Investor Update

Basel, 16 July 2014

Roche announces phase II clinical results of crenezumab in Alzheimer’s disease

  • Proof of concept study in mild-to-moderate Alzheimer’s disease did not meet its co-primary endpoints
  • Positive trend in cognition observed with greater effect in people with mild disease who received a high dose of crenezumab intravenously
  • Next steps to be determined following further analysis of data
  • Roche is committed to investigating medicines for Alzheimer’s disease and has a broad research programme underway across multiple pathways and disease stages

Roche (SIX: RO, ROG; OTCQX: RHHBY) today 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). 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 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.

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 Alzheimer’s disease

Alzheimer’s disease is a progressive, fatal disease of the brain that gradually destroys memory and thinking skills and impairs basic daily functions such as the ability to manage one’s own activities. Biological changes are believed to start many years before clinical symptoms of Alzheimer’s disease become evident. In the early stages (prodromal), people may have difficulty remembering things, but there are no signs of dementia. However, in the later stage of the disease people are often unable to communicate and increasingly become reliant on others for even simple day-to-day tasks. For people 65 and older, the disease typically progresses for four to eight years after diagnosis and eventually leads to death.1 Dementia affects 44 million people worldwide with 7.7 million new cases each year, of which Alzheimer’s is the most common form.2 There is no cure for Alzheimer’s disease. Current treatments focus on alleviating symptoms and are unable to stop Alzheimer’s from progressing because they do not affect the disease’s underlying cause.3

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 two anti-amyloid antibodies, crenezumab and gantenerumab, and a 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.

About Roche

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. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostics that enable tangible improvements in the health, quality of life and survival of patients. Founded in 1896, Roche has been making important contributions to global health for more than a century. Twenty-four medicines developed by Roche are included in the World Health Organisation Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and chemotherapy.

In 2013 the Roche Group employed over 85,000 people worldwide, invested 8.7 billion Swiss francs in R&D and posted sales of 46.8 billion Swiss francs. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com.

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1) 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.
2) Alzheimer’s Disease International. Dementia Statistics. Available at http://www.alz.co.uk/research/statistics. Accessed July 2014.
3) Alzheimer’s Association. 2012 Basics of Alzheimer’s Disease. Available at https://www.alz.org/national/documents/brochure_basicsofalz_low.pdf. Accessed July 2014.