12 Dec 2017

The room was packed at the recent Clinical Trials on Alzheimer’s Disease conference, when Mike Egan of Merck & Co. presented much-anticipated data of EPOCH, the first efficacy trial of his company’s BACE inhibitor verubecestat. An expert panel stood ready to field audience questions, and discussion spilled into the hallways, receptions, and dinner conversations.

Merck had terminated the trial nine months before (Feb 2017 news), so no one expected a positive outcome. Still, researchers were anxious to hear details, and they were particularly hoping to see a sign—any sign—that verubecestat might have shown at least a slight trend toward a benefit in the more mildly symptomatic subgroup of this mild to moderate AD trial. That would have been encouraging news to other companies that are currently enrolling for large, expensive trials of their own BACE inhibitors in essentially the same band of the Alzheimer’s disease continuum as the milder half of patients in this trial by Merck.

Alas, it was not to be. Egan said verubecestat showed no clinical benefit whatsoever in moderate or mild AD. If anything, a subgroup analyses Egan presented suggested a trend for worsening on verubecestat. The drug’s side effect profile in this trial was good enough to continue evaluating verubecestat in earlier-stage trials, though it did include psychiatric findings.

To some experts, the overall data simply meant that verubecestat is ineffective at this stage of AD but may work earlier. To them, it said nothing about the prospects of other BACE inhibitors. “This was a milestone trial. Merck did a convincing study to show this drug does not help in mild to moderate AD. It is one trial in one population,” said Jeff Cummings of the Lou Ruvo Center for Brain Health in Las Vegas. “I have every confidence that verubecestat, or another BACE inhibitor, will be successful in a prevention paradigm,” concurred Paul Aisen of USC’s Alzheimer’s Therapeutic Research Institute, San Diego.

To other experts, the data implied that perhaps verubecestat did have a cognitive effect that was concealed by a second, neuropsychiatric effect. Yet others argued that a BACE inhibitor ought to be paired with a plaque-removing antibody to prevent leakage of Aβ oligomers from plaques. Commentators applauded that Merck simply laid out the data, warts and all, without trying to massage it or read hopeful interpretations into underpowered post hoc analyses.

Egan noted that because verubecestat previously had been evaluated only for safety and target engagement, and skipped a conventional Phase 2, the Phase 3 part of the present EPOCH Phase 2/3 trial delivered the first set of efficacy data on this compound. Phase 3 randomized 1,958 people with AD, whose MMSE was between 15 and 28, to receive either 12 mg or 40 mg of drug or placebo for 18 months. Its participants included slightly more women than men, 80 percent Caucasians, and 63 percent with at least one ApoE4 allele. Most took a cholinesterase inhibitor and/or memantine. The trial engaged 238 sites in 21 countries in Europe, North America, and Japan.

Verubecestat was evaluated on a co-primary outcome of ADCD-ADL and ADAS-cog11. On both these measures, the curves of placebo and both verubecestat doses were almost superimposed—there was no statistically significant difference between the groups at any time point. If anything, on the ADAS-cog11, both verubecestat dose groups appeared to edge away ever so slightly from the placebo curve in the direction of worsening cognition at all but one time point after baseline. Egan also shared prespecified subgroup analyses of the ADAS-cog outcome by ApoE genotype and disease severity. This data hinted that ApoE4 noncarriers may have had a slight dose-dependent response in favor of placebo, not the BACE inhibitor. “It was very sad for all of us to see these results,” Egan told Alzforum.

One secondary outcome was the CDR sum of boxes. It showed no change between the treatment arms, indicating dementia worsened similarly in all groups. Another was total hippocampal volume, which shrank slightly faster on treatment than placebo. In response to an audience question, Egan said that whole-brain and ventricular volume showed similar small but treatment-related changes. This MRI finding echoes that of previous trials going back to the beginning of anti-amyloid therapy (Jul 2004 news), but the reason remains unclear. It could be related to reduced inflammation or plaque, Egan said.

The trial’s small flutemetamol PET sub-study indicated a 2 percent amyloid plaque reduction on the verubecestat low dose and a 4 percent reduction on the high dose. “Though these changes are small, they do suggest that verubecestat engaged its target in the brain,” Egan said. As expected from verubecestat Phase 1 data, the CSF sub-study of EPOCH showed a 70 percent reduction of Aβ40 on the low dose, and nearly 80 percent reduction on the high dose. Other scientists agreed that this data constitutes evidence of target engagement.

