- Phase 1 Data Demonstrate Favorable Safety, Tolerability and
Pharmacokinetics Supportive of Once-Daily Dosing Without
Ritonavir
- Preclinical Animal Data Indicate the Potential for EDP-235 to
Reduce Household Transmission and to Minimize SARS-CoV-2
Rebound
- High Throughput Screen Identifies Non-Nucleoside Small Molecule
Inhibitors of the SARS-CoV-2 RNA-Dependent RNA Polymerase
Enanta Pharmaceuticals, Inc. (NASDAQ: ENTA), a clinical-stage
biotechnology company dedicated to creating small molecule drugs
for viral infections, today announced new data supporting the
potential of EDP-235 for the treatment of COVID-19, which are being
presented at the 36th International Conference on Antiviral
Research (ICAR) being held March 13-17, 2023 at the Centre de
Congrès de Lyon (Lyon Convention Center) in Lyon, France. The
company will have one oral presentation and three poster
presentations, showcasing the potential of EDP-235 and Enanta’s
leadership in the development of small molecules for the treatment
of viral respiratory infections.
Phase 1 data presented continue to highlight EDP-235’s promising
overall safety, tolerability and pharmacokinetic (PK) profile, and
preclinical data demonstrate EDP-235’s ability to suppress viral
replication and transmission in an animal model. Additional
preclinical data show EDP-235’s targeted tissue penetration and
potential to mitigate rebound in COVID-19 patients. A fourth
presentation focuses on a high-throughput screen to identify
non-nucleoside inhibitors of the RNA-dependent RNA polymerase.
EDP-235 is currently being evaluated in SPRINT (SARS-Cov-2
PRotease INhibitor Treatment), a Phase 2 study
of non-hospitalized, symptomatic adults with mild or moderate
COVID-19, and has a data readout targeted for May 2023.
“We are excited to present new clinical and preclinical data
which continue to add to the robust findings supporting the
potential of EDP-235 as a differentiated, once-daily, oral
treatment for patients with COVID-19, as well as to demonstrate our
broad capabilities in developing small molecules against this
virus,” said Jay R. Luly, Ph.D., President and Chief Executive
Officer of Enanta Pharmaceuticals. “Findings from our Phase 1 study
continue to show EDP-235’s favorable safety, tolerability and
pharmacokinetics with strong exposure multiples over the EC90,
without ritonavir boosting, while preclinical animal studies
support the potential for EDP-235 to reduce household transmission.
Additional preclinical data demonstrate that EDP-235’s optimized
tissue targeting may help to minimize viral rebound. Given the
totality of these data, we are encouraged about EDP-235’s ability
to make a significant impact in the lives of COVID-19 patients and
look forward to a Phase 2 data readout in May.”
Abstract ID: #021, Oral Presentation,
Wednesday, March 15 from 10:15 – 11:30 am Central European Time
(CET)
“EDP-235, an Oral 3CL Protease Inhibitor for the Treatment of
COVID-19, Suppresses Viral Replication and Spread in
SARS-CoV-2-Infected Ferrets” Michael Rhodin, Ph.D.
EDP-235’s antiviral activity was evaluated in a ferret model of
acute SARS-CoV-2 infection and transmission. Therapeutic treatment
of infected animals with EDP-235 (either 200 mg/kg once daily or
twice daily) beginning 12 hours post-infection with SARS-CoV-2
resulted in a rapid and sustained reduction in both live virus
titer and viral RNA in nasal lavage samples. Only vehicle-treated
animals had detectable live virus in nasal turbinates four days
post-infection, demonstrating complete inhibition of viral
replication by both EDP-235 dosing regimens. Further, EDP-235
exposures in ferrets were comparable to previously announced Phase
1 clinical EDP-235 plasma exposures, representing strong multiples
over EC90. To evaluate the impact of EDP-235 treatment on
SARS-CoV-2 transmission, infected source animals were co-housed
with uninfected contact animals 60 hours post-infection. Live virus
was recoverable from the nasal lavages of contact animals housed
with vehicle-treated source animals from 12 hours onwards after
co-housing. In contrast, viral RNA and live virus were undetectable
in nasal lavage and terminal nasal turbinate samples from contact
ferrets co-housed with EDP-235-treated infected animals.
Collectively, these data support the potential for EDP-235 to
reduce household transmission.
