– A mean increase in CHOP-INTEND of 17.3 was
observed at three months post gene therapy in SMA Type 1 U.S.
pivotal trial –
AveXis, Inc. (NASDAQ:AVXS), a clinical-stage gene therapy company
developing treatments for patients suffering from rare and
life-threatening neurological genetic diseases, will present
initial results from the Type 1 U.S. Pivotal trial (STR1VE) and
24-month follow-up data from the Phase 1 trial of AVXS-101 for the
treatment of spinal muscular atrophy (SMA) Type 1 at the 2018
Annual Meeting of the American Academy of Neurology (AAN)
Annual Meeting in Los Angeles.
“With a population closely matched to the Phase 1 trial,
preliminary safety data and the early and rapid increases in
CHOP-INTEND scores achieved by infants in this pivotal STR1VE trial
are consistent with results of the Phase 1 trial of AVXS-101 in SMA
Type 1,” said John W. Day, MD, PhD, Professor, Neurology &
Pediatrics, and Director of the Stanford Neuromuscular Program,
Stanford University Medical Center, who will present these data at
AAN. “These early signs of efficacy and safety are promising, and I
look forward to seeing the trial progress.”
Initial Data from Pivotal Trial of AVXS-101 in SMA Type
1 (STR1VE) as of April 11, 2018As of April 11, 2018, 11
patients were enrolled in the trial, and six patients were
symptomatic and at least one-month post gene therapy treatment. All
patients had homozygous deletion of SMN1 and two copies of SMN2; no
patient had the known SMN2 gene modifier mutation (c.859G>C).
The patient population and baseline characteristics are closely
matched to the Phase 1 trial.
Event-free Survival and SafetyAll patients (6/6) were alive and
event-free as of April 11, 2018. AVXS-101 appeared to have a
favorable safety profile and to be generally well tolerated. At the
time of gene transfer, the mean age was 3.2 months, with the oldest
patient being 5.0 months of age.
In the six patients who were at least one-month post gene
transfer, a cumulative total of 25 adverse events (AEs) were
reported. Two patients experienced transient elevations in
transaminases greater than 3x ULN that were not clinically
significant and all resolved with prednisolone treatment without
any clinical manifestations or sequelae. There were no serious
adverse events (SAEs) reported.
Motor Function AchievementChildren’s Hospital of Philadelphia
Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores
increased by an average of 7.8 at one month after gene transfer (in
six patients) and 17.3 at three months after gene transfer (in
three patients), reflecting improvement in motor function. These
data correlate to CHOP-INTEND achievement by the proposed
therapeutic dose cohort (Cohort 2) in the Phase 1 trial, which
experienced mean increases of 9.8 points at one month and 15.4
points at three months. Early CHOP-INTEND increases have been
observed to be associated with eventual milestone achievement.
The open-label, single-arm, single-dose, multi-center trial –
known as STR1VE – is designed to evaluate the efficacy and safety
of a one-time IV infusion of AVXS-101 of 1.1 x 1014 vector
genomes/kg in patients with SMA Type 1 who are less than six months
of age at the time of gene therapy, have one or two copies of the
SMN2 backup gene as determined by genetic testing, and have
bi-allelic SMN1 gene deletion or point mutations. The
intent-to-treat population is defined as patients who are less than
six months of age and symptomatic at the time of gene therapy, with
two copies of the SMN2 gene as determined by genetic
testing, bi-allelic SMN1 gene deletion and no c.859G>C
mutation in SMN2.
The co-primary efficacy outcome measures include the achievement
of the developmental milestone of independent sitting for at least
30 seconds at 18 months of age and event-free survival at 14 months
of age, with an event 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. Co-secondary outcome measures include the
ability to thrive and the ability to remain independent of
ventilatory support at 18 months of age.
24-Month Follow-Up Data from Phase 1 Trial of AVXS-101
in SMA Type 1The following 24-month follow-up data from
the Phase 1 trial will be presented during platform presentations
by Samiah Al-Zaidy, MD, Co-Investigator for the trial; Linda Lowes,
PhD, Director of Clinical Therapies Research and a member of the
Center for Gene Therapy at the Research Institute of Nationwide
Children’s Hospital; and Richard Shell, MD, member of the Section
of Pulmonary Medicine at Nationwide Children’s Hospital.
The Phase 1, open-label, dose-escalation trial was designed to
evaluate the safety and tolerability of AVXS-101 in patients with
SMA Type 1. The key measures of efficacy were the time from birth
to an event and video confirmed achievement of ability to sit
unassisted. Additionally, several exploratory objective measures
were assessed, including a standard motor milestone development
survey and CHOP INTEND. After the 24-month follow-up, to date, 11
patients have enrolled in the Long-Term Follow-Up (LTFU) trial for
ongoing evaluation.
Event-free Survival and Safety
Twenty-four months following gene transfer, 15 of 15 (100%)
patients were alive and without need for permanent ventilation. The
median age at last follow-up was 27.8 months and 30.7 months for
patients in the Cohort 2 and low-dose cohort (Cohort 1),
respectively. Natural history indicates only eight percent of
untreated patients with SMA Type 1 survive event-free at 20 months
of age.
