In our recent catalyst cluster note, we highlighted both ProMIS Neurosciences (Nasdaq: PMN) and Acumen Pharmaceuticals (Nasdaq: ABOS), each developing antibodies against soluble amyloid-beta oligomers (AβO), as having important events before year-end. Late last month, ProMIS delivered on the easier of the two, reporting blinded six-month interim data from its 144-patient PRECISE-AD Phase 1b study. The results met or exceeded expectations, with a confident safety signal and breadcrumbs of optimism on efficacy. But the question ProMIS shareholders have to ask themselves isn’t whether these interim data predict success in the final data to be released early next year. It’s how comfortable they are holding ProMIS through Acumen’s Phase 2 readout at year-end.
Strong Safety Signal
Zero cases of ARIA-E (Amyloid-Related Imaging Abnormalities) across 136 evaluable patients and across all genotypes; total ARIA of 4.4%, all mild and asymptomatic; no treatment-related serious adverse events and no drug-related discontinuations. We quoted CEO Neil Warma in our initial January piece on ProMIS, saying he expected placebo-level ARIA for PMN310, and he was right. At six months, Lilly’s donanemab (Kisunla) ran roughly 24% ARIA-E and 31% total ARIA in TRAILBLAZER-ALZ 2; Eisai/Biogen’s lecanemab (Leqembi) roughly 12% and 16% in CLARITY AD; placebo in both trials sat near 1% and 3-5%. PMN310 came in at zero and 4.4%, and the zero is the number that counts, because ARIA-E (edema) is the more problematic of the two forms of ARIA, the other being ARIA-H (hemorrhage). It’s the one that turns symptomatic in 3-6% of treated patients and was the driver behind the deaths reported in the donanemab program.
The genotype breakdown is also where it could become commercially interesting. Homozygotes, patients carrying two copies of the APOE4 allele, constitute roughly 15% of the Alzheimer’s disease (AD) population and are precisely the group the EMA excluded from both Kisunla and Leqembi labels in Europe on the basis of ARIA risk. FDA took a softer line: both drugs carry a boxed warning for ARIA, and their labels advise APOE4 testing before treatment, but there are no restrictions on treating homozygotes. ProMIS’s interim data had a July 22 cutoff, by which point 78% of patients had received more than 9 months of dosing and 49% had completed all 12 infusions. If lecanemab and donanemab are any indication, ARIA-E occurs early, often within the first three months (>50%) and almost all within the first six months (>90%), so most of the risk window for PMN310 is already behind this dataset.
Blinded Breadcrumbs
The company presented its biomarker data as validation of target engagement, a conservative read that is probably an understatement. Plasma p-tau217 fell by 15% from baseline through Day 169, and cerebrospinal fluid (CSF) MTBR-tau243 fell by 13.3%, but blinded data, of course, pooling drug and placebo. In untreated early AD, these markers rise rather than fall, so a pooled 13-15% decline in a trial randomized three-to-one in favor of active treatment would suggest that PMN310 is having a meaningful effect on both biomarkers. What makes it harder to dismiss is that the two markers agree and sit at opposite ends of the disease process. P-tau217 is the early warning, the blood marker now used to confirm AD pathology in the first place. MTBR-tau243 measures tau tangles that most closely track how patients actually decline. Both rise as the disease progresses, so falling is the direction you want — and both falling in the same patients over the same window adds to our optimism for PMN310. Blinded breadcrumbs, but breadcrumbs nonetheless. CEO Warma was candid on the company’s webinar following the interim data release, noting that although their Phase 1b was designed for biomarker and safety readouts, he hopes to see clinical trends once the final 12-month data are available early next year.
Uncomfortable Reality
The uncomfortable reality for ProMIS shareholders is that the next catalyst for the stock isn’t even ProMIS’s own. Acumen’s 542-patient Phase 2 ALTITUDE-AD trial, with its AβO-targeting antibody sabirnetug, is scheduled to read out before year-end. This is the first genuine clinical test of the AβO hypothesis, and, like it or not, these data will significantly affect investors’ confidence in PMN310’s Phase 1b readout. Sure, ProMIS has emphasized PMN310’s unique attributes versus sabirnetug, arguing for its best-in-class selectivity for AβO, specifically low-molecular-weight species, and its complete absence of binding to plaques. The blinded safety data would certainly support the latter part of its argument for a differentiated mechanism. CEO Warma is hedging regarding Acumen’s impending readout, and rightly so. An Acumen hit, and he will celebrate it as mechanistic validation of the AβO hypothesis; an Acumen miss, and he will lean into PMN310’s differentiation, in an attempt to distance it from sabirnetug.
At this stage, we are not handicapping the Acumen outcome. Acumen has not disclosed how ALTITUDE-AD is powered or how its two dose arms are analyzed against placebo, and it declined to provide details when asked during its second-quarter call. It holds an investor day on September 16, and we expect to have considerably more to say once we see what is shared there.
This is a ProMIS-focused piece, and for that purpose Acumen matters mainly as a risk to be managed. But we want to emphasize that Acumen has its own appeal. A registration-quality Phase 2 readout within months, targeting an enormous market, with a valuation around $200 million, is about as asymmetric as biotech offers — arguably more so than ProMIS at this moment. Regardless, ProMIS shareholders should keep their heads on a swivel into year-end.
Awaiting The Verdict(s)
Back in January, we flagged CEO Warma’s confidence in PMN310’s safety. We hear a similar tone when discussing the potential for an efficacy signal in PRECISE-AD. He didn’t shy away from saying that the Phase 1b was robust enough that he would like to see a clinical signal at twelve months. It would be easy to fall back on safety and biomarkers, but he made it clear that he expects more from this study. He isn’t hedging on his own trial.
ProMIS remains inexpensive and is funded through its own readout. There is unquestionably downside on an Acumen miss, but also upside on a hit. Either way, ProMIS gets to write its own ending a quarter later. Acumen’s ALTITUDE-AD is a preliminary verdict on the broader mechanism; PRECISE-AD is a verdict on PMN310, and they are not the same question. Get all three — clean safety, biomarker separation, and a clinical trend — and PMN310 stands on its own regardless of what happened with sabirnetug in December. ProMIS holders should still watch Acumen closely, but not mistake it for the verdict on PMN310.