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spk33: Ladies and gentlemen, thank you for standing by. Welcome to Onconova Therapeutics third quarter 2023 financial results and business update conference call. At this time, all participants are in the listen only mode. Following management's prepared remarks, we will hold a question and answer session. To ask a question at that time, please press star followed by number one on your touchtone phone. If anyone has a difficulty hearing the conference, please press star zero for operator assistance. As a reminder, this call is being recorded today, November 14, 2023. At this time, I would like to turn the call over to Bruce Mantle of Lifestyle Advisors.
spk02: Thank you, operator, and welcome everyone to Anca Nova's third 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 www.onconova.com. Following my introduction, we will hear from Onconova's President and CEO, Dr. Steve Fruchman, Chief Medical Officer, Dr. Victor Moyo, and Chief Operating Officer and Chief Financial Officer, Mark Guerin. Ankanova's VP of Global Medical Affairs and Research and Development, Mina Arora, will also be available during a 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 Frothman.
spk22: Thanks, Bruce, and thanks to everyone who is joining us today for this call. I'll open by saying that Onconova has made excellent progress in the third quarter of 2023. During the call today, our Chief Medical Officer, Dr. Victor Moyo, and our Chief Operating Officer and Chief Financial Officer, Mark Gurin, and I will provide you with an update on our lead program, Neurasa Cycle. Review the data from our recent scientific presentation. outline our upcoming milestones, provide a brief update on the RegoCerta development program, summarize our third quarter financial results and outlook on our cash runway, and of course, importantly, open the call for your questions. As you know, our mission means to develop novel proprietary products for patients with hard-to-treat cancer and with an unmet medical need. Starting with our lead program, our internal efforts are dedicated to basic preparations for nirazacyclin, our proprietary multi-kinase inhibitor of CD8.6, as well as other components for cell growth and DNA synthesis. The CDK4-6 class of inhibitory drugs has changed the face of cancer care in several indications, particularly in hormone receptor positive to negative metastatic breast cancer. Mirazic cyclin, was designed by Ankanova scientists as a potent next generation entrance into this multi-billion dollar drug class. In addition to its multi-kinase activity, we believe Nerazociclib may be differentiated from the other approved CDK4-6 inhibitors because of the potential. for an improved tolerability profile, and based on our preclinical studies, improved efficacy as well. The ability to act on targets beyond CDK4 and 6 may lower the risk of drug resistance faced by other CDK4-6 inhibitors. Our expansive preclinical studies have helped to define Nerazacyclib's ability to impact on additional vital targets involved in cell signaling and cancer survival, including the proteins ARC5, also known as NUAC1, CSF1R, and BUB1. All important in how cancer establishes its presence in sites of metastatic disease, as well as proliferation of the cancer cells. We have selected low-grade endometrial cancer to be our lead registration indication for Neurasocycline in combination with the hormone therapy Letrozole. We believe this is the right choice in endometrial cancer for two main reasons. Number one, the proposed registrational trial has a high technical and regulatory success, probability of success. Publication of positive studies with other CDK4 and 6 inhibitors and letrozole combinations and compendia data indicating off-label use support the potential for a high probability of technical success. These data and the lack of an approved label underscore the unmet medical need and support the potential for high regulatory success. The second reason is the initial data from our dose ranging studies suggest The Razocyclic has the potential to be safer than the other DDK4-6 approved inhibitors with a wide dosing window that supports an excellent therapeutic index. Note that during our call today, we may use the acronym ALGEEC to describe this indication in endometrial cancer. To be registrational trial ready, we plan to, one, complete the dose escalation segment of our phase one and two programs and define a recommended phase two dose or RP2D. Secondly, engage with the FDA on the pivotal trial design under construction. Number three, work with key external clinical experts on the design and conduct of this trial, including the Gynecologic Oncology Group, or GOG, and the European Network for Gynecologic Oncology Trials, or NGOT. Our plan is to conduct the registration trial as part of our ongoing collaboration with both of these very prestigious groups. We intend to provide more information on each of these steps over the next few quarters. As you know, there are three early stage studies underway in the neurazocyclic program, including monotherapy and combination trials. Given Neuradicyclid's multi-kinase mechanism of action, we have conducted our dose escalation studies very carefully. While Victor will summarize the status of these studies based on the clinical and biological target engagement and the acceptable overall safety we are observing, we have decided to dose escalate to at least one more dosing cohort to fully evaluate the safety profile of Nuraziciclib and achieve the optimal recommended phase two dose. As a result of the phase one, two program, Nuraziciclib may continue into the first quarter of 2024. We believe this is very good news for the program because it underscores the potential for Neurazociclib to have a differentiated safety profile and a wide therapeutic index. Changing gears, I would