Tramiprosate Associated With High Response, Favorable Safety in APOE ε4 Homozygotes With Mild Alzheimer’s

The following article is part of conference coverage from the 2018 Alzheimer’s Association International Conference in Chicago, Illinois. Neurology Advisor’s staff will be reporting breaking news associated with research conducted by leading experts in neurology. Check back for the latest news from AAIC 2018.

CHICAGO — In a phase 3 trial, treatment with oral tramiprosate (ALZ-801) resulted in high response as well as favorable safety outcomes in patients with mild Alzheimer disease (AD) who were homozygous to the APOE ε4allele. The findings were presented by Susan Abushakra, MD, at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018, in Chicago, Illinois.

“ALZ-801, an oral pro-drug of tramiprosate, received Fast Track designation for development as a disease-modifying treatment for AD,” the researchers noted. “ALZ-801 provides consistent plasma levels of the active agent tramiprosate with improved PK and GI tolerability. Tramiprosate inhibits formation of toxic soluble amyloid oligomers and was evaluated in mild to moderate AD patients.”

Researchers assessed individual patient responses as well as overall response rates to oral tramiprosate and the effect of response on clinical outcomes. During a 78-week trial period, a total of 1053 patients with AD received either placebo, 100 mg BID tramiprosate, or 150 mg BID tramiprosate. The investigators also enrolled a total of 148 AD patients who were homozygous for the APOE ε4allele. Patients who were considered responders to therapy had changes on ADAS-cog (Alzheimer’s Disease Assessment Scale-cognitive subscale) ≤0 and Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) ≤0 (ie, indicating no worsening) and disability assessment (DAD) worsening of ≤4 points.

Patients homozygous to APOE ε4with mild AD experienced significant or clinically meaningful benefits on ADAS-cog and CDR-SB as well as DAD while receiving the 150 mg BID treatment dose. In the APOE ε4mild subgroups, patients were divided into either Mini–Mental State Examination (MMSE) ³20 (n=65) or MMSE ³22 (n=50).

Among those in the MMSE ³20 subgroup, response was higher among those receiving ALZ-801 vs placebo in regard to ADAS-cog (57% vs 21%, respectively; P =.011), CDR-SB (35% vs 25%, respectively), and DAD (46% vs 18%, respectively; P =.039). Active treatment also resulted in a higher proportion of responders in the MMSE ³22 group in terms of ADAS-cog (67% vs 24%; P =.011), CDR-SB (44% vs 29%), and DAD (56% vs 20%; P =.024). In addition, ALZ-801 had a favorable safety profile in the APOE ε4subgroup.

The researchers reported that the results of their trial may help dictate official “cut-off points for responder analyses in confirmatory ALZ-801 efficacy trials in this genetically defined AD population with high amyloid burden.”

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Reference

Abushakra S, Porsteinsson AP, Sadowsky CH. Clinical benefits of oral tramiprosate in APOE4/4 homozygotes with mild Alzheimer’s disease: responder analyses from the phase 3 North American trial. Presented at: 2018 Alzheimer’s Association International Conference. July 22-26, 2018; Chicago, IL. Abstract 27296.