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Yesterday was a big day for European biotechs. As if CatalYm’s $150 million series D round wasn’t enough for one day, the Swiss biotech Asceneuron bagged $100 million in a series C round led by Novo Holdings. Asceneuron is focused on developing therapeutics for neurodegenerative diseases and the funds will accelerate the development of their lead asset, ASN51, a promising candidate targeting tau proteins associated with Alzheimer’s disease.
Asceneuron’s approach to tackling Alzheimer’s disease sets it apart in the competitive landscape of neurodegenerative disease treatments. While approved therapies for Alzheimer’s, such as Leqembi, target amyloid-beta aggregates, Asceneuron focuses on tau proteins, which play a critical role in the progression of Alzheimer’s. Naveed Siddiqi, senior partner, Venture Investments at Novo Holdings, admitted the fund had its eye on the Swiss biotech for quite some time.
“Novo Holdings has been tracking Asceneuron for several years and recognizes the potential of its innovative oral small molecule drug targeting intracellular tau, which offers potential for a paradigm shift in the way this neurodegenerative disease is treated. Importantly, as an oral drug, Asceneuron’s therapy has the potential to benefit millions of Alzheimer’s disease patients and families,” said Siddiqi.
Are tau-targeting therapies the future of Alzheimer’s treatment? Asceneuron certainly makes a good case for it.
Tau protein targeting for Alzheimer’s: How does it work?
Tau proteins play a crucial role in maintaining the structure and function of neurons by stabilizing microtubules, which are essential for intracellular transport. In neurodegenerative diseases such as Alzheimer’s, tau proteins undergo abnormal phosphorylation, leading to the formation of neurofibrillary tangles (NFTs). These tangles disrupt neuronal communication and contribute to cell death. Basically, when tau proteins get modified in the wrong way, they form tangles inside neurons that block communication and lead to neuron death, driving the symptoms of Alzheimer’s.
Unlike amyloid-beta plaques, which accumulate outside neurons, tau tangles form inside neurons, directly impacting their health and function. Research indicates that the spread of tau pathology correlates more closely with disease progression and cognitive decline in Alzheimer’s patients than amyloid plaques. By preventing aggregation or promoting the clearance of abnormal tau, therapies can potentially halt or reverse the progression of neurodegenerative diseases.
“The majority of tau pathology, characterized by neurofibrillary tangles in Alzheimer’s disease is intracellular within neurons. This is hard to access with antibody-based treatment approaches. The development of OGA-inhibiting therapies, which are small molecule, oral drugs, offers a promising approach to address in particular this intracellular Tau pathology,” explained Siddiqi.
As the understanding of tau’s role in neurodegeneration deepens, therapies like Asceneuron’s ASN51 could redefine the treatment landscape for Alzheimer’s.
Asceneuron’s lead asset: ASN51
ASN51 is an oral small molecule O-GlcNAcase (OGA) inhibitor. OGA is an enzyme that removes O-GlcNAc groups from proteins, including tau. Barbara Angehrn Pavik, chief executive officer (CEO) of Asceneuron explained how OGA inhibition works. “One approach that has been widely validated in preclinical models of tau pathology is OGA inhibition, which leads to the modification of individual tau proteins and prevents their incorporation into aggregates. OGA inhibition works inside cells to prevent the removal of specific sugar molecules from proteins. In this way, OGA inhibition leads to a build-up of sugars on specific proteins, including the tau protein, and reduces their propensity to aggregate.”
Essentially, Asceneuron’s ASN51 works by stabilizing tau proteins in a state that is less likely to form harmful aggregates, helping to maintain normal neuronal function and potentially slowing the progression of neurodegenerative disease. This comes with a substantial advantage for potential patients: as ASN51’s formulation is a daily oral tablet, it is a much more convenient and accessible way of being treated. This contrasts with treatments like Leqembi, which require intravenous administration.
