BOSTON – A reputedly neuroprotective compound will advance along its developmental pathway after developers said it exerted a blood level–dependent relationship with both cognitive and functional measures in patients with mild to moderate Alzheimer’s.
Most of the 26 patients left in the ongoing phase 2a extension study of ANAVEX 2-73 declined cognitively and functionally by varying degrees over 1 year. But a few, most of whom had high drug plasma levels, did experience cognitive and functional changes for the better. Some maintained stability, and some improved on both measures over 109 weeks, according to Christopher U. Missling, PhD, president and chief executive officer of Anavex.
“Improvement of cognition or function was a rare occurrence, but our analysis showed that patients who had a plasma concentration of 4-12 ng/mL had the best chance of experiencing this,”said in an interview.
, presented these data at the Clinical Trials in Alzheimer’s Disease conference. He is the head of Ariana Pharmaceuticals, a firm hired to perform an independent analysis of the Anavex data. Concentrating on the pharmacodynamics data, he said exhibits a clear drug concentration–clinical response relationship, which supports taking the drug into a phase 2/3 study.
“When focusing on the best responders at week 57, they continued to perform well. Patients with a score of greater than 20 on the Mini-Mental State Exam at baseline tended to respond better, as well as those with the highest plasma concentration,” he said.
The concentration-response picture is not completely clear, however. While five patients with high levels did improve on theat 57 weeks, one patient with a low plasma level also improved, and four patients with high levels declined. Functional results appeared more clearly related to drug levels: All of the high-level patients except one improved, as did about half of those with moderate plasma levels. Everyone with a low level declined.
During a later interview, Dr. Missling reviewed the data with an eye toward understatement. The study’s primary endpoints are safety and tolerability, as well as dosing and pharmacokinetics, he noted – cognitive and functional endpoints are exploratory measures. The study never had a control arm, other than several historical cohorts that served as reference points for decline in typically managed Alzheimer’s patients. And of course, he said, the numbers are very, very small.
And yet, the results are a source of “cautious optimism,” Dr. Missling said.
“While we think this is remarkable – because no drug has yet shown this long a response in non-decline among Alzheimer’s patients – we want to be very cautious. We are only looking at six patients here. We can’t overinterpret this.”
Dr. Missling and his colleagues are trying to find commonalities in these patients’ characteristics and clinical responses, hoping to enroll a phase 2/3 cohort of similar profile – whatever that may be. “We’re looking at the patients who improved to try and identify characteristics and be sure to enroll people who match them, to try and maximize our chance of success in phase 2/3,” which he said should be announced by the end of this year.
Just as important, he said, is to scrutinize the outliers – patients whose high and low plasma levels didn’t line up with the group’s overall response curve. “We’re looking at them in depth,” Dr. Missling said, adding that every patient in the study will undergo a full genomic profile, along with both an RNA and gut microbiota profile.
ANAVEX 2-73 is a sigma 1 receptor agonist. A chaperone protein, sigma 1 is activated in response to acute and chronic cellular stressors, several of which are important in neurodegeneration. The sigma 1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates numerous processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma 1 receptor activation can induce neuronal regrowth and functional recovery after stroke. Sigma 1 also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
“Sigma 1 is never used except in times of trouble,” Dr. Missling said. “It’s only needed if we have a serious dysfunction in cells. By giving an agonist, we are increasing the expression of this protein, so it’s a bit like immune stimulation in oncology. We’re using the body’s own mechanism,” to fight neurodegeneration.
ANAVEX 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients; they were a mean of 71 years old, with a mean MMSE of 21. The initial phase was followed by a 52-week, open-label trial of 10, 20, 30, and 50 mg/day orally, titrating each patient to the maximum tolerated dose.
Dr. Afshar presented 57-week data for the 26 patients who were still in the trial at that point and 109-week data for the six patients who had the best response at 57 weeks. Patients in both analyses were grouped by plasma level, not by their dosage level, although Dr. Missling said higher dosage generally correlated with higher plasma levels.
At 57 weeks, six patients had improved on the MMSE: four with high plasma levels and two with low plasma levels – patients identified as “outliers.” One patient with a high level remained stable. The rest of the cohort declined: seven with low levels, eight with moderate levels, and four with high levels, who were also identified as outliers. Also at 57 weeks, 24 patients had full data on the functional measure, the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). Nine patients had improved: five with high plasma levels, three with moderate levels, and one with a low level, identified as an outlier. One patient, with a moderate level, remained stable. The remaining 14 patients declined: nine with moderate levels, four with low levels, and one with a high level, dubbed an outlier.
Dr. Afshar reported more detailed data on the six best-performing patients. These included the two patients with low plasma levels who were characterized in the 57-week MMSE data as outliers. Their mean baseline MMSE went from 23.2 to 25.7 at 57 weeks; their mean functional score on the ADCS-ADL scale rose from 72 to 73.7.
He then showed each of these patients’ 109-week changes. Each was identified with a unique number in both the 57- and 109-week datasets. Numbers here are estimates drawn from the company’s data slides, which are publicly available on the Anavex.
The ADCS-ADL is a caregiver-rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. On the 30-point MMSE scale, a score greater of 24 or higher indicates a normal cognition.
• 101009 (low plasma level)
MMSE: 20-29 ADCS-ADL: 73-71
• 101011 (low plasma level)
MMSE: 20-21 ADCS-ADL: 72-70
•101013 (high plasma level)
MMSE: 22-18 ADCS-ADL: 73-57
• 101014 (high plasma level)
MMSE: 20-25 ADCS-ADL: 75-74
• 102006 (high plasma level)
MMSE: 25-28 ADCS-ADL: 74-78
• 102010 (high plasma level)
MMSE: 25-28 ADCS-ADL: 64-68
Dr. Missling said ANAVEX 2-73 still appears safe and well tolerated. In the initial study phase, 98% of the subjects did have an adverse event; only one was considered serious. This was a case of delirium that developed in a patient who had several risk factors for the disorder, including a prior episode, and was not considered related to the study drug. Three patients withdrew because of an adverse event in the first 57 weeks; no one has withdrawn because of a side effect since then.
Dizziness was the most common adverse event (20 incidents in 15 patients), followed by headache (16 in 10 patients). Most (94%) occurred in the first week of treatment. All were mild or moderate. Headache and dizziness are considered signs that patients are approaching their maximum tolerated dose, Dr. Missling said.
The company’s task now is to find a standard minimum dose that is strong enough to get patients to at least 4 ng/mL plasma level, without inducing these side effects. The extension study will close out in November 2018. Anavex hopes to begin the drug’s next phase of development before then, with a phase 2/3 study of about 200 patients.
“We’re trying to gather as much data as possible so we can do this properly,” Dr. Missling said. “You can make the case that some developers have rushed into these studies after interpreting early results the wrong way. They said the glass was half-full when it was really half-empty. For us, it’s very important not to do that. We won’t go ahead with this until we are completely comfortable with what we see.”