Once a small medical device company, Celsion Corporation (Nasdaq: CLSN) is now a late stage oncology company that is focusing its endeavors on the treatment of cancer with its lead product candidate in development, Thermodox®. ThermoDox, a liposomal encapsulation of Doxorubicin, 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).
In the presence of heat, ThermoDox’s liposomal shell breaks down, releasing doxorubicin directly to the area targeted for treatment. ThermoDox is designed to expand the effective treatment zone of the heat-based modalities to capture micro-metastases which are most commonly responsible for post-treatment disease recurrence. Developed in partnership with Duke University, ThermoDox is currently being investigated in a Phase 2 trial of breast cancer, a Phase 2 trial of liver metastasis, and a promising Phase 3 study in the treatment of hepatocellular carcinoma (HCC), or primary liver cancer, in combination with RFA.
Awaiting the Phase 3 pivotal trial results is Michael Tardugno, President and CEO of Celsion. We interviewed Mr. Tardugno and spoke about this new innovative treatment and asked what can be expected from Celsion’s development plan and investment.
OBR: First, thank you for agreeing to talk with us and discussing your product. But, what exactly is ThermoDox and how does it work?
MT: Thank you for having me. ThermoDox is the foundation of Celsion’s oncology platform. It is a liposomal encapsulation of doxorubicin, a proven and frequently used cancer drug, that, very uniquely, is triggered in the presence of mild heat—just above body temperature. The drug payload it carries is quickly delivered directly to the targeted treatment area, allowing for drug concentrations in and around the tumor several orders of magnitude higher than systemically delivered therapy. This effect is achieved without increasing the system toxicity of the agent.
ThermoDox’s delivery to the treatment area can be attributed to two mechanisms of tumor biology: 1) tumors have leaky vasculature, which is permeable to liposomes and enables their accumulation within tumors, and 2) when heated, blood vessels in tumors become even leakier, further increasing accumulation of liposomes in tumors before releasing the encapsulated drug. The intention in drug design was a very high concentration and release during heat treatment, which is synergistic to clinical applications of hyperthermia or ablation which can last between 30 minutes to 2 hours.
ThermoDox can be triggered using a wide variety of hyperthermic, or heat-based, modalities, creating a versatility in multi-modality therapy that is very compelling to the clinical research community. Radio Frequency Ablation (RFA), for instance, uses high concentrations of heat—a range between 80°C and 100°C—to kill cancer cells. And, although the evidence is clear that RFA will completely eliminate tumor mass, tumor cells typically re-occur within 10 to 14 months of RFA treatment. This is because cancer cells in the margin surrounding the tumor are not sufficiently heated and killed with RFA and, as a result, they survive and go on to form new tumor masses—especially where the treated tumor is greater than 3 centimeters (cm) in diameter or if there are multiple lesions present.
Our thesis is that ThermoDox combined with RFA will improve these kinds of tumor treatment outcomes because when doxorubicin is released from our heat-activated liposome, it eliminates the cancer cells found in the surrounding margin of the tumor.
OBR: Potentially speaking, how could your liposome technology improve upon what’s already on the market?
MT: Celsion’s heat sensitive liposome differentiates itself from other liposomes in that it’s specifically engineered to release its payload only in the presence of heat, 39°C–42°C in this case, a clinically achievable temperature range. This low-temperature triggering mechanism is unique to ThermoDox and our low temperature sensitive-liposomes (LTSL) technology platform, and distinct from first generation liposome technology. For ThermoDox, this technology allows us to concentrate up to 25 times more drug in the treatment area than IV doxorubicin, and several fold the concentration of other liposomally encapsulated doxorubicins. The indications we are pursuing are all unmet medical needs, where effective treatment options are limited or unavailable.
OBR: Why did you choose liver cancer?
MT: The statistics for primary liver cancer are alarming. The US incidence has tripled from 1975 to 2005. There are approximately 750,000 cases of liver cancer reported annually worldwide, with more than 50% of these occurring in the Asia-Pacific region. It is currently the fifth most prevalent form of cancer, and ranks third in cause of cancer deaths. According to the World Health Organization, liver cancer is expected to become the most prevalent cancer, surpassing lung cancer, by the year 2020, due in large part to the prevalence of hepatitis B and C in the developing world.
Liver cancer also progresses rapidly. It is estimated that up to 90% of liver cancer patients will die within five years of diagnosis. Because it is often diagnosed in the later stages of disease, 80% to 90% of patients are ineligible for surgical resection, the most effective form of treatment. In the US, where primary liver cancer is considered an orphan disease, mortality rates have increased faster than mortality rates for any other leading cause of cancer. Although the incidence rate is relatively low compared with Asia, it’s nonetheless dramatically increasing in both men and women.
Given the high prevalence and unmet need in this disease, as well as the rapidly growing use of heat based therapy—primarily RFA—primary liver cancer was a natural initial goal for our clinical program. As further testament to the importance of this indication and ThermoDox’s potential, our Phase 3 HEAT Study was designated as a Priority Trial by the National Institutes of Health and was also granted Fast Track Designation by the US Food and Drug Administration (FDA).
OBR: What can you tell us about the Phase 3 trial of
ThermoDox with RFA in the treatment of HCC?
MT: The HEAT Study is a multinational, double-blind, placebo-controlled pivotal study of ThermoDox in combination with RFA for the treatment of primary liver cancer. The study is fully enrolled, with 700 patients recruited at 79 clinical sites in 11 countries. The study’s primary endpoint is progression-free survival (PFS), and a total of 380 PFS events are required to reach data unblinding and the planned final analysis, which is projected to occur in late 2012.
In the US, the HEAT Study is being conducted under an FDA Special Protocol Assessment (SPA) and has received FDA Fast Track Designation. The European Medicines Agency (EMA) has confirmed the HEAT Study is acceptable as a basis for submission of a marketing authorization application (MAA). In addition to meeting the FDA and EMA enrollment objectives, the HEAT Study has also enrolled a sufficient number of patients to support registrational filings in China, South Korea, and Taiwan, three large and important markets for ThermoDox.
The HEAT Study includes patients with tumors greater than 3 cm and less than 7 cm. We set this eligibility criterion because there is greater frequency of recurrence in tumors of that size compared with smaller tumors (2 cm or less), that are generally treated effectively with RFA alone. Patients are randomized 1:1 into a Thermodox plus RFA treatment arm or into a dummy infusion plus RFA arm. The primary endpoint is to measure a 33% improvement in PFS with a P value of .05. The study is powered to show a 30% improvement in PFS.
OBR: Assuming a positive outcome to the HEAT study and subsequent FDA approval, where would the treatment be administered, ie, hospital or academic centers?
MT: We expect it to be an outpatient treatment that will be administered by medical oncologists. Approximately 95% of the patients in our trial are treated using a percutaneous procedure, and the remaining 5% are treated using an open surgical procedure. Ultimately, we envision the procedure being performed by an interventional radiologist in a hospital outpatient setting.
OBR: How does the HEAT study compare with other trials going on for HCC?
MT: There are literally hundreds of clinical trials being conducted for HCC at any given time, all with therapies in various stages of development. We are very proud of the fact that the HEAT Study has been designated as a Priority Trial by and that the FDA has granted the study Fast Track Designation—both due to the urgent need for new treatments for liver cancer, as well as the rigor and potential of the HEAT Study.Clinical Trials Planning Meeting recognized the importance of our Phase 3 HEAT Study and published their recommendation in the JCO. We are extremely proud of our work thus far, and upon marketing approval, we believe ThermoDox plus RFA will provide an additional therapeutic option for patients afflicted with HCC. OBR