Abstract ID: #524, Poster Presentation,
Tuesday, March 14 from 6 – 7 pm and Wednesday, March 15 from 12:15
– 1:15 pm CET
“EDP-235, an Oral, Once Daily, Ritonavir-Free, 3CL Protease
Inhibitor for the Treatment of COVID-19: Results from Phase 1 Study
in Healthy Subjects” Guy De La Rosa, M.D.
EDP-235 was evaluated in a Phase 1, randomized, double-blind,
placebo (PBO)-controlled study to assess its safety and PK profile
during single ascending dose (SAD), multiple ascending dose (MAD)
and food effect cohorts in healthy subjects. A total of 72 subjects
were randomized. Forty subjects were enrolled into five SAD cohorts
and thirty-two subjects were enrolled into four MAD cohorts dosed
for seven days.
EDP-235 was generally safe and well-tolerated in healthy
subjects. Three MAD dosing discontinuations resulted from one
moderate headache in the 400 mg fasted cohort, one severe headache
in the 800 mg fed cohort, and one grade 3 ALT/grade 2 AST elevation
in the 800 mg fed cohort. There were no serious treatment emergent
adverse events. Linear PK supported once daily dosing, with strong
multiples over the EC90 without the need for ritonavir boosting. In
the SAD phase, EDP-235 exposure increased in an approximately
dose-proportional manner, up to 800 mg. Plasma PK from the 200 mg
fed cohort indicated a 4-fold food effect. Geometric mean t1/2 was
13-18 hours across dose range, supporting once daily dosing. In the
MAD phase, EDP-235 exposure increased with ascending multiple doses
in an approximately dose-proportional manner, up to 400 mg. Steady
state was reached 48 hours after the first dose and geometric mean
t1/2 ranging from 13-22 hours. EDP-235 administered once daily for
seven days resulted in steady state C24 concentrations up to
13-fold over the protein adjusted EC90 determined in Vero E6 cells
infected with the Omicron lineage. These data support the further
evaluation of EDP-235 which is currently being studied in a Phase 2
clinical trial in non-hospitalized adults with mild or moderate
COVID-19.
Abstract ID#: 523, Poster Presentation,
Tuesday, March 14 from 5 – 6 pm and Wednesday, March 15 from 2:15 –
3:15 pm CET
“EDP-235, a Potent, Once-daily, Oral Antiviral, Demonstrates
Excellent Penetration Into SARS-CoV-2 Target Tissues, with the
Potential for Mitigation of Viral Rebound in COVID-19 Patients”
Indy Zang, Ph.D.
EDP-235’s penetration into target tissues was compared to
nirmatrelvir in human cells and preclinical species infected with
SARS-CoV-2. Intracellular uptake of EDP-235 was tested side-by-side
with nirmatrelvir in human cells. The ratios of intracellular to
extracellular concentrations of EDP-235 were 8.7 in human lungs,
9.9 in cardiac myocytes, 11.3 in salivary glands, 18.0 in kidneys,
and 33.6 in adipocytes. In contrast, nirmatrelvir had ratios of 0.6
to 1.2 in these human cells.
To determine the in vivo drug distribution into SARS-CoV-2
target tissues, rats were dosed orally with 10 mg/kg of EDP-235 or
nirmatrelvir. EDP-235 showed favorable rat plasma exposure of 19.0
µg-hr/mL, whereas nirmatrelvir had a significantly lower rat plasma
exposure of 4.9 µg-hr/mL. Consistent with in vitro observations,
EDP-235 displayed excellent target tissue exposure in rats with
tissue to plasma ratios of 4.1 in lungs, 4.7 in heart, 6.5 in
salivary glands, 6.3 in kidneys, and 23.0 in adipose tissues,
whereas nirmatrelvir had corresponding ratios of 0.8, 0.9, 0.8, 1.2
and 0.6 in those tissues.
These data demonstrate a more targeted tissue distribution and
penetration, enabling EDP-235 to reach sites of potential viral
reservoirs, which may help minimize viral rebound in COVID-19
patients.
Abstract ID#: 528, Poster Presentation,
Tuesday, March 14 from 6 – 7 pm and Wednesday, March 15 from 12:15
– 1:15 pm CET
“High Throughput Screen to Identify Non-Nucleoside Small
Molecule Inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase”
Tessa Cressey, Ph.D.
