GMRx2 Cuts Recurrent Stroke Risk; LT3001 Shows Promise in Acute Ischemic Stroke

Two stroke trials presented new findings: the fixed-dose triple-combination antihypertensive GMRx2 reduced recurrent stroke risk by 39% in patients with prior intracerebral hemorrhage, and the first-in-class neuroprotective agent LT3001 was safe and showed potential day-90 recovery benefits in acute ischemic stroke, supporting advancement to a global phase 3 trial.

In the global, investigator-initiated, randomized, placebo-controlled TRIDENT trial, published in the New England Journal of Medicine, 1670 patients with a recent intracerebral hemorrhage receiving standard-of-care therapy and stable systolic blood pressure between 130 and 160 mm Hg at baseline were randomized to GMRx2 (telmisartan 20 mg, amlodipine 2.5 mg, indapamide 1.25 mg) or placebo. Over a median follow-up of 3 years, GMRx2 was associated with a 39% relative reduction in recurrent stroke compared with placebo. Recurrent stroke occurred in 4.6% of patients receiving GMRx2 versus 7.4% in the placebo group. Systolic blood pressure was approximately 9 mm Hg lower with GMRx2 than placebo, a difference maintained over time. Serious adverse events occurred in 23.8% of the GMRx2 group and 26.8% of the placebo group, and the safety profile was generally consistent with the known profiles of its individual components.

The combination is already approved in the United States under the brand name WIDAPLIK for hypertension management, including as initial therapy in patients likely to require multiple agents, and is investigational for stroke prevention. “For patients who have survived an intracerebral hemorrhage, the risk of a second stroke remains high,” the director of the Center for Brain & Mind Health at Yale School of Medicine said in a statement. “This trial showed that a structured, intensive blood pressure-lowering approach using a single-pill triple combination can translate into meaningful reductions in recurrent stroke risk. This finding has the potential to directly address the long-standing challenges of under-treatment, adherence issues prominent for this patient population, and therapeutic inertia that stand in the way of a safe and effective preventative treatment that can improve outcomes for patients.” The investigators noted that direct comparisons with stepwise titration strategies are lacking.

In separate phase 2 trials of LT3001 (Lumosa), a first-in-class multifunctional compound, the agent was safe in patients with disabling acute ischemic stroke and led to clinically meaningful improvements at day 90. Across both the 0.05 mg/kg and 0.025 mg/kg cohorts, there was no increase in symptomatic intracranial hemorrhage despite multi-dose administration over 3 days. Mortality was similar between groups: 1 death occurred in Study 202 (in the LT3001 0.025 mg/kg group) and 5 deaths in Study 205 (LT3001 0.05 mg/kg: n = 4; placebo: n = 1). Median ages were 64 years in Study 202 and 68 years in Study 205, and median NIHSS scores were around 8 in both studies.

In Study 202, conducted in China, patients on the higher dose had an absolute improvement of 7% in modified Rankin Scale (mRS) scores 0–2 overall over placebo. In the moderate stroke subgroup (NIHSS 7–10), both doses were associated with a 9% improvement in achieving mRS 0–2. In the severe subgroup (NIHSS 11–25), the 0.05 dose demonstrated a 12% improvement in mRS 0–2, whereas patients with mild stroke showed high placebo recovery rates and no observable treatment-related signal. Among patients with arm motor drift, mRS 0–2 was achieved in 63% of both treated groups compared with 42% in the placebo arm. For leg motor drift, mRS 0–2 rates were 69% and 71% with the active doses versus 57% with placebo. In those presenting with language deficits or aphasia, mRS 0–2 rates were 76% and 78% in the active treatment groups versus 62% with placebo. Across subgroups, relative risks favored treatment, although confidence intervals crossed unity in most comparisons.

In the global Study 205, outcomes at day 90 showed variable effects and no consistent positive signal when stratifying by NIHSS; the authors noted that the number of patients included to power the study was low due to early stopping. The investigators concluded that the findings from the two phase 2 trials support advancement into a global phase 3 trial, which is currently being planned.