Latrepirdine Improved Cognitive Symptoms in Huntington's

Major Finding: Latrepirdine was well tolerated, had low adverse event rates, and significantly improved MMSE scores by 1 point over 90 days.

Data Source: Randomized, placebo-controlled, phase II trial of 90 patients with mild to moderate Huntington's disease

Disclosures: Some investigators are employees of Medivation Inc., which manufactures latrepirdine and sponsored the study sponsor; others reported receiving prior research support from the company.

Cognitive impairment improved in patients with mild to moderate Huntington's disease without any noticeable increase in adverse events after a 90-day course of treatment with the investigational drug latrepirdine.

The drug, known most widely outside of the United States under the trade name Dimebon, was well tolerated in the trial and showed no signs of increasing the risk for particular adverse events, reported Dr. Karl Kieburtz of the University of Rochester (N.Y.), and his colleagues in the Dimebon in Subjects With Huntington Disease (DIMOND) study (Arch. Neurol. 2010;67:154-60).

Latrepirdine is a synthetic molecule that is known to stabilize mitochondrial membranes and increase neurite outgrowth. It is currently also being tested in phase III trials of patients with Alzheimer's disease.

The patients had a mean age of about 53 years and had to be ambulatory, have a total functional capacity score of 5 or higher at baseline on the Unified Huntington Disease Rating Scale (UHDRS), and be living in the community without requiring skilled nursing care.

After starting latrepirdine at 10 mg/day on day 1 and then 30 mg/day for the following 6 days, the dose was titrated up to 60 mg/day after the first week. The study, comprising 90 subjects, was completed by 87% of patients in the latrepirdine group and by 82% on placebo.

In the trial, all efficacy outcomes were secondary end points. On the Mini-Mental State Examination (MMSE), 46 latrepirdine-treated patients had a mean improvement of nearly 1 point on the MMSE, compared with no change in 44 placebo-treated patients. No significant differences in outcomes could be detected between the groups on other measures of cognitive function, such as the Alzheimer's Disease Assessment Scale–Cognitive subscale or the cognitive tests in the UHDRS.

Dr. Kieburtz and his associates thought that the “significant finding on the MMSE was surprising, given that the [examination] is generally considered a relatively insensitive measure of cognitive function.”

However, the researchers noted that the “MMSE provides a broader assessment of cognition than the other end points assessed” and “it is highly stable during a 6-month to 12-month period with low variability in patients who were untreated.”

A “substantial number” of patients in both groups had maximum or near-maximum scores on the MMSE at baseline. To determine the effect of latrepirdine in patients with more severe cognitive impairment, the investigators analyzed the outcomes for 51 patients with an MMSE score of 26 or lower. At 90 days, the mean MMSE score of patients in this subgroup who received latrepirdine was 1.63 points greater than the score of those who received placebo.

Adverse events occurred in similar percentages of patients treated with latrepirdine (70%) or placebo (80%); about half of these were moderate to severe in intensity. The only adverse events that occurred more often in latrepirdine-treated patients than in placebo-treated patients were headache (15% vs. 7%, respectively) and somnolence (7% vs. 2%).

My Take

Stage Set for Future Trials

This effort by Dr. Kieburtz and his colleagues is noteworthy for a number of reasons. Although Xenazine (tetrabenazine) is approved for the treatment of chorea and other motor manifestations of HD, there are no approved medications available for cognitive and behavioral symptoms in the disease.

Dr. Kieburtz presents data on the safety and tolerability of latrepirdine given 20 mg three times daily compared with placebo in patients diagnosed with HD. The treatment and placebo groups were similar and randomization methods were strict.

Although the study was not designed to detect a minimally clinically significant effect on any efficacy measure, a small positive change observed in MMSE testing suggests that further study with this agent is warranted. The unique proposed mechanism of action of latrepirdine to stabilize mitochondrial membranes distinguishes it from medications commonly used in HD such as anticholinesterase inhibitors and N-methyl-D-aspartate antagonists, giving hope for a new avenue of therapeutic intervention in this challenging neurodegenerative disorder.

The investigators' carefully designed and executed work sets the stage for future treatment trials focused on cognitive and behavioral efficacy in HD.

