Ladies and gentlemen, thank you for standing by. Welcome to the Onconova Therapeutics 1st Quarter 2023 Financial Results and Business Update Conference Call. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a question-and-answer session. To ask a question at this time, please press star followed by one on your touchtone phone. If anyone has difficulty hearing the conference, please press star zero for operator assistance. As a reminder, this call is being recorded today, May 15th, 2023. At this time, I would like to turn the call over to Bruce Mackle of LifeSci Advisors. Please go ahead, Bruce.
Thank you, operator, and welcome everyone to Onconova's 1st quarter 2023 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 yet 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. Steven Fruchtman, Interim Chief Medical Officer, Dr. Michael Saunders , and Chief Operating Officer and Chief Financial Officer, Mark Guerin. Onconova's VP of Regulatory Affairs and Quality Assurance, Fred Frullo , will also be available during the Q&A session following the prepared remarks.
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.
Thanks, Bruce, thanks to all for listening. Before we provide our update, I would like to take a moment to remember our late Chief Medical Officer, Dr. Mark Gelder. Mark made many valuable contributions to Onconova and had a very distinguished career as a biomedical innovator and oncologist dedicated to advancing the care of patients with female reproductive cancers. We continue to work tirelessly to honor his memory through the advancement of our clinical programs in endometrial and other cancers, and we are immensely grateful for the time we got to spend together. In addition to a colleague, we lost a friend and a very good man. Although big shoes to fill, Dr. Michael Saunders, our Interim Chief Medical Officer, is an amazing clinical scientist with a remarkable track record of success in developing some of our most innovative therapeutics for patients with advanced cancer.
I want to thank Michael for his efforts during these very difficult past few weeks. For our update today, we will focus primarily on two topics. The 1st will be the progress of our ongoing phase I/II-A trial of narazaciclib combined with letrozole in low-grade endometrioid endometrial cancer, which as announced this week, had the 1st patient dosed on the study. The 2nd point will be our planned regulatory interactions around Rigosertib's phase II program in RDEB or Recessive Dystrophic Epidermolysis Bullosa associated squamous cell carcinoma, which was the subject of a FDA Type B meeting request. These developments highlight what was a very productive quarter for Onconova. For those interested in details on our progress in our additional clinical and preclinical programs, I encourage you to see our recent press releases detailing key meetings where our science is presented, including our earnings release issued earlier today.
With that, I'll introduce our interim Chief Medical Officer, Dr. Michael Saunders . As I stated, but it is worth repeating, Michael is a deeply experienced drug developer with extensive knowledge of our programs, thanks to his work as a consultant to Onconova for over the past two-plus years. Prior to this, his most recent role was as Executive Director of Drug Safety and Pharmacovigilance for Array BioPharma and Pfizer. Michael, please go ahead with the update.
Thank you for that very kind introduction, Steve. I'll begin my portion of today's call by reporting that narazaciclib has continued to display an acceptable safety profile in the phase I monotherapy trial evaluating a continuous daily dosing schedule in participants with solid tumors. Patients are on the 240 mg cohort, and as we dose escalate, we are starting to see the effects of CDK4/6 inhibition on bone marrow function, telling us we are engaging our targets but without seeing any clinically meaningful cases of neutropenia or diarrhea, which are dose-limiting toxicities associated with the FDA-approved CDK4/6 inhibitors, among additional toxicities seen with agents targeting a variety of CDK pathways.
These findings suggest narazaciclib may overcome the safety and tolerability shortcomings of these agents and indicate the phase I program has accomplished its objective of providing the information needed to confidently advance our program to the next stage of development, which we already initiated in the trial of narazaciclib in combination with letrozole in endometrial cancer. Thus, during the next stage, we will evaluate the safety and efficacy of narazaciclib-based combinations in specific indications. For those familiar with our plans, the 1st indication we are targeting is recurrent low-grade endometrioid endometrial cancer, or LGEC. Last week, the 1st patient was dosed in a phase I/II-A trial in this indication, which is on track for a preliminary data readout in the fourth quarter of this year.
