Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage
biotechnology company developing treatments for serious
degenerative genetic diseases, today reported initial results from
the company’s Phase 1 multiple-ascending dose (MAD) clinical trial
of DT-216 in patients with Friedrich ataxia (FA). As of a data
cutoff date of August 7, 2023, results showed that DT-216 was
generally well-tolerated and achieved a statistically significant
and dose-related increase in frataxin (FXN) mRNA levels in skeletal
muscle biopsies.
FA is a multisystem degenerative disease caused by a GAA
nucleotide repeat expansion in the FXN gene that impairs
transcription and reduces FXN mRNA. Low FXN expression results in
mitochondrial and cellular dysfunction and leads to all FA disease
manifestations. DT-216 is a GeneTAC™ small molecule designed to
specifically target the GAA repeat expansion mutation, unblock the
transcriptional machinery, and restore the production of
functional, natural FXN mRNA.
“I’m encouraged by the data from the Phase 1 MAD trial of
DT-216, which is the first to show a drug candidate increasing
transcription of endogenous FXN mRNA in an affected tissue in FA,”
said Susan Perlman, M.D., Clinical Professor of Neurology and
Director of Neurogenetics Clinical Trials at UCLA. “Given the lack
of treatment options to address the root cause of this debilitating
disease, DT-216 is a highly promising candidate, and I am eager to
see its continued development.”
Observational Biomarker Study in Friedreich
AtaxiaIn parallel to the Phase 1 MAD study, Design
conducted an observational study to evaluate FA biomarker assays in
blood and skeletal muscle from individuals with FA, FA carriers and
normal healthy volunteer controls for use in DT-216 interventional
studies. The company developed procedures and methods to measure
both FXN mRNA and FXN protein in muscle. Initial data from the
observational study is based upon a data cutoff of August 7, 2023.
The observational study enrolled a total of 56 participants.
Skeletal muscle biopsies were obtained from study participants at
two visits several days apart to measure FXN mRNA and protein
levels and characterize inter-and intra-individual variability.
Study results showed that levels of endogenous FXN mRNA across
individuals with FA, FA carriers and healthy individuals differed
significantly. Additionally, levels in the interquartile range for
FA patients did not overlap with FA carriers, which shows FXN mRNA
levels between these two populations are distinct. Design believes
these data support use of the muscle FXN mRNA assay as a sensitive
indicator of clinical activity in FA, with the ability to
discriminate clinically meaningful changes in endogenous FXN
mRNA.
FXN protein measurements in skeletal muscle had substantial
overlap between FA patients and carriers and showed high
intra-individual variability. More than half of FA patients had 25%
or more variation in FXN protein levels between visits, with
intra-individual coefficient of variation of 69%. The variability
of results observed with this current method substantially limited
the utility of FXN protein measurements to assess DT-216
pharmacology.
DT-216 Phase 1 MAD Trial DesignThe Phase 1 MAD
clinical trial is a randomized, double-blind, placebo-controlled
study designed to evaluate multiple ascending doses of DT-216
administered intravenously in adult patients with FA. The primary
and secondary study objectives were to evaluate safety and
tolerability, and pharmacokinetics (PK) of three weekly doses of
DT-216 in FA patients. As an exploratory objective, the company
also evaluated FXN expression including levels of FXN mRNA and
protein in skeletal muscle biopsies obtained at pre-dose baseline
and two and seven days after the third weekly dose.
Initial data from the Phase 1 MAD trial is based upon a data
cutoff of August 7, 2023. The study is fully enrolled but currently
ongoing, with blinded PK and pharmacodynamic (PD) data available in
the full 100 and 200mg dose cohorts and 11 of 14 participants in
the 300mg dose cohort. Safety data remain blinded.
The study enrolled 29 adult participants with genetically
confirmed FA. Symptomatic FA patients were adequately distributed
across dose cohorts. Study participants received three weekly
intravenous injections across the 100mg, 200mg, and 300mg cohorts
(N=4, 11, and 14, respectively) and were randomized to receive
either DT-216 or matching placebo.
Blinded Safety DT-216 was generally
well-tolerated after three intravenous doses of DT-216 or
placebo:
- There were no treatment-related serious adverse events (SAEs)
and no treatment-related discontinuations.
- All adverse events (AEs) were mild or moderate.
- There were five cases of injection site thrombophlebitis
observed across all three cohorts; four were considered mild and
one was considered moderate.
- There were no new clinically significant safety
observations.