According to Angehrn Pavik, while OGA inhibitors are ideal as a standalone therapy because of their low dose and convenient oral route of administration, they also hold potential in combination therapy. “OGA inhibitors also have an advantage as a potential combination therapy with existing amyloid plaque lowering antibodies because they target the central pathology downstream of amyloid plaques in Alzheimer’s disease, tau, and do not require infusions,” said Asceneuron’s CEO.
In multiple phase 1 clinical trials, ASN51 was found to be well-tolerated with a favorable safety profile. Pharmacokinetic data indicated that the drug is effectively absorbed when taken orally and achieves the desired therapeutic levels in the body. “Asceneuron has completed five phase 1 clinical trials, demonstrating complete central nervous system uptake and high OGA enzyme occupancy, indicating a potential for differentiation from its competitors,” said Siddiqi.
The upcoming phase 2 trials will focus on evaluating the efficacy of ASN51 in patients with mild to moderate Alzheimer’s disease. These trials will measure the drug’s impact on cognitive function, biomarkers of tau pathology, and overall disease progression.
Alzheimer’s treatment, a landscape dominated by the amyloid-beta plaques approach
The current landscape of Alzheimer’s treatment includes several drugs targeting amyloid-beta aggregates. Biogen is a major player in this field – after it discontinued its controversial drug Aduhelm, the company managed to turn the tables around by obtaining U.S. Food and Drug Administration (FDA) approval for Leqembi.
Leqembi is an intravenous monoclonal antibody that binds to amyloid-beta, facilitating its removal from the brain. Eli Lilly’s Kisunla adopts the same pathway and has also been approved by the FDA. While this approach has shown some success in reducing amyloid plaque burden and slowing cognitive decline, its effectiveness is limited by the stage of disease and the need for intravenous administration. Indeed, amyloid-beta plaque-targeting therapies are designed to reduce the amyloid plaques that accumulate in the brain during the early stages of Alzheimer’s disease.
Angehrn Pavik sees lecanemab and donanemab, later branded as Leqembi and Kisunla, as paving the way for other Alzheimer’s therapies. “These approvals show that developing disease-modifying therapies in Alzheimer’s disease is possible. More importantly, data from those trials have demonstrated that tau biomarkers in Alzheimer’s, both as diagnostics and as treatment response markers, have advanced rapidly. The approvals overall are just the tip of the iceberg in the Alzheimer’s space and have opened a path for rapid precision development of novel therapies like Asceneuron’s ASN51.”
To put it in a nutshell, while Leqembi and Kisunla reduce plaque-associated toxicity, tau-targeted therapies address the intracellular pathology that more directly correlates with cognitive decline.
Beyond Asceneuron’s ASN51: The tau-protein pathway progressing through the pipelines
As promising as it is, Asceneuron’s ASN51 is not the only candidate adopting the tau protein approach progressing in clinical trials. Several other biotechs are in the race to treat Alzheimer’s to its roots.
Siddiqi foresees an acceleration of the field in the years to come. “Late last year Biogen reported encouraging phase 2 data from an intrathecally administered (through a lumbar puncture into the spinal canal) anti-tau ASO. We expect further emerging safety and efficacy monotherapy data from Asceneuron and others developing small molecule tau targeting therapies will further inform us on how the treatment paradigm may transform. Eventually, we may see combinations of anti-amyloid and anti-Tau approaches emerge to improve efficacy. The Alzheimer’s research field is likely to accelerate with these recent advances.”
In this space, four players stand out:
TauRx’s Hydromethylthionine Mesylate (HMTM)
- Mechanism: HMTM is a tau aggregation inhibitor. It aims to dissolve tau tangles by stabilizing the native conformation of tau, reducing its propensity to aggregate.
- Current status: HMTM completed the LUCIDITY phase 3 clinical trials. Patients treated with HMTM demonstrated significant cognitive benefits compared to the placebo group. These cognitive benefits were sustained over two years, suggesting the long-term efficacy of the treatment. The company submitted a marketing authorization application to the UK Medicines and Healthcare products Regulatory Agency (MHRA) earlier this month.
