Cybrexa Therapeutics Announces New Preclinical Data on Tumor-Selective Peptide-Drug Conjugates at ESMO Targeted Anticancer Therapies Congress 2025

• alphalex™ peptide-drug conjugates (PDCs) demonstrate tumor-selective delivery and potent anticancer activity
• Preclinical data show robust efficacy as monotherapy and in combination with standard-of-care treatments
• Findings potentially position alphalex PDCs in patients who have progressed following TOP1-based antibody-drug conjugates

NEW HAVEN, Conn., March 4, 2025 – Cybrexa Therapeutics, a clinical-stage oncology biotechnology company developing a novel class of tumor-targeting peptide-drug conjugate (PDC) therapeutics, today announced new preclinical data from its alphalex™ technology, which were presented at the ESMO Targeted Anticancer Therapies (TAT) Congress 2025 being held March 3-5 in Paris, France. The findings demonstrate that Cybrexa’s antigen-agnostic PDC platform selectively delivers highly potent microtubule inhibitors to tumor cells, suppressing tumor growth while inducing a durable anti-tumor immune response.

Unlike antibody-drug conjugates (ADCs), alphalex PDCs use a pH-driven targeting approach to enable broad tumor applicability and avoid the toxicities often associated with antigen-based drug targeting. By exploiting tumor acidity, the alphalex platform ensures precise intracellular drug delivery to potentially reduce off-target effects while enhancing therapeutic impact.

Preclinical Findings at ESMO TAT 2025
The poster, “Characterization of Antigen-Agnostic Tumor-Selective Delivery and Immunomodulatory Activities of Auristatin and Maytansinoid alphalex™ Peptide-Drug Conjugates,” highlighted preclinical results evaluating the efficacy, safety, and immune-modulating effects of alphalex conjugates across mouse and rat xenograft and syngeneic models, including colorectal, melanoma, renal, and breast cancers. The data demonstrate that alphalex PDCs achieved tumor-selective delivery, long-term stability in plasma, and potent anti-tumor effects as both monotherapy and in combination with standard-of-care therapies.

“These data reinforce the potential of the alphalex platform to overcome the challenges of antigen-based therapies, while providing a powerful, tumor-selective approach to delivering cytotoxic agents,” said Vishwas Paralkar, Ph.D., Chief Scientific Officer of Cybrexa Therapeutics. “In bypassing the limitations of antibody-drug conjugates, we are opening new therapeutic possibilities for patients with hard-to-treat solid tumors.”

Key findings:

• Tumor-selective drug delivery
  • Plasma stability and in vivo analyses confirmed that alphalex conjugates selectively deliver microtubule inhibitors to tumor tissue while sparing healthy immune cells.
• Potent efficacy in multiple tumor models
  • Monotherapy: alphalex conjugates led to complete tumor suppression in HCT116 human colorectal cancer models.
  • Combination therapy: In flank and metastatic models, alphalex PDCs demonstrated synergy with doxorubicin and anti-PD-L1 therapy, further enhancing tumor suppression.
• Induction of durable anti-tumor immunity
  • Immunogenic cell death following alphalex treatment-activated T- and B-cell responses, with evidence of tumor-binding IgG and long-term immune memory, support the potential for sustained anticancer effects.
• Potential following a topoisomerase-1 (TOP1)-based ADC
  • The antigen-agnostic delivery of auristatin and maytansinoid payloads potentially positions alphalex PDCs in patients who have progressed following TOP1-based ADCs.

Clinical Progress: Advancing alphalex in the Clinic
Cybrexa is actively advancing its alphalex platform into clinical development. In October 2024, the company dosed the first patient in its Phase 2 clinical trial of CBX-12 in platinum-resistant or refractory ovarian cancer. CBX-12 is a first-in-class PDC that utilizes Cybrexa’s proprietary alphalex technology to enhance the intracellular delivery of exatecan, a highly potent, well-established TOP1 inhibitor.

This trial builds upon promising Phase 1 data, which demonstrated broad activity across multiple tumor types, including ovarian, breast, non-small cell lung cancer (NSCLC), thymic, gallbladder, and colorectal cancers, alongside a manageable safety profile.

About the alphalex™ Technology Platform
Cybrexa’s alphalex technology is a novel antigen-independent, peptide-drug conjugate (PDC) platform that enables targeted delivery of highly potent anticancer treatments and aims to revolutionize the standard of care in oncology. The platform consists of a pH-Low Insertion Peptide (pHLIP^®), a linker, and a small molecule anticancer agent. pHLIP peptides are a family of pH-low insertion peptides that target acidic cell surfaces. pHLIP was developed at Yale University and the University of Rhode Island and is exclusively licensed to pHLIP, Inc., and Cybrexa is a sublicensee of pHLIP, Inc.

