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18-Month Results (Open Label Extension) of a Phase 2/3 Trial of Inhaled Insulin in People With MCI or Mild Alzheimer's
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https://www.alz.org/aaic/releases_2019/wedCLINICAL-jul17.asp
In a Phase 2/3 clinical trial led by Suzanne Craft, PhD, Professor of Gerontology and Geriatric Medicine at Wake Forest School of Medicine, in collaboration with the Alzheimer's Therapeutic Research Institute led by Paul Aisen, MD, 26 study sites enrolled 289 participants with MCI or Alzheimer's. Participants received either 40-IU of placebo or insulin (Humulin-RU100, Eli Lilly) daily for 12 months, followed by a 6-month open-label extension (OLE). Outcomes included the cognitive test Alzheimer's Disease Assessment Scale for Cognition-12 (ADASCog-12) at months 15 and 18, the functional measure Activities of Daily Living Scale for MCI (ADL-MCI), and Alzheimer's biomarkers in cerebrospinal fluid (CSF). Results from the OLE were reported for the first time at AAIC 2019.
For the first 49 study participants, the intranasal device that delivered the insulin (Kurve Technology/Device 1) had inconsistent reliability. A new device (Impel NeuroPharma/Device 2) was used for the remaining 240 participants. The Device 2 population was pre-specified for the primary intent-to-treat (ITT) analyses, while secondary analyses examined the Device 1 ITT cohort. At the end of the initial study (12 months), the researchers found no benefits of insulin for the Device 2 population, but the Device 1 group showed a trend for better performance for the insulin group (p=0.091).
Of the 289 participants in the study, 203 Device 2 participants and 44 Device 1 participants entered the OLE. The Device 1 group treated with insulin throughout the trial had better ADASCog-12 scores at months 15 and 18 (-5.70 and -5.78 points, nominal p=0.004 and 0.018), than did participants originally assigned to placebo, and better ADL-MCI scores at month 18 (4.85 points, nominal p=0.047). For the Device 2 participants, the insulin group did not differ from the placebo group on the ADASCog-12 or other outcomes. Compliance and adverse events were similar for both treatment groups and both cohorts.
"This is a large effect in the Device 1 group, particularly as it is on top of background treatment," Craft said. Participants in the clinical trials were able to continue to take other approved medicines for Alzheimer's. "At 18 months, the results show a prolonged, statistically significant benefit for the insulin-treated group who used the Device 1 that strengthens over time, with a pattern consistent with a disease modifying effect."
Reported for the first time at AAIC 2019, biomarker data for the Device 1 group showed the Abeta42/40 ratio (p=0.01) and Abeta42/tau ratio (p=0.03) significantly improved for the insulin treated group. These ratios provide integrated measures of Alzheimer's-related pathology in the brain and, according to Craft, favorable changes support a possible disease modifying effect of the intervention. Amyloid beta 42 (Abeta42) is the primary component of the amyloid plaques that are one of the hallmark brain lesions of Alzheimer's.
"While our Device 1 study population is small, the new data make a compelling case that there may be long-lasting beneficial effects of intranasal insulin for cognition, behavior and biomarkers that increase over time, as long as the device is getting insulin into the central nervous system," said Craft. "These new results provide sufficient evidence for a larger study to be conducted."
"It is very important to note that we are seeing what may prove to be an effective treatment for people who already are showing dementia symptoms," Craft added. "It is crucial that we amplify efforts to treat people living with Alzheimer's and other dementias today, and those who will get it in the coming years."
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Benefit Seen in the Use of Intranasal Insulin in Slowing Dementia
https://medworksmedia.com/benefit-seen-in-the-use-of-intranasal-insulin-in-slowing-dementia/
Daily intranasal insulin may be effective in slowing progression of mild cognitive impairment (MCI) or Alzheimer's disease (AD), new research suggests. The findings were presented at the Alzheimer's Association International Conference (AAIC) 2019.
Investigators found intranasal insulin administered via a novel delivery device slowed the rate of cognitive decline by 1 to 2 years. "The magnitude of the benefit is striking," study investigator Suzanne Craft, PhD, professor of gerontology and geriatric medicine at Wake Forest School of Medicine in Winston-Salem, North Carolina. The study was first reported by Medscape Medical News.
Insulin is essential for normal functions in the body and brain. It enhances communication between neurons, increases brain blood flow, and protects against beta-amyloid (Aβ) and abnormal tau.
"One of the things I think is very important for memory is that insulin protects the synapses against amyloid, and also generates new synapses. How well insulin works is the best predictor of how successfully one will age," said Craft.
It appears either patients with AD have low levels of insulin in the brain or the hormone is not working effectively. Boosting insulin levels in the brain might help. However, injecting insulin does not get the hormone straight into the brain, and might lower blood sugar levels, said Craft.
For the study, researchers used a novel mode of delivery - a device that facilitates intranasal applications. The technology involves creating very small aerosol-like droplets of insulin that are driven upwards, directly into the brain and not into the blood stream or lungs, said Craft.
There is growing interest in intranasal delivery of insulin, partly because it is able to penetrate the blood¬–brain barrier, she said. The study included 289 patients across 26 sites who had mini-mental state examination (MMSE) scores above 20.
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'Striking' Benefit of Intranasal Insulin in Slowing Dementia
Pauline Anderson
July 19, 2019
https://www.medscape.com/viewarticle/915828#vp_2
LOS ANGELES - Daily intranasal insulin may be effective in slowing progression of mild cognitive impairment (MCI) or Alzheimer's disease (AD), new research suggests.
