Approval Probability
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Risdiplam · 11 trials · 4 indications
The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor Scale is a commonly used measure of infant and toddler development (0 to 42 months). The normed-scores derived from the BSID-III are used in clinical practice to detect infants with developmental delays, as well as to evaluate developmental progress and the impact of therapeutic interventions. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22, "sits without support for 5 seconds", is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. An exact binomial test was performed. If the lower limit of the two-sided 90% CI was above the 5% threshold, the primary objective of the study was considered achieved.
An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Participants who discontinued treatment due to AEs are reported here.
Tanner staging of sexual development is a scale used to assess physical maturation as children transition through adolescence into adulthood. Scale defines physical development based on the following characteristics: pubic hair, penis, and testes development in boys; and pubic hair and breast development in girls. It consists of 5 stages, Stage I (prepubertal) to Stage V (mature adult). Participants under 9 years at screening began Tanner staging assessments at 1st visit following their 9th birthday. Tanner data are presented in three categories: Normal (expected stage of puberty based on participant's age at post-baseline visit), Delayed (pubertal development is behind expectations for age at post-baseline visit), \& Missing (participant did not attend scheduled visit). Tanner staging assessments were scheduled for participants aged 9-17 years but were also conducted in some older participants, up to age 22. Shift in puberty status from baseline to each week has been represented here.
Neurological examination was performed by asking questions to the participants and/or their caregiver, as well as observing the participants' behavior in general and while performing certain tasks. Questions and tasks were adapted to the age and motor ability of the participant. For very young participants, observing reaction to a sound, speech development, shifting attention to a newly introduced toy, observing the participant interact with the parent/caregiver \& for older participants examination of social interaction (school, friends, activities, job as appropriate), memory (e.g., with short word recall), reasoning \& language, drawing, etc. Participants with neurological conditions besides those expected with SMA and those expected with SMA are reported.
C-SSRS was used to assess the lifetime suicidality of a participant (baseline) as well as any new instances of suicidality (since last visit). The interview prompts recollection of suicidal ideation (SI), including the intensity of the ideation, behavior and attempts with actual/potential lethality. A modified and reduced version (pediatric version) was used for children (aged 6-11 years). Categories have binary responses (yes/no) \& include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active SI with Any Methods (Not Plan) without Intent to Act; Active SI with Some Intent to Act, without Specific Plan; Active SI with Specific Plan \& Intent, Preparatory Acts \& Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. SI or behavior is indicated by a "yes" answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. A score of 1 or higher indicates SI or behavior.
Weight was measured at baseline, Weeks 65, 91, and every 13 weeks thereafter for participants 2-17 years and at every visit for participants \<2 years. Per protocol, height was not measured at Day 7, Weeks 8, 17, 35, and thus not collected for all participants. No participants in the RO6885247 arm attended the Weeks 65, 169, 195, and 247 visit; none in the AVXS-101 arm attended the Week 247 visit. Symptom-directed height/weight assessments were done at clinically indicated visits as needed.
Height of all participants able to stand was measured while standing using a stadiometer, with at least 3 independent measurements, which were averaged. Participants unable to stand during the measurement, height was derived from measurement of ulna length. For very young children, height was measured with child in a lying position using an inflexible length board with fixed headboard \& movable footboard. Height was measured: baseline, Weeks 13,39,52,78 \& 104 for participants 2-17 years; Weeks 52 \& 104 for \>17 years \& every visit for participants \<2 years. After Week 104, measurements occurred every 26 weeks. Per protocol, height was not measured at Weeks 2,4,17,26,35,43,61,65,87,91,96,117,143,169,195,221 \&247 \& thus not collected for all participants. No participants \<17 years in RO6885247, Olesoxime, or AVXS-101 arms attended the Week 260 visit \& no participants in RO6885247 arm attended Week 39. Symptom-directed height assessments were done at clinically indicated visits as needed.