About Cybrexa Therapeutics
Cybrexa is a privately held clinical-stage biotechnology company pioneering novel antigen-independent, tumor-targeting peptide-drug conjugate (PDC) therapeutics. The company is led by a dynamic team of highly successful life science entrepreneurs and veteran drug development scientists. Cybrexa is on a mission to create therapeutics that revolutionize the standard of care in oncology, and its robust pipeline aims to combat breast, ovarian, non-small cell lung cancer, and a range of other tumors. Its assets are built on Cybrexa’s alphalex™ technology platform, which enables intracellular delivery of highly potent anticancer treatments. Cybrexa is based in New Haven, Connecticut and was founded in 2017. For more information, please visit www.cybrexa.com or follow us on LinkedIn and X.

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Investor Contact:
Per Hellsund, CEO, Cybrexa Therapeutics
860-717-2731
[email protected]

Media Contact:
Dan Boyle, SCIENT PR
[email protected]

Cybrexa Therapeutics Announces First Patient Dosed with First-in-Class Peptide-Drug Conjugate CBX-12 in Phase 2 Trial in Ovarian Cancer

Primary target patient population for the CBX-12 Phase 2 study is women with platinum-resistant or refractory ovarian cancer who are naïve to TOP1-targeted agents

Study initiation follows positive Phase 1 study results, which showed a 40% response rate in TOP1-naïve ovarian cancer patients, in addition to activity across five other solid tumor types and a favorable safety profile

Trial marks key milestone in driving pipeline progress with multiple Phase 2 programs planned for CBX-12 in 2025 as a monotherapy and in combination

NEW HAVEN, Conn. – October 7, 2024 – Cybrexa Therapeutics, a clinical-stage oncology biotechnology company developing a novel class of tumor-targeting peptide-drug conjugate (PDC) therapeutics, today announced that the first patient has been dosed in a Phase 2 clinical trial evaluating CBX-12 in patients with platinum-resistant or refractory ovarian cancer. CBX-12 is a first-in-class PDC that uses Cybrexa’s proprietary alphalex™ technology to enhance the delivery of exatecan, a potent, established topoisomerase 1 (TOP1) inhibitor, directly to tumor cells while sparing healthy tissue. This trial initiation follows promising Phase 1 results, which demonstrated CBX-12’s broad activity across ovarian, breast, non-small cell lung cancer (NSCLC), thymic, gallbladder, and colorectal cancers along with a manageable safety profile.

“Dosing the first patient marks an important milestone for the Phase 2 clinical trial in ovarian cancer and for patients facing this aggressive disease,” said Per Hellsund, President and Chief Executive Officer of Cybrexa. “CBX-12 recently demonstrated significant antitumor activity, broad application potential, and a favorable safety profile in a Phase 1 study, including encouraging response rates in TOP1-naïve ovarian and breast cancer patients. We are particularly excited about the potential for CBX-12 not only as a standalone treatment but also as a promising candidate for future combination therapies and look forward to its continued advancement in this and additional Phase 2 studies in solid tumors, which are planned for 2025.”

The Phase 2 trial is a randomized, open-label study designed to evaluate the safety, tolerability, and efficacy of CBX-12 in women with platinum-resistant or refractory ovarian cancer at two doses: 125 mg/m² every 21 days or 100 mg/m² every 21 days.

Cybrexa plans an additional Phase 2 study of CBX-12 in colorectal cancer in 2025 in collaboration with the National Cancer Institute (NCI), as well as other Phase 2 studies evaluating CBX-12 as a monotherapy and in combination across a range of solid tumors. Leveraging its alphalex platform to develop multiple promising assets in oncology, Cybrexa is progressing its broader pipeline, including CBX-15, which is expected to enter the clinic in 2025 for the treatment of solid tumors using MMAE (monomethyl auristatin E) as its payload.

Unlike antibody-drug conjugates, CBX-12 does not rely on antigen expression for targeting but rather uses a pH-low insertion peptide (pHLIP ^®) to selectively deliver its payload into the cytoplasm of cancer cells. Results from the Phase 1 study demonstrated that CBX-12 is well tolerated and exhibits promising activity across a range of advanced or metastatic solid tumors, highlighting the versatility of the alphalex platform and its ability to enhance the delivery of cancer therapeutics while limiting off-target effects. The Phase 1 study results were recently presented at the European Society for Medical Oncology Congress (ESMO 2024) in a poster session.

To learn more about the Phase 2 study of CBX-12, please visit ClinicalTrials.gov (NCT06315491).

