: Roche- "A Study of Gantenerumab in Patients With Prodromal Alzheimer's Disease" Trials in prodromal AD take a long time. I guess they will all try that with their no workin drugs. Prana is lucky to have the only drug that appears to work.:
Two points:
1. It makes eminent sense for pharma to run trials in prodromal AD, as it stands to reason that a neurodegenerative disease should be much easier to treat in its early stages.
The disincentive for pharma with this approach is that it's much more expensive. Cognitive decline in prodromal AD is much slower than in established disease, so a trial needs to be much longer to show any difference to placebo.
2. Can we put to bed this notion that "Prana (has) the only drug that appears to work!"
The following is a selective cut-and-paste from www.alzforum.org, and AD clinical trials database.
I've restricted my attention to only those agents that have a putative disease-modifying activity.
It can be seen that a number of agents have demonstrated "statistically significant" cognitive outcomes (among them the now discredited Dimebon and rosiglitazone). Some of these benefits have only been demonstrated in post-hoc analyses (such as Prana).
Don't read this as my being critical of Prana's drug, I'm not, and am still hopeful that the drug's development will progress. I'm just trying to bring a bit of objectivity to the discussion.
Extracts follow:
NAME: Bapineuzumab OTHER NAMES: AAB-001 FDA PHASE: Phase III MECHANISMS: Designed to bind and remove the Aβ peptide that accumulates in the brain. ROLE IN ALZHEIMER'S DISEASE: In ApoE4 non-carriers, statistically significant differences were observed in favor of bapineuzumab treated patients on both cognitive and functional efficacy endpoints ADAS-Cog, NTB and CDR-SB.
NAME: Docosahexanoic acid (DHA) OTHER NAMES: Omega 3 fatty acids FDA PHASE: Phase III MECHANISMS: DHA is a major component of neuron membranes and has multiple functions, including modulation of presenilin. ROLE IN ALZHEIMER'S DISEASE: An 18-month study in mild to moderate AD patients did not meet its primary endpoints, but a secondary analysis of data by ApoE4 genotype showed significant effects on the ADAS-Cog with DHA in patients without the ApoE4 gene. Significant results were also seen on MMSE scores at 18mths versus baseline in this group (Quinn et al 2009).
NAME: Intravenous Immunoglobulin OTHER NAMES: Gammagard, IVIg FDA PHASE: Phase III MECHANISMS: Natural anti-amyloid antibodies may reduce CNS and peripheral Aβ and improve cognition. ROLE IN ALZHEIMER'S DISEASE: In the phase 1 safety and preliminary efficacy clinical trial (U.S.), eight Alzheimer patients were treated with IVIg (Gammagard S/D Immune Globulin Intravenous Human), donated by Baxter Healthcare Corporation. Seven patients completed the study and were evaluated by cognitive testing after 6 months of therapy. Cognitive function stopped declining in all seven patients and improved in six of the seven patients. In a phase 1 safety and preliminary efficacy clinical trial (Germany) five ?clinically probable or possible? Alzheimer disease patients were treated with IVIg (Octagam?, donated by Octapharma [Langenfeld, Germany]) for 6 months. On the ADAS-cog a slight improvement was observed on neuropsychological testing at 6 months in all patients except one where the score did not change between baseline and at 6 months. A mean improvement of 3.7 ? 2.9 points was calculated. No patient deteriorated. A reduction in the CSF of total Aβ of 17.3?43.5 percent was also observed (Dodel et al., 2004). Results from the Phase 2 clinical trial testing of Gammagard presented at AAN in April 2010, showed that IVIg slowed clinical decline as well as reduced brain atrophy to the rate of age-matched normal control subjects. See Alzforum News 'Toronto: In Small Trial, IVIg Slows Brain Shrinkage'.
NAME: PBT2 FDA PHASE: Phase II/IIa/IIb MECHANISMS: Inhibits oligomer formation, disaggregates plaques, neutralizes Aβ toxicity. ROLE IN ALZHEIMER'S DISEASE A 12 week Phase IIa study testing safety and efficacy of PBT2, with biomarker analysis, in a double-blind, randomized, placebo-controlled trial showed that treated patients had a dose-dependent and significant reduction of CSF Aβ, and demonstrated significant improvement in two tests of executive function: the category fluency test and trail making part B test (Lannfelt et al., 2008). The parent compound clioquinol (PBT1) was tested in clinical trials for AD. It was not clear from this trial that clioquinol showed any positive clinical result. The two statistically significant positive results were seen for the more severely affected subgroup of patients; however, this effect was not maintained at the 36-week end- point, and this group was small (eight treated subjects). The sample size was small. Details of randomization procedure or blinding were not reported (Jenagaratnam & McShane, 2006).
NAME: Phenserine FDA PHASE: Inactive MECHANISMS: Acetylcholinesterase inhibitor; Aβ modulator ROLE IN ALZHEIMER'S DISEASE: Phenserine was in clinical study for Alzheimer disease for several years, after preclinical demonstrations of cognitive improvement in both rodents and dogs. Three Phase 3 clinical trials were initiated in 2003 and 2004. Phenserine showed no statistically significant effect on cognition endpoint ADAS-Cog in each of these two Phase 3 trials. Post-hoc analysis of all three Phase 3 clinical trials identified that the group of subjects receiving the highest tested dose (15 mg per day) for more than 12 weeks demonstrated a statistically significant benefit of phenserine over placebo in ADAS-Cog, but only a trend toward improvement in the CIBIC+ measure.
NAME: Rosiglitazone OTHER NAMES: 5-[[4-[2-(methyl-pyridin-2-yl-amino)ethoxy]phenyl]methyl]thiazolidine-2,4-dione, AVANDIA?, Rosiglitazone maleate FDA PHASE: Discontinued MECHANISMS: Rosiglitazone maleate is an oral anti-diabetic agent which acts primarily by increasing insulin sensitivity. ROLE IN ALZHEIMER'S DISEASE: Type 2 diabetes, insulin metabolism, and Alzheimer disease are linked in a variety of ways. Numerous epidemiological studies have shown that there is an increased risk of developing AD among type 2 diabetic patients (Arvanitakis et al., 2004; Leibson et al., 1997). Diet-induced peripheral insulin resistance in Tg2576 mice has been shown to increase γ-secretase activity and decrease insulin-degrading enzyme activity. These combined changes result in increased Aβ40 and Aβ42 levels and amyloid plaque burden in the brain, and impaired performance in a water maze test of learning and memory (Ho et al., 2004). ApoE4 allele-positive individuals account for 40-50 percent of sporadic late-onset AD (Risner et al., 2006). Glucose is the brain?s primary fuel, and it is metabolized by the tricarboxylic acid (TCA) cycle. ApoE4 carriers have declines in brain mitochondrial TCA enzyme activities (Gibson et al., 2000; Bubber et al., 2005). Rosiglitazone therapy has been shown to improve cognitive function in both a subset of human AD patients (Watson et al., 2005; Risner et al., 2006) as well as in preclinical AD model mice (Pedersen et al., 2006). In two small clinical trials, rosiglitazone treatment for 24 weeks resulted in a modest but significant improvement in cognition in non-ApoE4 subjects, but no improvement and rather a decline in cognition in ApoE4 allele carriers (Risner et al., 2006). Preliminary results from Phase III clinical study NCT00428090 were reported at ICAD 2009 (Rabiner et al 2009). This study failed to demonstrate significant efficacy at any dose, in any test group (by ApoE genotype) assessed by either ADAS-cog or CIBIC-Plus (Clinician Interview Based Impression of Change) tests.
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