Therapeutic advances in Dravet syndrome: a targeted literature review

Figures & data

Figure 1. Pharmacologic agents approved or in development for Dravet syndrome

Footnote: CLB, clobazam; CNS, central nervous system; DS, Dravet syndrome, LGS, Lennox-Gastaut syndrome; VPA, valproic acid.

Table 1. Study and baseline characteristics of the pivotal phase III studies for the treatment of Dravet syndrome

Author (year), study name, location	Study design	Population	Intervention/Comparator (n)	Age: mean (SD) [range or IQR], years	Male, n (%)	Seizure frequency per 28 days: mean (SD) [median: range or IQR]	Previous AEDs: mean (SD) [median: range]^a	Concomitant AEDs: mean (SD) [median: range]^a	Primary outcome
Stiripentol
Chiron [30,31] STICLO-France	Phase III, double-blind, multicentre placebo controlled, RCT	Patients with SMEI (DS) (≥3 years)	STP(+CLB+VPA) (n = 21)	9.4 (4) [IQR: 3–16.7]	6 (29)	17.9 (17.3) [18: IQR: 4–7; range 3.9–72.9]	6.6 (2.5) [3–11]	NR	Response rate^b
			Placebo (+CLB+VPA) (n = 20)	9.3 (4.86) [IQR:3.2–20.7]	11 (55)	18.5 (17.0) [19: IQR 4–76; range 4.1–76.2]	7.5 (2.9) [3–13]	NR
STICLO-Italy [31]	Phase III, double-blind, multicentre placebo controlled, RCT	Patients with SMEI (DS) (≥3 years)	STP(+CLB+VPA) (n = 12)	9.17 (3.63)	8 (66.7)	33.6 (28.2) [2.14–86.1]	NR	NR	Response rate^b
			Placebo (+CLB+VPA) (n = 11)	8.72 (4.43)	5 (45.5)	27.4 (28.6) [3.75–101]	NR	NR
Cannabidiol
Devinsky [43] GWPCARE1 part B (NCT02091375), Europe & USA	Phase III, double-blind, multinational placebo controlled, RCT	Patients with DS (2–18 years) with seizures not controlled with current AEDs	CBD 20 mg/kg/day (n = 61)	9.7 (4.7) [2.5–18.0]	35 (57)	[12.4: 3.9–1717]^b	4.6 (4.3)	3.0 (1.0)	Change from baseline MCSF
			Placebo (n = 59)	9.8 (4.8) [2.3–18.4]	27 (46)	[14.9: 3.7–718]^c	4.6 (3.3)	2.9 (1.0)
Miller [44] GWPCARE2 (NCT02224703), Europe, USA and Australia	Phase III, double-blind, multinational placebo controlled, RCT	Patients with DS (2–18 years) with seizures not controlled with current AEDs	CBD 10 mg/kg/day (n = 66)	9.2 (4.3) [2.3–17.7]	27 (41)	[14: IQR 6–31]^c	[4: 0–19]	[3: 1–5]	Change from baseline MCSF
			CBD 20 mg/kg/day (n = 67)	9.3 (4.3) [2.2–18.9]	36 (54)	[9: IQR: 6–21]^c	[4: 0–11]	[3: 1–4]
			Placebo (n = 65)	9.6 (4.6) [2.2–18.1]	31 (48)	[17: IQR: 7–51.1]^c	[4: 0–11]	[3: 1–5]
Fenfluramine
Lagae [47] NCT02682927 USA and Canada and NCT02826863 Europe and Australia FFA Study 1	Identical phase III, multinational, double-blind, placebo controlled, RCTs	Patients (2–18 years) with DS with seizures not completely controlled by current AEDs and other therapies.	FFA 0.7 mg/kg/day (n = 40)	8.8 (4.4) [2–18]	21 (52)	31.4 (30.6) [20.7: 4.8–124]^c	NR	2.3 (0.9)	Change from baseline MCSF (FFA 0.7 mg/kg per day vs placebo)
			FFA 0.2 mg/kg/day (n = 39)	9.0 (4.5) [2–17]	22 (56)	45.5 (99.8) [17.5: 4.7–623.5]^c	NR	2.5 (1.1)
			Placebo (n = 40)	9.2 (5.1) [2–18]	21 (52)	44.2 (40.2) [27.3: 3.3–147.3]^c	NR	2.5 (0.9)
Nabbout [48] NCT02926898, Europe, USA and Canada FFA Study ZX008-1504	Phase III, double-blind, multinational placebo controlled, RCT	Patients with DS (2–18 years) with seizures poorly controlled with current AEDs, including STP+CLB or VPA	FFA 0.4 mg/kg/day (n = 43)	8.8 (4.6) [2–18]	23 (53)	27.9 (36.9) [14.0: 3–213]^c	NR	NR (2 = 2%; 3 = 44%; 4 = 37%; 5 = 16%)	Change from baseline in MCSF vs placebo
			Placebo (n = 44)	9.4 (5.1) [2–19]	27 (61)	21.6 (27.6) [10.7: 3–163]^c	NR	NR (2 = 2%; 3 = 59%; 4 = 36%; 5 = 2%)

