The Life Sciences Report: Peter, Rexahn Pharmaceuticals Inc. (RNN:NYSE.MKT) has three clinical-stage molecules, and they all appear to have different targeting mechanisms. Archexin (Akt-1 antisense oligonucleotide inhibitor) is your lead candidate. It's an antisense oligonucleotide that specifically targets the gene Akt-1. RX-3117 (fluorocyclopentenylcytosine) prevents RNA and DNA synthesis in cancer cells, and it's also an epigenetic inhibitor. There is also Supinoxin (RX-5902), an oral drug that is an inhibitor of phosphorylated-p68 RNA helicase (P-p68). Are these molecules as different as they look to me? What is the common thread or platform among them?
Peter Suzdak: Mechanistically and structurally, these molecules are as different as they look. The common theme among the three candidates is the concept of targeted therapy for cancer. The targets they go after share the unique feature of being highly overexpressed, if not exclusively expressed, in cancer cells.
"The whole thesis of Rexahn was to come up with novel ways of developing a new generation of therapeutics to treat cancer patients that specifically went after cancer cells but did not affect normal healthy tissue."
There are different stories behind the way the company came up with each of these three programs, but the whole thesis of Rexahn was to come up with novel ways of developing a new generation of therapeutics to treat cancer patients that specifically went after cancer cells but did not affect normal healthy tissue. That would make them different from existing chemotherapy, which indiscriminately kills off both cancer cells and normal healthy tissue. The common thread was to find proteins exclusively present in cancer cells that also involved the key biological pathways that control cancer cell growth, proliferation, survival, new blood vessel formation and even drug resistance.
TLSR: You have a program targeting Akt-1 in renal cell carcinoma with Archexin, correct?
PS: Let me take one step back, if I may. Archexin, as you pointed out, is an antisense oligonucleotide that targets a member of the Akt family, specifically Akt-1. The reason we're going after Akt-1 is that activated, or phosphorylated Akt-1, is exclusively present in cancer cells.
We currently have an ongoing Phase 2a trial in patients with metastatic renal cell carcinoma (mRCC). That is our primary target within the Akt-1 family, and currently the only target we're going after with Archexin.
TLSR: Even though mRCC is the only target you're going after currently, you did have some success in pancreatic cancer with Archexin, didn't you?
PS: The company initially did a Phase 1 trial in cancer patients with solid tumors to look at safety and tolerability. This was a number of years ago. In that trial, Archexin was shown to be very safe and well tolerated. Based upon those data, the company conducted a small Phase 2a trial in patients with metastatic pancreatic cancer. These patients were progressing or failing in first-line treatment with gemcitabine (Gemzar; Eli Lilly and Co. [LLY:NYSE]) therapy. That particular patient population had a median survival of approximately six months. Archexin was added in a small, single-arm trial in that patient population on top of the gemcitabine, and it increased median survival to approximately 9.1 months without producing any increase in adverse events in the patients. It showed a good safety signal and a very preliminary signal of efficacy in this patient population.
TLSR: Why did you switch to mRCC and abandon metastatic pancreatic cancer?
PS: We decided to switch to mRCC based on the fact that these pancreatic patients are very sick, with a median survival of about six months, which makes it very hard to determine what the true survival benefit would be with a new therapeutic compound. We went through a very comprehensive analysis looking at potential therapeutic targets for Archexin. We know that Akt-1 is overexpressed in about 15 different types of human cancers, and we looked to see where we have good preclinical data. We also looked at what the clinical and regulatory pathways would be. We chose metastatic renal cell carcinoma because these patients have a median survival of about 1.25 years. We thought it would be easier to actually see what Archexin's true survival benefit would be, and we were able to start out doing a much larger trial in these patients.
TLSR: Bring me up to speed on Akt-1. Why is this a special target?
PS: I'll give you a bit of background. There are actually three members of the Akt family—Akt-1, Akt-2 and Akt-3. They have very different localizations in the body. Akt-1, especially phosphorylated Akt-1, is almost, if not solely, present in cancer cells. Akt-2 and Akt-3 are present throughout the body, and are involved in a number of different physiological processes, including cardiovascular function and glucose control. The reason Rexahn decided to go with the antisense-oligo approach instead of a small-molecule approach was based on the fact that if you look at these three members of the Akt family, they show about a 98% homology to each other. They almost look identical. The company felt that it would be almost impossible to find a small-molecule compound that inhibited only Akt-1.
TLSR: Peter, do you know if this kind of high selectivity is working in practice?