About CBX-12

CBX-12 is a first-in-class peptide-drug conjugate (PDC) that utilizes Cybrexa’s proprietary alphalex™ technology to enhance delivery of exatecan to tumor cells and is composed of a pH-Low Insertion Peptide (pHLIP^®), a linker, and exatecan. CBX-12 is designed to increase the efficacy and reduce the toxicity of topoisomerase 1 inhibition by delivering exatecan, a highly potent, second-generation topoisomerase 1 inhibitor, directly to the tumor cells. As an antigen-independent therapy, CBX-12 may have broad utility in patients who are not eligible for antigen-targeted therapies, including monoclonal antibodies and antibody-drug conjugates (ADCs), and has potential for use in combination regimens with other anti-cancer agents and immunotherapies.

About the alphalex™ Technology Platform

The Cybrexa alphalex technology is a novel antigen-independent, peptide-drug conjugate platform that enables targeted delivery of highly potent anti-cancer treatments and aims to revolutionize the standard of care in oncology. The platform consists of a pH-Low Insertion Peptide (pHLIP^®), a linker, and a small molecule anti-cancer agent. pHLIP peptides are a family of pH-low insertion peptides that target acidic cell surfaces. pHLIP was developed at Yale University and the University of Rhode Island and is exclusively licensed to pHLIP, Inc., and Cybrexa is a sublicensee of pHLIP, Inc.

About Cybrexa Therapeutics

Cybrexa is a privately held clinical-stage biotechnology company pioneering novel antigen-independent, tumor-targeting peptide-drug conjugate (PDC) therapeutics. The company is led by a dynamic team of highly successful life science entrepreneurs and veteran drug development scientists. Cybrexa is on a mission to create therapeutics that revolutionize the standard of care in oncology, and its robust pipeline aims to combat breast, ovarian, non-small cell lung cancer, and a range of other tumors. Its assets are built on Cybrexa’s alphalex™ technology platform, which enables intracellular delivery of highly potent anti-cancer treatments. Cybrexa is based in New Haven, Connecticut and was founded in 2017. For more information, please visit www.cybrexa.com or follow us on LinkedIn and X.

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Investor Contact:
Per Hellsund, CEO, Cybrexa Therapeutics
860-717-2731
[email protected]

Media Contact:
Robin Fastenau, Scient PR
[email protected]

Cybrexa Therapeutics Announces Positive Final Data at ESMO 2024 from Phase 1 Study of Peptide Drug Conjugate CBX-12 in Advanced Solid Tumors

• Data demonstrate broad activity of CBX-12 across six tumor types with a strong response rate in TOP1-naïve patients with ovarian (40%; N=10) and HR+ HER2- breast (43%; N=7) cancer, in addition to a favorable safety profile
• Phase 2 study in platinum-resistant ovarian cancer initiated in Q3 2024

NEW HAVEN, Conn. – September 16, 2024 – Cybrexa Therapeutics, a clinical-stage oncology biotechnology company developing a novel class of tumor-targeting peptide drug conjugate (PDC) therapeutics, today announced positive final results from its Phase 1 clinical trial of CBX-12 (alphalex™ exatecan). These data demonstrate that CBX-12 is well tolerated and exhibits promising activity across a range of advanced or metastatic solid tumors, including ovarian, breast, thymic, gall bladder, non-small cell lung cancer (NSCLC) and colorectal cancers, underscoring its potential as a highly differentiated conjugate with broad antitumor activity. The study results were presented in a poster session at the European Society for Medical Oncology (ESMO) Congress 2024.

“These Phase 1 study results highlight the potential of our alphalex™ Platform to create meaningful therapies that deliver a payload with an improved therapeutic index while sharply reducing the toxicities that often limit conventional therapies,” said Per Hellsund, President and Chief Executive Officer of Cybrexa. “We believe CBX-12 marks a new era in cancer therapy that potentially offers precision targeting and enhanced drug delivery that could redefine patient outcomes. These data support the continued development of CBX-12 across a wide range of tumor types, validating the broad applicability of the platform, and led us to initiate a randomized Phase 2 study in platinum-resistant ovarian cancer patients. Additional Phase 2 studies in solid tumors are planned to begin in 2025.”

CBX-12 is designed to deliver higher concentrations of exatecan, a topoisomerase 1 (TOP1) inhibitor, directly to tumor cells while sparing healthy tissue. Unlike antibody-drug conjugates, CBX-12 doesn’t rely on antigen expression for targeting but rather uses a pH-low insertion peptide (pHLIP) to selectively deliver its payload into the cytoplasm of cancer cells.

“In this study of CBX-12, we’ve seen encouraging clinical activity across six tumor types, including exciting response rates in TOP1-naïve ovarian and breast cancer patients,” said Mike  Needle, M.D., Chief Medical Officer of Cybrexa. “Importantly, the manageable safety profile of CBX-12 further enhances its potential not only as a standalone treatment but also as a promising candidate for future combination therapies. By bypassing the need for antigens and focusing on a universal feature of tumor microenvironments, we believe CBX-12 could benefit a larger population than currently available therapies.”

