Advancing Multi-Pathology Disease-Modifying Therapy For Neurodegenerative Diseases
A conversation between Amyl Therapeutics’ Pierre Vandepapeliere and Life Science Connect’s Michelle Raley
Neurodegenerative diseases present drug developers with a dual challenge: identifying the right biological targets and getting therapeutics to the areas of the brain where they can have an effect. In Alzheimer’s disease, for example, multiple protein aggregates, including amyloid beta and tau, are implicated in disease pathology, while the blood-brain barrier can severely limit the brain penetration of large molecule therapies.
In this Q&A with Drug Delivery Leader, Life Science Connect’s Michelle Raley caught up with Amyl Therapeutics’ cofounder, CEO, and CMO, Pierre Vandepapeliere, to discuss Amyl’s approach to addressing these challenges through therapeutics designed to target multiple amyloid fibrils and the use of brain shuttle technology to enhance delivery across the blood-brain barrier.
Current neurodegenerative disease therapies often focus on a single target, such as amyloid beta. Your platform is built around the idea that multiple misfolded proteins may contribute to disease pathology. From a scientific and drug delivery perspective, what are the advantages and challenges of designing therapies that address multiple protein aggregates simultaneously rather than pursuing highly specific single-target approaches?
The main advantage of Amyl Therapeutics’ technology is indeed its capacity to bind to and act on multiple amyloid fibrils with one compound. The presence and role of multiple amyloid fibrils in the pathogenesis and the severity of several neurodegenerative diseases have been clearly demonstrated. In Alzheimer’s disease, our initial target indication, two fibrils – amyloid beta and tau – are always involved, and a third aggregate, alpha-synuclein, is present in 50% of the patients and is associated with more severe disease progression.
Classical monoclonal antibodies, like those on the market or in development, are very specific to a single moiety on a single type of amyloid fibril. The general trend in the field of neurodegenerative diseases is to develop monoclonal antibodies (mAbs) against each of these fibrils and to combine them to increase the rather poor efficacy of the current anti-amyloid beta monoclonal antibodies. Acting on multiple fibrils therefore requires combining two or three monoclonal antibodies, with ensuing clinical and regulatory complexities. In addition, it implies several productions and cumbersome administration schemes for patients.
Amyl’s technology is based on a unique binding domain that binds to the fibril conformation that is common to all amyloid fibrils. The main challenge has been to ensure a binding potency to all three amyloid fibrils (amyloid beta, tau, alpha-synuclein) as strong as three individual monoclonal antibodies. It also imposes the need to perform many experiments in triplicate, including for demonstrating in vivo efficacy.
The blood-brain barrier (BBB) remains one of the biggest obstacles in CNS drug development. What strategies are you employing with your brain shuttle technology for Amyl’s drug candidates?
Indeed, the blood brain barrier is a major obstacle to the intracerebral passage of therapies, especially those of significant size, such as monoclonal antibodies. Only 1/1,000th of the drug injected in the blood will pass into the brain. Brain shuttles are revolutionizing the field. Roche demonstrated in a Phase 2 clinical study in patients with Alzheimer’s disease an eightfold increase in brain passage of their shuttled anti-amyloid beta monoclonal antibody (trontinemab), associated with a three to six times faster clearance of aggregates, as compared to the same monoclonal without a brain shuttle (gantenerumab). Unfortunately, this result is accompanied by development of anemia in 25% of patients. Denali obtained FDA approval for its brain shuttled AVLAYAH (tividenofusp alfa-eknm) for treatment of Hunter syndrome. Both brain shuttles target the transferin receptor (hTfR1) to increase passage through the brain.
Amyl Therapeutics has elected to use a similar clinically validated and FDA-approved mechanism of shuttling. We evaluated the technologies of 10 different companies and academic centers and selected one technology that increases the BBB passage even better than trontinemab. In addition, we engineered it to improve its safety profile, i.e., we suppressed the risk of anemia.
The amyloid hypothesis has undergone periods of enthusiasm, skepticism, and renewed interest. As the field evolves, how should drug delivery scientists approach amyloid biology and its role in disease progression, particularly when considering the interactions among amyloid-beta, tau, alpha-synuclein, and other pathological proteins?
The positive results of the anti-amyloid beta monoclonal antibodies (aducanumab, lecanemab, donanemab), albeit insufficient, have revived enthusiasm in R&D for Alzheimer’s disease and validated the anti-amyloid fibrils strategy. However, the efficacy is limited to a 30% slowing down of disease progression and the safety profile is hampered by the risk of severe side effects (ARIAs, i.e., brain edemas and microhemorrhages, in up to 25% of the patients).
The field is now evolving in two main directions: first, the current anti-amyloid beta technology is being optimized by adding a brain shuttle. In the same Roche Phase 2 study that I mentioned previously, a brain shuttle has increased passage into the brain by eightfold, accelerating the clearance of the beta amyloid plaques with a concomitant decrease in the ARIA frequency. The second direction is acting on several types of amyloid fibrils, i.e., amyloid beta, tau, and alpha-synuclein through a combination of monoclonal antibodies, to increase the therapeutic efficacy. A Phase 2a study is ongoing by Eisai to compare various combination schedules of an anti-amyloid beta mAb and an anti-tau mAb. This study is complex and long and will deliver results in 2029.
Many neurodegenerative diseases are diagnosed long after pathological processes have begun. How should drug delivery strategies evolve if the field increasingly shifts toward earlier intervention or even prevention, and what would that mean for the design requirements of next-generation CNS therapeutics?
The future objective should be to halt early disease progression. Several new biomarkers have been developed over the past few years that can predict disease risk and severity long before the clinical symptoms arise. A few clinical programs are already initiating anti-amyloid beta therapy prior to the onset of clinical symptoms, in an attempt to block disease development. However, amyloid beta fibrils are present sometimes decades before disease onset, followed by tau and, often, alpha-synuclein aggregates. Therefore, targeting and neutralizing up front all amyloid fibrils, even before their detection, will likely be more efficacious as a prevention strategy.
If we look ahead five to 10 years, what characteristics will define a truly next-generation biologic for neurodegenerative disease? Beyond efficacy, what advances in delivery, target engagement, manufacturability, patient experience, and safety will determine which therapeutic approaches ultimately succeed?
The main objective should be to halt early disease progression. Once the disease is advanced, there is no chance to revert back to normality. This will translate into wide diagnostic campaigns to identify at-risk subjects, initiate early “prevention” therapies, and ensure proper self-delivery of the amyloid fibrils targeting agent(s) to the intended site of action. This means crossing the BBB using a brain shuttle, diffusing deep inside the brain parenchyma, and even reaching the intracellular space to act on intracellular amyloid aggregates. The tools to reach these objectives are actively being developed and will eventually generate more effective and safe therapies.
About The Expert:
Pierre Vandepapeliere has been Amyl Therapeutics’ cofounder, CEO, and CMO since 2020. Previously, he was CEO of Imcyse from 2014 to 2019, transforming the company into a rapidly growing biotech and raising €35 million in Series B funding. During the COVID-19 pandemic, he contributed to several vaccine projects, including creating Astrivax. Vandepapeliere has also held leadership roles at Neovacs and GlaxoSmithKline. He holds a medical degree and a Ph.D.