AveXis Reports Interim Data from Ongoing Phase 1 Clinical Trial of AVXS-101 at the World Muscle Society Congress

By Cure SMA | Published On October 10, 2016

AveXis, Inc., a clinical-stage gene therapy company developing treatments for patients suffering from rare and life-threatening neurological genetic diseases, today provided an update on interim data from the ongoing Phase 1 trial of AVXS-101 in spinal muscular atrophy (SMA) Type 1 as of September 15, 2016. The data were presented by Jerry Mendell, M.D., director of the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital, at the 21st International Annual Congress of the World Muscle Society in Granada, Spain. Earlier this year, AveXis received breakthrough designation from the FDA for AVXS-101, the first SMA program to receive that designation.

For the first time, interim data from the trial were presented that highlighted patient achievement of key motor development milestones as of September 15, 2016. Two-thirds of patients in Cohort 2 (the proposed therapeutic dose) had achieved the ability to sit unassisted, including one patient whose achievement of this milestone was confirmed after September 15. In Cohort 2, 11 of 12 patients achieved head control, 7 of 12 patients could roll over completely and 11 of 12 patients could sit with support. Two patients are now walking independently, including one whose achievement of this milestone was confirmed after September 15. These two patients each achieved earlier and important developmental milestones such as crawling, standing with support, standing alone and walking with support.

“To date, the majority of patients who received the proposed therapeutic dose of AVXS-101 have achieved key milestones and two-thirds of these patients can sit independently – a fact completely inconsistent with the known disease course, as children with untreated SMA Type 1 will never sit unassisted,” said Sean Nolan, President and Chief Executive Officer, AveXis. “We are encouraged by these interim data, and continue to work diligently to bring this gene therapy to the children suffering from this devastating condition.”

Interim Phase 1 Data as of September 15, 2016

  • Data as of September 15, 2016 showed AVXS-101 continued to demonstrate a favorable safety profile and was generally well tolerated, with no new treatment-related safety or tolerability concerns identified.
    • There has been a cumulative total of 118 adverse events (AEs) reported as of September 15, 2016, 34 of which were determined to be serious adverse events (SAEs) and 84 were determined to be non-serious AEs. As previously reported, a total of 5 AEs in 4 patients were treatment-related. Two were deemed treatment-related SAEs (experienced by 2 patients) and three were deemed non-serious AEs (experienced by 3 patients). All consisted of clinically asymptomatic liver enzyme elevations.
    • All of the elevated liver enzyme AEs and SAEs were clinically asymptomatic and resolved with prednisolone treatment. There were no clinically significant elevations of gamma-glutamyl transferase (GGT), alkaline phosphatase or bilirubin, and as such Hy’s Law was not met.
    • Other non-treatment-related AEs were expected and were associated with SMA.
  • All patients in Cohort 2 (proposed therapeutic dose) are event-free, 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. The median age at last follow-up for Cohort 2 is 17.3 months, with the oldest patient at 27.4 months of age.
    • As previously reported, one patient in Cohort 1 (the low-dose cohort) did have a pulmonary event after July 1, 2016. The patient had increased use of bi-level positive airway pressure (BiPAP) in advance of surgery related to hypersalivation, a condition experienced by some SMA patients; the event was determined by independent review to represent progression of disease and not to be related to the use of AVXS-101.
  • Mean increases in CHOP-INTEND scores of 9.0 points in Cohort 1 and 24.8 points in Cohort 2 were observed, reflecting improvement in motor function. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) is a test developed to measure motor skills of patients with SMA Type 1.
    • 11 out of 12 patients in Cohort 2 achieved CHOP-INTEND scores of at least 40 points.
    • 9 out of 12 patients in Cohort 2 achieved CHOP-INTEND scores of at least 50 points.
    • 3 out of 12 patients in Cohort 2 achieved CHOP-INTEND scores of at least 60, which is in a range considered to be normal.
  • Patients on the proposed therapeutic dose of AVXS-101 consistently achieved and maintained key developmental motor milestones.
    • As of September 15, 2016, 11 out of 12 patients achieved head control; 7 out of 12 patients could roll over (completely); 11 out of 12 patients could sit with support; and 8 out of 12 patients could sit unassisted, including one patient whose achievement of this milestone was confirmed after September 15.
    • In addition, 7 patients are able to feed themselves, including one patient whose achievement of this milestone was confirmed after September 15, and 5 patients are speaking (1 bilingual).
    • 4 patients are now standing with support, including two whose achievements of this milestone were confirmed after September 15.
    • 2 patients are now walking independently, including one whose achievement of this milestone was confirmed after September 15. These two patients each achieved earlier and important developmental milestones such as crawling, standing with support, standing alone and walking with support.

“The preliminary clinical observations of extended event-free survival, sustained increases in motor function and achievement of developmental milestones in patients receiving a one-time infusion of AVXS-101 have far exceeded what has been observed with natural history,” said Suku Nagendran, MD, Senior Vice President and Chief Medical Officer, AveXis. “These preliminary results demonstrate the potential of AVXS-101 to positively impact quality of life and as such alter the course of disease in these children with SMA Type 1.”

Cure SMA Funds Multiple Gene Therapy Approaches

Beginning in 2010, Cure SMA made a series of grants to Nationwide Children’s Hospital to study gene therapy, also called gene transfer. Spinal muscular atrophy (SMA) is caused by a mutation in the survival motor neuron 1 gene (SMN1). Because of this mutation, the individual does not produce enough survival motor neuron (SMN) protein.

Gene transfer may increase SMN levels by using a virus, called a vector, to deliver the SMN1 gene to affected cells. Dr. Brian Kaspar and Dr. Mendell discovered that Adeno-associated virus serotype 9 (AAV9) had the unique ability to cross the blood brain barrier and the Blood-Cerebrospinal Fluid Barrier (CSF).

Currently, two approaches are being studied: an injection into a vein, known as systemic delivery, which is the process being tested in this current trial, and delivery directly into the cerebrospinal spinal fluid (CSF), a process known as CSF-delivered gene therapy. CSF-delivered gene therapy has shown promise for reducing the amount of drug required for larger and older patients. This could eventually make the treatment accessible to a wider population.

In total, Cure SMA has granted $845,000 for gene therapy, including support for both the systemic program and the CSF program. Using the data generated with our funding for CSF delivery, Dr. Kaspar and his team were able to secure a $4 million grant from NINDS in 2013, to develop this delivery approach for human clinical trials in SMA.

Topics: Clinical Trials, Front Page News

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