Dyne Therapeutics, Inc. (Nasdaq: DYN), a clinical-stage muscle
disease company focused on advancing innovative life-transforming
therapeutics for people living with genetically driven diseases,
today announced positive initial clinical data from its ACHIEVE
trial of DYNE-101 in patients with myotonic dystrophy type 1 (DM1)
and its DELIVER trial of DYNE-251 in patients with Duchenne
muscular dystrophy (DMD) who are amenable to exon 51 skipping.
“We are excited that Dyne’s first clinical data in two programs
have demonstrated proof-of-concept and validated the promise of the
FORCE™ platform in developing targeted therapeutics for rare muscle
diseases. In addition to the opportunity with our co-lead programs,
this clinical validation reinforces the potential of FORCE to
deliver for patients in other areas, including building a global
DMD franchise, addressing FSHD and exploring diseases involving the
CNS,” said Joshua Brumm, Dyne’s president and chief executive
officer. “The safety profiles for both DYNE-101 and DYNE-251 have
supported dose escalation to a combined 10 cohorts and the
administration of nearly 600 doses across both the ACHIEVE and
DELIVER trials. This positions us to optimize dose and dose regimen
in both trials with the goal of initiating registrational cohorts
as we end 2024. We anticipate reporting data for multiple, higher
dose cohorts from both trials in the second half of 2024, while
continuing to pursue expedited regulatory pathways and working to
help address the urgent need for therapeutics for people living
with DM1 and Duchenne.”
“These compelling initial data from our ACHIEVE and DELIVER
trials highlight the exciting opportunity we have to advance our
investigational therapeutics for devastating diseases with no or
limited treatment options. DYNE-101 demonstrated early
dose-dependent results, including in correction of splicing, the
key biomarker for DM1, as well as meaningful improvement in
myotonia at the lowest dose. Treatment with DYNE-251 surpassed the
level of dystrophin production reported for the standard of care
for DMD exon 51 with a fraction of the dose. Underpinning these
results are favorable safety profiles, which are critical in the
development of therapies for chronic diseases,” said Wildon
Farwell, M.D., MPH, Dyne’s chief medical officer. “We are grateful
to the participants, clinicians and the community for their ongoing
partnership as we collectively strive to transform the treatment of
rare muscle diseases.”
Phase 1/2 ACHIEVE Trial of DYNE-101 in DM1
The initial efficacy assessment of the DYNE-101 ACHIEVE trial is
based on data from 32 adult DM1 patients enrolled in the
randomized, placebo-controlled multiple ascending dose (MAD)
portion of the trial, including 6-month data from the 1.8 mg/kg
(approximate ASO dose) cohort (n=16) and 3-month data from the 3.4
mg/kg Q4W cohort (n=16). In each of these cohorts, participants
were randomized to receive either DYNE-101 (n=6) or placebo (n=4)
once every four weeks or participants in the recovery arm (n=6)
received two doses of DYNE-101 followed by placebo for the
remainder of the MAD portion of the trial.
In the ACHIEVE trial, DYNE-101 demonstrated a dose-dependent
splicing correction and increase in muscle delivery and DMPK
knockdown while also showing functional improvement in myotonia.
Key initial findings from ACHIEVE include:
- Muscle Delivery: Administration of 3.4 mg/kg
of DYNE-101 Q4W demonstrated a mean ASO muscle concentration of
21.5 ng/g at 3 months, while administration of 1.8 mg/kg Q4W showed
a mean ASO muscle concentration of 10.0 ng/g at 3 months.
- DMPK Knockdown: Evaluable
patients in the 3.4 mg/kg Q4W group had a 40% mean DMPK knockdown
from baseline compared to 25% in patients in the 1.8 mg/kg Q4W
group at 3 months.
- Splicing: Evaluable patients treated with 3.4
mg/kg Q4W of DYNE-101 had a 19% mean splicing correction from
baseline across a broad, 22-gene panel at 3 months, with all
evaluable participants experiencing an improvement. Patients in the
1.8 mg/kg Q4W group at 3 months had a 13% mean splicing
correction.
- Function: Patients treated with 1.8 mg/kg of
DYNE-101 Q4W had a mean 3.8 second benefit in myotonia at 6 months
as measured by video hand opening time (vHOT). Myotonia, which is
difficulty in relaxing muscles, is a common symptom of DM1
patients.
