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

Novartis

Status and phase

Completed

Phase 2

Phase 1

Conditions

Spinal Muscular Atrophy

Treatments

Drug: branaplam

Study type

Interventional

Funder types

Industry

Identifiers

NCT02268552

CLMI070X2201

Details and patient eligibility

About

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.

Full 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.

Enrollment

40 patients

Sex

All

Ages

28 to 182 days old

Volunteers

No Healthy Volunteers

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.