like to touch briefly on our second program, that is Regocertib. As you know, in keeping with our focus on capital efficiency, We have been exploring the clinical utility of RegoCertib through a series of signal-finding, investigator-sponsored trials focused on solid tumor indications driven by RegoCertib's impact on one of two mechanisms. The first is the PLK1 pathway involved in scramus ocrossanoma complicating recessive dystrophic epidermolysis pilosa, and the second mutated KRAS protein seen in KRAS mutated non-small cell lung cancer in combination with checkpoint inhibitors. As outlined in our second quarter call, we are focused on mapping out a registration study plan for the ultra-rare indication of RdEB-associated squamous cell carcinoma. that we would define that as RDEB associated SCC in this call. We selected this to be the lead registration or indication based on the very impressive clinical responses we have seen to date in previously refractory patients and with the significant unmet medical need for this desperate patient population. As you know, we had a Type B meeting with the FDA in June. Based on this meeting and feedback from the agency, and as outlined in our second quarter call, we intend to develop a protocol for a registration or trial following interactions with the rare disease group at FDA in pursuit of an orphan designation for RdBev-associated squamous cells. We plan to provide an update on next steps in the first half of 2024. Looking ahead to the rest of this year and into 2024, we are focusing on achieving the following milestone. In the RASA cycle, we intend to, one, continue the dose escalation segment of the Phase 1-2 program, which may bring us into the first quarter of 2024, so we can add at least one more dosing cohort to this study. Number two, provide a readout on neurotic cycle safety and pharmacology in the first half of 2024, once we have completed the dose escalation studies. Number three, provide an update on our registration trial readiness over the next couple of quarters, including the definition of the recommended phase two dose, our engagement with the FDA and the pivotal trial design, and obtaining rare disease indication, orphan disease indication, and our work with internal, external clinical experts, including the GOG and NDI. Achievement of these milestones will also enable us to establish a solid foundation to expand the program to include other indications, such as breast cancer and ovarian cancer. For rego certum, As I just noted, in the first half of 2024, we continue to plan to provide an update on the next steps to obtain orphan drug designation and for the registration program. Before I hand the call over, I would like to warmly congratulate Victor, formerly taking on the role of Chief Medical Officer, and warmly welcome Nina Arroyo as Vice President of Global Medical Affairs Research and Development. Victor and I previously worked together at J&J, where he was instrumental in getting approval for some of the most revolutionary and impactful drugs in both supportive care and hematology oncology. Both of them are accomplished experts in their fields and bring significant and wide depth of experience in drug development. I believe Victor's extensive track record as a clinical researcher in drug development in oncology and MENA's unique medical affairs expertise in rare diseases and oncology will be instrumental to the company's success as we prepare the clinical plan and regulatory strategy for New Azacyclib and Regocertib. Now, I would like to turn the call over to Victor to provide some more details on the Narada Cyclic Program. Victor?
spk36: Thank you, Steve, and good afternoon, everyone. Today, I'd like to provide you with an update on the Narada Cyclic Phase 1-2 Program and touch briefly on our recent and upcoming medical meeting presentations. Starting with Narasacyclib, as you may recall, there are three studies in the Phase I-II program in advanced solid tumors in patients. There's a Phase I monotherapy dose escalation study underway with our partner, Hanex, in China. It's a phase one monotherapy dose escalation study underway at three centers in the U.S. A phase one, two combination dose escalation and dose expansion study, which is underway at six centers in the United States. This study is evaluating the combination of increasing narazacyclic doses and a fixed 2.5 milligram per day dose of the widely prescribed anti-estrogen agent letrozole. This study has been conducted in patients with LBG and other gynecological tumors who are undergoing second and third line treatment. As of November 13, 2023, we have dosed about 30 patients across the entire Phase 1-2 program. In the U.S. Phase 1 monotherapy study, we are dosing patients in the seventh cohort at 280 milligrams per day. In the phase one, two combination study, we are starting the second cohort at 200 milligrams per day of narazacyclib with 2.5 milligrams per day of letrozole and have identified patients who could enroll on the next cohort. Based on the data we have observed to date, we have three important initial observations. Number one, Narazacyclib is safe and well tolerated to date. I'd like to make two points about the emerging safety characteristics of Narazacyclib. First, based on the initial safety data, pharmacokinetic studies, it may be possible to dose Narazacyclib once daily without the need for time off during treatment. This is important because it may address the need for a three-week on and one-week off dosing strategy that is required for bone marrow recovery following treatment with the most commonly prescribed CDK4-6 inhibitors. We believe this is an important potential feature of Narazacyclib because the requirement for a three weeks on, one week off dosing strategy may also permit tumor cell proliferation in between dosing. Secondly, initial data from our dosing studies suggest