^aIn STICLO France and Italy, patients were being treated with VPA and CLB [29–32]. In GWPCARE1 part B the most common AEDs at baseline were CLB (65%), VPA (59%), STP (42%), levetiracetam (28%), and topiramate (26%) [43]. In GWPCARE2 the most common concomitant AEDs were VPA (70.2%), CLB (63.6%), STP (36%), levetiracetam (27%), and topiramate (23%) [44]. In FFA Study 1, the most common AEDs at baseline included VPA (60%), CLB (59%), topiramate (25%), and levetiracetam (22%); 49% patients had previously been treated with STP and 26% with CBD [47]. In FFA Study ZX008-1504, as per protocol, all patients had and continued to be treated with STP; other concomitant AEDs included CLB (94%), VPA (89%), topiramate (24%) and levetiracetam (13%) [48]. ^b Responder is defined as a patient with a greater than 50% decrease in frequency of generalized tonic-clonic or clonic seizures; ^c Convulsive seizures.

AEDs, antiepileptic drug regimens, CBD, cannabidiol; CLB, clobazam, DS, Dravet syndrome; FFA, fenfluramine; IQR, inter-quartile range; MCSF, monthly convulsive seizure frequency; NR, not reported; SD, standard deviation; STP, stiripentol; SMEI, severe myoclonic epilepsy in infants; VPA, valproic acid.

Table 2. Efficacy in the pivotal phase III studies for the treatment of Dravet syndrome

