Travere Therapeutics, Inc. (Nasdaq: TVTX) today announced topline
two-year confirmatory secondary endpoint results from the Company’s
pivotal head-to-head Phase 3 PROTECT Study of FILSPARI®
(sparsentan) in IgA nephropathy (IgAN) versus irbesartan. FILSPARI
demonstrated long-term kidney function preservation and achieved a
clinically meaningful difference in estimated glomerular filtration
rate (eGFR) total and chronic slope versus irbesartan, narrowly
missing statistical significance in eGFR total slope while
achieving statistical significance in eGFR chronic slope for
purposes of regulatory review in the EU. FILSPARI is currently
available under accelerated approval in the U.S. The Company will
engage with regulators and expects to submit a supplemental New
Drug Application (sNDA) in 1H 2024 for full approval in the U.S.
PROTECT Study Results
In the PROTECT Study, a total of 404 patients with persistent
proteinuria despite active angiotensin-converting enzyme (ACE)
inhibitor or angiotensin-receptor blocker (ARB) treatment,
were randomized 1:1 to receive once daily oral doses of either
FILSPARI or irbesartan, the active control. eGFR total and chronic
slope are the secondary confirmatory endpoints for the U.S. and the
EU, respectively. All topline efficacy endpoints favored FILSPARI
as compared to irbesartan.
|
FILSPARI(N=202) |
Irbesartan(N=202) |
Difference (FILSPARI -
Irbesartan) |
eGFR total slope,mL/min/1.73m2 per yeara |
-2.9 |
-3.9 |
1.0, p=0.058(-0.03, 1.94) |
eGFR chronic slope, mL/min/1.73m2 per
yearb |
-2.7 |
-3.8 |
1.1, p=0.037(0.07, 2.12) |
UP/C (g/g)Mean % change from
baseline at week 110c |
-42.8 |
-4.4 |
GMR: 0.60(0.50, 0.72) |
Absolute change in eGFRMean change from baseline
at week 110d |
-5.8 |
-9.5 |
3.7(1.45, 5.99) |
Absolute change in eGFRMean change from baseline
at week 114e following 4 weeks post treatment (Patients who
completed blinded treatment period) |
-6.1 |
-9.0 |
2.9(0.45, 5.25) |
Confirmed 40% Reduction in eGFR, ESRD, or Death during the
Study n (%) |
18(8.9) |
26(12.9) |
RR: 0.68(0.37, 1.24)f |
a LS Means
and 95% CI from a random coefficient analysis including available
on-treatment eGFR data from Week 6 through Week 110 with
multiple imputation; mL/min/1.73m2 per yearb LS Means and
95% CI from a random coefficient analysis including available
on-treatment eGFR data through Week 110 with multiple
imputation; mL/min/1.73m2 per yearc Geometric LS Means,
Geometric LS Mean Ratio (GMR), and 95% CI from MMRM analysis
including on-treatment data through Week 110 with multiple
imputationd LS Means and 95% CI from MMRM analysis including
on-treatment data through Week 110; mL/min/1.73m2e ANCOVA adjusted
for eGFR at baseline; mL/min/1.73m2f Relative risk (RR) of events
and 95% CI from Poisson regression model |
A preliminary review of the safety results through 110 weeks of
treatment indicates FILSPARI was generally well-tolerated and the
overall safety profile in the study has been consistent between
treatment groups.
“The confirmatory results of the PROTECT Study demonstrated
treatment with FILSPARI resulted in the largest sustained reduction
in proteinuria and one of the slowest rates of eGFR decline in a
controlled study of IgAN patients, to date. This outcome is
incredibly important for IgAN patients, who face the risk of
progression to kidney failure in their lifetime. We’re proud of the
high bar we’ve set in delivering the only head-to-head study in
IgAN, which compares FILSPARI against a maximally tolerated dose of
irbesartan,” said Eric Dube, Ph.D., president and CEO of Travere
Therapeutics. “Since our accelerated approval, we’ve continued to
hear inspiring stories of the impact this medicine is having on
people living with IgAN. While eGFR total slope narrowly missed
statistical significance, the overall evidence from PROTECT
suggests potential long-term benefit of FILSPARI as a foundational
treatment for patients with IgAN. FILSPARI has the potential to
transform the treatment paradigm in this rare kidney disease, and
we look forward to engaging with FDA to discuss our planned sNDA
submission.”
