INP104: A Drug Evaluation of a Nonoral Product for the Acute Treatment of Migraine

Figures & data

Figure 1. Differences in nasal drug delivery.

Diagram of the nasal cavity illustrating nasal drug delivery through (A) traditional nasal routes into the lower nasal space and (B) INP104 delivery to the upper nasal space using Precision Olfactory Device (POD^®) technology [22,54,68,69,72,74].

Figure 2. INP104 Pharmacokinetics From the STOP 101 Study.

Mean plasma dihydroergotamine concentrations from (A) 0–4 h and (B) 0–48 h postdose from the STOP 101 Study (Safety Population) [63].

^aMeasures dihydroergotamine free base on a semilog scale.

^bDoses represent dihydroergotamine mesylate.

^cn = 31 for time points of 5, 10, 30, and 40 min in (A), and for (B), n = 31 for time points of 5, 10, 30, and 40 min and 12 and 36 h, n = 30 for time point of 8 h.

^dn = 30 for time point of 48 h.

Note: Dihydroergotamine concentration measurements begin at the 5-min time point. Represented as mean (SD). For the calculation of mean values, individual BLQ values were set to 0 before determining the mean. Figure was created using data from [63].

BLQ: Below limit of quantitation data; IV: Intravenous; SD: Standard deviation.

Table 1. INP104 Pharmacokinetic Parameters From the STOP 101 Study (Safety Population).

Parameter	INP104 1.45 mg (n = 31) ±SD	IV DHE Mesylate 1 mg (n = 31) ±SD	MIGRANAL^® 2 mg (n = 34)^† ±SD
Cmax (pg/mL)	1301 ± 668	14,190 ± 5248	299.6 ± 275.1
Cmax, CV (%)	51.4	37.0	91.8
AUC0-last (h*pg/mL)	5930 ± 2521	7091 ± 1225	1834 ± 1590
AUC0-inf (h*pg/mL)	6275 ± 2621	7490 ± 1246	2199 ± 1643
AUC0-inf CV (%)	41.8	16.6	74.7
Tmax (median [min, max])	0.50 (0.33, 2.05)	0.08 (0.07, 0.78)	0.78 (0.50, 3.08)
T½ (h)	11.8 ± 2.8	14.2 ± 3.5	10.4 ± 3.1
Kel (L/h)	0.06 ± 0.01	0.05 ± 0.01	0.07 ± 0.03
CL/F (L/h)	267 ± 224	118 ± 20	1293 ± 917
Vz/F (L)	4314 ± 2859	2432 ± 771	16,860 ± 9380
Absolute bioavailability (%)^‡	58.9	100	15.2

† n = 31 for AUC_0-inf, K_el, T_1/2, CL/F, and Vz/F.

‡ PK population, n = 27 each for INP104, IV DHE mesylate, and MIGRANAL arms.

Note: Table was reused from [63].

AUC_0-inf: Area under the drug concentration-time curve from time 0 to infinity; AUC_0-last: Area under the concentration-time curve from dosing (time 0) to the time of the last measured concentration; CL/F: Apparent clearance; C_max: Maximum Observed plasma concentration; CV: Coefficient of variation; DHE: Dihydroergotamine; IV: Intravenous; K_el: Apparent terminal elimination rate constant; PK: Pharmacokinetic; SD: Standard deviation; t_1/2: Apparent elimination half-life; T_max: Time to maximum plasma concentration; Vz/F: Apparent volume of distribution at the terminal phase.

Table 2. Safety summary of INP104 from the STOP 101 study (safety population).