Recurrent LGEC was chosen as narazaciclib's 1st target indication because it marries a clear need for improved therapies with what we believe is a high probability of technical and regulatory success. Based on compendia listings, patients with recurrent LGEC are currently treated off-label with letrozole combined with one of the CDK4/6 inhibitors, palbociclib, ribociclib, or abemaciclib, which are approved only for the treatment of hormone receptor-positive, HER2-negative breast cancer. While these compendia listings are based on the results of both single-arm trials and a randomized study that demonstrated improved clinical benefit based on the improvement in progression-free survival with the combination of letrozole and palbociclib versus letrozole alone, it's clear that the off-label combinations currently employed are marked by shortcomings related to safety, tolerability, and treatment resistance.
We believe narazaciclib has a high probability of technical and regulatory success in LGEC because like palbociclib, ribociclib, and abemaciclib, it inhibits CDK4 and CDK6 with high potency. However, in addition, we also potently target a novel protein, BUB1. The overexpression of BUB1 has been correlated with poor outcomes in certain cancers, including breast and endometrial cancer. This data was presented at the recent AACR meeting in Orlando. The narazaciclib-letrozole combination targets endometrial cancers with a mechanism of action for which clinical proof of concept has been demonstrated. It is worth repeating that in addition to targeting CDK4 and six, narazaciclib inhibits kinases not targeted by the aforementioned commercially available agents. These include a variety of important kinases, such as the previously mentioned BUB1, which was shown in a presentation at AACR last month to be associated with poor survival in a key subtype of endometrial cancer.
Narazaciclib's ability to target these additional kinases such as CSF1R and ARK5, together with the clinical safety findings to date I referenced earlier, fuel our belief that a narazaciclib-letrozole combination can provide LGEC patients with a much-improved treatment option. Beyond LGEC, we continue to evaluate opportunities for combination studies of narazaciclib in additional indications and presented data at AACR last month that provide evidence of its potential to combine synergistically with a variety of therapeutic agents in additional indications. We expect to begin at least one additional combination study of narazaciclib by the end of the year, and we'll provide additional details once a clinical protocol is finalized. Next, I'd like to speak about Rigosertib's investigator-sponsored phase II program in advanced squamous cell carcinoma complicating Recessive Dystrophic Epidermolysis Bullosa or RDEB-associated SCC as it is often referred to.
The most recent data from this program show that both initial and evaluable patients achieving complete clinical responses of all cancerous skin lesions. The responses are durable, were seen with either intravenous or oral Rigosertib administration, and Rigosertib has been well-tolerated with no additional toxicities in this subset of cancer patients with an unusual defect of having genomic mutations of collagen VII. This data was presented last week at the International Societies for Investigative Dermatology meeting with enormous interest from the international experts in the disease. Excitingly, new additional patients were identified at the meeting to be consolidated onto or considered onto study entry. These patients are ultra-rare, and we are very pleased to have identified additional patients whom we hope Rigosertib will be as helpful to as with the patients already treated to date.
Though these data are only from 2 patients, it's important to realize that RDEB-associated SCC is an ultra-rare disease with extraordinarily high unmet need. The cumulative risk of death is tragically 70% by the age of 45. Once recurrent metastatic squamous cell cancer occurs following surgery, it is almost always invariably fatal with no effective treatment options. Because of this high and urgent unmet need, we believe the most prudent next step for the program is to discuss our early findings with regulators to determine the optimal, most expeditious path towards an NDA filing and potential approval. In this regard, we have requested a Type B meeting with FDA. Based on regulatory timelines associated with the Type B meeting, we expect to provide an update on Rigosertib's regulatory pathway in RDEB-associated SCC in the 3rd quarter after we have completed the Type B meeting and received written feedback.
Notably, Rigosertib's results in RDEB-associated SCC may have positive read-through into more prevalent indications, as a key driver of the disease is PLK1, a kinase that is overexpressed in other cancers and is potently inhibited by Rigosertib. To further explore this possibility, we recently began collaborating with Pangea Biomed to use their proprietary Tumor Intelligence Pro platform to identify biomarkers that could predict patient response to Rigosertib. This platform makes predictions by evaluating in vitro, preclinical, and clinical data sets to build genetic social networks that reveal tumor vulnerabilities to specified therapies. These analyses are focused both on Rigosertib's ability to inhibit PLK1 as well as the other pathways targeted by its multifaceted mechanism of action. The results of these collaborative analyses may then form an artificial intelligence-driven precision medicine approach toward selectively identifying additional indications and biomarkers for Rigosertib's potential efficacy evaluation.
