Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease. https://www.ncbi.nlm.nih.gov/pubmed/29063518
CONCLUSIONS: ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.
In terms of demonstrating efficacy of cognitive improvement, the following paper is cited:
Conclusions: The Mild subgroup of APOE4/4 AD patients (MMSE 22-26) showed larger benefits on the high dose of tramiprosate than the overall Mild and Moderate group. Consistent with its preclinical effects on Aβ oligomers, tramiprosate seemed to stabilize cognitive performance, supporting its disease modification potential. Confirmatory studies using ALZ-801, an improved pro-drug formulation of tramiprosate, will target APOE4/4 patients with Mild AD.
Hmmm . . . I really would like to believe in a silver bullet. But I don't think I'm quite ready to take this drug. There always seems to be a downside:
Tramiprosate, a drug of potential interest for the treatment of
Alzheimer's disease, promotes an abnormal aggregation of tau
Ismael Santa-Maria1, Félix Hernández1, Joaquín Del Rio2,3,
Francisco J Moreno1 and Jesús Avila*
Abstract
Alzheimer's disease (AD) is characterized by the presence of two histopathological hallmarks; the
senile plaques, or extracellular deposits mainly composed of amyloid-β peptide (Aβ), and the
neurofibrillary tangles, or intraneuronal inclusions composed of hyperphosphorylated tau protein.
Since Aβ aggregates are found in the pathological cases, several strategies are under way to develop
drugs that interact with Aβ to reduce its assembly. One of them is 3-amino-1-propane sulfonic acid
(Tramiprosate, 3-APS, Alzhemed™), that was developed as a sulfated glycosaminoglycan mimetic,
that could interact with Aβ peptide, preventing its aggregation.
However, little is known about the action of 3-APS on tau protein aggregation. In this work, we
have tested the action of 3-APS on cell viability, microtubule network, actin organization and tau
aggregation. Our results indicate that 3-APS favours tau aggregation, in tau transfected nonneuronal
cells, and in neuronal cells. We also found that 3-APS does not affect the binding of tau
to microtubules but may prevent the formation of tau-actin aggregates. We like to emphasize the
importance of testing on both types of pathology (amyloid and tau) the potential drugs to be used
for AD treatment.
Hmmm . . . I really would like to believe in a silver bullet. But I don't think I'm quite ready to take this drug. There always seems to be a downside
Agree; for now it's more like silver buckshot for us . Scary that Tramiprosate PROMOTES the aggregation of tau- especially bad for us. Strange that it improved cognition in 4/4s... I'm keeping an eye on this one.
I don't have time to read full-text today, but here's the latest. I'd love to hear commentary from anyone who can read the paper:
Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer's Disease Suggest Disease Modification Potential. https://www.ncbi.nlm.nih.gov/pubmed/29182706
Abstract
BACKGROUND:
Alzheimer's Disease (AD) patients homozygous for the APOE4 allele (APOE4/4) have a distinct clinical and biological phenotype with high levels of beta amyloid (Aβ) pathology and toxic Aβ oligomers. Tramiprosate, an oral agent that inhibits Aβ monomer aggregation into toxic oligomers, was evaluated in two Phase 3 Mild to Moderate AD studies which did not show efficacy in the overall population. Re-analyses of these trials showed the most consistent clinical benefits in APOE4/4 patients. We analyzed efficacy in the APOE4/4 patients with Mild disease.
OBJECTIVES:
To determine the optimal stage of AD for future trials in APOE4/4 homozygotes.
DESIGN:
Two randomized, double-blind, placebo-controlled parallel-arm multi-center studies of 78-weeks duration.
SETTING:
Academic Alzheimer's disease centers, community-based memory clinics, and neuropsychiatric research sites.
PARTICIPANTS:
Participants included 2,025 AD patients with MMSE 16-26. Approximately 13-15% had APOE4/4 genotype (N= 147 and 110 per study), mean age 71.1 years, 56% females. Almost all were on stable symptomatic drugs.
INTERVENTION:
Randomized subjects received oral placebo, 100mg BID, or 150mg BID of tramiprosate.
MEASUREMENTS:
Co-primary outcomes were change from baseline in the ADAS-cog11 and CDR-SB. Disability assessment for dementia (DAD) was a secondary outcome.
RESULTS:
In APOE4/4 homozygotes receiving 150mg BID tramiprosate, efficacy in the traditional Mild AD patients (MMSE 20-26) was higher than the overall group (MMSE 16-26) and efficacy in the Mild patients (MMSE 22-26) was highest. Tramiprosate benefits compared to placebo on ADAS-cog, CDR-SB, and DAD were 125%, 81% and 71%, respectively (p<0.02). The Mild subgroup (MMSE 22-26) showed cognitive stabilization with no decline over 78 weeks, both ADAS-cog and DAD effects increased over time. Tramiprosate safety in APOE4/4 patients was favorable. Most common adverse events were nausea, vomiting, depression and decreased weight.
CONCLUSIONS:
The Mild subgroup of APOE4/4 AD patients (MMSE 22-26) showed larger benefits on the high dose of tramiprosate than the overall Mild and Moderate group. Consistent with its preclinical effects on Aβ oligomers, tramiprosate seemed to stabilize cognitive performance, supporting its disease modification potential. Confirmatory studies using ALZ-801, an improved pro-drug formulation of tramiprosate, will target APOE4/4 patients with Mild AD.
I read this article recently and have already told my husband to sign me up for this in the future, if needed, and if nothing better comes along. I would definitely take a chance on this now if I were in the mild AD range as a 4/4. (That's not a plug; just my personal choice if I were in that position.)
Note that the ApoE 4/4s numbered 257--a healthy cohort size. The next iteration of the drug for a clinical trial is going to be known as ALZ801. (Parent company Alzheon.)
Tramiprosate benefits compared to placebo on ADAS-cog, CDR-SB, and DAD were 125%, 81% and 71%, respectively (p<0.02). The Mild subgroup (MMSE 22-26) showed cognitive stabilization with no decline over 78 weeks, both ADAS-cog and DAD effects increased over time. Tramiprosate safety in APOE4/4 patients was favorable. Most common adverse events were nausea, vomiting, depression and decreased weight.
I'm fascinated that folks are focusing on theories of AD etiology. We know so little about causality. However, as a physician I focus on clinical utility not theories that are changing daily. If repeated studies show that unique among all medicines that have been tried that Tramiprosate has been shown to alter the downward trajectory of AD if one has homozygous APOE4 then I think that one is being short sighted to not try it. Other then diet and exercise, there is no other option for homozygous folks.
It is available from Canada and Amazon UK as homotaurine.
Harvey Schwartz MD
Ah, that was my question also, Stavia. Taking a look thru the links posted here, it seems that Alz-801, an improved formulation of tramiprosate, may have fewer potential side effects (nausea, vomiting, depression, weight loss) than tramiprosate (homotaurine). Any of those side effects would be a problem for me as long as I'm cognitively healthy. Alz-801,though, should it become available might be a different story. Also, further clarification regarding impact on tau aggregation would be helpful.
However, I'm in NF52's camp. If I (or someone else!) started to notice a decline, I'm pretty sure I'd give the commercially available homotaurine a trial and just deal with the side effects. The lesser evil, so to speak!
. Scary that Tramiprosate PROMOTES the aggregation of tau- especially bad for us. Strange that it 
