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AveXis data reinforce effectiveness of Zolgensma® in treating spinal muscular atrophy (SMA) Type 1

  • Ph 3 STR1VE data show prolonged event-free survival, early and rapid increases in CHOP-INTEND and significant milestone achievement in SMA Type 1, consistent with START trial
  • First-in-human biodistribution data show transduction in intended CNS targets and widespread SMN expression comparable to tissue from unaffected control
  • More than 150 patients treated with Zolgensma, only 5% of screened patients up to 5 years old excluded due to AAV9 antibody titers greater than 1:50

Basel, April 16, 2019 – AveXis, a  Novartis company, today announced that interim data from its Phase 3 STR1VE  trial of Zolgensma®(onasemnogene  abeparvovec-xioi; AVXS-101)1 in spinal muscular atrophy (SMA)  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.

"These STR1VE data reinforce what was  seen in the pivotal Phase 1 START trial, including trends toward prolonged  survival and milestone achievement never seen in the natural history of the untreated  disease," said Olga Santiago, MD, Chief Medical Officer, AveXis. "With a  patient population and baseline characteristics closely matched to the START  trial, these data build upon the body of evidence supporting the use of  Zolgensma for SMA Type 1."

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.2 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 age3.

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).


Milestone Achieved, n (%)a

Phase 3 STR1VE Study, n=22

September 27, 2018

December 31, 2018

Holds head erect ≥3 seconds without supportb

12 (54.5)c

17 (77.3)

Turns from back to both right and left sided

3 (13.6)

7 (31.8)

Sits without support for ≥30 secondse

3 (13.6)

8 (36.4)

Stands with assistancef


1 (4.5)

Median duration of follow-up at data cut

5.5 months

8.1 months

Median age at data cut

9.4 months

12.5 months

Patients older than 12 months, n (%)

5 (22.7)

13 (59.1)

Bayley-III, Bayley  Scales of Infant and Toddler Development, V.3; SMA1, spinal muscular atrophy  type 1.
  aDevelopmental milestones were confirmed by video; bIn  accordance with Bayley-III, gross motor subtest item #4; cOne  patient reached the milestone of head control at the first screening visit  (prior to dosing); dIn accordance with Bayley-III, gross motor subtest gross  motor subtest item #20; eIn accordance with Bayley-III, gross motor  subtest item #26; fIn accordance with Bayley-III, gross motor subtest item  #33 – supports own weight for ≥2 seconds.

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.

AveXis is grateful to the courageous patients  and families who participate in our trials, enabling us to further our efforts  to make a meaningful difference in the lives of patients with rare genetic  diseases.  

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.

Evaluation of Zolgensma transgene DNA, mRNA and SMN protein biodistribution  was assessed by ddPCR™, RT-PCR and immunohistochemical SMN protein staining,  respectively. The results of these analyses consistently demonstrated that Zolgensma  vector genomes, RNA transcripts and SMN protein were broadly distributed and  detected in all organs tested. Zolgensma vector genomes per diploid genome were  detected in cervical, thoracic, lumbar and sacral regions. Correspondingly, in  each of these spinal cord regions, SMN protein was expressed in spinal motor  neurons at levels similar to non-SMA Type 1 tissues. SMN protein expression was  also detected in cortical and subcortical regions of the motor cortex and  medulla. Both Zolgensma and non-SMA Type 1 tissues were clearly distinct from tissues  from untreated SMA Type 1 patients. 

Analysis of the motor neuron marker choline acetyltransferase (ChAT)  demonstrated that motor neurons were abundant and of normal size and shape in the  Zolgensma-treated patient tissue. In contrast, ChAT motor neuron staining in  the non-treated SMA Type 1 patient tissue was sparse, suggesting the motor  neurons were sick and/or dying.

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 vector4,5,6.

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.

About Zolgensma®
Zolgensma® (onasemnogene  abeparvovec-xioi; AVXS-101) is an investigational gene therapy currently in  development as a one-time infusion for SMA Type 1. Zolgensma is designed to  address the monogenic root cause of SMA and prevent further muscle degeneration  by providing a copy of the human SMN gene to halt disease progression through  rapid and sustained SMN protein expression. Zolgensma represents the first in a  proprietary platform to treat rare, monogenic diseases using gene therapy. In  December, the FDA accepted the company's Biologics License Application for use  of Zolgensma with SMA Type 1 patients. The drug previously received  Breakthrough Therapy designation and has been granted Priority Review by the  FDA, with regulatory action anticipated in May 2019.  In addition, the drug is anticipated to receive approval in Japan and the European Union later this year.

