STRONG - Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting but Non-ambulatory Patients with Spinal Muscular Atrophy

Study ID: STU 062016-082

Summary

The proposed clinical study is a Phase i, open-label, single-dose administration study of infants and children with a genetic diagnosis consistent with SMa, bi-allelic deletion of SMn1 and 3 copies of SMn2 without the genetic modifier who are able to sit but cannot stand or walk at the time of study entry. Patients will receive aVXS-101 in a dose comparison safety study of up to three (3) potential therapeutic doses. The first cohort will enroll three (3) patients (Cohort 1) [GreaterThanorequalTo]6 months and [Less Than] 24 months of age who will receive administration of 6.0 x 1013 vg of aVXS-101 (Dose a). There will be at least a four (4) week interval between the dosing of each patient within the cohort. The investigators will confer with the Data Safety Monitoring Board (DSMB) on all Grade iii or higher aes within 48 hours of awareness that are possibly, probably, or definitely related to the study agent before continuing enrollment. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the first three patients and based upon the available safety data a decision will be made whether to: a) stop due to toxicity, or b) proceed to Cohort 2 using Dose B. if safe to advance to Dose B, three (3) patients [Less Than] 60 months of age will be enrolled to receive administration of 1.2 x 1014 vg of aVXS-101 (Dose B). again, there will be at least a 4-week interval between dosing of the three patients within the cohort. Based on the available safety data from the three Cohort 2 patients and all of the Cohort 1 patients, the DSMB may decide and document during quarterly meetings that further 4-week intervals between patients dosing is unnecessary. The investigators will confer with the DSMB on all Grade iii or higher aes within 48 hours that are possibly, probably, or definitely related to the study agent before continuing enrollment. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the first six (6) patients and based upon available safety data, a decision will be made whether to a) stop due to toxicity, or b) continue to enroll an additional 21 patients until twelve (12) patients [GreaterThanorequalTo]6 months and [Less Than] 24 months and twelve (12) patients [GreaterThanorequalTo] 24 months and [Less Than] 60 months have received Dose B.. Based on safety, an option for testing of a third dose (Dose C), will be considered. if, based on all available data, this is judged to be necessary, three (3) patients [Less Than] 60 months of age will receive Dose C, which will be no greater than 2.4 x 1014 vg administered intrathecally. a meeting of the DSMB will be called to obtain agreement on the safety of escalating to a higher dose prior to proceeding. if agreement is obtained from the DSMB, there will again be a four-week interval between dosing of the first three patients receiving Dose C, as in Cohorts 1 and 2. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the first three (3) Dose C patients and based upon available safety data, a decision will be made whether to: a) stop due to toxicity, or b) continue to enroll an additional 21 patients until there are a total of twelve (12) patients [Greater Than] 6 months and [Less Than] 24 months and twelve (12) patients [GreaterThanorequalTo] 24 and [Less Than] 60 months that have received Dose C. Patients will be observed at the hospital for 48 hours post intrathecal injection. Patients will return for follow up visits on Days 7, 14, 21, and 30. Patients will return monthly thereafter, following the Day 30 visit, for 12 months from dose administration. 6.0 x 1013 vg (Dose a) 1.2 x 1014 vg (Dose B) no more than 2.4 x 1014 vg (Dose C)

Participant Eligibility

1. Patients > or equal to 6 months of age and up to 60 months (1800 days) of age at time of dosing following diagnostic confirmation during screening period by genotype who demonstrate the ability to sit unassisted for 10 or more seconds but cannot stand or walk [?] Diagnostic confirmation by genotype includes lab documentation of homozygous absence of SMN1 exon 7; with exactly three copies of SMN22. 2. Negative gene testing for SMN2 gene modifier mutation (c.859G>C) 3. Onset of clinical signs and symptoms consistent with SMA at < 12 months of age 4. Able to sit independently and not standing or walking independently. Definition of sitting independently is defined by the World Health Organization (WHO)-MGRS criteria of being able to sit up unsupported with head erect for at least 10 seconds. Child should not use arms or hands to balance body or support position (Wijnhoven 2004) 5. Meet age-appropriate institutional criteria for use of anesthesia and sedation, if determined necessary by the investigator 6. Be up-to-date on childhood vaccines. Seasonal vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics (AAP 2009) 7. Parent(s)/legal guardian(s) willing and able to complete the informed consent process

Cancer Related: No
Healthy Volunteers: No
UT Southwestern Principal Investigator: SUSAN THERESA IANNACCONE

Contact:

Tammy Ramm

Tammy.Ramm@UTSouthwestern.edu

assess the safety and tolerability of intrathecal administration of aVXS-101 by the incidence and severity of adverse events Determine the optimal dose of aVXS-101 that demonstrates acceptable safety with maximum preliminary efficacy administered by intrathecal injection efficacy for patients [GreaterThanorequalTo]6 months and [Less Than] 24 months at time of dosing: Primary: Proportion of patients [GreaterThanorequalTo]6 months and [Less Than] 24 months at time of dosing achieving the ability to stand without support for at least three seconds Secondary: Proportion of patients that achieve ability to walk without assistance defined as taking at least five steps independently displaying coordination and balance exploratory: Change from baseline in fine and gross motor components of the Bayley Scales of infant and Toddler Development. Change in Hammersmith Functional Motor Scale-expanded (HFMSe) from baseline among patients [Less Than] 24 months at time of dosing who continue in study past 24 months of age efficacy for patients [GreaterThanorequalTo] 24 months and [Less Than] 60 months at time of dosing: Primary: Change in Hammersmith Functional Motor Scale-expanded from baseline among patients [GreaterThanorequalTo] 24 months at time of dosing Secondary: Proportion of patients that achieve ability to walk without assistance defined as taking at least five steps independently displaying coordination and balance exploratory: Change from baseline in fine and gross motor components of the Bayley Scales of infant and Toddler Development Safety will be assessed independently for each age cohort: incidence of Common Terminology Criteria (CTC) Grade iii or higher toxicity, treatment-emergent aes incidence of complications or aes related to intrathecal injection Clinically significant changes in laboratory values, physical exams, cardiovascular evaluations or vital signs Research immunology Blood Labs: Serum antibody to aaV9 and SMn, iFn- [and] #947; eLiSpot (enzyme-Linked immunoSpot) to detect T-cell responses to aaV9 and SMn efficacy for patients [GreaterThanorequalTo]6 months and [Less Than] 24 months at time of dosing: Primary: Proportion of patients [GreaterThanorequalTo]6 months and [Less Than] 24 months at time of dosing that achieve ability to stand alone Secondary: Proportion of patients that achieve ability to walk without assistance defined as taking at least five steps independently displaying coordination and balance exploratory: Change from baseline in fine and gross motor components of the Bayley Scales of infant and Toddler Development Hammersmith Functional Motor Scale- expanded score among patients [Less Than] 24 months of age at time of dosing who continue in study past 24 months of age efficacy for patients [GreaterThanorequalTo] 24 months and [Less Than] 60 months at time of dosing: Primary: Change from baseline in Hammersmith Functional Motor Scale- expanded among patients [GreaterThanorequalTo] 24 months of age at time of dosing Secondary: Proportion of patients that achieve ability to walk without assistance defined as taking at least five steps independently displaying coordination and balance exploratory: Change from baseline in fine and gross motor components of the Bayley Scales of infant and Toddler Development additionally, compelling, demonstrable, documented evidence of efficacy as determined by changes in development abilities as captured during videotaping sessions during site visits and/or provided by parent/legal guardian will be collected for all patients in both age groups.