by Dr. Andrea Pfeifer, CEO of AC Immune SA
The clinical success we recently saw with two monoclonal antibodies targeting amyloid beta (Abeta) protein has provided hope for patients, a significant boost for the sector but also a powerful validation of the “amyloid hypothesis”: removing Abeta plaques is a strategy. valid therapy for the treatment of Alzheimer’s disease.
It follows years of development and research that provided the scientific basis for achieving this widely recognized advancement. It also shows that there is still hope: Alzheimer’s is not incurable – but there is still room for improvement.
Toxic misfolded proteins promote disease development
Alzheimer’s disease (AD) is caused by many 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.
Recent positive results from clinical studies with monoclonal antibodies targeting the toxic form of Abeta also support that early diagnosis and preventive treatment is the best strategy.
Dr Andrea Pfeifer
AD is characterized by inappropriate deposition between nerve cells, which is formed by clumping of certain toxic species of normal human brain proteins, particularly misfolded amyloid beta (Abeta) or Tau. Because these clots are closely related to normal human proteins, the human immune system is not aware that it has to remove them, but if left in the brain, they cause nerve damage which eventually leads to nerve degeneration. However, in the majority of patients, several different toxic species are present, which often interact with each other.
So clinically, we’re talking about a very complex situation. Because these toxic proteins – or proteinopathies – are slightly altered versions of self proteins, targeting them is a challenge. The key to any drug is being able to tell the difference between the healthy and misfolded versions of the protein.
In addition, these misfolded proteins accumulate for years before clinical symptoms appear, meaning the disease progresses silently long before a diagnosis is made. The most promising strategy is to identify those at risk early enough to take precautions to protect brain cells before they are permanently lost. Recent positive results from clinical studies with monoclonal antibodies targeting the toxic form of Abeta also support that early diagnosis and preventive treatment is the best strategy.
Removes Abeta plaque: a valid therapeutic strategy for the treatment of Alzheimer’s disease
As of September 2022, the monoclonal antibody lecanemab, which targets a toxic species of protein Abeta, slowed cognitive decline in early Alzheimer’s disease by about 30% in a phase 3 study. Considering that AD is a slow-moving disease, in which patients decline over a decade or more, while Far from being cured, this achievement has the potential to mean a lot to many patients and their families. This year, a second antibody, donanemab, directed against another Abeta toxic species, yielded encouraging results.
Both provide important confirmation of the Abeta hypothesis in the treatment of Alzheimer’s disease, namely that targeting the Abeta protein with potent antibodies at the correct stage of the disease can slow its progression.
As we have believed for years, the goal of Alzheimer’s treatment is to remove these disease-causing proteins from the brain, and specifically target the most toxic species that have negative effects.
Lecanemab and donanemab target distinct protein subgroups that differ in structure: lecanemab mainly binds to smaller, soluble aggregates, called oligomers. Donanemab targets a second, noxious Abeta species, pyroGlu-Abeta, which is found primarily in plaque and is thought to act as “glue”.
While antibodies, which are usually designed to target one particular toxic species, already offer benefits, other modalities may prove superior. For example, vaccines essentially offer a polyclonal response that can target more than one toxic species. Vaccines “teach” the immune system to recognize and produce antibodies against toxic species of human proteins. At AC Immune, the SupraAntigen discovery and development platform was created precisely for this purpose.
The Abeta and Tau vaccine, which is already in clinical development, has 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 the vaccine can also be used successfully to clear Abeta plaques or Tau tangles from the brains of AD patients.
Using imaging to measure Abeta reduction: a good indicator for assessing the success of an Alzheimer’s treatment strategy
Importantly, the amount of Abeta accumulation can be measured directly in a patient’s brain using an imaging technique called Abeta Positron Emission Tomography (PET). On brain scans, both lecanemab and donanemab showed rapid and significant reductions in Abeta plaques in patients with early Alzheimer’s compared with placebo-treated patients and, in both studies, large reductions correlated with slowed cognitive decline.
These results clearly demonstrate that measuring Abeta accumulation using PET can be used as a quantitative indicator to assess the success of a treatment strategy. This is very important for the clinical development of therapy. By measuring changes in Abeta accumulation directly in the brain, we can now determine more quickly whether an approach has a chance of working or not – thereby significantly speeding up clinical trials and ultimately time to approval of new therapies.
Both therapies have been tested in the early stages of Alzheimer’s disease, so the new results suggest that dangerous Abeta must be removed early in the disease to slow its progression. The best approach is to intervene before other proteins in the brain start to misfold. The question then arises: can we prevent AD?
Passive immunotherapy proved to be a major challenge for the participants, who were already in the early stages of Alzheimer’s disease. Donanemab is given by intravenous infusion every four weeks, whereas with lecanemab, patients even have to go to the clinic every week to receive perfusions. Side effects, including edema and cerebral hemorrhage, were observed. These risks and the burden of routine treatment visits limit the use of this antibody therapy in the prevention setting.
Thus, a safer vaccine would offer an avenue for treating pre-symptomatic patients. They also offer several other potentially significant advantages:
• Vaccines stimulate the immune system to produce antibodies directed against several harmful forms of a toxic protein species at the same time; Therefore, the response of these “polyclonal” antibodies is expected to be more efficient compared to externally generated “monoclonal” antibodies.
• Because vaccines cause antibodies to be produced naturally and progressively by the immune system, there is a long lasting therapeutic effect
• 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 valleys of monoclonal antibody concentrations, which occur around injections.
• Because of its long-lasting efficacy, the vaccine can easily and quickly be administered annually or semiannually, which is convenient and improves adherence compared to more frequent injections or infusions
• The vaccine can be made stable for 2-3 years in refrigerator or room temperature and is therefore available globally.
Vaccines can also be cheaper to manufacture and distribute and administer than antibody therapy.
We are developing a vaccine, currently in mid to late stage clinical development, that has been shown to target the toxic forms of Abeta and Tau. In the first half of 2024, the first PET biomarker data from the Abeta phase 2 vaccine will be available, which will show whether or not the vaccine successfully removes Abeta plaques in the brains of AD patients.
At AC Immune, we believe that vaccines used as a key component of a precision drug-based prevention and care plan will ultimately prove to be the best way to tackle neurodegenerative diseases. This will be a major breakthrough in our field.
In order to implement a large-scale prevention approach, we also need a non-invasive and highly specific diagnosis capable of identifying at-risk patients as early as possible. It can be as simple as a blood test. We need to determine the risk of developing Alzheimer’s as early as possible. A reliable diagnosis will also help doctors select the best therapeutic interventions and support patients to make informed decisions.