This longitudinal study in elderly subjects with AD was necessary for assessing safety and possible Notch-related toxicities, which would not likely be revealed by single dose studies.12
Notch toxicity encompasses much of the drug related tolerability concerns for gamma secretase inhibitors.13
Notch is a transmembrane protein that plays a role in nuclear signaling, and, like the amyloid precursor protein, it appears to be cleaved by a presenilin-dependent γ-secretase complex.7
It plays an important role in programmed cellular death. Organ systems with rapid cellular turnover have therefore been the primary concern for Notch-related toxicity. Both gastrointestinal and immune cell functions have been altered in preclinical studies with LY450139 (data on file, Eli Lilly and Company). No previous human study with LY450139 has demonstrated clinically significant toxic effects on the immune system.3, 5, 6
Diffuse macular rash, on the extremities and torso, as well as hair color changes in some participants were likely the result of treatment with LY450139. However, there was no evidence of other toxicities associated with these. Both the rash and the hypopigmentation were reversible. Gastrointestinal symptoms, somnolence/asthenia and ECG changes were not found to be statistically different between groups, yet they should still be considered potentially important drug related adverse events given the known mechanism of action of this drug and the limited statistical power of this study.
As shown in , the plasma level of Aβ40
is above study baseline prior to dosing at visit fourteen. In previous single dose studies a biphasic response of plasma Aβ to LY450139 is observed at 60 mg, 100mg or 140mg, with an initial reduction in plasma Aβ followed by an elevation above baseline levels eight to ten hours after the dose.3
Doses of 100mg or greater prolonged plasma reductions and reduced plasma elevations over 24 hours compared to 60mg.3
Similar patterns of peripheral changes in Aβ have been seen in pre-clinical studies of guinea pigs14
with LY450139 and in studies of other γ-secretase inhibitors15
. But, similar increases in CSF or brain Aβ levels have not been demonstrated in previous pre-clinical studies of LY450139 at multiple post-dosing intervals up to 24 hours (data on file). In addition, studies using very low doses of LY450139 showed an increase in plasma Aβ without a period of reduction.5, 14
Thus, one possible explanation for a transient increase in plasma Aβ is that, in peripheral but not in central tissue(s), γ-secretase inhibitors have a stimulatory effect on the enzyme at low concentrations that is overcome by the inhibitory effects at higher concentrations. Although steady state Aβ reductions would be desirable, twice daily dosing is not possible due to observed Notch-related toxicity in multiple organ systems in pre-clinical studies of Fischer 344 rats and dogs (data on file). The clinical implications of this are unclear.
Clear changes in CSF Aβ levels were not demonstrated in this study as expected despite robust reductions in plasma Aβ40
and dose related LY450139 concentrations in the CSF. Correlation analyses between csf drug levels and Aβ levels suggest a pharmicodynamic response, but perhaps lack in statistical power. In preclinical studies CSF Aβ-lowering effects have been seen in both PDAPP mice1
and dogs (data on file). Lack of CSF changes in the setting of clear serum changes may reflect rapid transport of Aβ from CSF into plasma and a lengthened time period for Aβ to reach equilibrium in CSF. In a trial of a similar γ-secretase inhibitor, changes in CSF Aβ lagged behind changes in plasma Aβ, with significant decreases seen at 12 hours.15
One study demonstrated that 13
C labeled Aβ did not reach equilibrium in lumbar CSF until approximately 13 hours after the beginning of the infusion.16
In our current study, Aβ levels were measured at approximately six hours after morning drug dosing. It may require longer periods of time to identify CSF changes. Furthermore, transgenic PDAPP mice1
, wildtype mice1
, and guinea pigs14
show a clear association between the reduction of plasma Aβ and brain Aβ following administration of LY450139. Whether or not CSF changes in Aβ can be detected in people with AD after oral dosing of LY450139 requires additional studies.
The long term efficacy of this drug is not known. Given the slow rate of clinical progression in AD, we did not expect to see drug effects on measures of cognition or ADLs in this fourteen week trial. Without this, a full risk to benefit assessment cannot be made. This current trial sufficiently demonstrated that LY450139 could be tolerated, though not without risk. Given the potential for disease modifying effects of this Aβ lowering agent, and the arguably acceptable tolerance and safety profile of LY450139 demonstrated in this study, further large scale efficacy trials are justified. Based in part on the results from this phase 2 study, Eli Lilly and company is launching a multinational phase 3 trial in the second quarter of 2008, enrolling 1500 AD subjects.