Biogen’s BIIB080
- Mechanism: BIIB080 is an antisense oligonucleotide designed to target and reduce the production of tau protein by binding to its mRNA. This prevents the translation of the tau protein, thereby reducing its accumulation and the formation of neurofibrillary tangles.
- Current status: BIIB080 is currently in phase 2 clinical trials. Phase 1 results showed that BIIB080 significantly reduced tau levels in cerebrospinal fluid, and it was well-tolerated with a good safety profile.
Eli Lilly’s LY3372689
- Mechanism: LY3372689 is an O-GlcNAcase inhibitor, similar to Asceneuron’s ASN51. It works by increasing the levels of O-GlcNAc on tau proteins, which helps prevent their abnormal phosphorylation and aggregation into neurofibrillary tangles.
- Current status: LY3372689 is currently in phase 2 clinical trials.
Voyager Therapeutics’ gene therapies
- Mechanism: Voyager Therapeutics is developing gene therapies targeting tau. VY-TAU01 uses an anti-tau antibody, while the tau silencing gene therapy utilizes adeno-associated virus (AAV) vectors to deliver microRNA designed to silence tau expression.
- Current status: VY-TAU01 has shown significant reductions in tau levels in preclinical models and is currently in phase 1a, with the first patient dosed in May. The tau silencing therapy is still in the preclinical stages.
ASN51 and tau-protein pathway’s potential beyond Alzheimer’s
While the tau pathway is extremely promising for Alzheimer’s treatment, it is not the only neurodegenerative disease that could benefit from this approach. “In addition to Alzheimer’s disease, OGA inhibition has also shown promising potential to prevent the aggregation of proteins that are central to other neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis,” said Henrijette Richter, managing partner at Sofinnova Partners, a VC firm investing in Ascerneuron since its first round.
“Since our initial investment in 2015, Asceneuron has made remarkable strides in developing treatments for a wide range of neurodegenerative diseases. For instance, in 2023, Asceneuron successfully licensed out ASN90, an O-GlcNAcase inhibitor specifically designed for progressive supranuclear palsy (PSP),” added Richter.
PSP is a rare neurodegenerative disorder characterized by problems with balance, movement, vision, speech, and swallowing. It primarily involves the accumulation of tau proteins in specific brain regions, leading to neuronal damage and brain atrophy. Tau-targeting therapies, such as Asceneuron’s ASN51, could slow the progression of PSP by reducing the pathological tau burden.
Corticobasal degeneration (CBD) is another tauopathy involving progressive degeneration of the cerebral cortex and basal ganglia, leading to symptoms like motor dysfunction, cognitive decline, and apraxia. Tau-targeting approaches, including small molecules like O-GlcNAcase inhibitors and tau aggregation inhibitors, are being developed to alleviate these symptoms by targeting the underlying tau pathology.
Frontotemporal dementia (FTD), a group of disorders caused by progressive nerve cell loss in the brain’s frontal and temporal lobes, chronic traumatic encephalopathy (CTE) associated with repeated head injuries, or primary age-related tauopathy (PART) characterized by tau accumulation in the brains of elderly individuals without amyloid pathology, are other examples of potential targets for the tau-protein pathway.
Additionally, while Parkinson’s disease (PD) is primarily associated with alpha-synuclein pathology, research indicates that tau also plays a significant role in the disease. Tau pathology is often observed in the brains of Parkinson’s patients, particularly in those with dementia.
ASN51 and other tau-protein therapies are definitely worth following closely for Alzheimer’s disease treatment but also for the broader neurodegenerative space. And it might not be too long before we hear again about Asceneuron’s candidate again: as Angehrn Pavik told us, “Asceneuron is focused on advancing the development of its lead asset ASN51 into phase 2 and is planning to recruit the first patient in the second half of 2024. Further updates on clinical development will be announced at a later date”.
