Joe C. Loy leads Zetagen Therapeutics, a mission-driven company committed to developing first-in-class therapeutics for both metastatic and primary breast cancer.
Credit: Joe C. Loy
Metastatic cancer that spreads to the bone is one of the most painful and life-altering complications patients face. Lytic bone lesions weaken the skeleton, increase the risk of fractures, and often lead to severe pain and reduced mobility. Despite their prevalence, the current standard of care remains largely palliative, offering temporary symptom relief but no true repair of the underlying bone damage.
DDN spoke with Joe C. Loy, the CEO of Zetagen Therapeutics, about a new class of locally delivered therapies designed not only to stop tumor activity in bone and soft tissue but also to regenerate healthy bone. Early clinical results, including complete responses and evidence of bone regeneration in metastatic breast cancer lesions, suggest that this approach could represent a major shift in how metastatic disease is treated.
What makes Zetagen’s approach to treating metastatic bone and soft tissue lesions different from other therapies?
Our approach is different because we deliver our therapies directly into the tumor itself, enabling direct tumoricidal activity at the site of malignancy. This approach circumvents hepatic first-pass metabolism, which typically reduces drug bioavailability and forces conventional systemic therapies to be dosed at higher levels. As a result, traditional agents often produce residual exposure that contributes to off-target toxicities such as gastrointestinal disturbances and immune deficiencies, such as diarrhea, nausea, and neutropenia.
Another benefit is the simplicity of the procedure. It’s performed under sedation, takes less than 30 minutes, and so far, we haven’t observed any adverse effects related to the injection. It’s a very controlled, predictable intervention.
Perhaps most importantly, during the course of our research, we identified a novel molecular pathway associated with the small molecule-receptor interaction we are targeting. This nuclear receptor is highly conserved across species, with minimal evolutionary divergence over millions of years. Consequently, our in vivo models closely recapitulate human biology, providing a high degree of translational predictability from preclinical dosing to clinical application — what we describe as a true “bench-to-bedside” advantage.
This combination of targeted delivery, reduced systemic toxicity, and a strong mechanistic insight not only benefits patients but also accelerates the overall efficiency of the drug development process.
How does your platform work at a molecular or cellular level?
Each of our first-of-its-kind therapies — ZetaMet (Zeta-BC-003), ZetaMast (Zeta-MBC-005), and ZetaPrime (Zeta-PBC-007) — uses a proprietary carrier system specifically engineered for the anatomical environment in which they are administered. These carriers enable controlled release and solubilization of the active compounds while maintaining bio-adhesion, thereby optimizing local bioavailability.
Although each drug employs distinct carriers and small molecules, they share critical pharmacological features that contribute to consistent therapeutic responses. Each therapy incorporates the same small molecule that binds selectively to the OGFR (opioid growth factor receptor), providing a predictable and reproducible therapeutic effect across indications.
At the molecular level, once the small molecule is injected directly into the tumor microenvironment, it directly targets OGFR and triggers a novel regulatory pathway. The interaction functions almost like a therapeutic “thermostat.” By adjusting the concentration of the molecule, we have learned that we can modulate OGFR activity — increasing or decreasing the biological response to achieve the intended outcome.
ZetaMet achieved complete responses in all treated metastatic breast cancer bone lesions in your Phase 2a trial. Can you describe how it both stops tumor activity and regenerates bone?
In the case of ZetaMet, this cascade induces transcriptional upregulation of the p21 pathway, which suppresses the activity of osteoclasts — the cells that break down bone — stopping the destructive osteolytic process caused by metastasized breast cancer cells. At the same time, it stimulates osteoblasts, the cells responsible for building bone, which encourages new trabecular bone formation.
This dual modulation — osteoclast inhibition and osteoblast stimulation — in parallel with tumoricidal effects, ceases tumor activity and possibly recurrence, while reducing the risk of skeletal-related events (SREs), including pathologic fractures. Published data demonstrates that mitigation of SREs is directly correlated with improvements in quality of life and overall survival (OS), underscoring the clinical significance of this therapeutic approach.
