Biogen and Eli Lilly both presented much-anticipated data at the 2015 Alzheimer’s Association International Conference (AAIC) in Washington DC for their respective anti-beta amyloid antibodies aducanumab and solanezumab. While these data continue to support the drugs’ clinical profiles and further development – which Biogen and Eli Lilly are already committed to – there was no further information that might help more accurately gauge each drug’s likelihood of success in Phase III and potential commercial opportunity.
Biogen released further data from its Phase Ib trial of aducanumab in patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease. The trial had previously generated a huge amount of interest as 54-week data for the highest dose evaluated (10mg/kg) showed statistically significant improvement versus placebo on both a cognitive endpoint (Mini-Mental State Examination [MMSE]) as well as a functional endpoint (Clinical Dementia Rating scale – Sum of Boxes [CDR-SB]). This came at a cost of a high incidence of amyloid-related imaging events (ARIA-Es) which describe brain swelling (17% among ApoE4 non-carriers; 55% among carriers). This led Biogen to test an intermediate 6mg/kg dose, hoping to match the efficacy profile of the 10mg/kg dose against the greatly reduced incidence of ARIA-Es noted at a lower 3mg/kg dose. However, the 6mg/kg dose failed to achieve statistical significance on either clinical endpoint, as well as being associated with a high incidence of ARIA-Es (22% among ApoE4 non-carriers; 43% among carriers). Furthermore, the previously clear dose-dependent relationship between aducanumab, MMSE, and CDR-SB was skewed as the 6mg/kg dose actually came in worse than the 3mg/kg dose on MMSE at 54 weeks. However, it should be noted that the trial was not powered to examine changes in clinical outcomes, and that pre-specified analyses of all doses combined did give evidence for dose-dependent efficacy.
The data as a whole for Biogen’s study are still compelling and support the company’s decision to advance aducanumab into two pivotal Phase III trials, ENGAGE and EMERGE, which are both currently recruiting 1,350 patients with MCI due to Alzheimer’s disease or mild Alzheimer’s disease, and which will complete in 2020. Biogen has not yet disclosed which doses it is taking forward, although considering that the top 10mg/kg dose is the only one to have demonstrated statistically significant efficacy then it is likely that this will be investigated. Biogen will therefore need to carefully mitigate the risk of ARIA-Es through stringent monitoring.
Following the partial failure of the EXPEDITION program of solanezumab in 2012, Eli Lilly extended its two clinical trials in the mild subset of patients, in which there was evidence for a significant treatment effect. This extension study, EXPEDITION-EXT, allowed mild Alzheimer’s disease patients to continue to receive solanezumab for a further two years, while placebo patients were switched to solanezumab. This delayed-start trial design can theoretically provide evidence for disease modification, provided the placebo converts do not catch up to those that have been receiving solanezumab from the start.
Data presented at AAIC showed that on the two co-primary endpoints, Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) and Alzheimer’s Disease Cooperative Study – Activities of Daily Living, patients receiving solanezumab from the start fared better than those on placebo. It also showed that the disease trajectory of the two groups was parallel. The difference between the two treatment groups was statistically significant for up to 132 weeks, and was numerically superior thereafter.
Eli Lilly’s analysis of EXPEDITION-EXT is certainly interesting and confirms that there are benefits to starting solanezumab treatment as early as possible. However, there is not much else that can be definitively answered by the data presented at AAIC 2015. The third Phase III trial of solanezumab, EXPEDITION3, which is investigating drug treatment solely in mild Alzheimer’s disease patients, will be a truer test of solanezumab’s efficacy. This trial is not due to complete until the end of 2016. EXPEDITION and its extension clearly show that solanezumab has a treatment effect in patients with mild Alzheimer’s disease, although there are certainly questions about the magnitude of this benefit and whether it is clinically meaningful, despite being statistically significant. The original pre-specified pooled analysis of EXPEDITION in mild Alzheimer’s disease showed a 34% slowing of cognitive decline versus placebo, as measured by ADAS-Cog. While there was a slowing in the trajectory of decline, this treatment effect was only a relatively meagre 2.1 ADAS-Cog points after 18 months. By comparison, symptomatic drugs such as donepezil can produce a 3.0-point benefit within 12 weeks.
For the full dataset of these two trials, as well as a broader coverage and analysis of AAIC 2015, please note that Datamonitor Healthcare’s sister product BioMedTracker is publishing a white paper review of the conference. Furthermore, Datamonitor Healthcare is currently conducting a large primary research study with neurologists in the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK) on the diagnosis and treatment of Alzheimer’s disease, as well as updating Epidemiology: Alzheimer’s Disease to include 20-year patient forecasts for the Alzheimer’s disease and MCI due to Alzheimer’s disease populations