Acumen Pharmaceuticals, a clinical-stage biopharmaceutical company focused on Alzheimer's disease, held its first-quarter earnings call on May 14, 2024. While the focus was understandably on the recent commencement of their Phase II ALTITUDE-AD trial, a subtle detail tucked away within the discussion about their subcutaneous formulation development warrants further attention. This detail, I believe, may have implications that other analysts have overlooked, potentially holding the key to a significant competitive advantage for Acumen.

The excitement surrounding ALTITUDE-AD is palpable. Acumen is pursuing a unique approach, targeting soluble amyloid-beta oligomers, believed to be the primary drivers of Alzheimer's pathology. Their Phase I INTERCEPT trial showed encouraging results, with significant biomarker improvements after just three doses of their drug, sabirnetug. This impressive early data, coupled with the open-label extension of the ALTITUDE trial, which offers patients 12 months of active treatment following the 18-month placebo-controlled period, is fueling investigator and patient interest.

However, the subcutaneous development program, seemingly relegated to a secondary narrative, might be harboring a pivotal piece of the puzzle. Acumen's CEO, Dan O'Connell, mentioned the initiation of a Phase I study in healthy subjects for a subcutaneous formulation of sabirnetug in mid-2024. The intent is clear: to offer a more patient-friendly alternative to intravenous administration. While the focus, for now, remains on matching the area under the curve (AUC) of the IV formulation, the potential of this subcutaneous development extends far beyond mere convenience.

During the Q&A session, an intriguing exchange occurred. An analyst inquired whether Acumen could achieve a "plaque-busting" dose with the subcutaneous formulation, or if it would be primarily focused on oligomers. Dr. Eric Siemers, Acumen's Chief Medical Officer, responded that the goal for the subcutaneous route is "really no different than we saw in our INTERCEPT study in terms of plaque reduction versus oligomer target engagement." This seemingly innocuous statement has profound implications.

Here's the crux of the matter: most amyloid-beta targeting antibodies currently in development, including the recently approved lecanemab, focus primarily on plaque reduction. However, Acumen's INTERCEPT trial demonstrated that sabirnetug, while achieving significant oligomer target engagement, also showed notable plaque reduction, albeit at a lower rate than other plaque-centric antibodies. This balance, I believe, is precisely what sets Acumen apart.

While plaque reduction has been shown to correlate with clinical benefit in Alzheimer's, it is also associated with a significant side effect: amyloid-related imaging abnormalities (ARIA). ARIA, particularly the edema form (ARIA-E), can manifest as brain swelling and microhemorrhages, causing concerning symptoms and potentially complicating treatment. Acumen's INTERCEPT trial, remarkably, did not observe any ARIA-E in patients homozygous for the APOE4 gene, a genetic variant strongly associated with increased risk of Alzheimer's and ARIA.

This observation, coupled with Dr. Siemers' statement about the subcutaneous formulation aiming for a similar profile, suggests that Acumen might be on the cusp of achieving a seemingly impossible feat: significant plaque reduction *without* the burden of ARIA. If the subcutaneous formulation achieves the same balance of oligomer engagement and plaque reduction as the IV version, and maintains the promising safety profile seen in INTERCEPT, it could offer a compelling advantage over competitors.

Imagine a subcutaneous, self-administered antibody that effectively tackles both oligomers and plaques, potentially mitigating disease progression without the fear of ARIA. This would be a game-changer, not just for patients and caregivers but also for Acumen's market prospects.

R&D Expenditure Trend

Based on the information provided by Acumen's CFO, Matt Zuga, in the Q1 2024 earnings call, R&D expenditure is expected to increase for the next couple of quarters before flattening out and then decreasing. The following chart represents this anticipated trend.

This is where the numbers come into play. The current Alzheimer's disease market is dominated by Biogen's Aduhelm, despite its controversial approval and limited uptake. Lecanemab, with its demonstrated clinical benefit and lower ARIA rates, is poised to capture a significant market share. However, it still requires bi-weekly intravenous infusions, posing a logistical challenge for patients. Donanemab, another promising candidate, is on the cusp of approval but faces similar ARIA concerns.

The global Alzheimer's disease treatment market is projected to reach a staggering $19.6 billion by 2028. A convenient, self-administered antibody with strong efficacy and a favorable safety profile could potentially capture a substantial portion of this market.

Acumen's market cap currently sits around $144 million. While early, the potential for a subcutaneous formulation of sabirnetug that mirrors the safety and efficacy profile of its IV counterpart could catapult the company's valuation significantly. The combination of addressing both oligomers and plaques, while potentially minimizing ARIA, could position Acumen as a leader in the rapidly evolving Alzheimer's treatment landscape.

This hypothesis, of course, hinges on the success of their ongoing subcutaneous development program. The upcoming Phase I study will be crucial in determining whether the subcutaneous formulation can achieve the desired PK profile and maintain the unique balance of target engagement and plaque reduction observed with the IV version.

However, the breadcrumbs left on Acumen's earnings call suggest that a groundbreaking subcutaneous surprise might be hiding in plain sight. If this hypothesis proves true, the implications for patients, the company, and the entire Alzheimer's treatment market could be profound.

"Fun Fact: Alzheimer's disease was first described by German psychiatrist and pathologist Alois Alzheimer in 1906. He presented the case of a woman named Auguste Deter who suffered from memory loss, language problems, and unpredictable behavior."