About Spinal  Muscular Atrophy (SMA)
SMA is a severe neuromuscular disease characterized  by the loss of motor neurons leading to progressive muscle weakness and  paralysis. SMA is caused by a genetic defect in the SMN1 gene  that codes SMN, a protein necessary for survival of motor neurons. The  incidence of SMA is approximately one in 10,000 live births and is the leading  genetic cause of infant mortality. The most severe form of SMA is Type 1, a  lethal genetic disorder characterized by rapid motor neuron loss and associated  muscle deterioration, which results in mortality or the need for permanent  ventilation support by 24 months of age for more than 90 percent of patients.

This press release contains forward-looking statements  within the meaning of the United States Private Securities Litigation Reform  Act of 1995. Forward-looking statements can generally be identified by words  such as "potential," "can," "will," "plan," "expect," "anticipate," "look  forward," "believe," "committed," "investigational," "pipeline," "launch," or  similar terms, or by express or implied discussions regarding potential  marketing approvals, new indications or labeling for Zolgensma  and the other investigational products described in this press release, or  regarding potential future revenues from such products. You should not place  undue reliance on these statements. Such forward-looking statements are based  on our current beliefs and expectations regarding future events, and are  subject to significant known and unknown risks and uncertainties. Should one or  more of these risks or uncertainties materialize, or should underlying  assumptions prove incorrect, actual results may vary materially from those set  forth in the forward-looking statements. There can be no guarantee that Zolgensma or the other investigational products described in this  press release will be submitted or approved for sale or for any additional  indications or labeling in any market, or at any particular time. Nor can there  be any guarantee that such products will be commercially successful in the  future. In particular, our expectations regarding such products could be  affected by, among other things, the uncertainties inherent in research and  development, including clinical trial results and additional analysis of  existing clinical data; regulatory actions or delays or government regulation  generally; global trends toward health care cost containment, including  government, payor and general public pricing and reimbursement pressures and  requirements for increased pricing transparency; our ability to obtain or  maintain proprietary intellectual property protection; the particular  prescribing preferences of physicians and patients; general political and economic  conditions; safety, quality or manufacturing issues; potential or actual data  security and data privacy breaches, or disruptions of our information  technology systems, and other risks and factors referred to in Novartis AG's  current Form 20-F on file with the US Securities and Exchange Commission.  Novartis is providing the information in this press release as of this date and  does not undertake any obligation to update any forward-looking statements  contained in this press release as a result of new information, future events  or otherwise.

About AveXis
AveXis, a Novartis company, is dedicated to developing and commercializing novel  treatments for patients suffering from rare and life-threatening neurological  genetic diseases. Our initial product candidate, Zolgensma, is a proprietary  gene therapy currently in development for the treatment of spinal muscular  atrophy, or SMA. In addition to developing Zolgensma to treat SMA, AveXis also  plans to develop other novel treatments for rare neurological diseases,  including Rett syndrome and a genetic form of amyotrophic lateral sclerosis  caused by mutations in the superoxide dismutase 1 (SOD1) gene. For  additional information, please visit

About Novartis
Novartis is  reimagining medicine to improve and extend people's lives. As a leading global  medicines company, we use innovative science and digital technologies to create  transformative treatments in areas of great medical need. In our quest to find  new medicines, we consistently rank among the world's top companies investing  in research and development. Novartis products reach more than 750 million  people globally and we are finding innovative ways to expand access to our  latest treatments. About 105 000 people of more than 140 nationalities work at  Novartis around the world. Find out more at

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  1. The brand name Zolgensma® (onasemnogene abeparvovec-xioi) has been provisionally approved by the FDA for the investigational product AVXS-101, but the product itself has not received marketing authorization or BLA approval from any regulatory authorities.
  2. An event is 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 perioperative change.
  3. Finkel RS, et al. Neurology. 2014;83:810–817.
  4. Colella P, et al. Mol Ther Methods Clin Dev. 2017;8:87–104.
  5. Calcedo R, et al. Clin Vaccine Immunol. 2011;18:1586–8.
  6. Mimuro J, et al. J Med Virol. 2014;86:1990–7.


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