Ladies and gentlemen, thank you for standing by. Welcome to the Onconova Therapeutics Fourth Quarter and Full Year 2022 Financial Results and Business Update Conference Call. [Operator Instructions]. At this time, I would like to turn the call over to Bruce Mackle of LifeSci Advisors.

Thank you, operator, and welcome, everyone, to Onconova's fourth quarter and full year 2022 financial results and business update conference call. Earlier this afternoon, Onconova issued a press release reporting its financial results and business progress. If you have not seen this press release, it is available in the Investors and Media section of the company's website at onconova.com. Following my introduction, we will hear from Onconova's President and CEO, Dr. Steve Fruchtman; Chief Medical Officer; Dr. Mark Gelder; and Chief Operating Officer and Chief Financial Officer, Mark Guerin. These prepared remarks will then be followed by a question-and-answer session. Before we begin, I would like to remind everyone that statements made during this conference call will include forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties that can cause actual results to differ materially. Forward-looking statements speak only as of the date they are made as the underlying facts and circumstances may change. Except as required by law, Onconova disclaims any obligation to update these forward-looking statements to reflect future information, events or circumstances. For more information on forward-looking statements, please review the disclaimer in today's press release and the risk factors in the company's SEC filings. With that, I will now turn the call over to Onconova's President and CEO, Dr. Steve Fruchtman.

Thank you, Bruce, and thanks to all who have joined the call today. We are entering a very exciting time for Onconova as our recent progress has us moving toward anticipated milestones that we believe will serve as key value inflection points. I'll begin today by providing the highlights of this progress. Before turning the call over to Dr. Mark Gelder, our Chief Medical Officer, to elaborate further. Let me begin with a discussion of our lead asset, narazaciclib, which, as a reminder, is a multi-kinase inhibitor, targeting CDK4/6 and other kinase important for tumor growth and metastasis. We are pursuing narazaciclib's development in multiple cancer indications based on both preclinical and clinical science, and we are pleased to say that narazaciclib's Phase I/IIa combination trial with estrogen blockade in endometrial cancer is on track to open for enrollment and screening patients later this quarter. In parallel, our Phase I trials of single-agent narazaciclib in the U.S. and China have continued to demonstrate the asset's favorable safety profile through their fifth dose escalation cohorts. Based on these studies, we will be able to place patients on a once-daily continuous dosing regimen in endometrial cancer as well as in future studies. Once daily continuous dosing differentiates narazaciclib from each of the 3 health authority approved CDK4/6 inhibitors. Of these agents, which are multibillion-dollar franchises with approvals only in hormone receptive positive add to negative breast cancer, 2 of them require a 1-week drug holiday and every fourth week, mainly due to their bone marrow toxicity, leading to neutropenia or a low white blood cell count, while the third requires twice-daily dosing due to its shorter half-life. By dosing narazaciclib once daily continuously, we can provide patients with a more convenient and safer dosing regimen from a myelosuppression perspective. They will not…

Thanks, Steve. I'll start with a quick update on narazaciclib's Phase I solid tumor program. I'm going to focus on the program's U.S. study, referred to as study 1901. This study is evaluating the continuous once-daily dosing regimen that we plan to utilize with narazaciclib moving forward. The trial recently completed the fifth dose cohort. This was a cohort of patients who took 200 milligrams a day by mouth on a continuous daily basis, days 1 through 28, each cycle being 28 days. We expect, it will advance to the sixth dose escalation cohort, which will evaluate the safety, tolerability, PK and PD of a 240-milligram dose of narazaciclib orally once daily. We expect to move to the sixth dose escalation cohort after the Safety Monitoring Committee has reviewed the data from the fifth dose cohort. Data from the trial continues to be highly encouraging with anticipated on-target effects of narazaciclib observed, but in the absence of any clinically meaningful cases of neutropenia or diarrhea. This is important, since as Steve pointed out, neutropenia is the dose-limiting toxicity for 2 out of the 3 approved CDK4/6 inhibitors, while diarrhea is the primary dose-limiting toxicity for the third one abemaciclib. These early clinical findings are also notably consistent with narazaciclib's differentiated kinase inhibitory profile as well as its preclinical data that showed reduced neutropenia when directly compared to the most widely prescribed CDK4/6 inhibitor, palbociclib. On our last earnings call, you heard Steve and I speak about how narazaciclib's differentiated inhibitory profile positions it as a potentially best-in-class therapy when combined with letrozole in patients with recurrent or metastatic low-grade endometrioid endometrial cancer, or LGEEC. We also announced that we plan to begin exploring this hypothesis in a Phase I/IIa trial, which has received IRB approval at New York University Langone…