“In clinical practice, nephrologists managing IgA nephropathy
patients work to reduce proteinuria as much as possible because
this leads to a slower rate of decline in kidney function. Our main
goal is to avoid the need for dialysis or kidney transplantation.
The results of the PROTECT trial clearly show that when compared to
an active control of maximally tolerated irbesartan, FILSPARI
delivered a rapid and sustained antiproteinuric effect over two
years along with a clinically meaningful attenuation in the decline
of eGFR that should preserve long-term kidney function in patients
with IgAN,” said Brad Rovin, M.D., Medical Director at Ohio
State University Center for Clinical Research Management, Director
of the Division for Nephrology, and steering committee member for
the PROTECT clinical trial. “Because FILSPARI is not an
immunosuppressive agent and has a safety profile similar to
irbesartan, it has the potential to become long-term foundational
therapy for IgAN that could be combined with other therapies as
appropriate. This is a promising outcome for patients suffering
from IgAN who are at risk for progressive kidney failure.”
The Company will complete a full evaluation of the data from the
PROTECT Study and work with the study investigators on future
presentations and publications of the results at an upcoming
medical meeting and in a peer-reviewed publication.
In August 2022, the European Medicines Agency (EMA) accepted for
review the Conditional Marketing Authorization (CMA) application of
sparsentan for the treatment of IgAN. Together with its partner CSL
Vifor, the Company anticipates a review opinion by the Committee
for Medicinal Products for Human Use (CHMP) on the CMA application
for sparsentan for the treatment of IgAN in the EU around
year-end.
Conference Call Information
Travere Therapeutics will host a conference call and
webcast today, Thursday, September 21, 2023, at 8:30
a.m. ET to discuss the Phase 3 PROTECT Study
results. To participate in the conference call, dial +1 (888)
254-3590 (U.S.) or +1 (323) 994-2093 (International), confirmation
code 5916006. The webcast can be accessed on the Investor page of
Travere’s website at ir.travere.com/events-presentations.
Following the live webcast, an archived version of the call will be
available for 30 days on the Company’s website.
About IgA Nephropathy
IgA nephropathy (IgAN), also called Berger's disease, is a rare
progressive kidney disease characterized by the buildup of
immunoglobulin A (IgA), a protein that helps the body fight
infections, in the kidneys. The deposits of IgA cause a breakdown
of the normal filtering mechanisms in the kidney, leading to blood
in the urine (hematuria), protein in the urine (proteinuria) and a
progressive loss of kidney function. Other symptoms of IgAN may
include swelling (edema) and high blood pressure.
IgAN is the most common type of primary glomerulonephritis
worldwide and a leading cause of kidney failure due to glomerular
disease. IgAN is estimated to affect up to 150,000 people in the
U.S. and is one of the most common glomerular diseases in Europe
and Japan.
About the PROTECT Study
The PROTECT Study is one of the largest interventional studies
to date in IgA nephropathy (IgAN) and the only head-to-head trial
in this rare kidney disease. It is a global, randomized,
multicenter, double-blind, parallel-arm, active-controlled clinical
trial evaluating the safety and efficacy of 400 mg of sparsentan,
compared to 300 mg of irbesartan, in 404 patients ages 18 years and
up with IgAN and persistent proteinuria despite receiving at least
50% of max label dose and maximally tolerated ACE or ARB therapy.
In August 2021, the Company announced the PROTECT Study met its
pre-specified interim primary efficacy endpoint with statistical
significance. Based on the pre-specified, primary analyses set,
after 36 weeks of treatment, patients receiving sparsentan achieved
a mean reduction in proteinuria from baseline of 49.8%, compared to
a mean reduction in proteinuria from baseline of 15.1% for
irbesartan-treated patients (p<0.0001). The study’s confirmatory
secondary endpoint in the U.S. is eGFR total slope from day 1 to
week 110 of treatment. The confirmatory secondary endpoint in the
EU is eGFR chronic slope from week 6 to week 110 of treatment,
following the initial acute effect of randomized treatment.
