Can BACE inhibitors be resurrected as an Alzheimer’s therapy? Data presented at the 15th International Conference on Alzheimer’s and Parkinson’s Diseases, held virtually March 9–14, suggested that the possibility remains. Alas, the path to get there looks rocky.
- Elenbecestat caused no cognitive deficit, showing this was not a class effect.
- It modestly lowered amyloid plaque but also brain volume.
- Safety issues, including liver and neuropsychiatric effects, cropped up.
Michelle Gee of Eisai went over data from the terminated Phase 3 MISSION AD trials of Eisai and Biogen’s elenbecestat. In a bit of good news, the full dataset for this compound showed none of the cognitive decline seen with previous BACE1 inhibitors. However, neither did elenbecestat help cognition. Plus, it brought many of the other worrisome side effects seen with this class of drugs at the initial, high doses used—volume loss in the brain, weight loss, skin rashes—as well as new ones, with a few participants having abnormal liver readings and dwindling white blood cell counts. It was this safety profile, along with the lack of efficacy, that led to the early trial termination. “The results support a lack of benefit for elenbecestat in this specific, early AD population,” Gee concluded.
Meanwhile, basic science research continues to unravel the complex effects of BACE inhibition on the body. Stefan Lichtenthaler of the German Center for Neurodegenerative Diseases in Munich identified a new BACE1 substrate, the cytokine receptor glycoprotein 130 (Gp130). BACE1 inhibition boosts signaling through Gp130, possibly leading to pro-inflammatory or synaptic effects, Lichtenthaler said. Another study cast doubt on the idea that lowering the dose of inhibitors to avoid side effects would fix everything. Gerhard Multhaup of McGill University, Montreal, argued that BACE1 plays a role in degrading toxic Aβ42, as well as forming it. At low doses of inhibitor, BACE1’s protective role is more curtailed than its harmful one. That might leave but a narrow therapeutic window, Multhaup suggested (see Part 12 of this series).
Some see the odds for BACE inhibitor therapy as long. “BACE inhibitors have a very high hurdle [to overcome] if they’re going to progress as a treatment for AD,” Gee said at AD/PD. Others were encouraged. “I do think BACE1 inhibitors are still viable,” Robert Vassar of Chicago’s Northwestern University told Alzforum. To Lichtenthaler’s mind, the elenbecestat data confirm that BACE can be inhibited without causing cognitive decline. “With this new data on elenbecestat, there is a convincing reason to continue using BACE1 as a drug target. … We now need comparative studies of different BACE inhibitors, ranging from studies on synaptic deficits in mice to detailed plasma and CSF biomarker analytics, including different BACE1 substrates,” Lichtenthaler wrote to Alzforum (full comment below).
Cognitive Readout: No Harm, But No Gain Either
During the great clinical reckoning for late-stage BACE inhibitors, elenbecestat was the last one to fall (Sep 2019 news). Since then, pharma researchers have been comparing data in hopes of gaining insights into what causes the adverse effects seen with this class of drugs, and whether they can be avoided (Dec 2019 conference news; Dec 2020 news).
At AD/PD, Gee provided the first detailed look at the final MISSION AD dataset. Together, the two trials enrolled 2,209 people with early symptomatic AD and an average age of 72. They had a mean MMSE of 25.7, indicating mild impairment. Half the participants, 1,101 people, took 50 mg elenbecestat as a pill once daily. This strongly suppressed BACE1 activity, lowering Aβ40 and Aβ42 by 70 percent.
In the final dataset, 1,472 participants had completed one year in the study, while only 189 had made it out to two years. Decline on all cognitive measures—comprising the CDR-SB, MMSE, ADCOMS, ADAS-Cog11, ADASCog14, and the word list from the ADASCog14—was identical in both groups at every time point except at six months. At that point, people on elenbecestat performed slightly worse on the MMSE and the three ADAS tests, with the difference reaching statistical significance on the ADASCog11 and the word list. This difference had disappeared by 12 months and did not reoccur.
Preliminary data from the MISSION AD studies, taken before data lock when there were only about 40 people with two-year data, had suggested a deficit in the CDR-SB at this final time point in people on elenbecestat; however, this did not hold up in the full analysis (Dec 2019 conference news). A functional measure, FAQ, was identical in both groups throughout the study.
It is unclear why elenbecestat did not cause the cognitive worsening of other BACE inhibitors. Elenbecestat is more selective for BACE1 over BACE2 than some of the other compounds, but so was umibecestat. That drug was terminated after subtle cognitive decline was seen at the three- and six-month time points (Jul 2019 conference news). At the time, some scientists privately grumbled that they would have liked to have seen the trials continue, even if just to learn.
Gee noted that in animal studies, high doses of elenbecestat did not reduce dendritic spine density, in contrast to other BACE inhibitors. This could indicate a lesser effect of this drug on the substrates that are suspected to cause cognitive worsening, such as SEZ6 and CHL1, Lichtenthaler speculated. SEZ6 is the leading candidate for this synaptic effect, since deleting this protein in mice prevents spine loss after BACE inhibition (Oct 2016 conference news). CHL1, on the other hand, guides axons to their targets, and BACE1 inhibition of its cleavage comes with stunted axons in the hippocampus (Dec 2013 conference news; Sep 2018 news).
