Travere Therapeutics, Inc. (Nasdaq: TVTX) today announced
additional data from two pivotal clinical studies demonstrating
sparsentan has the potential to preserve kidney function and
significantly delay time to kidney failure compared to an active
comparator, suggesting long-term benefits in IgA nephropathy (IgAN)
and focal segmental glomerulosclerosis (FSGS). Data from the Phase
3 PROTECT and DUPLEX Studies were presented as late-breaking oral
presentations at the American Society of Nephrology (ASN) Kidney
Week 2023 and simultaneously published in The Lancet (PROTECT) and
The New England Journal of Medicine (DUPLEX).
“We’re proud to have set the bar very high in
delivering clinically meaningful data from two of the most rigorous
Phase 3 clinical trials to date in IgAN and FSGS and to now share
these two-year data in prestigious peer-reviewed journals and at
ASN Kidney Week,” said Jula Inrig, M.D., chief medical officer of
Travere Therapeutics. “These data from PROTECT suggest that
FILSPARI has the potential to significantly delay time to kidney
failure, which based on recently published data is projected to be
an additional eight years versus being treated with standard of
care.”
Key Findings from the Two-Year PROTECT
Study in IgAN:
- Treatment with
FILSPARI resulted in one of the slowest rates of kidney function
decline in an IgAN trial of its kind (-2.7 and -2.9
ml/min/1.73m2/year with chronic and total eGFR slope,
respectively).
- The absolute
overall change in kidney function from baseline to the end of the
study for patients treated with FILSPARI was -5.8 mL/min/1.73m2
compared to -9.5 mL/min/1.73m2 with irbesartan. This translates
into a 3.7 mL/min/1.73m2 higher eGFR at two years with FILSPARI
compared to irbesartan. This beneficial effect on preserving kidney
function was durable post washout.
- Treatment effects
on eGFR slope were consistent across baseline eGFR and proteinuria,
supporting the potential for FILSPARI as a foundational treatment
option across different stages of disease.
- When imbalances
between treatment arms were factored into pre-specified eGFR
analyses (early treatment discontinuations and higher rates of
rescue immunosuppression, both of which occurred more in the
irbesartan arm) the beneficial effects of FILSPARI on kidney
function preservation were strengthened.
- Treatment with
FILSPARI demonstrated lower rates of the composite endpoint of 40%
decline in eGFR, kidney failure or death compared to
irbesartan.
- Treatment with
FILSPARI resulted in the largest magnitude of sustained reduction
in proteinuria shown in a pivotal trial over two years with
FILSPARI-treated patients achieving a mean reduction in proteinuria
from baseline of 43% compared to 4% for irbesartan-treated
patients.
- More patients
treated with FILSPARI achieved complete remission of proteinuria of
less than 0.3 grams compared to those treated with irbesartan (31%
vs 11%).
- FILSPARI was
well-tolerated with a safety profile that was consistent across all
clinical trials conducted to date and comparable to the active
control, irbesartan, including no drug-induced liver injury and no
fluid overload.
“The totality of data from the PROTECT study
demonstrates FILSPARI is effective, safe and has an important place
in the IgAN treatment landscape as a long-term foundational
therapy,” 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.
Key Findings from the Two-Year DUPLEX
Study in FSGS:
- Treatment with
sparsentan demonstrated a clinically meaningful and durable
reduction in proteinuria, with FSGS patients achieving a 50%
reduction from baseline, compared to a 32% reduction with the
active control irbesartan.
- Sparsentan
showed a consistent and sustained achievement of complete remission
of proteinuria in 18.5% of patients on sparsentan vs. 7.5% for
irbesartan.
- The combined
hard endpoints of confirmed 50% reduction in eGFR, end-stage renal
disease or death, trended in favor of sparsentan with fewer
patients progressing to kidney failure.
- Sparsentan was
well-tolerated with a safety profile that was consistent across all
clinical trials conducted to date and comparable to the active
control, irbesartan, including no drug-induced liver injury and no
fluid overload.
“FSGS is an incredibly complex and heterogeneous rare kidney
disease that can be difficult to study and currently has no
approved pharmacologic treatment options. In the DUPLEX Study,
which is the largest study in FSGS ever conducted, we are seeing
for the first time a non-immunosuppressive medicine making a
clinically meaningful impact in patients’ lives by reducing
proteinuria, a proven indicator of kidney damage, by 50%,”
said Michelle N. Rheault, M.D., Director at the Division of
Pediatric Nephrology, University of Minnesota Medical School and
steering committee member for the DUPLEX clinical trial.
Additional abstracts presented at Kidney Week
2023 reinforce the potential for FILSPARI to play an important
foundational role in the IgAN treatment landscape, including in
exploring the potential combination with sodium-glucose
cotransporter-2 (SGLT2) inhibitors, and provide insights into
patient quality of life and the impact of proteinuria on kidney
survival.
