Oncternal Therapeutics Inc (ONCT) 2013 Q3 法說會逐字稿

Good morning, everyone, and welcome to the GTx Incorporated conference call. Today's call is being recorded. I will turn the call over to Dr. Mitchell Steiner, CEO of GTx. Please go ahead, sir.

Thank you, operator. I will be making forward-looking comments during today's call, and I direct you to the press release of our financial results we filed this morning, as well as the quarterly report we are filing on Form 10-Q with the SEC later today, where we discuss the risks and uncertainties that may affect our business.

I will begin today with an update on the progress of our three late stage clinical programs. First, enobosarm 3 milligrams for the prevention and treatment of muscle wasting in patients with non-small cell lung cancer; second, enobosarm 9 milligrams being developed for the treatment of androgen receptor positive and estrogen receptor positive metastatic breast cancer; and lastly, we'll talk about GTx-758, which is being developed for the treatment of advanced prostate cancer.

As for enobosarm 3 milligrams, we released topline data in August from our two Phase III clinical studies, POWER 1 and POWER 2, to support the indication for the prevention and treatment of muscle wasting in patients who have advanced non-small cell lung cancer. We have had time now to better understand the safety and efficacy of enobosarm 3 milligrams for this indication, after reviewing the complete data set collected from these studies. And we are in the process of preparing and submitting meeting requests, and plan to meet with the regulatory agencies. These additional POWER trial analyses may give more support for a potential regulatory path for enobosarm, and we remain excited about the opportunity and our prospects for pursuing a marketing application for this indication.

First, let me remind you that each clinical study enrolled approximately 325 patients who had either Stage III or Stage IV non-small cell lung cancer, in over 80 clinical sites located in the United States, Europe, Russia, and South America. The objective of the studies was to determine the potential of enobosarm 3 milligrams versus placebo to prevent and treat muscle wasting in advanced non-small cell lung cancer patients when given at the same time they initiate standard first-line chemotherapy consisting of a platinum doublet.

In the design of the trials, FDA and European National Authorities' advice focus on the need to control for chemotherapy in the Phase III program for this indication. The discussions with these agencies share the concern that chemotherapy is frequently given to these patients throughout the course of their disease to control cancer-related symptoms. There was concern expressed that chemotherapy itself may potentially influence the clinical measurements of lean body mass and stairclimb power, and affect the trial results in patients with non-small cell lung cancer.

Two possible situations could happen. Responses to chemotherapy may confound the results, but overestimating the benefit of enobosarm on lean body mass and physical function in patients, or conversely, the potential benefits of enobosarm on lean body mass and physical function could be masked by imbalances in the toxicities associated with the chemotherapy, such as peripheral neuropathy or anemia. The intention of the clinical development program was not to test enobosarm in combination with every possible type of chemotherapy used in the treatment of non-small cell lung cancer, but rather to control for chemotherapy to minimize the concerns the agencies had regarding the potential for imbalances in efficacy or toxicity.

The original advice received recommended we use a single approved standard platinum doublet chemotherapy regimen as a way to control for the potential effects of chemotherapy on lean body mass and physical function. GTx chose to expand that the choices of first-line platinum doublet chemotherapy regimens to better reflect current clinical practice and standard of care in the majority of academic and community oncology settings in the United States and Europe, and at the same time, control for chemotherapy.

Accordingly, GTx conducted two Phase III clinical trials with identical inclusion/exclusion criteria, endpoints and duration, but differing in patient population space on their planned first-line chemotherapy, either a platinum plus a taxane, or platinum plus a non-taxane, respectively, to which an add-on therapy with placebo or enobosarm 3 milligrams would be used, so that any possible imbalances and benefit of toxicity-related chemotherapy that may confound the results on lean body mass and physical function could be determined. The endpoints for the two studies were lean body mass assessed by DEXA and physical function assessed by the stairclimb test.

Although we did not have a special protocol assessment with FDA, we agreed with FDA, and so stated in our statistical analysis plan for the studies, that we would make lean body mass and physical function measurements at day 84, the co-primary endpoints, and we would analyze these endpoints statistically by responders analyses. The responder analyses required at day 84, more patients in the study had maintained or showed an improvement in lean body mass, and that there were more patients who had at least a 10% improvement in physical function in the treated group compared to the placebo.

