Developing truly disease-changing treatments for Alzheimer’s disease and other neurodegenerative conditions has proved challenging, with many failed trials over the last few decades. The approval of Eisai/Biogen’s monoclonal antibody lecanemab in 2023, the first such treatment to have a positive, albeit modest, impact on symptoms of Alzheimer’s disease, was therefore received with enthusiasm by many.
Critics of lecanemab and Eli Lilly’s donanemab, approved a year later for the same indication, argue that the small benefit gained from the drugs does not outweigh the economic costs, possible side effects, and burden of regular intravenous infusions.
Using a vaccine-style approach, where the treatment prompts the body to generate its own antibodies, has the potential to solve these problems. Several companies are developing active immunotherapies to target Alzheimer’s and Parkinson’s disease, as well as other neurological conditions.
CEO and Co-founder
AC Immune
“What we’re trying to do is link the antigen to a carrier and bring it into a form which mimics the pathology,” explained Andrea Pfeifer, PhD, CEO and co-founder of Swiss company AC Immune, a leading biotech taking the active immunotherapy route to target Alzheimer’s and Parkinson’s disease.
“We inject it into the immune system, and what it recognizes is the misfolded protein. So, because of that, the immune system only makes antibodies against this pathological protein.”
Although none have yet reached the market, the active vaccine-style approach potentially has a number of advantages over passive treatment with monoclonal antibodies. Importantly, fewer rounds of treatment are required. The exact dosing is yet to be determined, but it would certainly be less frequent than the regular infusions of lecanemab or donanemab that are currently prescribed. This would help reduce costs and treatment burdens for patients and their families. There is also likely to be less risk of amyloid-related imaging abnormalities (ARIA) due to the relatively slower onset of antibody generation by the body.
“If you have to take the patient every two to four weeks to get a two-hour infusion in a hospital, and then you have to wait and do imaging, it’s really burdensome,” said Pfeifer.
“After a certain while, they just don’t want to go. … They say, ‘Sorry, we believe your science, we believe everything, but we don’t want this.”
To date, most vaccine trials have enrolled people with at least some degree of Alzheimer’s or Parkinson’s disease, as preventive vaccine trials need to be large and long in duration. Theoretically, developing a preventive vaccine is a feasible approach, as many neurodegenerative diseases typically have a slow onset before noticeable symptoms appear. However, reliable biomarkers that can accurately predict disease onset have been in short supply.
This is changing, though. Last year, two blood tests that measure phosphorylated tau and amyloid ratios were approved by the U.S. Food and Drug Administration (FDA) for Alzheimer’s diagnosis. The biomarker field is less developed for Parkinson’s and other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), but things are slowly improving.
Promising mid-stage results from front-runners like AC Immune and Alzinova suggest that this pathway has merit, but whether they can succeed in larger registrational trials going forward is unclear.
CEO, Alzinova
“It remains to be seen how our immune system reacts. I think that when we look at the titers we see from the vaccine, they’re similar to what we get with passive immunizations. So I think there are a lot of things that point in the right direction,” said Tord Labuda, PhD, CEO of Swedish biotech Alzinova, which has an amyloid beta vaccine in development.
“Personally, I don’t think that the vaccine or passive immunization is the real challenge. The real challenge is to have the right target.”
Taking a more active approach to immunotherapy
While passive immunotherapies like lecanemab and donanemab are groundbreaking in that they are the first disease-modifying treatments for Alzheimer’s to be approved by the FDA and they slow cognitive decline by around 25%–35% over two years, these drugs can cause significant side effects such as ARIA.
This can cause brain swelling and bleeding in some people. Individuals at highest risk for some neurodegenerative conditions, such as carriers of the APOE4 gene variant, are prevented from accessing these therapies at all, as they have a higher-than-average risk of experiencing ARIA-like side effects.
Treating neurodegenerative diseases like Alzheimer’s and Parkinson’s disease when symptoms commence is problematic, as currently, there is no known method of regaining neuronal function once it has been lost.
Classic pathology studies suggest that, by the time the typical motor symptoms of Parkinson’s appear, around 50%–70% of dopaminergic neurons are already lost from the brain. Similarly, in early clinical Alzheimer’s disease, where those affected have mild dementia, hippocampal volume in the brain seen on imaging is already up to 25% lower than that of age-matched controls. This means, however good the treatment is, the patients will never regain complete function.
“There’s no way we can restore these neurons,” said Roman Kniazev, CEO of U.S.-biotech Nuravax, which is developing several different Alzheimer’s vaccines. “They are gone forever. So that is why the best strategy, and this is our motto in our company, is to not let the pathology kill the neurons.”