AVXS-101 appeared to have a favorable safety profile and to be
generally well tolerated, with no new treatment-related safety or
tolerability concerns identified at the 24-month follow-up.
- A cumulative total of 319 AEs (five treatment-related AEs and
314 non-treatment related AEs) were reported following monitoring
and source verification. Of these, 60 were determined to be SAEs
and 259 were non-serious AEs.
- As reported in 2016, one patient in Cohort 1 had a pulmonary
event that required 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. Following
surgery, the respiratory support needs decreased below event
definition threshold.
- As has been previously reported, a total of five AEs in four
patients were deemed treatment-related. Of these, two were SAEs
experienced by two patients, and three were non-serious AEs
experienced by two patients. All consisted of clinically
asymptomatic liver enzyme elevations and were resolved with
prednisolone treatment. There were no clinically significant
elevations of gamma-glutamyl transferase, 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.
Treatment Durability and Motor Milestone Achievement from
Long-Term Follow-Up Study
Patients in Cohort 2 continued to achieve new milestones during
the LTFU trial. Detailed Cohort 2 motor milestone data is included
in the chart below.
- Two additional patients achieved the ability to sit unassisted
for 30 seconds or more. Eleven of 12 (92%) patients could sit
unassisted.
- Two additional patients achieved the ability to stand with
assistance. Four of 12 (33%) could stand with assistance.
- Three of four patients achieving these new milestones were on
AVXS-101 alone (one sitting and two standing with assistance).
- The oldest child from Cohort 2 at the time of last visit in the
LTFU study was 46.2 months and 40.6 months post gene therapy.
|
|
|
|
|
Cohort 2 |
Age at Gene Transfer (mos) |
Event-Free Survivala |
Event-free Survival and Motor and Other
Milestones Among the 12 Patients in Cohort 2 as of December 15,
2017* |
|
Brings Hand to Mouth |
Controls Head |
Rolls Overb |
Sits with Assistance |
Sits Unassistedc |
Other Achievements |
|
|
≥5 seconds |
≥10 seconds |
≥30 seconds |
Speaks |
Swallows |
No NIV Use |
No Nutritional Supportd |
|
E.04 |
5.6 |
31.1 |
|
+ |
+ |
+ |
+ |
+ |
O |
O |
+ |
+ |
|
|
|
E.05 |
4.2 |
28.5 |
|
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
|
E.06 |
1.9 |
26.1 |
|
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
|
E.07 |
3.6 |
28.1 |
|
+ |
+ |
+ |
+ |
+ |
+ |
O |
+ |
+ |
+ |
|
|
E.08 |
7.9 |
32.4 |
|
+ |
|
|
|
|
|
|
|
|
|
|
|
E.09 |
4.9 |
28.9 |
|
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
|
E.10 |
0.9 |
25.3 |
|
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
|
E.11 |
2.3 |
27.7 |
|
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
|
|
|
E.12 |
2.6 |
26.8 |
|
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
|
E.13 |
0.9 |
25.4 |
|
+ |
+ |
|
+ |
+ |
+ |
+ |
+ |
+ |
|
|
|
E.14 |
4.1 |
27.9 |
|
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
|
E.15 |
2.1 |
26.3 |
|
+ |
+ |
|
+ |
+ |
+ |
+ |
+ |
+ |
|
|
|
Patient with Outcome (%) |
|
This Trial |
100 |
% |
100 |
% |
92 |
% |
75 |
% |
92 |
% |
92 |
% |
92 |
% |
92 |
% |
92 |
% |
92 |
% |
58 |
% |
50 |
% |
|
Natural History |
8% by 20 monthse |
NA |
0 |
|
0** |
0** |
0** |
0** |
0** |
NA |
NA |
NA |
25% by 13 monthsf |
|
*At baseline, none of the patients in Cohort 2 had achieved any
of the listed motor milestones except for bringing a hand to the
mouth. As of December 15, 2017, the majority of these patients had
reached at least one major motor milestone. No patients in Cohort 1
are listed, since none attained any motor milestones. NA denotes
not available, and NIV denotes noninvasive ventilation. Plus signs
indicate achievement of milestone.a. Event-free survival (the
primary efficacy outcome) was defined as the age at the end of the
trial at which patients were free of ventilatory support, which was
defined as the need for ventilation for at least 16 hours per day
for at least 14 consecutive days in the absence of acute reversible
illness or perioperatively. b.
According to item 20 on the Bayley Scales of Infant and Toddler
Development, rolling over is defined as movement of at least 180
degrees both left and right from a position of lying on the
back. c. Sitting unassisted for at least 5 seconds is in
accordance with the criteria of item 22 on the Bayley Scales of
Infant and Toddler Development gross motor subtest and surpasses
the 3-second count that is used as a basis for sitting (test item
1) on the Hammersmith Functional Motor Scale–Expanded for SMA.