		Percentage change in MCSF	Difference from placebo in MCSF	≥50% reduction in MCSF from baseline, n (%)		Percentage change in total seizure frequency		Seizure free patients
Study: Treatment period/follow-up	Study arms	Median (range)	Median (95% CI); p value	n (%) [95% CI]	OR (95% CI; p value	Median (range); p value	Change from placebo (95% CI); p value	n (%) [95% CI]; p value
Stiripentol
Chiron [29–31] STICLO-France 2-month (8 week) treatment period	STP (+CLB+VPA) (n = 21)	Mean (SD): −69 (42) Median (range): −91 (−100 to 28)^a	0.0002	15 (71) [52.1 to 90.7]	p < 0.0001	NR	NR	9 (43) [21.9 to 65.9]; p = 0.0013
	Placebo (+CLB+VPA) (n = 20)	Mean (SD): 7.6 (38) Median (range): 7.4 (−75 to 65)	-	1 (5) [0 to 14.6]	-	NR	NR	0 [0.0 to 13.9]
STICLO-Italy [29,31] 2-month (8 week) treatment period	STP(+CLB+VPA) (n = 12)	Mean (SD): -74 (27) Median (range): −81 (−100 to −33)^a	0.0056	8 (66.7) [34.9 to 90.2]	p = 0.0094	NR	NR	3/11 (27); p = 0.05
	Placebo (+CLB+VPA) (n = 11)	Mean (SD): −13 (62) Median (range) -27 (−87 to 140)	-	1 (9.1) [0.0 to 41.3]	-	NR	NR	0/9 (0)
Cannabidiol
Devinsky [43] GWPCARE1 part B; GWEP1332B NCT02091375 14-week treatment period	CBD 20 mg/kg/day (n = 61)	−38.9 (−100 to 337)	−22.8 (−41.1 to −5.4); p = 0.01	26 (43)	2.00 (0.93 to 4.30); p = 0.08	−28.6	−19.20 (−39.25 to −1.17); p = 0.03	3 (5); p = 0.08
	Placebo (n = 59)	−13.3 (−91.5 to 230)	-	16 (27)	-	−9.0	-	0
	CBD 20 mg/kg/day + CLB subgroup (n = 40)	53.6	42.8 (17.4 to 60.4) p = 0.0032	19 (47.5)	p = 0.0382	NR^b	NR	NR
	Placebo + CLB subgroup (n = 38)	18.9		9 (23.7)	-	NR	NR	NR
Miller [44] GWPCARE2/GWEP1424/NCT02224703 14-week treatment period	CBD 10 mg/kg/day (n = 66)	−48.7	29.8 (8.4 to 46.2); p = 0.01	29 (43.9)	2.21 (1.06 to 4.62); p = 0.03	56.4;	38.0 (20.1 to 51.9); p < 0.001	2
	CBD 20 mg/kg/day (n = 67)	−45.7	25.7 (32.9 to 43.2); p = 0.03	33 (49.3)	2.74 (1.32 to 5.70); p = 0.007	47.3	25.1 (3.5 to 41.9); p = 0.03	2
	Placebo (n = 65)	−26.9	-	17 (26.2)	-	29.7	-	1
	CBD 10 mg/kg/day + CLB subgroup (n = 45)	60.9	37.4 (13.9 to 54.5); p = 0.0042	25 (55.6)	p = 0.0623	NR^b	NR	NR
	CBD 20 mg/kg/day + CLB subgroup (n = 40)	56.8	30.8 (3.6, 50.4); p = 0.0297	25 (62.5)	p = 0.0130	NR	NR	NR
	Placebo (n = 65) + CLB subgroup (n = 41)	37.6	-	15 (36.6)	-	NR	NR	NR
Fenfluramine
Lagae [47] NCT02682927 NCT02826863 FFA Study 1 14-week treatment period	FFA 0.7 mg/kg/day (n = 40)	−74.9 (−100 to 196.4); p < 0.0001	−62.3 (−47.7 to −72.8); p < 0.0001	27 (68)	15.0 (4.5 to 50.0); p < 0.0001	−68.3 (−100 to 35.6)	p < 0.0001	3 (8) (≤1 convulsive seizure: 10 (25))
	FFA 0.2 mg/kg/day (n = 39)	−42.3 (−100 to 197.6); p = 0.2035	−32.4 (−6.2 to −51.3); p = 0.0209	15 (38)	4.8 (1.5 to 15.0); p = 0.0091	−41.1 (−100 to 292);	p = 0.0202	3 (8) (≤1 convulsive seizure: 5 (12.8))
	Placebo (n = 40)	−19.2 (−76.1 to 51.8)	-	5 (12)	-	−16.2 (−77.6 to 601)	-	0 (≤1 convulsive seizure: 0)
Nabbout [48] NCT02926898 FFA Study ZX008-1504 Combined titration (3 weeks) and maintenance period (12 weeks)	FFA 0.4 mg/kg/day (n = 43)	63.1 (−100.0 to 115.0); p < 0.001	−54.0 (35.6–67.2; p < 0.001	23 (54)	26.0 (5.5–123.2); p < 0.001	−41.1 (−100.0 to 133.2)	p = 0.003	1 (2) [0.1–12.3]; p = 0.49 (≤1convulsive seizure: 5 (12) [3.9–25.1]; p = 0.03)
	Placebo (n = 44)	1.1 (−82.8% – 435.1%)	-	2 (5)	-	−5.9 (−73.8 to 375.6)	-	0 (0) [0.0–8.0] (≤1convulsive seizure: 0 (0) [0.0–8.0])

