20 Nov 2018

This is Part 2 of a two-part story. Click here for Part 1.

The highs and lows of diabetes-related therapies were on display at the Clinical Trials on Alzheimer’s Disease Conference, held October 24–27 in Barcelona, Spain. This time around, it was mostly the lows. Intranasal insulin presented a puzzle, the RAGE inhibitor azeliragon attempted another artful save to keep more study going, and MCI prevention with pioglitazone got a lessons-learned epilogue.

Special Delivery?
CTAD afforded a first look at results from a Phase 2/3 trial of intranasal insulin, which attempted to reverse the waning brain concentration and function of this hormone in people with AD. Interest in this approach was sparked by a single-site pilot study of 104 people with amnestic MCI or AD, which reported that four months of insulin treatment appeared to stave off cognitive decline and improve brain glucose uptake (Craft et al., 2012). In the SNIFF trial, Suzanne Craft, Wake Forest School of Medicine, Winston Salem, North Carolina, and colleagues expanded to 25 sites with a 12-month, blinded, placebo-controlled treatment phase plus six months of open-label extension. The blinded portion wrapped up in June of 2018, and Craft presented primary data. The upshot: Insulin had no effect on cognition. Craft believes a change in the delivery device partway through the trial may have influenced the results. 

The study enrolled 289 volunteers with MCI or mild AD, who took 20 units twice a day of insulin or placebo. The primary outcome was their ADAS12-Cog score, measured quarterly. They started out using Kurve Technology’s ViaNase spray device, the same as in the pilot trial. However, the device had been redesigned and frequently malfunctioned, so the investigators switched to NeuroPharma’s Precision Olfactory Delivery™ device for the bulk of the participants. At the end of the trial, they decided to conduct the primary analysis with the 240 people in that cohort. They found the treatment had no effect on change from baseline on ADAS12-Cog, or secondary cognitive outcomes, or CSF Aβ and tau biomarkers. Treatment did result in more hippocampal shrinkage, and a trend toward more entorhinal cortex thinning.

When Craft looked separately at the 49 people who used the ViaNase device in secondary analyses, she saw different results. In them, insulin appeared to slow the worsening on ADAS12-Cog, as in the pilot study. The difference was significant only at six months; at nine or 12 months there was a trend in the same direction (p=0.09). The ViaNase group was similar in size to the pilot cohort, but was recruited from multiple sites. Safety and compliance were good with both devices, Craft said.

Still to come are results of a prespecified responder analysis by APOE genotype, disease severity and AD biomarker status, and analysis of the open-label extension, which will wrap up this year, Craft said.

What about drug delivery and exposure? The investigators did not fully investigate these aspects before conducting the SNIFF trial, but will now, Craft said. They collected CSF samples at baseline and one year for more than 150 participants, and can analyze those to estimate insulin exposure. They did test acute delivery by dosing and then collecting CSF to analyze for insulin with the Kurve device. This generated a dose-response curve, Craft said. This was not done with the new device prior to its use in this trial, but is now underway.

Pioglitazone Epilogue
The TOMMORROW secondary AD prevention trial is over, and at CTAD researchers got to see its data, presented by Robert Alexander, Takeda, Cambridge, Massachusetts. TOMMORROW tested whether the diabetes drug pioglitazone would prevent mild cognitive impairment in asymptomatic people at genetic risk for AD. It stopped earlier this year after a futility analysis gave it only a 15 percent chance of success (Jan 2018 news). 

The trial enrolled 3,494 cognitively normal participants between 65 and 83, who were judged to be at risk of developing cognitive impairment in the next five years by an algorithm that weighed their APOE and TOMM40 genotypes and ages. The treatment plan called for low-dose pioglitazone or placebo to continue until 202 people reached the primary endpoint, which was progression to MCI. As a group, participants skewed slightly female and were overwhelmingly Caucasian. Most took the drug or placebo for less than three years.

Pioglitazone did not slow progression. In the treatment group, 2.8 percent developed MCI, the same as placebo, and time to progression was also the same in both groups. Pioglitazone had no effect on secondary endpoints assessed out to 36 months. The cognitive composite battery score increased over time in both groups, while ADCS-ADL scores remained constant.

A second objective of the study was to test the algorithm’s ability to identify high-risk people. To do that, investigators included 433 low-risks participants, who were treated with placebo. When the study was halted, 73 people had mild cognitive impairment, including 3.3 percent of the high-risk group risk and 1 percent of the low risk group. That gave an adjusted risk ratio of 3.26 for the high-risk participants, which was statistically significant, Alexander said. The time from enrollment to MCI was faster in the high-risk group, too, with a median time of 383 days compared with 634 days in the low-risk group.

More than 60 percent of people in the high-risk group had APOE4. Attendees questioned whether the investigators detected any contribution of the TOMM40 polymorphism above and beyond age and APOE4. Alexander said they haven’t had a chance to look at the relative contribution of each component, but are working on that.

Subgroup to the Rescue?
In contrast to pioglitazone’s postmortem, a different drug was presented as still offering a faint glimmer of hope. Azeliragon has been in clinical trials since before 2005. It is an inhibitor of the receptor for advanced glycation end products (RAGE). Advanced glycation end products are overproduced in chronic hyperglycemia; the receptor also counts Aβ fibrils among its ligands. Azeliragon was pursued in hopes it would block brain inflammation and amyloid toxicity. Earlier this year, its current owner, vTv Therapeutics of High Point, North Carolina, terminated a Phase 3 trial after it failed to show any benefit over placebo on cognitive endpoints in patients with probable Alzheimer’s disease (Apr 2018 news). 

At CTAD, Marwan Sabbagh, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, presented—no surprise to veteran observers of Alzheimer’s trials—a subgroup analysis that he said may offer a lifeline for this compound. Asking what kind of patient might have high levels of RAGE, or its ligands, led the researchers to look at people with elevated concentrations of glycated hemoglobin HbA1c, a RAGE ligand linked to tissue damage and vascular complications of diabetes. Lo and behold, in the subgroup of trial participants who had diabetes and high HbA1c, the researchers reportedly observed a significant benefit of azeliragon on both the ADAS-Cog and CDR-SB.

The group sizes are tiny, with but 22 placebo and 33 treated participants. Still, to Sabbagh’s mind, the result suggests that azeliragon could help patients who have both Type 2 diabetes and AD. Carmen Valcarce of vTv said her company will try to raise money to pursue this subgroup signal in a bigger study.—Pat McCaffrey

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References

News Citations

1. Fits and Starts: Trial Results from the CTAD Conference 20 Nov 2018
2. There’s No Tomorrow for TOMMORROW 25 Jan 2018
3. Fighting RAGE No Help to Alzheimer’s Disease Patients 10 Apr 2018

Therapeutics Citations

1. Azeliragon
2. Nasal Insulin
3. Pioglitazone

Paper Citations

1. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. PubMed.

External Citations

1. SNIFF

Further Reading

No Available Further Reading