Developing Novel Drugs for Treatment and Diagnosis of Cancer

I-124-CLR1404 (LIGHT)

I-124-CLR1404 (LIGHT) is a small-molecule, broad-spectrum, cancer-targeted imaging agent that we believe has the potential to be the first of its kind for the selective detection of tumors and metastases in a broad range of cancers. LIGHT is comprised of a proprietary PLE, acting as a cancer-targeted delivery and retention vehicle, covalently labeled with iodine-124, a short-lived PET imaging radioisotope. PET imaging used in conjunction with CT scanning has now become the imaging method of choice in oncology. In studies to date, LIGHT selectively illuminated malignant tumors in 52 of 54 animal models of different cancer types, demonstrating broad-spectrum, cancer-selective uptake and retention. Investigator-sponsored Phase 1-2 trials of LIGHT as a PET imaging agent are ongoing at the University of Wisconsin across 11 solid tumor indications. The investigator-sponsored Investigational New Drug (IND) application for LIGHT was approved by the FDA in 2003. The IND is held by Dr. Lance Hall at the University of Wisconsin, who both initiates and conducts the investigation and under whose immediate direction the investigational drug is administered. Novelos, the National Cancer Institute or the University of Wisconsin Institute for Clinical and Translational Research provide funding for the trials and the data is shared with Novelos while the trials progress and at the conclusion of the trials. Initial positive imaging results have been established in patients with lung and brain cancers. These human trials, if successful, would likely provide proof-of-concept for LIGHT as a PET imaging agent with the potential to supplant the current “gold standard” agents, 18F-fluoro-deoxyglucose (FDG) for various solid tumors or MRI in the case of brain cancers, due to what we believe to be LIGHT’s superior cancer-specificity versus FDG and MRI, and more favorable logistics of clinical use versus FDG. As a chemically identical biomarker for HOT, we believe that LIGHT tumor uptake data could accelerate clinical development of HOT by guiding selection of indications for HOT Phase 2 trials and potentially be used in such trials to identify suitable patients and assess therapeutic efficacy. For the same reason, and in view of the quantitative nature of PET imaging, LIGHT imaging may be capable of estimating an efficacious dose of HOT in individual patients.

Chemically, LIGHT is comprised of our proprietary PLE, 18-(p-[I-124]iodophenyl) octadecyl phosphocholine, acting as a cancer-targeted delivery and retention vehicle, covalently labeled with iodine -124, a radioactive isotope with a radiation half-life of four days.

During 2006, we compared LIGHT and FDG side by side (24 hours apart) in the same tumor-bearing mouse (PC3 human prostate carcinoma) that was also treated with carrageenan to induce inflammation. As expected, FDG demonstrated significant uptake into the inflammatory lesion and organs such as heart and bladder compared to the malignant tumors, which were poorly imaged. LIGHT, on the other hand, showed no uptake into the inflammatory lesion and organs, yet clear and demonstrable uptake into the tumors.

Furthermore, the radioisotopic half-life of only 110 minutes for fluorine-18 labeled agents, such as FDG, severely limits their delivery range relative to the point of manufacture. I-124 has a four-day half-life that permits worldwide distribution of LIGHT from one manufacturing location. Additionally, the longer half-life affords a longer imaging window of up to seven days following injection.

