Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as TAK-935, TAK-935 Oral Tablet, OV935
Soticlestat · 8 trials · 10 indications
MMD seizure frequency per 28 days was defined as the total number of MMD seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the full Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
MMD seizure frequency per 28 days was defined as the total number of MMD seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
Convulsive seizure frequency per 28 days was defined as the total number of convulsive seizures reported during the period divided by the number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during the Full Treatment Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
Convulsive seizure frequency per 28 days was defined as the total number of convulsive seizures reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline was defined as (frequency of seizures per 28 days during Maintenance Period - frequency of seizures per 28 days at Baseline) divided by the frequency of seizures per 28 days at Baseline multiplied by 100.
The 24-hour average pain intensity was calculated from current pain intensity scores collected three times a day as measured by the electronic pain diary daily using NPS. NPS is an 11-point scale, where scores range from 0-10, 0= no pain to 10 = most pain imaginable. Negative change from Baseline indicated improvement.
Seizure frequency per 28 days is defined as total number of Seizures reported during the period divided by number of days with no missing seizure count during the period multiplied by 28. Percent Change from Baseline is defined as (frequency of seizures per 28 days during maintenance period - frequency of seizures per 28 days at Baseline) divided by frequency of seizures per 28 days at Baseline multiplied by 100. Positive percent change from Baseline indicates seizure increase and negative percent change from Baseline indicates seizure decrease.
Seizure frequency per 28 days is defined as total number of seizures (convulsive seizures for DS, drop seizures for LGS) reported during the period divided by number of days during the period seizures were assessed multiplied by 28. Percent change from Baseline is defined as (frequency of seizures per 28 days during maintenance period - frequency of seizures per 28 days at baseline) divided by frequency of seizures per 28 days at baseline multiplied by 100. Negative percent change from Baseline indicates improvement.
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug
CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: total volume of distribution \[VT\] (Baseline) - VT (Day 1) = Occupancy (Day 1) \* (VT \[Baseline\] - non-displaceable volume of distribution \[VND\]), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept. Data was reported only for TAK-935 600 mg because only first two participants were analyzed at 45 minutes post-TAK-935 dose.
CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) \* (VT \[Baseline\] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept.
CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) \* (VT \[Baseline\] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept. Data was reported only for TAK-935 600 mg because only first two participants were analyzed at 10 hour post-TAK-935 dose.
CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) \* (VT \[Baseline\] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept.
| Arm | Type | Description |
|---|---|---|
| Placebo | PLACEBO_COMPARATOR | Soticlestat placebo-matching mini-tablets or tablets, orally or via G-tube or MIC-KEY button or J-tube, BID, up to 4 weeks during titration. Participants continued to receive soticlestat placebo-matching mini-tablets or tablets for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period). Soticlestat matching tapering was done to maintain the blind if participants decided to discontinue the treatment. |
| Soticlestat | EXPERIMENTAL | Participants weighing \<45 kg: Soticlestat, mini-tablets, at the dose of 40 mg to 200 mg, orally or via G-tube or MIC-KEY button or J-tube, BID based on body weight up to 4 weeks during titration. Participants continued to receive the dose that they were on at the end of the titration, for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with the dose tapered down if participants decided to discontinue the treatment. Participants weighing ≥45 kg: Soticlestat mini-tablets or tablets with a starting dose of 100 mg BID followed by 200 mg BID and, then 300 mg BID, up to 4 weeks during titration. Participants continued to receive 300 mg BID for 12 weeks during maintenance. The total duration of the treatment was up to 16 weeks (Full Treatment Period) with the dose tapered down if participants decided to discontinue the treatment. |
| Double-Blind Treatment Period - Part A: Placebo | PLACEBO_COMPARATOR | Soticlestat matching placebo tablets, orally, twice daily (BID) for Weeks 1, 2 and 3 in Double blind Titration Period. Soticlestat matching placebo tablets, orally BID for 12 weeks in Double blind Maintenance Period. Taper period (if participant did not continue to Part B): Dose of soticlestat matching placebo tablets was reduced to next lower dose every 3 days (maximum 6 days) until discontinuation. |
| Double-Blind Treatment Period - Part A: Soticlestat | EXPERIMENTAL | Soticlestat, tablet, orally, 100 mg BID for Week 1, followed by 2×100 mg tablets, soticlestat, orally BID for Week 2, further followed by 3×100 mg tablets, soticlestat, orally BID for Week 3. Dose was uptitrated every week based on safety and tolerability. Part A (Double blind Maintenance Period): 3×100 mg tablets, soticlestat, orally BID for 12 weeks. Dose was adjusted during Maintenance Period due to safety and tolerability. Taper Period (if participant did not continue to Part B): Dose of soticlestat was reduced to next lower dose every 3 days (maximum 6 days) until soticlestat was discontinued. |
