PALO
ALTO, Calif., July 24,
2023 /PRNewswire/ -- Kodiak Sciences Inc. (NASDAQ:
KOD) announced today topline results from three Phase 3 studies of
tarcocimab tedromer, a novel antibody biopolymer conjugate.
The DAYLIGHT study was a randomized, double-masked, active
comparator-controlled study evaluating the efficacy and safety of a
high intensity dosing regimen of tarcocimab tedromer in 557
treatment-naïve subjects with wet AMD. The DAYLIGHT study met the
primary endpoint of non-inferior visual acuity gains for tarcocimab
dosed monthly compared to aflibercept dosed every 8 weeks following
3 monthly loading doses. Tarcocimab was safe and well tolerated in
the study and with a low rate of intraocular inflammation.
The GLEAM and GLIMMER studies are identically designed,
randomized, double-masked, active comparator-controlled studies
evaluating the efficacy, durability and safety of tarcocimab
tedromer in 460 and 457 treatment-naïve subjects with DME,
respectively. Although high proportions of patients on meaningfully
longer treatment intervals were observed with tarcocimab, with half
of patients on every 24-week dosing at the primary endpoint, the
GLEAM and GLIMMER studies did not meet their primary efficacy
endpoints of showing non-inferior visual acuity gains for
tarcocimab dosed every 8 to 24 weeks after 3 monthly loading doses
compared to aflibercept given every 8 weeks after 5 monthly loading
doses. An unexpected increase in cataracts was observed over time
in the tarcocimab arms of both GLEAM and GLIMMER, and Kodiak's
initial evaluation suggests that this contributed meaningfully to
the failure of each study. In the DAYLIGHT study, no imbalance in
cataracts was observed between wet AMD patients receiving
tarcocimab or aflibercept throughout the one-year study period
despite the intensive monthly tarcocimab dosing regimen.
Based on these data, and despite demonstrating great potential,
Kodiak has made a business decision to discontinue further
development of tarcocimab.
"A successful efficacy, durability and safety outcome in both
GLEAM and GLIMMER was the basis of our regulatory and clinical
development strategy for tarcocimab," said Victor Perlroth, MD, Kodiak's Chief Executive
Officer, in explaining the decision. "After our unsuccessful Phase
2b study in wet AMD last year, we
made a number of changes to the GLEAM and GLIMMER study design to
increase their probability of success, and we saw the positive
impact of those changes in the GLEAM and GLIMMER data. Notably, the
conjugate delivered on the promise of early potency and strong
consistent durability through the study. After getting these
results, the immediate question is why did the GLEAM and GLIMMER
studies fail?"
"We have gained three main insights from the initial data
analysis. First, through the matched three loading doses, vision
and anatomic improvements were strong and comparable between
tarcocimab and aflibercept. Second, in a subset of patients to be
determined, additional loading doses with tarcocimab might have
helped better achieve early disease control to set an even higher
visual acuity base entering into the dose interval adjustment
phase, but the overall effect of this was not a primary driver of
study failure. Third, and most critically, an unforeseen imbalance
in cataract adverse events emerged in the last third of the study
(19% of patients on tarcocimab versus 9% of patients on aflibercept
by the primary endpoint), and we believe this likely was the
primary driver for tarcocimab failing to achieve BCVA
non-inferiority to aflibercept in these studies. A sub-analysis of
the pseudophakic patients (who enter the study having already had
cataract surgery) and who represented 25% of the total study
population supports this view as does initial analysis of the OCT
anatomic data from the two studies. The development of cataracts
did not appear to correlate with the timing or number of tarcocimab
doses patients had received. Importantly, in the DAYLIGHT study
which explored a maximal, monthly regimen of tarcocimab 5mg in wet
AMD patients, a median of 12 tarcocimab doses were given over one
year and patients experienced fewer events of cataract on
tarcocimab than on aflibercept (3% versus 5%). Thus, what drove the
increased incidence of cataracts with tarcocimab in DME remains
unclear at this time. Given these findings and results, we are
discontinuing development of the tarcocimab program," concluded Dr.