Thank you, Mark. Onconova finished 2022 in a strong financial position with cash and cash equivalents of $38.8 million as of the end of the year. This compares with cash and equivalents of $55.1 million at the end of 2021. Based on our current projections, we believe our current cash position will be sufficient to fund our ongoing clinical trials and operations into the first quarter of 2024. This cash runway is expected to take us through key milestones, including a first data readout from our combination trial of narazaciclib and letrozole in advanced endometrial cancer later in 2023. Turning now to our full year financial results. Research and development expenses for 2022 were $11.4 million compared to $7.3 million for 2021. General and administrative expenses were -- for 2022 were $8.4 million compared to $9.4 million for 2021.%. Our net loss for 2022 was $19 million or $0.91 per share on 20.9 million weighted average shares outstanding. This compares with a net loss for 2021 of $16.2 million or $0.96 per share on 16.8 million weighted shares outstanding. The increase in net loss for 2022 compared with 2021 was primarily a result of higher spending in the narazaciclib development program and drug manufacturing in 2022. That completes my financial review. I'll now pass the call back to Steve.

Thanks to both of you, Marks. I'll start my closing remarks by thanking all of those who made the progress we spoke about today possible. At the top of this list are our clinical trial participants and their caregivers who's bravery is a constant source of inspiration to all of us. I'd like to also thank our employees, investigators, partners and shareholders for their support, which has us advancing towards multiple key milestones that you heard about today. They are expected between now and the year-end. In our narazaciclib program, we expect to report preliminary data from our combination trial of narazaciclib and letrozole in advanced endometrial cancer in the fourth quarter of this year. We also expect continued progress of our Phase I trials to enable the selection of a recommended Phase II dose in the first half of the year and to initiate a clinical program of narazaciclib in one or more additional cancer indications. Regarding rigosertib, we look forward to discussing our recent RDEB-associated squamous cell carcinoma data with the FDA in order to help determine the optimal regulatory pathway of these exciting clinical outcomes. We also look forward to opening the combination trial of rigosertib and pembrolizumab in melanoma later this quarter and expect that the Phase I/IIa trial of rigosertib plus nivolumab in KRAS-mutated non-small cell lung cancer will have additional important data to report in quarter 2. In parallel with the progress of our clinical programs, we will continue to evaluate potential opportunities to expand our pipeline, and we'll focus any such efforts on assets that have a strong body of evidence, demonstrating their best-in-class potential and an indication with a high unmet medical need. We plan to be very highly selective as we make these corporate development assessments as our current programs are backed by compelling data and provide us with multiple shots on goals and opportunities to generate value for our investors and the patients. With that, we'll begin today's Q&A session. And operator?

[Operator Instructions]. And our first question comes from Charles Zhu from Guggenheim Securities.

This is Edouard on for Charles Zhu at Guggenheim. My first question is on narazaciclib, the monotherapy dose escalation. I'm curious if you can give any more color on how the dose escalation is going beyond the prepared remarks? Do you think you're in the potentially therapeutically efficacious range for the doses? And how much higher do you think you could go? And then as a potential -- and as a follow-up, I know you've guided to the letrozole combo data in 4Q, but so how should we be thinking about the monotherapy dose escalation data update? Would you -- could that come before the 4Q update?

Thanks, Ed. I'll ask Dr. Gelder to take that, please?

Sure. So more clarity on the Phase I dose escalation study. What I can tell you is that we do believe that we're getting close to a "dose" that we can use as our recommended Phase II dose. We are beginning to see some effects that we would anticipate from a CDK4/6 i.e., we're beginning to see a little more grade 1, grade 2 neutropenia. We're not seeing a whole lot other than that. We're seeing some low-grade diarrhea, but nothing significant. The PD work, the pharmacodynamic work with the 200-milligram cohort is still pending. It's still out. So I can't say anything for certain about that. But just based on what I'm seeing, do I think that we're getting relatively close? Yes, I do. Does that mean 240 milligrams is going to be the dose, 280 milligrams, 320 milligrams? I don't know. Do I think we're going to have to push this to 500 or 600 milligrams? No, I do not. So I do think we're getting closer, but I can't give you a firm answer today.

