The figure above outlines the reduced affinity
of crenezumab’s IgG4 backbone for FcγRs translates into increase in cell survival and less release of an inflammatory
response when compared to the IgG1 backbone variant of crenezumab (MABT-IgG1). When challenged with neurotoxic Abeta oligomers,
crenezumab (MABT) significantly increases cell survival (A) and reduces the production of the pro-inflammatory cytokine TNF-α
(B), when comparing to the IgG1 backbone variant of crenezumab (MABT-IgG1). MABT is crenezumab; MABT-IgG1 is IgG1 backbone variant
of crenezumab; and MABT-IgG1-D265A IgG1 backbone variant of crenezumab carrying the D265A mutation reducing the Ab-FcγR interaction
of an IgG1 backbone.
The evidence described above suggests that
a human IgG4 backbone would have a better safety profile than an IgG1 when administered to patients, a thesis that is reinforced
by the safety findings reported from both Phase 1 and Phase II clinical studies of crenezumab. Following either single or multiple
ascending doses, no increase in ARIA-E was reported (Cummings et al., 2014 and Cummings et al, 2018).
Phase 2 Studies
Phase 2 Study Design Overview
Crenezumab has been studied in two Phase
2 clinical studies, the ABBY proof-of-concept study and the BLAZE biomarker study. These two studies enrolled a total of 522 patients.
The purpose of these studies was to investigate whether crenezumab could delay cognitive and functional decline and reduce the
accumulation of brain amyloid in patients with mild to moderate AD. The sample size of the studies was not expected to have adequate
power to detect a modest but clinically significant difference between active medication and placebo at the 5% significance level
(as is commonly the case in Phase 2 studies in AD). Instead, consistent trends across different endpoints and dose dependency are
considered indicators of a response in this learning phase of development, with confirmation then sought in Phase 3. Both studies
had two active arms: a low dose arm receiving 300mg subcutaneous injection, which is an injection administered beneath the skin,
every two weeks and a higher dose arm receiving 15mg/kg intravenously every four weeks. The primary analysis was conducted at 73
weeks, after 68 weeks of treatment. Safety and tolerability measures included repeated MRI scans to assess for the development
of ARIA, both vasogenic edema (E) and hemorrhages (H).
ABBY Study Results
In the ABBY study, a positive trend in
cognition was observed with a greater effect on cognition in patients with a milder stage of AD (MMSE 22-26), although the study
did not meet its co-primary endpoints in mild-to-moderate AD (MMSE 18-26) patients. There was no significant change in cognition
in patients who received low-dose subcutaneous crenezumab. Results of an exploratory analysis of the high-dose intravenous arm
demonstrated that patients with the mildest cognitive impairment at screening (MMSE 22-26) showed a statistically significant 35%
slowing of the rate of cognitive decline over 73 weeks. The effect became greater over time, as shown by the increasing separation
of the crenezumab (solid line) and placebo (dashed line) curves in the diagram below. The milder group was not pre-specified, meaning
the group of milder AD patients was not identified before commencing the Phase 2 clinical studies.