Based on input from the EMEA representatives, however, rather than having co-primary endpoints, we specified physical function as the primary endpoint, and lean body mass as the most important secondary endpoint. We prespecified in our statistical analysis plan that these same endpoints would be assessed using the longitudinal continuous variable statistical analyses. This would allow us to compare the changes over time in physical function and lean body mass in the treated versus the placebo groups in each study, especially if they have a decline in lean body mass and/or physical function from baseline. The EMEA representatives we met with stated that they wanted to see the effects on physical function as the primary endpoint, and the effects on lean body mass as a key secondary endpoint for the studies, and also indicated they would look at the totality of the data to determine clinical benefit.

As we stated in our August 19 press release, and during our conference call that morning, we failed to meet the co-primary endpoints of lean body mass and physical function assessed statistically using the responder analyses as agreed upon with FDA. It remains clear, though, that enobosarm had a consistent positive effect on maintaining or improving lean body mass compared to placebo in both studies. By the responder analyses, a larger proportion of patients receiving enobosarm maintained or increased lean body mass at both day 84 and day 147 in both clinical trials compared to placebo.

In the POWER 1 trial with taxanes, this equated to a P value of 0.036 at day 84 and a P value of 0.026 at day 147; and in the POWER 2 trial with non-taxanes, the P values were 0.113 and 0.013, respectively. Using the longitudinal continuous variable statistical analyses, declines in lean body mass and stairclimb power were observed in the placebo groups in both studies. The POWER 1 taxane clinical study met the prespecified primary endpoints for physical function of change in stairclimb power through day 84, with a P value equaling 0.0147; and the secondary endpoints of change and lean body mass through day 84, 0.002 and change in stairclimb power through day 147, P equals 0.0492, and change in lean body mass at day 147, which was less than 0.0001.

In contrast, POWER 2, the study using non-taxanes, did not meet the primary endpoint of change in physical function, but had consistent effects on improving lean body mass through day 84 and day 147 with P equals 0.0227 and 0.0036, respectively. Enobosarm was well-tolerated in both clinical studies. And although only minor differences in adverse events were observed between the enobosarm 3 milligram and placebo groups in each of the POWER 1 and POWER 2 trials, there were notable differences in the adverse event profile between studies, with anemia and other hematologic toxicities, and nausea and vomiting being more prevalent in the POWER 2 non-taxane clinical trial.

By controlling for chemotherapy, GTx is able to better understand the impact of chemotherapy side effects as possible confounders that could explain the physical function endpoint in POWER 2 non-taxane study. We are still evaluating these results.

Survival is being assessed as another safety endpoint. As specified in our statistical analysis plan, pooled overall survival data will be assessed after 450 of the approximately 650 patients in the two studies have died, which we currently expect will have occurred by March or April of next year. We have seen no adverse effects on overall survival from enobosarm treatment from the survival data received to date, and we expect this to remain the case. Interestingly, however, we have seen in a post-HOK landmark survival analysis of patients who have had their day 84 clinical assessment, a potential survival benefit among patients who maintained or increased lean body mass regardless of treatment. If this continues to be the case following the survival assessment after 450 deaths, we believe there's even a stronger case to be made for focusing on maintaining or improving lean body mass in this critically ill patient population, with enobosarm 3 milligram treatment.

While we're disappointed that both POWER studies did not meet the prespecified responder analyses criteria at day 84, we believe the overall results are compelling, including the consistent positive effects on physical function and muscle in the POWER 1 taxane study, and on muscle in the POWER 2 non-taxane study, and the fact that enobosarm was well-tolerated by patients in both studies, and the association of maintaining improving lean body mass as a potential survival signal. Accordingly, we're in the process of preparing and submitting meeting requests to both FDA and European authorities to discuss a feasible regulatory path forward, and will report back once we have better regulatory clarity.