- Patient Reported Outcome (PRO): Patients in
the DYNE-101 1.8 mg/kg Q4W group experienced an overall improvement
at 6 months in the Myotonic Dystrophy Health Index (MDHI),
including the fatigue subscale, suggesting potential benefit of
DYNE-101 in the CNS.
Safety and tolerability data in this initial assessment of the
ACHIEVE trial are based on 45 patients enrolled through the 5.4
mg/kg Q8W cohort of the MAD portion. As of the data cutoff date2,
DYNE-101 has demonstrated a favorable safety profile. The majority
of treatment-emergent adverse events were mild or moderate and no
related serious treatment-emergent adverse events have been
identified. In addition, no participants demonstrated
treatment-emergent anemia, and no clinically meaningful changes
were observed in kidney or liver parameters. All participants who
have completed the MAD portion of ACHIEVE have enrolled in the
24-week open-label extension (OLE).
Enrollment is complete through the 5.4 mg/kg Q8W cohort of the
ACHIEVE trial (48 total patients enrolled), and approximately 300
doses have been administered to date, supporting dose escalation up
to 6.8 mg/kg. Dyne anticipates providing its next clinical data
update from the ACHIEVE trial in the second half of 2024.
Phase 1/2 DELIVER Trial of DYNE-251 in DMD
The initial efficacy assessment of the DYNE-251 DELIVER trial is
based on 6-month data from 6 male patients with DMD amenable to
exon 51 skipping enrolled in the 5 mg/kg (approximate PMO dose)
cohort of the randomized, placebo-controlled MAD portion of the
trial. Patients were randomized to receive either DYNE-251 (n=4) or
placebo (n=2) once every four weeks. Once every 4-week
administration of DYNE-251 reached levels of dystrophin expression,
exon skipping and percent dystrophin positive fibers that exceeded
levels reported in a clinical trial for the current weekly standard
of care for DMD exon 51, eteplirsen, at 6 months1 with a 24-fold
lower total PMO dose. Key initial findings from DELIVER
include:
- Muscle delivery: DYNE-251 showed a mean 657
ng/g PMO muscle drug concentration at 6 months.
- Exon 51 skipping: DYNE-251 demonstrated a mean
absolute exon skipping level of 0.90% and a 0.80% change from
baseline at 6 months. The current standard of care, eteplirsen,
which is administered weekly, showed a 0.59% mean absolute exon
skipping level and a 0.40% change from baseline at 6 months. 1
- Dystrophin expression measured by Western
blot: Patients treated with DYNE-251 had a mean absolute
dystrophin level of 0.88% of normal and a 0.28% change from
baseline at 6 months. Eteplirsen reached a mean absolute dystrophin
level of 0.30% of normal and a 0.06% change from baseline at 6
months.1
- Percent dystrophin positive fibers: DYNE-251
demonstrated 22.2% mean level of dystrophin positive fibers (PDPF)
and a 19.8% change from baseline at 6 months. Eteplirsen showed a
19.6% mean level of PDPF and a 10.7% change from baseline at 6
months.1
Safety and tolerability data in the DELIVER trial are based on
37 patients enrolled through the 20 mg/kg cohort of the MAD
portion. As of the data cutoff date2, DYNE-251 has demonstrated a
favorable safety profile. The majority of treatment-emergent
adverse events were mild or moderate and no related serious adverse
events have been identified. In addition, no participants
demonstrated treatment-emergent anemia, and no clinically
meaningful changes were observed in kidney parameters or
electrolytes, including magnesium. All participants who have
completed the MAD portion of DELIVER have enrolled in the 24-week
OLE.
Enrollment is complete through the 20 mg/kg cohort of the
DELIVER trial (40 total patients enrolled) and approximately 275
doses have been administered to date, supporting dose escalation up
to 40 mg/kg. Dyne anticipates providing its next clinical data
update from the DELIVER trial in the second half of 2024.
Virtual Event
Dyne will host a live video webcast event, “Achieving the
Promise of FORCE to Deliver for Patients,” to discuss these ACHIEVE
and DELIVER data today, January 3, 2024, at 8:00 a.m. ET. Dyne’s
leadership team will be joined by two leading neuromuscular disease
experts: Valeria A. Sansone, M.D., Ph.D., and Perry Shieh, M.D.,
Ph.D. Dr. Sansone is Clinical and Scientific Director at the
Clinical Center NeMO in Milan, Professor of Neurology, University
of Milan, and a principal investigator for the ACHIEVE trial. Dr.
