Cardiovascular Profile of Dihydroergotamine Mesylate (DHE) Delivered by INP104 Compared to D.H.E. 45® for Injection from the INP104-101 Clinical Trial

Poster presented at AHS 2019 Annual Meeting, poster #P31.

Authors: Craig KL, Hoekman J, Jeleva M, Satterly KH, Shrewsbury SB. 

BACKGROUND: 

DHE is effective for acute migraine. The approved label warns of potential cardiovascular effects although the clinical experience of DHE over 70 years of use has been good¹. Work has shown the high C_max of IV DHE may account for increased pulmonary arterial systolic pressure² through increased adrenergic receptor binding³. Migranal is an easy-to-use, tolerable nasal spray formulation of DHE, but with poor bioavailability.  

DESIGN/METHODS: 

Cardiovascular data obtained from a Phase I trial^4,5 assessing the safety, tolerability and comparative bioavailability of a single dose of DHE delivered to the upper nasal cavity by INP104 (1.45 mg DHE) compared to D.H.E. 45^® for injection, intravenous (IV) (1.0 mg) and Migranal^® Nasal Spray (2.0 mg) in healthy subjects was analyzed. Changes in blood pressure after each treatment were analyzed statistically and compared to DHE plasma levels. 

RESULTS: 

Thirty-six healthy volunteers received at least one dose of DHE. IV DHE caused a transient but statistically significant (p < 10^-6) increase from baseline in mean systolic and diastolic blood pressure (BP) (11.4 and 13.3 mmHg, respectively) at 5 minutes (min) which was not observed to this degree with INP104 (3.7 and 1.5 mmHg, respectively) or Migranal (-1.8 and -1.8 mmHg, respectively). Further, the rise in BP for IV DHE compared to baseline (pre-dose) for the first 30 min post treatment was statistically significant (p < 10^-3). The onset and duration of BP elevation appeared to correlate with the large spike in plasma DHE concentration at 5 min after IV DHE administration (14,190 ng/mL), which decreased to the same plasma level of DHE as seen after INP104 administration by 30 minutes (1301 ng/mL), which coincided with the C_max of INP104. Plasma levels of DHE were similar for INP104 and IV DHE from 30 minutes onward and were 3 to 4-fold higher than Migranal, demonstrating increased bioavailability of INP104 to Migranal. A single TEAE of vascular flushing was reported in each of 2 subjects after IV DHE treatment; there were no vascular TEAEs reported following INP104 or Migranal administration. There were no clinically significant changes in ECG or other cardiovascular TEAEs observed following IV DHE, INP104 or Migranal administration. 

CONCLUSIONS: 

Administration of INP104 led to only small increases in BP compared to much larger, statistically significant elevations following IV DHE. INP104 is a promising potential alternative to both the IV route of DHE administration and current nasal sprays, with a short T_max, high levels from 30 minutes onward, and no untoward cardiovascular impacts. 

References: 

¹ Baron, E., & Tepper, S. (2010). Revisiting the Role of Ergots in the Treatment of Migraine and Headache. Headache: The Journal of Head and Face Pain, 50(8), 1353-1361. 

²Berenberg E, Clemons D, Kellerman D, Kori S, Noveck R. A Randomized, Double-Blind, Placebo-Controlled, Three-Period Crossover Study Comparing the Acute Effects of LEVADEX^TM (MAP0004, Orally Inhaled DHE) and Intravenous DHE on Pulmonary Arterial Systolic Pressure. 53^rd Annual Meeting of the Americal Headache Society, June 26-29, 2014. 

³ Cook, R., Shrewsbury, S., & Ramadan, N. (2009). Reduced Adverse Event Profile of Orally Inhaled DHE (MAP0004) vs IV DHE: Potential Mechanism. Headache: The Journal of Head and Face Pain, 49(10), 1423-1434. 

⁴Clinicaltrials.gov: NCT03624322 

⁵ Shrewsbury SB, Jeleva M, Satterly KH, Lickliter J, Hoekman J. (2019) STOP101: A Phase 1, Randomized, Open-Label, Comparative Bioavailability Study of INP104, Dihydroergotamine Mesylate (DHE) Administered Intranasally by a I123 Precision Olfactory Delivery (POD^®) Device, in Healthy Adult Subjects.  Headache, in press.