Turning to our ongoing Phase II clinical study evaluating enobosarm 9 milligrams for the treatment of androgen receptor positive and estrogen receptor positive metastatic breast cancer in women who have been previously -- women who previously responded to hormonal therapy. We plan to be fully involved in this 20-patient clinical study this quarter, and expect that the last patient in the study will have reached the six-month assessment endpoint late in the second quarter of next year. Literature suggests that up to 80% of women with metastatic breast cancer will be positive for both estrogen receptor and androgen receptor, and our current study is certainly confirming this observation.

Prior clinical studies have shown that women with metastatic breast cancer who have been previously treated with Tamoxifen, and whose cancer has progressed, have responded to non-selective, non-aromatizable androgens, which are androgens that cannot be converted to estrogen, and with overall response rates ranging from 20% to 60%. Although these nonselective non-aromatizable androgens have been used, and are recommended in the NCCN guidelines as treatment for metastatic breast cancer, the unwanted virilizing side effects, including an increase in facial and body hair, enlargement of the voicebox, acne, and edema, have limited their widespread clinical use. GTx believes that a selective androgen receptor modulator like enobosarm, by targeting the androgen receptor in metastatic breast cancer, has the potential to provide clinical benefit to women with advanced breast cancer by treating their disease while minimizing the unwanted masculinizing side effects associated with androgens.

Unlike steroidal androgens, enobosarm cannot be converted to an estrogen that could be detrimental in breast cancer. The women in our Phase II clinical trial are receiving an oral 9 milligram dose of enobosarm once a day until they show evidence of clinical progression or have completed 336 days of treatment with enobosarm. The primary endpoint of the study is clinical benefit response, which will be assessed at six months, and is defined as either those women receiving treatment who have demonstrated a complete response, disappearance of all targeted lesions; partial response, at least a 30% decrease in the sum of the diameters of the targeted lesions; or stable disease, no disease progression from baseline.

Assuming we see evidence after six months of treatment that enobosarm 9 milligrams has sufficient clinical benefit responses, we will either expand the study to include additional women with metastatic breast cancer to confirm the dose; or if safety remains satisfactory, we may increase the dose to further define efficacy and safety. To date, enobosarm treatment has been well-tolerated at the 9 milligram oral daily dose.

With regard to the GTx-758 Capesaris program, GTx is enrolling an open-label Phase II clinical study of GTx-758 to treat men with metastatic castration-resistant prostate cancer. The Phase II study was originally designed to evaluate the safety and effectiveness of three doses of GTx-758, 125 milligrams, 250 milligrams, and 500 milligrams oral daily dose. The primary endpoint of the study is the proportion of patients with a greater-than-50% reduction from baseline and serum PSA by day 90.

Other key endpoints include free testosterone levels, sex hormone binding globulin levels, and total testosterone levels in the study subjects. Prostate cancer progression is also being monitored, in addition to clinical studies evaluating the ability of GTx-758 to treat certain estrogen deficiency side effects associated with androgen deprivation therapy, such as hot flashes, bone loss and insulin resistance.

After reviewing data collected to date from the GTx-758 125 milligram dosing arm showing the ability of the drug to substantially increase sex hormone binding globulin and lower free testosterone, the clinical protocol was recently amended to eliminate the third dosing arm of 500 milligrams originally designed for the study, and to increase the number of subjects to be enrolled in the 125 milligram and 250 milligram dosing arms to 38 subjects per arm.

The number of subjects per arm was increased to provide greater confidence in the safety of GTx-758, and to date, we have seen no evidence of venous thrombotic events or SAEs. The enrollment in the 125 milligram cohort is ongoing. And assuming there continues to be no unacceptable incidence of venous thrombotic events observed in patients in this cohort, GTx will then make the decision whether to proceed with dosing of the 250 milligram cohort.

Treatment of prostate cancer with primary androgen deprivation therapy improves prostate cancer symptoms, but patients eventually develop castration-resistant prostate cancer, as their cancer adapts and uses the available free testosterone in the bloodstream to grow. When primary androgen deprivation therapy fails, the majority of patients develop nonmetastatic castration-resistant prostate cancer for which there are no approved secondary hormonal therapies. We believe GTx can offer a unique secondary hormonal treatment option for men with nonmetastatic castration-resistant prostate cancer.

