Developing Innovative Therapies for the Treatment of Cancer
XRad Therapeutics is a privately-held, clinical stage biopharmaceutical company focused on developing dual kinase inhibitors for treating cancer. The company’s lead product, XRD-0394, is currently being evaluated in the clinic.
XRD-0394, is a first-in-class dual inhibitor of ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK). Initial development efforts are focused on evaluating XRD-0394’s ability to enhance radiation therapy when used in combination. In parallel, the company is exploring the potential benefits of using XRad’s dual kinase inhibitors in combination with targeted radionuclides, immune checkpoint inhibitors, polyadenosine diphosphate-ribose polymerase (PARP) inhibitors and antibody drug conjugates (ADCs).
All cells in the human body are susceptible to DNA damage which may result from a variety of sources including radiation, chemotherapy, UV light and reactive oxygen species. To maintain genomic integrity, cells have developed several, sophisiticated mechanisms to repair this damage which is collectively referred to as the DNA Damage Response (DDR).
While it is critical for healthy cells to effectively repair DNA damage, there are instances when inducing severe DNA damage or preventing DNA repair in unhealthy cells, such as tumor cells, is beneficial. For example, radiation therapy is the most widely used cancer therapy and works by causing severe DNA damage to tumor cells in the form of double-stranded breaks which ultimately leads to cell death.
In addition to radiation therapy, recent research has shown that blocking certain enzymes in the DDR pathways shows promise as an emerging therapeutic strategy for treating cancer. Two targets of particular interest include ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK). Both ATM and DNA-PK are well-characterized, genetically-validated targets which play central roles in regulating cellular responses to DNA double-strand breaks.
Preclinical data have shown that inhibition of either ATM or DNA-PK (when combined with radiation therapy) results in a higher level of tumor cell death versus radiation therapy alone. Further, dual inhibition of both ATM and DNA-PK (when combined with radiation therapy) yields an even greater effect suggesting that dual inhibition of these targets could offer a potential therapeutic benefit.
Scientific Rationale for Dual Inhibition
ATM & DNA-PK play central roles in regulating the cell’s response to DNA damage. These enzymes appear to have compensatory relationships. Dual inhibition of both targets overcomes this effect.
Clinical Opportunities for XRad Dual-kinase Inhibitors
In addition to improved radiosensitization, inhibition of ATM and DNA-PK has additional therapeutic potential across several mechanistic pathways. XRad has generated encouraging preclinical data in these areas to better understand future applications.
Radiosensitization and Radiation Sparing
- Opportunity to treat patients using lower doses of RT + XRD-0394
- IMRT, SBRT, proton beam therapy, brachytherapy
RT + Immunotherapy
- Phosphorylation of TBK1 is a marker of activation of the type 1 IFN response and has been linked to enhanced tumor response to immune checkpoint blockade therapy
Combination w/ ADCs
- Combination with drug conjugates
- Combination with radiopharmaceuticals
Combination w/ Other DDR Targets
- Combination with other DDR targets including PARP
DDR Mutant Tumors
- Opportunity for synthetic lethality (e.g., BRCA1 & BRCA2)
XRad is currently conducting a Phase 1 study to evaluate the safety and tolerability of single ascending doses of XRD-0394 administered with palliative RT in patients with metastatic, locally advanced or recurrent cancer.
The study is being conducted at two centers, Memorial Sloan Kettering Cancer Center and the Stanford Cancer Institute.
XRad’s leadership brings together a powerful team with academic research, clinical practice and industry expertise, focused on the design, discovery and development of novel therapies targeting DNA damage repair.
- Former Global Director of Oncology Translational Research, GSK
- Expertise in molecular/cellular biology, pharmacology, biomarker discovery
- Experience in target ID through post-NDA approval
- Key leader and member of research and project teams for Tykerb, Votrient, Tafinlar and Mekinist
- Executive Director, Duke Cancer Institute (DCI)
- Elected to National Academy of Sciences, National Academy of Medicine, and American Academy of Arts and Sciences;
- Leading expert in DNA damage & repair, tumor suppressor genes, and cancer causation related to genetic predisposition
- Prof Radiation Oncology & Pharmacology & Cancer Biology, Duke;
- Vice Chair for Basic & Translational Research in Radiation Oncology & Leader of the Radiation Oncology & Imaging Program in DCI;
- MD/PhD at J Hopkins; post-doc at MIT, Radiation Oncology at MGH
- President and Chief Executive Officer for Zentalis Pharmaceuticals.
- Fmr Partner at Aisling Capital and Perseus-Soros Biopharmaceutical Fund
- BS in Electrical Engineering from Cornell University, an MD from Temple University School of Medicine, an MBA from the Wharton School of Business
If you are interested in partnering with XRad or have other business development inquiries, please get in touch.