Pfizer Inc. (NYSE: PFE) today announced updated Phase 1b
clinical data on PF-06939926, an investigational gene therapy being
developed to treat Duchenne muscular dystrophy (DMD). The
preliminary data from 9 ambulatory boys with DMD, aged 6 to 12
(mean age: 8 years) indicate that the intravenous administration of
PF-06939926 was well-tolerated during the infusion period, with
encouraging efficacy and manageable safety events, even when
considering those adverse events that were more severe in nature.
The treatment provided durable and statistically significant
improvements across multiple efficacy-related endpoints measured at
12 months post-infusion, including sustained levels of
mini-dystrophin expression and improvements on the North Star
Ambulatory Assessment (NSAA) rating scale, which is a validated
measure of muscle function. Three serious adverse events (SAEs)
were recorded, two of which reflected likely complement activation.
While these two SAEs were severe in nature, all three events fully
resolved within 2 weeks, providing encouragement that close
monitoring and early intervention can help mitigate the effects of
complement activation. This new dataset, which includes updated
12-month results on safety, dystrophin expression, and exploratory
functional endpoints for 3 additional boys, was presented for the
first time during a virtual oral session today at the American
Society of Gene & Cell Therapy (ASGCT) Annual Meeting.
DMD is a devastating and life-threatening X-linked disease that
is caused by mutations in the gene encoding dystrophin, which is
needed for proper muscle membrane stability and function. Patients
present with muscle degeneration that progressively worsens with
age to the extent that they require wheelchair assistance when they
are in their early teens, and unfortunately, usually succumb to
their disease by the time they are in their late twenties. It is
estimated that there are ~10-12,000 individuals affected with DMD
in the US.
“Based on the encouraging preliminary efficacy data and
manageable safety events from our Phase 1b study, we believe we may
have a potential breakthrough therapy for boys with Duchenne
muscular dystrophy, a devastating disease for which there remains a
significant medical need,” said Seng Cheng, PhD, Chief Scientific
Officer, Pfizer Rare Disease Research Unit. “ We are advancing our
Phase 3 program as quickly as possible and plan to begin dosing
patients in the second half of 2020 pending regulatory approval.
Our program has the potential to be the first DMD gene therapy
Phase 3 trial start using a commercial-scale manufacturing process.
If the program is successful, this manufacturing capability is
expected to help position us to deliver this medicine to patients
quickly following regulatory approval.”
Data presented at the ASGCT virtual meeting included results
from the study of 9 ambulatory boys with DMD, aged 6 to 12 (mean
age: 8 years). Three of those 9 patients received a one-time
intravenous infusion of PF-06939926 at 1E14 vector genomes per
kilogram (vg/kg) (considered to be the low dose) and the other 6
received a one-time intravenous dose of 3E14 vg/kg (considered to
be the high dose).
Preliminary Safety Results
The primary endpoint of the Phase 1b study is to assess the
safety and tolerability of this investigational gene therapy in
ambulatory boys with Duchenne muscular dystrophy through 12 months
following treatment. Based on the data to date, the most common
adverse events (AEs) suspected to be related to PF-06939926
(occurring in >40% of patients) were vomiting, nausea, decreased
appetite, and pyrexia. There was no evidence of clinically relevant
anti-dystrophin responses or hepatic dysfunction with the
protocol-defined daily glucocorticoid regimen.
Among the 9 patients, 3 serious adverse events (SAEs) were
reported in the first 14 days following administration, one more
SAE than at Pfizer’s previous update. Importantly, each of these
SAEs was fully resolved and at their last clinic visits, all
patients were doing well. The first SAE involved persistent
vomiting resulting in dehydration, which required admission for IV
anti-emetics and fluids. The second SAE involved acute kidney
injury with atypical hemolytic uremic syndrome (aHUS)-like
complement activation, which required hemodialysis and treatment
with eculizumab. The most recent SAE involved thrombocytopenia with
aHUS-like complement activation which required platelet transfusion
and treatment with eculizumab. Based on safety observations over
the course of the study, Pfizer amended the clinical study protocol
to include increased monitoring and management regimes, which
helped enable timely intervention and mitigation in the case of the
third SAE.
