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

Phase 1

Completed

Conditions: Spinal Muscular Atrophy

Interventions: Drug: branaplam

Registration Number: NCT02268552

Lead Sponsor: Novartis Pharmaceuticals

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 was 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 was 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 was 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 1,2 and 3 were intended to be non-confirmatory.

In Part 1 of the study, patients were dosed once weekly with branaplam. The branaplam dose was escalated in subsequent cohorts until MTD was determined or when sufficient PK results confirmed that the MTD could not be reached due to a potential pharmacokinetic plateau at higher doses. A decision to dose escalate the next cohort was made after safety data was collected for 14 days following the first dose (14-day DLT window). PK was used to confirm that there was no accumulation of the compound. After 13 weeks treatment, participants in part 1 could enter an extension treatment phase until they discontinued from the study or were transferred into part 3.

Part 2 of the study enrolled new patients into one 2 dose cohorts with once weekly dosing for 52 weeks. The branaplam dose was escalated in subsequent cohorts after 6 patients were enrolled and at least 3 patients from the previous cohort completed 13 weeks of treatment. After 52 weeks, patients may have continued treatment in part 3 if it was in the best interest of the patient.

Part 3, participants from part 1 and 2 who have completed at least 52 weeks of banaplam treatment were elegible to continue receiving treatment as long as in the best interest of the patient. In all cases continuation of the treatment was done at a dose selected as optimum, considering existing safety as well as efficacy data.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
branaplam	branaplam	branaplam Treatment

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS)	Baseline up to 2 weeks for Part 1	A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant therapies that occurs within the first 14 days of treatment with LMI070 and meets any of the criteria for blood and lymphatic system disorders, gastrointestinal disorders, investigations and other toxicities considered clinically significant.
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS	Baseline up to approximately 83 months	TEAEs are defined as adverse events starting on or after the first dose of study treatment that were absent pre-treatment, or events present prior to the first dose but increased in severity after the first dose. Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post last treatment.

Secondary Outcome Measures

Name	Time	Method
Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS)	from 0 h to 168 h after first/single dose	The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume\]
Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS	from 0 h to 168 h after first/single dose	The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume
Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) After a Single Dose - Part 2 - PAS	from 0 h to 168 h after first/single dose	The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume)
Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS	from 0 h to 168 h after first/single dose	The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume\] for all observations. AUC values used for comparison are combined from AUCinf values after single dose and AUC 0-168h values after repeated administration.
Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS	from 0 h to 168 h after first/single dose	The observed maximum plasma concentration following drug administration \[mass / volume).
Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for a Single Dose - Part 2 - PAS	from 0 h to 168 h after first/single dose	The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume)
Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) for All Observation Periods - Part 2 - PAS	from 0 h to 168 h after first/single dose	The area under the plasma (or serum or blood) concentration-time curve from time zero to infinity \[mass x time / volume). AUC values used for comparison are combined from AUCinf values after single dose and AUC0-168h values after repeated administration.
Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 2 - PAS	from 0 h to 168 h after first/single dose	The observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume)
Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS)	Baseline, Week 52 and Month 6 of Part 3	The effect of branaplam on growth parameters: Length (measured from the top of the head to the sole of the foot), Head circumference and Chest circumference (measured across nipple line). Mean change from baseline in cm is presented In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Change From Baseline in Growth Parameter: Body Weight - FAS	Baseline, Week 52 and Month 6 of Part 3	The effect of Branaplam on body weight in Kg was measured using a weight scale. Mean change from baseline in Kg is presented In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Change From Baseline in Respiratory Function: Pulse Oximetry - FAS	Baseline, Week 52 and Month 6 of Part 3	The effect of branaplam on pulse oximetry in percentage of oxygen saturation was evaluated using a probe that measures oxygen in the blood. Mean change from baseline in percentage of oxygen saturation is reported. Negative numbers indicate a decrease from baseline In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Change From Baseline in Respiratory Function: Respiratory Rate - FAS	Baseline, Week 52 and Month 6 of Part 3	The effect of branaplam on respiratory rate was evaluated by counting the number of breaths for one minute. Mean change from baseline in breaths per minute is reported" In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Number of Participants With Presence of Paradoxical Breathing - FAS	Baseline, Week 52 and Month 6 of Part 3	A paradoxical breathing occurs when one compartment moves out of phase compared to another one. In SMA type I, paradoxical breathing is often a sign of breathing problems where the pulmonary ribcage moves inward during inspiration rather than outward while the abdomen expands. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Change From Baseline in Respiratory Function: Chest Circumference During Quiet Breathing - End of Inspiration and Expiration - FAS	Baseline, Week 52 and Month 6 of Part 3	The effect of branaplam on respiratory status was evaluated by measuring the circumference of the ribcage while taking a breathe in and out while quiet or sleeping. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Summary of CHOP INTEND Total Score - Parts 1 and 3 and Parts 2 and 3 - FAS	Baseline, Week 52 and Month 6 of Part 3	CHOP INTEND is a motor test measure for SMA Type 1 and similarly weak infants with neuromuscular disease. The CHOP INTEND provides a useful measure of motor skills and strength in this population. It is a 16 item, 64 point scale. Each item (motor skill) is given a score from zero to 4: zero indicates can't complete the movement, 1 to 3 indicates partial performance and a 4 indicates person can complete the movement on their own without assistance. These scores are added up to a possible total score of 64 and higher scores indicate better outcomes. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS	Baseline up Week 78	To evaluate the efficacy of branaplam on preservation of oral feeding In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS	Week 52 and Month 6 of Part 3	HINE Section 2 is a standardized evaluation of motor function. It evaluates 8 items; grasp, head control, kicking, rolling over, sitting up, crawling, standing and walking. Motor skills are assigned a score of 0 to 3 to 5 points and zero means the child lacks that motor skill. The maximum score is 26 which is dependent on age, level of development and severity of disease. A higher score is a better outcome. This assessment was added with amendment 6, therefore no baseline was available. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS	Week 52 and Month 6 of Part 3	HINE Section 2 is a standardized evaluation of motor function. It evaluates 8 items; grasp, head control, kicking, rolling over, sitting up, crawling, standing and walking. Motor skills are assigned a score of 0 to 3 to 5 points and zero means the child lacks that motor skill. The maximum score is 26 which is dependent on age, level of development and severity of disease. A higher score is a better outcome. This assessment was added with amendment 6, therefore no baseline was available. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.
Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS	Baseline up to 82 months	BiBAP (bilevel positive airway pressure) ventilation is a 2 level breathing support which has a tube that connects to a mask. It provides a different level of air pressure for inhalation vs. exhalation, whereas a CPAP (continuous positive airway pressure) only pumps one level of air pressure but is also non-invasiive. Invasive ventilation is delivered via an endotracheal or tracheostomy tube. In alignment with the study objectives and protocol defined analyses, secondary efficacy endpoints were analyzed according to the treatment group that participants were assigned at baseline (Part 1\&3 and Part 2\&3) irrespective of study dose or route of administration.