Scientific programme

A03.e  Posters - Theme A - Beta-Amyloid Diseases
A03.e. Drug Development, Clinical Trials: Aggregation inhibitors

31-Mar-2017 08:00 18:00
 
 
Abstract: 105
ALZ-801 BRAIN PENETRATION, PK/PD ANALYSES AND CLINICAL DOSE PROJECTION FORM BASIS FOR CONFIRMATORY PHASE 3 IN ALZHEIMER’S DISEASE
Aims

OBJECTIVES

ALZ-801 is a novel prodrug of tramiprosate with improved pharmacokinetics (PK) and oral tolerability in development for treatment of Alzheimer’s disease (AD). Tramiprosate acts to prevent β-amyloid (Aβ) oligomer formation and neurotoxicity. Tramiprosate achieved compelling cognitive and functional efficacy in a subset of patients homozygous for the e4 allele of apolipoprotein E (Abushakra 2016). We present a summary of the bridging pharmacokinetic/pharmacodynamic (PK/PD) data and a dose projection underpinning the anti-amyloid activity that supports the pivotal ALZ-801 Phase 3 program.

Method

METHODS

We determined the ALZ-801 clinical dose based on the single- and multiple-dose Phase 1 studies in healthy elderly volunteers, and established AUC bioequivalence to the 150 mg BID dose from the tramiprosate Phase 3 studies. Steady-state brain drug exposure was projected using the brain/plasma relationships.

Results

RESULTS

ALZ-801 administered as loose-filled capsule or tablet demonstrated excellent PK dose linearity under fasted and fed conditions, supporting a clinical dose that yields an AUC equivalent to tramiprosate 150 mg BID. Improved intersubject PK variability and gastrointestinal toleration were observed. PK/PD analyses indicate that ALZ-801, at 265 mg BID, achieved target human brain exposure of tramiprosate three orders of magnitude higher than soluble Aβ42 levels.

Conclusion

CONCLUSIONS

We established a 265 mg clinical dose of ALZ-801 to produce an exposure of tramiprosate that is bioequivalent to the 150 mg dose in tramiprosate Phase 3 studies. This dose is projected to achieve steady-state brain drug levels that block toxic Ab oligomer formation and amyloid aggregation, and will be evaluated in a confirmatory study in APOE4/4 homozygous AD subjects.

 
Co-authors
H. John 1, J. Yu 2, P. Kocis 3, S. Abushakra 4, A. Power 3, M. Versavel 1, M. Tolar 5
1Alzheon- Inc., CSO, Framingham, USA
2Alzheon- Inc., Research Fellow, Framingham, USA
3Alzheon- Inc., VP, Framingham, USA
4Alzheon- Inc., CMO, Framingham, USA
5Alzheon- Inc., CEO, Framingham, USA