Head circumference for participants aged \< 5 years was measured to the nearest 0.1 cm using a flexible, non-stretchable tape. Head circumference was measured around the widest part of the head from the most prominent point on the back of the head (occiput) to the most prominent part of the forehead between the eyebrows. The measurement was repeated three times, and the largest measurement was recorded. Head circumference was assessed for participants \< 5 years of age. Since all participants in the RO6885247 and Olesoxime arms were \> 5 years, data were not collected for these arms. Head circumference was not collected at Weeks 35 and 61 (AVXS-101 arm) and Weeks 87, 182, and 208 (Nusinersen arm) because the protocol only required this measurement for participants \< 5 years of age. At these timepoints, neither of the participants \< 5 years attended the visit, and other participants may have been \> 5 years of age.
As pre-specified in the protocol, the PK data were not to be compared between participants who received different prior treatments (RO6885247, nusinersen, olesoxime and AVXS-101) received before entering this study, but to analyze the PK parameters of risdiplam. Hence, PK data have been presented in a single arm group irrespective of prior therapies received by the participants in previous studies.
As pre-specified in the protocol, the PK data were not to be compared between participants who received different prior treatments (RO6885247, nusinersen, olesoxime and AVXS-101) received before entering this study, but to analyze the PK parameters of risdiplam. Hence, PK data have been presented in a single arm group irrespective of prior therapies received by the participants in previous studies.
As pre-specified in the protocol, the PK data were not to be compared between participants who received different prior treatments (RO6885247, nusinersen, olesoxime and AVXS-101) received before entering this study, but to analyze the PK parameters of risdiplam. Hence, PK data have been presented in a single arm group irrespective of prior therapies received by the participants in previous studies.
All safety, tolerability, PK and PD data available up to the clinical cut-off date of 5 January 2018, plus data that became available prior to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The IMC was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng\*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
The Motor Function Measure 32 (MFM32) is a scale constructed for use in neuromuscular disorders. It comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and "normally". The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on primary efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for pharmacokinetic (PK) analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
In Part 2 of the study, all study participants received a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day once daily (QD) treatment period with risdiplam began, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam). The following treatment sequence was used in Part 2 of the study: Day 1: 2 mg midazolam; Days 3 to 14: 8 mg risdiplam QD; Day 15: 2 mg midazolam and 8 mg risdiplam QD; Day 16: 8 mg risdiplam QD. Blood samples for PK analysis were taken at defined timepoints on Day 1 for midazolam administered alone and on Day 15 for midazolam administered in combination with risdiplam.
| Arm | Type | Description |
|---|---|---|
| Risdiplam | EXPERIMENTAL | Participants will receive risdiplam once daily for 28 days. |
| Open-label Risdiplam | EXPERIMENTAL | Participants will be enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range. |
| Part 1 (Dose Finding): Risdiplam (RO7034067) | EXPERIMENTAL | Participants will receive multiple ascending doses of risdiplam (RO7034067), administered orally once daily for a minimum of 4 weeks to select the dose for Part 2. During the first year of treatment, most participants will switch to the Part 2 dose. During the second year of treatment, all Part 1 participants will be receiving the Part 2 dose. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose. |
| Part 2 (Confirmatory): Risdiplam (RO7034067) | EXPERIMENTAL | Participants will receive risdiplam (RO7034067), administered orally once daily at the dose defined in Part 1 of the study, for a duration of 24 months. They will thereafter enter a 3-year open-label extension phase and continue to receive risdiplam at the same dose. |
