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An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome

An Open-Label Extension Trial to Assess the Long-Term Safety of ZX008 (Fenfluramine Hydrochloride) Oral Solution as an Adjunctive Therapy in Children and Young Adults with Dravet Syndrome

375

A total of 375 subjects were enrolled in this OLE study, 343 of them were enrolled following participation in 1 of the 3 core studies, and 32 de novo subjects were also enrolled (1 de novo subject withdrew consent prior to starting dosing with study drug). The mean (standard deviation [SD]) age of 374 subjects at the time of entry was 10.3 (6.12) years, with the majority in the 6 to 18 years age group (250 [66.8%] subjects); 202 (54.0%) were male and 172 (46.0%) were female.

Subjects enrolling from Study 1, Study 2 Cohort 2, and Study 3 were transitioned to the 0.2 mg/kg/day dose and kept on that dose for Month 1. De novo subjects and Subjects enrolling from Study 2 Cohort 1 also began the OLE Treatment Period at a dose of ZX008 0.2 mg/kg/day and kept on that dose for Month 1. Thereafter, titration to higher doses was permitted to enable each subject to reach their optimal dose, balancing effectiveness, safety and tolerability. A total of 375 subjects were enrolled in this OLE study and 374 had received >= 1 dose of ZX008. The majority of subjects (225 [60.0%]) who discontinued the OLE Treatment period early did so to transition to OLE Study 1900 and continue treatment with open-label ZX008. Forty eight (12.8%) subjects discontinued study participation due to lack of efficacy. Eleven (2.9%) subjects discontinued study participation due to a TEAE. Sixteen (4.3%) subjects withdrew from the study early due to subject's decision, 1 subject withdrew due to caregiver's decision and 2 subjects withdrew due to physician's decision. A total of 3 subjects experienced SAEs of SUDEP with fatal outcomes during the OLE treatment period.

ZX008, as assessed in final analysis for subjects in this OLE study, demonstrates it to have an acceptable safety profile and be well tolerated for the long-term treatment of seizures associated with Dravet syndrome. Most TEAEs were known AEs associated with fenfluramine, such as decreased appetite and weight loss, which are straightforward to monitor in clinical practice. No signs of cardiotoxicity were observed, consistent with other cuts of data reported from this long-term study. - A total of 3 deaths occurred during the OLE. All 3 deaths were due to sudden unexplained death in epilepsy (SUDEP) and were assessed by the Investigators as not related to the study drug. - 99 (26.5%) subjects experienced treatment-emergent SAEs during the study of which 9 (2.4%) subjects' SAEs were assessed as related to study drug. - 13 (3.5%) subjects discontinued study participation due to a TEAE. - The most common TEAEs reported for >= 10% subjects during the OLE Treatment Period included pyrexia (112 [29.9%]), nasopharyngitis (104 [27.8%]), decreased appetite (100 [26.7%]), seizure (58 [15.5%]), blood glucose deceased (89 [23.8%]), diarrhoea (73 [19.5%]), echocardiogram abnormal (limited to physiologic regurgitation 67 [17.9%]), upper respiratory tract infection (66 [17.6%]), influenza (51 [13.6%]), vomiting (39 [10.4%]), and ear infection (39 [10.4%]). - 87 (23.3%) subjects had at least 1 treatment-emergent AESI of decreased blood glucose, and 31 (8.3%) subjects had at least 1 treatment-emergent AESI of hypoglycemia. For 13 subjects, the events were assessed as related to study drug. There were no AESI reported for suicidal thoughts, ideation, or gestures during the OLE Treatment Period. - Few sporadic clinically significant abnormalities were observed in hematology, chemistry, and urinalysis parameters and measures of growth, precocious puberty, and thyroid function. - At the EOS, 30 (8.0%) subjects experienced weight loss from OLE Baseline of >= 7% and had not regained the body weight loss. This is not unexpected given the anorectic effects of fenfluramine. - No subject in this study experienced any clinically meaningful cardiovascular changes, VHD, or PAH as measured by ECGs, ECHOs, or clinical symptoms. - No trends were observed over the OLE Treatment Period to indicate alteration in physical maturation or puberty. - No negative effects on executive function were observed, as measured by the BRIEF-P, BRIEF, and BRIEF-A.