And Mark, the second question was the strategy of the monotherapy trial when we also have already begun the combo trial with letrozole. Make some comments on that.

So we're looking at different options right now, whether we do continued work with -- in combination with either letrozole or other anti-estrogens, whether we do work as a monotherapy, whether we do some continued work with narazaciclib in combination with, say, a checkpoint inhibitor or in combination with a BTK inhibitor or in combination with a MEK inhibitor, we're looking at several different options now. So I can't give you any more specific details at this time. What I will tell you is that we do have -- we believe we do have several good options in terms of additional development programs to start moving forward with other than the low-grade endometrioid endometrial cancer. And so exactly what our second program and third program and fourth program will look like at this time, I just can't say. Steve, you may want to give a little more away, but I'll hold my comments there.

I think Ed's question -- and correct me if I'm wrong, Ed, is how do we start a combination trial with narazaciclib before we know the recommended Phase II monotherapy dose. So I think the answer, Ed -- the answer is that as Dr. Gelder said, we believe we're close to the recommended Phase II dose. And anytime you do a Phase I new combination, you always decrease the dose of the experimental agent. In this case, narazaciclib. So since we think we're close, we went back one step, one cohort, take that dose of narazaciclib in combination with letrozole. And it's, by design, we'll again continue to increase the dose of narazaciclib in combination with that result based on the safety profile that Dr. Gelder will be observing. So I hope that answers your question, Ed.

Our next question comes from Ahu Demir from Ladenburg Thalmann.

Congrats on the progress. I have 2 questions. One of them, we heard you say the entity was not and also you don't have observed the neutropenia and diarrhea. I am curious to hear if you could provide more color on the similarities or differences between narazaciclib with other CDK4/6 inhibitors. Do you observe similar safety profile? Or is it very differentiating? If you could provide some color on that, that would be helpful.

Mark?

Yes. So I think when I look at what really differentiates us, as you're well aware, palbo and ribo are the 2 "purest" CDK4/6 inhibitors with ribo being the purest followed closely by palbo. Abemaciclib, like narazaciclib, is truly a multi-targeted kinase inhibitor. It hits several different kinases at low nanomolar concentration, but the kinases that abemaciclib hits are very different than the kinases that narazaciclib hits. All of them are very potent, very effective CDK4/6 inhibitors. What differentiates narazaciclib are the other kinases that it hits at low nanomolar concentration, particularly the ARK5 orn NUAK1 and the CSF1R. But there are others, the FLT3, the [indiscernible], et cetera. So there are actually several kinases that we hit that we think have the potential to be very important in terms of the overall efficacy as well as the safety of narazaciclib. We -- This is all preclinical data. We're just getting into the clinic. We've now had in our Phase I dose escalation study. We've now had 21 patients total who have been exposed to the narazaciclib at escalating doses. And as I said, so far, the safety profile looks very, very good. Very similar to what we had anticipated based on all of our preclinical data. And we are very excited, as we've said, to be moving into the low-grade endometrioid endometrial cancer study because now rather than using a typical Phase I solid tumor population, we will be using a population where we expect -- where we anticipate to start to see some really significant activity. So this is sort of where we are. I hope that answers your question, but it all has to do with the other kinases that we inhibit.

And actually, there will be more data that -- Mark alluded to, there will be greater detail at the AACR meeting in Orlando.

That's helpful. I have one more question on the letrozole combination trial. For the -- since the both drugs are administered daily, I am curious if you have looked at the safety profile. Are there any overlapping toxicity? Are you expecting anything major in the combination trials?

Mark?

So when I look at letrozole and it's got a very well-established AE profile. And when I look at what we've seen so far with narazaciclib and what we expected based on the other CDK4/6 inhibitors that are already approved, and based on our preclinical data, there really is very little, very little overlapping toxicities of the 2. The biggest one is really fatigue.

And if I can add to that and also add to the previous question because letrozole is an anti-estrogen, and as Mark just said, a very different safety profile and a very acceptable safety profile, a very different mechanism of action as an anti-estrogen. That's why rather than waiting to -- wait for the phase -- the recommended Phase II dose of mono narazaciclib study to read out, we are comfortable combining narazaciclib with letrozole with a lower dose of narazaciclib to make sure [indiscernible]. But this approach of already opening the combination trial and endometrial saves us 2 key factors, which are both very important, time and money. But we now will have, as we mentioned in this quarter, the first patient on this combination trial with endometrial cancer, studying the combination.