Safety Outcomes	INP104 1.45 mg (n = 31)	IV DHE Mesylate 1 mg (n = 32)	MIGRANAL^® 2 mg (n = 34)
Any related TEAE, n (%)	6 (19.4)	11 (34.4)	4 (11.8)
Headache	1 (3.2)	5 (15.6)	1 (2.9)
Somnolence	1 (3.2)	4 (12.5)	1 (2.9)
Dizziness	0	5 (15.6)	0
Mental impairment	0	1 (3.1)	0
Lethargy	0	1 (3.1)	0
Nausea	0	3 (9.4)	1 (2.9)
Vomiting	0	2 (6.3)	1 (2.9)
Abdominal pain	0	1 (3.1)	0
Restlessness	0	2 (6.3)	1 (2.9)
Agitation	0	1 (3.1)	0
Oropharyngeal pain	0	1 (3.1)	0
Nasal discomfort	1 (3.2)	0	0
Intranasal paresthesia	0	0	1 (2.9)
Fatigue	1 (3.2)	0	0
Feeling hot	0	1 (3.1)	0
URTI	0	0	1 (2.9)
Gastroenteritis viral	1 (3.2)	0	0
Myalgia	0	1 (3.1)	0
Musculoskeletal discomfort	0	1 (3.1)	0
Metrorrhagia	1 (3.2)	0	1 (2.9)
Breast tenderness	0	0	1 (2.9)
Hot flush	0	2 (6.3)	0
Pruritus	1 (3.2)	0	0
Serious AEs, n (%)	1 (3.2)	0	0
Discontinued for AEs, n (%)	1 (3.2)	0	1 (2.9)

Note: Table was reused from [63].

AE: Adverse event; DHE: Dihydroergotamine; IV: Intravenous; TEAE: Treatment-emergent adverse event; URTI: Upper respiratory tract infection.

Table 3. Safety summary of INP104 from the Phase III STOP 301 Study (full safety set).

Safety Outcomes	24-week treatment period (weeks 1–24; n = 354)	52-week treatment period (weeks 1–52; n = 73)
Any INP104-related TEAE, n (%)	130 (36.7)	33 (45.2)
INP104-related TEAEs (≥1% of patients in the 24-week FSS), n (%)
Nasal congestion	53 (15.0)	13 (17.8)
Nausea	24 (6.8)	5 (6.8)
Nasal discomfort	18 (5.1)	5 (6.8)
INP104 taste abnormal	18 (5.1)	3 (4.1)
Vomiting	9 (2.5)	2 (2.7)
Olfactory test abnormal	8 (2.3)	5 (6.8)
Sinus congestion	7 (2.0)	—
Package associated injury	6 (1.7)	4 (5.5)
Dizziness	5 (1.4)	3 (4.1)
Nasal mucosal disorder	5 (1.4)	1 (1.4)
Epistaxis	5 (1.4)	1 (1.4)
Dysgeusia	4 (1.1)	1 (1.4)
Rhinorrhea	4 (1.1)	1 (1.4)
Serious INP104-related TEAEs, n (%)	0 (0)	0 (0)
Discontinued treatment due to AEs, n (%)	24 (6.8)	1 (1.4)

Note: Table was reused from [77].

AE: Adverse event; FSS: Full safety set; TEAE: Treatment-emergent adverse event.

Table 4. Summary of self-reported exploratory efficacy data from the phase III STOP 301 study for the first INP104-treated migraine attack (full safety set).

Exploratory efficacy outcomes	INP104 (n = 354)
Pain freedom at 2 h, % (n/N)
Treated within 2 h of migraine onset	38.0 (126/332)
Treated >2–4 h of migraine onset	39.4 (13/33)
Treated >4 h of migraine onset	30.9 (17/55)
MBS freedom at 2 h, % (n/N)
Treated within 2 h of migraine onset	52.1 (173/332)
Treated >2–4 h of migraine onset	57.6 (19/33)
Treated >4 h of migraine onset	40.0 (22/55)
Pain relief, % (n/N)^†
15 min	16.3 (42/257)
30 min	29.6 (76/257)
1 h	47.6 (121/254)
2 h	66.3 (167/252)
Recurrence, % (n/N)^‡
24 h	7.1 (9/126)
48 h	14.3 (18/126)

† Pain relief was defined as a decrease from severe or moderate pain to mild or no pain, or a decrease from mild pain to no pain. Only patients with Time 0 pain assessments and pain assessments at the post-treatment time points are included in the analysis.

‡ Recurrence was defined as the onset of a new headache before 24 or 48 h after dosing in patients who were pain-free at 2 h after dosing.

Note: Table was created using data from [77].

FSS: Full safety set; MBS: Most bothersome symptom; min: Minutes.

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