6 May 2008. A trickle of data is starting to emerge from a Phase 2 clinical trial of a neuroprotective peptide first discovered by Illana Gozes and colleagues at Tel Aviv University, Israel. Partial trial results, presented by Bruce Morimoto of Allon Therapeutics Inc., Vancouver, British Columbia, last week at a conference in Boston, indicate that the peptide, AL-108 or NAP, improved some measures of memory in people with mild cognitive impairment (MCI). The company hopes to present the full data set from the trial at a conference later this year, Morimoto told ARF. In the meantime, the results have spurred Allon to pursue further testing.
The peptide under scrutiny is an eight-residue fragment of glial-derived activity-dependent neuroprotective protein (ADNP). Gozes and colleagues have shown that ADNP is required during development for neural tube closure in mice, but that the protein also plays a role in memory and cognition in mature mice. Heterozygote ADNP knockouts show impaired performance in the Morris water maze, which can be reversed by four to five days of intranasal dosing with the NAP peptide (Vulih-Shultzman et al., 2007). Additional data from the same lab indicated that in the triple transgenic mouse model of AD, NAP reduces both amyloid accumulation and tau hyperphosphorylation (see ARF related news story) and improves performance in the Morris water maze (Matsuoka et al., 2008).
Speaking at the Strategic Research Institute’s Alzheimer Disease Conference on 1 May in Boston, Massachusetts, Morimoto reported that Allon and collaborators have tested the peptide in 17 different animal models, including for AD, stroke, traumatic brain injury, and fetal alcohol syndrome, where the peptide appears to have a general neuroprotective action. The researchers attribute the neuroprotective effect of NAP to its ability to stabilize microtubules (see ARF related news story).
After two Phase 1 trials showed that study volunteers tolerated nasal dosing of NAP well, the investigators decided that rather than proceed directly to Phase 2 testing in AD (the company’s intended indication), Allon would do a proof-of-concept trial in patients with mild cognitive impairment of the amnestic subtype (aMCI, often a prodrome of AD). Using six cognitive tests, four from the CANTAB series of computer-based tests, plus the digit span counting test and an anxiety inventory, Allon set out to determine if the peptide could improve memory measures that are impaired in amnestic MCI, and also relevant to AD. (The CANTAB series of tests, developed by Cambridge Cognition of Cambridge, Massachusetts, and Cambridge, England, is currently being used by eight large pharmaceutical companies in MCI and AD trials, Morimoto said. For more on the hot topic of evaluating the effectiveness of AD drugs, see ARF related news story)
The trial, under principal investigator Donald Schmechel of Duke University, Durham, North Carolina, enrolled 144 people with aMCI at 16 community-based memory clinics. Treatment consisted of nasal spray delivery of placebo, low-dose (5 mg once per day) or high-dose (15 mg twice per day) NAP for 12 weeks. Morimoto presented data on the CANTAB delayed match-to-sample test, a measure of working memory, recognition, and short-term memory. He also showed data on the digit span test. Data on the other endpoints are still being evaluated, he said.
In both cases, the high-dose treatment was associated with a statistically significant improvement in test performance compared to placebo at eight weeks and 16 weeks, but not 12 weeks. There was a suggestion of a placebo effect, with improvement seen in mock-treated patients and peaking at 12 weeks, the end of the treatment period. That increase was not statistically significant compared to baseline, but it lessened the apparent effect of treatment. (For additional details on study design and results, see Allon’s press release of February 26). The clinical significance of the improvements in memory function is not clear, since by definition patients with MCI do not show impairments in daily activities. The results need to be replicated in AD patients. Morimoto also noted that the observed effects on working memory are potentially important, since working memory is known to deteriorate during the course of AD progression.
Allon has expanded its pharmacokinetic testing of NAP to AD patients and will begin a Phase 2 trial of the treatment in AD this year, Morimoto said. In addition, AL-108 is currently being tested in a Phase 2 trial to treat cognitive deficits in schizophrenia, and an intravenous formulation is undergoing testing for cognitive impairment that occurs after coronary artery bypass surgery. The results of these last two trials are expected this year.—Pat McCaffrey.