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

NCT02268552 | Completed Phase 1 Results DMC

• 1 other identifier: CLMI070X2201
• Study Type: interventional
• Target: 40
• Locations: 7 countries
• Sites: 14

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.

Conditions

Spinal Muscular Atrophy

Keywords

Type 1 Spinal Muscular Atrophy

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Dose Limiting Toxicities (DLT) in Part 1 - Safety Analysis Set (SAS)

  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.

  Baseline up to 2 weeks for Part 1

• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events and Deaths- SAS

  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.

  Baseline up to approximately 83 months

Secondary Outcomes (19)

• 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

• 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

• Summary of Plasma Pharmacokinetic (PK) Parameter Cmax After a Single Dose - Part 1 - PAS

  from 0 h to 168 h after first/single dose

• Summary of Plasma Pharmacokinetic (PK) Parameter Cmax for All Observation Periods - Part 1 - PAS

  from 0 h to 168 h after first/single dose

• 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

Study Arms (1)

branaplam

EXPERIMENTAL

branaplam Treatment

Drug: branaplam

Interventions

branaplam DRUG

branaplam

Eligibility Criteria

• Age: 28 Days - 182 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (14)

Novartis Investigative Site

Ghent, 9000, Belgium

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Sofia, 1606, Bulgaria

Location

Novartis Investigative Site

Copenhagen, 2100 O, Denmark

Location

Novartis Investigative Site

Essen, 45147, Germany

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Roma, RM, 00165, Italy

Location

Novartis Investigative Site

Warsaw, 04 730, Poland

Location

Novartis Investigative Site

Wroclaw, 50 420, Poland

Location

Novartis Investigative Site

Moscow, 119049, Russia

Location

Novartis Investigative Site

Moscow, 127412, Russia

Location

Novartis Investigative Site

Saint Petersburg, 197341, Russia

Location

Novartis Investigative Site

Volgograd, 400120, Russia

Location

Novartis Investigative Site

Yekaterinburg, 620134, Russia

Location

Related Publications (1)

• 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.

  PMID: 35241644 DERIVED

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Limitations and Caveats

In alignment with the study objectives, safety and tolerability of branaplam irrespective of the dose, 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. The fact that no dose limiting toxicity was observed in any of the doses and the lack of evidence for dose dependent safety findings further supports this strategy.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2014
• First Posted: October 20, 2014
• Study Start: April 2, 2015
• Primary Completion: December 29, 2022
• Study Completion: December 29, 2022
• Last Updated: April 9, 2025
• Results First Posted: April 9, 2025

Record last verified: 2025-03

Locations

DK (1); BU (1); PL (2); DE (1); BE (2); IT (2); RU (5)