| Part 1 Group A: Adolescents and Adults (Risdiplam) | EXPERIMENTAL | Adolescent and adult participants aged 12-25 years will receive risdiplam for at least 12 weeks. Once the placebo-controlled period is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase. |
| Part 1 Group A: Adolescents and Adults (Placebo) | PLACEBO_COMPARATOR | Adolescent and adult participants aged 12-25 years will receive placebo matching to risdiplam for at least 12 weeks. Once placebo-controlled period is completed, participants will be first switched to their cohort risdiplam dose. After the Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase. |
| Part 1 Group B: Children (Placebo) | PLACEBO_COMPARATOR | Children aged 2-11 years will receive placebo matching to risdiplam for at least 12 weeks. Once placebo-controlled period is completed, participants will be first switched to their cohort risdiplam dose. After the Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase. |
| Part 1 Group B: Children (Risdiplam) | EXPERIMENTAL | Children aged 2-11 years will receive risdiplam for at least 12 weeks. Once the placebo-controlled period is completed and Part 2 dose is selected, participants will be switched to Part 2 dose and will be treated in an open-label phase. |
| Part 2: Placebo | PLACEBO_COMPARATOR | Participants aged 2-25 years will receive placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants will be switched to risdiplam (5 mg once daily for participants with a body weight (BW) \>/=20kg or 0.25 mg/kg for participants with a BW \<20) in a blinded manner and participants will continue with treatment until Month 24. After Month 24, participants will be offered the opportunity to enter the open-label phase. |
| Part 2: Risdiplam | EXPERIMENTAL | Participants aged 2-25 years will receive risdiplam at the dose selected based on the results from Part 1 of the study (5 mg once daily for participants with a body weight (BW) \>/=20kg or 0.25 mg/kg for participants with a BW \<20 kg), for 24 months. After 24-month treatment, participants will be offered the opportunity to enter the open-label phase. |
| Part 1 | EXPERIMENTAL | Cohort A+B: participants will receive, in a five-period crossover way, a single oral dose of risdiplam oral solution 5 mg in fasted state and thereafter risdiplam/F21 or F22 dispersible tablet 5 mg as tablet in fasted and fed states; tablet dispersed in water in fasted and fed states, with a 14-day wash-out period in between the single-dose administrations. Cohort C+D: participants will receive, in a two-period fixed sequence design, a single dose of risdiplam/F21 or F22 dispersible tablet 5 mg in fasted state and omeprazole 40 mg once daily for 7 days + a single dose of risdiplam/F21 or F22 dispersible tablet 5 mg in fasted state, on the 7th day of omeprazole. There will be a 14-day wash-out between the two treatment periods. Cohort E: participants will receive, in a two-period crossover design, a single oral dose of risdiplam oral solution 5 mg in fasted and fed states, with a 14-day wash-out period in between the single-dose administrations. |
| Part 2 (optional) | EXPERIMENTAL | Group 1: participants will receive, in four-period crossover design, a single oral dose of risdiplam oral solution 5 mg in both fed and fasted states and the selected dispersible tablet (F21) as swallowed tablet in both fed and fasted states. Group 2: participants will receive, in four-period crossover design, a single oral dose of risdiplam oral solution 5 mg in both fed and fasted states and the selected dispersible tablet (F21) as tablet dispersed in water in both fed and fasted states. |
| Part 3 (optional) | EXPERIMENTAL | Group 1: participants will receive, in four-period crossover design, a single oral dose of risdiplam oral solution 5 mg in both fed and fasted states and the selected dispersible tablet (F22) as swallowed tablet in both fed and fasted states. Group 2: participants will receive, in four-period crossover design, a single oral dose of risdiplam oral solution 5 mg in both fed and fasted states and the selected dispersible tablet (F22) as tablet dispersed in water in both fed and fasted states. |
| Part 2 | EXPERIMENTAL | All study participants will receive a single oral dose of 2 mg midazolam on Day 1. On Day 3, the 14-day QD treatment period with risdiplam will begin. The precise dose will be based on the results of Part 1, with single dose administration of 2 mg midazolam again on Day 15 (1 hour after the thirteenth dose of risdiplam) |
| Risdiplam '2' Milligrams (mg) | EXPERIMENTAL | A single dose of 2 mg Risdiplam will be administered to all participants randomized to this arm under fasted conditions as an oral drinking solution on Day 1. |