Study Highlights

The Phase 1 study of CBX-12 demonstrated significant antitumor activity, broad application potential, and a favorable safety profile in patients with various advanced and metastatic cancers.

Efficacy:

• CBX-12 treatment resulted in activity across multiple different types of solid tumors, including breast, ovarian, NSCLC, colorectal (CRC), thymic and gallbladder cancers.
• Responses were observed in ovarian cancer, breast cancer, NSCLC and CRC.
• Specifically, in 10 ovarian cancer patients who were TOP1-naïve, there was one confirmed complete response, one confirmed partial response (PR), and two unconfirmed PRs, with eight out of 12 patients showing clinical benefit.
• In seven TOP1-naïve breast cancer patients, there were two confirmed PRs and one unconfirmed PR. All evaluable breast participants were HER-2 negative and HR positive.

Safety:

• The most frequent treatment-related adverse events included anemia (53.6%, with 24.6% Grade 3-4), leukopenia (42.0%, with 21.7% Grade 3-4), and neutropenia (40.6%, with 27.5% Grade 3-4).
• Notably, no cases of interstitial lung disease or ophthalmic toxicity, commonly associated with ADCs, were reported, and minimal GI toxicity was observed.
• The dose-limiting toxicity was myelosuppression, which was reversible.

Pharmacokinetics (PK) and Dose Optimization:

• The PK of CBX-12 and exatecan exhibited linear dose-proportional behavior, with a mean half-life ranging from 14 to 22 hours across the dose range studied. Two doses, 100 mg/m² and 125 mg/m², every 21 days are being studied in an ongoing Phase 2 trial, supporting further dose optimization to balance safety and efficacy in future studies.

The promising Phase 1 data provides strong validation for Cybrexa’s alphalex™ Platform, which enables multiple opportunities for value creation as Cybrexa deepens its efforts in oncology.  This foundational science has enabled the rapid advancement of CBX-12 into a recently initiated Phase 2 study in platinum-resistant ovarian cancer. An additional Phase 2 study in colorectal cancer is planned for 2025 in collaboration with the National Cancer Institute (NCI), as well as other Phase 2 studies in solid tumors as a monotherapy and in combination. CBX-15 is also being developed for solid tumors and is expected to be in the clinic in 2025 utilizing MMAE as the warhead.

About CBX-12

CBX-12 is a clinical-stage, first-in-class peptide drug conjugate (PDC) that utilizes Cybrexa’s proprietary alphalex™ technology to enhance delivery of exatecan to tumor cells and is composed of a pH-Low Insertion Peptide (pHLIP®), a linker, and exatecan. CBX-12 is designed to increase the efficacy and reduce the toxicity of topoisomerase I inhibition by delivering exatecan, a highly potent, second-generation topoisomerase I inhibitor, directly to the tumor cells. As an antigen-independent therapy, CBX-12 may have broad utility in patients who are not eligible for antigen-targeted therapies, including monoclonal antibodies and antibody-drug conjugates (ADCs), and has potential for use in combination regimens with other anti-cancer agents and immunotherapies.

About the alphalex™ Technology Platform

The Cybrexa alphalex technology is a novel antigen-independent, peptide-drug conjugate (PDC) platform that enables targeted delivery of highly potent anti-cancer treatments and aims to revolutionize the standard of care in oncology. The platform consists of a pH-Low Insertion Peptide (pHLIP®), a linker, and a small molecule anti-cancer agent. pHLIP peptides are a family of pH-low insertion peptides that target acidic cell surfaces. pHLIP was developed at Yale University and the University of Rhode Island and is exclusively licensed to pHLIP, Inc., and Cybrexa is a sublicensee of pHLIP, Inc.

About Cybrexa Therapeutics

Cybrexa is a privately held clinical-stage biotechnology company pioneering novel antigen-independent, tumor-targeting peptide drug conjugate (PDC) therapeutics. The company is led by a dynamic team of highly successful life science entrepreneurs and veteran drug development scientists. Cybrexa is on a mission to create therapeutics that revolutionize the standard of care in oncology, and its robust pipeline aims to combat breast, ovarian, non-small cell lung cancer, and a range of other tumors. Its assets are built on Cybrexa’s alphalex™ technology platform, which enables intracellular delivery of highly potent anti-cancer treatments.  Cybrexa is based in New Haven, Connecticut and was founded in 2017. For more information, please visit www.cybrexa.com or follow us on LinkedIn and X.

Investor Contact:
Per Hellsund, CEO, Cybrexa Therapeutics
860-799-1517
[email protected]

Media Contact:
Robin Fastenau, Scient PR
[email protected]