Q&A: Hitching a ride to treat acute myeloid leukemia
A discussion with Dr. Kaushik J. Dave and Dr. John Pagel about the potential of a therapeutic platform based on mAbs and alpha particle emitters
Actinium Pharmaceuticals Inc. (API) is a public biopharmaceutical company whose product candidates are based on its patented technology for combining the cancer-targeting precision of monoclonal antibodies (mAb) with the power of alpha-emitting radioisotopes, among the most potent cancer killing agents—a technology co-developed with Memorial Sloan Kettering Cancer Center. API’s first drug for the treatment of acute myeloid leukemia is now in clinical trials and has been administered to 49 patients with promising results. DDNews spoke with CEO Dr. Kaushik J. Dave and his colleague, Dr. John Pagel of the Fred Hutchinson Cancer Research Center, about the status and prospects of the technology.
DDNews: How and where was your therapeutic platform based on mAbs and alpha particle emitters developed?
Kaushik J. Dave: The alpha immunotherapy platform has been under development both internally and in collaboration with Memorial Sloan Kettering Cancer Center. Although monoclonal antibodies have been very successful in targeting cancer cells, the majority of antibodies that were under development fail to kill the target cancer cells. There are several reasons for this: most of the injected antibody dose remains in the blood and only a small portion gets to cancer cells; there may be too few receptors on the cancer cell; the patient’s immune system may be inefficient in effecting the killing; cancer cells often “swallow” antibodies bound to their surface, thus removing the target that the patient’s immune system can act upon; etc.
So the thinking at Sloan Kettering and scientists at Organon [a company acquired by Merck as part of the Shering-Plough merger] was: Can we make use of antibodies’ great targeting while overcoming most of the listed limitations? The answer to that was usage of a payload that contains the most effective killing agent known at a cellular level, alpha particles. When alpha particles are on the antibody, it is sufficient for the antibody to bind to the target cell, and then alpha particles do the killing without relying on the patient’s immune system, and if cancer cells “swallow” the antibody, so much the better—they are killed from inside. In addition, due to the extraordinary potency of alpha emission—a single atom can kill a cell—even if only a small portion of the injected antibody makes it to the cancer cells, it’s enough. Based on these insights, our technology was developed and it worked as advertised.
DDNews: Attaching a therapeutic entity to a targeting molecule such as a mAb is a well-known technique. Why has your approach been more successful than many other attempts?
Dave: For several reasons. Although the idea behind the technique is now well understood, it is not easy to implement. First, it is difficult to bind a killing agent to an antibody without severely damaging the antibody in the process. Once the agent is bound to the antibody, one must make sure that it doesn’t fall off once it is inside the body. Those were major pitfalls for many companies. We are looking at complex, technically challenging processes; I spent most of my career developing complex technologies, and I can say that labeling antibodies in therapeutic doses is among the most challenging ones. We have not only spent many years developing and perfecting these technologies, but we also continue to do so constantly. We are really pushing the envelope and challenging ourselves and the others in this field.
Secondly, even when you are successful in labeling, you will face the limitations inherent to the antibodies; in many cases, you simply cannot get enough of the antibody-killing agent combination to cancer cells. By using an alpha emitter, we overcome that problem to a large extent; we simply don’t need much of an antibody to get to the target. In fact, in our alpha emitter-based trials, we have been using the amount of the antibody that is 50 or 100 or 200 times less than what is used with antibodies armed with other technologies. Compared to naked antibodies, our doses are 800 or more times lower.
Finally, when working with beta emitters, we choose our indications very carefully and focus only on specific disease states where this approach can make the most difference.
DDNews: What have been the results of the Phase 1 and Phase 2 clinical trials conducted to date?
Dave: In Phase 1 and 2 clinical trials, both of our clinical-stage platforms have shown great promise in several diseases, including the disease that is among the most difficult to treat cancers, acute myeloid leukemia. With one of our drugs, we were able to eradicate leukemia cells in 20 percent of highest-risk older patients, and with another we were able to put 100 percent of those patients in a complete remission and cure almost 20 percent of them.
DDNews: When will the pivotal trial of Iomab begin, and what will be its primary endpoint?
Dave: The primary endpoint will be durable complete remission rate, i.e., our ability to provide a transfusion-independent, disease-free state of at least six months to patients who currently have no available standard of care and no approved drugs at their disposal in a disease that today unfortunately almost invariably ends with a quick demise.
DDNews: To what level must blood cancers cells be depressed before the patient receives hematopoietic stem cell transplantation (HSCT)?
John Pagel: Cancer cells need to be depressed to undetectable levels prior to HSCT. In addition, all or the vast majority of a patient’s normal bone marrow has to be eradicated. That’s why transplants in acute myeloid leukemia patients proceed in two steps: first, chemotherapy aimed at destroying cancer cells, followed by another round of chemotherapy, sometimes combined with external irradiation, to destroy remaining bone marrow. Our drug candidate Iomab enables us to combine these two steps into one, destroying both cancer cells and bone marrow in a single procedure. In that way we decrease side effects and increase efficacy of the treatment.
DDNews: What developments in your pipeline are likely to progress into clinical trials in the near future (12 to 18 months)?
Dave: We have a number of preclinical programs and expect at least one of them to enter the clinic in that time frame.
DDNews: Your website mentions an interesting strategy for extending the patent protection for mAbs by coupling them to Actinium technology. Could you describe how you will implement this strategy and when it might become a reality?
Dave: Actinium’s technology is already patent protected, so the use of that technology confers patent protection to resulting drug candidates. In other words, the strategy is already implemented. We will extend it to additional antibodies as we expand our pipeline.
Kaushik J. Dave, Ph.D., the CEO of Actinium Pharma Inc., joined the company from Antares Pharmaceuticals Inc. where he was the executive vice president of product development. As part of the core leadership team at Antares, he was instrumental in setting strategy, vision, product portfolio development and business development for that company. Dave led the clinical and regulatory approval of Anturol and was also a key contributor to the change in company vision to combination products using Antares’ medical device technology, which resulted in a robust pipeline that included development and New Drug Application submission for Otrexup, which was approved Oct. 11, 2013. As a result of these efforts, Antares Pharma grew from a market capitalization of $40 million to about a half billion during his tenure. Dave has also held senior positions at Palatin Technologies Inc., Schering-Plough Inc. and Merck & Co. Inc.
John Pagel, Ph.D., is an assistant professor with the Department of Medicine, Division of Oncology at Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance. Pagel leads leukemia studies of radioimmunotherapy at the center as the principal investigator of several human clinical trials. He is working to increase the usefulness of antibody therapy by “pretargeting” radiation directly to the cells. He is also researching nonradioactive chemical partners to antibodies.
