Clinical Trials

Date: 2018-07-25

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the Alzheimer's Association International Conference (AAIC© 2018)

Company: AC Immune (Switzerland) Genentech, a member of Roche Group (USA - Switzerland)

Product: anti-Abeta antibody MABT5102A (crenezumab)

Action mechanism:

• monoclonal antibody. MABT5102A (crenezumab) is a fully humanized IgG4 monoclonal antibody to Abeta that binds both monomeric and oligomeric forms of Abeta, inhibits Abeta aggregation, and promotes Abeta disaggregation. MABT5102A was discovered and humanized by AC Immune through its proprietary SupraAntigen technology. The drug candidate was discovered by AC Immune. In 2006 AC Immune closed an exclusive out-licensing agreement for its anti-Abeta program with Genentech, under which Genentech develops the anti-Abeta antibody for the treatment of Alzheimer´s Disease. Genentech has full ownership and global responsibility for clinical development, manufacturing and commercialization of the antibody, including all regulatory activities. In return, AC Immune received an upfront payment, a milestone payment when the first patient was dosed under the Phase I clinical trial, and now another payment upon the start of Phase II. In addition AC Immune obtained funding through a research collaboration that was successfully concluded after three years in 2009. The contract provides potential revenues of over $ 300 million for AC Immune through payments upon successful completion of clinical and regulatory milestones in Alzheimer´s disease and additional applications. Additionally, upon commercialization of a product AC Immune will receive royalties.

Disease: mild to moderate Alzheimer's disease

Therapeutic area: Neurodegenerative diseases

Country: USA, Canada, France, Germany, Spain, UK

Trial details:

• ABBY (ABE4869g, NCT01343966) is a phase II, randomised, double-blind, parallel-group, placebo-controlled study that evaluated the effects of IV or subcutaneous (an injection administered beneath the skin) crenezumab from baseline to Week 73 in patients with mild-to-moderate AD, as determined by a Mini-Mental State Examination (MMSE) score of 18-26 at baseline.The co-primary endpoints were to measure a reduction in cognitive decline by change in the ADAS-cog12 and global functional decline by change in the CDR-SOB. Other endpoints included change in the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scores (ADCS-ADL) and volumetric MRI (a measure of changes in brain volume associated with AD). An exploratory analysis of biomarkers was performed on data from people who provided an optional cerebrospinal fluid (CSF) sample. In this study, 431 patients with a baseline MMSE score of 18-26 received either 300 mg of subcutaneous crenezumab (low dose) every other week (or matching placebo) or 15 mg/kg IV crenezumab (high dose) every 4 weeks (or matching placebo) for 68 weeks.
• BLAZE (ABE4955g, NCT0139757) is a phase II, randomised, double-blind, parallel-group, placebo-controlled study that evaluated the effects of IV or subcutaneous crenezumab from baseline to Week 73 in patients with mild-to-moderate AD, as determined by a MMSE score of 18-26 at baseline. • The primary endpoint was to measure the change in brain amyloid load using florbetapir-PET. These data will be presented at an upcoming medical meeting. Other endpoints included longitudinal changes from baseline in other biomarkers (CSF, vMRI), cognition (ADAS-cog12), global function (CDR-SOB), and activities of daily living (ADCS-ADL). • In this study, 91 patients with a baseline MMSE score of 18-26 and a positive amyloid PET scan received either 300 mg of subcutaneous crenezumab (low dose) every other week (or matching placebo) or 15 mg/kg IV crenezumab (high dose) every 4 weeks (or matching placebo) for 68 weeks.

Latest news:

