"ALZ-201, a monoclonal antibody therapy for specific neutralization of toxic amyloid-β in Alzheimer's disease”. This is the title of the poster presentation presented by the Alzheimer's Society Alzinova's Chief Scientific Officer Anders Sandberg will hold on CTAD in San Francisco – a conference focused on the clinical development of new drug candidates for the treatment of Alzheimer's disease and which is usually attended by many key opinion leaders in academia, research and industry.
The focus of the presentation is the Mölndal-based biopharmaceutical company's candidate ALZ-201, a monoclonal antibody being developed for the treatment of Alzheimer's and currently in preclinical development.
The primary candidate ALZ-101
However, it is usually the candidate ALZ-101 which is usually highlighted when Alzinova's pipeline is mentioned, for obvious reasons. The disease-modifying vaccine ALZ-101 is in clinical phase Ib and is thus the most advanced in the company's pipeline. The goal is that treatment with ALZ-101 will enable the body to generate its own antibodies that are specifically directed against toxic accumulations of amyloid-beta oligomers in the brain. This in turn will neutralize these toxic protein clumps and protect the brain's synapses from damage - and thereby prevent the development of Alzheimer's disease.
ALZ-201
Regarding the candidate ALZ-201, Alzinova's preclinical data indicates that ALZ-201 can specifically neutralize the toxic forms of amyloid-beta in the brains of Alzheimer's patients, which is believed to support that ALZ-201 has the potential to halt or slow the progressive decline in cognition seen in patients with Alzheimer's disease.
The company believes that ALZ-201 cannot be equated with the plaque-reducing therapies that are currently in late development phases because these primarily treat a form of amyloid-beta that is not the toxic one that kills nerve cells.
ALZ-201 – a candidate with best-in-class potential
According to Alzinova, preclinical data indicates that both candidates have so-called “best-in-class” potential. This means that they have the potential to become a new standard of treatment by offering a better treatment effect than alternative antibody treatments.
By specifically targeting amyloid-beta oligomers, Alzinova believes that these candidates, unlike other candidates, likely have great potential to neutralize the neurotoxic protein clumps that break down brain tissue in Alzheimer's disease. According to the company, this specificity should also reduce the risk of serious side effects observed in, for example, Biogen drug aduhelm and Eiasis similar treatment lecanemab, which are monoclonal antibody therapies just like ALZ-201.
Incidentally, Aduhelm is also an example of a first in class-drug, but which, due to its side effect profile, could theoretically be a less good alternative to a drug that instead has best-in-class-potential.
Alzinova's CSO comments
Due to the fact that Alzinova will hold a poster presentation for ALZ-201 at the annual Alzheimer's conference CTAD, Clinical Trials in Alzheimer's Disease, which will be held in San Francisco from November 29 to December 2, 2022, BioStock contacted the company's Chief Scientific Officer, Anders Sandberg.
Anders, how do you view the treatment effect that, for example, Aduhelm has demonstrated in clinical studies and how do these insights affect your view of the chances of success with ALZ-201?
– The treatment effect of this and similar antibody therapies seems to be limited by a substandard selectivity towards what is truly toxic in patients' brains. It is quite clear that the treatment effect in these comes from plaque reduction, and that this effect is small, which means that in the order of 2000 patients is required to demonstrate a clinically significant effect. Interestingly, the effect is fairly similar for the two different groups of antibody therapies that target plaque – one is based on specificity against a form of amyloid-beta that is only found in plaques, while the other is instead based on selectivity against aggregated (clumped) forms of amyloid-beta in general. The antibody donanemab belongs to the first group, and aducanumab and lecanemab the other group.
– But note that selectivity against aggregated amyloid-beta do not involves selectivity towards toxic clumped together amyloid-beta that is different from the form of the peptide found in plaques and that is present in small amounts. To access this toxic form, it seems that specificity for it is needed – in other words, 100% selectivity – which is what we, based on strong preclinical data, seem to be able to achieve with our drug candidates. There are still questions about how safe it actually is to treat patients with antibodies targeting plaques. However, therapies that, like ALZ-201, do not affect either the plaques or the insoluble amyloid-beta that is found in the fine blood vessels in the brains of many patients should have a significantly lower risk of the serious side effects observed with this group of therapies.
You will be giving a poster presentation at CTAD in the coming days. What do you hope your participation will lead to for Alzinova?
– Being able to present more about our unique antibody ALZ-201 at a prominent scientific conference like CTAD is important from a marketing perspective and demonstrates the potential of the antibody. We see that it contributes to positioning Alzinova as a global player in the market and that it provides increased interest in the company's unique technology and products.
What is the most important thing you want to emphasize with your presentation?
– That the binding profile of the antibody ALZ-201 is unique in this context. In the poster we show that ALZ-201 has specificity for a structural form, or conformation, of oligomeric amyloid-beta (the toxic form of amyloid-beta) which neither aducanumab, lecanemab, or gantenerumab have. We also want to emphasize that our candidate, ALZ-201, has as great a neutralizing effect on the toxic form of amyloid-beta extracted from the brains of deceased Alzheimer's patients as an antibody that binds all amyloid-beta, which we have communicated previously. Taken together, the data strongly indicate that ALZ-201 targets precisely the right form of amyloid-beta with a specificity that is unprecedented and likely necessary to achieve efficacy.
Your communicated timeline for the candidate is to conduct preclinical efficacy and toxicology studies and develop and scale up the manufacturing of ALZ-201 next year. Are there already preparations for the planned clinical phase Ib study in Alzheimer's patients?
– Absolutely. We are looking at a possible clinical study design and will, on this basis, put together a toxicology program that supports the clinical study. In parallel, we are looking for suitable research units for its implementation. My guess is that the patient population will be similar to the one we have in the ongoing clinical study with the ALZ-101 vaccine, but details about this will be presented later.