^aFrequency of generalized tonic-clonic or clonic seizures during month 2

^bThe SmPC for CBD reported that in a subgroup of patients treated with concomitant CLB patients receiving CBD experienced a greater percentage reduction in total seizures compared with placebo (66% 10 mg/kg/day, 54% to 58% 20 mg/kg/day, 27% to 41% placebo; p = 0.0003 for 10 mg/kg/day and p = 0.0341 and 0.0211 for 20 mg/kg/day vs. placebo) [42].

CBD, cannabidiol; CI, confidence interval; FFA, fenfluramine; MCSF, monthly convulsive seizure frequency; NR, not reported; OR, odds ratio; STP, stiripentol.

Figure 2. Treatment-emergent adverse events occurring in ≥10% patients in the pivotal Dravet syndrome phase III trials

Footnote: CBD10 and 20, cannabidiol 10, and 20 mg/kg per day; CI, confidence interval; FFA0.2, 0.4 and 0.7, fenfluramine 0.2, 0.4, and 0.7 mg/kg per day; PBO, placebo; STP, stiripentol.

Figure 3. Drug interactions with stiripentol, cannabidiol and fenfluramine

Footnote: From [29,34,41,42,49,57,58]: CLB, clobazam; PK, pharmacokinetic; VPA, valproic acid.

Table 3. Additional secondary efficacy outcomes in pivotal phase III studies

		Percentage change in nonconvulsive seizure frequency per 28 days		Seizure-free days	Seizure free interval		CGIC
Study: Treatment period/follow-up	Study arms	Median (range); p value	Change from placebo (95% CI); p value	N; p value	Median (range)	Treatment differences vs placebo, median (95% CI)	Very much or much improved	Any improvement
Stiripentol
Chiron (2000) STICLO-France 2-month (8 week) treatment period	STP(+CLB+VPA) (n = 21)	NR	NR	NR	NR	NR	NR	NR
	Placebo (+CLB+VPA) (n = 20)	NR	NR	NR	NR	NR	NR	NR
STICLO-Italy 2-month (8 week) treatment period	STP(+CLB+VPA) (n = 12)	NR	NR	NR	NR	NR	NR	NR
	Placebo (+CLB+VPA) (n = 11)	NR	-	NR	NR	NR	NR	NR
Cannabidiol
Devinsky (2017) GWPCARE1 part B; GWEP1332B NCT02091375 14-week treatment period	CBD20 mg/kg/day (n = 61)	NR	0.00 (−21.36 to 31.59); 0.88	NR^a	NR	NR	NR	Parent/caregiver rating: 37/60 (62); p = 0.02^b
	Placebo (n = 59)	NR	-	NR	NR	NR	NR	Parent/caregiver rating: 20/58 (34)
Miller (2020) GWPCARE2/GWEP1424/NCT02224703 14-week treatment period	CBD 10 mg/kg/day (n = 66)	NR	40.7 (12.4 to 59.9)	NR^a	NR	NR	Parent/caregiver rating: 21/66 (32)	Parent/caregiver rating: 45/66 (68.2); p < 0.001^b
	CBD 20 mg/kg/day (n = 67)	NR	20.6 (−18.1 to 46.6)	NR	NR	NR	Parent/caregiver rating: 24/66 (36)	Parent/caregiver rating: 40/66 (60.6); p = 0.03
	Placebo (n = 65)	NR	-	NR	NR	NR	Parent/caregiver rating: 9/65 (14)	Parent/caregiver rating: 27/65 (41.5)
Fenfluramine
Lagae (2020) NCT02682927 NCT02826863 FFA Study 1 14-week treatment period	FFA 0.7 mg/kg/day (n = 40)	−76.0 (−100 to 69.2); p = 0.0458 ^c	NR	NR	25.0 (2 to 97)	15.5 (6 to 25); p = 0.0001	Parent/caregiver rating: 22 (55); p < 0.0001 Investigator rating: 25 (62); p < 0.0001	NR
	FFA 0.2 mg/kg/day (n = 39)	−50.6 (−100 to 534); p = 0.7585 ^c	NR	NR	15 (3 to 106)	4.5 (0 to 9); p = 0.0352	Parent/caregiver rating: 16 (41); p = 0.0036 Investigator rating: 16 (41); p = 0.0032	NR
	Placebo (n = 40)	−55.6 (−100 to 723.6)^c	NR	NR	9.5 (2 to 23)	-	Parent/caregiver rating: 4 (10) Investigator rating: 4 (10)	NR
Nabbout (2019) NCT02926898 FFA Study ZX008-1504 Combined titration (3 weeks) and maintenance period (12 weeks)	FFA 0.4 mg/kg/day (n = 43)	−0.5 (−100.0 to 611.2); p = 0.18	NR	24.4 [1.9–28.0]; p = 0.001	22.0 (3.0–105.0)	NR; p = 0.004	Parent/caregiver rating: 14 (33); p = 0.14 Investigator rating: 19 (44); p = 0.008	Parent/caregiver rating: 26 (61); p = 0.009 Investigator rating: 31 (72); p < 0.001
	Placebo (n = 44)	−49.7 (−100.0 to 529.4)	NR	20.3 [0.0–26.4]	13.0 (1.0–40.0)	-	Parent/caregiver rating: 9 (21) Investigator rating: 7 (16)	Parent/caregiver rating: 16 (36) Investigator rating: 14 (32)