Sitting unassisted for at least 10 seconds is in accordance with
the criteria used in the World Health Organization Multicentre
Growth Reference Study. Sitting unassisted for at least 30 seconds
defines functional independent sitting and is in accordance with
the criteria of item 26 on the Bayley Scales of Infant and Toddler
Development gross motor subtest. d. Nutritional support refers to
the placement of either a gastrostomy tube or a nasogastric tube,
as determined by the preference of the parents or the primary
physician. Once enrolled in the trial, all the patients who
required nutritional support underwent gastrostomy-tube placement,
and none were removed during the
trial.
e. Data are from Finkel et al. f. Defined as nasogastric tube
or gastrostomy tube. Data are from Finkel et
al. ** Data are from De Sanctis et
al.
O Denotes milestone achieved during LTFU.
Nutritional and Respiratory Support Patients in Cohort 2 showed
a reduced need for nutritional and ventilatory support and
improvement in swallowing function. According to natural history,
nearly all patients with SMA Type 1 require nutritional and
respiratory support by 12 months of age, and most patients are not
able to swallow or speak effectively.
- Six of seven (86%) patients in Cohort 2 that did not require
feeding support before treatment continued without feeding support
after treatment; seven of 10 (70%) patients that did not require
BiPAP support before treatment continued without any BiPAP after
treatment.
- Eleven of 12 (92%) patients in Cohort 2 were fed orally, and
six of 12 (50%) patients were exclusively fed orally; and eleven of
12 (92%) patients were able to speak.
“The long-term follow-up data from the Phase 1 trial showed
unprecedented event-free survival, continued developmental
milestone achievement and long-term durability, with no new safety
findings,” said Dr. Sukumar Nagendran, Chief Medical Officer of
AveXis. “In aggregate, these data presented at AAN demonstrate a
one-time administration of AVXS-101 appears to have a potentially
clinically transformative and durable impact on patients with SMA
Type 1.”
About SMASMA 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 motor neuron loss and associated muscle
deterioration, which results in mortality or the need for permanent
ventilation support before the age of two for greater than 90
percent of patients. SMA Type 2 typically presents between six and
18 months of age, and those affected will never walk without
support and most will never stand without support. SMA Type 2
results in mortality in more than 30 percent of patients by the age
of 25.
About AVXS-101AveXis’ initial product
candidate, AVXS-101, is its proprietary gene therapy currently in
development for the one-time treatment of SMA Types 1 and 2,
designed to address the monogenic root cause of SMA and prevent
further muscle degeneration by addressing the defective and/or loss
of the primary SMN gene. AVXS-101 also targets motor neurons,
providing rapid onset of effect and crossing the blood brain
barrier to allow effective targeting of both central and systemic
features.
About AveXis, Inc.AveXis, Inc. is a
clinical-stage gene therapy company, dedicated to developing and
commercializing novel treatments for patients suffering from rare
and life-threatening neurological genetic diseases. Our initial
product candidate, AVXS-101, is our proprietary gene therapy
currently in development for the treatment of spinal muscular
atrophy, or SMA, Type 1, the leading genetic cause of infant
mortality, and SMA Type 2. The U.S. Food and Drug Administration,
or FDA, has granted AVXS-101 Orphan Drug Designation for the
treatment of all types of SMA and Breakthrough Therapy Designation,
as well as Fast Track Designation for the treatment of SMA Type 1.
In addition to developing AVXS-101 to treat SMA Type 1 and Type 2,
we also plan 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.
Forward-Looking Statements This press release
contains "forward-looking statements," within the meaning of the
Private Securities Litigation Reform Act of 1995, regarding, among
other things, the potential long-term safety and efficacy of
AVXS-101, the potential durability of a single administration of
AVXS-101 and the potential future progress of patients in the
STR1VE trial and the LTFU study. Such forward-looking
statements are based on current expectations and involve inherent
risks and uncertainties, including factors that could delay, divert
or change any of them, and could cause actual results to differ
materially from those projected in its forward-looking statements.
Meaningful factors which could cause actual results to differ
include, but are not limited to, uncertainties concerning the
long-term efficacy and safety of AVXS-101, as well as other factors
discussed in the "Risk Factors" and the "Management's Discussion
and Analysis of Financial Condition and Results of Operations"
sections of AveXis’ Annual Report on Form 10-K for the year ended
December 31, 2017, filed with the SEC on February 28, 2018. In
addition to the risks described above and in the Annual Reports on
Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form
8-K and other filings with the SEC, other unknown or unpredictable
factors also could affect AveXis’ results. There can be no
assurance that the actual results or developments anticipated by
AveXis will be realized or, even if substantially realized, that
they will have the expected consequences to, or effects on, AveXis.
Therefore, no assurance can be given that the outcomes stated in
such forward-looking statements and estimates will be achieved.
Media Inquiries:Lauren BarbieroW2O
Group646-564-2156lbarbiero@w2ogroup.com
Investor Inquiries:Jim GoffAveXis,
Inc.650-862-4134jgoff@avexis.com
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