PS: History has proven it correct. Several other companies either have had or still do have compounds in the clinic going after Akt, but these compounds are nonspecific inhibitors. They inhibit all three forms of Akt. Two examples are Merck & Co. Inc. (MRK:NYSE), which had a nonspecific Akt inhibitor in the clinic about two years ago, as did ArQule Inc. (ARQL:NASDAQ). These compounds showed cardiovascular toxicity and significant changes in glucose metabolism in patients. For that reason, both companies discontinued their programs. Two or three other companies still have small molecule compounds in the clinic, but I would imagine their ability to escalate dose is limited by toxicities to the cardiovascular system and glucose control.
TLSR: The difference in Rexahn's approach is that you are actually knocking down the gene that expresses Akt-1. How has the safety profile been so far?
PS: We have not seen any cardiovascular toxicity in patients to date, and we have not seen any changes in glucose control to date. It's interesting, because if you look at the Phase 1 data from our Archexin program, the dose-limiting toxicity was grade 3 fatigue. It made patients tired, but there were no cardiovascular changes, no hematological changes or any other types of toxicities normally associated with chemotherapeutic agents. It gets back to our focus. It's the cancer-cell specificity of that mechanism and the way we are targeting that mechanism. In this case, we are inhibiting the gene that expresses Akt-1, which is exclusive to cancer cells.
TLSR: Are you still on target to show investors safety data from your Phase 2a proof-of-concept trial with Archexin in metastatic renal cell carcinoma in Q1/15?
PS: Yes. It will be sometime in Q1/15.
TLSR: I understand that you still have quite a long time before you collect final data on this Phase 2a study—December 2016 is what I've read. Archexin appears to be what investors are watching right now. When will you be able to start a Phase 2b trial with Archexin in renal cell carcinoma?
PS: I think we should have the randomized efficacy component of that trial in Q1/16.
TLSR: I assume that your Phase 2b would be randomized and double blind. Would that be right?
PS: Right.
TLSR: What other programs and milestones should investors be paying attention to?
PS: I think the other two programs we have in the clinic are going to start garnering a lot of interest for different reasons.
RX-3117 is an orally active small molecule in a Phase 1b dose-finding study. Its unique attribute is that in preclinical studies, it is fully effective in killing off cancer cells that have become resistant to gemcitabine.
Let me explain the importance of that. Gemcitabine is one of the more commonly used anticancer compounds. It's used as first-line and second-line therapy in a whole host of different cancers, despite the fact that it has several issues. Probably, from a medical standpoint and aside from toxicity, its biggest issue is that between 20–40% of patients who receive gemcitabine for more than one cycle, which is only 30 days, become totally resistant to the anticancer effects of the drug. An example of that would be in pancreatic cancer patients, about 40% of whom become resistant to gemcitabine after 30 days of treatment. Another example would be patients with breast cancer or bladder cancer. About 20% of these patients become resistant to gemcitabine after about 30 days of treatment. The real problem is that when these patients become resistant to gemcitabine, very few other anticancer compounds work going forward. An effective treatment following treatment with gemcitabine represents a very large, unmet medical need in the treatment of cancer patients.
TLSR: Peter, this Phase 1b trial testing RX-3117 in solid tumors is only a 30-patient study at most, and final data collection won't occur until April 2015. How do you know RX-3117 kills gemcitabine-resistant tumor cells?
PS: This unique attribute was demonstrated by an outside group led by G.J. Peters at VU University Medical Center in Amsterdam, The Netherlands. It was published in 2013 (Metabolism, mechanism of action and sensitivity profile of fluorocyclopentenylcytosine [RX-3117; TV-1360]). In human cancer cells derived from patients who became resistant to gemcitabine, RX-3117 was fully effective in killing off the gemcitabine-resistant cancer cells. We'll be publishing another paper very shortly that characterizes this in more detail. If you think about the potential clinical utility of RX-3117, it would be in treating patients with gemcitabine-resistant cancer.
"Should these compounds work in the clinic and be approved by regulatory authorities, I think they would command a substantial part of the existing market in these different types of cancers."
The regulatory pathway to the marketplace is very straightforward for this compound and indication. We're in the middle of this Phase 1b trial here in the U.S. with RX-3117, which began in January 2014. These patients have solid tumors, and before coming into the trial, their tumors are scanned via CT or MRI. The patients can stay on whatever dose they come in on for up to six months, and they are scanned every two months. We'll be able to see initial safety data, as well as preliminary efficacy data and which types of tumors may be responding to the anticancer effect of RX-3117, over the next five months; we hope to release the safety data as well as some preliminary efficacy data at the end of Q1/15.