The third part of an investigator-sponsored Phase 1-2 trial of LIGHT as a PET imaging agent for patients with advanced non-small cell lung cancer (NSCLC) was initiated in December 2011 at the University of Wisconsin Carbone Cancer Center (UWCCC) and the first patient was enrolled in February 2012. Dr. Anne M. Traynor at UWCCC is the principal investigator for this trial. Novelos provides funding for the trial and the data is shared with Novelos both as the study progresses and upon the conclusion of the study. A total of up to 9 patients will be enrolled across two dose levels (5 mCi and 3 mCi) in this Phase 1-2 trial. The first cohort comprising three patients dosed with LIGHT at 5mCi has been successfully completed. We saw clear and sustained uptake of LIGHT in cancerous tumors against low background and have not observed any adverse safety signals. Although still early and in a small number of subjects, there is some suggestion that LIGHT imaging was more tumor-selective than the comparator modality 18F-fluoro-deoxyglucose (18F-FDG) PET. In addition, in one patient, three brain metastases were detected with LIGHT that were not seen with FDG, which prompted an alteration of the treatment plan for this patient. Having observed initial cancer-specific uptake with LIGHT at 5 mCi dose in NSCLC patients, we continue exploration of dose and imaging time points in an effort to optimize dosing and results.

An investigator-sponsored Phase 1-2 trial of LIGHT as a PET imaging agent for brain cancer was initiated in December 2011 at UWCCC and first patient was enrolled in March 2012. Dr. Lance Hall at the UWCCC is the principal investigator for this trial. This trial is being funded by UWCCC and a UW Institute for Clinical and Translational Research (ICTR) grant, but the data is shared with Novelos while the study progresses and at the conclusion of the study. Up to 20 patients will be enrolled at a 5 mCi dose. In June 2012, we announced that three glioma patients were dosed with LIGHT at 5 mCi. The preliminary results from these three glioma patients showed strong and sustained uptake of LIGHT in cancerous tumors visible against very low background, and no adverse safety signals were observed. Patient enrollment is continuing.

An investigator-sponsored Phase 1-2 trial of LIGHT as a PET imaging agent for patients with multiple solid tumor types (triple negative breast, prostate, colorectal, gastric, ovarian, pancreatic, esophageal, soft tissue sarcoma, and head & neck cancer) was initiated in August 2012 at the UWCCC and the first patient was enrolled in October 2012. Dr. Glenn Liu at UWCCC is the principal investigator for this trial. Novelos provides funding for the trial and the data is shared with Novelos while the study progresses and at the conclusion of the study. Up to 9 patients per tumor type will be enrolled across two dose levels (5 mCi and 3 mCi) in this Phase 1-2 trial.

An investigator-sponsored Phase 1-2 trial of LIGHT as a PET imaging agent for metastatic brain cancer was initiated in January 2012 at UWCCC and the clinical trial protocol is being amended to facilitate patient enrollment. Dr. Lance Hall at the UWCCC is the principal investigator for this clinical trial. Dr. Jamey Weichert is the primary principal investigator for the $1.2 million grant from the National Cancer Institute, which funds the trial.

LIGHT is currently manufactured by our collaborator, the University of Wisconsin in Madison. We are evaluating contract manufacturing options for larger scale production.

We plan to initiate Company-sponsored LIGHT Phase 2 trials in solid tumor indications, subject to additional funding, starting in the first quarter of 2014. The objectives of these Phase 2 trials will include comparison to standard-of-care cancer imaging with pathology confirmation, as well as optimization of dosing and imaging parameters. Meanwhile, we will continue exploration of dose and imaging time points, along with comparison to standard-of-care cancer imaging, in the ongoing investigator-sponsored LIGHT Phase 1-2 trials.

According to Bio-Tech Systems (November 2010), sales of FDG in the US in 2009 were approximately $300 million and projected to grow to approximately $900 million in 2017. FDG accumulates in any tissue having increased glucose metabolism compared to surrounding tissue. As a result and in contrast to LIGHT, FDG is not selective for malignant tumors. FDG localizes in certain normal tissue such as heart, kidney and brain tissues that also have high glucose metabolism. FDG is also known to localize in inflammatory sites. Other major limitations to the use of FDG are found in pelvic imaging due to the high renal (kidney) clearance of the compound. These characteristics of FDG, therefore, decrease its diagnostic specificity for certain malignancies. FDG is no longer covered by patent and is typically manufactured onsite at PET imaging medical facilities because of its limited (110 minute) half-life.