Press Release: Novartis: AveXis data reinforce effectiveness of Zolgensma(R) in treating spinal muscular atrophy (SMA) Type 1

Novartis International AG / AveXis data reinforce effectiveness of

Zolgensma(R) in treating spinal muscular atrophy (SMA) Type 1.

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responsible for the content of this announcement.

-- 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(R) (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 age[3].

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

support(b) 12 (54.5)(c) 17 (77.3)

Turns from back to both right and left

side(d) 3 (13.6) 7 (31.8)

Sits without support for >=30

seconds(e) 3 (13.6) 8 (36.4)

Stands with assistance(f) 0 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.

(a) Developmental milestones were confirmed by video; (b) In accordance

with Bayley-III, gross motor subtest item #4; (c) One patient reached

the milestone of head control at the first screening visit (prior to

dosing); (d) In accordance with Bayley-III, gross motor subtest gross

motor subtest item #20; (e) In accordance with Bayley-III, gross motor

subtest item #26; (f) In 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(TM), 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 vector[4],[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(R)

Zolgensma(R) (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

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April 16, 2019 16:45 ET (20:45 GMT)