Tricida, Inc. (Nasdaq: TCDA), a pharmaceutical company focused
on the development and commercialization of its investigational
drug candidate, veverimer, a non-absorbed, orally-administered
polymer designed to treat metabolic acidosis in patients with
chronic kidney disease (CKD), today provided an update on its U.S.
Food and Drug Administration (FDA) interactions.
Tricida has received an Appeal Denied Letter (ADL), from the
Office of New Drugs (OND) of the FDA in response to its Formal
Dispute Resolution Request (FDRR) submitted in December 2020. While
the FDRR was focused on whether the magnitude and durability of
serum bicarbonate change seen in the TRCA-301/TRCA-301E trial is
reasonably likely to predict clinical benefit in the treatment of
metabolic acidosis in patients with CKD, the OND’s decision
additionally addressed other deficiencies identified in the
Complete Response Letter (CRL), which Tricida received in August
2020. The additional issues addressed included the reliability of
the data from the TRCA-301/TRCA-301E trial due to the
disproportionate impact of data from a single high-enrolling
clinical site on the trial’s results and the applicability of the
trial results to the U.S. patient population given that the
majority of the subjects in the study were enrolled in sites
outside of the United States or were in regions that the FDA does
not consider “U.S.-like,” such as Eastern Europe.
In the ADL, the OND acknowledged that the TRCA-301/TRCA-301E
trial met its serum bicarbonate endpoints with statistical
significance but concluded that the extent of serum bicarbonate
increase observed in the TRCA-301/TRCA-301E trial is not reasonably
likely to provide a discernible reduction in CKD progression. The
OND also concluded that the confirmatory trial, VALOR-CKD, is
underpowered to detect the effect size (13%) predicted by the
original Tangri model (also known as the Predictive MA Model) based
upon the placebo-subtracted mean treatment effect observed in the
TRCA-301/TRCA-301E trial.
The OND also provided feedback on other concerns that are
particularly relevant in an NDA supported by a single
registrational trial. The OND noted concerns around the trial
results being strongly influenced by a single site, and the
majority of sites for the TRCA-301/TRCA-301E trial being in Eastern
Europe, where differences in patient management, including
concomitant medications and diet, might affect the treatment
response to veverimer and raise a concern of the applicability to a
U.S. patient population. The FDA did not raise any concerns related
to its completed inspection of the highest-enrolling clinical trial
site and there was no FDA Form 483 issued. Also, while the OND did
not suggest that there was a specific unblinding issue in the
TRCA-301/TRCA-301E trial, the OND noted concerns around adequate
blinding and that, while the measures in place to protect the study
blind in the TRCA-301/TRCA-301E trial were reasonable, they may not
have optimally protected the blind.
Although the ADL provides greater clarity on the potential path
for approval of veverimer through the Accelerated Approval Program,
Tricida believes the timeline to meet the requirements for
accelerated approval as suggested in the ADL may not result in the
most rapid development path for veverimer. For example, the OND
suggested that Tricida meet with the Division of Cardiology and
Nephrology (the Division) to discuss submission of 52-week serum
bicarbonate results from the fully randomized VALOR-CKD trial and
that such submission should include a substantial proportion of
U.S. and “U.S.-like” patients. The OND also indicated that, if the
results of this trial were to demonstrate a meaningfully larger
treatment effect on serum bicarbonate than seen in the
TRCA-301/TRCA-301E trial, results from VALOR-CKD, along with the
results from the TRCA-301/TRCA-301E trial, could address the
deficiencies identified in the CRL. However, the OND noted that
whether these data would support accelerated approval would remain
a review issue and therefore would be subject to the Division’s
assessment of the adequacy of the magnitude of increase in serum
bicarbonate. Moreover, based on the concerns expressed, we believe
that the FDA could require an additional trial or trials to confirm
the magnitude, durability of effect or applicability to the U.S.
population for resubmission of the veverimer NDA through the
Accelerated Approval Program.
Given the feedback provided by the FDA in the ADL, Tricida
intends to continue the VALOR-CKD trial without further
modifications at the present time with consideration of both the
accelerated and traditional approval pathways. Tricida’s planned
interim analyses in the VALOR-CKD trial could result in early
stopping for efficacy and resubmission of the NDA through a
traditional approval pathway with a potential indication of
treatment of metabolic acidosis to slow CKD progression. Tricida is
also evaluating several options with respect to the VALOR-CKD trial
that are focused on obtaining additional data prior to the end of
2022 on the effect of veverimer on (1) CKD progression;
(2) physical functioning; and (3) serum bicarbonate.
