Development of ALZ-801 2018-01-31T11:14:46+00:00

combined under ALZ-801


An oral drug candidate with the ability to interfere with the beta amyloid oligomer pathology of Alzheimer’s disease.

ALZ-801 is an oral, substantially optimized prodrug of the active molecule tramiprosate. Our team re-examined the tramiprosate data from two large Phase 3 studies in more than 2,000 patients with Alzheimer’s disease (AD). Then we created a prodrug, ALZ-801, to improve the critical pharmaceutical properties of tramiprosate – tolerability, pharmacokinetic and pharmacodynamic profile, and metabolic stability, to make our drug candidate better suited as a treatment for patients with AD. Following cleavage from ALZ-801, tramiprosate is released in the body and penetrates the brain, where it directly interacts with soluble beta amyloid peptide monomers to block the pathological beta amyloid cascade.

Subsequently, we have studied interaction of tramiprosate with beta amyloid proteins and uncovered a novel mechanism of action for tramiprosate – enveloping of Aβ42 to prevent monomers from assembling into toxic soluble amyloid oligomers (Kocis et al. 2017) . Blocking the assembly of beta amyloid monomers prevents the formation of oligomers and subsequent damage to brain cells. Tramiprosate has been found to maintain beta amyloid protein in a non-toxic, non-fibrillary, soluble form.

Finally, we have connected these insights with biomarker effects in AD patients observed in completed clinical studies, suggesting decrease in CSF Aβ42 amyloid protein and amelioration of hippocampal brain atrophy in response to treatment with tramiprosate.


Accelerating Development of ALZ-801

Applying our understanding of the genetics of AD, has enabled us to accelerate ALZ-801 into the late-stage clinical development and pioneer the Precision Medicine approach to Alzheimer’s Disease (AD). Since the initial clinical evaluation of tramiprosate, the role of genetics in influencing the response to AD treatments has become an important consideration. The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for patients with late-onset AD, and is associated with greater beta amyloid pathology in the brain. APOE4 is currently the most important biomarker to identify and stratify Alzheimer’s patients.

Our development plan for ALZ-801 is focusing on patients who have the greatest urgency and medical need, and who are more likely to have an earlier onset and more rapid progression of AD.

ALZ-801_APOE4 strongest genetic risk factor

APOE4 is the strongest genetic risk factor for patients with late-onset Alzheimer’s disease.

We applied genetic understanding of APOE4 in AD to re-analyze the clinical data from the Phase 3 studies with tramiprosate, which demonstrated safety but did not show conclusive clinical efficacy. Our team completed an extensive subgroup analysis of APOE4-positive patients receiving the active molecule tramiprosate and found a clinically compelling and statistically significant improvement in cognition (as measured on the ADAS-cog scale, nominal p-values <0.05), as well as a positive trend on function (as measured on the CDR-SB scale) that was sustained through 18 months of treatment (Abushakra et al., 2016; Abushakra et al., 2017).  Importantly, the efficacy was demonstrated on top of the maximum standard of care symptomatic therapy currently used today. The favorable safety profile of tramiprosate can be leveraged in the pivotal clinical program for ALZ-801.

Our development program is designed to confirm the efficacy of ALZ-801 in the treatment of AD. We are pioneering the Precision Medicine approach in AD: based on the compelling efficacy in subgroup analyses of APOE4 gene carriers, our first studies will be in patients who are homozygous for APOE4 (APOE4/4). These patients suffer from the most aggressive disease course but, as our data suggests, can derive the strongest potential benefit from a beta amyloid-targeted therapy. Moreover, APOE4 is a reliable biomarker for AD patient identification, allowing us to greatly improve diagnostic accuracy, a problem which has plagued previous Alzheimer’s studies.

Because beta amyloid aggregation is the key underlying mechanism that is commonly recognized to drive the Alzheimer’s disease pathology, and our drug effectively blocks this process, all patients with Alzheimer’s disease may benefit from ALZ-801. We have designed a sequential development program for ALZ-801, starting with studies in genetically-defined high risk Alzheimer’s populations, followed by expansion into a broader population of all patients with AD.  Learn about the Underlying Clinical Data of ALZ-801 here.