Major Finding: Latrepirdine was well tolerated, had low adverse event rates, and significantly improved MMSE scores by 1 point over 90 days.

Data Source: Randomized, placebo-controlled, phase II trial of 90 patients with mild to moderate Huntington's disease

Disclosures: Some investigators are employees of Medivation Inc., which manufactures latrepirdine and sponsored the study sponsor; others reported receiving prior research support from the company.

Cognitive impairment improved in patients with mild to moderate Huntington's disease without any noticeable increase in adverse events after a 90-day course of treatment with the investigational drug latrepirdine.

The drug, known most widely outside of the United States under the trade name Dimebon, was well tolerated in the trial and showed no signs of increasing the risk for particular adverse events, reported Dr. Karl Kieburtz of the University of Rochester (N.Y.), and his colleagues in the Dimebon in Subjects With Huntington Disease (DIMOND) study (Arch. Neurol. 2010;67:154-60).

Latrepirdine is a synthetic molecule that is known to stabilize mitochondrial membranes and increase neurite outgrowth. It is currently also being tested in phase III trials of patients with Alzheimer's disease.

The patients had a mean age of about 53 years and had to be ambulatory, have a total functional capacity score of 5 or higher at baseline on the Unified Huntington Disease Rating Scale (UHDRS), and be living in the community without requiring skilled nursing care.

After starting latrepirdine at 10 mg/day on day 1 and then 30 mg/day for the following 6 days, the dose was titrated up to 60 mg/day after the first week. The study, comprising 90 subjects, was completed by 87% of patients in the latrepirdine group and by 82% on placebo.

In the trial, all efficacy outcomes were secondary end points. On the Mini-Mental State Examination (MMSE), 46 latrepirdine-treated patients had a mean improvement of nearly 1 point on the MMSE, compared with no change in 44 placebo-treated patients. No significant differences in outcomes could be detected between the groups on other measures of cognitive function, such as the Alzheimer's Disease Assessment Scale–Cognitive subscale or the cognitive tests in the UHDRS.

Dr. Kieburtz and his associates thought that the “significant finding on the MMSE was surprising, given that the [examination] is generally considered a relatively insensitive measure of cognitive function.”

However, the researchers noted that the “MMSE provides a broader assessment of cognition than the other end points assessed” and “it is highly stable during a 6-month to 12-month period with low variability in patients who were untreated.”

A “substantial number” of patients in both groups had maximum or near-maximum scores on the MMSE at baseline. To determine the effect of latrepirdine in patients with more severe cognitive impairment, the investigators analyzed the outcomes for 51 patients with an MMSE score of 26 or lower. At 90 days, the mean MMSE score of patients in this subgroup who received latrepirdine was 1.63 points greater than the score of those who received placebo.

Adverse events occurred in similar percentages of patients treated with latrepirdine (70%) or placebo (80%); about half of these were moderate to severe in intensity. The only adverse events that occurred more often in latrepirdine-treated patients than in placebo-treated patients were headache (15% vs. 7%, respectively) and somnolence (7% vs. 2%).

My Take

Stage Set for Future Trials

This effort by Dr. Kieburtz and his colleagues is noteworthy for a number of reasons. Although Xenazine (tetrabenazine) is approved for the treatment of chorea and other motor manifestations of HD, there are no approved medications available for cognitive and behavioral symptoms in the disease.

Dr. Kieburtz presents data on the safety and tolerability of latrepirdine given 20 mg three times daily compared with placebo in patients diagnosed with HD. The treatment and placebo groups were similar and randomization methods were strict.

Although the study was not designed to detect a minimally clinically significant effect on any efficacy measure, a small positive change observed in MMSE testing suggests that further study with this agent is warranted. The unique proposed mechanism of action of latrepirdine to stabilize mitochondrial membranes distinguishes it from medications commonly used in HD such as anticholinesterase inhibitors and N-methyl-D-aspartate antagonists, giving hope for a new avenue of therapeutic intervention in this challenging neurodegenerative disorder.

The investigators' carefully designed and executed work sets the stage for future treatment trials focused on cognitive and behavioral efficacy in HD.

