Eli Lilly and Company announced yesterday that it has halted its Semagacestat γ-secretase inhibitor program. Preliminary results from two ongoing Phase 3 trials (the IDENTITY and IDENTITY-2 trials) revealed that the drug not only failed to slow cognitive decline in people with mild to moderate Alzheimer disease, but that it actually made them worse (see company press release). Cognition as measured by the ADAS-cog and Activities of Daily Living Scale declined faster in volunteers in the treatment arms compared to those on placebo. “Obviously, we are clearly disappointed about the results for patients, their caregivers, and everyone else,” said Eric Siemers, Medical Director, Alzheimer's Disease Team at Lilly, in an interview with ARF.
“The billion-dollar questions on everyone's mind are whether this is a body blow to the amyloid theory and what this means for all the planned prevention trials using similar drugs,” suggested Murali Doraiswamy, Duke University Medical Center, Durham, North Carolina (see full comment below). Siemers said that there are numerous explanations for the outcome, among them being the possibility that lowering Aβ in the brain makes cognition worse. That would be a difficult pill to swallow for supporters of the amyloid hypothesis, and would raise questions about pursuing other γ-secretase inhibitors and BACE inhibitors as therapies for AD. “I would be surprised if that was the explanation, but at this point we really don’t know,” said Siemers.
Other possible explanations for the accelerated deterioration envisage roles for C-terminal fragments of APP in cognition. Blocking γ-secretase would lead to an increase in the β-secretase product C99, and a decrease in the APP intracellular domain (AICD), which is cleaved from C99 by γ-secretase. “Perhaps the increase in C99 may have some deleterious effect, or maybe decreasing AICD has an adverse effect,” suggested Siemers. Either scenario would raise questions about pursuing any type of γ-secretase inhibitor, trials of which are currently ongoing.
Alternatively, the disappointing trial outcome may have nothing to do with APP or Aβ. “The general concern about γ-secretase inhibitors has been mechanism-based toxicity,” according one of the trial site investigators, who wished to remain anonymous. “The factor(s) that led to faster clinical decline need to be understood in order to guide progress with secretase inhibition or modulation, or, more broadly, anti-amyloid treatment in the future.”
Toxicity concerns stem from γ-secretase’s penchant for processing a multitude of substrates. In particular, researchers in the field have tried to develop modulators that, while lowering production of the more toxic Aβ42, do not block cleavage of Notch, a crucial signaling molecule that regulates the fate of a wide variety of cell types. Semagacestat is not “Notch sparing,” and even though the doses used in the IDENTITY trials (140 mg per day) were conservatively chosen to reduce Aβ production by about 25 percent daily (see ARF related news story), Notch signaling may have suffered. “This needs close investigation, especially since the increase in skin cancer in the treated patients also suggests Notch signaling inhibition,” suggested Bart De Strooper, KU Leuven, Belgium. “The implication is that we should explore now, even more, Notch- (and other substrate-) sparing modulation of γ-secretase activity (e.g., blocking selectively Aph1B-γ-secretase).” (See full comment below.)
Siemers suggested that one positive thing that came from the trials was a justification for the rationale of using biomarker analysis to determine adequate dosing. In Phase 2 trials, the company used CSF analysis to determine whether the drug got into the brain and had an effect (see ARF related news story and ARF news story). “The fact that people were worse shows that we did get [the drug] into the brain and have an effect,” said Siemers. “Obviously it is not the effect that we wanted, but in a sense it tells you that this biomarker strategy does help you make some conclusions.”
Siemers said that Lilly will eventually release more data from the trials, which together enrolled more than 2,600 patients worldwide. Dosing has stopped, but the company plans to follow patients for at least another six months. Lilly has also been going through a major restructuring that has led to some downsizing (see related IndyStar.com news).—Tom Fagan.
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