Following the 110-week blinded treatment period, treatment with
study medication is discontinued for 4 weeks -- at this time, the
investigator resumes standard of care treatment. Patients that
completed the PROTECT double-blind portion of the study on
treatment were eligible to participate in the open-label portion of
the trial.
FILSPARI®
(sparsentan) U.S. Indication
FILSPARI is an endothelin and angiotensin II
receptor antagonist indicated to reduce proteinuria in adults with
primary immunoglobulin A nephropathy (IgAN) at risk of rapid
disease progression, generally a UPCR ≥1.5 g/g.
This indication is granted under accelerated
approval based on reduction in proteinuria. It has not been
established whether FILSPARI slows kidney function decline in
patients with IgAN. Continued approval for this indication may be
contingent upon verification and description of clinical benefit in
a confirmatory clinical trial.
FILSPARI®
(sparsentan) Important Safety Information
BOXED WARNING: HEPATOTOXICITY AND
EMBRYO-FETAL TOXICITYBecause of the risks of
hepatotoxicity and birth defects, FILSPARI is available only
through a restricted program called the FILSPARI REMS. Under the
FILSPARI REMS, prescribers, patients and pharmacies must enroll in
the program.
HepatotoxicitySome
Endothelin Receptor Antagonists (ERAs) have caused elevations of
aminotransferases, hepatotoxicity, and liver failure. In clinical
studies, elevations in aminotransferases (ALT or AST) of at least
3-times the Upper Limit of Normal (ULN) have been observed in up to
2.5% of FILSPARI-treated patients, including cases confirmed with
rechallenge.
Measure transaminases and bilirubin
before initiating treatment and monthly for the first 12 months,
and then every 3 months during treatment. Interrupt treatment and
closely monitor patients who develop aminotransferase elevations
more than 3x ULN.
FILSPARI should generally be avoided in
patients with elevated aminotransferases (>3x ULN) at baseline
because monitoring for hepatotoxicity may be more difficult and
these patients may be at increased risk for serious
hepatotoxicity.
Embryo-Fetal
ToxicityFILSPARI can cause major birth defects if
used by pregnant patients based on animal data. Therefore,
pregnancy testing is required before the initiation of treatment,
during treatment and one month after discontinuation of treatment
with FILSPARI. Patients who can become pregnant must use effective
contraception before the initiation of treatment, during treatment,
and for one month after discontinuation of treatment with
FILSPARI.
Contraindications: FILSPARI is
contraindicated in patients who are pregnant. Do not coadminister
FILSPARI with angiotensin receptor blockers (ARBs), ERAs, or
aliskiren.
Warnings and Precautions
Hepatotoxicity: Elevations in ALT or AST of at
least 3-fold ULN have been observed. To reduce the risk of
potential serious hepatotoxicity, measure serum aminotransferase
levels and total bilirubin prior to initiation of treatment,
monthly for the first 12 months, then every 3 months during
treatment.
Advise patients with symptoms suggesting
hepatotoxicity (nausea, vomiting, right upper quadrant pain,
fatigue, anorexia, jaundice, dark urine, fever, or itching) to
immediately stop treatment with FILSPARI and seek medical
attention. If aminotransferase levels are abnormal at any time
during treatment, interrupt FILSPARI and monitor as
recommended.
Consider re-initiation of FILSPARI only when
hepatic enzyme levels and bilirubin return to pretreatment values
and only in patients who have not experienced clinical symptoms of
hepatotoxicity.
Avoid initiation of FILSPARI in patients with
elevated aminotransferases (>3x ULN) prior to drug
initiation.
Embryo-Fetal Toxicity: FILSPARI
can cause fetal harm. Advise patients who can become pregnant of
the potential risk to a fetus. Obtain a pregnancy test and advise
patients who can become pregnant to use effective contraception
prior to, during, and one month after discontinuation of FILSPARI
treatment.
FILSPARI REMS: FILSPARI is
available only through a restricted program under a REMS called the
FILSPARI REMS.
Important
requirements include:
— Prescribers must be
certified with the FILSPARI REMS by enrolling and completing
training.
— All patients must
enroll in the FILSPARI REMS prior to initiating treatment and
comply with monitoring requirements.
