Aclaris Therapeutics Announces Positive Results From Phase 1 Single and Multiple Ascending Dose Trial of ATI-450, an Investig...
January 09 2020 - 4:27PM
Aclaris Therapeutics, Inc. (NASDAQ: ACRS), a physician-led
biopharmaceutical company focused on immuno-inflammatory diseases,
today announced positive results from ATI-450-PKPD-101, a Single
Ascending Dose and Multiple Ascending Dose (SAD/MAD) Phase 1
clinical trial of the investigational compound ATI-450. Preliminary
data demonstrated that ATI-450:
- resulted in marked inhibition of TNFα, IL1β, IL8, and IL6;
- was generally well-tolerated at all doses tested in the
trial;
- had dose proportional pharmacokinetics (PK) with a terminal
half-life of 9-12 hours; and
- had no meaningful food effect or drug-drug interaction (DDI)
with methotrexate.
ATI-450-PKPD-101 was a first-in-human, randomized,
observer-blind, placebo-controlled Phase 1 clinical trial designed
to evaluate the safety, tolerability, pharmacokinetics, and
pharmacodynamics of orally administered ATI-450 in healthy subjects
(n=77). The trial consisted of three parts:
- Single Ascending Dose (SAD) plus food effect (n=32, 8 subjects
per dose cohort - 2 placebo, 6 active). A single dose of 10mg,
30mg, 50mg and 100mg was tested.
- Multiple Ascending Dose (MAD) (n=30, 10 subjects per dose
cohort - 2 placebo, 8 active). 10mg BID, 30mg BID and 50mg BID
doses were tested over 7 days of administration.
- Methotrexate DDI (n=15). Single 7.5-mg oral doses of
methotrexate given alone or after ATI-450 50mg BID.
No serious adverse events or severe adverse events were
reported, and no adverse events led to discontinuation of the study
medication. The most common adverse events (reported by 2 or more
subjects who received ATI-450) observed during the trial were
dizziness, headache, upper respiratory tract infection,
constipation, nausea, and abdominal pain. All adverse events were
mild. A trend of a decrease in absolute neutrophil count (ANC) was
observed without correlated clinical sequelae. This effect is
consistent with the pharmacodynamic profile of certain anti-TNF
therapies1. Other laboratory findings were generally
unremarkable.
In this trial, ATI-450 had dose proportional pharmacokinetics
with a terminal half-life of 9-12 hours in the MAD cohort on day 7.
The PK profile was not meaningfully affected when taking ATI-450
with a high fat meal. Further, co-administration of ATI-450 with
methotrexate had little impact on methotrexate
pharmacokinetics.
The pharmacodynamics of ATI-450 were evaluated by investigating
the potential to inhibit production of key cytokines in ex vivo
stimulated blood samples collected from subjects. At the 50mg BID
dose (the dose with the highest degree of inhibition) at day 7 (12
hours post last dose): the mean trough drug levels were above the
IC80 for TNFα, IL1β and IL8; IL6 plasma levels were inhibited by
more than 50% for part of the dosing interval; and the mean trough
drug level was above the IC80 for phosphorylation of Heat Shock
Protein 27, a downstream substrate of MK2 (and marker of inhibition
of the MK2 target).
“We believe these data support the progression of ATI-450 into
Phase 2 clinical development,” said Dr. David Gordon, Chief Medical
Officer of Aclaris. “The potential for an oral small molecule which
suppresses multiple proinflammatory cytokines could be very
meaningful for the treatment of a number of immuno-inflammatory
diseases.”
Aclaris intends to initiate the first Phase 2 clinical trial in
subjects with rheumatoid arthritis in the first half of 2020.
About ATI-450
ATI-450 is an investigational oral small molecule inhibitor of
the p38α mitogen-activated protein kinase-activated protein kinase
2 (MK2) inflammatory signaling pathway. This pathway drives the
expression of multiple cytokines, chemokines, matrix
metalloproteases and other inflammatory signals. Key inflammatory
cytokines driven by this pathway include tumor necrosis factor α
(TNFα), interleukin-1α and -1β (IL1α and IL1β), and interleukin-6
(IL6). On the basis of this mechanism, Aclaris is developing
ATI-450 as a potential treatment for immuno-inflammatory
diseases.
About Aclaris Therapeutics, Inc.
Aclaris Therapeutics, Inc. is a physician-led biopharmaceutical
company committed to addressing the needs of patients with
immuno-inflammatory diseases who lack satisfactory treatment
options. The company’s diverse and multi-stage portfolio includes
one late-stage investigational drug candidate and a pipeline
powered by a robust R&D engine exploring protein kinase
regulation. For additional information, please visit
www.aclaristx.com and follow Aclaris on LinkedIn or Twitter
@aclaristx.
Cautionary Note Regarding Forward-Looking
Statements
Any statements contained in this press release that do not
describe historical facts may constitute forward-looking statements
as that term is defined in the Private Securities Litigation Reform
Act of 1995. These statements may be identified by words such as
"believe," "expect," "may," "plan," "potential," "will," and
similar expressions, and are based on Aclaris' current beliefs and
expectations. These forward-looking statements include expectations
regarding the development of Aclaris’ drug candidates and the
timing of the initiation of clinical trials. These statements
involve risks and uncertainties that could cause actual results to
differ materially from those reflected in such statements. Risks
and uncertainties that may cause actual results to differ
materially include uncertainties inherent in the conduct of
clinical trials, Aclaris' reliance on third parties over which it
may not always have full control, and other risks and uncertainties
that are described in the Risk Factors section of Aclaris' Annual
Report on Form 10-K for the year ended December 31, 2018, Aclaris’
Quarterly Report on Form 10-Q for the quarter ended September 30,
2019, and other filings Aclaris makes with the U.S. Securities and
Exchange Commission from time to time. These documents are
available under the "SEC filings” section of the Investors page of
Aclaris' website at http://www.aclaristx.com. Any forward-looking
statements speak only as of the date of this press release and are
based on information available to Aclaris as of the date of this
release, and Aclaris assumes no obligation to, and does not intend
to, update any forward-looking statements, whether as a result of
new information, future events or otherwise.
Aclaris ContactMichael Tung, M.D.Senior Vice PresidentCorporate
Strategy/Investor Relations484-329-2140mtung@aclaristx.com
1 Dillingh M, et al. Front. Immunol. 2016;7(508):1-9.
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