These options include the possibility of stopping the trial early
for administrative reasons, which would allow analysis of the data
using all alpha remaining at that time. In any event, Tricida
believes data from VALOR-CKD will be very important in furthering
the understanding of the regulatory path for approval of
veverimer.
“The feedback that we received from OND makes clear that the
results from the TRCA-301/TRCA-301E trial alone will not support
accelerated approval of veverimer,” said Gerrit Klaerner, Ph.D.,
Tricida’s Chief Executive Officer and President. “We certainly hear
and understand the need for additional data and believe that the
VALOR-CKD trial is the best near-term source to provide that
information.”
Tricida Conference Call Information
Tricida will host its Fourth Quarter Financial Results and
Business Update Conference Call and webcast today at 4:30 pm
Eastern Time. The webcast or conference call may be accessed as
follows:
Tricida Conference Call |
Thursday, February 25, 20214:30 pm Eastern
Time |
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Webcast: |
IR.Tricida.com |
|
|
Dial-in: |
(800)
773-2954 |
|
|
International: |
(847) 413-3731 |
|
|
Conference
ID: |
50111253 |
|
A replay of the webcast will be available on Tricida’s website
approximately two hours following the completion of the call and
will be available for up to 90 days following the presentation.
About the VALOR-CKD Clinical Trial
The ongoing VALOR-CKD trial is a renal outcomes clinical trial
designed to determine if veverimer slows CKD progression in
patients with metabolic acidosis associated with CKD. The VALOR-CKD
trial is a randomized, double-blind, placebo-controlled,
time-to-event trial. The primary endpoint in VALOR-CKD is defined
as a composite of renal death, end-stage renal disease (ESRD) or a
confirmed ≥ 40% reduction in estimated glomerular filtration rate
(eGFR) (DD40). We anticipate randomizing approximately 1,600
subjects in VALOR-CKD and the trial is currently designed to
terminate when the independent blinded Clinical Endpoint
Adjudication Committee has positively adjudicated 511 subjects with
primary efficacy endpoint events, which is anticipated to occur in
the first half of 2024. The VALOR-CKD trial also includes two
interim analyses for early stopping for efficacy after the accrual
of 150 primary endpoint events, which is anticipated in the second
half of 2021, and 250 primary endpoint events, which is anticipated
in mid-2022. The VALOR-CKD trial also includes, as its first two
secondary efficacy endpoints, evaluation of the effect of veverimer
versus placebo after one year of treatment on patient-reported and
objective measures of physical functioning, using the Kidney
Disease and Quality of Life Physical Functioning Survey, or KDQOL
Physical Functioning Survey, and the Repeated Chair Stand test,
respectively. Although not part of any efficacy endpoints, the
VALOR-CKD trial will also provide information regarding the change
from baseline in serum bicarbonate in veverimer and placebo-treated
subjects.
In November 2020, following the receipt of the CRL, Tricida
revised the protocol for the VALOR-CKD trial based on feedback from
the FDA in a July 2020 advice letter as well as additional work to
understand both the hazard ratio and the anticipated serum
bicarbonate effect of veverimer. In collaboration with Dr. Navdeep
Tangri, M.D., Ph.D., of the University of Manitoba, Canada, Tricida
developed a Time-Dependent Predictive Model in a cohort of more
than 24,000 U.S. patients with metabolic acidosis and CKD. The
results from this model show an 8.4% lower risk of CKD progression
for each 1 mEq/L increase in serum bicarbonate. In addition,
we believe the magnitude of the veverimer treatment effect in the
TRCA-301/TRCA-301E trial is best described by the between-group
difference in the medians, rather than the difference in the LS
means, as the data are not normally distributed. The Week 52 median
placebo-subtracted treatment effect in the TRCA-301/TRCA-301E trial
was an increase in serum bicarbonate of 3.15 mEq/L. Using the
Time-dependent Predictive Model, we predict that a median treatment
effect of 3.15 mEq/L is associated with a hazard ratio of 0.76
for the VALOR-CKD renal outcome trial. Thus, with a sample size of
1,600 subjects, the trial has 87% power to show a 24% difference in
primary endpoint events. These current assumptions for the powering
of the VALOR-CKD trial were not considered by the OND in their
response to the FDRR, and we have not yet received FDA comments on
this revised draft protocol.