— Pharmacies
that dispense FILSPARI must be certified with the FILSPARI REMS and
must dispense only to patients who are authorized to receive
FILSPARI.
Further information is available at
www.filsparirems.com or 1-833-513-1325.
Hypotension: There was a
greater incidence of hypotension-associated adverse events, some
serious, including dizziness, in patients treated with FILSPARI
compared to irbesartan. In patients at risk for hypotension,
consider eliminating or adjusting other antihypertensive
medications and maintaining appropriate volume status. If
hypotension develops, consider a dose reduction or dose
interruption of FILSPARI.
Acute Kidney Injury: Monitor
kidney function periodically. Patients whose kidney function may
depend in part on the activity of the renin-angiotensin system
(e.g., patients with renal artery stenosis, chronic kidney disease,
severe congestive heart failure, or volume depletion) may be at
particular risk of developing acute kidney injury on FILSPARI.
Consider withholding or discontinuing therapy in patients who
develop a clinically significant decrease in kidney function while
on FILSPARI.
Hyperkalemia: Monitor serum
potassium periodically and treat appropriately. Patients with
advanced kidney disease, taking concomitant potassium-increasing
drugs (e.g., potassium supplements, potassium-sparing diuretics),
or using potassium-containing salt substitutes are at increased
risk for developing hyperkalemia. Dosage reduction or
discontinuation of FILSPARI may be required.
Fluid Retention: Fluid
retention may occur with ERAs, and has been observed with FILSPARI.
If clinically significant fluid retention develops, after
evaluation, consider modifying the dose of FILSPARI.
Most common adverse reactions (5%) with
FILSPARI are peripheral edema, hypotension (including
orthostatic hypotension), dizziness, hyperkalemia, and anemia.
Drug interactions
- Renin-Angiotensin System
(RAS) Inhibitors and ERAs: Do not coadminister FILSPARI
with angiotensin receptor blockers (ARBs), ERAs, or aliskiren.
- Strong and Moderate CYP3A
Inhibitors: Avoid concomitant use of FILSPARI with strong
CYP3A inhibitors. Monitor blood pressure, serum potassium, edema,
and kidney function regularly when used concomitantly with moderate
CYP3A inhibitors.
- Strong CYP3A
Inducers: Avoid concomitant use with a strong CYP3A
inducer.
- Antacids and Acid Reducing
Agents: Administer FILSPARI 2 hours before or after
administration of antacids. Avoid concomitant use of acid reducing
agents (histamine H2 receptor antagonist and PPI proton pump
inhibitor) with FILSPARI.
- Non-Steroidal
Anti-Inflammatory Agents (NSAIDs), Including Selective
Cyclooxygenase-2 (COX-2) Inhibitors: Monitor for signs of
worsening renal function.
- CYP2B6, 2C9, and 2C19
Substrates: Monitor for efficacy of the concurrently
administered CYP2B6, 2C9, and 2C19 substrates and consider dosage
adjustment in accordance with the Prescribing Information.
- P-gp and BCRP Substrates:
Avoid concomitant use of sensitive substrates of P-gp and
BCRP with FILSPARI.
- Agents Increasing Serum
Potassium: Monitor serum potassium frequently. Concomitant
use of FILSPARI with potassium-sparing diuretics, potassium
supplements, potassium-containing salt substitutes, or other drugs
that raise serum potassium levels may result in hyperkalemia.
Use in specific populations
- Pregnancy / Females and
Males of Reproductive Potential: FILSPARI can cause fetal
harm, including birth defects and fetal death, when administered to
a pregnant patient and is contraindicated during pregnancy.
- Pregnancy Testing /
Contraception: Verify the pregnancy status and effective
method of contraception prior to, during, and one month after
discontinuation of FILSPARI treatment. The patient should contact
their physician immediately for pregnancy testing if onset of
menses is delayed or pregnancy is suspected.
- Lactation: Advise
patients not to breastfeed during treatment with FILSPARI.
- Hepatic
Impairment: Avoid use of FILSPARI in patients with any
hepatic impairment (Child-Pugh class A-C).
Please see Full Prescribing Information
for FILSPARI here.