Researchers trying to develop new therapies for Alzheimer’s and Parkinson’s are increasingly moving towards an early or even preventive approach. The idea of a vaccine-like approach to targeting Alzheimer’s is not new. Animal work in the late 1990s showed that vaccinating against amyloid‑beta could clear plaques and improve cognition in transgenic mouse models. This led to the development of Elan/Wyeth’s amyloid‑beta vaccine, AN1792.
It entered Phase I/II trials for mild‑to‑moderate Alzheimer’s and successfully induced anti‑amyloid beta antibodies in some patients. But the study had to be stopped in 2002 because around six percent of the participants developed meningoencephalitis, linked to T cell–mediated inflammation in the brain. Despite strong amyloid plaque clearance, there was little impact on symptoms in the clinical trial participants.
Several other candidates, designed to avoid the T-cell activation seen with AN1792, have been unsuccessfully trialed over the last two decades. Although largely safe and antibody-producing, most of these programs were discontinued due to a lack of efficacy.
The field has persevered despite this, with improvements in technology, safety, biomarkers, and clinical trial design having led to a new generation of vaccine candidates that, while not yet approved, are showing good results in Phase I and II trials.
CEO, ProMIS Neurosciences
“I think what we’ve learned over the past five or 10 years from other vaccine approaches is that the next generation are those that come with a very precise approach to generating antibodies against the toxic species of a given protein for that specific neurodegenerative disease,” said Neil Warma, CEO of ProMIS Neurosciences, a U.S.-based company taking an antibody and a vaccine-based approach to treating Alzheimer’s and other neurodegenerative diseases.
“Those are really the things that make the vaccine approach much more interesting now. The sophistication of the biomarkers, the data we’ve learned from past and current products in the market, and then this ability to design and create antibodies that are highly specific to a targeted pathogenic form of the protein.”
AC Immune has three active immunotherapy candidates in Phase II: an anti-amyloid beta therapy, ACI-24, that is being developed with Takeda; an anti-tau therapy, ACF 35, being developed with Johnson & Johnson; and an anti-alpha synuclein candidate targeting Parkinson’s disease.
The company reported good results for its Parkinson’s Phase II study at the end of last year. The interim study results showed a 100% response rate and a good safety profile in people with early Parkinson’s disease. Alpha-synuclein and neurofilament light levels in the blood, as well as scores from standard movement tests, suggested that disease stabilization had occurred.
If confirmed by results from the second part of the study, this would be the first time that disease modification, rather than symptom management, has shown promise for Parkinson’s disease. It would also confirm alpha synuclein as a pathogenic contributor to the condition.
“The statistical variability was very, very small, which was a surprise to us. Every single marker, preclinical biomarker, clinical imaging, went into the same direction,” said Pfeifer. “For me, what was particularly rewarding was that there was a connection between the titers, so the antibody response in the people versus the reduction of this pathology … the alpha-synuclein versus the imaging, which showed that the neurons can be protected.”
Better targeting to improve safety and efficacy
A common theme among vaccine developers in the neurodegeneration space is precision targeting. There is a strong consensus that a lack of specificity when picking targets is likely why many trials failed to show efficacy and had significant side effect issues in the past.
Different companies or research groups back slightly different protein targets, but the experts all emphasize the importance of avoiding binding to inert plaque in the brain in Alzheimer’s disease, and of targeting toxic, misfolded proteins that are disease-specific.
“We provide the body with active immunotherapy, and then the body induces the antibodies. But what is important is that these antibodies are really specific for the pathological form,” said Pfeifer.
AC Immune is not the only company with a keen focus on tightening up targeting in this area. Alzinova is specifically targeting toxic amyloid beta oligomers with its lead candidate ALZ-101, a therapeutic Alzheimer’s vaccine.
It received a recent FDA Fast Track designation for ALZ-101 after good safety and efficacy data were reported last year from its completed Phase Ib clinical trial.
“They have shown in many in vitro and in vivo models that … when you remove these toxic oligomers using antibodies towards them, you can basically neutralize the toxicity in these extracts towards the neurons,” explained Labuda.
He added that many of the “vaccines, as well as the monoclonal antibodies, are going for the N-terminal part of the protein. … By doing that, you will target the monomers, all the fibrils, but most importantly, also the plaques. Very little will be left to bind to something else that might be more important for the disease. I think this is what we see with the current treatments on the market. There’s a lot of off-target effects … and that’s why we have these huge challenges.”
ProMIS is also targeting amyloid beta oligomers in Alzheimer’s using both a monoclonal antibody and vaccine approach. It has developed a special method with the help of artificial intelligence to develop antibodies, taking both conformational shape and protein sequence into account.
“These three-dimensional shapes don’t exist on monomers, and they’re buried in plaque. We’ve tried and tried and tried to get these antibodies to bind monomers, to bind plaque, and they really don’t, which is good,” said Warma.