The last studies I'll speak about today are two investigator-sponsored trials evaluating Rigosertib in combination with checkpoint inhibition. The 1st of these studies I'll mention is the phase II trial evaluating Rigosertib combined with Keytruda in checkpoint blockade refractory metastatic melanoma. Enrollment recently opened in this study, which is being conducted in collaboration with investigators at Vanderbilt University Medical Center, who are sponsoring the trial, and Merck, who is supplying Keytruda. Lastly, I'll provide a brief update on the phase I/II-A trial of Rigosertib combined with Bristol Myers Squibb's Opdivo in KRAS-mutated non-small cell lung cancer patients who have failed prior therapy with PD-1 checkpoint inhibition.
This trial continues to recruit patients at the dose featured in our most recent data update on the trial, namely 560 mgs 2x daily for 3 weeks on and 1 week off, which was presented at ESMO last year and showed an encouraging signal of efficacy with a studied doublet across multiple KRAS mutations. Based on these results, as well as an acceptable safety data from the trial to date, the protocol has been amended so that we can assess further increasing the dose of rigosertib in the trial, which will lead to an enhanced efficacy signal as well as continued acceptable safety. We plan to present data on patients receiving the increased dose of rigosertib alongside a broader update from the trial.
Taking into account the time needed to enroll patients on the higher dose, we now expect to report updated data from the trial in the 2nd half of this year. With that, I'll conclude my remarks and my portion of the call and hand it off to Mark.
Thank you, Mike. Onconova closed the 1st quarter of 2023 with cash and cash equivalents of $34.2 million compared to $38.8 million as of December 31st, 2022. Based on our current projections, we believe that our cash position will be sufficient to fund our ongoing clinical trials and business operations past key clinical and regulatory milestones and into the 1st quarter of 2024. Research and development expenses for the 1st quarter of 2023 were $4.1 million, compared to $2 million for the 1st quarter of 2022. General and administrative expenses for the 1st quarter of 2023 were $2.1 million. This compares with $2.2 million for the 1st quarter of 2022.
Net loss for the 1st quarter of 2023 was $5.8 million, or $0.28 per share on 20.9 million weighted shares outstanding. This compares with the net loss for the 1st quarter of 2022 of $4.1 million or $0.20 per share on 20.9 million weighted shares outstanding. The increase in net loss for the 1st quarter of 2023 compared to 2022 was primarily a result of narazaciclib clinical development and manufacturing expenses in the 2023 period. With my financial review complete, I'll now hand the call back to Steve for his concluding remarks.
Thanks, Mark. I'll conclude by reminding listeners that we have seen remarkable efficacy data with Rigosertib in RDEB squamous cell carcinoma and very encouraging data across various KRAS mutations in KRAS-mutated non-small cell lung cancer. Our progress has us on track to achieve several important clinical and regulatory milestones this year. These include, 1, the 1st readout to establish the combination dose from our phase I/II-A trial of narazaciclib combined with letrozole in endometrial cancer. 2, an important regulatory update on Rigosertib's RDEB-associated squamous cell carcinoma program. 3, updated efficacy and safety data to include additional patients from the phase I/II-A trial of Rigosertib plus Opdivo in non-small cell lung KRAS-mutated cancer. We are on track for these milestones due to the hard work of our employees, partners, and investigators, and mostly due to the bravery and dedication of our clinical trial participants.
I thank each of these individuals for their important contributions. With that, we will begin today's Q&A session. Operator, I will turn it over to you, and thank you.
Ladies and gentlemen, if you wish to register a question for today's question-and-answer session, you will need to press the star then the number one on your telephone keypad. If your question has been answered and you wish to withdraw your request, you may do so by pressing the pound key. Actually, sorry, correction on that. It's gonna be star one again to remove your question. If you're using a speakerphone, please pick up your handset before entering your request. One moment, please, for your 1st question. Your 1st question comes from the line of Joseph Pantginis of H.C. Wainwright. Please go ahead.
Hey, everybody. Good afternoon. Thank you for taking my questions. 1st, let me offer my condolences for the big shock of Mark's loss. He was great for the team. He was a great man. Very sorry to hear that. 1st, I wanted to ask about narazaciclib's profile here. As you're looking to push the dose in the phase I and dosing within the LGEC study, I was just curious, will or when or will you expect to eventually see the hematologic adverse events or and/or will you expect still some lessened impacts on the adverse event profile due to how the drug hits the kinome tree?