Perlroth.
"While vision improvements were more closely matched in the
first two-thirds of each study, at the primary efficacy endpoint of
the GLEAM study patients treated with tarcocimab gained an average
of 6.4 eye chart letters (to 73.1 letters) compared with 10.3
letters for patients treated with aflibercept (to 76.5 letters),"
said Jason Ehrlich, MD, PhD,
Kodiak's Chief Medical Officer. "In GLIMMER, patients treated with
tarcocimab gained an average of 7.4 eye chart letters at the
primary endpoint (to 72.5 letters) compared with 12.2 letters (to
76.4 letters) for patients treated with aflibercept. Half of
tarcocimab treated patients were on every 6-month dosing at the
primary endpoint, two-thirds achieved at least one 6-month dosing
interval during the studies, and three-quarters achieved at least
one 5-month or longer treatment interval. Aside from the increase
in cataracts, no new or unexpected safety signals were identified
in GLEAM and GLIMMER. Intraocular inflammation was rare, occurring
in 1.3% and 0.2% of tarcocimab and aflibercept treated patients,
respectively. No cases of intraocular inflammation with vasculitis
or vascular occlusion were observed. In the DAYLIGHT study,
intraocular inflammation occurred in 3.3% of patients treated with
monthly tarcocimab and 0.4% of patients treated with aflibercept,
again with no vasculitis or occlusion."
"We sincerely thank the participants, clinicians and site staff
who participated in the tarcocimab clinical trials and who continue
to participate in the ongoing clinical program of our second
investigational medicine, KSI-501," said Drs. Perlroth and Ehrlich.
"We are also especially grateful to all of the Kodiak team members
and our partners who are dedicated to developing novel therapeutics
for eye diseases and have made these projects possible."
Dr. Perlroth continued, "Kodiak remains well financed with
approximately $379 million cash and
cash equivalents as of June 30, 2023
(unaudited) providing us with significant optionality following the
wind-down of the tarcocimab program. We will be assessing our
capabilities and the many learnings gained by Kodiak during the
development of tarcocimab as we reset our near-term plan."
"While we have not come to a final conclusion, we remain
committed to our vision and mission of developing transformative
therapies for high prevalence diseases. In this regard, we believe
our KSI-501 program has a differentiated mechanism of action
targeting both IL-6 mediated immune-inflammation as well as VEGF
mediated angiogenesis and vascular permeability. The KSI-501
clinical program is underway with enrollment in the Phase 1
multiple dose escalation study nearly complete. In light of the
emergence of late onset cataracts observed with tarcocimab in GLEAM
and GLIMMER but not DAYLIGHT, we are assessing whether to continue
development of KSI-501 both as (i) its unconjugated protein which
is itself a novel bispecific anti-IL-6 antibody / anti-VEGF trap
fusion protein and (ii) its bioconjugate form. In this manner, we
would continue development of this novel retina program while
decreasing our reliance on the ABC platform, thus allowing a more
thorough exploration of platform versus product profiles.
Meanwhile, we look forward to advancing our triplet platform and
other protein therapeutic and small molecule programs. Our triplet
platform is designed to enable multi-mechanism targeting of
multifactorial diseases by embedding small molecules in the
biopolymer backbone to provide a high drug-antibody ratio (DAR).
The small molecules can be released over time to achieve sustained
inhibition of targeted biological pathways. We plan to explore the
utility of this unique combination of high DAR and extended
therapeutic benefit in retinal and systemic diseases."
"In summary, we are deeply disappointed with the GLEAM and
GLIMMER outcome. We recognize the risks inherent to innovative drug
development and expect to continue to work towards the goal of
translating our capabilities and substantive cash position into
value for our stakeholders."