that Narazacyclib may be able to avoid the difficult adverse event of diarrhea. We believe that these two distinctive characteristics may enable a wide dosing window that supports an excellent therapeutic index for narizocyclic. Number two, we're seeing target engagement based on the observation of grade one and two neutropenia in patients receiving a dose of at least 120 milligrams per day. Number three, we're seeing biological target engagement based on the results of the thymidine kinase assay at doses of 200 milligrams and above. As indicated by Steve, based on the good target engagement and overall safety that we are observing, we believe that it would be reasonable to dose escalate to at least one more dosing cohort in order to fully explore the safety profile of Narazacyclib and to enable us to achieve the optimal recommended Phase 2 dose. This will extend the Phase 1-2 program for Narazacyclib into the first quarter. I would like to echo Steve's comment that our decision to add at least one more dosing cohort to the dose escalation study is very good news for the program because it underscores the potential for narraza-cyclib to have a differentiated safety profile and wide therapeutic index. We expect to provide a readout on safety and pharmacology in the first half of 2024, once we've completed the dose escalation study. This approach will help define the optimal recommended phase two dose, and we believe it is also in keeping with the FDA guidance from Project Optimus for dose optimization prior to approval. Also in the third quarter, there were two medical meeting presentations related to our programs. This included presentation number one of clinical data affirming the potential for regocertib in RDEB-associated squamous cell carcinoma. which was made by our colleagues from the University Hospital in Salzburg, Austria, and Thomas Jefferson in Philadelphia. These data were presented as a late breaker at the European Academy of Dermatology and Venerology, or EADV. The second presentation of promising preclinical data in combination with the of narazacyclib in combination with ibrutinib in the treatment of sensitive and resistant metal cell lymphoma cell line was given at the European MCL or mental cell network lymphoma annual meeting. Each of these presentations underscore the biology and activity for Narazacyclib and Rigocetin. Looking ahead to December, we plan to present two additional preclinical abstracts. The first one is at San Antonio at the Breast Cancer Symposium, often called SABCS. One of our collaborators will present a poster titled Narazacyclib's differentiated targets and kinase inhibitory activity contribute to the enhanced inhibition of tumor growth in preclinical models. We have a second presentation at the American Society for Hematology, or ASH, where our collaborators will present a poster titled Narazacyclib, a differentiated CDK4-6 antagonist prolongs cell cycle arrest and metabolic reprogramming, enabling restoration of ibrutinib sensitivity in BTKI-resistant mental cell lymphoma. We will share more of these abstracts in the coming weeks. In closing, I am optimistic about our programs, our progress, and the outlook for RegoCyte and narazacyclib in 2024. For regocertib, the promising activity that we have observed in R-DEB-associated squamous cell cancer is distinct and could address a critical medical need for this ultra-rare condition. These data show plus its unique activity on PLK1 and KRAS pathways make Rigocertib a very interesting anti-cancer agent. Now that we have better defined the indications where we believe we'll be more likely to be successful based on its mechanism of action and studying cancers where these targets can be engaged by Rigocertib. For Narazacyclib, CDK4-6 inhibitors have substantially changed the face of cancer for the better. There is consistent positive clinical data on the class in endometrial cancer. In addition to target engagement, our program is showing acceptable initial safety, which could give Narazacyclib a unique profile. Based on our expansive large preclinical studies, we have defined a multi-kinase profile that could result in differentiated activity and the potential for broader clinical utility. These features are the cornerstone of my enthusiasm and optimism for Narazacycline. With that, I'll conclude my portion of the call and hand it off to Mark.
spk40: Thanks very much, Victor, and good afternoon, everyone. Ancanova closed the third quarter of 2023 with cash and cash equivalents of $25.2 million, compared to $38.8 million as of December 31st, 2022. Based on our current projections, we believe our current cash position will be sufficient to fund our ongoing clinical trials and business operations into the third quarter of 2024. Research and development expenses for the third quarter of 2023 were $2.5 million, compared to $3.6 million for the same period in 2022. General and administrative expenses for the third quarter of 2023 were $2.7 million, and this compares with $2.1 million for the same period in 2022. Net loss for the third quarter of 2023 was $4.7 million or 23 cents per share on 21 million weighted average shares outstanding. This compares with a net loss for the third quarter of 2022 of 5.4 million or 26 cents per share on 20.9 million weighted average shares outstanding. The change in net loss for the third quarter of 2023 compared with the same period in 2022 was primarily a result of the timing of manufacturing batch production and clinical trial expenses, partially offset by higher general and administrative costs related to our AGM in the 2023 period. From a corporate development perspective, we continue to actively engage in a range of discussions related to partnering opportunities to support the progression of our programs. With my financial review complete, I'll now hand the call back to Steve for his concluding remarks.
