To investigate treatment factors predicting favorable clinical response to EP102 (oral fospropofol), a propofol prodrug under development for acute treatment of migraine.
Subanesthetic intravenous propofol has been demonstrated to be an effective acute treatment for refractory migraine, but an oral delivery strategy has not been studied.
Subjects experiencing severe or moderate migraine headache pain traveled to a study center and received 800 mg EP102. With travel time, treatment was 1.9–4 h after pain onset (median 3.3 h). We assessed associations of pain freedom or clinical response (improvement of at least 2 points on a 4-point scale) at 2 h with time-to-treatment; maximal propofol plasma concentration (Cmax) within 40 min, 1 h, or 2 h; and propofol AUC to 1 h or 2 h.
Of 23 subjects with analyzable pharmacokinetic data, 10 (43.5%) showed a clinical response at 2 h; 5 (21.7%) were pain free. Time-to-treatment was unrelated to pretreatment pain severity. Pain freedom and clinical response were inversely related to time-to-treatment (Kruskal-Wallace p=0.048 and p=0.002, respectively) and unrelated to any exposure metric. In logistic regressions, only time-to-treatment was predictive of clinical response (p=0.012). Clinical response odds decreased by 4.8% (90% CI 1.7, 7.8) per min. Of 11 subjects treated before 3.3 h, 9 (81.8%) were responders; 5 (45%) were pain free. Responders overall (n=10) exhibited a wide range of propofol exposure [Cmax_2h, 76-838 (median: 212) ng/mL; AUC0-2h, 101-789 (median: 249) ng.h/mL].
EP102 produced high rates of clinical response and pain freedom when administered within 2–3 h after pain onset. Clinical response and pain freedom were observed at low propofol exposures not associated with sedation or other CNS effects. EP102 represents a promising therapy for acute migraine that is likely to be highly efficacious when dosed even up to 3 h after migraine onset.