TLSR: Peter, RX-3117 has a dual action. It inhibits synthesis of RNA and DNA, and it is also a DNA methyltransferase-1 inhibitor. We have seen great successes with some of these DNA methyltransferase inhibitors in blood cancers, especially myelodysplastic syndromes, where the drugs were used in low doses and high intensity. You could get much quicker data in hematologic disease than in solid tumor diseases. Why did you choose test RX-3117 in solid tumors?
PS: It was because of the striking efficacy data we've seen in a host of different preclinical models.
TLSR: Do you attribute this extraordinary preclinical efficacy to this dual mechanism of action?
PS: Yes—to both the uniqueness of the mechanism and the cancer-cell specificity of the mechanism.
TLSR: When you get to Phase 2b, or perhaps the first Phase 3 trial, will the RX-3117 studies have to be run in combination with cytotoxic therapies versus standard of care?
PS: It's hard to answer that right now, because the clinical data that we see in these initial trials will help define what the pivotal trials will look like. We know from preclinical studies that the activity of this compound is synergistic with existing cytotoxic agents. However, we also know that all these approaches have anticancer effects on their own. What the best route will be in treating patients in pivotal trials is hard to say because the results from earlier trials will help refine that pathway.
TLSR: Peter, can you tell me about Supinoxin?
PS: Our third development candidate, Supinoxin (RX-5902), targets P-p68, which is highly overexpressed in different types of human cancers. We have published very good preclinical data showing that Supinoxin, which has a novel mechanism, is very effective in stopping or reversing the growth of different types of human cancer. Again, it is in the middle of a Phase 1 trial, with approximately 30 patients with solid tumors; the trial should be completed during Q1/15. We will release those safety and initial efficacy data at that point.
TLSR: Although your stock is up 64% from a year ago, you are still a micro-cap company. Your market cap is about $123M. Any agent that could move the needle significantly on renal cell carcinoma would have tremendous value in the marketplace. How do you see the market opportunity in renal cell carcinoma and other Akt-1 indications? What could these compounds be worth?
PS: The numbers are all published marketing data, not anything proprietary that we've generated. Renal cell carcinoma is probably a +$5 billion (+$5B) market, which is very significant. Looking at gemcitabine-resistant cancer, that's probably a $6B or $7B market. We are targeting very large markets.
TLSR: Do you believe that if you can show medical oncologists a higher therapeutic index with better efficacy and lower off-target effects and toxicity, they will migrate to these products?
PS: Yes. We have to show good safety combined with good activity in slowing down or stopping the growth of human cancer cells in preclinical models. Should these compounds work in the clinic and be approved by regulatory authorities, I think they would command a substantial part of the existing market in these different types of cancers.
TLSR: Tell me what you think investors need to understand and what catalysts they might look forward to.
PS: We have three near-term catalysts over the next five months, between now and the end of Q1/15. They are: (1) the safety data from Archexin, (2) the safety data and initial efficacy data from the Phase 1b trial with RX-3117, and (3) the safety data and initial efficacy data from an ongoing Phase 1 trial with our third candidate in development, Supinoxin.
I think, from an investor standpoint, the value proposition is that Rexahn is a very diversified company. We have three different therapeutic approaches to treat cancer that work by three separate mechanisms, and all are in clinical development at this point. We have three different shots on goal. Considering what our market cap is currently, as you pointed out, I think that if we are able to get encouraging data from any one of those three programs, it would have a very significant effect on our stock price.
TLSR: Thank you, Peter.
PS: Thank you.
Dr. Peter Suzdak joined Rexahn Pharmaceuticals in February 2013. Dr. Suzdak has over 25 years of diverse experience, including holding several management positions in the pharmaceutical industry. Most recently, Dr. Suzdak was chief scientific officer (CSO) of Corridor Pharmaceuticals, a company developing small molecule compounds to treat pulmonary and vascular disorders. Prior to that, he was cofounder, CEO and CSO of Cardioxyl Pharmaceuticals, a company focused on therapies for the treatment of cardiovascular disease. Previous to Cardioxyl Pharmaceuticals, he was president and CEO of Artesian Therapeutics, a company engaged in the development of small molecule therapeutics for cardiovascular diseases. Dr. Suzdak's experience also includes his position as senior vice president of research and development with Guilford Pharmaceuticals, a company that developed therapeutics and diagnostics for neurological diseases and cancer, and as director of neurobiology for Novo Nordisk. Dr. Suzdak holds a Ph.D. in pharmacology and toxicology from the University of Connecticut.
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