“We’ve done side-by-side testing with other antibodies to see if ours is truly differentiated. … In many different studies before we got to the clinic, PMN-310, our therapeutic antibody, was the only one that bound oligomers and avoided monomers and plaque. All the others cross-reacted with everything.”
ProMIS is testing its PMN-310 antibody before moving on to the vaccine approach. “If we can come with that one-two punch to say we’ve got a drug now that can treat patients with Alzheimer’s, we’ve got the ability to detect the onset of disease pathology in Alzheimer’s, and we have a vaccine that prevents you from developing that disease, I mean, that would be a pretty powerful combination,” noted Warma.
Nuravax is aiming to address two key shortcomings of first‑generation Alzheimer’s vaccines, such as AN1792: the risk of problematic T cell-driven inflammation and uneven immune responses in older adults. Its MultiTEP‑based candidates (AV‑1959R, AV‑1980R, and Duvax) are engineered to elicit a strong, antibody‑dominant response against amyloid‑beta and tau while minimizing activation of potentially autoreactive T cells and maintaining effectiveness.
“The platform which we developed makes the vaccine highly immunogenic, and this high immunogenic feature is essential for diseases in the brain,” said Kniazev.
Professor
University of New Mexico
Kiran Bhaskar, PhD, is a professor and group leader at the University of New Mexico. He has worked on Alzheimer’s disease for many years and is also a scientific co-founder of TheraVac Biologics. He and his colleagues are developing an anti-tau Alzheimer’s vaccine that is about to start human trials.
They are also aiming to reduce risks associated with immune reactions to vaccine adjuvants, which can contribute to ARIA, and have created a vaccine that does not need an adjuvant.
“We use a strategy called a virus-like particle,” he explained. “You don’t need to expect any side effects because of adjuvants. In this way, we trick the immune system into thinking that there is a viral attack on the body. It immediately starts an immune response against the virus-like particle and also anything sticking to the surface of those virus-like particles, which in this case is pathological or phosphorylated tau proteins.”
Overall, in the trials carried out so far in the active immune therapy space in Alzheimer’s disease, rates of ARIA have been very low, which is another selling point for the vaccine approach. “We don’t expect to see ARIA in active immunotherapy because we are using the host’s own immune response system to generate antibodies. … So that way there’ll be less unanticipated immune response,” explained Bhaskar.
Overcoming challenges on the road to the clinic
There is no doubt that active immunotherapies or vaccines to target Alzheimer’s and Parkinson’s disease are more advanced than they have ever been before, but they are still a long way from a mainstream rollout.
One reason the conversation has shifted is that the approval and broader use of the first anti-amyloid antibodies, for all their modest effect sizes and ARIA issues, shows that lowering the right protein species can slow deterioration. Using a more vaccine-like approach, where people make their own antibodies, does have the potential to make targeting these conditions safer, cheaper, and more accessible for patients.
But basic clinical questions remain unanswered. For example, how long vaccine-induced protection will last, how often boosters will be needed, and whether early stabilization of biomarkers and motor or cognitive scores—such as AC Immune’s interim Parkinson’s data or Alzinova’s Phase Ib Alzheimer’s study results—will translate into true preserved function a decade later.
Biomarkers are a big potential stumbling block for the development of preventive vaccines. The position is better for Alzheimer’s disease; the FDA’s approval of two blood-based Alzheimer’s biomarkers now gives developers a way to find people with silent pathologies without relying solely on positron emission tomography imaging. But there is still a lot more to do on this front, particularly in diseases like Parkinson’s, ALS, or other neurological or neurodegenerative diseases where less is known.
“We need better and safer treatments, but it’s also linked to having the right biomarkers, because if you have a risk factor, it doesn’t mean necessarily that you have the disease,” said Pfeifer. “These biomarkers are still not very well established. … The goal is absolutely to go to preclinical, and preclinical will require these biomarkers. If you ask me what is needed most in Parkinson’s right now, [it] is definitely to have better biomarkers.”
A second stumbling block for companies that want to develop vaccines that can effectively immunize people against neurodegenerative disease is that clinical trials of vaccines in populations of people with no symptoms have historically been large, expensive, and time-consuming—something out of reach of most biotechs without significant outside investment.
ProMIS and others are hoping that the efficacy of their therapeutic antibodies will boost their vaccine pipeline in the future. “If we show that it works in Alzheimer’s, then a similar approach should work in these other diseases,” said Warma. “Since it’s an almost identical process for vaccines, it also shows proof of concept for this whole wave of vaccines coming behind it.”
For now, active immunotherapies promise something that is more modest than true disease prevention but still crucially important. Namely, cheaper, less burdensome, and potentially safer ways to target the same disease biology as today’s monoclonal antibodies, ideally years earlier in the process.