The trial showed that treated lesions and nearby non-treated lesions within the same spinal bone responded. How does the therapy act beyond the injection site?
We first observed evidence of this phenomenon, which we term “therapeutic spread,” in the treatment of a patient under compassionate use. Her case report was subsequently published, including a two-year follow-up demonstrating sustained benefit.
Further confirmation was obtained during our Phase 2a study at the University of British Columbia. In multiple instances, when a lesion within the same spinal bone, or vertebral body, was treated, we consistently documented a complete response in adjacent, untreated lesions within the same vertebral body.
We believe this happens because of the vascular structure within cortical and cancellous bone, which allows the drug’s effect to propagate locally. The exciting part is that this activity seems to stay within the bone itself, maximizing the therapeutic benefit while minimizing systemic exposure.
ZetaMet is delivered via a proprietary controlled-release carrier. Can you explain why that delivery method is important for efficacy and safety?
For patients, this means reduced pain, fewer skeletal-related events, and a lower risk of local tumor recurrence. By preserving bone structure and function, we also see the potential to improve quality of life and, ultimately, overall survival.
- Joe C. Loy, Zetagen Therapeutics
The proprietary carrier in ZetaMet allows us to deliver the therapy directly to the tumor site, maximizing local drug availability. This targeted delivery enhances the therapy’s effectiveness by both stopping the cancer from destroying bone and promoting new bone growth.
For patients, this means reduced pain, fewer SREs, and a lower risk of local tumor recurrence. By preserving bone structure and function, we also see the potential to improve quality of life and, ultimately, OS. The carrier essentially lets us concentrate the therapy where it’s needed most, while minimizing exposure to the rest of the body, which helps keep it safe and well-tolerated.
ZetaMet-P and ZetaMAST extend your platform to prostate and liver metastases. How are these therapies similar or different in their approach compared to ZetaMet?
Both ZetaMet-P (Zeta-PC-004) and ZetaMAST use intratumoral delivery and share one of the same small molecules that targets OGFR, a conserved nuclear receptor — so they’re built on the same core science as ZetaMet.
Beyond that, each therapy is tailored to the specific tissue it treats. They use proprietary carriers designed for the unique environment of the prostate or liver, ensuring the drug stays where it’s needed and is released effectively. Each formulation also includes supporting compounds that work together to enhance the therapy’s specific goals.
Right now, we’ve temporarily paused ZetaMet-P development to focus on advancing the breast cancer program, but once that’s complete, we plan to resume work on ZetaMet-P and explore other indications where our approach could have a meaningful impact, such as lung cancer and glioblastoma.
Are there specific patient populations or tumor types that you believe could benefit most from your therapies, and why?
Yes. With ZetaMet, we’ve seen consistent outcomes in both compassionate use patients and our Phase 2a trial across multiple breast cancer subtypes, including hormone receptor-positive (HR+), triple-negative, and human epidermal growth factor receptor 2-positive (HER2+). Patients demonstrated cessation of tumor activity, absence of SREs, and evidence of therapeutic spread, which has led to a complete response.
ZetaMast is specifically designed for triple-negative breast cancer, a particularly aggressive subtype that often spreads to the liver. Its targeted delivery and proprietary carrier help maximize effectiveness for this high-risk group.
ZetaPrime is intended for primary HR+ breast cancer as a neo-adjuvant therapy. Delivered locally via a specialized hydrogel-like lipid carrier, it allows controlled release of our small molecule and potentially other compatible therapies. Designed for solubility within adipose tissue, ZetaPrime is a paradigm-shifting intratumoral approach to adjuvant therapy that targets primary breast cancer, aiming to mitigate off-target effects, reduce the necessity for lumpectomies and mastectomies, postpone radiation exposure, and enhance patient survival.