Shieh is Professor of Neurology and Pediatrics at the David Geffen
School of Medicine at UCLA, a Neurologist at the Ronald Reagan UCLA
Medical Center in Los Angeles, and a principal investigator for the
DELIVER trial.
The live webcast will be available in the Events &
Presentations page of the Investors & Media section of Dyne’s
website and a replay will be accessible for 90 days following the
presentation. An accompanying slide presentation will also be
available. To access the presentation, register for the live
webcast and replay, please visit
https://investors.dyne-tx.com/news-and-events/events-and-presentations.
About ACHIEVE
ACHIEVE is a Phase 1/2 global clinical trial evaluating
DYNE-101, consisting of a 24-week multiple ascending dose (MAD)
randomized placebo-controlled period, a 24-week open-label
extension and a 96-week long-term extension. The trial, which is
designed to be registrational, is enrolling adult patients with
myotonic dystrophy type 1 (DM1) who are 18 to 49 years of age. The
primary endpoints are safety and tolerability, with secondary
endpoints of pharmacokinetics and pharmacodynamics, including
change from baseline in splicing, as well as measures of muscle
strength and function. For more information on the ACHIEVE trial,
visit https://www.clinicaltrials.gov/ (NCT05481879).
About DYNE-101
DYNE-101 is an investigational therapeutic being evaluated in
the Phase 1/2 global ACHIEVE clinical trial for people living with
DM1. DYNE-101 consists of an antisense oligonucleotide (ASO)
conjugated to a fragment antibody (Fab) that binds to the
transferrin receptor 1 (TfR1) which is highly expressed on muscle.
It is designed to enable targeted muscle tissue delivery with the
goal of reducing toxic DMPK RNA in the nucleus, releasing splicing
proteins, allowing normal mRNA processing and translation of normal
proteins, and potentially stopping or reversing the disease
progression. DYNE-101 has been granted orphan drug designation by
the European Medicines Agency and the U.S. Food and Drug
Administration for the treatment of DM1.
About Myotonic Dystrophy Type 1 (DM1)
DM1 is a rare, progressive, genetic disease that affects
skeletal, cardiac and smooth muscle. It is a monogenic, autosomal
dominant disease caused by an abnormal trinucleotide expansion in a
region of the DMPK gene. This expansion of CTG repeats causes toxic
RNA to cluster in the nucleus, forming nuclear foci and altering
the splicing of multiple proteins essential for normal cellular
function. This altered splicing, or spliceopathy, results in a wide
range of symptoms. People living with DM1 typically experience
myotonia and progressive weakness of major muscle groups, which can
affect mobility, breathing, heart function, speech, digestion and
vision as well as cognition. DM1 is estimated to affect more than
40,000 people in the United States and over 74,000 people in
Europe, but there are currently no approved disease-modifying
therapies.
About the DELIVER Trial
DELIVER is a Phase 1/2 global clinical trial evaluating
DYNE-251, consisting of a 24-week multiple ascending dose (MAD)
randomized placebo-controlled period, a 24-week open-label
extension and a 96-week long-term extension. The trial, which is
designed to be registrational, is enrolling ambulant and
non-ambulant males with Duchenne muscular dystrophy who are ages 4
to 16 and have mutations amenable to exon 51 skipping. The primary
endpoints are safety, tolerability and change from baseline in
dystrophin levels as measured by Western blot. Secondary endpoints
include measures of muscle function, exon skipping and
pharmacokinetics. For more information on the DELIVER trial,
visit https://www.clinicaltrials.gov/ (NCT05524883).
About DYNE-251
DYNE-251 is an investigational therapeutic being evaluated in
the Phase 1/2 global DELIVER clinical trial for people living with
DMD who are amenable to exon 51 skipping. DYNE-251 consists of a
phosphorodiamidate morpholino oligomer (PMO) conjugated to a
fragment antibody (Fab) that binds to the transferrin receptor 1
(TfR1) which is highly expressed on muscle. It is designed to
enable targeted muscle tissue delivery and promote exon skipping in
the nucleus, allowing muscle cells to create a truncated,
functional dystrophin protein, with the goal of stopping or
reversing disease progression. DYNE-251 has been granted fast
track, orphan drug and rare pediatric disease designations by the
U.S. Food and Drug Administration for the treatment of DMD
mutations amenable to exon 51 skipping.
