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At the 2016 Clinical Trials on Alzheimer’s Disease (CTAD) meeting, Eli Lilly provided a more detailed explanation for the failure of solanezumab in its pivotal EXPEDITION 3 study in mild Alzheimer’s disease. While the drug trended toward improvements over a range of endpoints, its clinical effect was weak and ultimately the antibody was only having a marginal effect in the brain. This lack of strong biological efficacy will strengthen the resolve of other companies with a vested interest in the amyloid hypothesis, as there is a reasonable scientific rationale to expect that other approaches may yield a more robust effect on meaningful cognitive and functional endpoints.

 

Eli Lilly presents the results of the failed EXPEDITION 3 study

 

On 8 December 2016, Dr Lawrence S. Honig, director of the Clinical Core of the Alzheimer's Disease Research Center at Columbia University and a professor at the university’s medical school in New York City, presented the results of EXPEDITION 3 at the CTAD conference in San Diego, US. This was Eli Lilly’s third large Phase III trial that failed to demonstrate solanezumab’s therapeutic benefits in patients with mild Alzheimer’s disease. EXPEDITION 3 was a global, double-blind, placebo-controlled trial in patients with mild Alzheimer’s disease, in which patients received intravenous infusions of solanezumab 400mg or placebo every four weeks, for 80 weeks (ClinicalTrials.gov identifier: NCT01900665).

 

While largely similar to the earlier unsuccessful Phase III trials, Eli Lilly enriched its patient population by targeting those with confirmed amyloid pathology and earlier stages of the disease. This was in line with the current view of what anti-amyloid antibodies should be targeting. To further increase EXPEDITION 3’s likelihood of success, Eli Lilly has also increased the sample size to 2,129 patients, and limited the primary endpoint to only Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog). However, despite the company’s attempts to secure a statistically significant outcome from EXPEDITION 3, the study failed to meet its primary endpoint.

 

While solanezumab exhibited target engagement, this did not translate into a clinical response

 

Solanezumab is a mid-domain-targeting antibody that is thought to bind soluble amyloid-beta monomers, helping in their excretion into the periphery. To confirm the drug’s mechanism of action, plasma levels of amyloid-beta were measured throughout the study. Indeed, solanezumab significantly raised plasma amyloid-beta 1–40 and 1–42 levels during EXPEDITION 3. This confirms that solanezumab is engaging with its target the way it is expected to, and removes any doubt about the drug’s mechanism of action.

 

While solanezumab exhibited strong target engagement, this did not translate into a clinically relevant response. The extent of solanezumab’s clinical effects were rather small. There was a slowing of cognitive decline relative to placebo, as assessed by ADAS-Cog in week 80, but the decline was only by 11% and was not significant (p=0.095). Furthermore, while solanezumab demonstrated statistically significant improvements on cognition and function as part of secondary measures, the effect size was again small (13−15% improvement; p<0.05). Nevertheless, while the treatment benefit of solanezumab was not prominent, it was consistent across the different clinical measures. There was a continual separation of curves between solanezumab and placebo across the study and for the different measured endpoints. The reliability of this pattern suggests that modulating amyloid can translate into clinical improvements, but that solanezumab itself had insufficient biological activity on Alzheimer’s pathology.

 

Solanezumab’s weak effect on brain amyloid plaque suggests amyloid hypothesis is not yet invalid

 

Despite being an amyloid-beta antibody, solanezumab’s mechanism actually involves the indirect targeting of the main pathology in Alzheimer’s disease: amyloid plaques. It is theorized that the sequestration and excretion of soluble amyloid monomers from the brain would cause the insoluble amyloid forms, including plaques and intermediate oligomers, to come back into solution. This would lead to their capture by the antibody and excretion into the periphery. This hypothesis is otherwise known as the peripheral sink mechanism. To determine whether the weak clinical efficacy can be explained by weak biological activity on brain amyloid plaques, amyloid positron emission tomography with the imaging agent florbetapir was measured in patients. The results showed a trend towards a decrease in brain amyloid plaques, but the decrease was small and was not statistically significant (p=0.181). This lack of a significant impact on brain amyloid load suggests that EXPEDITION 3 has not yet invalidated the wider amyloid hypothesis. There are a number of factors that could explain the lack of impact on brain amyloid load. Solanezumab’s dose may have been insufficient, there could have been limited brain penetration, and/or the drug’s peripheral sink mechanism is inadequate to exert a meaningful impact on brain amyloid plaques. It is also important to note that solanezumab may have been administered too late in patients where neurodegeneration was overpowering, and a weak biological impact on brain amyloid plaques is not sufficient to result in a clinically meaningful response.

 

Eli Lilly and Biogen will continue to test the amyloid hypothesis

 

Eli Lilly is determined to address some of these concerns in another large Phase III study, ExpeditionPRO, in which solanezumab will be given to patients with prodromal stages of Alzheimer’s disease. Furthermore, the company is currently in discussions on whether to dose solanezumab higher to further enhance its biological impact on brain amyloid plaques. This trial is an indication that Eli Lilly has not lost hope on the potential benefits of solanezumab or on the validity of the amyloid hypothesis. By carrying out ExpeditionPRO it would address questions about whether solanezumab can still be considered a viable immunotherapy option for patients with earlier stages of Alzheimer’s, or whether its peripheral sink mechanism renders an ineffective product. As another indication of its confidence in the amyloid hypothesis, Eli Lilly has also agreed to a worldwide collaboration with AstraZeneca to co-develop MEDI1814, an antibody selective for amyloid-beta 42, which is currently in Phase I trials as a potential disease-modifying treatment for Alzheimer’s.

 

Advocates of the amyloid hypothesis will also point toward aducanumab (Biogen/Eisai), another amyloid-targeting antibody. Results from the Phase Ib PRIME trial indicate a significant decrease in amyloid load that was closely associated with an improvement in clinical response following a 12-month treatment period. At CTAD, Biogen presented the results of a long-term extension of PRIME showing that the effects were maintained for another 12 months, further supporting the drug’s disease-modifying properties. These results are important supportive evidence for the amyloid hypothesis and are arguably unaffected by the failure of EXPEDITION 3.

 

There are a number of factors that could differentiate aducanumab and solanezumab. Despite both being amyloid-beta antibodies, aducanumab recognizes a different epitope, directly binding insoluble forms of amyloid. In addition, the positive PRIME trial assessed patients with earlier stages of the disease (ie prodromal and mild Alzheimer’s). These patients are likely experiencing less prominent neurodegeneration. Lastly, aducanumab can be administered at a much higher dose, with the 10mg/kg arm in PRIME corresponding to twice the comparable solanezumab dose in the EXPEDITION studies. All of these differences suggest that the failure of solanezumab’s EXPEDITION 3 trial does not necessarily imply the subsequent failure of aducanumab and other amyloid-beta antibodies. Furthermore, Eli Lilly has not yet discounted solanezumab, with continued investment in ExpeditionPRO, meaning the amyloid hypothesis will live on.

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