An Alzheimer’s vaccination called crenezumab just finished 2 trials. The drug showed clear, positive cognitive improvements in people with mild Alzheimer’s. Learn more about the results and where crenezumab goes from here.
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 (AD). The larger study, known as ABBY, 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.
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 an exploratory analysis of people with milder disease treated with intravenous (IV) crenezumab, there was a positive trend toward increasing reduction in cognitive decline in progressively milder subsets relative to placebo.
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).
Biomarker results from the ABBY and BLAZE studies will be presented at an upcoming medical meeting.
“Data from these phase II studies provide valuable information about crenezumab’s potential clinical activity in people with Alzheimer’s disease, where there is a great need for treatment options,” said Richard Scheller, Ph.D., Executive Vice President and Head of Genentech Research and Early Development. “These findings support the importance of testing potential disease-modifying agents, such as beta amyloid antibodies, early in the course of the disease.”
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.
Despite crenezumab’s successes in these trials, it did not achieve everything it set out to accomplish. Conclusions need to be drawn from the clinical trial data, adjustments need to be made, and another round of trials conducted. On the upside, since these were Phase II trials that were completed, in some ways the trials have made it past the halfway mark on the road to becoming approved medications.
The findings were presented at the Alzheimer’s Association International Conference (AAIC).
About crenezumab and the ABBY and BLAZE studies
Crenezumab is an investigational, fully humanized, monoclonal antibody designed to target all forms of beta amyloid. Discovered by Swiss biotechnology company AC Immune, crenezumab is being developed by Genentech, a member of the Roche Group.
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.
- 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.
BLAZE (ABE4955g, NCT01397578) 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.
- 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.
Safety Data from ABBY and BLAZE
- There was no imbalance in the overall rate of Adverse Events (AEs); AEs were observed in 91.3 percent of patients treated with crenezumab versus 90.3 percent of patients who received placebo. AEs were generally mild-to-moderate and transient. AEs did not appear to be related to crenezumab exposure.
- A single case of asymptomatic amyloid-related imaging abnormalities (ARIA-E; sulcal effusion – or a buildup of fluid in the grooves of the brain) was observed in a person who received high-dose IV crenezumab in the ABBY study. No case of ARIA-E was reported in the placebo arm or the BLAZE study.
- Five deaths occurred during ABBY and BLAZE, all in patients who received crenezumab during the randomized placebo-controlled period (1.4 percent of the crenezumab-treated population). The overall rate of deaths is consistent with the background rate of death in the elderly AD population. There was no consistent pattern for the cause of death and none were considered by the investigators to be related to crenezumab.
- There was an imbalance in the rate of serious and non-serious events of pneumonia, with a 3.2 percent in crenezumab-treated patients reported to develop pneumonia versus 0.6 percent in placebo-treated patients during the randomized placebo-controlled period of ABBY and BLAZE. The rate of pneumonia cases in crenezumab-treated patients is consistent with the expected rate in the elderly population (2.5-4.4 percent) and no drug-related mechanism for pneumonia was identified.
About Roche in neuroscience
With 12 investigational medicines in clinical development, neuroscience is a major focus of research and development at Roche. Our goal is to develop more effective treatment options based on the biology of the nervous system to improve the lives of people with chronic and potentially devastating diseases.
Roche has a broad AD research programme that focuses on several proteins and pathways believed to play an important role in the disease, including beta amyloid and monoamine oxidase B (MAO-B). Researchers at Roche are developing medicines designed to target these proteins in multiple ways and disease stages. Our late-stage AD pipeline includes:
- Anti-amyloid antibody crenezumab
- Anti-amyloid antibody gantenerumab
- MAO-B inhibitor RG1577.
In addition, two separate landmark AD prevention studies are evaluating crenezumab and gantenerumab in people at risk for, or with, early-onset AD.
Headquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and neuroscience.
- Alzheimer’s Association. 2014 Alzheimer’s Disease Facts and Figures. Available at http://www.alz.org/alzheimers_disease_facts_and_figures.asp. Accessed July 2014.
- Alzheimer’s Disease International. Dementia Statistics. Available at http://www.alz.co.uk/research/statistics. Accessed July 2014.
- Alzheimer’s Association. 2012 Basics of Alzheimer’s Disease. Available at https://www.alz.org/national/documents/brochure_basicsofalz_low.pdf. Accessed July 2014.
- F. Hoffmann-La Roche Ltd
In an article published in the prestigeous scientific site Alzheimer Research Forum , about the prestigious and updated Alzheimer's Association International Conference (AAIC) 2014 , with the title : “CRENEZUMAB DISAPPOINTS IN PHASE 2”, published in 22 Jul 2014 we can read about the catastrophic Failures with Crenezumab, as in the part of the test of Alzheimer Research Forum that I pasted bellow : “The anti-Aβ antibody crenezumab missed both its primary endpoints in two Phase 2 clinical trials, according to results presented at the Alzheimer’s Association International Conference 2014, held in Copenhagen July 12-17.
a) The ABBY trial fell short on goals set for cognition and function.In ABBY, 122 patients with mild to moderate Alzheimer’s were randomized to 300 mg of crenezumab injected subcutaneously every two weeks, while 62 volunteers got placebo. b) The smaller BLAZE study, which was designed to measure biomarker effects, showed no effect on cognition as a secondary endpoint. “ (part of the text of the site AlzForum).
I guess that something it is NOT fiting in the text of Roche trying to "save" the drug crenezumab …
Persisting in the use of the term "catastrophic failure" for Phase II clinical trial results indicates a fundamental misunderstanding of the purpose of the trials and how the results are used — as has been pointed out to you before. If results were indeed "catastrophic", Genentech would drop the drug like a hot potato. Why throw good money after bad?
For people who wish to read the article Carlos cites, it's at:
Note, for example, such excerpts as:
"Results of both trials indicated that the drug was safe and well-tolerated."
In the larger ABBY trial: "In prespecified analysis of patients with an MMSE score of 20-26, i.e. the milder subgroup, the higher IV dose tended to slow cognitive decline, but the results missed statistical significance. A second, exploratory analysis of the 121 patients with even milder AD, an MMSE of 22-26, showed a trend toward efficacy at 49 weeks and a statistically significant effect at the end of the trial."
" "We believe that this was a very good outcome for a Phase 2 trial designed and powered as it was," Andrea Pfeifer, CEO of AC Immune, told Alzforum. "We believe showing a signal and target engagement is a positive outcome for a trial that was not designed to be a pivotal one," she said. Pfeifer stressed that it was important to estimate a treatment effect in Phase 2, because this provides a baseline from which to power a Phase 3 trial. Rachelle Doody, Baylor College of Medicine, Houston, told Alzforum she was concerned that many people, particularly in the media, were jumping to the conclusion that crenezumab was doomed, looking at the data as if it were a Phase 3 trial. "They are trying to emphasize a message that is at best a small piece of what was learned, and at worst a distortion," she said."
Low and high doses were also tested in the smaller BLAZE study. The primary outcome, i.e., the result on PET amyloid imaging, will be presented in November. The effect on cognitive function, which was presented, was a secondary endpoint: "The higher dose of crenezumab trended toward preserving cognition in this trial."
"Doody called the parallels between the crenezumab and solanezumab data thought-provoking. In both, ADAS-Cog trends showed separation between placebo and treatment groups that grew over time. Both treatments target soluble Aβ. "While we have to wait for the biomarker data, if both [solanezumab and crenezumab] have similar signals, it makes you wonder if it is necessary to target fibrillar Aβ," she suggested."
They have to keeps the investors with some hope until….