Pharmacokinetics Plasma PK data were available
in participants at 100mg, 200mg, and 300mg DT-216 doses. Plasma
levels of DT-216 were approximately dose proportional. The average
DT-216 concentration in muscle was approximately 8-10nM two days
after the third weekly dose and approximately 1nM seven days after
the third weekly dose in both the 200mg and 300mg cohorts. DT-216
muscle exposure in FA patients was lower than projected from animal
studies but was sufficient to result in significant PD response in
skeletal muscle.
DT-216 PharmacodynamicsTo better understand the
pharmacodynamics of DT-216 directly in tissues relevant for FA
disease symptoms, the company developed procedures and methods to
measure FXN expression in skeletal muscle. As of the data cutoff
date, exploratory analyses of muscle FXN mRNA levels from the Phase
1 MAD study showed that:
- FA patients in the 300mg cohort had a 30% mean increase from
baseline in FXN mRNA two days after the third weekly dose, which
was significant compared to placebo (p<0.05), with a trend in
increased FXN mRNA seven days post dose.
- The mean increase in FXN mRNA of the 300 mg cohort was above
the 75th percentile of FA patients from the observational
study
- There was a significant DT-216 dose-response trend (p<0.05)
and tissue exposure-response relationship (p<0.05) with muscle
FXN mRNA expression
Based on current methods and procedures, the treatment effect of
DT-216 on FXN protein was inconclusive due to high intra-individual
variability, consistent with what was seen in the observational
study.
There was a transient increase of FXN mRNA in peripheral blood
mononuclear cells (PBMCs) 24 hours after dose, which is consistent
with and confirms the results from the Phase 1 single ascending
dose study. As of this data cutoff, PBMC FXN protein results are
not available.
DT-216 Program Next StepsThe initial results
from Design’s Phase 1 multiple ascending dose trial underscore the
promise of DT-216 as a potential disease-modifying treatment for
FA.
The favorable systemic safety profile and FXN response support
continued development of DT-216. However, the company has elected
to complete dose escalation in this Phase 1 study at the 300mg
cohort due to concern for potential worsening of injection site
thrombophlebitis at higher doses with multiple administration.
Design has shifted focus to developing DT-216 with an improved
formulation to enable higher exposures and chronic intravenous
administration for treatment of FA. Nonclinical studies showed that
the injection site reactions were attributable to the excipients in
the current DT-216 formulation, and that improving the formulation
composition could enable higher doses and chronic administration.
Design has since shown that an improved formulation had favorable
injection site tolerability following multiple intravenous
administrations and enabled dosing to increase tissue exposure.
The company is now conducting bridging nonclinical studies to
resume clinical development and expects to begin a multiple-dose
Phase 1 clinical trial to assess safety, pharmacokinetics and
pharmacodynamics of an improved DT-216 formulation in the second
half of 2024, with initial clinical data expected in the first half
of 2025.
“Data from the Phase 1 program showed that the therapeutic
hypothesis of DT-216 is playing out in FA patients —restoring
endogenous transcription of FXN into therapeutically relevant
levels,” said João Siffert, M.D., president and chief executive
officer of Design Therapeutics. “The totality of the data from our
Phase 1 program supports the continued development of DT-216 for
FA, and we believe leveraging an improved formulation will enable
us to explore the full DT-216 therapeutic potential for treatment
of people with FA, which is our ultimate goal. Our team will
continue to work tirelessly such that clinical development with
DT-216 can be resumed and we can report data from a multiple dose
Phase 1 clinical trial in the first half of 2025. I am proud of the
Design team for its incredible efforts, and we extend our sincerest
gratitude to the patients and caregivers participating in our
clinical trials.”
Webcast and Conference Call InformationDesign
will host a live webcast and conference call today at 4:30 pm ET to
discuss these updates. The event is accessible through the "Events"
section of the Investors page of www.designtx.com. A replay of the
webcast will be archived on the Design website for 30 days.
Dial-in information for conference participants may be obtained
by registering for the event here.
About Design TherapeuticsDesign Therapeutics is
a clinical-stage biotechnology company developing a new class of
therapies based on its platform of GeneTAC™ gene targeted chimera
small molecules. The company’s GeneTAC™ molecules are designed to
either dial up or dial down the expression of a specific
disease-causing gene to address the underlying cause of disease. In
addition to its lead GeneTAC™ small molecule, DT-216, in
development for patients with Friedreich ataxia, the company is
advancing programs in Fuchs endothelial corneal dystrophy and
myotonic dystrophy type-1. Discovery efforts for multiple other
serious degenerative disorders caused by nucleotide repeat
expansions are also underway, including for fragile X syndrome,
spinocerebellar ataxias, Huntington disease, spinobulbar muscular
atrophy, and C9orf72-amyotrophic lateral sclerosis/frontotemporal
dementia. For more information, please visit designtx.com.