Results from Secondary and Exploratory Endpoints
Secondary endpoints of the clinical study included measurement
of mini-dystrophin concentration by liquid chromatography mass
spectrometry (LCMS) and distribution within muscle fibers by
immunofluorescence.
Dystrophin concentration
Dystrophin concentrations in healthy or “normal” muscle, or
muscle with no known disease, vary widely between samples and
individuals, and no industry standard currently exists for defining
a “normal” level. Historically, dystrophin concentration was
measured by Western Blot. However, due to limitations of this
methodology, Pfizer leveraged its internal expertise in
immuno-affinity mass spectrometry protein quantification and
developed a proprietary assay to measure dystrophin concentration
with a wide dynamic range and low variability. This novel LCMS
assay is an anti-peptide antibody enriched, immunoaffinity liquid
chromatography tandem mass spectrometry (IA LCMS/MS) assay that has
been validated by Pfizer in preclinical species and human tissues
and discussed with the United States Food and Drug Administration
(FDA).
Using this LCMS assay, “normal” concentrations of dystrophin
were established to compare to secondary endpoint results in
patients. These “normal” reference levels were based on pooled
skeletal muscle biopsies from 60 pediatric samples. In the Phase 1b
trial, new results from open muscle biopsies of the biceps of the 3
patients in the low dose cohort showed that the mean percent normal
dystrophin at 12 months was 24.0%. For the 3 patients in the
high-dose cohort for whom 12-month data are available, the mean
percent normal dystrophin at 12 months was 51.6%. Comparisons
between baseline and post-treatment measures were significant (p
< 0.005 at 2 months [N=9], and p < 0.05 at 12 months [N=6]).
The increases in dystrophin levels observed at 2 months were
generally sustained at 12 months, and 5 of the 6 boys showed an
increase in mini-dystrophin concentration between the 2- and
12-month time points.
Dystrophin distribution
New results from open muscle biopsies of the biceps at both dose
levels using an updated digital platform and analysis with a new
quantitative imaging algorithm show dystrophin immunofluorescence,
measured as the proportion of muscle fibers expressing dystrophin.
Of the 3 patients in the low dose cohort, the mean percent positive
fibers was 28.5% at 2 months and 21.2% at 12 months. Of the 6
patients in the high dose cohort, the mean percent positive fibers
at 2 months was 48.4%. For the 3 patients in the high dose cohort
for whom 12-month data are available, the mean percent positive
fibers was 50.6% at 12 months.
Functional assessment
Functional assessments are considered exploratory in this study,
due to the small number of planned patients and the risk for bias
in an open-label study. However, preliminary results for the North
Star Ambulatory Assessment (NSAA) are available for the six
patients with at least 1 year of follow-up, 3 of whom received
PF-06939926 at the low dose and 3 of whom received it at the high
dose. While baseline natural history NSAA scores are variable,
generally scores are stable or decline in DMD patients over 6 years
old, with the rate of progression associated with the baseline age
and function. This pattern has been reported in a natural history
database from the UK (Muntoni et al, PLoS ONE, 2019). The patients
in Pfizer’s Phase 1b study, showed a significant functional
improvement from baseline NSAA scores after one year, compared with
the scores in an independent, external control group derived from
recent prior clinical trials involving boys with DMD, who were
matched specifically by age, weight and function (i.e. median loss
of 4 points in NSAA total score for external placebo group [N=61]
vs. improvement of 3.5 points in the Phase 1b patients [N=6], p =
0.003).
A second exploratory analysis using MRI showed a reduction in
fat fraction in the thighs of boys treated with the high dose at 12
months post-treatment. Boys with DMD typically exhibit a
progressive loss of contractile or lean muscle and replacement with
fat and fibrotic tissue. In this study, a reduction in fat fraction
was observed in boys from the high dose-treated cohort when
compared to an external placebo group, suggesting that gene therapy
may have improved muscle fiber health and quality in these boys. No
reduction in fat fraction was seen in the low dose group.
