Dr Maria Carrillo
Although controversial, the approval of the first anti-amyloid drug aducanumab (Biogen/Eisai) by the US Food and Drug Administration (FDA) has energized the dementia field, with growing excitement surrounding other promising treatments for Alzheimer’s disease (AD), experts say.
“We know that with an approval, there’s significant infusion and investment into a field,” Maria Carrillo, PhD, chief science officer at the Alzheimer’s Association, told Medscape Medical News.
And this extends beyond the class of drugs that is approved, Carrillo added.
“Small biotech companies are saying they’ve got people calling up wanting to invest in them, and their strategies are not monoclonal antibodies against amyloid. History has shown us these types of approvals stimulate the entire field,” she said.
This is “a new era in terms of positivity, hope, and investment,” said Carrillo.
Several approaches that are currently “in the pipeline” were highlighted here at the Alzheimer’s Association International Conference (AAIC) 2021.
More Anti-amyloid Research
In addition to ongoing anti-amyloid research, there is an enormous amount of work looking into tau strategies, anti-inflammatory targets, gamma sensory stimulation, and other lines of investigation.
Researchers continue to investigate aducanumab, but are also pinning hopes on other anti-amyloid monoclonal antibodies, including lecanemab (Biogen/Eisai) and donanemab (Eli Lilly). Both of these agents target a different piece of the amyloid beta (Aβ) protein.
Although it is early days, lecanemab appears promising — maybe even more so than aducanumab, said Carrillo.
“These two drugs have very similar trials, protocols, measurements; they’re just two different drugs. And it looks like lecanemab has more potential to remove amyloid [and] is more powerful than aducanumab,” she added.
However, she emphasized that it’s still early days. “We’ll see what turns out in the phase 3 trial that’s going to read out probably within 12 months,” said Carrillo.
As reported by Medscape Medical News, the FDA granted breakthrough therapy designation for the drug in June. A day later, it granted the same designation for donanemab.
Carrillo noted that donanemab may also have more potential to remove amyloid than aducanumab and cited the phase 2 TRAILBLAZER-ALZ trial that reported up to a 32% reduction in amyloid.
Some individuals taking this agent got to “squeaky clean levels” of amyloid in their brain, Carrillo said. “It was like they never had amyloid plaques.”
She added that patients in the donanemab trial also had “intermediate levels” of tau tangles in the brain. Results showed the drug removed tau tangles by up to 27%, and participants had clinical benefit, she reported.
“To the naysayers who say amyloid does nothing, that’s not true. That’s been proven in these results that show removing amyloid impacts tau which impacts clinical benefit,” Carrillo said.
Also at the AAIC meeting, investigators announced the design of the first anti-tau Dominantly Inherited Alzheimer’s Disease (DIAD) trial, which will test an antibody targeting soluble tau species.
Targeting Toxic Signaling
Other researchers are investigating simufilam, a small molecule shown to reduce tau hyperphosphorylation and neuroinflammation in the brain.
Taken orally twice daily, simufilam “binds very tightly” to a protein in the brain, which in AD exists in an altered shape, said Lindsay Burns, PhD, senior vice president of Cassava Sciences, the company developing the drug.
This altered shape is “critical for the toxic signaling of soluble amyloid A beta 42. Restoring the normal shape of the protein stops the toxic signaling,” Burns told Medscape Medical News.
Results from a phase 2B study of 64 patients with mild to moderate AD showed significant improvements in biomarkers in those receiving 15- or 100-mg doses of simufilam versus those receiving placebo and “very encouraging early indications of cognitive benefit even at 1 month,” said Burns.
Although the study wasn’t powered to show significance, the effect sizes for cognition “were very encouraging” for both doses, she added.
In addition, newly reported results at 9 months in the first 50 participants in an open-label extension trial show a 3-point improvement on the ADAS-Cog 11 cognitive test in patients taking simufilam.
This compares to about a 4-point decline that would be expected in this patient population over the same time period, said Burns. “That’s pretty huge. We’re showing improvements in a population that is supposed to be declining.”
In addition, in 25 patients at 6 months, there were “even more profound improvements in biomarkers” than in the 1-month study, Burns reported.
For example, there was a 72% drop from baseline in neurogranin, a marker of neurodegeneration that tends to be elevated in patients with AD; and a 55% reduction in neurofilament light chain, which indicates neuronal injury.
“Many new drugs are only going after neuroinflammation, which is a big part of the disease, but not the whole story,” said Burns.
Simufilam also improved insulin receptor functioning. Impaired insulin signaling in the brain has been linked to AD. In addition, it appears to be safe.
“We don’t see any safety signals [or] anything that looks to be drug-related,” said Burns.
Researchers are launching two phase 3 studies of simufilam at sites in the United States and Canada, both of which will begin in the fall.
An agent that can reduce tau hyperphosphorylation as well as neuroinflammation is “hopeful” and may have a place in treating non-amyloid, non-tau dementias, or in other tauopathies, said Carrillo.
“The possibilities of its use will go beyond Alzheimer’s disease and that’s important to think about. Yes, we are very focused on Alzheimer’s, but there are many other dementias that also need to be pursued; so this has the possibility to be more expansive,” she added.
Gamma Stimulation
Another innovative approach to AD treatment is gamma sensory stimulation, as patients with AD tend to have reduced gamma wave activity.
Researchers at Cognito Therapeutics developed a device that uses light and sound to generate gamma frequency electrical signals in the brain. Participants wear a headphone that provides these signals, and a remote control adjusts frequency and intensity.
“Almost immediately, we see the brain respond,” Brent Vaughan, CEO of Cognito Therapeutics, told Medscape Medical News.
“The brain starts to reconnect at gamma frequency oscillations and the neurons start to fire together,” Vaughan said.
A double-blind study in patients with mild cognitive impairment and mild-to-moderate AD compared 30 participants who received this treatment with 19 who received a sham treatment.
After a baseline EEG in clinic, and researchers were satisfied neurons were spontaneously firing in the same frequency, patients started using the device at home for 1 hour per day.
Results showed that the intervention affected brain atrophy. After 6 months, those in the control group had whole brain volume loss of 1.5% vs 0.6% in the treatment group — a 65% between-group difference.
“This is a substantial and significant difference in volume loss,” said Vaughan.
Back to Normal Rates of Loss
Patients with progressive AD typically lose about 1.5% to 2% of brain volume per year. “So it’s back to a healthy, normal rate of loss” in the study, Vaughan said. “As far as we know, no one’s ever shown that before.”
He noted the intervention is doing the same thing some drugs do in the brain, but without their side effects. In addition, the intervention was well tolerated, with a compliance rate that was more than 90%.
The company has already received breakthrough designation for the device from the FDA.
“We see this as a primary therapeutic intervention that could be used either in combination or as an alternative to approved drugs, Vaughan said.
The next step will be to determine if the intervention works better in milder AD cases, and whether modulating electrical activity in the brain using light and sound may also work for diseases other than AD, he added.
Stimulating brain circuits ensure neurons “stay active and healthy,” Carrillo commented. As neurons start to die, the “use it or lose it” idea becomes important, she added.
She noted that although research using gamma sensory stimulation to reduce brain atrophy is at an early stage in humans, it has been successful in previous research in animals.
AAIC 2021. Abstracts 57320, 54395, and 57849. Presented July 2021.
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