Our next question comes from Joe Pantginis from H.C. Wainwright.

So this might be jumping the gun a bit here. Obviously, you need to talk to the FDA first with regard to rigosertib's potential in RDEB. But with that said, do you have, I guess, any sort of broad strokes to take right now, both internally and maybe from any external sort of regulatory consultants that might give you an early wish list that you can share with us regarding a potential design?

Well, the wish list, Joe, won't require a design. The results that Dr. Gelder shared with us, the patients and the experts who see these patients are extraordinary. They have failed everything else, and as we mentioned, we have complete cutaneous responses. This is an ultra rare disease, and we have already demonstrated complete responses where nothing else works. Our regulatory consultants are the one saying, we should go to the FDA now and ask the question, what will it take to get rigosertib approved in squamous cell complicating RDEB. We don't know if the current 2 patients are enough. Will they want an additional 2 patients? We really don't know what the end is going to be. And as Mark said, hopefully, before we meet with the FDA, maybe we'll have 1 or 2 additional patients. The incidents of this disease in the U.S. is 100 -- about 100 RDEB patients a year. Maybe 50 live long enough to develop squamous cell carcinoma, but it's very hard to identify these patients as you know. In addition, the other wish is because this is a pediatric disease, the RDEB expresses itself in the pediatric age population. We are told that periodically a child [indiscernible] with squamous cell, mostly the young adults who developed the squamous cells. The 2 patients that we treated are, in fact, young adults. This will be presented in greater detail at the International Dermatology Meeting in Tokyo, Japan that's coming up, but we are continuing to look for additional patients. And if we're very lucky -- but it may not be necessary to find a pediatric, it's hard to say lucky to find a cancer in a child. But if there is a child out there anywhere in the globe that we become aware of, we, of course, would be very interested in treating that child with rigosertib and discussing the possibility of a pediatric voucher for squamous cell complicating RDEB. So those are our wishlist to get rigosertib approved in this indication and to discuss the possibility of a pediatric voucher with the FDA.

Our next question comes from Robert LeBoyer from NOBLE Capital Markets.

I had a question that I think was partially answered earlier. But if you're going into a sixth cohort for narazaciclib, could you give any kind of timeframes as to when the sixth might be completed or the seventh or even an eighth, if you go that far? And when you might start the Phase II?

Mark?

So it's impossible to say when a cohort is going to get completed. You have a 3 plus 3 design, and it depends on if you get a DLT, it depends on how many screen fails you have, et cetera, et cetera. So typically, it takes -- if you can -- if you don't have any significant problems, don't have a lot of screen failures, et cetera, you can complete a cohort of 3 in 2 to 3 months. But if you have a DLT and then have to expand it out to 6 or if you start having several screen failures, et cetera, it can take 4, 5, 6 months to complete a single cohort. So it's really impossible to say. Our fifth cohort, as you're all well aware, took several months to complete because we had several screen failures, et cetera, but that's just the nature of clinical research. The first 4 cohorts, we all completed. We completed each one of them in 2 to 3 months. And in terms of how many cohorts we're going to have to go, I do not have a crystal ball. I can't tell you. Do I -- in my gut, do I think we're probably getting close? Yes, I do. The sixth cohort is at 240 milligrams. Will that be as high as we need to go? Or do we need to go to 280? It won't -- that decision won't just be driven by the AE profile. It will also be driven by the PD data, the pharmacodynamic data, because we're going to look for a dose that maybe isn't the MTD, or maximum tolerated dose, but look for a dose where we see maximum biologic effectiveness, too. So it's just hard to say.

I'm showing no further questions in queue. At this time, I'd like to turn the call back over to the speakers for closing remarks.

Thank you all again for joining today to hear about our recent progress and outlook for the rest of the year. We are obviously excited to be nearing several important clinical milestones and appreciate your continued interest in the important, if not crucial, work we are doing. Thanks, again, and enjoy your evening and look forward to seeing many of you going forward. Thank you.

Ladies and gentlemen, thank you for your participation on today's conference call. This concludes today's event. You may now disconnect.