Primary Outcome Overview of number of subjects with a TEAE during the OLE treatment period (Safety population is 374 subjects) as follows; - A total of 367 (98.1%) subjects experienced at least 1 TEAE. - A total of 99 (26.5%) subjects experienced at least 1 Serious TEAE. - A total of 13 (3.5%) subjects discontinued study treatment due to a TEAE. Secondary Outcome The key effectiveness outcome was the change in CSF per 28 days between the core Baseline and OLE Treatment Period. Data from this OLE study demonstrate that the robust effect observed during the core studies was durable and long-lasting - the reduction in convulsive seizures for subjects in the open-label study was maintained throughout study participation. The median percentage change from Baseline in CSF during the overall OLE Treatment Period in the mITT Population (Endpoint 1: Day 1 to end of study [EOS]) was -66.81% (p < 0.001). The median percentage change in CSF for the OLE Month 2 to EOS (Endpoint 2: Day 31 to EOS) period was compared with that of the core study Baseline period to account for any loss of efficacy that may have occurred in subjects who down-titrated ZX008 during the transition from the core studies to Study 1503. The median percentage change in CSF for the OLE Month 2 to EOS period (-67.82% [p < 0.001]) was similar to the overall OLE Treatment Period and did not indicate better seizure control when Month 1 was removed from the calculation. The reduction in CSF was also calculated during Months 1, 2, 3, and then in 3-month periods up to Months 33 - 36. A statistically significant median percentage reduction from Baseline in CSF was observed in Month 1 and was maintained through Month 36. All secondary effectiveness outcome measures demonstrated clinically meaningful and durable improvement in seizures. The long-term effectiveness of ZX008 in reducing convulsive seizures was robust: a profound (>=75%) reduction in CSF at EOS (ie, the last visit by the cut-off date for this interim report) was observed in 39.8% of subjects. The percentage of subjects who achieved >= 25% and >= 50% reductions at EOS was 76.5% and 64.2%, respectively. 2 (0.6%) subjects were convulsive seizure-free during their entire participation, 81 days for one subject and 456 days for the second subject at the end of the study. This period takes into account a 1-month period in which subjects were required to stay on the ZX008 0.2 mg/kg/day dose. When assessing seizure freedom from Month 2 and beyond, 3 (0.9%) subjects were seizure free. A total of 276 (85.2%) subjects in the mITT Population used at least 1 rescue medication during the entire OLE Treatment Period. However, the mean (SD) number of days rescue medication was used per 28 days during the OLE Treatment Period was only 1.38 (3.145) days, and the mean number of days that rescue medication was used as subjects progressed through the OLE trended downward. Subjects on the lowest mean daily dose of ZX008 experienced a slightly greater percentage reduction in CSF than subjects on higher doses: the median percentage reduction compared with Baseline CSF was -70.17%, -64.31%, and -66.70% in the ZX008 0 to < 0.4 mg/kg/day, 0.4 to < 0.6 mg/kg/day and >= 0.6 mg/kg/day mean daily dose groups, respectively. Thus, some subjects may respond well on the lowest ZX008 dose of 0.2 mg/kg/day, while other's optimal dose may be at the highest dose of 0.8 mg/kg/day, supporting the dosing algorithm for ZX008 in which therapy is initiated at 0.2 mg/kg/day and the dose is titrated to effect based upon individual response. A statistically significant change in non-convulsive seizure frequency for the OLE Treatment Period compared with core study Baseline was observed. The median percentage change from Baseline in non-convulsive seizure frequency for the overall OLE Treatment Period (ie, Day 1 to EOS) was -84.3% (p < 0.001). Likewise, when CSF and non-convulsive seizure frequency were combined, a statistically significant change in CSF + nonconvulsive seizure frequency for the OLE Treatment Period compared with core study Baseline was observed. The median percentage change from Baseline in CSF + non-convulsive seizure frequency for the overall OLE Treatment Period (ie, Day 1 to EOS) was -64.0% (p < 0.001). In the mITT Population, 86 (26.5%) subjects had a change in antiepileptic drug medication during the first 6 months of the OLE Treatment Period.

This final report of Study 1503 strongly supports the continued, long-term clinical benefit and safety of ZX008 for the adjunctive treatment of convulsive seizures associated with Dravet syndrome. Robust and sustained, clinically meaningful reductions in seizures were accompanied by expected and manageable TEAEs, no negative effects on executive function, and no cardiovascular abnormalities. Study 1503 thus far supports the persistent profound effectiveness of ZX008 with a favorable benefit: risk profile.

Aug. 12, 2023

Oct. 19, 2020

https://onlinelibrary.wiley.com/doi/10.1111/epi.16722

Yes

Data from this trial may be requested by qualified researchers six months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal. This plan may change if the risk of re-identifying trial participants is determined to be too high after the trial is completed; in this case and to protect participants, individual patient-level data would not be made available.

https://jrct.mhlw.go.jp/latest-detail/jRCT2041200095

YAMAMOTO Hideichiro

Syneos Health Clinical K.K.

10F Umeda Daibiru, 3-3-10, Umeda, Kita-ku, Osaka

hideichiro.yamamoto@syneoshealth.com

YAMAMOTO Hideichiro

Syneos Health Clinical K.K.

10F Umeda Daibiru, 3-3-10, Umeda, Kita-ku, Osaka

+81-6-7638-6683

hideichiro.yamamoto@syneoshealth.com

Complete

Nov. 18, 2019

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

- Male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the core study Screening Visit.
- Satisfactory completion of the core study in the opinion of the investigator and the sponsor.
- A documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
- Parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.
- Subject's parent/caregiver has been compliant with diary completion during the core study, in the opinion of the investigator (eg, at least 90% compliant).

- Current or past history of cardiovascular or cerebrovascular disease, myocardial infarction or stroke.
- Current or past history of glaucoma.
- Moderate or severe hepatic impairment.
- Receiving concomitant therapy with: centrally-acting anorectic agents; monoamineoxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates.
- Currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
- A clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness at Visit 1, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.

Both

Dravet syndrome

ZX008 (Fenfluramine Hydrochloride) Oral Solution
Initial dose: 0.2mg/kg, Max daily dose: 30mg

Long-term safety and tolerability as measured by treatment emergent adverse events, including clinical labs, vital signs, and examination findings.

+81-54-245-5680

Aug. 30, 2019

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