Abstract Body: CCM is a rare disease characterized by highly permeable vascular malformations in the brain and spinal cord, leading to neurologic impairment, seizures, headaches, and potentially fatal hemorrhagic stroke. REC-994 is a potent nitroxide functioning as a superoxide scavenger protecting against ROS damage. In preclinical models, REC-994 reduced lesion size and number while maintaining vascular tone and decreasing vascular leak. There are no approved pharmacologic treatments and no prior completed phase 2 trials for CCM patients.

This was a 2-part, phase 2 randomized, double-blind, placebo-controlled trial to evaluate the safety, efficacy, and PK of REC-994 followed by a long-term blinded extension in adults with symptomatic CCM. Inclusion criteria: ≥18 years, MRI-confirmed CCM, Modified Rankin Score (mRS) ≥1.

Sixty-two participants were randomized (1:1:1) to REC-994 200mg, 400mg, and placebo administered PO QD for 12 mo. Patient demographics and disease characteristics were well balanced across treatment arms. The primary endpoint of safety was met as evidenced by comparable TEAE frequencies across treatment arms (Table 1).

At 12 mo, 400mg trends with reduced mean lesion volume (LV) vs placebo (−456.7 vs +53.1 mm³) and increased the percent of patients responding to treatment as measured by MRI-based lesion size (50% vs 28%) (Table 2, Fig 1). In exploratory analyses, 400mg trends decreasing mean LV and increasing the percent of patients responding across 4 subpopulations: a) sporadic CCM, b) patients diagnosed by stroke/hemorrhage, c) brainstem lesion patients, and d) sporadic brainstem lesion patients (Table 2). In contrast, 200mg did not show any LV changes vs placebo (Fig 1). When assessing impact on functional disability, mRS showed stabilization/improvements with 400mg vs worsening in the placebo in all populations.

REC-994 was safe and well tolerated. Results suggest REC-994 may reduce/stabilize lesion size/number, slow lesion growth, and reduce the risk of spontaneous hemorrhage. This may decrease lesion-associated symptoms such as neurologic impairment, headaches or seizures, which improves QOL. Overall, REC-994 has the potential to help CCM patients who have no pharmacologic treatment and few medical options. This is especially important to those with greatest unmet need such as patients with multiple lesions due to genetic abnormalities (chronic disease) and where CCM lesions are located in inaccessible locations too risky for resection.