Well, thank you, Joe. I'll take that question. The answer is, you know, you don't really know until you continue to dose escalate. We're already starting to see some minor decreases in total white counts and ANC in the patients. That's why we believe we're getting close. For that reason, Joe, translating the monotherapy trial with narazaciclib, we've already opened the doublet trial. 'Cause usually, as you know, you wait for the recommended phase II dose before you do combination studies. To expedite our timelines, of course, as you follow the white count, you could start to see a decrease. We recognize that we're probably getting close and thus was able to open the endometrial cancer trial in combination at one dose back from where we were when we started that study at NYU.
We believe that rationale makes perfect sense as you get closer to the single agent recommended phase two, and therefore will expedite our understanding, which is the most important question, 'cause these drugs are always given in combination with antiestrogens, and we're already doing that in the NYU phase one endometrial trial.
Got it. Got it. Thanks for that. Switching over to rigosertib for RDEB-associated SCC. Obviously the big thing we're looking for, as you've mentioned, is the feedback from your Type B meeting. We discussed this previously, but if you wanted to highlight again some of the wish list coming from that. The main part of my question is, looking beyond to potential commercialization and even a pivotal study, you know, before that is patient identification. You know, what's the process you're going through? Obviously, it's an ultra-orphan indication. Are you working with or will you be working with organizations like DEBRA, you know, that really have the pulse of the RDEB population or the DEB population?
It's amazing to me, Joe, how rapidly you become an expert in whatever the science and the clinical information the companies you cover. DEBRA is the main international non-profit involved in this disease. The leadership of DEBRA typically has children who suffer from RDEB. At the meeting that we just presented in Osaka, in Japan, DEBRA was very well present there. Many of the investigators, including ourselves, by the way, I don't know if you know this, our trial coming out of Philadelphia is supported by DEBRA. The experts in the world who were all present in Osaka were very impressed with a disease that's invariably lethal once a recurrent squamous cell occurs, not just the fact that it's lethal, no therapeutic maneuvers work.
The responses we've seen with Rigosertib, in my humble and clinical opinion, are totally remarkable, how you could have these masses of fungating cancer to disappear. Based on the responses we're seeing, as Michael said, we're going to interact with the agency, show them our data, 'cause what we really need is guidance from the agency in an ultra-rare disease with a tremendous unmet medical need. How many patients would they like for us to have to get an approval? The other thing that came out of Osaka, we've already identified additional patients throughout the world 'cause the caregivers for these patients were all present in Osaka.
That's another very important development for us to be able to put additional patients on and hopefully, the preliminary results with either IV or oral Rigosertib will continue to be as extraordinary as we've seen in the patients put on to study to date, and we will have more patients with this disease treated with Rigosertib.
Thank you. Your next question comes from the line of Ahu Demir of, Ladenburg. Please go ahead.
Good afternoon, team. Thank you for taking my question and congrats on the quarter. In addition, my condolences on Mark Gelder . It was a pleasure to work with him. A few questions from us. 1st one is on the narazaciclib program. Could you comment on the CDK4/6 activity in the endometrial cancer? We know, I think it's not approved, but it is used in the patients. If you could maybe provide some color on the percentage of patients who treated with CDK4. Also, are the patients excluded if they have CDK4/6 treatment previously?
Ahu, I cannot comment. I think your question is how many patients in the U.S. are treated off-label with the FDA-approved CDK4/6 inhibitors. I do not know the number. I know with certainty that the CDK4/6 inhibitors are prescribed. How many patients in the U.S.? I do not know. There are many similarities between breast cancer and endometrial cancer, especially the subtype we are studying. They are both hormonally driven. That's why they're given in combination with an anti-estrogen. There have been clinical trials, and that's why they're used off-label, suggesting that the progression-free survival of the combination of a CDK4/6 inhibitor, specifically palbociclib plus letrozole, prolonged the PFS two and a half to three times what it was with letrozole alone. The clinical data in a randomized trial supports our approach.
The fact is it does not have FDA approval in this indication. We believe because these tumors are driven by CDK4/6, are driven by estrogen as is breast cancer, that our logic is good to pursue the endometrial cancer space, and, you know, we're excited by our 1st patient. We anticipate the recommended phase II dosing of the combination should be done before the end of this year.
That's helpful, Steve. Are those patients excluded if a patient receives?
Oh.
CDK4/6 previously? Are they excluded in the trial?