Detailed results of the GLEAM and GLIMMER studies are scheduled
to be presented by study investigator Dr. Charles C. Wykoff, MD, PhD, as a late-breaking
presentation at the 41st Annual Scientific Meeting of
the American Society of Retina Specialists, which will be held
beginning next week in Seattle,
WA. The presentation is currently scheduled for Sunday, July 30, 2023 at 3:51pm Pacific Time. A copy of the slides will be
made available on the Kodiak Investor Relations website.
It is anticipated that data from the DAYLIGHT study and
additional results and insights from the tarcocimab development
program, such as the pending BEACON study year one data in retinal
vein occlusion and pending topline results of the GLOW study in
non-proliferative diabetic retinopathy, will be presented at
upcoming medical conferences.
About the GLEAM and GLIMMER Studies
The GLEAM and GLIMMER studies together randomized 919 patients
into two treatment arms: tarcocimab 5 mg or aflibercept 2 mg.
Tarcocimab was dosed every 8, 12, 16, 20 or 24 weeks following 3
monthly loading doses. Aflibercept was dosed as per its label, on a
fixed every 8-week interval following 5 monthly loading doses.
Subjects on tarcocimab were assessed 8 weeks after the completion
of their loading phase and, based on predefined disease activity
criteria, were assigned to a base treatment interval of every 8 to
24 weeks. Patients were evaluated monthly thereafter, and treatment
intervals were extended, maintained or reduced based on disease
activity. The primary endpoint of the study was the average change
in best-corrected visual acuity (BCVA) score (a measure of the best
vision a person can achieve when reading letters on an eye chart,
including with correction such as glasses) from baseline averaged
over weeks 60 and 64. For the assessment of the primary efficacy
endpoint, the BCVA of tarcocimab patients in all dosing intervals
was compared as a single group to the aflibercept group dosed every
8 weeks. Additional information about GLEAM (also called Study
KS301P104) and GLIMMER (also called Study KS301P105) can be found
on www.clinicaltrials.gov under Trial Identifiers NCT04611152 and
NCT04603937, respectively
(https://clinicaltrials.gov/ct2/show/NCT04611152 and
https://clinicaltrials.gov/ct2/show/NCT04603937).
About the DAYLIGHT Study
The Phase 3 DAYLIGHT study is a global, multi-center, randomized
pivotal study designed to evaluate the efficacy and safety of
high-frequency tarcocimab in patients with treatment-naïve wet
age-related macular degeneration (wet "AMD"). The DAYLIGHT study
randomized 557 patients to receive either tarcocimab on a monthly
dosing regimen or to receive aflibercept on a fixed dosing regimen
of every 8-weeks after three monthly loading doses per its label.
The primary endpoint is at year one. The DAYLIGHT study is intended
to evaluate the safety and efficacy of tarcocimab in treating high
need patients with wet AMD. Additional information about DAYLIGHT
(also called Study KS301P107) can be found on
www.clinicaltrials.gov under Trial Identifier NCT04964089
(https://clinicaltrials.gov/show/NCT04964089).
About KSI-501
KSI-501 is a first-in-class bispecific investigational medicine
designed to inhibit two mechanisms implicated in retinal diseases:
interleukin-6 (IL-6) and vascular endothelial growth factor
("VEGF"). IL-6 is a pro-inflammatory cytokine and growth factor
implicated in the pathophysiology of multiple retinal diseases and,
in conditions for which anti-VEGF treatment is used, elevated
levels of ocular IL-6 have been associated with poor anti-VEGF
treatment response. KSI-501 is a trap-antibody fusion biopolymer
conjugate designed to provide potent inhibition of (i)
VEGF-mediated angiogenesis and vascular permeability through a
soluble decoy receptor inhibiting the binding of VEGF-A and PLGF to
their cognate receptors and (ii) IL-6 mediated inflammation through
an antibody that binds soluble interleukin-6, inhibiting its
binding to both soluble and membrane-bound IL-6 receptors. In
cell-based assays, KSI-501 inhibits angiogenesis and also
normalizes inner and outer blood retinal barriers; dual inhibition
of VEGF and IL-6 by KSI-501 confers superior normalization of cell
morphology and junctional biology compared to either anti-VEGF or
anti-IL-6 monotherapy. We believe KSI-501 has the potential to
become a new category of retinal medicines with greater therapeutic
utility than existing therapies. A Phase 1 study of KSI-501 is
currently dosing patients in the United
States to evaluate the safety, tolerability and bioactivity
of KSI-501 in patients with DME.