| Open-Label Extension Period - Part B: Soticlestat | EXPERIMENTAL | Soticlestat, 2×100 mg tablets, orally, BID for Week 1, followed by 3×100 mg tablets, soticlestat, orally, BID for Week 2. Dose was uptitrated every week based on safety and tolerability. Part B (Open label extension: Maintenance Period): 3×100 mg tablets, soticlestat, orally, BID for 12 weeks. Dose was adjusted during Maintenance Period due to safety and tolerability. Taper Period: Dose of soticlestat was reduced to next lower dose every 3 days (maximum 6 days) until soticlestat was discontinued. |
| Soticlestat Dup 15q | EXPERIMENTAL | Soticlestat tablets twice daily (BID) orally or via gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, BID. Participants with Dup 15q weighing \<60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. |
| Soticlestat CDD | EXPERIMENTAL | Soticlestat tablets BID orally or via G-tube/ PEG tube, BID. Participants with CDD weighing \<60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. |
| TAK-935 | EXPERIMENTAL | TAK-935 tablets orally or via G-tube/PEG tube, BID. Participants weighing \<60 kg received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. |
| Part 1: Placebo | PLACEBO_COMPARATOR | TAK-935 matching-placebo tablets, orally or through gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, twice daily (BID) from Days 1 to 30 in dose titration period. |
| Part 1: TAK-935 | EXPERIMENTAL | TAK-935 100 mg, tablet, orally or through G-tube/PEG tube, BID from Days 1 to 10 followed by TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID from Days 11 to 20 followed by TAK-935 100 mg tablets x3, orally or through G-tube/PEG tube, BID from Days 21 to 30 in dose titration period. The dose of TAK-935 was escalated or de-escalated during Part 1 as per investigator's discretion. |
| Part 2: TAK-935 | EXPERIMENTAL | TAK-935 100 mg tablets x2, orally or through G-tube/PEG tube, BID from Days 31 to 40 followed by TAK-935 100 mg tablets x1, x2 or x3, orally or through G-tube/PEG tube, BID from Days 31 to Day 85 as per investigator's discretion in the maintenance period. At the end of Part 2, the dose of TAK-935 was de-escalated until discontinuation. |
| Part 1, Cohort 1: TAK-935 100 mg QD | EXPERIMENTAL | TAK-935 100 milligram (mg), solution, orally, once daily (QD) or TAK-935 placebo-matching solution, orally, QD for up to 14 days. |
| Part 1, Cohort 2: TAK-935 300 mg QD | EXPERIMENTAL | TAK-935 300 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days. |
| Part 1, Cohort 3: TAK-935 300 mg BID | EXPERIMENTAL | TAK-935 300 mg, solution, orally, twice daily (BID) or TAK-935 placebo-matching solution, orally, BID for up to 10 days. |
| Part 1, Cohort 4: TAK-935 600 mg QD | EXPERIMENTAL | TAK-935 600 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 10 days. |
| Part 1, Cohort 5: TAK-935 400 mg QD | EXPERIMENTAL | TAK-935 400 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days. |
| Part 2, Cohort 6: TAK-935 Dose 1 | EXPERIMENTAL | TAK-935 first decided dose as determined from other TAK-935 trials and Cohorts 1 to 4 of Part 1, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days. |
| Part 2, Cohort 7: TAK-935 Dose 2 | EXPERIMENTAL | TAK-935 second decided dose as determined from other TAK-935 trials and Cohorts 1 to 4 of Part 1, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days. |
| Name | Type | Description |
|---|---|---|
| Placebo | DRUG | Soticlestat placebo-matching mini-tablets or tablets. |
| Soticlestat | DRUG | Soticlestat mini-tablets or tablets. |
| TAK-935 | DRUG | TAK-935 tablets or mini-tablets. |
| [18F]MNI-792 (tracer) | DRUG | \[18F\]MNI-792 injection. |
Inclusion Criteria: 1. Has documented clinical diagnosis of LGS. 2. Has had ≥8 MMD seizures each month in the 3 months prior to Screening based on the historical information and has had ≥8 MMD seizures per 28 days during the 4 to 6 week prospective Baseline Period. 3. Weighs ≥10 kg at the Screening...
Soticlestat is an investigational small molecule developed by Takeda Pharmaceutical Company Limited for rare disease indications. It has been studied as an add-on therapy in Dravet syndrome, Lennox-Gastaut syndrome, 15q duplication syndrome, and complex regional pain syndrome. It is also known as soticlestat 300 mg and was previously coded TAK-935.
Soticlestat has been studied as an add-on therapy for Dravet syndrome and Lennox-Gastaut syndrome, two severe childhood-onset epilepsies. It has also been evaluated in 15q duplication syndrome and in adults with complex regional pain syndrome. These programs are investigational and the drug is not approved for these uses.
Soticlestat targets CYP46A1, also known as cholesterol 24-hydroxylase, and acts as an inhibitor of that enzyme. CYP46A1 converts cholesterol into 24S-hydroxycholesterol in the brain, so inhibiting it modulates this pathway. This mechanism underlies its development as a treatment for seizure disorders and other neurological conditions.
Soticlestat is developed by Takeda Pharmaceutical Company Limited, which trades on the New York Stock Exchange under the ticker TAK. Takeda holds the soticlestat program, including the Dravet syndrome, Lennox-Gastaut syndrome, 15q duplication syndrome, and complex regional pain syndrome studies.
Soticlestat is investigational and remains in clinical development. Its Phase 3 trials in Dravet syndrome and Lennox-Gastaut syndrome have completed, and Phase 2 studies in 15q duplication syndrome and complex regional pain syndrome have also completed. It is not approved by the FDA for any indication.
Completed soticlestat trials include NCT04940624, a Phase 3 add-on therapy study in children and young adults with Dravet syndrome, and NCT04938427, a Phase 3 add-on study in Lennox-Gastaut syndrome. Phase 2 studies include NCT03990649 in complex regional pain syndrome and NCT03694275, the open-label ARCADE study in 15q duplication syndrome and CDKL5 deficiency disorder.