Doxorubicin dramatically enhanced with Lyso-Thermosenstive Liposomal Doxorubicin (LTLD)

Using our LTLD technology, Celsion has encapsulated doxorubicin, a proven and frequently used cancer drug, to create ThermoDox®. The heat-sensitive liposome rapidly changes structure when heated to a specific temperature, creating openings in the liposome which release doxorubicin directly into the targeted tumor.

ThermoDox, delivered by intravenous (IV) infusion, is designed to be used in combination with hyperthermic (heat-based) treatments, such as radiofrequency thermal ablation (RFA), microwave hyperthermia, and high- intensity focused ultrasound (HIFU). The goal of the ThermoDox approach is to expand the effective treatment zone of these technologies to capture micro-metastases, which are most commonly responsible for post-treatment disease recurrence. For example, in patients with primary liver cancer, there is a very high one-year recurrence rate in the immediate area of the original ablated region; addressing this expanded area as part of the treatment regimen may potentially reduce recurrence rates and improve patient outcomes.

ThermoDox leverages two mechanisms of tumor biology to deliver higher concentrations of drug directly to the targeted tumor site. First, tumors have leaky vasculature, which is permeable to liposomes and enables their accumulation within tumors. Second, when heated, blood vessels in tumors become even more permeable, further increasing the accumulation of liposomes in tumors before releasing the drug payload. The potential of this approach has been demonstrated in vivo; in animal models, ThermoDox has been shown to deliver 25 times more doxorubicin than IV doxorubicin into tumors, and five times more doxorubicin than standard liposomal formulations of the drug.

Celsion recently received Food and Drug Administration (FDA) clearance to initiate the Phase III OPTIMA trial, which is designed to evaluate ThermoDox in combination with standardized RFA (sRFA 45) in primary liver cancer (hepatocellular carcinoma, or HCC). The two-arm, double-blinded, placebo-controlled, randomized study will enroll approximately 550 patients at up to 100 sites in North America, Europe, China, and the Asia-Pacific region. The primary endpoint is overall survival (OS), and the study is powered to demonstrate a 33% improvement in OS.

The OPTIMA study design is supported by an exhaustive retrospective analysis of a large subgroup of 285 patients in a previous Phase III trial in primary liver cancer, is based on convincing post-hoc OS data, and is further reinforced by prospective confirmatory preclinical data and computational models. In a subgroup of 285 HEAT study participants as of July 2014, we noted a 57% improvement in OS in the ThermoDox + sRFA arm 45, compared to those who received sRFA 45 alone; these findings have remained constant over six quarterly data sweeps (p = 0.037). Supported by key opinion leaders in HCC clinical research, our post-hoc analysis suggests that a 33% improvement in OS is an attainable target for the OPTIMA study.

As of July 2015, patients who received an optimized RFA procedure, 285 patients or 41% of the Study, showed an average 58% improvement in overall survival. ThermoDox improved OS in this subgroup from 53.6 months with optimized RFA alone to 79 months with doxorubicin plus optimized RFA.

Sub-group Analysis of HEAT Study Data:

The HEAT study results are instructive in that they demonstrate that RFA must be used within its engineered design limitations, and that the duration of heating time directly affects clinical outcome, in that a longer RFA time (45-90 minutes) is associated with better outcomes. The HEAT study also showed that a high tissue concentration of ThermoDox prevents disease recurrence, and that effective dosing is a function of both pharmacokinetics and local perfusion.

Additionally, the Phase II DIGNITY study is evaluating ThermoDox plus local hyperthermia in patients with recurrent chest wall (RCW) breast cancer, a difficult-to-treat population of patients who have failed to respond to at least two lines of chemotherapy following mastectomy, and have failed to respond to radiation before enrolling in the trial. Interim results show impressive and compelling clinical activity, with a local response rate of 50%, including three complete responses and two partial responses. Additionally, 60% of DIGNITY study participants have experienced disease stabilization. Those findings are consistent with the local response rate of 48.3% observed in 24 patients enrolled in two previous Phase I studies.

To generate growth over the long-term, we are supporting a broad range of studies using MRI-guided high-intensity focused ultrasound (HIFU) to provide ThermoDox activation in multiple indications. The most advanced program is recruiting patients with colorectal liver metastases in a Phase II study, in partnership with Oxford University in Britain. That program is followed closely by a Phase II study of ThermoDox + HIFU in patients with breast cancer in The Netherlands. Both of these programs are co-funded in Europe by government grants. Beyond those indications, ThermoDox holds promise in a wide variety of tumor types for which doxorubicin is widely used, including pancreatic cancer and glioblastoma, a type of brain cancer. We also continue to invest in our liposomal technology, developing proprietary formulations of other marketed chemotherapeutics.