AveXis Data Reinforces Effectiveness of Zolgensma® in Treating SMA Type 1

By Cure SMA | Published On April 17, 2019

AveXis Data Reinforces Effectiveness of Zolgensma® in Treating SMA Type 1

AveXis, a Novartis company, today announced that interim data from its Phase 3 STR1VE trial of Zolgensma®(AVXS-101) in spinal muscular atrophy Type 1 showed prolonged event-free survival, an early and rapid increase in CHOP-INTEND scores and significant milestone achievement compared to untreated natural history, consistent with data from the pivotal Phase 1 START trial. First-in-human biodistribution individual case study data from STR1VE showed Zolgensma successfully transduced intended targets in the central nervous system (CNS) and provided widespread SMN expression comparable to tissue from unaffected individual. Additional data presented showed 95 percent of patients screened across the Zolgensma clinical development program and Managed Access Program were not excluded from treatment due to elevated AAV9 antibody titers greater than 1:50. These data were presented today at the 2019 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in Orlando, Florida.

Interim Phase 3 STR1VE Data as of September 27, 2018

STR1VE is an ongoing, open-label, single-arm, single-dose, multi-center trial designed to evaluate the efficacy and safety of a one-time intravenous infusion of Zolgensma in patients with SMA Type 1 who are less than six months of age at the time of gene therapy. The study was designed to enroll the broadest possible population of SMA Type 1 patients with one or two copies of the SMN2 backup gene and who have bi-allelic SMN1 gene deletion or point mutations. These criteria are well-matched to the patient population that was enrolled in the pivotal Phase 1 START trial while potentially providing treatment to some of the rarer subpopulations on an exploratory basis. STR1VE is projected to complete in 2020.

As of September 27, 2018, 21 of 22 (95 percent) patients were alive and event-free. The median age was 9.5 months, with 6 of 7 (86 percent) patients who could have reached 10.5 months of age or older surviving event-free. Untreated natural history indicates that 50 percent of babies with SMA Type 1 will not survive or will require permanent ventilation by the time they reach 10.5 months of age.

Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores increased by an average of 7.0 points one month after gene transfer and 11.8 points three months after gene transfer, reflecting improvement in motor function from baseline. These data are similar to CHOP-INTEND achievement by the proposed therapeutic dose cohort (Cohort 2) in the pivotal START trial, which demonstrated mean increases of 9.8 and 15.4 points at the same time points, respectively. Early CHOP-INTEND increases appear to be associated with eventual milestone achievement.

Preliminary assessments of patients treated with Zolgensma showed the achievement of motor milestones, including three patients who could sit without support for at least 30 seconds as of September 27, 2018 (median of 9.4 months), increasing to eight patients who could achieve the same milestone as of December 31, 2018 (median age of 12.5 months).

Safety observations are comparable to those seen in the pivotal Phase 1 START trial. Adverse events of special interest, including elevated transaminases, platelet count decrease and thrombocytopenia, were transient and did not cause any long-term sequelae. One patient died from respiratory failure, which was deemed by the investigator and independent Data Safety Monitoring Board to be unrelated to treatment. This patient had demonstrated significant motor improvement, with a 27-point increase in CHOP-INTEND from baseline five months post-infusion.

Biodistribution of Zolgensma

First-in-human analysis of tissues from the deceased patient showed that Zolgensma successfully transduced tissues of the CNS, including brain and spinal cord motor neurons, and showed widespread expression of SMN comparable to tissue from an unaffected individual and clearly distinguishable from untreated SMA patient samples.

These human data support the mechanism of action initially identified in non-human non-clinical studies in murine and non-human primate models, that a single intravenous administration of Zolgensma is able to restore SMN expression to motor neurons that lack a functional SMN1 gene, thereby addressing the root cause of SMA.

AAV9 Antibody Data

Zolgensma introduces a functional copy of the SMN gene using the adeno-associated viral vector 9 (AAV9). AAV9 is a common virus not known to cause disease in humans, and there is a low prevalence of anti-AAV antibodies in young children, lowering the probability of immunological reaction to the AAV9 vector.

Approximately five percent of patients (9/177) up to five years of age who underwent screening for Zolgensma were excluded from treatment across the clinical development program (including intravenous and intrathecal administration) and Managed Access Program due to elevated AAV9 antibody titers greater than 1:50. Of those screened, more than 150 patients have been dosed with Zolgensma to date.

Cure SMA Supports 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. Adeno-associated virus serotype 9 (AAV9) has 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 IV delivery, and injection directly into the CSF, a process known as IT delivery. The IV delivery approach is currently under review for approval by the FDA.

IT delivery of 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. IT delivery of gene therapy is currently being tested in clinical trials.

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Topics: Clinical Trials, Research, Front Page News

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