGO – An updated version of the drug methylene blue appears to slow cognitive decline significantly in patients with moderate Alzheimer's disease by dissolving tau tangles in the brain, according to the results of a phase II trial.

This is the first Alzheimer's agent to target tau, and the first time any purported disease-modifying agent has achieved its primary cognitive end point, Dr. Claude Wischik said at the International Conference on Alzheimer's Disease.

“Our data show that we are able to halt the progression of Alzheimer's disease by targeting the neurofibrillatory tangle with a tau aggregation inhibitor,” said Dr. Wischik, founder and director of TauRX Therapeutics Ltd, the Singapore company that funded and conducted the research.

In the wake of two failed phase III trials of anti-amyloid drugs, Dr. Wischik's study has drawn enormous media attention, with newspapers hailing the drug as a breakthrough and potential cure. But other researchers at the meeting took a more tempered view. Potential problems with blinding (the study drug turns the urine of some patients green), an apparent lack of efficacy in the overall analysis, and the folding-in of one of the active groups into the placebo group, all were red flags for Dr. Lon Schneider, professor of psychiatry and behavioral sciences at the University of Southern California, Los Angeles.

“If they had [shown] the overall results of the combined group, as they should have, instead of just focusing on the moderates, it would have looked much more clearly like what it really was: an unremarkable, underpowered study,” said Dr. Schneider, a respected expert on Alz-heimer's research, at the meeting sponsored by the Alzheimer's Association. “However, that's not all bad for a phase II trial, if you show general safety and no toxicity, which they did.”

The drug, trade-named Rember, is a purified version of methylene blue, a dye that has a weak antibacterial effect. Rember works two ways: by blocking the formation of tau oligomers and converting them to paired helical filaments, and by dissolving existing tau tangles, according to the company's Web site.

The phase II dose-finding study included 321 patients with mild-moderate Alzheimer's and was conducted in the United Kingdom and Singapore. Patients were randomized to placebo or one of three drug doses: 30 mg three times daily, 60 mg three times daily, or 100 mg three times daily. The compound was contained in a gelatin capsule.

The study was conducted in two parts: an initial 24-week blinded placebo-controlled study, followed by 60 weeks of blinded active treatment. At baseline and throughout the trial, subjects received cognitive testing; functional brain imaging was performed on some at baseline and at 25 weeks.

Although he said none of the patients was taking cholinesterase inhibitors, Dr. Wischik's presentation did not include data on any other baseline characteristics of the group, how many were randomized to each treatment arm, or the dropout rate.

At no time were the results of the 100-mg dose discussed. Dr. Wischik said the gelatin capsule containing this dose was defective, which delayed release of the drug until it was in the intestine. He said the defect rendered the 100-mg dose completely ineffective.

Instead of analyzing this group, Dr. Wischik folded all its data into the placebo arm analysis, an unusual practice, Dr. Schneider noted. “If they thought the 100-mg dose was badly put together, they should have eliminated it entirely and performed a conservative analysis on what they had.”

Describing the study's primary end point–cognitive decline at 24 weeks–Dr. Wischik did not give the overall results of the entire group. Instead, he presented separate results for the mild and moderate patients. The drug did not show any cognitive benefit among the mild patients at 24 weeks; neither the placebo group nor the active groups declined significantly from baseline. However, among the moderate patients, Rember appeared to have a positive effect.

The use of methylene blue predates the Food and Drug Administration. Dr. Wischik, who predicted that Rember would be available within 4 years, said he was counting on this grandfathered status to speed it through the approval process.

CHICAGO – An updated version of the drug methylene blue appears to slow cognitive decline significantly in patients with moderate Alzheimer's disease by dissolving tau tangles in the brain, according to the results of a phase II trial.

This is the first Alzheimer's agent to target tau, and the first time any purported disease-modifying agent has achieved its primary cognitive end point, Dr. Claude Wischik said at the International Conference on Alzheimer's Disease.

“Our data show that we are able to halt the progression of Alzheimer's disease by targeting the neurofibrillatory tangle with a tau aggregation inhibitor,” said Dr. Wischik, founder and director of TauRX Therapeutics Ltd, the Singapore company that funded and conducted the research.

In the wake of two failed phase III trials of anti-amyloid drugs, Dr. Wischik's study has drawn enormous media attention, with newspapers hailing the drug as a breakthrough and potential cure. But other researchers at the meeting took a more tempered view. Potential problems with blinding (the study drug turns the urine of some patients green), an apparent lack of efficacy in the overall analysis, and the folding-in of one of the active groups into the placebo group, all were red flags for Dr. Lon Schneider, professor of psychiatry and behavioral sciences at the University of Southern California, Los Angeles.

“If they had [shown] the overall results of the combined group, as they should have, instead of just focusing on the moderates, it would have looked much more clearly like what it really was: an unremarkable, underpowered study,” said Dr. Schneider, a respected expert on Alz-heimer's research, at the meeting sponsored by the Alzheimer's Association. “However, that's not all bad for a phase II trial, if you show general safety and no toxicity, which they did.”

The drug, trade-named Rember, is a purified version of methylene blue, a dye that has a weak antibacterial effect. Rember works two ways: by blocking the formation of tau oligomers and converting them to paired helical filaments, and by dissolving existing tau tangles, according to the company's Web site.

