ABOS - Acumen Pharmaceuticals: Novel Alzheimer's Molecule With Positive Early Data

2023-10-03 05:15:10 ET

Summary

• Acumen Pharmaceuticals is developing a monoclonal antibody, ACU193, that targets Amyloid beta oligomers (A?Os) in Alzheimer's disease.
• A?Os are small, soluble aggregates of amyloid-beta peptides that are believed to be more toxic to neurons than amyloid plaques.
• ACU193 demonstrated proof-of-mechanism in a phase 1 trial, showing significant reduction in amyloid plaques and a favorable safety profile. A phase 2/3 trial is planned for next year.

Acumen Pharmaceuticals (ABOS) targets a novel mechanism hypothesized as responsible for Alzheimer's. Lead candidate ACU193 is a monoclonal antibody that selectively targets Amyloid-beta oligomers (A?Os).

Amyloid-beta oligomers are small, soluble aggregates of amyloid-beta (A?) peptides that are associated with neurodegenerative diseases, particularly Alzheimer's disease. Amyloid-beta peptides are naturally occurring proteins in the brain, but in Alzheimer's disease and certain other neurodegenerative disorders, they can misfold and accumulate in the brain, forming various forms of aggregated structures.

Amyloid-beta oligomers are one of the intermediate forms in the aggregation process of amyloid-beta. These oligomers are believed to be more toxic to neurons and synapses than the larger, insoluble amyloid plaques that are often associated with Alzheimer's disease. The exact mechanisms through which amyloid-beta oligomers cause damage to brain cells and contribute to the development of cognitive impairment are still an active area of research, but they are thought to disrupt synaptic function, induce inflammation, and promote neuronal cell death.

There is considerable research surrounding the role of A?Os in AD pathology. In rat models, it was seen that neurons had markedly reduced density of dendritic spines and active synapses after being exposed to A?Os, which demonstrates that A?Os impair synaptic function. Unlike monomers, these oligomers block hippocampal long-term potentiation (LTP), a synaptic correlate of memory and learning. They also induce tau hyperphosphorylation. a pathological process that occurs in several neurodegenerative diseases, including Alzheimer's disease. Hyperphosphorylation is an abnormal chemical modification that hinders taus from carrying on their proper function, which is to stabilize microtubules, which are essential for the structure and function of nerve cells.

ACU193 was developed through a research collaboration between Acumen and Merck. It has >500-fold greater selectivity for A?Os over A? monomers, and >85-fold selectivity for AbOs over Ab fibrils. We are aware of the development of a number of anti-plaque mAbs; indeed, that is the core AD research in today's world. However, what this company is saying is that A?Os are the most toxic part of this plaque, and therefore, an anti A?Os molecule that is highly selective of A?Os while sparing other parts of the plaque will have a much stronger safety and efficacy profile.

In July, Acumen rallied 60% after posting positive phase 1 data from a trial of ACU193 in early-stage Alzheimer's patients. Key data :

Topline results from INTERCEPT-AD trial met primary and secondary objectives, demonstrating proof-of-mechanism for ACU193, the first clinical-stage amyloid beta oligomer (A?O)-targeting antibody

Rapid, dose-related, statistically significant (p=0.01) amyloid plaque reduction observed within higher dose cohorts (25% reduction in 60 mg/kg Q4W cohort at day 63 and 20% reduction in 25 mg/kg Q2W cohort at day 70)

ACU193 approached maximal central target engagement of toxic A?Os beyond expected levels, establishing broad therapeutic index and path to convenient monthly dosing ?

ACU193 was well-tolerated in patients with early Alzheimer's disease and resulted in no drug-related serious adverse events, with a low rate of ARIA-E across all cohorts

Note that proof of mechanism is proof that the molecule engages with the target, and not proof that the molecule has the desired therapeutic effect. Here, however, reduction in Ab plaque has long been considered a key parameter for clinical trial success in AD, and, as the company stated, ACU193's Ab plaque reduction at this stage in its development is comparable to what has been historically seen in approved products. Interestingly, since ACU193 targets A?Os, ability to remove AB plaques came as a pleasant surprise. Of course, there aren't many of those approved drugs in AD, and the few there are, do not work. So that's not much of a competition to beat. A number of Acumen's team members have worked at Eli Lilly, so they will know that Lilly's donanemab is the one they will need to beat. Donanemab has a difficult safety profile, whereas ACU193 did very well in the safety department. The key problem is with Aria-E side effects, which is also a noted problem with Eisai's Leqembi. However, the two trials, put side by side (a most unscientific comparison), does not show much numerical difference between the Aria-E figures.

Notably, as regards A?O target engagement, here's what management noted:

I am thrilled to announce that ACU193 bound to toxic A?Os in patients and did so in a dose-proportional manner with evidence of near-maximal target engagement. I'm also proud that our team has made significant progress developing the first target engagement assay for an A? oligomer-targeted antibody. Taken together with the compelling safety profile at doses that engage the target, and pharmacokinetic data that supports monthly dosing, ACU193 has the distinct potential to be a differentiated antibody for the treatment of early Alzheimer's disease.

The company raised $100mn on the data drop, and plans to run a phase 2/3 trial next year.

Financials

ABOS has a market cap of $240mn and a cash balance of $172mn as of June. They raised $122mn from that secondary offering in July. R&D expenses were $9.1 million for the three-month period ended June 30, 2023, while G&A expenses were $4.3 million. At that rate, they have a cash runway well into 2026.

ABOS has a healthy mix of retail and smart money ownership, with the former owning 25%.

Risks

Any Alzheimer's molecule has huge risks - even after approval. There's a large gap between target engagement and treatment benefit, a gap that must be reduced before any molecule can be approved. Moreover, given the recent cash infusion, this company is trading below cash. Whenever that happens, I, if I am an investor, suffer from low confidence issues. Meaning, if the entire market thinks so poorly of the company, could it be that I am right and they are wrong?

Bottom Line

ABOS has crossed its first couple of hurdles successfully, and yet, despite a 60% spike on news, the stock is now less than where it was before the good news, even though nothing untoward has happened to the stock since then. That makes ABOS attractive. However, since this is Alzheimer's, therefore, in an overabundance of caution, I will wait to hear what guidance the FDA gives the company in the meeting they are going to have in Q4, before I take a call.

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