Investigators found intranasal insulin administered via a novel delivery device slowed the rate of cognitive decline by 1 to 2 years.
"The magnitude of the benefit is striking," study investigator Suzanne Craft, PhD, professor of gerontology and geriatric medicine at Wake Forest School of Medicine in Winston-Salem, North Carolina, told Medscape Medical News.
"This is the first trial where a medication has been delivered intranasally to treat AD," said Craft.
The findings were presented here at the Alzheimer's Association International Conference (AAIC) 2019.
Protective Effect
Insulin is essential for normal functions in the body and brain. It enhances communication between neurons, increases brain blood flow, and protects against beta-amyloid (Aβ) and abnormal tau.
"One of the things I think is very important for memory is that insulin protects the synapses against amyloid, and also generates new synapses. How well insulin works is the best predictor of how successfully one will age," said Craft.
It appears either patients with AD have low levels of insulin in the brain or the hormone is not working effectively. Boosting insulin levels in the brain might help. However, injecting insulin does not get the hormone straight into the brain, and might lower blood sugar levels, said Craft.
For the study, researchers used a novel mode of delivery - a device that facilitates intranasal applications. The technology involves creating very small aerosol-like droplets of insulin that are driven upwards, directly into the brain and not into the blood stream or lungs, said Craft.
There is growing interest in intranasal delivery of insulin, partly because it is able to penetrate the blood-brain barrier, she said.
The study included 289 patients across 26 sites who had mini-mental state examination (MMSE) scores above 20. Participants were randomly assigned to receive 20 international units (IUs) of insulin or placebo twice daily for 12 months, after which they could opt to receive inulin for 6 months in an open-label phase.
The study began with the Kurve Vianase device, which the researchers had used in all their previous studies. The manufacturer tried to improve the device for this trial, "but unfortunately that improvement resulted in unreliability of that device," said Craft.
She explained that the manufacturer put a new timer switch on the device that "worked erratically," meaning study participants "kept having to replace" the device.
The study then switched to a second delivery system, the Impel Precision Olfactory Device. This meant 49 study subjects were assessed with the first device and 240 with the second device.
There were no safety issues with either device, and there was "respectable compliance" for both, said Craft.
Clinically Significant
The primary outcome was Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), with higher scores indicating worse outcomes. Researchers administered other cognitive and behavioral tests and measured abnormal amyloid and tau proteins - ratios of Aβ42/Aβ40 and Aβ42/tau - in cerebrospinal fluid (CSF) samples.
"These ratios provide an integrated measure of Alzheimer's pathology and have been found to be better predictors than individual biomarkers in some studies," noted Craft.
In the analysis of patients using the second device, both groups worsened cognitively. "So there was no benefit" from the intranasal insulin in either the 12-month trial or this open-label phase, said Craft.
Also in this group, there were no differences between those receiving placebo and those getting insulin in any other measures that researchers incorporated into the study.
However, it was "a different picture" with the first device, said Craft. Here, the insulin group showed an advantage over 12 months, and by 18 months, that group had a 6-point advantage on the ADAS-Cog compared with those who were originally assigned to placebo (P = .018).
"This is a clinically significant effect," said Craft. "We estimate it to be a 1-to-2 year slowing in the rate of disease progression."
Adults with AD typically worsen by about 3 ADAS-Cog points per year, noted Craft.
The Earlier, the Better?
In addition, the CSF biomarker ratios improved with the insulin group using the first device, suggesting a slowing of brain injury associated with AD.
"This showed us that we were affecting the proteins and pathology that is part of Alzheimer's disease, in addition to the cognitive symptoms," said Craft.
It is possible the cognitive benefits will increase as more time passes, she added.
The researchers tested the ability of the first device to deliver insulin into the brain. They did so by administering saline and insulin at different times, each followed by a lumbar puncture to assess CSF levels.
"The data are showing that insulin levels were elevated with insulin treatment by that device at every occasion. That was significant; it showed that the device was getting insulin into the brain," said Craft.
The investigators are conducting further analyses to determine whether cognitive worsening of those with higher MMSE scores at baseline slowed more than in participants with lower baseline scores.
"We can't say that's the case yet, but that's what we are thinking is going on - that the earlier you get the insulin, the better," she said.
It's not clear why the two devices produced different results. Craft noted that devices may differ in their ability to deliver insulin to the brain. "All devices are not created equal," she noted.
A phase 3 trial is being planned to confirm the beneficial effects of intranasal insulin in patients with MCI and AD. It is not yet clear which device will be selected for this next study although "we will validate the device prior to the beginning of the study," said Craft.
Potential New Mechanism
Commenting on these findings for Medscape Medical News, Rebecca Edelmayer, PhD, director of scientific engagement for the Alzheimer's Association, said the study is "an example of how we're diversifying the clinical trial pipeline with new ideas, of how we are sort of thinking outside the box."
Intranasal insulin may represent a potential new mechanism for treating AD, she said.
"Any type of treatment, whether it be a medicine or a lifestyle intervention, that's going to delay the onset or slow the progression of the disease would be a win for this disease field."
The Alzheimer's Association "wants to continue to make sure" that promising treatments undergo "a rigorous clinical trial," which will be "the next step" for intranasal insulin, said Edelmayer.
Study funding was provided by National Institute on Aging (NIA). Eli Lilly provided placebo for the trial blinded phase, and Humulin-R U100 for the open label extension. Craft and Edelmayer have disclosed no relevant financial relationships.
Alzheimer's Association International Conference (AAIC) 2019: Abstract 35542. Presented July 17, 2019.
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