An investigational drug for Alzheimer’s disease failed to meet primary treatment goals in an advanced study testing it in people with mild to moderate forms of neurodegenerative disease, raising questions about its future and making a setback to its developer.
Still, the company behind the trial, California-based biotech Cortexyme, sees reasons for optimism, pointing to the drug’s apparent advantage over placebo in slowing cognitive decline in a smaller subgroup of trial participants.
“This is definitely a clinically significant difference, both in the percentage of slowdown and the point difference,” said Casey Lynch, CEO of Cortexyme, referring in an interview to the rating scale used to measure brain function.
Interpreting slice results from a clinical trial can be difficult and potentially misleading, although Cortexyme said it planned in advance to release the results for the subgroup in question. The company is currently scheduling a meeting with the Food and Drug Administration to further discuss the results and potential next steps.
“I’m focusing on efficacy, whether it’s another study just to expand the database or to confirm efficacy, or if there’s another more direct way to put that between the two. hands of more patients, ”said Chris Lowe, COO and CFO of Cortexyme.
“I feel really good knowing who our patient is and we know we can have a significant impact on their cognition.”
Generally, a negative trial would not merit FDA review. But the agency has shown it can be flexible in its treatment of potential Alzheimer’s drugs, controversially endorsing Biogen’s Aduhelm earlier this year despite conflicting results in two Phase 3 trials.
In this case, however, one of Biogen’s studies served its primary purpose, while in the case of Cortexyme’s trial, both primary measurements were missed.
Only limited information is available from Cortexyme, which disclosed the news of its results in a press release. Notably, the company’s statement did not include specific data on the drug’s performance on the two primary endpoints of the study, which assessed the impact of the disease on cognition and activities of daily living. .
More details will be released at the upcoming Alzheimer’s Disease Clinical Trials Conference, or CTAD, on Nov. 11, Cortexyme said.
“The weight of evidence, in addition to the one-off differences that you’ll see, any additional evidence that we can present to CTAD will be very compelling,” Lynch said.
The company has not authorized BioPharma Dive to solicit comments from outside experts as a condition of reviewing the results before their public release. Cortexyme shares fell about 70% in post-trade trading on Tuesday after the news broke.
The Cortexyme study is the first of its kind to test an alternative approach to treating Alzheimer’s disease other than the dominant hypothesis of targeting a protein called beta-amyloid. Aduhelm, for example, specifically targets and binds to toxic aggregate plaques of beta-amyloid. But dozens of other drug candidates targeting this protein have failed in clinical trials dating back decades.
Cortexyme is trying something very different, hypothesizing that at least in some cases Alzheimer’s disease is caused by infection with the bacteria P. gingivalis, the same pathogen that causes gum disease. While unorthodox, the company’s case is based on animal research that suggests chronic P. gingivalis infection can lead to inflammation of the brain and the production of beta-amyloid. Signs of P. gingivalis have also been found in the brains of patients with Alzheimer’s disease, while other studies have indicated an association between gum disease and the decline of Alzheimer’s disease.
The company’s Phase 2/3 study is the most significant test to date of this hypothesis and, in the opinion of Cortexyme executives, offers validation of the idea even if the trial failed.
Almost 650 people with mild to moderate Alzheimer’s disease were enrolled in the trial, which began in March 2019 and randomized participants to either receive one of two doses of the drug Cortexyme or a placebo.
Overall, the researchers found no statistically significant differences between people on treatment and those on placebo, as measured by a commonly used cognitive rating scale called ADAS-Cog11 and a measure of activities of daily living. called ADCS-ADL. No specific data on either point was disclosed.
However, among 242 participants whose P. gingivalis DNA was detectable in their saliva at the start of the study, treatment appeared to significantly slow cognitive decline. Cortexyme said participants at an 80 mg dose declined 57% slower than the placebo group on the ADAS-Cog11 scale. Those at the 40 mg dose decreased 42% slower, according to the company.
No significant benefit over placebo was observed on the ADCS-ADL scale, even in this subgroup.
“ADL was, for some reason, a bit of a fun aberration, and we have a few theories about it that we need to dig a little deeper into,” said Michael Detke, chief medical officer at Cortexyme.
The company used several other methods to detect the presence of P. gingivalis and all of the study participants had antibodies in their blood that indicated previous systemic exposure to the bacteria. Cortexyme said there were “similar findings” indicating a cognitive advantage of its drug among other subgroups linked to the infection, but did not release the data on Tuesday.
Side effects from the treatment were mostly mild or moderate, according to the company, although diarrhea and nausea were more common in participants receiving the drug.
Fifteen percent of participants in the high dose group had elevations in liver enzymes that were three times the upper limit of normal, compared to 7% in the low dose group and 2% in the placebo. “Virtually all of the patients were asymptomatic,” Cortexyme said, and the elevations then reversed.
When asked, Cortexyme did not confirm whether there had been any Grade 3 adverse events reported, only saying that he planned to share more with the CTAD.
While it is not clear, and likely will be for some time, what advice the FDA will give to Cortexyme, company executives say the results should allow for further exploration of the role P. gingivalis plays in the disease. Alzheimer’s disease.
“This bacteria can explain a lot of what we know about the disease and it requires more and more research to understand,” Lynch said.
Note: This story has been updated with the Cortexyme share price movement during Tuesday’s trading session.