Earlier this month we wrote about precision oncology, which involves injecting multiple drugs into the same tumor to determine which agent is most effective. Once this is known, a follow up question would be how best to deliver that agent so that it maximizes destruction of the cancer while minimizing harm to healthy tissue. In order to answer this question we had the opportunity to speak with Endocyte‘s VP of Research and Development, Christopher Leamon, about the innovative work his company is doing on small molecule drug conjugates (SMDCs) as targeted delivery vehicle.
Shiv Gaglani, Medgadget: Can you describe the origins of Endocyte’s technology?
Christopher Leamon: Endocyte’s technology was first developed at Purdue University, in the lab of Philip S. Low Ph.D., the current chief scientific officer of the company, where I completed my graduate work. We were studying a method that involved using the folate receptor to deliver drugs selectively to cancer cells, which is the basis of Endocyte’s technology. Folate is required for cellular division; therefore many cancers, including ovarian, breast, lung and kidney, highly express the folate receptor. By attaching a potent chemotherapy drug to folate, a highly targeted cancer drug can be created that kills cancer cells while leaving healthy cells unharmed.
Using this approach, we developed our lead small molecule drug conjugate (SMDC), vintafolide, which was partnered with Merck last year, as well as a companion imaging agent, etarfolatide, which was created by replacing the chemotherapy drug with an imaging agent. This test is used to identify patients that express the folate receptor, and therefore would likely respond to treatment with vintafolide. Both are currently under review by the EMA for potential conditional approval for the treatment of platinum-resistant ovarian cancer.
We are using this same approach to build additional SMDCs, which consist of a targeted small molecule, a serum-stable linker and a very potent drug, for a variety of cancers and other diseases such as inflammatory disorders or kidney disease. For each SMDC we also develop, early on, a companion imaging agent that will help us during the development process to validate the target and to later on identify patients who will most likely benefit from treatment with the targeted drug.
Medgadget: What is unique about the delivery system? What are the benefits of this approach?
Leamon: This delivery system is unique for multiple reasons, including the attachment of a small high affinity ligand molecule (the targeting moiety) to a potent drug to form the SMDC, and the co-development of a companion imaging agent which predicts what tissues will accumulate the SMDC.
Compared to other targeted approaches, such as antibody drug conjugates (ADCs), we use small molecule high affinity ligands which allows for a deep penetration of the SMDC into solid tumors which potentially improves efficacy. Targeting a receptor that is expressed or overexpressed on cancer cells, such as the folate receptor, enables the selective uptake of the drug by cancer cells over healthy cells, thereby reducing off-target effects and potentially improving both efficacy and safety. Upon internalization of the drug via a natural endocytosis process, the serum-stable linker selectively releases the potent drug inside the targeted cell which, in case of our lead drug candidate vintafolide, is a potent cytotoxic that arrests cell division to induce cell death.
Utilizing a companion imaging agent to visualize the cells expressing the chosen target, such as the folate receptor, holds numerous advantages, especially in light of recent studies that have shown how the underlying genetics of cancer can vary within and across tumors, as well as change over time. This poses a challenge for personalized medicine, and also presents limitations for biopsies, which are not often taken at the time of treatment. With an imaging approach, in our case SPECT or CT technology, a non-invasive, real-time, full-body image of the patient’s cancer can be obtained, providing the physician with a comprehensive status of the receptor expression in all lesions and therefore may provide information about the success of the treatment.
Overall, this personalized approach of identifying the patients that would likely respond to a targeted treatment with a real-time test does hold numerous advantages, including increased potential for demonstrating efficacy of the targeted drug, as well as increased likelihood of regulatory approval and payer reimbursement. Furthermore, smaller, more cost-effective and faster clinical trials can be conducted, thereby conserving resources and bringing drugs to market more quickly.
Medgadget: Which disease areas will Endocyte be exploring first?
Leamon: A Phase 3 study in platinum-resistant ovarian cancer, PROCEED, is ongoing as well as a Phase 2b study in non-small cell lung cancer, called TARGET. Both trials are investigating vintafolide along with the investigational companion imaging agent, etarfolatide, which identifies tumors that express the folate receptor, the molecular target of vintafolide. The second folate receptor-targeting SMDC, EC1456, which has a highly potent cytotoxic, called tubulysin, as its payload is currently in a Phase 1 trial using the same companion imaging agent, etarfolatide.
Other drug candidates utilizing Endocyte’s technology platform include a small molecule drug conjugate targeting prostate-specific membrane antigen (PSMA), EC1169, as well as its companion imaging agent also targeting PSMA, called EC0652. The INDs for these agents are expected to be filed in the first half of 2014.
In addition, the folate receptor is also highly expressed in certain inflammatory disorders, which is another therapeutic area of focus for the company.
Medgadget: How can this technology be further improved? What is Endocyte working on now?
Leamon: The SMDC approach can be used to develop drugs with even more improved potency, having a different mechanism of action which would enable new cancers to be pursued or to overcome potential resistance to certain drugs. As mentioned, Endocyte is developing EC1456 which combines the proven FR targeting component of vintafolide with the extremely potent cytotoxic molecule, tubulysin. As demonstrated with strong preclinical data, EC1456 holds promise for treating FR-positive patients that have become resistant to other drugs, such as vintafolide and the taxane, paclitaxel, as well as in treating cancers that express lower levels of the folate receptor. We are currently screening patients for enrollment in a Phase 1 trial.
Medgadget: What is your background in medical technology and innovation?
Leamon: Prior to joining Endocyte, where I’m the vice president of research, I conducted discovery research for GlaxoWellcome and Isis Pharmaceuticals. I completed my doctorate in biochemistry at Purdue University, in Phil Low’s laboratory. Before that I completed a bachelor’s degree in chemistry from Baldwin-Wallace College.
On a personal note, my passion for developing better cancer treatments stems from my early days in college, when my mother sadly lost her battle with pancreatic cancer. This opened my eyes to the limitations of chemotherapy, which only made her sicker, and the need for targeted cancer drugs. This passion lead to the invention of vintafolide and etarfolatide, and it is exciting to be nearing the point this drug and companion imaging agent could be available to patients.
Here’s Philip Low, Endocyte’s Chief Science Officer, at TEDxPurdueU discussing the company’s technology:
Link: Endocyte homepage…