An Open Label Study of LMI070 (Branaplam) in Type 1 Spinal Muscular Atrophy (SMA)

Study Overview
=================
Brief Summary
-----------------
An open-label, multi-part, first-in-human study of oral branaplam in infants with Type 1 spinal muscular atrophy. The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy after 13 weeks; and to estimate the Maximum Tolerated Dose (MTD) of orally administered branaplam; and to identify the dose that is safe for long term use as well as that can provide durable efficacy optimal dosing regimen in patients with Type 1 SMA.

Detailed Description
-----------------
This is an open-label, multi-part, first-in-human, proof of concept study in infants with Type 1 spinal muscular atrophy who have exactly 2 copies of SMN2, to evaluate safety, tolerability, PK, PD and efficacy of oral branaplam after 13 weeks treatment. Parts 1 and 2 are intended to be non-confirmatory. In Part 1 of the study, patients will be dosed once weekly with branaplam. The branaplam dose will be escalated in subsequent cohorts until MTD is determined or when sufficient PK results confirm that the MTD cannot be reached due to a potential pharmacokinetic plateau at higher doses. A decision to dose escalate the next cohort will be made after safety data have been collected for 14 days following the first dose (14-day DLT window). PK will be used to confirm that there is no accumulation of the compound. Part 2 of the study will enroll new patients into one of up to 3 dose cohorts with once weekly dosing for 52 weeks. The branaplam dose will be escalated in subsequent cohorts after 6 patients have been enrolled and at least 3 patients from the previous cohort will have completed 13 weeks of treatment. After 52 weeks, patients may continue treatment if Novartis, the investigator and the independent DMC agree that this is in the best interest of the patient. In all cases continuation of the treatment will be done at a dose selected as optimum, considering existing safety as well as efficacy data

Official Title
-----------------
An Open Label Multi-part First-in-human Study of Oral LMI070 in Infants With Type 1 Spinal Muscular Atrophy

Conditions
-----------------
Spinal Muscular Atrophy

Intervention / Treatment
-----------------
* Drug: branaplam


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Common for both Parts 1 and 2: Type 1 SMA, diagnosed clinically, with symptom onset <6 months of age and genetic confirmation of mutations in both alleles of the SMN1 gene, and with SMN2 copy number of 2. Best supportive care in place and stable for at least 14 days before screening. Must be able to demonstrate antigravity strength in both biceps. At birth gestational age >32 weeks and body weight at birth >2 kg. Must live within 2 hours drive of study center. Clearance should be obtained from the site investigator and sponsor if the patient resides more than 2 hours ground travel from the study center Specific for Part 1 Age at screening between 1 and 7 months Must have or agree to have placement of feeding tube for enteral access via nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube for administration of branaplam (for patients in whom branaplam cannot be administered orally ; NG tube may be removed between doses). Specific for Part 2 Age at screening between 30 and 180 days of age Must have or agree to have placement of feeding tube for enteral access via nasogastric (NG), nasojejunal (NJ), percutaneous gastrostomy (PEG), or percutaneous jejunostomy (PEJ) tube for administration of branaplam (for the first administration only and for patients in whom branaplam cannot be administered orally; NG tube may be removed between doses). Minimum CHOP INTEND score of 15 at baseline Must be able to feed orally for all nutritional needs and be greater than the 2nd percentile for weight on the standard growth curves for the country of origin Exclusion Criteria: Common for both Parts 1 and 2: Neurologic, or neuromuscular conditions other than SMA. Anemia, leukopenia, neutropenia or thrombocytopenia Hepatic dysfunction Age adjusted renal dysfunction Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period. Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period. Excluding SMA, any medically unstable condition including cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine disorder, GI disorders, prematurity of <32 weeks gestation, metabolic disorders, severe respiratory compromise and significant brain abnormalities or injuries including hypoxic-ischemic encephalopathy. Current diagnosis of cardiac and/or vascular abnormalities or ECG abnormalities Acute or ongoing medical condition that, according to the Site Investigator and discussed with sponsor, would interfere with the conduct and assessments of the study. Examples are medical disability other than SMA that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures including be assessed by CHOP INTEND motor scale, changes in hematologic parameters or gastrointestinal dysfunction that would compromise the ability of adequate assessment of safety Specific for Part 1 Use of other investigational drugs within 14 days. Intractable seizure disorder (other than inactive febrile seizures). Persistent (in the opinion of the Investigator) hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%, without ventilation support) or requiring oral suctioning >2 per day, or presence of a tracheostomy. Specific for Part 2 Use of nusinersen or gene transfer at any time or other investigational drugs within 14 days. Intractable epilepsy Persistent (in the opinion of the Investigator) hypoxemia (O2 saturation awake <92% or O2 saturation asleep <91%, without ventilation support), or presence of a tracheostomy.