Major Finding: Latrepirdine was well tolerated, had low adverse event rates, and significantly improved MMSE scores by 1 point over 90 days.

Data Source: Randomized, placebo-controlled, phase II trial of 90 patients with mild to moderate Huntington's disease

Disclosures: Some investigators are employees of Medivation Inc., which manufactures latrepirdine and sponsored the study sponsor; others reported receiving prior research support from the company.

Cognitive impairment improved in patients with mild to moderate Huntington's disease without any noticeable increase in adverse events after a 90-day course of treatment with the investigational drug latrepirdine.

The drug, known most widely outside of the United States under the trade name Dimebon, was well tolerated in the trial and showed no signs of increasing the risk for particular adverse events, reported Dr. Karl Kieburtz of the University of Rochester (N.Y.), and his colleagues in the Dimebon in Subjects With Huntington Disease (DIMOND) study (Arch. Neurol. 2010;67:154-60).

Latrepirdine is a synthetic molecule that is known to stabilize mitochondrial membranes and increase neurite outgrowth. It is currently also being tested in phase III trials of patients with Alzheimer's disease.

The patients had a mean age of about 53 years and had to be ambulatory, have a total functional capacity score of 5 or higher at baseline on the Unified Huntington Disease Rating Scale (UHDRS), and be living in the community without requiring skilled nursing care.

After starting latrepirdine at 10 mg/day on day 1 and then 30 mg/day for the following 6 days, the dose was titrated up to 60 mg/day after the first week. The study, comprising 90 subjects, was completed by 87% of patients in the latrepirdine group and by 82% on placebo.

In the trial, all efficacy outcomes were secondary end points. On the Mini-Mental State Examination (MMSE), 46 latrepirdine-treated patients had a mean improvement of nearly 1 point on the MMSE, compared with no change in 44 placebo-treated patients. No significant differences in outcomes could be detected between the groups on other measures of cognitive function, such as the Alzheimer's Disease Assessment Scale–Cognitive subscale or the cognitive tests in the UHDRS.

Dr. Kieburtz and his associates thought that the “significant finding on the MMSE was surprising, given that the [examination] is generally considered a relatively insensitive measure of cognitive function.”

However, the researchers noted that the “MMSE provides a broader assessment of cognition than the other end points assessed” and “it is highly stable during a 6-month to 12-month period with low variability in patients who were untreated.”

A “substantial number” of patients in both groups had maximum or near-maximum scores on the MMSE at baseline. To determine the effect of latrepirdine in patients with more severe cognitive impairment, the investigators analyzed the outcomes for 51 patients with an MMSE score of 26 or lower. At 90 days, the mean MMSE score of patients in this subgroup who received latrepirdine was 1.63 points greater than the score of those who received placebo.

Adverse events occurred in similar percentages of patients treated with latrepirdine (70%) or placebo (80%); about half of these were moderate to severe in intensity. The only adverse events that occurred more often in latrepirdine-treated patients than in placebo-treated patients were headache (15% vs. 7%, respectively) and somnolence (7% vs. 2%).

My Take

Stage Set for Future Trials

This effort by Dr. Kieburtz and his colleagues is noteworthy for a number of reasons. Although Xenazine (tetrabenazine) is approved for the treatment of chorea and other motor manifestations of HD, there are no approved medications available for cognitive and behavioral symptoms in the disease.

Dr. Kieburtz presents data on the safety and tolerability of latrepirdine given 20 mg three times daily compared with placebo in patients diagnosed with HD. The treatment and placebo groups were similar and randomization methods were strict.

Although the study was not designed to detect a minimally clinically significant effect on any efficacy measure, a small positive change observed in MMSE testing suggests that further study with this agent is warranted. The unique proposed mechanism of action of latrepirdine to stabilize mitochondrial membranes distinguishes it from medications commonly used in HD such as anticholinesterase inhibitors and N-methyl-D-aspartate antagonists, giving hope for a new avenue of therapeutic intervention in this challenging neurodegenerative disorder.

The investigators' carefully designed and executed work sets the stage for future treatment trials focused on cognitive and behavioral efficacy in HD.