About Travere Therapeutics
At Travere Therapeutics, we are in rare for
life. We are a biopharmaceutical company that comes together every
day to help patients, families and caregivers of all backgrounds as
they navigate life with a rare disease. On this path, we know the
need for treatment options is urgent – that is why our global team
works with the rare disease community to identify, develop and
deliver life-changing therapies. In pursuit of this mission, we
continuously seek to understand the diverse perspectives of rare
patients and to courageously forge new paths to make a difference
in their lives and provide hope – today and tomorrow. For more
information, visit travere.com
Forward Looking Statements
This press release contains “forward-looking statements” as that
term is defined in the Private Securities Litigation Reform Act of
1995. Without limiting the foregoing, these statements are often
identified by the words “anticipate,” “believe,” “expect,”
“intend,” “may,” “might,” “objective,” “plan,” “will” or similar
expressions. In addition, expressions of our strategies, intentions
or plans are also forward-looking statements. Such forward-looking
statements include, but are not limited to, references to: the
Company’s expectations regarding planned future engagement with FDA
regarding the filing of an sNDA for full approval of FILSPARI for
patients with IgAN in the U.S. and the timing and outcome thereof;
statements regarding the potential long-term benefit of FILSPARI as
a foundational treatment for patients with IgAN, the potential to
transform the treatment paradigm, and the potential for
preservation of long-term kidney function in patients with IgAN;
the potential for FILSPARI to be combined with other therapies;
statements regarding the Company’s further evaluation of the data
from the PROTECT Study and work with the study investigators on
future presentations and publications; and statements regarding
expectations related to the regulatory approval pathway in the US
and Europe. Such forward-looking statements are based on current
expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them,
and could cause actual outcomes and results to differ materially
from current expectations. No forward-looking statement can be
guaranteed. Among the factors that could cause actual results to
differ materially from those indicated in the forward-looking
statements are risks and uncertainties associated with the
commercial launch of a new product, the regulatory review and
approval process, including traditional approval in the United
States and the CMA and subsequent variation pathway in the European
Union, the Company’s business and finances in general, success of
its commercial products and the Company’s preclinical and clinical
stage pipeline. Specifically, the Company faces risks associated
with market acceptance of FILSPARI and its other products,
including efficacy, safety, price, reimbursement and benefit over
competing therapies; the risk that the results of the Phase 3
PROTECT Study of sparsentan in IgAN will not be deemed sufficient
by the FDA to to serve as the basis for an sNDA submission for
traditional approval of sparsentan; and for each of the Company’s
programs, risk associated with enrollment of clinical trials for
rare diseases and risk that ongoing or planned clinical trials may
not succeed or may be delayed for safety, regulatory or other
reasons. There is no guarantee that the FDA will grant full
approval of sparsentan for IgAN. The Company faces the risk that
its cash runway will not extend as far as anticipated and that it
will be unable to raise additional funding that may be required to
successfully launch FILSPARI in the United States or complete
development of any or all of its product candidates, including as a
result of macroeconomic conditions; risk relating to the Company’s
dependence on contractors for clinical drug supply and commercial
manufacturing; uncertainties relating to patent protection and
exclusivity periods and intellectual property rights of third
parties; risks associated with regulatory interactions; risks and
uncertainties relating to competitive products, including current
and potential future generic competition with certain of the
Company’s products, and technological changes that may limit demand
for the Company’s products. The Company also faces additional risks
associated with global and macroeconomic conditions, including
health epidemics and pandemics, including risks related to
potential disruptions to clinical trials, commercialization
activity, supply chain, and manufacturing operations. You are
cautioned not to place undue reliance on these forward-looking
statements as there are important factors that could cause actual
results to differ materially from those in forward-looking
statements, many of which are beyond our control. The Company
undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events,
or otherwise. Investors are referred to the full discussion of
risks and uncertainties, including under the heading “Risk
Factors”, as included in The Company’s most recent Form 10-K, Form
10-Q and other filings with the Securities and Exchange
Commission.
Contact Info
Media:Nivi NehraVice President,
Corporate Communications888-969-7879mediarelations@travere.com |
Investors:Naomi EichenbaumVice
President, Investor Relations888-969-7879IR@travere.com |
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