Pharmaceutical Technology Europe interviews Llew Keltner, President, CEO and Director of Light Science Oncology (WA, USA). The company has developed a promising new cancer treatment that uses light-emitting diodes to activate a drug inside solid tumours.

Q1: Light Sciences Oncology (LSO) has developed its Light Infusion Therapy (Litx) for the treatment of solid tumours. What makes this technology a safer and more effective treatment for patients?
Current cancer treatments —surgery, radiation therapy, chemotherapy, and other local ablative therapies — have significant shortcomings, such as severe toxicity, limited efficacy, stimulation of tumour growth and resistance, immune suppression, high set-up and usage costs, complicated administration, and poor patient quality-of-life. Litx is designed to address all of those disadvantages.

There is no evidence that Litx produces the typical side effects from the systemic damage to rapidly-dividing normal cells caused by chemotherapy, radiation, and other cancer treatments. Litx does not cause nausea, hair loss, digestive disruption, skin and mouth sores, immune system degradation, or cardiac or neurological damage. The technology has been shown in animal and human studies to be a reliable method for destruction of tumor tissue without the side effect profiles of other therapies.

Q2: What does the technology involve?
Litx is designed as an entirely new mode of therapy compared with the older, laser based generation of photodynamic drug therapies (PDT). Litx uses light-emitting diodes (LEDs) to activate LS11 (talaporfin sodium), a light-activated, water-soluble drug. An LS11 molecule activated by the Litx system results in the production of singlet oxygen, which can kill target tissues with minimal side effects. Litx uses low-intensity light that causes vascular closure and apoptosis, or 'programmed cell death'. Illumination with low-intensity light can activate each molecule of LS11 many times, resulting in a continuous supply of singlet oxygen molecules.

The Litx device contains a tiny array of LEDs at the end of a very narrow (only 1.2 mm wide) flexible coated micro-wire. Administering physicians insert the LED array into a tumour using a biopsy-like procedure, requiring only a mild anesthetic, followed by intravenous injection of LS11. The device emits red light at a discrete frequency and intensity, for a fixed time period, to activate LS11 and create a 2 cm by 4 cm 'kill zone' around the LED array.

Additionally, Litx may stimulate a patient’s immune system to attack untreated tumours. Since 2007, data from a number of published animal and human studies has demonstrated that the production of large apoptotic masses in tumors with light-activated drug therapies, including Litx, yields tumour-specific clones of CD8+ T-cells that infiltrate distant, untreated tumours and destroys them. Human trials of Litx have produced images that demonstrate destruction of large tumours not directly treated with Litx.

Q3: The potential of Litx is already being explored in several clinical trials. What have the results been like thus far?
Preclinical, Phase I, Phase II, and Phase III data support the safety profile of Litx. FDA allows the Litx Phase II trial in colorectal cancer metastatic to the liver (MCRC) to be its only formal Phase II study for solid tumour indications. Studies have overwhelmingly shown that destruction or removal of tumours yields great survival improvements. These studies, combined with the evidence from many human and animal studies that Litx treatment always causes destruction of tumour tissue, provide the statistical foundation for the endpoints of the Litx Phase III trials.

Q4: What further steps are required before the treatment is available to patients?
LSO is nearing completion of a Phase III trial in hepatocellular carcinoma (HCC) and is enrolling patients in a Phase III trial for metastatic colorectal cancer (MCRC). FDA must approve the initial indication for Litx (HCC) before it is available to patients as a commercial product. LSO expects to complete patient enrollment in the HCC indication during the fourth quarter of 2008. LSO will file an NDA for the HCC indication with FDA (and with EMEA) when it has data from the trial that meets the objectives in the statistical analysis plan.

LSO is initially developing Litx for the treatment of three solid tumours — metastatic colorectal cancer, hepatoma, and glioma. In January 2007, LSO reached an agreement with FDA on a Special Protocol Assessment (SPA) for a Phase III clinical trial comparing use of Litx plus standard treatment for MCRC versus standard treatment alone. The SPA for MCRC follows an August 2005 SPA for the Phase III trial of Litx in HCC comparing survival in patients treated with Litx versus patients given standard treatment. The Phase III Litx HCC trial began in August 2006, and treatment of patients in the Phase III Litx MCRC trial began in July 2007. In addition, a Phase II study of Litx in the treatment of glioma was completed in February 2008.

Q5: If approved, what advantages do you expect the technology to offer over existing therapies?
As mentioned, there is no evidence that Litx causes the serious toxicities associated with traditional cancer treatments. Litx kills solid tumor cells through vascular closure and apoptosis, rather than necrosis, avoiding inflammation, scarring, fever and other complications. Litx is designed to address the major disadvantages of current cancer treatments—severe toxicity, limited efficacy, stimulation of tumor re-growth and resistance, high set-up and usage costs, complicated administration, and poor patient quality-of-life.

Litx advantages include:

• It is a targeted treatment. Destruction of tissue occurs only where light is delivered in sufficient quantity.
• It may access a wide range of solid tumours throughout the body. Life-threatening tumours can be located in areas of the body where surgery is not feasible.
• It is independent of tumour-specific biochemistry and therefore its efficacy may not depend on the type of solid tumour treated.
• It is a repeatable treatment. LSO's studies to date indicate that Litx is not susceptible to resistance associated with repeated use.
• Litx does not require expensive equipment, unlike radiation therapy, laser-based therapies, or thermal tissue destruction methods. It consists of a drug and a disposable light emitting device — all components needed for the procedure are included in the Litx package.

Q6: Do you foresee any other potential future applications for this technology?
Based on the mechanism of action and the effect of Litx treatment, LSO may develop additional applications of Litx, including benign neoplasms — growths of non-cancerous tissue that, nonetheless, have implications for patient morbidity and even mortality. Using light-activated devices based on those used in LSO's cancer treatments, LSO plans to develop Litx as a new treatment for benign prostatic hypertrophy (BPH). Preclinical animal studies of the use of Litx in BPH were concluded in 2007, and Phase I/II studies in patients with BPH are underway. A Phase I/II dose-escalation study began at four sites in the US in July 2008, and a 40-patient, Phase IIa study in Australia is expected to begin in 2009.

Litx is designed to treat BPH by eliminating prostate tissue impeding urine flow. LSO believes Litx advantages over existing ablative BPH therapies would include treatment simplicity, safety and repeatability employing a single-use disposable device.

In vascular disease, Litx has been shown in animal studies to prevent restenosis (re-narrowing) of arteries after angioplasty as a regional endovascular intervention, and human trials are planned to demonstrate protection against the rupture of unstable plaque in arteries affected by advanced atherosclerotic disease. Requiring no device to remain in the vessel at the end of the short procedure, Litx is designed to move endovascular intervention beyond the limitations of focal, stent-based technologies. Two currently targeted applications are peripheral arterial disease (PAD) of the lower extremities and coronary artery disease (CAD).

Also in preclinical stages are studies with Litx in prostate cancer and cutaneous vascular malformations.

Q7: What are the company's plans for the future?
LSO plans to commercialize its products through partnerships with pharmaceutical companies, relying on the established disease-area expertise and distribution channels of existing dominant players. LSO will develop Litx for additional indications in cancer with its partners, and will seek development and marketing partners in BPH, uterine disease, dermatology, cardiovascular disease, and other clinical disciplines. In some cases, LSO may complete clinical development without a corporate partner and build specialized marketing capabilities for commercialization of Litx.

www.lsoncology.com