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

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

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.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: branaplam

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

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1606
    • Novartis Investigative Site
• Denmark
  • Copenhagen, Denmark, 2100 O
    • Novartis Investigative Site
• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00165
      • Novartis Investigative Site
• Poland
  • Warsaw, Poland, 04 730
    • Novartis Investigative Site
  • Wroclaw, Poland, 50 420
    • Novartis Investigative Site
• Russian Federation
  • Ekaterinburg, Russian Federation, 620134
    • Novartis Investigative Site
  • Moscow, Russian Federation, 127412
    • Novartis Investigative Site
  • Moscow, Russian Federation, 119049
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197341
    • Novartis Investigative Site
  • Volgograd, Russian Federation, 400120
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 5 months (Child)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: branaplam; branaplam Treatment	Drug: branaplam

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2015
• Primary Completion (Actual): December 29, 2022
• Study Completion (Actual): December 29, 2022

Study Registration Dates

• First Submitted: October 1, 2014
• First Submitted That Met QC Criteria: October 15, 2014
• First Posted (Estimate): October 20, 2014

Study Record Updates

• Last Update Posted (Actual): April 25, 2023
• Last Update Submitted That Met QC Criteria: April 21, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Type 1 Spinal Muscular Atrophy
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: CLMI070X2201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No