How safe and tolerable was verubecestat in these patients? Adverse events were significantly more frequent on drug than placebo, but not in the way the field might have expected. For example, Merck closely monitored vision and skin discoloration, in part because mouse studies had raised flags. Nothing untoward happened on these counts, Egan showed.

There were other notable side effects, however. Dropouts due to side effects were significantly more common on the high dose than low dose or placebo. Among the prespecified side effects, neither ARIA nor delirium was a problem; however, 3.5 times as many people on drug than on placebo developed rashes, which were treatable, Egan said. More worrisome to some observers were psychiatric effects such as anxiety, suicidal ideation, and insomnia, as well as falls and weight loss.

Eric Siemers of Eli Lilly and Co. asked if the totality of these side effects could perhaps mean that verubecestat has multiple effects in the brain, where one worsens the patient’s neuropsychiatric status and in this way possibly masks a parallel, cognitive effect. This point echoed in hallway discussions. Some prominent clinicians expressed concern about the psychiatric effects, while others said that in older people with symptomatic Alzheimer’s, the brain can be so ill and fragile that such effects are common with any centrally active drug, even memantine. “It would be better if we had not seen those effects, but I would not expect them to show up in younger, cognitively normal people,” said Randy Bateman of Washington University in St. Louis. Bateman is in the process of selecting a BACE inhibitor for evaluation in a DIAN-TU primary prevention trial of autosomal-dominant mutation carriers.

Lawrence Honig of Columbia University Medical School in New York articulated an unspoken question in the wake of a major trial showing that target engagement yielded no clinical benefit. “The big concern the field has now is whether this a class effect or a molecule effect,” Honig said. He hopes that the results will not come to resemble those of semagacestat and avagacestat, γ-secretase inhibitors that proved deleterious to cognition. Will this data slow enrollment of other BACE inhibitor trials? “I don’t think so. We need to do the experiment. There is enormous need for advances in AD treatment, and hope usually trumps nihilism,” Honig told Alzforum.

Tobias Bittner of Roche asked why a BACE inhibitor would reduce the PET amyloid signal. After all, the drug itself does nothing to plaques, but it could affect the balance of Aβ production and clearance. Speaking on background, other scientists speculated that verubecestat, by stopping monomer production, could have shifted an equilibrium of monomer versus oligomer/protofibrillar Aβ species to the left. That could have allowed oligomers to leach out of plaques, where they could have affected nearby synapses and impaired their function. This could explain the trial’s overall finding that Aβ monomer was dramatically reduced and amyloid plaques slightly reduced, yet cognition slightly favored placebo, if anything.

If that were the case, several leading scientists agreed, then BACE inhibition in people with significant amyloid load might have to be paired with plaque removal. The idea of combining a BACE inhibitor and an antibody to both shut off production and remove plaques so that smaller species will not leach out appealed to many scientists, and renewed calls to move forward with combination trials were heard throughout CTAD.

On the other hand, the antibody solanezumab reduced monomeric Aβ and did achieve a small, if insufficient, cognitive benefit in mild AD. Scientists at CTAD were puzzled by the comparison.

To Aisen and others, the main point of the data available thus far was that verubecestat is an oral drug that is safe, well-tolerated, engages its target in the brain, and stands a better chance of success in prevention trials. “Mild to moderate dementia is end-stage disease with a heavy fibrillary amyloid load, extensive tau pathology, and neurodegeneration. BACE inhibition is going to belong to earlier stages of the disease process,” Aisen said. A Phase 3 trial of verubecestat, aka MK-8931, in prodromal AD is ongoing.

Above all, many scientists at CTAD emphasized that negative trials are important. “Negative studies occur in most fields, and are necessary for learning,” said Maria Carrillo of the Alzheimer’s Association. She added, “We are trying to treat and prevent dementia, one of the most difficult things science is doing in this century. We have to work together and share negative and positive findings.” Many others agreed. “We can only advance the field if we do this kind of trial,” Cummings said.—Gabrielle Strobel

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Therapeutics Citations

1. Verubecestat
2. Memantine
3. Semagacestat
4. Avagacestat
5. Solanezumab

News Citations

1. Merck Pulls Plug on Phase 2/3 BACE Inhibitor Trial 15 Feb 2017
2. Philadelphia: Can a Shrinking Brain Be Good for You? 22 Jul 2004

External Citations

1. Phase 3 trial

Further Reading

News

1. Paper Alert: Verubecestat Preclinical and Phase 1 Data Published 4 Nov 2016
2. Will Next-Gen BACE Inhibitors Dodge Side Effects? 3 Nov 2016