Alector, Inc. presented baseline characteristics from the INVOKE-2 Phase 2 clinical trial evaluating AL002 for early Alzheimer's disease (AD) at the Alzheimer's Association International Conference (AAIC) 2024. INVOKE-2 is a global trial assessing the safety and efficacy of AL002 in slowing disease progression in individuals with early AD.
AL002 is an investigational humanized monoclonal antibody that acts as a TREM2 agonist. It binds to triggering receptor expressed on myeloid cells 2 (TREM2), a key microglial membrane receptor. The drug is being developed in collaboration with AbbVie.
INVOKE-2 Trial Design and Baseline Characteristics
The INVOKE-2 trial (NCT04592874) is a double-blind, placebo-controlled, dose-ranging, multi-center, randomized clinical trial. It includes patients with early AD, utilizing a common close design with up to 96 weeks of randomized treatment. Participants were randomized to receive either 15mg/kg, 40mg/kg, or 60mg/kg of AL002 intravenously every four weeks, or placebo.
Baseline characteristics of the 381 participants enrolled showed a median age of 71 years (range: 51-85 years), with 78% of participants aged 65 years or older. Fifty percent of participants were female, and 94% were Caucasian. The clinical diagnosis at enrollment was mild cognitive impairment due to AD for 67% of participants and mild dementia due to AD for 33% of participants.
"The baseline characteristics of the patients in INVOKE-2 are important for assessing the quality of our double-blind, placebo-controlled Phase 2 clinical trial evaluating the safety and efficacy of AL002, the most advanced TREM2-activating candidate in clinical development for early Alzheimer’s disease," said Gary Romano, M.D., Ph.D., Chief Medical Officer of Alector.
Safety and ARIA Observations
Treatment-emergent brain MRI changes resembling amyloid-related imaging abnormalities (ARIA) were observed in the trial. These changes occurred with greater incidence and severity in homozygous APOE e4 carriers, leading to the early discontinuation of this subgroup. Of the enrolled participants, 59% were heterozygous APOE e4 carriers. Amyloid positivity was confirmed in all participants prior to enrollment via cerebrospinal fluid analysis or amyloid PET. For participants with amyloid PET assessed at baseline (n=244), the mean standard deviation (SD) in centiloids was 100.1 (38.9).
AL002 Mechanism and Prior Studies
AL002 is designed to increase TREM2 signaling and enhance microglia proliferation, survival, and function. Higher levels of soluble TREM2 are associated with lower amyloid and tau accumulation, as well as attenuated cognitive and clinical decline. A Phase 1 study of AL002 demonstrated dose-dependent target engagement and effects on microglial signaling biomarkers, with the treatment being well-tolerated in healthy volunteers at multiple doses.
Anticipated Results and Long-Term Extension
Results from the INVOKE-2 trial are expected in the fourth quarter of 2024. A long-term extension (LTE) study is ongoing for participants who completed the planned treatment period, with nearly all eligible participants rolling over into the LTE study to better understand the long-term effects of AL002.
