Alzheimer's disease: novel therapeutic strategies

Results from four studies of potential new treatments for Alzheimer's increase the field's knowledge and point scientists toward advances in therapies for the disease, according to research reported at the 2008 Alzheimer's Association International Conference on Alzheimer's Disease ( ICAD 2008 ), in Chicago.

The reports included the following data:

Phase III trial of Tarenflurbil

A Phase III trial of Tarenflurbil ( Flurizan ) failed to achieve statistical significance on either of its two primary endpoints, and that the company was abandoning development of the compound for Alzheimer's disease.

Tarenflurbil is classified as a selective amyloid lowering agent, which was shown in nonclinical studies to modulate gamma secretase activity. The drug was in trials in people with mild Alzheimer's to determine if its ability to lower the amount of toxic beta-amyloid would slow or stop the course of the disease.

In the randomized, double-blind, placebo-controlled trial, 1,649 individuals with mild Alzheimer's ( mean MMSE in both groups = 23.3 ) were randomized 1:1 to receive Tarenflurbil 800 mg twice-a-day or placebo for 18 months. The co-primary outcome measures of efficacy were two standard measures of cognition and the ability to accomplish activities of daily living, respectively the ADAS-cog and the ADCS-ADL, with assessments conducted every three months. The secondary outcome measure was the Clinical Dementia Rating scale. Exploratory outcomes included the Neuropsychiatric Inventory ( NPI ), Quality of Life-Alzheimer's test, and Caregiver Burden Inventory.

The researchers found that the drug did not achieve statistical significance in either of its primary endpoints of cognition and activities of daily living. Also, it did not achieve statistical significance on the secondary endpoint. By the end of the 18-month trial, patients in both the Tarenflurbil and placebo groups had declined approximately seven points on the ADAS-cog scale and 10 points on the ADCS-ADL scale.

The reported adverse effects reflect the expected profile of the elderly population with Alzheimer's and, in most participants, symptoms were well balanced between the Tarenflurbil and placebo groups. However, in the Tarenflurbil treatment group, there was increased frequency of anemia ( 9.7 percent vs. 4.5 percent ), infections ( pneumonia, herpes zoster, sepsis ) ( 6.9 percent vs. 2.9 percent ), and gastrointestinal ulcers ( 1.7 percent vs. 0.4 percent ).

Phase IIa trial of PBT2

PBT2 is a metal-protein attenuating compound ( MPAC ), developed as a potential Alzheimer's therapy. In previous research, ions of copper and zinc were found to play a role in the aggregation of beta amyloid protein, which is believed to cause functional damage in Alzheimer's.
PBT2 reduces the toxic form of beta amyloid by preventing the interaction of beta amyloid with copper and zinc. MPACs have been shown to restore normal function to beta amyloid-impaired synapses and improve cognitive performance in mouse models of Alzheimer's.

A Phase IIa randomised, double-blind, placebo-controlled trial of PBT2 has assessed the safety, tolerability, biochemical impact on the body, and preliminary efficacy of two different doses of the compound in patients with early Alzheimer's. This was done by looking at how treatment with PBT2 changed the levels of proteins that are believed to be linked to Alzheimer's in the blood and spinal fluid ( CSF ) and using memory and thinking tests to assess any change in the participants' mental capacity.

Seventy-eight people with mild Alzheimer's ( mean MMSE=22.9 ) were randomized to receive placebo ( n=29 ), PBT2 50mg ( n=20 ) or PBT2 250mg ( n=29 ) capsules orally, once per day for 12 weeks. Biomarker assessment included the mean change from baseline to week 12 of proteins Abeta42 and Abeta40 in CSF. Preliminary efficacy assessments included the mean change from baseline to week 12 on a Neuropsychological Test Battery ( NTB ) and the ADAS-cog.

The researchers found that PBT2 250mg demonstrated a statistically significant reduction of CSF Abeta42 after 12 weeks of treatment compared with placebo ( p=0.006 ), which was dose-dependent ( p=0.023 ). PBT2 250mg demonstrated statistically significant improvements in both the Trail Making Test Part B and the Category Fluency Test ( components of the NTB related to executive function ) compared with placebo ( p=0.009 and p=0.041, respectively ). PBT2 had no effect on the ADAS-cog in this trial.

The researchers found the safety and tolerability profile to be similar between PBT2 and placebo. The overall withdrawal rate in the study was 5 percent, with no withdrawals attributed to adverse events. There were no serious adverse events reported with PBT2.

A phase IIb trial of a tau aggregation inhibitor therapy

As an alternative to anti-amyloid therapies for Alzheimer's, researchers continue to examine a variety of treatments and targets with the potential to curb the disease. This includes presenting data supporting the viability of therapies targeting tau protein and its aggregation into the tangles originally discovered by Alois Alzheimer.

Previous research has shown that the buildup of brain lesions known as neurofibrillary tangles, which are composed of a short fragment of a protein called tau, is correlated with increasing levels of dementia symptoms. And, these tangles first appear in the brain long before symptoms of the disease become clinically apparent. Methylthioninium chloride ( MTC ) has been shown in the test tube to dissolve tau tangle filaments and prevent aggregation of tau into tangles. MTC has also been shown to block the toxic effects of aggregated tau in cells. In animal models, MTC has demonstrated cognitive and behavioral benefits in line with reduced tau pathology.

