Zymeworks Inc. (Nasdaq: ZYME), a clinical-stage biotechnology
company developing novel, multifunctional biotherapeutics, today
announced 11 presentations including new data from its clinical and
preclinical development-stage programs at the 2023 American
Association for Cancer Research (AACR) Annual Meeting being held in
Orlando, Florida.
“We are very excited to showcase new data from our portfolio of
antibody-drug conjugates and multispecific antibody therapeutics
including our anticipated 2024 IND candidates, ZW191 and ZW171,”
said Paul Moore, Ph.D., Chief Scientific Officer at Zymeworks.
“These findings provide many new and exciting insights about the
potential of our therapies to represent significant advances in the
treatment of cancer and other diseases, while also highlighting our
cohesive strategy and path forward in developing a broad portfolio
of novel antibody-drug conjugates and multispecific antibody
therapeutics. The significant number of presented abstracts is a
reflection of the power and breadth of our protein engineering
platforms, and our capabilities and experience to engineer
potentially differentiated and novel medicines. We look forward to
advancing at least five novel medicines into clinical studies by
2027 under our previously-announced ZYME 5 x 5 R&D
objectives.”
Presentation Highlights
ZW191, a novel FRα-targeting antibody-drug conjugate bearing a
topoisomerase 1 inhibitor payloadAbstract: 2641Session Category:
Experimental and Molecular TherapeuticsSession Title: Antibody
Technologies
Human folate receptor alpha (FRα) is a
glycosyl-phosphatidylinositol-linked membrane protein. Expression
of FRα is rare in normal tissue, but frequently elevated in several
solid tumour types including epithelial ovarian cancer, endometrial
cancer and lung adenocarcinoma. ZW191 is an antibody-drug conjugate
(ADC) targeting FRα comprised of a novel fully humanized IgG1
antibody covalently conjugated to a novel topoisomerase 1 inhibitor
ZD06519, a camptothecin derivative, via endogenous interchain
cysteines with a drug to antibody ratio (DAR) of eight. The linker
in ZW191 consists of a maleimidocaproyl anchor and a glycyl glycyl
phenylalanyl glycine-aminomethyl protease-cleavable sequence. Upon
target binding and receptor-mediated internalization of ZW191,
intracellular release of bystander-active ZD06519 induces cell
death of FRα positive cells and FRα negative cells through
bystander-mediated killing.
Key Results:
- ZW191 exhibited a compelling preclinical activity profile that
supports potential activity in targeting FRα-high/mid/low ovarian
cancers.
- ZW191 demonstrated strong responses in FRα-low expressing PDX
models, indicating potential activity in other oncology indications
with lower levels of FRα.
- ZW191 displayed favorable pharmacokinetics (PK) and is well
tolerated in non-human primates (NHP) at exposure levels above
those projected to be efficacious.
ZW171, a T cell-engaging, bispecific antibody for the treatment
of mesothelin-expressing solid tumorsAbstract: 2942Session
Category: ImmunologySession Title: Therapeutic Antibodies 2
Mesothelin (MSLN) is a glycosylphosphatidylinositol-linked
membrane glycoprotein that is overexpressed in many cancer
indications, including pancreatic, mesothelioma, and ovarian¹, for
which there is a high unmet medical need. While MSLN-targeting
agents have shown early signs of clinical activity, there remains a
need for therapies with improved safety and efficacy². T cell
engager (TCE) therapies have exhibited clinical utility against
hematological malignancies but have shown limited success against
solid tumors due to dose-limiting toxicities associated with risk
of cytokine release syndrome (CRS) and on-target off-tumor
effects³.
To improve the therapeutic intervention of MSLN-expressing
tumors, Zymeworks utilized proprietary technologies based on the
company’s Azymetric™ and EFECT™ platforms as well as focused
engineering strategies to generate a panel of MSLN-targeting TCEs
with a variety of formats, geometries, and paratope affinities.
ZW171 was selected for development from this panel based on its
enhanced anti-tumor activity and safety.
Key Results:
- ZW171 induced potent preferential killing of
MSLN-overexpressing target cells and stimulated MSLN-dependent T
cell activation, mitigating the risk of on-target off-tumor
toxicity and peripheral T cell activation and CRS.
- ZW171 exhibited potent tumor growth inhibition in
MSLN-expressing tumor models and was well tolerated in cynomolgus
monkeys up to a single dose of 30 mg/kg.
- Data suggest that ZW171 could overcome the issues impeding the
success of other TCEs developed to treat solid tumors and provide
the therapeutic rationale to support the development of ZW171 for
the treatment of MLSN-expressing tumors.
