Active immune therapies hold promise for preventing or slowing disease onset, but some experts warn of potential safety risks.
A handful of companies are developing active immune therapies that may prevent or slow the development of symptoms in Alzheimer’s disease. As both preventatives and therapies, these emerging solutions may have a unique place in the armamentarium against one of the world’s most prevalent illnesses.
The Alzheimer’s Association reports that around 32 million people have Alzheimer’s, the most common form of dementia. That includes more than 5.8 million Americans. Globally, some 10 million new cases of dementia are diagnosed each year.
AC Immune and Vaxxinity both have Phase II clinical trials underway assessing active immune therapies against Alzheimer’s disease. Others in clinical trials include Prothena Biosciences, which holds Fast Track designation for its combined amyloid beta/tau vaccine; Bristol Myers Squibb, which licensed an anti-tau antibody from Prothena that is now in mid-stage clinical trials; and Araclon, which last fall reported on the safety of its vaccine against the Aβ40 peptide.
“The immune system is the best weapon we have,” Mei Mei Hu, CEO of Vaxxinity, told BioSpace.
The notion of an immunotherapy approach to treating Alzheimer’s disease emerged after multiple studies of centenarians, she continued. “When they spun down their blood, scientists found these folks had antibodies against aggregated amyloids. Their immune systems protected them against plaque formation. So, we’re teaching the body to behave like those of high-performing centenarians.”
Active immune therapies are unique in the milieu of Alzheimer’s disease in that they stimulate the immune system to generate antibodies against amyloid beta or tau proteins. They can also be administered as an injection a few times per year, according to researchers studying Vaxxinity’s lead compound, UB-311, writing in eBioMedicine. Consequently, it may be possible to administer active therapies at home.
In contrast, passive immune therapies like Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla deliver the relevant antibodies, which are infused over one or two hours at a hospital every two to four weeks.
A proprietary report from analyst Sung Jun Hong at BTIG, “Donanemab AdCom Makes it Clear that Patient Stratification is the Road Forward,” suggests this approach “seems likely to be very attractive across neurodegeneration.” Active immune therapy also offers “reduced costs, simpler delivery, and better safety” compared to passive immunotherapy, according to another BTIG report.
A Sheep in Wolf’s Clothing
Vaxxinity’s Active Immunotherapy Medicine (AIM) platform activates CD4+ cells and stimulates B cells. Rather than the “wolf in sheep’s clothing” analogy that commonly applies to other therapies, this is the reverse: “a sheep in wolf’s clothing,” Hu said.
Basically, the AIM platform uses a synthetic version of a pathogenic protein—amyloid beta, in this instance—that the body makes naturally and considers safe. That safe “sheep” is linked to a synthetic peptide that the immune system knows is harmful, triggering the helper T cells to react.
“We ran two trials in Alzheimer’s patients, and 97% of the patients responded,” Hu said. Vaxxinity’s lead compound, UB-311, which targets amyloid beta, reduced cognitive decline by 50% in patients with mild Alzheimer’s. In contrast, the recently approved passive immune therapies Leqembi and Kisunla reduced cognitive decline by 27% and 29%, respectively, on the Clinical Dementia Rating-Sum of Boxes.
Targeting Pathological Proteins
Meanwhile, AC Immune’s approach coats liposomes with antibodies that conform to the structure of the pathological proteins that make up the plaques and tangles in the brain. “This is important because the amyloid beta, tau and alpha synuclein all occur naturally in the body,” Andrea Pfeifer, CEO of AC Immune, told BioSpace. “The only difference between a sick and healthy person [regarding Alzheimer’s disease] is when these proteins change their structure and become pathological.”
AC Immune has three therapies in Phase II clinical testing: one against beta-amyloid plaques, one against tau tangles, and another against alpha-synuclein, a protein implicated in Parkinson’s. “After treating hundreds of patients, we have not seen any safety [concerns] like hemorrhages, edema or ARIA (amyloid-related imaging abnormality), which you see with antibodies,” Pfeifer said.
Not Clear-Cut
But the approach isn’t as clear-cut as it may seem.
When treating Alzheimer’s disease with immunotherapy, “the real problem is the presence of amyloid in blood vessels as well as in the brain,” John Hardy, group leader at the U.K. Dementia Research Institute, told BioSpace. “When [amyloid targeting] antibodies hit the amyloid in the blood vessels, it sometimes causes ARIA. In most cases, that’s not a serious problem, but occasionally it causes hemorrhages. Very occasionally, those hemorrhages have been fatal, particularly among people taking anti-clotting agents.”
Additionally, Hardy said, “Some clinicians are understandably reluctant to give these antibodies to people with high blood pressure or vascular problems. That [constitutes] quite a high proportion of the elderly.”
Active immune therapies face those challenges, plus one more. Because active therapies stimulate the immune system to create antibodies, “If there are side effects, there’s not much you can do about it,” Hardy said, “so people are a bit worried about active immunization.”
Some physicians also remember the first active vaccine clinical trial for Alzheimer’s disease, conducted by Elan Pharmaceuticals. It was halted in 2002 because some of the patients developed meningoencephalitis. It did, nonetheless, suggest the potential of amyloid beta immunotherapy for Alzheimer’s disease.
To that point, in 2019, researchers at the University of Southampton performed a follow-up study of 22 of the 300 original participants in the Elan Pharmaceuticals study. “Patients with Alzheimer’s disease who were actively immunized against amyloid-beta can remain virtually plaque-free for 14 years,” they concluded. Most of those patients, however, had progressed to severe dementia during that time.
Early Diagnosis is Key
The whole concept of active immune therapy relies on early diagnosis, Pfeifer said. Diagnostics using blood-based biomarkers, as well as those in development for biomarkers in saliva and urine, may make diagnosis relatively fast, simple and accurate, even before symptoms appear.
From a public health perspective, if Alzheimer’s disease can be identified presymptomatically, it may be possible for active immune therapy to prevent the disease from advancing.
At that point, Hu added, “treating Alzheimer’s disease [will become] more scalable and accessible because if you can prevent Alzheimer’s disease, there’s not much left to treat.
“People will still develop Alzheimer’s disease, and some may not respond, so there’s a place for multiple therapies,” Hu said. But, for active immune therapy, “It’s a bit of a winner-take-all scenario.”
