-
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 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 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 |
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.
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 ddPCRTM,
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®
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.
Disclaimer
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 www.avexis.com.
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 www.novartis.com.
Novartis is on Twitter. Sign up to follow
@Novartis at http://twitter.com/novartis
For Novartis multimedia content, please visit
www.novartis.com/news/media-library
For questions about the site or required registration, please
contact media.relations@novartis.com
References
[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.
# # #
Novartis Media
Relations
Central media line: +41 61 324 2200
E-mail: media.relations@novartis.com
Eric
Althoff
Novartis Global Media Relations
+41 61 324 7999 (direct)
+41 79 593 4202 (mobile)
eric.althoff@novartis.com |
Farah
Bulsara Speer
VP, Corporate Communications, AveXis
+1 312 543 2881 (mobile)
fSpeer259@avexis.com
|
Novartis Investor
Relations
Central investor relations line: +41 61 324 7944
E-mail: investor.relations@novartis.com
Central |
|
North
America |
|
Samir
Shah |
+41 61
324 7944 |
Richard
Pulik |
+1 862
778 3275 |
Pierre-Michel Bringer |
+41 61
324 1065 |
Cory
Twining |
+1 862
778 3258 |
Thomas
Hungerbuehler |
+41 61
324 8425 |
|
|
Isabella
Zinck |
+41 61
324 7188 |
|
|
Media release (PDF)