Toward a side-by-side comparison of these drugs, umibecestat did not harm axon length, suggesting that this drug leaves CHL1 cleavage alone, yet it still harmed cognition (May 2019 conference news). There was no data on elenbecestat on axonal health.
So is SEZ6 the likely culprit? This remains unclear, but Novartis is analyzing CSF from the umibecestat trials to find out which BACE1 substrates correlate most with cognitive worsening (Aug 2020 conference news).
Mixed Message on Biomarkers: Less Plaque, More Shrinkage
While elebecestat did not affect cognition in the Phase 3 trials, biomarkers did show differences between the treatment groups. On amyloid PET, people on placebo gained an average of 8 centiloids of plaque over two years, while those on elenbecestat lost 5. This difference is much smaller than that seen with anti-amyloid antibodies, yet it was statistically significant, with a p value below 0.001.
On volumetric MRI, both treatment groups showed brain shrinkage, but people on elenbecestat lost more volume in the whole brain, hippocampus, and on a measure of cortical thickness. The differences were significant at p=0.001. These data match findings from the other four BACE inhibitors that entered late-stage trials—verubecestat, atabecestat, lanabecestat, and umibecestat—all of which have been found to accelerate brain volume loss (Sperling et al., 2021). Previous analyses do not chalk this up to neuron death or plaque removal. The leading contenders are fluid changes due to reduced inflammation, or synapse loss (Sur et al., 2020).
Fluid biomarker data were more ambiguous. The neurodegeneration marker plasma NfL was slightly worse at six months in people taking elenbecestat than controls, but Gee said NfL levels did not correlate with cognitive scores at this time point. At other time points, plasma NfL was identical in both treatment groups. In cerebrospinal fluid, there were hints of a benefit on elenbecestat, with total tau rising less than in the placebo group, and the neurodegeneration marker neurogranin trending down on drug while rising on placebo. However, Gee cautioned that these were sub-studies, and there were too few CSF samples to draw conclusions from these data. Lichtenthaler bemoaned the fact that the early trial termination deprived the field of this biomarker data.
Safety at High Doses Signals Caution
As did other BACE inhibitors, elenbecestat caused people to lose some weight. Participants on elenbecestat dropped an average of 1.4 kilograms, compared with 0.2 in the placebo group. Perhaps more concerning, about 6 percent of people on elenbecestat developed skin rashes and 5 percent reported abnormal dreams, also matching findings from other drugs in this class. Gee mentioned an increase in neuropsychiatric events as well, another common side effect, but did not show those data.
Other adverse effects were more specific to elenbecestat. The most troubling were a transient drop in white blood cell count, seen in 6.5 percent of people on drug, and elevation of several liver enzymes and markers of liver injury, occurring in 9.5 percent of the elenbecestat group compared with 4 percent of controls. Liver enzyme changes were what brought down atabecestat. Gee noted that the prevalence of these effects was low, with most people tolerating the drug well.
While these safety signals by themselves did not knock out elenbecestat, the lack of any signal for a treatment benefit prompted the safety monitoring board to pull the plug. “One commonality across [BACE inhibitor] trials is that we haven’t yet seen evidence of clinical effectiveness in early [symptomatic] AD,” Gee noted.
Some researchers think that if these drugs still hold potential, it will be as a preventative treatment in people at very early preclinical stages of Alzheimer's disease. Vassar, Lichtenthaler, and others argue for running 13-week trials of low-dose BACE inhibitors in people at risk of AD, while collecting plasma and CSF. “If cognitive worsening is avoided, but at least 30 percent Aβ lowering achieved, and beneficial effects on p-tau and NfL observed, then a large Phase 2/3 trial at the safe doses may be undertaken to see if conversion to MCI/AD could be delayed,” Vassar wrote to Alzforum (full comment below). If BACE can be inhibited safely, these drugs could also be used after anti-amyloid immunotherapy to keep Aβ from building up again, Vassar added.
“BACE1 remains a validated target, but the side effects are a concern. We need to understand these side effects and be able to control them,” Lichtenthaler said at AD/PD.—Madolyn Bowman Rogers
- What BACE Hits: New Substrates Create New Headaches
- End of the BACE Inhibitors? Elenbecestat Trials Halted Amid Safety Concerns
- Picking Through the Rubble, Field Tries to Salvage BACE Inhibitors
- New Data from Past BACE Inhibitor Trials Shed Light on Side Effects
- Cognitive Decline Trips Up API Trials of BACE Inhibitor
- BACE Inhibition and the Synapse—Insights from Seeon
- BACE—Substrates, Functions, Developmental Phenotypes
- In Conditional BACE1 Knockouts, Hippocampal Axons Compromised
- BACE Inhibitors: Postmortem on One, Live Updates on Two
- Umibecestat-Driven Cognitive Decline Is Reversible
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