Clinical trial NCT02268552: An Open Label Study of LMI070 (Branaplam) in Type 1 Spinal Muscular Atrophy (SMA)
Official title: An Open Label Multi-part First-in-human Study of Oral LMI070 in Infants With Type 1 Spinal Muscular Atrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Spinal Muscular Atrophy
Keywords: Type 1 Spinal Muscular Atrophy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-10-20
Enrollment: 40
Sex: ALL
Minimum age (years): 28
Maximum age (years): 182
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS)
timeFrame: Baseline up to 2 weeks for Part 1
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS
timeFrame: Baseline up to approximately 83 months
Secondary outcomes:
measure: Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) After a Single Dose - Part 1 - Pharmacokinetics Analysis Set (PAS)
timeFrame: from 0 h to 168 h after first/single dose
measure: Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUCinf) for All Observation Periods - Part 1 - PAS
timeFrame: from 0 h to 168 h after first/single dose
measure: Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS
timeFrame: from 0 h to 168 h after first/single dose
measure: Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS
timeFrame: from 0 h to 168 h after first/single dose
measure: Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) After a Single Dose - Part 2 - PAS
timeFrame: from 0 h to 168 h after first/single dose
measure: Summary of Plasma Pharmacokinetic (PK) Parameter Area Under the Curve (AUC) for All Observation Periods - Part 2 - PAS
timeFrame: from 0 h to 168 h after first/single dose
measure: Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for a Single Dose - Part 2 - PAS
timeFrame: from 0 h to 168 h after first/single dose
measure: Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 2 - PAS
timeFrame: from 0 h to 168 h after first/single dose
measure: Change From Baseline in Growth Parameters: Chest Circumference, Head Circumference and Body Length - Full Analysis Set (FAS)
timeFrame: Baseline, Week 52 and Month 6 of Part 3
measure: Change From Baseline in Growth Parameter: Body Weight - FAS
timeFrame: Baseline, Week 52 and Month 6 of Part 3
measure: Change From Baseline in Respiratory Function: Pulse Oximetry - FAS
timeFrame: Baseline, Week 52 and Month 6 of Part 3
measure: Change From Baseline in Respiratory Function: Respiratory Rate - FAS
timeFrame: Baseline, Week 52 and Month 6 of Part 3
measure: Number of Participants With Presence of Paradoxical Breathing - FAS
timeFrame: Baseline, Week 52 and Month 6 of Part 3
measure: Change From Baseline in Respiratory Function: Chest Circumference During Quiet Breathing - End of Inspiration and Expiration - FAS
timeFrame: Baseline, Week 52 and Month 6 of Part 3
measure: Summary of CHOP INTEND Total Score - Parts 1 and 3 and Parts 2 and 3 - FAS
timeFrame: Baseline, Week 52 and Month 6 of Part 3
measure: Number of Participants Fed Orally or by Feeding Tube for Parts 1 and 3 and Parts 2 and 3 - FAS
timeFrame: Baseline up Week 78
measure: Number of Participants and HINE Motor Subscale Milestones (Ability to Sit, Stand or Walk Without Support) - FAS
timeFrame: Week 52 and Month 6 of Part 3
measure: Summary of Hammersmith Infant Neurologic Examination Section 2 (HINE-2) - FAS
timeFrame: Week 52 and Month 6 of Part 3
measure: Ventilation Use for Parts 1 and 3 and Parts 2 and 3 - FAS
timeFrame: Baseline up to 82 months
Other outcomes:
Locations:
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Sofia
country: Bulgaria
facility: Novartis Investigative Site
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Warsaw
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Ekaterinburg
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Volgograd
country: Russian Federation
facility: Novartis Investigative Site
Study officials:
References:
citation: Keller CG, Shin Y, Monteys AM, Renaud N, Beibel M, Teider N, Peters T, Faller T, St-Cyr S, Knehr J, Roma G, Reyes A, Hild M, Lukashev D, Theil D, Dales N, Cha JH, Borowsky B, Dolmetsch R, Davidson BL, Sivasankaran R. An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion. Nat Commun. 2022 Mar 3;13(1):1150. doi: 10.1038/s41467-022-28653-6.