Tricida initiated enrollment in the VALOR-CKD trial in the
fourth quarter of 2018 and has established sites throughout North
America, Europe, Latin America and Asia-Pacific. As of February 22,
2021, the VALOR-CKD trial has randomized 1,433 of 1,600 subjects
with an average treatment duration of approximately one year and
has accrued 69 subjects with positively adjudicated primary
endpoint events. In November 2020, based on feedback from the FDA,
recruitment for VALOR-CKD was closed in all regions except for the
United States, Canada and Western Europe. At the end of
recruitment, Tricida anticipates approximately 67% of subjects to
be enrolled at Eastern European sites, 19% at US, Western European
and Canadian sites, 7% at Latin American sites, and 7% at sites in
the Asia-Pacific region. Tricida’s goal is to complete enrollment
in the trial by the end of 2021; to meet this goal it may need to
reopen recruitment at sites outside of the United States, but it
will not reopen recruitment at sites in Eastern Europe. Tricida
intends to ensure that no single site in the VALOR-CKD trial
provides ≥ 5% of the total number of trial subjects. FDA’s
acceptance of the VALOR-CKD data in support of an NDA resubmission,
including the acceptability of the data from non-US countries or
regions which will comprise a substantial proportion of the data
from the trial, will ultimately be a review issue.
About Tricida
Tricida, Inc. is a pharmaceutical company focused on the
development and commercialization of its investigational drug
candidate, veverimer (TRC101), a non-absorbed, orally-administered
polymer designed to treat metabolic acidosis in patients with CKD.
Tricida is currently conducting a renal outcomes clinical trial,
VALOR-CKD, to determine if veverimer slows CKD progression in
patients with metabolic acidosis associated with CKD. There are no
FDA-approved treatments for chronic metabolic acidosis, a condition
commonly caused by CKD that is believed to accelerate the
progression of kidney deterioration. It is estimated to pose a
health risk to approximately three million patients with CKD in the
United States.
For more information about Tricida, please
visit www.Tricida.com.
Cautionary Note on Forward-Looking
Statements
This press release includes forward-looking statements within
the meaning of Section 27A of the Securities Act of 1933 and
Section 21E of the Securities Exchange Act of 1934. Forward-looking
statements relate to expectations concerning matters that are not
historical facts. Words such as “projects,” “believes,”
“anticipates,” “plans,” “expects,” “intends,” “may,” “will,”
“could,” “should,” “would,” and similar words and expressions are
intended to identify forward-looking statements. Any statements
contained herein which do not describe historical facts, including
the Company’s expectations with regard to its interactions and
communications with the FDA, its plans and expectations as to the
pathway to approval of veverimer by the FDA and the design of its
ongoing clinical trial, VALOR-CKD, and its expectations regarding
financial runway are forward-looking statements which involve risks
and uncertainties that could cause actual results to differ
materially from those discussed in such forward-looking statements.
Such risks and uncertainties include, without limitation, whether
the FDA will accept the Company’s resubmission of an NDA for
veverimer; the timing of the FDA’s approval of veverimer, if at
all; the potential availability of the Accelerated Approval Program
and the approvability of veverimer under that program; the
Company’s plans and expectations with regard to its interactions
with the FDA; the Company’s plans and expectations for VALOR-CKD
and future clinical and product development milestones; the
Company’s financial projections and cost estimates; and risks
associated with the Company’s business prospects, financial results
and business operations. These and other factors that may affect
the Company’s future business prospects, results and operations are
identified and described in more detail in the Company’s filings
with the Securities and Exchange Commission (SEC), including the
Company’s most recent Annual Report filed on Form 10-K and the
subsequently filed Quarterly Report(s) on Form 10-Q. You should not
place undue reliance on these forward-looking statements, which
speak only as of the date of this press release. Except as required
by applicable law, the Company does not intend to update any of the
forward-looking statements to conform these statements to actual
results, later events or circumstances or to reflect the occurrence
of unanticipated events.
Contact:Jackie Cossmon, IRCTricida, Inc.Senior Vice President
ofInvestor Relations and CommunicationsIR@Tricida.com
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