Other agents under development basically have the same mechanism of action as androgen receptor antagonists, and only have activity against the androgen receptor signaling pathway and prostate cancer cells as a means to prevent metastatic progression. As an oral estrogen receptor agonist, GTx-758 is a new chemical entity with a unique drug mechanism. GTx-758 not only affects the androgen receptor signaling pathway in prostate cancer cells by maximally suppressing circulating free testosterone, but also, through its estrogenic effects, provides the potential to improve bone quality by decreasing bone turnover.

Bone-only agents, such as bisphosphonate and denosumab, have been shown to prevent bone metastatic disease and treat skeletal-related events in patients -- excuse me -- in prostate and other cancers. With a dual mechanism to prevent metastatic disease -- that is directly by reducing available free testosterone to prostate cancer cells, and indirectly by improving bone quality to make the bone environment more resistant to metastases -- GTx-758 could become a preferred secondary hormonal therapy for men with nonmetastatic castration-resistant prostate cancer. Moreover, by replacing estrogen, GTx-758 may also provide the pro-estrogenic benefits to improve other estrogen deficiency side effects commonly associated with primary androgen deprivation therapy, such as hot flashes, bone loss and fractures, and metabolic syndrome and insulin resistance.

We plan to meet with FDA to discuss data from our ongoing Phase II clinical study and our proposal to use GTx-758 to treat men with advanced prostate cancer. Our goal is to develop GTx-758 as the first secondary hormonal therapy in men who have nonmetastatic castration-resistant prostate cancer. The short-term objective is to complete our current Phase II safety and dose-finding clinical study of GTx-758 in metastatic castration-resistant prostate cancer patients. Our regulatory objective is to find a way forward with the regulatory agency that will allow us to use an earlier endpoint, like progression-free survival rather than overall survival, as the clinical benefit endpoint required for approval in men with nonmetastatic castration-resistant prostate cancer.

This morning, we also released our financial results for the third quarter ended September 30, 2013. While I will not review the financial results in detail, let me point out that we reported $21 million in cash short-term investments as of September 30, 2013, and we have no debt or warrants outstanding.

Marc Hanover and I will be happy to answer any questions you may have about our financial results during the Q&A. Operator, we're now ready for the first question.

(Operator Instructions). Brian Klein, Stifel.

Thanks for taking my questions. So, first, on enobosarm, as you think about the path forward, and as you head forward -- move forward with the FDA, would you consider conducting another study in the US to confirm what are positive trends in benefit?

Right. So, good question. So, the way we're looking at it right now is we need to really -- let's take a step back. So the first step is that we -- the drug has continued to perform in the manner that the drug was developed. It's a muscle drug, and in every single clinical study that we have done, it builds -- it improves muscle. And we also learned in the two Phase III's that we performed -- again, unambiguously, this drug builds muscle.

And we also learned in these two Phase III's, and also the additional other eight clinical studies that we have done, that it's a safe drug. And so now it's safety and the ability to build muscle; and, in many of these trials, also showing an improvement in physical function. You know, the first thing we have to say to ourselves is we've got -- the drug works. The drug works. So now the question is, what do we need to do to get this to work with the regulators and get and find a path forward?

And so the way to handle that is that we provide the information both to EMEA and to US. And the goal here is to let the regulators tell us what the next steps will be to -- with this drug. Because the drug has efficacy in muscle and safe, from the studies that we've done so far, including the two large Phase III's, we believe there is a path forward; but it will be up to the regulators to tell us what that path forward could be.

Great, thanks. And then on Capesaris, following the data from a competitor product, enzalutamide, with the PREVAIL data where they showed a survival advantage, just wondering -- I know your comments -- you suggested you might be able to move forward with a PFS endpoint. Do you find that the patient population will be changing at the point where you're going to be starting your final registrational program? And do you think that the commercial opportunity begins to diminish as additional agents come into approval?

Great question. So the first thing is, the way I see it is that when the drugs -- when prostate cancer drugs started coming out in patients with metastatic castration-resistant prostate cancer, overall survival was the -- is what you needed to hit in order to get a drug approved. And then, as they moved into the pre-chemo space, it wasn't just overall survival, but it was sort of a combination of progression-free survival and overall survival.