| Risdiplam '6' mg | EXPERIMENTAL | A single dose of 6 mg Risdiplam will be administered to all participants randomized to this arm under fasted conditions as an oral drinking solution on Day 1. |
| Risdiplam '12' mg | EXPERIMENTAL | A single dose of 12 mg Risdiplam will be administered to all participants randomized to this arm under fasted conditions as an oral drinking solution on Day 1. |
| Placebo | PLACEBO_COMPARATOR | A single dose of placebo will be administered to all participants randomized to this arm under fasted conditions as an oral drinking solution on Day 1. |
| [^14C]-Risdiplam | EXPERIMENTAL | Participants will be administered with \[\^14C\]-Risdiplam solution orally under fasted conditions on Day 1. |
| Part 1: Single Ascending Dose: Placebo | PLACEBO_COMPARATOR | Participants will receive a single dose of matching placebo orally on Day 1 of Part 1. |
| Part 1: Single Ascending Dose: Risdiplam | EXPERIMENTAL | Participants will receive a single ascending dose (SAD) of Risdiplam orally on Day 1 of Part 1. |
| Part 2: Food Effect: Fasted-Fed | EXPERIMENTAL | This arm consists of two periods. In Period 1 participants will receive one oral dose of Risdiplam in the fasted state on Day 1. In Period 2 participants will receive one oral dose of Risdiplam in the fed state on Day 1. |
| Part 2: Food Effect: Fed-Fasted | EXPERIMENTAL | This arm consists of two periods. In Period 1 participants will receive one oral dose of Risdiplam in the fed state on Day 1. In Period 2 participants will receive one oral dose of Risdiplam in the fasted state on Day 1. |
| Part 3: Itraconazole Interaction | EXPERIMENTAL | In Period 1 a single oral dose of Risdiplam will be administered. After a wash-out period in Period 2 participants will be administered oral doses of itraconazole twice daily from Day 1 to Day 8. On Day 4 participants will receive a single oral dose of Risdiplam in the fed state in combination with itraconazole. |
| Name | Type | Description |
|---|---|---|
| Risdiplam | DRUG | Participants will receive 0.15 mg/kg risdiplam orally once daily for 28 days. |
| Placebo | DRUG | Placebo will be administered orally (via mouth) or through a feeding tube (naso-gastric or gastrostomy tube). |
| omeprazole | DRUG | Omeprazole will be administered orally as a capsule at a dose of 40 mg per day |
| Midazolam | DRUG | single dose administration of 2 mg midazolam |
| [^14C]-Risdiplam | DRUG | \[\^14C\]-Risdiplam 18 mg oral solution with approximately 0.75 megabecquerel MBq (20 microcuries \[μCi\]) of \[14C\]-labeled Risdiplam. |
| Itraconazole | DRUG | Itraconazole will be administered as an oral 200 mg dose twice daily from Day 1 to Day 8 in Part 3. |
Inclusion Criteria: * Male or female newborn infant aged \<20 days at first dose * Newborn infants with genetic diagnosis of 5q-autosomal recessive SMA or newborn infants identified as positive for SMA via newborn screening or via prenatal testing. * Gestational age equal to or greater than 37 week...
Risdiplam is an investigational small molecule being studied for the treatment of Spinal Muscular Atrophy (SMA). It is currently in Phase 1 clinical development and has not been approved by regulatory authorities. The drug is being evaluated in both adult and pediatric participants with SMA, as well as in healthy volunteers for safety and pharmacokinetic studies.
Risdiplam is being developed by Roche Holding AG, which trades under the ticker symbol RHHBY. The company is conducting clinical trials to evaluate the drug's safety, tolerability, and pharmacokinetics in healthy volunteers and in patients with Spinal Muscular Atrophy.
Risdiplam is currently in Phase 1 clinical development. It is an investigational drug and has not received FDA approval. The clinical program includes completed Phase 1 and Phase 2 trials, with one active Phase 1 trial ongoing, studying the drug in healthy volunteers and in patients with Spinal Muscular Atrophy.
Risdiplam has been studied in several clinical trials, including NCT02633709, a Phase 1 study in healthy volunteers; NCT03032172, a Phase 2 study in adult and pediatric participants with Spinal Muscular Atrophy; NCT03036501, a Phase 1 excretion balance study; and NCT03988907, a drug-drug interaction study. These trials have collectively enrolled 487 participants.
Yes, Risdiplam is also known as RO7034067. Clinical trial records for the drug list both names, with RO7034067 being the compound identifier used in study titles and documentation. Researchers and investors may encounter either name when reviewing the drug's clinical development program.