About Kodiak Sciences Inc.
Kodiak (Nasdaq: KOD) is a biopharmaceutical company committed to
researching, developing and commercializing transformative
therapeutics to treat high prevalence retinal diseases. We are
focused on bringing new science to the design and manufacture of
next generation retinal medicines to prevent and treat the leading
causes of blindness globally. KSI-501 is Kodiak's first-in-class
bispecific investigational medicine targeting both IL-6 (anti-IL-6
antibody) and VEGF (VEGF-trap) and is being investigated in a Phase
1 clinical study initially in patients with diabetic macular edema.
We are expanding our early research pipeline to include ABC
Platform based triplet inhibitors for multifactorial diseases.
Kodiak is based in Palo Alto, CA.
For more information, please visit www.kodiak.com.
Kodiak®, Kodiak Sciences®, ABC™, ABC Platform™ and the Kodiak
logo are registered trademarks or trademarks of Kodiak Sciences
Inc. in various global jurisdictions.
Forward-Looking Statements
This release contains "forward-looking statements" within the
meaning of Section 27A of the Securities Act of 1933, Section 21E
of the Securities Exchange Act of 1934 and the Private Securities
Litigation Reform Act of 1995. These forward-looking statements are
not based on historical fact and include statements regarding: the
realignment of our priorities after tarcocimab clinical study
readouts; and potential expansion of our research pipeline.
Forward-looking statements generally include statements that are
predictive in nature and depend upon or refer to future events or
conditions, and include words such as "may," "will," "should,"
"would," "could," "expect," "plan," "believe," "intend," "pursue,"
and other similar expressions among others. Any forward-looking
statements are based on management's current expectations of future
events and are subject to a number of risks and uncertainties that
could cause actual results to differ materially and adversely from
those set forth in or implied by such forward-looking statements.
These risks and uncertainties include, but are not limited to: the
risk that cessation or delay of any of the ongoing clinical studies
and our development of KSI-501 may occur; the risk that preliminary
safety, efficacy and durability data for our product candidates may
not continue or persist; our research and development efforts and
our ability to advance our product candidates into later stages of
development may fail; the risk that any one or more of our product
candidates may not be successfully developed, approved or
commercialized; adverse conditions in the general domestic and
global economic markets, which may significantly impact our
business and operations, including our clinical trial sites, as
well as the business or operations of our manufacturers, contract
research organizations or other third parties with whom we conduct
business; as well as the other risks identified in our filings with
the Securities and Exchange Commission. In addition, the Company's
unaudited cash and cash equivalents as of June 30, 2023 is subject to revision based upon
the Company's quarter-end closing procedures and the completion and
external review of the Company's financial statements as of and for
the quarter ended June 30, 2023. For
a discussion of other risks and uncertainties, and other important
factors, any of which could cause our actual results to differ from
those contained in the forward-looking statements, see the section
entitled "Risk Factors" in our most recent Form 10-K, as well as
discussions of potential risks, uncertainties, and other important
factors in our subsequent filings with the Securities and Exchange
Commission. These forward-looking statements speak only as of the
date hereof and Kodiak undertakes no obligation to update
forward-looking statements, and readers are cautioned not to place
undue reliance on such forward-looking statements. Kodiak®, Kodiak
Sciences®, ABC™, ABC Platform™ and the Kodiak logo are registered
trademarks or trademarks of Kodiak Sciences Inc. in various global
jurisdictions.
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