An experimental drug for Alzheimer's disease failed to meet the main treatment goals of a late-stage study testing it in people with mild or moderate forms of the neurodegenerative disease, raising questions about its future and dealing a setback to its developer.
Yet the company behind the trial, the California-based biotech Cortexyme, sees cause for optimism, pointing to the drug's apparent benefit versus placebo in slowing cognitive decline among a smaller subgroup of participants in the trial.
"It's definitely a clinically significant difference, both from the percent slowing and the points difference," said Cortexyme CEO Casey Lynch, referring in an interview to the rating scale used to measure brain function.
Interpreting results from slices of a clinical trial can be challenging and potentially misleading, although Cortexyme said it planned ahead of time to break out results for the subgroup in question. The company is in the process of scheduling a meeting with the Food and Drug Administration to further discuss the results and potential next steps.
"I'm focused on the efficiency, whether that means another study that's just simply to expand the database or to confirm the efficacy, or if there's some other path that's more direct to putting this into more patients' hands," said Chris Lowe, Cortexyme's chief operating and chief financial officer.
"I just feel really good that we know who our patient is and we know we can have a meaningful impact on their cognition."
Typically, a negative trial would not merit an FDA review. But the agency has shown it can be flexible in its treatment of would-be Alzheimer's drugs, controversially approving Biogen's Aduhelm earlier this year despite conflicting results in two Phase 3 trials.
In that case, however, one of Biogen's studies met its primary goal, while in the case of Cortexyme's trial both primary measures were missed.
Only limited information is available from Cortexyme, which disclosed news of its results in a press release. Notably, the company's statement did not include specific data on how the drug performed on the study's two primary endpoints, which assessed the disease's impact on cognition and daily living activities.
More details will be disclosed at the upcoming Clinical Trials on Alzheimer's Disease, or CTAD, conference on Nov. 11, Cortexyme said.
"The weight of the evidence, in addition to the point differences that you'll be seeing, all the additional evidence we'll be able to present at CTAD, will be very convincing," Lynch said.
The company did not allow BioPharma Dive to seek comment from outside experts as a condition of reviewing the results before they were released publicly. Shares in Cortexyme fell by roughly 70% in post-market trading Tuesday after the news was announced.
Cortexyme's study is the first of its type to test an alternative approach to treating Alzheimer's other than the prevailing hypothesis of targeting a protein called amyloid beta. Aduhelm, for example, specifically targets and binds to toxic, aggregate plaques of amyloid beta. But dozens of other drug candidates aimed at that protein have failed in clinical trials going back decades.
Cortexyme is trying something very different, hypothesizing that at least in some cases Alzheimer's is caused by infection with P. gingivalis bacteria, the same pathogen that causes gum disease. While unorthodox, the company's case is based in research in animals that suggest chronic P. gingivalis infection can lead to brain inflammation and production of amyloid beta. Signs of P. gingivalis have also been found in the brains of Alzheimer's patients, while other studies have indicated an association between gum disease and Alzheimer's decline.
The company's Phase 2/3 study is the most significant test yet of that hypothesis and, in the view of Cortexyme's executives, offers validation of the idea even though the trial failed.
Nearly 650 people with mild-to-moderate Alzheimer's were enrolled in the trial, which began in March 2019 and randomized participants to receive either one of two doses of Cortexyme's drug, or placebo.
Overall, researchers found no statistically significant difference between those on treatment and those given placebo, as measured by a commonly used cognitive rating scale called ADAS-Cog11 and a measure of daily living activities called ADCS-ADL. No specific data on either point were disclosed.
However, among 242 participants with P. gingivalis DNA detectable in their saliva at the study's start, treatment appeared to substantially slow cognitive decline. Cortexyme said participants on an 80 mg dose declined 57% slower than the placebo group on the ADAS-Cog11 scale. Those on the 40 mg dose declined 42% slower, according to the company.
Significant benefits over placebo were not observed on the ADCS-ADL scale, even among this subgroup.
"The ADL was, for whatever reason, a bit of a funny outlier, and we have a couple theories about that that we need to dig into a little bit more," said Michael Detke, Cortexyme's chief medical officer.
The company used several other methods to detect the presence of P. gingivalis and all participants in the study had blood antibodies that indicated previous systemic exposure to the bacteria. Cortexyme said there were "similar results" indicating a cognitive benefit to its drug among other infection-related subgroups, but did not disclose the data on Tuesday.
Side effects to treatment were mostly mild or moderate, according to the company, although diarrhea and nausea were more common in participants given the drug.
Fifteen percent of participants in the high dose group had liver enzyme elevations that were three times the upper limit of normal, compared to 7% on the low dose and 2% on the placebo. "Virtually all patients were asymptomatic," Cortexyme said, and the elevations later reversed.
When asked, Cortexyme would not confirm whether there were any Grade 3 adverse events reported, saying only that it plans to share more at CTAD.
While it's unclear, and likely will be for some time, what advice the FDA will give Cortexyme, the company's executives argue the findings should result in greater exploration of the role P. gingivalis plays in Alzheimer's.
"This bacteria can explain so much of what we know about the disease and it requires more and more research to understand," said Lynch.
Note: This story was updated with movement in Cortexyme's share price during Tuesday post-market trading.