Adrenomedullin Safe to Treat Ischemic Stroke, May Lead to Improved Outcomes

Masafumi Ihara, MD, PhD, FACP

Findings from an investigator-initiated AMFIS phase 2 trial showed that treatment with intravenous (IV) adrenomedullin (AM), a vasoactive peptide, was safe to use within the 24 hour window in patients with acute ischemic stroke (AIS). Although outcomes were not statistically significant vs placebo, investigators concluded that this therapy may contribute to improved AIS prognosis.¹

Presented at the 2024 International Stroke Conference (ISC), held February 7-9, in Phoenix, Arizona, the double-blind study tested the safety and tolerability of IV AM administration in 60 patients with non-cardioembolic IS who had National Institutes of Health Stroke Scale (NIHSS) severity scores of at least 1. Patients were randomly allocated to the intermittent IV AM (I-AM group)(30 ug/kg in total for 7 days; n = 20) or placebo group (n = 10) in the first cohort and a combination of continuous (the first 3 days) and intermittent (the following 4 days) IV AM (C/I-AM group)(56 ug/kg in total for 7 days; n = 20) or placebo group (n = 10) in the second cohort.

Led by senior author Masafumi Ihara, MD, PhD, FACP, director of neurology at the National Cerebral and Cardiovascular Center in Suita, Japan, the primary end point of serious adverse events (AEs) related to treatment did not occur in all groups. Between the I-AM group and those on placebo, the rates of favorable outcome (75.0% vs 68.9%; adjusted OR [aOR], 1.45; 95% CI, 0.32-6.53) and good outcome (90.0% vs 73.7%; aOR, 3.86; 95% CI, 0.67-22.11) on modified Rankin Scale were not statistically different. Furthermore, the rates of good outcome in the C/I-AM group were comparable with those in the placebo group (85.0% vs 73.7%; aOR, 1.56; 95% CI, 0.72-3.39).

READ MORE: Optimizing Poststroke Recovery for Patients Through Use of Comprehensive Care Teams

AM is a vasodilator peptide produced by numerous areas of the central nervous system and peripheral tissues. Research has shown that AM levels constitute an independent predictor of future cardiovascular events and will increase following ischemic insults to the brain and traumatic brain injuries. Currently, blood pressure management, coagulation reversal, neurosurgical treatment, and intracranial pressure control are the mainstays of hemorrhagic stroke treatment.

In 2021, data from a published study showed that AM may be a prognostic biomarker for acute intracerebral hemorrhage. In the study, serum AM and nitrate-nitrite and S-nitroso compounds levels were measured and compared between healthy volunteers (n = 50) and patients with acute hemorrhagic stroke. Findings showed that AM levels were high in patients with stroke at all times when compared with healthy controls (P <.0001). Additionally, a receiving operating characteristic curve analysis identified that AM levels at admission greater than 69.0 pg/mL had a great value as a diagnostic biomarker (area under the curve, 0.89; sensitivity = 80.0%; specificity = 100%).²

In the study protocol for AMFIS published in 2021, Ihara et al wrote, "Despite substantial investment from pharmaceutical companies, clinical trials of many drugs for cardiovascular diseases have been unsuccessful. However, several endogenously occurring peptides or peptidomimetics have been approved and used in clinics as components of 'pre-built' drugs that the human body has created in the evolutionary process. These include tissue plasminogen activator for IS, anti-natriuretic peptide for chronic heart failure, and insulin for diabetes."³

They added, "Notably, AM is highly conserved throughout vertebrae evolution and the AM gene dates as far back as the evolutionally distant teleost fish species. Such endogenous substances generally have a higher possibility of crossing the “valley of death” in clinical trials due to their low antigenicity and high safety profile. On the basis of such advantages, AM is expected to have therapeutic applications in IS."

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REFERENCES
1. Yoshimoto T, Saito S, Omae K, et al. A randomized, double-blind, placebo-controlled, phase II trial in acute non-cardioembolic ischemic stroke with adrenomedullin. Presented at: ISC 2024; February 7-9; Phoenix, Arizona. Abstract WMP2.
2. Julian-Villaverde FJ, Ochoa-Callejero L, Siles E, Martinez-Lara E, Martinez A. Adrenomedullin is a diagnostic and prognostic biomarker for acute intracererbral hemorrhage. Curr Issues Mol Bio. 2021;43(1):324-334. doi:10.3390/cimb43010027.
3. Yoshimoto T, Saito S, Omae K, et al. Study rationale for a randomized, double-blind, placebo-controlled, phase II trial: AdrenoMedullin for ischemic stroke study. J Stroke Cerebrovasc Disc. 2021;30(6):105761. doi:10.1016/j.jstrokecerebrovascdis.2021.105761.