Approaches for developing small molecule antivirals include
targeting non-structural proteins such as the proteases 3CL pro and
PLpro, nsp13, nsp14, nsp16, and the RNA-dependent RNA polymerase
(RdRp). Remdesivir, a nucleoside analog targeting the SARS-CoV-2
RdRp, has been successfully used for the treatment of hospitalized
or high-risk patients with COVID-19, but its utility is limited by
the intravenous delivery route. A high throughput screen was
conducted to identify non-nucleoside RdRp inhibitors, which could
be useful additions to the SARS-CoV-2 treatment arsenal.
A biochemical assay was developed where purified recombinant
RdRp consisting of nsp12, nsp7, and nsp8 elongates a primer in an
annealed primer/template pair and incorporates a fluorescent UTP
analog, releasing the fluorophore. Using this assay, a library of
approximately 400,000 small molecules was screened for RdRp
inhibition. After counter-screens to remove RNA intercalators,
redox cyclers, and compounds with undesirable medicinal chemistry
properties, 15 compounds from 11 structural families with
half-maximal inhibitory concentrations (IC50s) <10 μM were
selected for mechanism of inhibition studies. None of the compounds
were RNA or NTP competitive inhibitors. Biochemical assays and
analytical size-exclusion chromatography showed 11 compounds
disrupted nsp12-nsp8 protein-protein interactions. Nano
differential scanning fluorimetry analysis suggested five compounds
target nsp12 directly. This high throughput screen identified
multiple, structurally diverse, non-nucleoside SARS-CoV-2 RdRp
inhibitors as potential starting points for hit optimization.
About Enanta Pharmaceuticals, Inc.
Enanta is using its robust, chemistry-driven approach and drug
discovery capabilities to become a leader in the discovery and
development of small molecule drugs for the treatment of viral
infections. Enanta’s research and development programs include
clinical candidates for the following disease targets: respiratory
syncytial virus (RSV), SARS-CoV-2 (COVID-19) and hepatitis B virus
(HBV). Enanta is also conducting research on a single agent
targeting both RSV and human metapneumovirus (hMPV).
Enanta’s research and development activities are funded by
royalties from hepatitis C virus (HCV) products developed under its
collaboration with AbbVie. Glecaprevir, a protease inhibitor
discovered by Enanta, is part of one of the leading treatment
regimens for curing chronic HCV infection and is sold by AbbVie in
numerous countries under the tradenames MAVYRET® (U.S.) and
MAVIRET® (ex-U.S.) (glecaprevir/pibrentasvir). Please visit
www.enanta.com for more information.
Forward Looking Statements
This press release contains forward-looking statements,
including statements with respect to the prospects for advancement
of Enanta’s clinical programs in COVID-19. Statements that are not
historical facts are based on management’s current expectations,
estimates, forecasts and projections about Enanta’s business and
the industry in which it operates and management’s beliefs and
assumptions. The statements contained in this release are not
guarantees of future performance and involve certain risks,
uncertainties and assumptions, which are difficult to predict.
Therefore, actual outcomes and results may differ materially from
what is expressed in such forward-looking statements. Important
factors and risks that may affect actual results include: the
impact of development, regulatory and marketing efforts of others
with respect to competitive treatments for COVID-19; the discovery
and development risks of Enanta’s COVID-19 program; the competitive
impact of development, regulatory and marketing efforts of others
in this disease area; any continuing impact of the COVID-19
pandemic on business operations and clinical trials; Enanta’s lack
of clinical development experience; Enanta’s need to attract and
retain senior management and key research and development
personnel; Enanta’s need to obtain and maintain patent protection
for its product candidates and avoid potential infringement of the
intellectual property rights of others; and other risk factors
described or referred to in “Risk Factors” in Enanta’s Form 10-K
for the fiscal year ended September 30, 2022, and any other
periodic reports filed more recently with the Securities and
Exchange Commission. Enanta cautions investors not to place undue
reliance on the forward-looking statements contained in this
release. These statements speak only as of the date of this
release, and Enanta undertakes no obligation to update or revise
these statements, except as may be required by law.
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version on businesswire.com: https://www.businesswire.com/news/home/20230314005318/en/
Media and Investors Jennifer Viera 617-744-3848
jviera@enanta.com
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