Immunotherapy has shown great promise in cancer care but reports of relatively low overall patient response rates are spurring the search for ways to enhance its efficacy. One of the most intriguing avenues of research involves combination treatments in which immunotherapies are administered in tandem with additional agents. In recent years, researchers have identified several compounds that not only have shown to be powerful cytotoxic agents, but may also be highly selective toward only destroying tumor cells. Studies to date have shown encouraging data for these drugs as potential combination therapies in indications such as metastatic pancreatic cancer, advanced bladder cancer and triple negative bladder cancer. Drug Discovery and Development (DDD) Magazine spoke with Peter D. Suzdak, PhD, CEO of Rexahn Pharmaceuticals, whose company is on the forefront of some of these efforts, about the motivations and hopes for this area of research.
Suzdak joined Rexahn Pharmaceuticals as CEO in February 2013. Prior to this, he was Chief Scientific Officer of Corridor Pharmaceuticals, a company developing small molecule compounds to treat pulmonary and vascular disorders. He earlier served as co-Founder, Chief Executive Officer and Chief Scientific Officer of Cardioxyl Pharmaceuticals and President and Chief Executive Officer of Artesian Therapeutics. He also held positions at Guilford Pharmaceuticals and Novo Nordisk. Suzdak holds a Ph.D. in pharmacology and toxicology from the University of Connecticut.
DDD: Immunotherapy has been at the forefront of cancer research; however, we know there are still some challenges. What are those challenges?
Suzdak: The major challenge with immunotherapy is the low overall response rate, in general, only approximately 20 percent of patients who are treated with immunotherapy respond clinically. And there is no good biomarker to predict which patients are going to respond. This means that while some patients do really well on immunotherapy, the large majority of patients derive no benefit. So, we need to look at ways to improve the efficacy of immunotherapy including combinations with other agents. Also, there are certain tumors that just don’t respond to an immune modulating approach such as pancreatic cancer—either because the tumors are not immunogenic or because the immune cells cannot infiltrate into the tumor. Immunotherapy can give rise to serious toxicities such as pneumonitis and pancreatitis due to a non-specific enhancement of immune function and those effects can persist or even appear for the first time after treatment has stopped.
DDD: Please discuss your approach to target specific proteins that are selectively localized in human cancer. Do you plan on studying it for a stand-alone treatment or will it serve as an adjunct therapy to standard immunotherapies?
Suzdak: RX-3117 and RX-5902 are designed to inhibit specific biological pathways that are present in cancer cells and are involved in the growth and proliferation of tumors. We initially tested these drug candidates as monotherapy in patients who had failed multiple prior anti-cancer agents to examine their safety, tolerability and initial efficacy and verified that they worked as monotherapy. We are now progressing to use these agents in first-line patients who have had no prior anticancer treatments. In these patients, it is usual clinical practice to use combinations of drugs rather than monotherapy to maximize efficacy. Safety and tolerability is usually the limiting factor for dosing and duration of treatment with combination therapy. RX-3117 and RX-5902 have been well tolerated in clinical studies to date, so it is our expectation that they will be well tolerated in combination with cytotoxics or immunotherapy. In fact, we have just completed a small safety study evaluating RX-3117 in combination with Abraxane (nab-paclitaxel) in first-line metastatic pancreatic cancer and the combination was well tolerated, which allows us to proceed with the efficacy evaluation using doses optimized for efficacy.
DDD: How easily could targeted therapies be combined with immunotherapy?
Suzdak: The rationale for combining a drug with immunotherapy is to enhance the overall response rate/efficacy of an immunotherapy agent. The key question for any specific agent is whether or not there is a good pharmacological rationale for the combination that would lead to the expectation of enhanced efficacy and of course safety is key—you would not want to use anything in combination with a checkpoint inhibitor that would augment the inflammation side effects. There is a sound rationale for the use of Rexahn’s compounds in combination with checkpoint inhibitors and we have seen very nice synergistic effects in animal models. RX-5902 has shown to decrease beta catenin, a protein that is associated with shutting down the body’s natural tumor immunity. By inhibiting beta catenin, RX-5902 improves the ability of the immune system to kill tumor cells and this enhances the effectiveness of checkpoint inhibitors, as shown in animal models. RX-3117 kills tumor cells and exposes the antigens to tumor-killing immune cells, so it may also have the ability to increase the efficacy of immunotherapy via a different mechanism.
DDD: What is the mechanism of action involved in targeting molecules that could allow immunogenicity to be enhanced in cancer cells?
Suzdak: RX-5902 has been shown to increase the infiltration of T-cells into the cancer tumor making the tumor more susceptible to the effects of immunotherapy (potentiating the tumor growth inhibition produced by immunotherapy alone).
DDD: Which cancers are you targeting with your approach and where are they in clinical trials?
Suzdak: Rexahn is currently targeting metastatic pancreatic cancer (RX-3117), advanced bladder cancer (RX-3117) and triple negative breast cancer (RX-5902). All three of these are in Phase 2a clinical trials.
DDD: Why is Rexahn targeting these cancers?
Suzdak: We are targeting cancers where there is good mechanistic rationale for our targeted therapies and therefore a higher likelihood of success. For RX-3117, we have chosen pancreatic and bladder cancer because drugs with a similar mechanism of action have worked well in those tumor types and there is a very well-defined pathway to regulatory approval. Because RX-3117 is targeted to tumor cells, we hope to see better efficacy and a prolonged response. With RX-5902, we have progressed development in triple negative breast cancer because it is associated with activation of the biological pathway targeted by RX-5902. Also, there is currently no drug approved for TNBC, so there may be a faster regulatory route to approval assuming good efficacy.
DDD: Can you give us a brief overview on the data that was presented at ASCO on RX-5902 in triple negative breast cancer (TBNC)?
Suzdak: An interim analysis of the first 10 evaluable patients in a Phase II a trial of RX-5902 in TNBC showed five patients exhibited a clinical response including one patient who had an 18 percent reduction in tumor size and two patients experiencing progression free survival (PFS) greater than 200 days. RX-5902 was safe and well tolerated in this study and the study met the predefined criteria for advancement to the second stage. Enrollment of additional patients is ongoing.
DDD: Can you also describe the data on RX-3117 in advanced bladder cancer that was presented at ASCO?
Suzdak: Updated interim data from a Phase II a clinical trial of RX-3117 monotherapy for the treatment of advanced bladder cancer showed that, of the 24 evaluable patients enrolled into the study, one patient had a complete response (100 percent tumor reduction) and an additional four patients had tumor reductions of greater than 15 percent. In addition, six patients (25 percent) showed disease stabilization for greater than four months (range 133-315 days). RX-3117 was also safe and well tolerated in these patients.
DDD: What is on the horizon from your company next?
Suzdak: Upcoming clinical milestones include, the initial clinical data from the ongoing Phase II a clinical trial combining RX-3117 and Abraxane in newly diagnosed (first-line) metastatic pancreatic cancer patients, additional clinical data from the Phase II a clinical trial of RX-5902 monotherapy in TNBC, and the initiation of Phase II a combination trial of RX-5902 in newly diagnosed metastatic TNBC patients.
Filed Under: Drug Discovery