A 24-week, double-blind, randomized, dose-ranging, parallel design trial of MTC monotherapy was conducted in 321 people with Alzheimer's at 17 centers in the United Kingdom and Singapore, followed by a 60-week, blinded, active treatment extension. The control group received placebo for the initial 24 weeks and then a minimal efficacy dose subsequently.
The primary objective was to investigate the effects of oral MTC at 30, 60 and 100 mg doses three times per day, compared with placebo, over 24 weeks on cognitive function as measured by the ADAS-cog in patients with mild or moderate Alzheimer's, stratified by stage of the disease. Another objective was to determine MTC's potential to modify the course of Alzheimer's over 19 months. Imaging results from SPECT and PET scans were collected at baseline and after 24 weeks of treatment.

The researchers found that, at 24 weeks, MTC produced a significant improvement relative to placebo of -5.5 ADAS-cog units in moderate subjects at the 60 mg dose ( p = 0.0208 ). There was no placebo decline in people with mild Alzheimer's in the control group over the first 24 weeks preventing initial efficacy analysis, although efficacy was demonstrated in mild Alzheimer's by SPECT-scan outcomes over the same period. MTC stabilized the progression of Alzheimer's over 50 weeks in both mild and moderate Alzheimer's. The overall effect size was -6.8 ADAS-cog units vs. decline of 7.8 units in the control arm ( p < 0.0001 ), with significant efficacy demonstrated separately in mild and moderate subgroups.

According to the researchers, as a first approximation to supporting disease modifying efficacy, treatment with MTC at the 60mg dose produced a significantly larger effect size at 50 weeks than at 24 weeks implying an effect on the rate of cognitive decline ( p = 0.0014 ). This was confirmed in a mixed effects slope analysis, showing an 81 percent reduction of long run rate of progression of decline over 50 weeks ( p < 0.0001 ). The final 84-week analysis confirmed the long term effect of the 60mg dose in subjects remaining on treatment, with apparent decline still not significantly different from baseline at the final assessment, whereas there was significant decline in the other study arms.

The researchers added that brain imaging using SPECT and PET confirmed the clinical trial results. SPECT measures regional cerebral blood flow ( rCBF ) which is closely related to brain cell activity. The study showed that treatment with MTC at the 60mg dose eliminated the rCBF decline that was seen in control subjects. The effect was greatest in brain regions that had the most severe tau aggregation pathology, namely the hippocampus and the entorhinal cortex, which are regions affected early and most severely in Alzheimer's.

Clinical trial of Souvenaid

People with Alzheimer's exhibit a significant loss of brain synapses, and this loss correlates with the loss of cognitive function. Pre-clinical research has shown that specific combinations of nutrients can increase synapse formation.

Souvenaid is designed to improve synapse formation and synaptic transmission via the synergistic action of a combination of nutrients ( specifically, it contains Uridine monophosphate, Choline, the omega-3 fatty acids ( EPA, DHA ), phospholipids, B vitamins and antioxidants ).
Pre-clinical research has shown that specific combinations of certain nutrients interact to enhance brain cell outgrowth, synapse formation, and neurotransmitter release and also improved cognitive function in several pre-clinical models. This specific combination of nutrients showed also reduced amyloid production and toxicity in the pre-clinical models.

A randomised, double-blind, controlled 12-week trial, has evaluated the safety and effect of Souvenaid on memory and cognitive performance in people with mild Alzheimer's ( MMSE 20-26, mean=23.9 ) who had never taken any Alzheimer's drugs.

Two hundred twelve ( 212 ) people with mild Alzheimer's were recruited for the trial at 28 sites mainly in the Netherlands, Germany, and Belgium, with a single site in the U.S.; 106 were assigned to Souvenaid, a 125 ml ( 125 kcal ) once-a-day drink, and 106 to control in the 12-week study.

Primary outcome measures were a delayed verbal memory task derived from the Wechsler Memory Scale-revised and the 13-item modified ADAS-cog. Secondary outcomes included the MMSE, 23-item Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory ( ADCS-ADL ), 12-item Neuropsychiatric Inventory ( NPI ), Clinician's Interview Based Impression of Change plus Caregiver Input ( CIBIC-plus ) and Quality of Life in Alzheimer's Disease ( QOL-AD ).
A separate analysis was performed on a pre-specified subgroup of very mild Alzheimer's ( MMSE>23 ). In an optional, double-blind, 12-week extension phase, patients continued to receive the same study product ( 85 percent of the week 12 completers continued into the extension phase ).

The investigators found a statistically significant benefit in mild Alzheimer's patients on the delayed verbal memory task in the Souvenaid group, and also a significant effect in the subgroup of very mild patients. The unadjusted analyses showed no significant effect on the modified ADAS-cog. However, the baseline modified ADAS-cog score was a predictor for the intervention effect. Thus, patients with a higher baseline score showed a greater effect of Souvenaid on cognition. The investigators noted that there was no decline in modified ADAS-cog and verbal memory in the control group during the 12 weeks of the study.

Souvenaid was well tolerated ( compliance=94 percent ) and showed a good safety profile. The drop-out rate in the study was low – 6.6 percent in first 12 weeks, 4.8 percent in the 12-week extension. They found no significant difference in adverse effects between the study groups throughout the study period.

Source: ICAD 2008


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