One of the biggest biopharma events in years, readout of the Expedition 3 trial of Lilly’s Alzheimer’s candidate solanezumab, has turned into a car crash. As well as having an immediate negative impact on Lilly – shares plunged 14% at the open – the news could also sour investor sentiment going into 2017 after an already turbulent year.
The warning signs were there, but many did not heed them, with investors and the sellside alike wildly optimistic ahead of the topline readout. Lilly has confirmed that this is the end for sola in mild Alzheimer’s, posing the question of whether this is also the final nail in the coffin for the amyloid theory. If it is, this would have a knock-on effect on others developing amyloid-targeting drugs, including Biogen (see table below).
Expedition 3 could go some way to answering this conundrum as it included a biomarker element – specifically, PET scanning to measure the impact of sola on brain amyloid. More details on this should emerge at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting on December 8.
One thing will not change between then and now: Expedition 3 was an unalloyed failure. It did not hit its primary endpoint, change in cognition measured by ADAS-Cog14, with a p value of 0.095. And secondary endpoints, while apparently trending in the right direction, only showed a small benefit.
The amyloid hypothesis had already been thrown into doubt by the the failure of Elan's bapineuzumab and the earlier flops of the Expedition 1 and 2 studies, but Lilly ploughed on after a pooled analysis suggested a benefit in mild patients. The idea was that these patients had not had as much time to accumulate amyloid, so the damage to the brain might be prevented. This theory now looks decidedly shaky.
Others taking a punt on amyloid, including Biogen and Roche, will hope that the problem is not with the amyloid hypothesis itself, but instead with sola’s ability to clear the aberrant protein.
|Monoclonal antibodies targeting amyloid in Alzheimer's|
|Project||Company||2022e sales ($m)|
|Phase III||Solanezumab||Eli Lilly||1,700|
|Phase I||KHK6640||Kyowa Hakko Kirin||-|
Biogen had already gone into damage-limitation mode before the Expedition 3 results came out, highlighting “substantial differences” between its antibody and sola. In addition, its phase III trials are in a milder population, have more rigorous confirmation of amyloid, and use a higher dose of antibody and different endpoints, Leerink analysts noted – but they nevertheless described the latest data as a serious blow.
Roche’s crenezumab has a binding profile similar to aducanumab and is being tested at higher doses than sola, so still has a shot in the phase III Cread study, they wrote.
Amazingly, some Biogen bulls touted the news as a plus. Bernstein analysts wrote that the trend seen in Expedition 3 “suggests that the amyloid beta hypothesis seems correct and eliminates an early competitor”, while Stifel said the development was a “near perfect scenario” for Biogen.
But investors were not buying it, with Biogen’s stock opening 6% down. And it was not just amyloid-targeting drug developers that suffered – others in the broader Alzheimer’s space also had a bad morning, with Axovant Sciences opening 5% lower.
Another puzzle is what comes next for Lilly; sellside forecasts compiled by EvaluatePharma had pegged sola as the group’s fifth-biggest product in 2022 with sales $1.7bn, and the rest of its pipeline looks somewhat lacklustre.
|Lilly’s top five pipeline assets (excluding sola)|
|Product||Indication||Pharmacological class||Status||2022e sales ($m)|
|Baricitinib||Rheumatoid arthritis||Jak-1/2 inhibitor||Filed||1,774|
|Abemaciclib||Oncology||CDK 4 & 6 inhibitor||Phase III||1,526|
|Galcanezumab||Migraine||Anti-CGRP MAb||Phase III||452|
|BioChaperone Lispro U100||Diabetes||Insulin analogue||Phase II||115|
|LY2510924||Oncology||CXCR4 peptide inhibitor||Phase II||59|
Even its brightest hope, the rheumatoid arthritis contender baricitinib, will be a latecomer to the Jak inhibitor field if approved.
Lilly noted that sola was still being studied in prodromal Alzheimer’s, in the Expedition-Pro study, but surely this does not have legs after the latest failure. It looks like a pretty miserable Thanksgiving is in store for Lilly in particular and Alzheimer’s drug developers in general.