“Taken together, we believe these data support the view that
administration of PF-06939926 at a dose of 3E14 vg/kg can lead to
expression of potentially therapeutic levels of mini-dystrophin
that may translate to a measurable improvement in muscle function
and health in DMD patients,” said Cheng. “We also want to give our
heartfelt thanks to all the patients, their families, the
researchers, investigators, other clinicians and advocacy
organizations for their passion, expertise and engagement in
helping to advance clinical research and care for the Duchenne
muscular dystrophy community.”
About PF-06939926
PF-06939926 is an investigational, recombinant adeno-associated
virus serotype 9 (AAV9) capsid carrying a shortened version of the
human dystrophin gene (mini-dystrophin) under the control of a
human muscle-specific promotor. The AAV9 capsid was chosen as the
delivery vector because of its potential to target muscle tissue.
Pfizer initiated the Phase 1b multi-center, open-label,
non-randomized, ascending dose study of a single intravenous
infusion of PF-06939926 in 2018. The goal of the study is to assess
the safety and tolerability of this investigational gene therapy.
Other objectives of the clinical study include measurement of
dystrophin expression and distribution, as well as assessments of
muscle strength, quality and function.
About Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a serious genetic disease
characterized by progressive muscle degeneration and weakness.
Symptoms usually manifest in early childhood between the ages of 3
and 5. The disease primarily affects boys. Muscle weakness can
begin as early as age 3, first affecting the muscles of the hips,
pelvic area, thighs and shoulders, and later the skeletal
(voluntary) muscles in the arms, legs and trunk. By the early
teens, patients typically lose their ability to walk and the heart
and respiratory muscles are also affected, ultimately resulting in
premature death. DMD is the most common form of muscular dystrophy
worldwide with incidence of 1 in every 3500 to 5000 live male
births.
About Pfizer: Breakthroughs That Change Patients’
Lives
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
products, including innovative medicines and vaccines. Every day,
Pfizer colleagues work across developed and emerging markets to
advance wellness, prevention, treatments and cures that challenge
the most feared diseases of our time. Consistent with our
responsibility as one of the world's premier innovative
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DISCLOSURE NOTICE: The information contained in this release is
as of May 15, 2020. Pfizer assumes no obligation to update
forward-looking statements contained in this release as the result
of new information or future events or developments.
This release contains forward-looking information about gene
therapy and PF-06939926, an investigational gene therapy to
potentially treat Duchenne muscular dystrophy, including their
potential benefits and a potential Phase 3 study for PF-06939926,
that involve substantial risks and uncertainties that could cause
actual results to differ materially from those expressed or implied
by such statements. Risks and uncertainties include, among other
things, the uncertainties inherent in research and development,
including the ability to meet anticipated clinical endpoints,
commencement and/or completion dates for our clinical trials,
regulatory submission dates, regulatory approval dates and/or
launch dates, as well as the possibility of unfavorable new
clinical data and further analyses of existing clinical data; the
risks associated with initial and preliminary data; the risk that
clinical trial data are subject to differing interpretations and
assessments by regulatory authorities; whether regulatory
authorities will be satisfied with the design of and results from
our clinical studies; whether and when regulatory authorities will
approve the commencement of our planned Phase 3 study; whether and
when drug applications may be filed in any jurisdictions for any
potential indication for PF-06939926; whether and when any such
applications may be approved by regulatory authorities, which will
depend on myriad factors, including making a determination as to
whether the product's benefits outweigh its known risks and
determination of the product's efficacy and, if approved, whether
PF-06939926 will be commercially successful; decisions by
regulatory authorities impacting labeling, manufacturing processes,
safety and/or other matters that could affect the availability or
commercial potential of PF-06939926; uncertainties regarding the
impact of COVID-19 on our business, operations and financial
results; and competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2019 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information and Factors That May Affect Future
Results,” as well as in its subsequent reports on Form 8-K, all of
which are filed with the U.S. Securities and Exchange Commission
and available at www.sec.gov and www.pfizer.com.
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Media Contact: Steven Danehy (212) 733-1538
steve.danehy@pfizer.com
Investors: Bryan Dunn (212) 733-8917 bryan.dunn@pfizer.com
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