- PEP503 (crystalline hafnium oxide, NBTXR3)


There are several cancer treatment modalities including surgery, medication, radiation therapy, and others, depending on the site of the tumor, grade and stage of cancer, and the physical condition of the patients. About 50% of cancer patients receive radiotherapy throughout their cancer treatment. Radiation therapy causes breaks to the double helix of DNA using a high energy beam, which may induce cell death. However, radiation therapy also has notable disadvantages, such as a longer treatment period and unavoidable side effects. Over the past decades, many technologies and methods have been developed to address this, and while they ameliorate some of the drawbacks of traditional radiation therapy, there is much need for further improvement.

In August 2012, PharmaEngine, Inc. and Nanobiotix, S.A. entered into a License and Collaboration Agreement on a nanoparticle radio-enhancer, PEP503 (NBTXR3). In the preclinical studies, PEP503 (NBTXR3) showed the ability in enhancing tumor killing capability of radiation therapy, while spared the damaging side effects to the healthy tissues. PEP503 is currently undergoing a pivotal phase III clinical study in soft tissue sarcoma in Europe, South Africa, and Asia Pacific countries.

About PEP503(NBTXR3)

Radiation therapy uses ionizing radiation to generate free radicals and reactive oxygen species (ROS ) when it is directed toward the tumor and interacts with water molecules. The free radicals and ROS can then further break the DNA and lead to cell apoptosis.

PEP503 is a nanoparticle formulation of hafnium oxide crystals (HfO2), a radio-enhancer for local treatment. Hafnium oxide represents a high electron density nanomaterial designed to interact with ionizing radiation in order to locally (i.e. where the nanoparticles are) generate energy dose deposit.

When PEP503 is in the tumor cell, due to the high density and atomic number of hafnium, the probability of energy absorption is higher than it of water molecular. Therefore, PEP503 will generate the same type of effect as water molecules in tumor cell under radiotherapy, but by several orders of magnitude higher.

Clincal Development

PEP503 (NBTXR3) has been designated as a class III medical device by some EU regulatory authorities. Unlike the three clinical phases required for drug approval, the regulatory approval of a medical device requires only the pilot and pivotal studies. In September 2011, PEP503 was granted approval by ANSM, the French regulatory authority (formerly AFSSAPS), to start the phase I clinical trial. A total of 22 patients were recruited in this soft tissue sarcoma study. The first preliminary clinical results were presented at the ASCO annual meeting in May 2015 and the final results were presented at ESTRO in April 2015. With the proof of concept data from the phase I trial, a pivotal study of soft tissue sarcoma was launched in Europe, South Africa, and several Asia Pacific countries. Also, Nanobiotix is conducting a phase I trial in head and neck cancer, phase I trial in liver cancer and phase I trial in prostate cancer.

Under the license and collaboration agreement, PharmaEngine is responsible for the clinical development in the Asia Pacific region. In Taiwan, a phase Ib/II study in rectal cancer and a phase Ib/II study in head and neck cancer are ongoing. With a comprehensive clinical development plan in place, we believe that the clinical applications of PEP503 in different indications can be accelerated.

Market Potential

Nowadays about 50% of cancer patients worldwide receive radiation treatment. In Asia, potential indications for PEP503 include head and neck cancer, oral cavity cancer, rectal cancer, esophageal cancer, brain cancer and hepatocellular carcinoma. There is a niche role for PEP503 in this huge radiotherapy market.


  • S. Bonvalot, C.L. Pechoux, T.D. Baere, et al; Phase I study of NBTXR3 nanoparticles, in patients with advanced soft tissue sarcoma (STS). J Clin Oncol 32:5s, 2014 (suppl; abstr 10563)
  • Marill J, Anesary NM, Zhang P, Vivet S, Borghi E, Levy L, Pottier A. Hafnium oxide nanoparticles: toward an in vitro predictive biological effect? Radiat Oncol. 2014 Jun 30;9:150.
  • Pottier A, Borghi E, Levy L. New use of metals as nanosized radioenhancers. Anticancer Res. 2014 Jan;34(1):443-53. Review.
  • Bonvalot S, Le Pechoux C, De Baere T, et al; First-in-Human Study Testing a New Radioenhancer Using Nanoparticles (NBTXR3) Activated by Radiation