Forward-Looking StatementsStatements in this
press release that are not purely historical in nature are
“forward-looking statements” within the meaning of the Private
Securities Litigation Reform Act of 1995. These statements include,
but are not limited to projections from early-stage programs,
nonclinical data and early-stage clinical data; the potential
benefits of restoring FXN in FA patients; the side effect profile
observed in nonclinical testing of improved formulations of DT-216
being indicative of the side effect profile that may be expected in
clinical studies, and in general the ability to an improved
formulation of DT-216 to prevent injection site thrombophlebitis or
other limiting side effects; expectations for resuming clinical
development in FA and announcing data therefrom and the timing
thereof; the muscle FXN mRNA assay being a sensitive indicator of
clinical activity in FA; Design’s ability to meet its stated
milestones, near-term catalysts and advance the GeneTACTM platform;
the potential of Design’s platform and approach; the potential of
Design’s GeneTAC™ small molecules to be a new class of therapies
for patients suffering from devastating genetic diseases; and the
capabilities and potential advantages of Design’s pipeline of
GeneTAC™ molecules. Because such statements are subject to risks
and uncertainties, actual results may differ materially from those
expressed or implied by such forward-looking statements. Words such
as “believes,” “designed to,” “anticipates,” “aims,” “plans to,”
“expects,” “estimate,” “intends,” “will,” “potential” and similar
expressions are intended to identify forward-looking statements.
These forward-looking statements are based upon Design’s current
expectations and involve assumptions that may never materialize or
may prove to be incorrect. Actual results and the timing of events
could differ materially from those anticipated in such
forward-looking statements as a result of various risks and
uncertainties, which include, without limitation, risks associated
with the acceptance of INDs by the FDA for the conduct of planned
clinical trials of our product candidates and our proposed design
of future clinical trials; risks associated with designing and
implementing investigational drug product formulation improvements;
risks associated with conducting a clinical trial and patient
enrollment, which is affected by many factors, and any difficulties
or delays encountered with such clinical trial or patient
enrollment may delay or otherwise adversely affect Design’s planned
clinical development of DT-216; the process of discovering and
developing therapies that are safe and effective for use as human
therapeutics and operating as a development stage company; the risk
that undesirable side effects or other properties could cause
Design or regulatory authorities to suspend or discontinue clinical
trials which could delay or prevent Design’s product candidates’
development or regulatory approval; Design’s ability to develop,
initiate or complete nonclinical studies and clinical trials for
its product candidates; the risk that promising early research or
clinical trials do not demonstrate safety and/or efficacy in later
nonclinical studies or clinical trials; changes in Design’s plans
to develop its product candidates; uncertainties associated with
performing clinical trials, regulatory filings and applications;
risks associated with reliance on third parties to successfully
conduct clinical trials and nonclinical studies; Design’s reliance
on key third parties, including contract manufacturers and contract
research organizations; Design’s ability to raise any additional
funding it will need to continue to pursue its business and product
development plans; regulatory developments in the United States and
foreign countries; Design’s ability to obtain and maintain
intellectual property protection for its product candidates;
Design’s ability to recruit and retain key scientific or management
personnel; competition in the industry in which Design operates,
which may result in others discovering, developing or
commercializing competitive products before or more successfully
than Design; and market conditions. For a more detailed discussion
of these and other factors, please refer to Design’s filings with
the Securities and Exchange Commission (“SEC”), including under the
“Risk Factors” heading of Design’s Quarterly Report on Form 10-Q
for the quarter ended March 31, 2023, as filed with the SEC on May
9, 2023, and under the “Risk Factors” heading of Design’s Quarterly
Report on Form 10-Q for the quarter ended June 30, 2023, being
filed with the SEC later today. You are cautioned not to place
undue reliance on these forward-looking statements, which speak
only as of the date hereof. All forward-looking statements are
qualified in their entirety by this cautionary statement and Design
undertakes no obligation to revise or update this press release to
reflect events or circumstances after the date hereof, except as
required by law.
Investor Contact:Chelcie ListerTHRUST Strategic
Communicationschelcie@thrustsc.com
Media Contact:Amanda SellersVerge Scientific
Communicationsasellers@vergescientific.com
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