The phase II dose-finding study included 321 patients with mild-moderate Alzheimer's and was conducted in the United Kingdom and Singapore. Patients were randomized to placebo or one of three drug doses: 30 mg three times daily, 60 mg three times daily, or 100 mg three times daily. The compound was contained in a gelatin capsule.

The study was conducted in two parts: an initial 24-week blinded placebo-controlled study, followed by 60 weeks of blinded active treatment. At baseline and throughout the trial, subjects received cognitive testing; functional brain imaging was performed on some at baseline and at 25 weeks.

Although he said none of the patients was taking cholinesterase inhibitors, Dr. Wischik's presentation did not include data on any other baseline characteristics of the group, how many were randomized to each treatment arm, or the dropout rate.

At no time were the results of the 100-mg dose discussed. Dr. Wischik said the gelatin capsule containing this dose was defective, which delayed release of the drug until it was in the intestine. He said the defect rendered the 100-mg dose completely ineffective.

Instead of analyzing this group, Dr. Wischik folded all its data into the placebo arm analysis, an unusual practice, Dr. Schneider noted. “If they thought the 100-mg dose was badly put together, they should have eliminated it entirely and performed a conservative analysis on what they had.”

Describing the study's primary end point–cognitive decline at 24 weeks–Dr. Wischik did not give the overall results of the entire group. Instead, he presented separate results for the mild and moderate patients. The drug did not show any cognitive benefit among the mild patients at 24 weeks; neither the placebo group nor the active groups declined significantly from baseline. However, among the moderate patients, Rember appeared to have a positive effect.

The use of methylene blue predates the Food and Drug Administration. Dr. Wischik, who predicted that Rember would be available within 4 years, said he was counting on this grandfathered status to speed it through the approval process.

CHICAGO – An updated version of the drug methylene blue appears to slow cognitive decline significantly in patients with moderate Alzheimer's disease by dissolving tau tangles in the brain, according to the results of a phase II trial.

This is the first Alzheimer's agent to target tau, and the first time any purported disease-modifying agent has achieved its primary cognitive end point, Dr. Claude Wischik said at the International Conference on Alzheimer's Disease.

“Our data show that we are able to halt the progression of Alzheimer's disease by targeting the neurofibrillatory tangle with a tau aggregation inhibitor,” said Dr. Wischik, founder and director of TauRX Therapeutics Ltd, the Singapore company that funded and conducted the research.

In the wake of two failed phase III trials of anti-amyloid drugs, Dr. Wischik's study has drawn enormous media attention, with newspapers hailing the drug as a breakthrough and potential cure. But other researchers at the meeting took a more tempered view. Potential problems with blinding (the study drug turns the urine of some patients green), an apparent lack of efficacy in the overall analysis, and the folding-in of one of the active groups into the placebo group, all were red flags for Dr. Lon Schneider, professor of psychiatry and behavioral sciences at the University of Southern California, Los Angeles.

“If they had [shown] the overall results of the combined group, as they should have, instead of just focusing on the moderates, it would have looked much more clearly like what it really was: an unremarkable, underpowered study,” said Dr. Schneider, a respected expert on Alz-heimer's research, at the meeting sponsored by the Alzheimer's Association. “However, that's not all bad for a phase II trial, if you show general safety and no toxicity, which they did.”

The drug, trade-named Rember, is a purified version of methylene blue, a dye that has a weak antibacterial effect. Rember works two ways: by blocking the formation of tau oligomers and converting them to paired helical filaments, and by dissolving existing tau tangles, according to the company's Web site.

The phase II dose-finding study included 321 patients with mild-moderate Alzheimer's and was conducted in the United Kingdom and Singapore. Patients were randomized to placebo or one of three drug doses: 30 mg three times daily, 60 mg three times daily, or 100 mg three times daily. The compound was contained in a gelatin capsule.

The study was conducted in two parts: an initial 24-week blinded placebo-controlled study, followed by 60 weeks of blinded active treatment. At baseline and throughout the trial, subjects received cognitive testing; functional brain imaging was performed on some at baseline and at 25 weeks.

Although he said none of the patients was taking cholinesterase inhibitors, Dr. Wischik's presentation did not include data on any other baseline characteristics of the group, how many were randomized to each treatment arm, or the dropout rate.

At no time were the results of the 100-mg dose discussed. Dr. Wischik said the gelatin capsule containing this dose was defective, which delayed release of the drug until it was in the intestine. He said the defect rendered the 100-mg dose completely ineffective.

Instead of analyzing this group, Dr. Wischik folded all its data into the placebo arm analysis, an unusual practice, Dr. Schneider noted. “If they thought the 100-mg dose was badly put together, they should have eliminated it entirely and performed a conservative analysis on what they had.”

Describing the study's primary end point–cognitive decline at 24 weeks–Dr. Wischik did not give the overall results of the entire group. Instead, he presented separate results for the mild and moderate patients. The drug did not show any cognitive benefit among the mild patients at 24 weeks; neither the placebo group nor the active groups declined significantly from baseline. However, among the moderate patients, Rember appeared to have a positive effect.

The use of methylene blue predates the Food and Drug Administration. Dr. Wischik, who predicted that Rember would be available within 4 years, said he was counting on this grandfathered status to speed it through the approval process.