• • On July 25, 2018, AC Immune announced that important data on crenezumab - currently in two Phase 3 clinical trials conducted by Genentech were presented in a late-breaking session at the Alzheimer's Association International Conference (AAIC© 2018).  The data presented were from 98 subjects treated in the ABBY and BLAZE Phase 2 trials for mild-to-moderate Alzheimer's disease (AD). The data showed:
• Treatment with crenezumab was associated with a consistent decrease in Abeta oligomer levels in the CSF
• 86% of IV patients and 89% of SC patients had lower levels of Abeta oligomers at week 69 than at baseline (p<0.01 for IV and p<0.001 for SC vs. placebo). The median change was -43% (p=0.01) in those treated intravenously (IV) and -48% (p=0.001) in those treated subcutaneously (SC), with 20% (IV) and 14% (SC) of patients falling below the LLoQ after treatment, respectively. Andrea Pfeifer, CEO, AC Immune, said: "These first of their kind data are very promising as they support the proposed mechanism of action of crenezumab to preferentially bind to and promote removal of neurotoxic oligomers, a form of Abeta. "
• • On July 16, 2014, Roche presented data from two phase II studies investigating whether crenezumab can delay cognitive and functional decline in people with mild-to-moderate Alzheimer’s disease. Although the larger study, known as ABBY, did not meet its co-primary endpoints in people with mild-to-moderate AD, it demonstrated initial evidence of a crenezumab treatment effect in people with mild AD. Similar effects on clinical decline were observed in BLAZE, a smaller biomarker study. The findings were presented at the Alzheimer’s Association International Conference (AAIC) 2014 in Copenhagen, Denmark.  In the ABBY study, crenezumab treatment in people with mild-to-moderate AD demonstrated a trend toward slowing the decline of cognitive abilities, measured by the 12-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog12), but no effect on global functioning, measured by Clinical Dementia Rating-Sum of Boxes (CDR-SOB), the co-primary endpoints. In patients with mild-to-moderate AD (MMSE score of 18-26) treated with high-dose IV crenezumab, there was a 16.8 percent reduction in cognitive decline (p=0.19). A 3.1 percent reduction in global functional decline was observed (p=0.85). There was no significant change in cognition in patients who received low-dose subcutaneous crenezumab. In the pre-specified subgroup analysis in patients with mild AD (MMSE score of 20-26), treatment with high-dose IV crenezumab led to a 23.8 percent reduction in cognitive decline (p=0.13), but not in global functional decline (-1.0 percent reduction; p=0.96). An exploratory analysis in patients with milder symptoms (MMSE 22-26) showed a 35.4 percent reduction in cognitive decline (p=0.036) and a 19.6 percent reduction in global functional decline (p=0.42). Effect sizes and p-values for exploratory analyses were not adjusted for multiplicity
• In the BLAZE study, which enrolled people who tested positive for an amyloid imaging biomarker, the primary endpoint was a change in brain amyloid load. In a secondary endpoint analysis, treatment with IV crenezumab was associated with a trend towards slowing cognitive decline in those with mild disease (as measured by ADAS-cog12). In patients with mild-to-moderate AD (MMSE 18-26) treated with high-dose IV crenezumab, there was a 10.3 percent reduction in cognitive decline (p=0.84) and a 7.4 percent reduction in global functional decline (p=0.84). There was no significant cognitive change in patients who received low-dose subcutaneous crenezumab. In a post-hoc analysis of a group of patients with mild AD (MMSE 20-26) treated with high-dose IV crenezumab, there was a 52.0 percent reduction in cognitive decline (p=0.29) and a 41.5 percent reduction in global functional decline (p=0.44). Effect sizes and p-values were not adjusted for multiplicity.
• There was no imbalance in the overall rate of adverse events (AEs); however, there was an imbalance in the rates of serious and non-serious events of pneumonia, with 3.2 percent of patients treated with crenezumab reported to develop pneumonia versus 0.6 percent of patients treated with placebo. The rate of pneumonia cases in crenezumab-treated patients is consistent with the expected rate in the elderly population (2.5-4.4 percent). In total, there were five deaths in crenezumab-treated patients across the two randomized studies; none of which were considered by the investigators to be related to crenezumab. In both studies combined, only a single case of asymptomatic amyloid-related imaging abnormalities (ARIA-E) was observed in a patient treated with crenezumab.
• Although generally not reaching statistical significance, changes in both studies were consistent over time, providing evidence for a beneficial effect of crenezumab in people with mild AD. Clinical results to date for crenezumab suggest a favorable risk benefit profile, with positive effects on both cognitive and global functional endpoints, particularly in patients with milder Alzheimer's disease, and a minimal incidence of amyloid related imaging abnormalities. Next steps wil be determined by Roche following further analysis of data.
• • On May 9, 2011, AC Immune has announced that it has received a significant milestone payment from Genentech, a member of the Roche Group. The milestone was reached upon the first patient being dosed with the anti-Abeta antibody MABT5102A under a Phase II clinical trial in patients with mild to moderate Alzheimer´s disease. The Phase I clinical trial with MABT5102A in patients with mild to moderate Alzheimer´s disease was concluded in 2010 showing encouraging safety data. The anti-Abeta antibody showed no signs of cerebral vasogenic edema in any of the patients at any dose. Dose proportional pharmacokinetics were observed following both single and multiple doses. Furthermore, plasma Abeta levels correlated with serum MABT5102A concentration.

 

Is general: Yes