Ages Eligible for Study
-----------------
Minimum Age: 28 Days
Maximum Age: 182 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: branaplam<br>branaplam Treatment | Drug: branaplam<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs), serious adverse events (SAEs) | Participants are monitored for safety throughout the study | 13 weeks | 
| Number of participants with adverse events (AEs), serious adverse events (SAEs) | Participants are monitored for safety throughout the study | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in length | To evaluate the effect of branaplam on length in cm | Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study. | 
| Change from baseline in pulse oximetry | To evaluate the effect of branaplam on respiratory function by measurement of Pulse oximetry in percentage (%) of oxygen saturation | Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study. | 
| Change from baseline in Hammersmith Infant Neurology Examination (HINE) section 2 | To evaluate the effect of branaplam on infant motor development using HINE section 2 | Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study. | 
| Pharmacokinetic: AUC | To evaluate branaplam pharmacokinetics in plasma after single and repeated doses of branaplam by determination of AUC. | Parts 1 and 2: Day 1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose), Days 2, 3, 5, 8, 29. Part 1: Day 43. Part 2: Day 57, 57, 92 (Pre-dose + 4 & 24 hours post-dose), 94, 99, 274 (Pre-dose + 4 & 24 hours post-dose), 276, 281 | 
| In addition to the above for Part 2 - Change from baseline in feeding status | To evaluate the efficacy of branaplam on preservation of oral feeding | Baseline, Day 15, Day 36, Day 57, Day 88 + End of Study | 
| In addition to the above for Part 2 - Changes in Ulnar Nerve Compound Motor Action Potential (CMAP) from baseline | To evaluate the efficacy of branaplam on Ulnar and Peroneal Nerve Compound Motor Action Potentials (CMAPs) in terms of % increase from baseline | Baseline, Day 88 + End of Study | 
| In addition to the above for Part 2 - Changes from baseline on the ability to site without support | To evaluate the efficacy of branaplam on the ability to sit without support | 52 weeks | 
| Change from baseline in weight | To evaluate the effect of branaplam on weight in kilograms | Screening, Day 1, Day 8 to Day 85. Extended treatment periods: every 4 weeks and at the End of Study | 
| Change from baseline in head circumference | To evaluate the effect of branaplam on head circumference in cm | Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study. | 
| Change from baseline in chest circumference | To evaluate the effect of branaplam on chest circumference | Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study. | 
| Change from baseline in Children's Hospital of Philadelphia Infant Neuromuscular Disorders (CHOP INTEND) | To evaluate the effect of branaplam on infant motor development using CHOP INTEND | Part 1: Baseline, Day 36, Day 85, and every 6 to 7 weeks in the extended treatment periods, and at the End of Study. Part 2: Baseline, Day 36, Day 85, Day 127, Day 176, Day 218, Day 267, Day 309, Day 358 and End of Study | 
| Change from baseline in respiratory rate | To evaluate the effect of branaplam on respiratory function by measurement of the respiratory rate | Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study. | 
| Change from baseline in chest circumference during quiet breathing | To evaluate the effect of branaplam on respiratory function by measurement of the chest circumference in cm during expiration and during inspiration | Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study. | 
| Change from baseline in paradoxical breathing | To evaluate the effect of branaplam on respiratory function by evaluation of the presence of absence of paradoxical breathing | Part 1 Screening, Days 1, 8 to 85. Extended treatment periods: every 4 weeks and at the end of study. Part 2: Screening, days 1 through 358 and end of study. | 
| Pharmacokinetic: Cmax | To evaluate branaplam pharmacokinetics in plasma after single and repeated doses of branaplam by determination of Cmax. | Parts 1 and 2: Day 1 (Pre-dose + 1, 2, 4, 8 & 24 hours post-dose), Days 2, 3, 5, 8, 29. Part 1: Day 43. Part 2: Day 57, 57, 92 (Pre-dose + 4 & 24 hours post-dose), 94, 99, 274 (Pre-dose + 4 & 24 hours post-dose), 276, 281 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 1 Spinal Muscular Atrophy