Safety and Efficacy of Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA)

Novartis Pharmaceuticals24 enrolled

Overview

To evaluate the safety, tolerability and efficacy of intravenous administration of OAV101 (AVXS-101) in patients with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene weighing ≥ 8.5 kg and ≤ 21 kg, over a 12 month period.

This was an open-label, single arm, multi-center study designed to evaluate the safety, tolerability and efficacy of OAV101 in participants with SMA who weigh ≥ 8.5 kg and ≤ 21 kg. The study aimed to enroll approximately 24 to 30 participants, with approximately 6 to 10 participants across each of 3 weight brackets (8.5 to 13 kg, \>13 to 17 kg, \>17 to 21 kg). Eligible participants received a single administration of OAV101 at the approved dose of 1.1e14 vg/kg on Day 1 (Treatment period), and were followed for a period of 12 months. Participants were admitted to the hospital on Day -1 for pre-treatment baseline procedures. After receiving OAV101 on Day 1, participants underwent in-patient safety monitoring over the next 48 hours, after which the participant could be discharged, based on Investigator judgment. After study completion, eligible participants could enroll into a Long Term follow-up study to collect additional safety and efficacy data. (COAV101A12308 (NCT05335876) https://classic.clinicaltrials.gov/ct2/show/NCT05335876?term=COAV101A12308\&draw=2\&rank=1))

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Spinal Muscular Atrophy

Interventions

OAV101GENETIC

Gene Therapy - 1.1e14 vector genome (vg)/kg as a one-time IV infusion was administered over approximately 60 minutes.

Eligibility

Sex: ALLMax age: 17 Years

Medical Language ↔ Plain English

Inclusion * Symptomatic SMA diagnosis based on gene mutation analysis with bi-allelic survival motor neuron 1 (SMN1) mutations (deletion or point mutations) and any copy of the survival motor neuron 2 (SMN2) gene. * Weight ≥ 8.5 kg and ≤ 21 kg at the time of Screening Visit 2 * Naive to treatment or have discontinued an approved drug/therapy Exclusion: * Previous OAV101 use or previous use of any adeno-associated virus serotype 9 (AAV9) gene therapy * BMI \< 3rd percentile * Participant with history of aspiration pneumonia or signs of aspiration * Elevated anti-AAV9 antibody * History of gene therapy, hematopoietic transplantation, or solid organ transplantation * Inability to take corticosteroids * Concomitant use of immunosuppressive therapy * Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation 9. Administration of vaccines 2 weeks prior to infusion of OAV101 * Awake hypoxemia or awake oxygen saturation level decrease * Hepatic dysfunction * Presence of a confirmed or suspected infection * If previously treated with disease modifying therapy, specified washout times apply * Documented any parental consanguinity.

Locations (13)

Novartis Investigative Site

Boston, Massachusetts, United States

Novartis Investigative Site

St Louis, Missouri, United States

Novartis Investigative Site

Randwick, New South Wales, Australia

Outcomes

Primary Outcomes

Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) by Weight Bracket

An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.

Time frame: Up to Month 12

Number of Participants With Important Identified and Important Potential Risks (Adverse Events of Special Interest (AESI)) by Risk Name and Weight Bracket

Important identified and important potential risks included the following AESIs: Hepatotoxicity, Thrombocytopenia, Cardiac adverse events, Dorsal root ganglia toxicity and Thrombotic microangiopathy. These were assessed by the investigator.

Time frame: Up to Month 12

Summary of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values by Weight Bracket - Systolic and Diastolic Blood Pressure

Change from baseline in vital signs measurements - systolic and diastolic blood pressure (mmHg). Systolic Blood Pressure-Low:\<=5th percentile of the age(Any Age), High:\>=90th percentile of the age, gender, and height group (\<18 yrs). Diastolic Blood Pressure-High:\>=90th percentile of the age, gender, and height group(\<18 yrs).

Time frame: 12 months

Change From Baseline in Vital Signs Measurements - Systolic Blood Pressure (mmHg)

Time frame: Baseline, Days 2 and 3, Weeks 1, 2, 3, 4, 6, 8, 10, 13, 26, 39 and 52

Change From Baseline in Vital Signs Measurements - Diastolic Blood Pressure (mmHg)

Time frame: Baseline, Days 2 and 3, Weeks 1, 2, 3, 4, 6, 8, 10, 13, 26, 39 and 52

Change From Baseline in Vital Signs Measurements - Respiratory Rate (Breaths/Min)

Change from baseline in vital signs measurements - Respiratory Rate (breaths/min)

Data from ClinicalTrials.gov

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Secondary Outcomes

Achievement of Development Motor Milestones According to the Modified and Combined WHO-MGRS and Bayley Scale of Infant and Toddler Development.

The World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) and Bayley scale of Infant and Toddler Development was modified and combined into a single scale expressly for this study, to measure developmental motor milestones. These were assessed via the milestone checklist, formed of 10 yes/no questions with optional video documentation. The developmental milestones are: head control, sitting with support, sitting without support, sitting without support for 30 seconds, hands-and-knees crawling, pulls to stand, standing with assistance, walking with assistance, standing alone and walking alone. A yes response indicates that the patient reached a particular development milestone.

Time frame: Baseline, Week 26 and Week 52

Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE), as Appropriate According to Participant Age

The HFMSE was devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE is formed of 33 assessments. Each motor skill item is scored on a 3 point Likert scale from 0 (no response) to 2 (full response), with a total score range of 0 to 66. A higher score indicates a higher level of ability.

Time frame: Baseline, Week 4, Week 13, Week 26, Week 39 and Week 52

Change From Baseline in Revised Upper Limb Module (RULM), as Appropriate According to Participant Age.

The RULM assesses motor performance in the upper limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with SMA. 'The scale consists of an entry item to establish functional levels and 19 items covering distal to proximal movements. The entry item is a modified version of the Brooke scale, including activities ranging from no functional use of hands (score 0) to full bilateral shoulder abduction (score 6). The entry item does not contribute to the total score but serves as a functional classification of overall upper limb functional ability. Of the remaining 19 items, 18 are scored on a 3 point scoring system and 1 item is scored on a 2 point scoring system. The test is performed unilaterally using the limb preferred by the participant. The total score ranges from 0, if all the items cannot be performed, to 37, if all the activities are achieved fully without any compensation. ' Higher scores indicate higher levels of motor ability.

Time frame: Baseline, Week 4, Week 13, Week 26, Week 39 and Week 52