The answer is I do not believe they are because we believe we're differentiating, who based on, they could have been given, let's say, one of the other CDK4/6 inhibitors, and they stopped it, for instance, due to safety concerns, be that neutropenia or diarrhea. Because we target, we differentiate also 'cause we target resistant pathways in these diseases. Patients who have failed a FDA-approved CDK4/6 inhibitor will be permitted on a trial 'cause again, the goal is to get the dose. It's really not an efficacy trial. It's really to get the optimal dose of the combination, not necessary to study efficacy in a phase one study with no control arm.
Thank you. Your next question comes from the line of Robert LeBoyer of Noble Capital Markets. Please go ahead.
Thank you. 1st I'd like to offer my sympathies on Dr. Mark Gelder's loss to the company and his family. My question has to do with the solid tumor trial and whether the timeframe for announcing results has been established and what you're expecting going forward.
Rob, when you say the solid tumor trial, are you speaking both of narazaciclib and rigosertib? I could take both.
Uh.
I'm not sure which compound you're asking about.
Yeah. sure. I was thinking of.
Okay.
narazaciclib, but please take both.
Sure. Thanks, Robert. We anticipate the recommended phase II dose in endometrial cancer, as I mentioned, before the end of the year. Once we have that dose, our plan will be to initiate a randomized pivotal phase III trial in the same indication, studying narazaciclib plus letrozole versus letrozole alone. We anticipate beginning that trial early in 2024. Regarding Rigosertib in non-small cell lung cancer, probably similar timelines. This will be more of an exploratory trial. We're very encouraged by a complete response and partial responses seen in highly refractory KRAS mutated non-small cell lung cancer. As we've discussed previously, not just the interesting response rate that we're seeing, but the fact that we are mutant agnostic.
We have responses in at least 3 different KRAS mutations, which there is no other drug that is FDA-approved that does that. As you know, the approved drugs only target G12C. Approximately 20%-25% of all patients may have a mutation of G12C, so the 70%-80% of the other patients have other mutations that we hope to target. We anticipate that study also coming to completion in 2024. I'm sorry, in 2023 by the end of the year. As Michael mentioned, because the safety appears to be very accepted with the combination of Rigosertib and nivolumab, we may make a decision to continue to dose escalate the Rigosertib, in fact, to doses that we have not given to patients previously.
I can't predict a safety profile, but we really wanna make sure we've optimized the efficacy for this combination. We believe by increasing rigosertib, if the safety permits us to do that, we will be confident that we'll have the most efficacious dose of the combination.
Okay, great. Thank you very much.
I'm showing no further questions at this queue.
Operator, if I can interrupt you. I realize, and I thank Joe for not stopping me. I didn't answer both of Joe's questions, and I'd like to take an opportunity to do so 'cause Joe was also asking about commercialization regarding squamous cell RDEB, and I didn't answer that question. I'd like the opportunity to do so, Joe.
Go ahead, Steve.
Thank you. Clearly our goal would be to get Rigosertib approved in this ultra-rare disease just to get Rigo the evaluant of the value of Rigosertib we think is extremely valuable to Onconova. After the previous studies done, we believe and have stated many times, we believe we're on the right path by studying squamous cell complicating RDEB because of the science that brought us here. In addition to this very rare disease, there are more common squamous cells of humanity also due to damaged skin. It's just that they're spontaneous squamous cells, not complicating RDEB, but the damaged skin is from sunburn, for instance. Patients who have too much sun exposure may also develop squamous cell carcinoma. Other squamous cell carcinomas exist as well.
Squamous cell, for instance, of the lung, which is probably due to other environmental toxins that we inhale that damage the lungs. There's cervical squamous cell as well. There's a variety of squamous cells that are more common that we can attempt to address. The question that we're working on with both Pangea and other sources, because there's no approved PLK1 drug approved, pathology labs are not typically testing for the overexpression of PLK1. We plan to look at what percentage of squamous cells, regardless of the histological site, lung, skin, cervix, et cetera, and neck as well, which I neglected to say. What is the overall percentage of PLK-driven squamous cell? That is a group we'd be very interested in studying. That a group such as that would be a very large, commercial success, we believe.
I'm showing no further questions in the queue. At this time, I'd like to turn the call back to the speakers for any closing remarks.
Well, thank you all for participating in today's call. We are pleased to be approaching very important milestones across our pipeline and look forward to providing additional updates as they are achieved. Thanks again for participating, have a great evening. Goodbye.
Ladies and gentlemen, thank you for your participation on today's conference call. This concludes today's event. You may now disconnect.