ZW251, a novel glypican-3-targeting antibody-drug conjugate
bearing a topoisomerase 1 inhibitor payloadAbstract: 2658Session
Category: Experimental and Molecular TherapeuticsSession Title:
Antibody Technologies
Glypican-3 (GPC3) is a membrane-associated proteoglycan that is
specifically up-regulated in a substantial proportion of patients
with hepatocellular carcinoma (HCC)⁴, the most common type of liver
cancer. Liver cancer is a major cause of death in many countries,
and the number of people diagnosed with liver cancer is expected to
rise⁵. ZW251 is an ADC consisting of a topoisomerase 1 inhibitor
payload conjugated to an antibody targeting GPC3. Topoisomerase 1
inhibiting ADCs have demonstrated wide clinical benefit in solid
tumors and ZW251 aims to apply this against a target expressed in
hepatocellular carcinoma (HCC), a disease with high unmet need and
limited treatment options.
Key Results:
- ZW251 exhibited robust anti-tumor activity in a large panel of
HCC cell line-derived xenograft (CDX) and PDX models at both DAR 4
and DAR 8.
- Anti-tumor activity (tumor growth inhibition > 50%) for
ZW251 was evident in 82% of models with GPC3 H-score > 200 and
50-75% of models with GPC3 H-score < 200, providing evidence of
ZW251’s potential activity in a range of GPC3-expression
levels.
- No mortality was observed in a repeat dose NHP toxicology study
with doses up to 60 mg/kg (DAR 8) or 120 mg/kg (DAR 4).
- ZW251 is a potentially first-in class glypican-3 targeting
ADC.
Additional ADC Program Presentations
Revisiting the dogma of antibody-drug conjugates (ADCs):
Emerging data challenge the benefit of linker stability and the
primacy of payload deliveryAbstract: 1538Session Category:
Experimental and Molecular TherapeuticsSession Title: Antibody Drug
Conjugates
ZW220, a novel NaPi2b-targeting antibody-drug conjugate bearing
a topoisomerase 1 inhibitor payloadAbstract: 1533Session Category:
Experimental and Molecular TherapeuticsSession Title: Antibody Drug
Conjugates
Additional Multispecific Antibody Therapeutics Program
Presentations
TriTCE Co-stim, next generation costimulatory trispecific T cell
engagers for the treatment of solid tumorsAbstract: 5121Session
Category: ImmunologySession Title: Combination Immunotherapies
2
TriTCE CPI, next generation trispecific T cell engagers with
integrated checkpoint inhibition (CPI) for the treatment of solid
tumorsAbstract: 2982Session Category: ImmunologySession Title:
Therapeutic Antibodies 3
PROTECT™, a novel trispecific antibody masking platform with
integrated immune modulation displays unique activity and
differentiated modes of actionAbstract: 2926Session Category:
ImmunologySession Title: Therapeutic Antibodies 2
ZW270, a conditionally masked IL-12 cytokine fusion protein
displaying potent anti-tumor activity absent systemic
toxicityAbstract: 2935Session Category: ImmunologySession Title:
Therapeutic Antibodies 2
Clinical Product Candidate Presentations
ERBB2 amplification detected in ctDNA as a surrogate for tumor
tissue FISH analysis of HER2 status in a phase 1 study with
zanidatamab for the treatment of locally advanced or metastatic
HER2 expressing cancersAbstract: CT278Session Category: Clinical
Trials PostersSession Title: Phase I Clinical Trials 2
Zanidatamab zovodotin (ZW49) induces hallmarks of immunogenic
cell death and is active in patient-derived xenograft models of
gastric cancerAbstract: 2633Session Category: Experimental and
Molecular TherapeuticsSession Title: Antibody Technologies
Conference Call and Webcast Information:
Zymeworks management will host a conference call and
webcast for investors and analysts on April 18, 2023,
at 6:30 pm EDT. The event will be webcast live with dial-in
details and webcast replays available on Zymeworks’ website
at http://ir.zymeworks.com/events-and-presentations.
About Zymeworks Inc.
Zymeworks Inc. (Nasdaq: ZYME) is a global biotechnology company
committed to the discovery, development, and commercialization of
novel, multifunctional biotherapeutics. Zymeworks' mission is to
make a meaningful difference for people impacted by
difficult-to-treat cancers and other serious diseases. Zymeworks'
complementary therapeutic platforms and fully integrated drug
development engine provide the flexibility and compatibility to
precisely engineer and develop highly differentiated antibody-based
therapeutic candidates. Zymeworks engineered and developed
zanidatamab, a HER2-targeted bispecific antibody using Zymeworks'
proprietary Azymetric™ technology. Zymeworks has entered into
separate agreements with BeiGene, Ltd. (BeiGene) and Jazz
Pharmaceuticals Ireland Limited (Jazz), granting each of
BeiGene and Jazz with exclusive rights to develop and commercialize
zanidatamab in different territories. Zanidatamab is currently
being evaluated in global Phase 1, Phase 2, and Phase 3 clinical
trials, including certain ongoing pivotal clinical trials as a
treatment for patients with HER2-expressing cancers. Zymeworks'
next clinical candidate, zanidatamab zovodotin (ZW49), is a
HER2-targeted bispecific antibody-drug conjugate (ADC) developed
using Zymeworks' proprietary Azymetric™ and ZymeLink™ Auristatin
technologies. Zanidatamab zovodotin is currently being evaluated in
a Phase 1 clinical trial for patients with a variety of
HER2-expressing, HER2-amplified or HER2-mutant cancers. Zymeworks
is also advancing a deep pipeline of product candidates based on
its experience and capabilities in both ADC and multispecific
antibodies (MSAT). In addition to Zymeworks' wholly owned pipeline,
its therapeutic platforms have been further leveraged through
strategic partnerships with global biopharmaceutical companies. For
information about Zymeworks, visit www.zymeworks.com and
follow @ZymeworksInc on Twitter.
