Regeneron reported on November 12 that a single subcutaneous dose of baloncibart, its investigational first in class monoclonal antibody blocking natriuretic peptide receptor 1 (NPR1), reduced the exaggerated heart rate response to standing and improved orthostatic symptoms through four weeks in adults with postural orthostatic tachycardia syndrome. The data, from the Phase 2 PINNACLE trial, were presented at the American Autonomic Society annual meeting in San Diego. There is no FDA approved treatment for POTS, and care today is symptom management.
PINNACLE was a randomised, double blind trial of a single dose of baloncibart 150 mg (27 patients) or 450 mg (28 patients) against placebo (27 patients). At day 8, the primary endpoint, the 450 mg dose reduced the change in heart rate from lying to standing by a least squares mean of 11.4 beats per minute versus placebo (nominal p of 0.0007), and the difference was still 7.4 beats per minute at day 29 (nominal p of 0.0124). The 150 mg dose also beat placebo at day 8, by 9.5 beats per minute, but the effect was not maintained at day 29. Biomarker changes were consistent with plasma volume expansion, the intended effect of NPR1 blockade.
On Regeneron’s Living With POTS Questionnaire, a patient reported outcome tool developed under FDA patient focused drug development guidance, the 450 mg dose improved orthostatic symptoms by 12.9 points, physical functioning by 13.8 points and activities of daily living by 8.7 points versus placebo at day 29. Treatment emergent adverse events were reported in 67.9 percent of patients on the 450 mg dose against 48.1 percent on placebo, per coverage of the full dataset. Regeneron estimates POTS affects 500,000 to several million people in the United States.
Regeneron plans to start a potentially pivotal Phase 3 trial in the first half of 2027. The cautions are the usual Phase 2 ones and they are real here: 82 patients, a single dose, nominal p values, and a high dose effect that was already fading between day 8 and day 29. The Phase 3 design, in particular its dosing regimen and durability, is where this programme will be decided.