^aThe SmPC for CBD reported that in a subgroup of patients treated with concomitant CLB, CBD was associated with an increase in the number of convulsive seizure-free days during the treatment period in each trial, equivalent to 2.7 days per 28 days (10 mg/kg/day) and 1.3 to 2.2 days per 28 days (20 mg/kg/day).

^bThe SmPC for CBD reported that in a subgroup of patients treated with concomitant CLB greater improvements in overall condition were reported by caregivers and patients with both doses of cannabidiol (73% on 10 mg/kg/day, 62 to 77% on 20 mg/kg/day, 30% to 41% on placebo; p = 0.0009 for 10 mg/kg/day

and p = 0.0018 and 0.0136 for 20 mg/kg/day vs. placebo).

^cOther seizure types, which included focal seizures without clearly observable motor signs, absence or atypical absence, myoclonic, atonic, and other or unclassifiable

CGIC, Caregiver Global Impression of Change; CBD, cannabidiol; CI, confidence interval; FFA, fenfluramine; NR, not reported; NS, non-significant; OR, odds ratio

Figure 4. Current and potential future treatment pathway in Dravet syndrome

Footnote: Adapted from Wirrel et al 2017 [3]; Wirrel and Nabbout 2019 [22] and Cross et al. 2019 [19]The current treatment strategy is based on the recommendations from the North American consensus panel [3], however not all therapies are available in all regions^aAgreed upon by strong consensus; ^bAgreed upon by moderate consensus; ^cNot approved for use in all jurisdictions; ^dKetogenic diet is not suitable for all patients, its use is not required before moving to third-line therapies; ^e No consensus, however, of note bromide was the second most commonly used AED in a real-world study in Germany commonly used in second-line, whereas levetiracetam (strong consensus) was rarely prescribed [21]; the efficacy of bromide has also been demonstrated in other studies [95–97]AEDs, antiepileptic drugs; CLB, clobazam; STP, stiripentol; VNS, vagus nerve stimulation; VPA, valproic acid.

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