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 estimated glomerular filtration rate (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 was discontinued for 4
weeks -- at this time, the investigator resumed standard of care
treatment. In September 2023, the Company announced topline
two-year confirmatory secondary endpoint results from the
PROTECT Study of sparsentan in IgAN. FILSPARI demonstrated
long-term kidney function preservation and achieved a clinically
meaningful difference in 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. Patients who
completed the PROTECT double-blind portion of the study on
treatment were eligible to participate in the open-label extension
of the trial.
About FSGS
Focal segmental glomerulosclerosis (FSGS) is a
rare proteinuric kidney disorder in both children and adults that
is estimated to affect more than 40,000 patients in the U.S. with
similar prevalence in Europe. The disorder is defined by
progressive scarring of the kidney and often leads to kidney
failure. FSGS is characterized by proteinuria, where protein leaks
into the urine due to a breakdown of the normal filtration
mechanism in the kidney. Once in the urine, protein is considered
to be toxic to other parts of the kidney, especially the tubules,
and is believed to contribute to further disease progression. Other
common symptoms include swelling in parts of the body, known as
edema, as well as low blood albumin levels, abnormal lipid profiles
and hypertension. There is currently no approved pharmacologic
indicated for the treatment of FSGS.
About the DUPLEX Study
The DUPLEX Study is the largest interventional
study to date in FSGS. It is a global, randomized, multicenter,
double-blind, parallel-arm, active-controlled Phase 3 clinical
trial assessing the efficacy and safety of sparsentan in 371
patients ages 8 to 75 years with primary FSGS. After a two-week
washout period, patients are randomized 1:1 to receive either
sparsentan or irbesartan, the active control, and subsequently dose
titrated to the maximum dose of 800 mg of sparsentan or 300 mg of
irbesartan, as tolerated. In February 2021, the Company
announced that the pivotal Phase 3 DUPLEX Study of sparsentan in
FSGS achieved its pre-specified interim FSGS partial remission of
proteinuria (FPRE) endpoint with statistical significance. FPRE is
a clinically meaningful endpoint defined as urine
protein-to-creatinine ratio (UP/C) ≤1.5 g/g and a >40 percent
reduction in UP/C from baseline. After 36 weeks of treatment, 42.0
percent of patients receiving sparsentan achieved FPRE, compared to
26.0 percent of irbesartan-treated patients (p=0.0094). The study’s
primary efficacy endpoint in the U.S. is the eGFR total slope from
day 1 to week 108 of treatment. The primary efficacy endpoint
in Europe is the eGFR chronic slope, from week 6 to week
108 of treatment, following the initial acute effect of randomized
treatment. In May 2023, the Company announced topline primary
efficacy results from the DUPLEX Study of sparsentan in FSGS. The
DUPLEX Study did not achieve the primary efficacy eGFR slope
endpoint over 108 weeks of treatment. Secondary and topline
exploratory endpoints trended favorably for sparsentan. Treatment
with sparsentan resulted in a reduction of proteinuria that was
sustained through 108 weeks of treatment. Results from the two-year
analysis demonstrated that sparsentan was well-tolerated and has
shown a comparable safety profile to irbesartan. Patients who
completed the DUPLEX double-blind portion of the study on treatment
were eligible to participate in the open-label extension of the
trial. Sparsentan is not FDA-approved for treatment of FSGS.
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
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.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
potential for FILSPARI (sparsentan) to play an important
foundational role in the IgAN treatment landscape and the
exploration of the potential combination of FILSPARI with SGLT2
inhibitors, references to data on the long-term efficacy and
tolerability of FILSPARI in IgAN and of sparsentan in FSGS,
references to the PROTECT and DUPLEX trials, and references to
potential long-term benefits and the potential magnitude thereof,
including preservation of kidney function and delay of time to
kidney failure, including projections of the period of potential
delay based on the models derived from published data. 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 regulatory review and
approval process, risks associated with enrollment of clinical
trials for rare diseases, and risks that ongoing or planned
clinical trials may not succeed or may be delayed for safety,
regulatory or other reasons. The Company faces risks related to the
commercial launch of a new product; risks associated with market
acceptance of FILSPARI and other current and future 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 serve as the basis for an sNDA submission for
traditional approval of sparsentan; and the risk that the results
from the Phase 3 DUPLEX study of sparsentan in FSGS will not serve
as a basis for a regulatory submission for approval of sparsentan
for FSGS. There is no guarantee that regulators will grant full
approval of sparsentan for IgAN or FSGS. The Company also faces the
risk that it will be unable to raise additional funding that may be
required to complete development of any or all of its product
candidates, including as a result of macroeconomic conditions;
risks 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; and 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
Communications888-969-7879 mediarelations@travere.com |
Investors:Naomi EichenbaumVice
President, Investor
Relations888-969-7879 IR@travere.com |
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