Cautionary Note Regarding Forward-Looking
Statements
This press release includes “forward-looking statements” or
information within the meaning of the applicable securities
legislation, including Section 27A of the Securities Act of 1933,
as amended, and Section 21E of the Securities Exchange Act of 1934,
as amended. Forward-looking statements in this press release
include, but are not limited to, statements that relate to
Zymeworks’ preclinical pipeline; the potential therapeutic effects
of zanidatamab and Zymeworks’ other product candidates; anticipated
regulatory submissions and the timing thereof; Zymeworks’ clinical
development of its product candidates and enrollment in its
clinical trials; anticipated preclinical and clinical data
presentations; the ability to advance product candidates into later
stages of development; and other information that is not historical
information. When used herein, words such as “plan”, “believe”,
“expect”, “may”, “anticipate”, “potential”, “will”, “continues”,
and similar expressions are intended to identify forward-looking
statements. In addition, any statements or information that refer
to expectations, beliefs, plans, projections, objectives,
performance or other characterizations of future events or
circumstances, including any underlying assumptions, are
forward-looking. All forward-looking statements are based upon
Zymeworks’ current expectations and various assumptions. Zymeworks
believes there is a reasonable basis for its expectations and
beliefs, but they are inherently uncertain. Zymeworks may not
realize its expectations, and its beliefs may not prove correct.
Actual results could differ materially from those described or
implied by such forward-looking statements as a result of various
factors, including, without limitation: future clinical trials may
not demonstrate safety and efficacy of any of Zymeworks’ or its
collaborators’ product candidates; clinical trials may not
demonstrate safety and efficacy of any of Zymeworks’ or its
collaborators’ product candidates; any of Zymeworks’ or its
partners’ product candidates may fail in development, may not
receive required regulatory approvals, or may be delayed to a point
where they are not commercially viable; regulatory agencies may
impose additional requirements or delay the initiation of clinical
trials; the impact of the COVID-19 pandemic on Zymeworks’ business,
research and clinical development plans and timelines and results
of operations, including impact on its clinical trial sites,
collaborators, and contractors who act for or on Zymeworks’ behalf,
may be more severe and more prolonged than currently anticipated;
the impact of new or changing laws and regulations; market
conditions; inability to maintain or enter into new partnerships or
strategic collaborations; and the factors described under “Risk
Factors” in Zymeworks’ quarterly and annual reports filed with the
Securities and Exchange Commission, including its Annual Report on
Form 10-K for its year ended December 31, 2022 (a copy of which may
be obtained at www.sec.gov and www.sedar.com).
Although Zymeworks believes that such forward-looking statements
are reasonable, there can be no assurance they will prove to be
correct. Investors should not place undue reliance on
forward-looking statements. The above assumptions, risks and
uncertainties are not exhaustive. Forward-looking statements are
made as of the date hereof and, except as may be required by law,
Zymeworks undertakes no obligation to update, republish, or revise
any forward-looking statements to reflect new information, future
events or circumstances, or to reflect the occurrences of
unanticipated events.
Contacts:
Investor Inquiries:Jack Spinks Director, Investor Relations(604)
678-1388ir@zymeworks.com
Media Inquiries:Diana PapoveDirector, Corporate
Communications(604) 678-1388media@zymeworks.com
___________________________________
¹ Morello, A., Sadelain, M., & Adusumilli, P.S. (2016).
Mesothelin-Targeted CARs: Driving T Cells to Solid
Tumors. Cancer discovery, 6(2), 133-46.² Faust, J. R., Hamill,
D., Kolb, E. A., Gopalakrishnapillai, A., & Barwe, S. P.
(2022). Mesothelin: An Immunotherapeutic Target beyond Solid
Tumors. Cancers, 14(6), 1550.³ Arvedson, T, Mailis, J.M.,
Britten, C.D., Klinger, M., Nagorsen, D., Coxon, A., Egen, J.G.,
Martin, F. (2022). Targeting Solid Tumors with Bispecific T Cell
Engager Immune Therapy. Annual Review of Cancer Biology, 6, 7-14.⁴
Wang HL et al., Arch pathol Lab Med, 2008 132(11)⁵ Rumgay H et al.,
Global burden of primary liver cancer in 2020 and prediction to
2040; Journal of Hepatology. vol 77 (6) 2022.
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