Lilly’s Phase III data for solanezumab disappoint yet tantalize.
Lilly's Phase III data for solanezumab disappoint yet tantalize
Solanezumab has failed to meet its primary endpoints in two pivotal Phase III studies in Alzheimer’s disease. Significantly, however, efficacy signals were discovered in prespecified secondary analyses. This suggests that Lilly’s drug – widely expected to fail completely – may still have a potential path to market, pending discussions with regulators and further clinical trials.
The two studies, termed EXPEDITION and EXPEDITION2, were designed to test whether solanezumab improved cognition and function over the course of 80 weeks’ treatment in patients with mild to moderate Alzheimer’s disease.
Solanezumab was widely expected to fail, given its inconclusive results from a prior clinical trial and the drug’s untried mode of action. Solanezumab is a monoclonal antibody against beta amyloid, a protein that accumulates in the brains of Alzheimer’s patients and is thought to be instrumental in the pathogenesis of the disease. In a Phase II trial, Lilly demonstrated that solanezumab affected amyloid concentrations in the blood and cerebrospinal fluid of Alzheimer’s disease patients, although these changes did not correlate to cognitive improvements over a 12-week period. Also counting against solanezumab was the recent discontinuation of bapineuzumab, a related beta amyloid antibody formerly under development by Pfizer and Johnson & Johnson.
However, despite the failure of solanezumab to meet its primary endpoints in the EXPEDITION studies, a possible efficacy signal was discovered in prespecified secondary analyses, offering Lilly a glimmer of hope. When data from the two trials were pooled, the results suggested a significant slowing of cognitive decline in the overall study population. Furthermore, a statistically significant effect on cognition was noted in the mild Alzheimer’s disease patient subgroup compared to placebo. In its statement, Lilly emphasized that these are the first Phase III data with an anti-beta amyloid agent that appear to show a slowing of cognitive decline, and that the pooled data support the amyloid hypothesis. Nevertheless, it should be noted that no effect on functional improvement was reported.
The suggestion of greater efficacy in milder severity Alzheimer’s disease is a particularly interesting result from the EXPEDITION program. It has long been argued that the anti-amyloid treatments should be administered as early as possible to Alzheimer’s disease patients, as amyloid accumulation can occur many years in advance of the first signs of dementia. As such, it would simply be too late for an antibody against beta amyloid to be effective by the time a patient has progressed to moderate or severe Alzheimer’s disease.
Industry critics may argue that Lilly’s considerable outlay on the inconclusive EXPEDITION trials could have been avoided. Had the company decided to embark on a second, longer-term Phase II study then it is possible that a similar efficacy signal could have been discovered, but at a fraction of the EXPEDITION cost. A more appropriate Phase III program could then have been drawn up, possibly excluding patients with moderate Alzheimer’s disease and including those with mild cognitive impairment that display Alzheimer’s pathology. However, the lure of being first to market and the considerable pressure applied by the competitive dynamics involving bapineuzumab may have forced Lilly’s hand.
Eli Lilly will now have the luxury of time to decide the next steps for solanezumab. Following Pfizer’s and Johnson & Johnson’s decision to call time on intravenous bapineuzumab, solanezumab’s closest rivals are still in the middle of Phase II development. Discussions with regulators may yet reveal a potential path to market for solanezumab, although further clinical studies will almost certainly be warranted. The Alzheimer’s disease community will now look to the upcoming American Neurological Association and Clinical Trials on Alzheimer’s disease conferences in October, as further information on the pooled and subgroup analyses are released.