By Dr. Andrea Pfeifer, CEO of AC Immune SA
The clinical success we’ve recently seen with two monoclonal antibodies that target the protein amyloid beta (Abeta) has provided hope for patients, a significant boost to the sector but also a strong validation of the “amyloid hypothesis”: removing Abeta plaques is a valid therapeutic strategy for treatment of Alzheimer’s disease.
This follows many years of development and research that provided the scientific basis to achieve this broadly recognized progress. It also shows that there is hope: Alzheimer’s is not untreatable – but there is also room for improvement.
Toxic misfolded proteins drive disease progression
Alzheimer’s disease (AD) is caused by multiple factors – including genetics and lifestyle choices. We also know from decades of research that certain types of proteins play a decisive role in the development of AD as well as most other neurodegenerative diseases.
The latest positive results from clinical studies with monoclonal antibodies targeting toxic forms of Abeta also support that earlier diagnosis and preventive treatments are the best strategy.
AD is characterized by inappropriate deposits between nerve cells, formed by the clumping together of certain toxic species of normal human brain proteins, specifically misfolded amyloid beta (Abeta) or Tau. As these clumps are closely related to normal human proteins the human immune system does not realize it should remove them but, if left in the brain, they cause neuronal damage ultimately leading to neurodegeneration. In most patients, however, there are several different toxic species, which often interact among each other.
So clinically, we are talking about a very complex situation. Since these toxic proteins – or proteinopathies – are slightly altered versions of self-proteins, targeting them is a challenge. The key for any drug is being able to distinguish between the healthy and misfolded versions of these proteins.
In addition, these misfolded proteins accumulate over several years before clinical symptoms appear, which means the disease develops silently long before a diagnosis is established. The most promising strategy would be to identify those at risk early enough to take preventive action to protect brain cells before they are permanently lost. The latest positive results from clinical studies with monoclonal antibodies targeting toxic forms of Abeta also support that earlier diagnosis and preventive treatments are the best strategy.
Removing Abeta plaques: a valid therapeutic strategy for treatment of Alzheimer’s disease
In September 2022, the monoclonal antibody lecanemab, which targets a toxic species of Abeta protein, slowed cognitive decline in early Alzheimer’s disease by approximately 30% in a phase 3 study. Considering that AD is a slow-moving disease, where patients decline over a decade or more, while far from a cure, this achievement is potentially very meaningful for many patients and their families. This year, a second antibody, donanemab, which is directed against another toxic species of Abeta, showed similarly encouraging results.
Both provided the crucial confirmation of the Abeta hypothesis in the treatment of Alzheimer’s disease, i.e. targeting the protein Abeta with potent antibodies at the right stage of the disease can slow its progression.
As we’ve believed for many years, the goal for an Alzheimer’s treatment is to remove these disease-causing proteins from the brain, and to specifically target the most toxic species that have negative effects.
Lecanemab and donanemab target different subgroups of proteins that differ in their structure: lecanemab primarily binds the smaller, soluble aggregates, so-called oligomers. Donanemab targets a second harmful Abeta species, pyroGlu-Abeta, which is found primarily in plaques and is thought to act as a “glue.”
While the antibodies, which typically are designed to target one specific toxic species, already offer a benefit, other modalities might prove superior. For example, vaccines by nature offer a polyclonal response that can target more than one toxic species. A vaccine “teaches” the immune system to recognize and generate antibodies against toxic species of human proteins. At AC Immune, the SupraAntigen discovery and development platform was created for precisely this purpose.
Abeta and Tau vaccines, which are already in clinical development, have been shown to target toxic forms of Abeta and Tau, such as Abeta oligomers, pyroGlu-Abeta, phosphorylated Tau and Tau tangles. The next step is to show that vaccines could also be successfully used to clear Abeta plaques or Tau tangles from the brains of AD patients.
Using imaging to measure reductions in Abeta: a good indicator to assess success of Alzheimer’s treatment strategies
Importantly, the amount of Abeta accumulations can be measured directly in the brain of patients using an imaging technique called Abeta Positron Emission Tomography (PET). On brain scans, both lecanemab and donanemab showed a rapid and significant reduction of Abeta plaques in patients with early Alzheimer’s compared to the placebo treated patients and, in both studies, a large reduction correlated with slowing cognitive decline.
These results clearly show that measuring Abeta accumulations using PET can be used as a quantitative indicator to assess the success of treatment strategies. This is extremely important for the clinical development of therapies. By measuring the changes in Abeta accumulation directly in the brain, we can now determine more quickly whether an approach has a chance of success or not – thus significantly accelerating clinical trials and ultimately the time to approval for new therapeutics.
Both therapies have been tested in early symptomatic Alzheimer’s disease, so these latest results show that it is necessary to remove harmful Abeta early in the disease to slow its progression. The best approach is to intervene before other proteins in the brain have started misfolding. The question then arises: can we prevent AD?
The promise of prevention
A passive immunotherapy proves to be an enormous challenge for participants, who are already in the early stages of Alzheimer’s. Donanemab was administered by an intravenous infusion every four weeks, while with lecanemab, the patients even had to go to the clinic every other week to receive a perfusion. Side effects, including oedema and brain bleeds, were observed. These risks and the burden of regular treatment visits limit the use of these antibody therapies in a prevention setting.
Thus, a safer vaccine would offer a path to treating pre-symptomatic patients. They also offer several other potentially significant advantages:
• Vaccines stimulate the body’s immune system to produce antibodies that are directed against several harmful forms of toxic protein species at the same time; this “polyclonal” antibody response is therefore expected to be more efficient compared to an externally generated “monoclonal” antibodies
• Because vaccines cause antibodies to be produced naturally and progressively by the body’s immune system, there are long-lasting therapeutic effects
• Because vaccines cause polyclonal antibodies to be produced by the patient’s own immune system, these antibodies are naturally better tolerated than monoclonal antibodies.
• In addition, some monoclonal antibody side effects have been associated with peaks and troughs in the concentration of monoclonal antibodies, which occur around injections.
• Because of their long-lasting efficacy, vaccines can be easily and rapidly administered annually or semi-annually, which is convenient and improves compliance compared to more frequent injections or infusions
• Vaccines can be made stable for 2-3 years at refrigerator or room temperature and can therefore be made available globally.
Vaccines also can be less costly to manufacture and distribute and administer than antibody therapies.
We are developing vaccines, currently in mid-to-late-stage clinical development, that have been shown to target toxic forms of Abeta and Tau. In the first half of 2024, the first PET biomarker data from the Abeta vaccine phase 2 will be available, which will show whether or not the vaccine is successfully removing Abeta plaque in the brains of the AD patients.
At AC Immune, we believe that vaccines used as a key component of a precision medicine-based treatment and prevention plan will ultimately prove to be the best way to address neurodegenerative diseases. This would represent a major breakthrough in our field.
To implement a large-scale prevention approach, we will also need non-invasive and highly specific diagnostics that are able to identify at-risk patients as early as possible. This could be as simple as a blood test. We need to determine the risk of developing Alzheimer’s as early as possible. Reliable diagnoses will also help physicians to select the best therapeutic interventions and support patients to make the right decisions.