And now with enzalutamide and abiraterone, it's become clear that there is a correlation between PFS and overall survival to a point that we hope that the Agency would agree that going for an earlier timepoint, using just a PFS endpoint would be acceptable. We've watched the same evolution occur in other cancer types, and we also have watched in other cancer types how multiple agents are being used in other cancer. In fact, in lung cancer, how many different flavors of an estrogen -- how many different flavors of EGR receptor molecules are out there, between antibodies and small molecules all going for the same target?

So, I think in prostate cancer, we're just beginning; we're not ending. I think that if we have an agent that has a different mechanism of action, then I think there's going to be so advantages. I think if you have a drug that has the same exact mechanism of action, then the questions are going to become, well, what does your drug have that -- you know, what are the features of your drug, whether it's efficacy or safety, that will allow us to make a decision, as a physician, why we want to use one androgen receptor antagonist versus another?

But coming in with a new drug like this one, in which, in addition to having potential efficacy in treating the cancer itself, and making bones stronger so that you can prevent meds, and then on top of that, treating the side effects of androgen deprivation therapy, we think we have a place. One of the biggest concerns of primary ADT -- primary androgen deprivation therapy -- is it does lower testosterone. And any agent that continues to work by lowering testosterone will continue to increase the side effects, the estrogen deficiency side effects, which can be quite serious, including fractures, hot flashes, and metabolic syndrome and insulin resistance.

So, any of these other drugs that are coming out, whether it's abiraterone, prednisone, enzalutamide, Aragon's drug -- I mean, these drugs are very effective in dealing with testosterone. But at the end of the -- testosterone and testosterone pathways -- but at the end of the day, they're going to continue to make the estrogen deficiency side effects worse, or they're going to have to be given, in addition with potentially expensive drugs like Xgiva, to treat the -- or Prolia, to treat the bone loss or to treat patients to prevent skeletal-related events.

GTx-758 is uniquely positioned, because we could be a bone drug and a prostate cancer drug, and could be given as a -- and the reason I made the comment is the first secondary hormonal therapy, the concept there is, as soon as a patient breaks through primary androgen deprivation therapy, and has a rising PSA, and has nonmetastatic castrate-resistant prostate cancer, what are you going to go to? Do you want to try to find something that will treat the side effects of ADT and treat the cancer itself? And use an endpoint that is clinically meaningful, such as a progression-free survival? Or do you want to go for something that's going to shut down testosterone and potentially aggravate or make the estrogen deficiency side effects worse?

So I think that commercial opportunity for GTx-758, given these -- this kind of potential therapeutic profile, is attractive. And it's very different. And if I came back and said I had the third androgen receptor antagonist, or I had the third lyase inhibitor, I mean, you've already seen one company bow out that had a lyase inhibitor, recognizing that that space is going to -- you know, is taken. With that said, I think that running these trials -- there are 100,000 patients a year with nonmetastatic castration-resistant prostate cancer -- it is a large market opportunity, and patients will continuously look for therapies that will improve their symptoms, and more importantly, treat their cancer.

So I think we will have a place. And I do think that the goal would be to be able to do these studies against placebo. And these other drugs will always be available if the patients fail. And I'm hoping what we'll do is we'll convert prostate cancer into more of a chronic disease, which means that it's not you use one and then the patient dies; you use one hormonal therapy, and then you follow it by a second, you follow it by a third, and the goal is like in breast cancer -- to continue to treat these patients that are hormonally-sensitive.

Unfortunately, there's still a large subset of patients, probably over 50% of the patients, that have disease, that are not hormonally-sensitive, and they'll march right through all kinds of hormone therapy, very much like triple-negative disease in breast cancer. And those patients will need other therapies. So I think this is really just a beginning in prostate cancer, and it's not a mop-up operation at this point.

Great, thank you.

(Operator Instructions) There are no further questions. And I would now like to turn the call back over to Dr. Steiner for closing remarks.

Thank you very much, operator. We would like to thank you all for your interest in GTx, and we look forward to updating you in the near future. Thank you for being on our call.

Thank you for your participation in today's conference. This concludes the presentation. You may now disconnect. Good day.