Outcome Measures for Patients Between 24 and 60 Months of Age
• The primary outcome measure for patients between 24 months and 60 months of age at the time of dosing is the achievement of change in Hammersmith Functional Motor Scale Expanded from baseline.
• The secondary outcome measure is the proportion of patients who achieve the ability to walk without assistance, defined as taking at least five steps independently displaying coordination and balance.
• Developmental abilities, including motor function, will be evaluated as exploratory objectives.
The trial is projected to be conducted at 11 sites in the United States, including Ann and Robert H. Lurie Children's Hospital of Chicago, Boston Children's Hospital, Children's Hospital of Philadelphia, David Geffen School of Medicine at UCLA, Johns Hopkins Pediatric Neurology, Nationwide Children's Hospital, Stanford University Medical Center, University of Central Florida College of Medicine, University of Texas Southwestern Medical Center, University of Utah and Washington University School of Medicine.
Planned Pivotal Trial of AVXS-101 in SMA Type 1 in Europe
We intend to initiate a pivotal trial of AVXS-101 for the treatment of SMA Type 1 in Europe in the first half of 2018. The planned trial design, which incorporates scientific advice from the EMA, is expected to reflect a single-arm design, using natural history of the disease as a comparator, and is expected to enroll approximately 30 patients with SMA Type 1 who are less than six months of age at the time of gene therapy. The trial is designed to evaluate safety and efficacy of a one-time IV dose of AVXS-101, including achievement of motor milestones, specifically patients’ ability to sit unassisted, as well as an efficacy measure defined by the time from birth to an “event,” defined as death or requiring at least 16 hours per day of ventilation support for breathing for greater than two weeks in the absence of an acute reversible illness, or perioperatively.
Completed Phase 1 Clinical Trial for SMA Type 1
In April 2014, an open‑label, dose‑escalation Phase 1 clinical trial of AVXS‑101 in patients with SMA Type 1 was initiated as an investigator‑sponsored trial at NCH under an IND, held by Dr. Jerry Mendell, the principal investigator at NCH. We completed the transfer of the IND to AveXis in November 2015. The trial design allowed for the enrollment of up to 15 patients across a maximum of three dosing cohorts. Key inclusion criteria included the presence of typical clinical symptoms before 6 months of age, SMA Type 1 patients with bi‑allelic SMN1 gene deletions or mutations (all patients in the trial had bi‑allelic deletions) and with two copies of the SMN2 backup gene as confirmed by genetic testing in an independent laboratory. Confirmed absence of the Exon 7 genetic modifier (c.859G>C) was made through the laboratory of Dr. Tom Prior, the scientist who described the impact of this mutation on clinical phenotype. Furthermore, all patients were re‑tested at an independent laboratory to re‑confirm all genetic results. Additionally, patients must have been no older than nine months of age (for the first nine patients) and six months of age (for the last six patients) at the time of vector infusion.
The primary outcome measure of our Phase 1 clinical trial was safety and tolerability. The key efficacy measures were defined as the time from birth to an “event,” which was defined as either death or at least 16 hours per day of required ventilation support for breathing for 14 consecutive days in the absence of acute reversible illness or perioperatively, and video confirmed achievement of ability to sit unassisted. We also assessed several exploratory objective measures in the clinical trial. These exploratory measures were included to assess additional testing protocols on patients in an effort to identify objective testing criteria for measuring the results of the therapy. These exploratory tests included administering a standard motor milestone development survey and CHOP INTEND, the need for pulmonary and feeding support, evaluation of swallowing function, compound motor action potentials testing (CMAP), motor unit number estimation testing (MUNE), non‑invasive electrical impedance myography testing (EIM) and “ability captured through interactive video evaluation‑mini” testing (ACTIVE‑mini).
Once a patient met the screening criteria for the clinical trial, the patient received a one‑time dose of AVXS‑101, by intravenous injection over a one‑hour period. The patient remained at NCH for 48 hours after dosing for monitoring, and then was discharged. For one month after dosing, weekly follow‑up evaluations were conducted. After