In addition to DYNE-251, Dyne is building a global DMD franchise
and has preclinical programs targeting other exons, including 53,
45 and 44.
About Duchenne Muscular Dystrophy (DMD)
DMD is a rare disease caused by mutations in the gene that
encodes for dystrophin, a protein critical for the normal function
of muscle cells. These mutations, the majority of which are
deletions, result in the lack of dystrophin protein and progressive
loss of muscle function. DMD occurs primarily in males and affects
an estimated 12,000 to 15,000 individuals in the U.S. and 25,000 in
Europe. Loss of strength and function typically first appears in
pre-school age boys and worsens as they age. As the disease
progresses, the severity of damage to skeletal and cardiac muscle
often results in patients experiencing total loss of ambulation by
their early teenage years and includes worsening cardiac and
respiratory symptoms and loss of upper body function by the later
teens. There is no cure for DMD and currently approved therapies
provide limited benefit.
About Dyne Therapeutics
Dyne Therapeutics is a clinical-stage muscle disease company
focused on advancing innovative life-transforming therapeutics for
people living with genetically driven diseases. With its
proprietary FORCE™ platform, Dyne is developing modern
oligonucleotide therapeutics that are designed to overcome
limitations in delivery to muscle tissue. Dyne has a broad pipeline
for serious muscle diseases, including clinical programs for
myotonic dystrophy type 1 (DM1) and Duchenne muscular dystrophy
(DMD) and a preclinical program for facioscapulohumeral muscular
dystrophy (FSHD). For more information, please
visit https://www.dyne-tx.com, and follow us on X,
LinkedIn and Facebook.
Forward-Looking Statements
This press release contains forward-looking statements that
involve substantial risks and uncertainties. All statements, other
than statements of historical facts, contained in this press
release, including statements regarding Dyne’s strategy, future
operations, prospects and plans, objectives of management, the
potential of the FORCE platform, the anticipated timelines for
reporting data from the DYNE-101 and DYNE-251 clinical trials, and
plans to optimize dose and dose regimen for DYNE-101 and DYNE-251,
constitute forward-looking statements within the meaning of The
Private Securities Litigation Reform Act of 1995. The words
“anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,”
“intend,” “may,” “might,” “objective,” “ongoing,” “plan,”
“predict,” “project,” “potential,” “should,” or “would,” or the
negative of these terms, or other comparable terminology are
intended to identify forward-looking statements, although not all
forward-looking statements contain these identifying words. Dyne
may not actually achieve the plans, intentions or expectations
disclosed in these forward-looking statements, and you should not
place undue reliance on these forward-looking statements. Actual
results or events could differ materially from the plans,
intentions and expectations disclosed in these forward-looking
statements as a result of various important factors, including:
uncertainties inherent in the identification and development of
product candidates, including the initiation and completion of
preclinical studies and clinical trials; uncertainties as to the
availability and timing of results from preclinical studies and
clinical trials; the timing of and Dyne’s ability to initiate and
enroll patients in clinical trials; whether results from
preclinical studies and initial data from early clinical trials
will be predictive of the final results of the clinical trials or
future trials; whether Dyne’s cash resources will be sufficient to
fund the Company’s foreseeable and unforeseeable operating expenses
and capital expenditure requirements; as well as the risks and
uncertainties identified in Dyne’s filings with the Securities and
Exchange Commission (SEC), including the Company’s most recent Form
10-Q and in subsequent filings Dyne may make with the SEC. In
addition, the forward-looking statements included in this press
release represent Dyne’s views as of the date of this press
release. Dyne anticipates that subsequent events and developments
will cause its views to change. However, while Dyne may elect to
update these forward-looking statements at some point in the
future, it specifically disclaims any obligation to do so. These
forward-looking statements should not be relied upon as
representing Dyne’s views as of any date subsequent to the date of
this press release.
1. No head-to-head trials have been conducted comparing DYNE-251
to eteplirsen. Eteplirsen data may not be directly comparable due
to differences in trial protocols, dosing regimens and patient
populations. Accordingly, these cross-trial comparisons may not be
reliable. Eteplirsen data from J Neuromuscul Dis. 2021; 8(6):
989–10012. Safety data as of December 6, 2023
Contacts:
InvestorsAmy Reillyareilly@dyne-tx.com
857-341-1203
MediaStacy Nartkersnartker@dyne-tx.com
781-317-1938
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