spk26: Thank you, Mark.
spk22: In closing, we are enthusiastic about the excellent progress that has been made for both Narada Cycle and Regal Certum in the third quarter. We look forward to building on that progress as we wrap up 2023. and begin the new year. Looking ahead, we are focused on achieving the following milestones. For our differentiated multi-kinase inhibitor neurazocyclic, we intend to, one, present two abstracts at the December important medical meetings. Two, continue the dose escalation segment of the phase one, two program, which may bring us into the first quarter of 2024. Three, provide a readout on neurodiscipline safety and pharmacology for the first half of 2024. Four, provide an update on our phase three readiness over the next couple of quarters, including definition of our recommended phase two dose, our engagement with the FDA on the PIV filtration trial design, and plans to work to continue our work with external clinical experts, including the Gynecological Oncology Group, GOG, and the European Network for Gynecological Oncology Trials, NGOT. Our plan is to conduct a registration trial as part of our ongoing collaboration with both of these groups. These milestones, will provide a strong foundation for the next steps for nerazocycline and L-geek with added potential indications, including breast cancer, ovarian cancer, and mantle cell lymphoma. For regocertum, our program has utilized an investigative trial strategy with several solid two-minute indications underway. Our main effort here is to remain focused on RDEV-associated squamous cell carcinoma, and we continue to plan to provide an update on the next steps to obtain orphan drug designation and a registrational program in the first half of 2024. In closing, I want to recognize diligent and dedicated work of our management team, employees, partners, and investigators. And most important, as well as the brave and dedicated patients who participate in our clinical trials and the investment of the investment community for the support of Onconova and our very important work. We look forward to updating you when I'll continue to progress. With that, we'll begin today's question and answer session. Operator?
spk33: Ladies and gentlemen, if you wish to register for a question for today's question and answer session, you will need to press star then the number one on your telephone. If your question has been answered and you wish to withdraw your request, you may do so by pressing the pound key. If you are using a speakerphone, please pick up your handset before entering your request.
spk26: One moment, please, for the first question.
spk33: Our first question comes from the line of Charles Xu from Guggenheim Parkers. Your line is now open.
spk09: Hi, everyone. This is Edward On for Charles Xu at Guggenheim. Maybe I have to start off with just a question on how the narizocyclib plus letrozole combination, how that trial is tracking, and maybe when we could see potential initial efficacy data. I think you talked about in the past for a data update at 4Q 2023, so I'm just wondering how you're thinking about that now.
spk26: Sure. Victor, would you like to take that?
spk36: Yes. Thank you for that question. Right now, we are still in the process of dose escalation. As both Steve and I mentioned, we are seeing a wider therapeutic index requiring us to go to patients to higher doses before we go into expansion mode. So this study will extend into 2024 as a result as well, along with the monotherapy study.
spk22: And just to add to what Victor said, I want to remind everybody that the approved CDK4-6 inhibitors were approved not on response, but a prolongation of progression-free survival and overall survival. The reason for that are CDK4-6 inhibitors are not cytotoxic drugs. They don't cause response. They prevent tumor proliferation, thus improvement, hopefully, in PFS and overall survival. which we anticipate seeing in our registration trial.
spk09: Great. And maybe just a follow-up question, if I can. On the monotherapy dose escalation, it sounds like you have both the neutropenia and the thiamidine kinase assay. I guess, how much room, at least on the PKPD characterization, do you think you have to keep escalating, do you think you still have sufficient room to gain efficacy by escalating further? How are you thinking about that?
spk36: Yes, ultimately to make a decision of whether we've reached an optimal dose for the phase two, we would look at a combination of the safety and the PK characteristics as well as the pharmacodynamic studies. You do raise a good, you do point out that since we might not see the same degree of neutropenia and diarrhea as some of the other CD4K inhibitors, we will be focusing on data coming from the PK including the tolerability, of course, but as well as pharmacodynamics. We have had to expand the last couple of cohorts, and usually when you see that, it would suggest that we are close to reaching what might be really... the optimal dose or the maximum tolerated dose.
spk33: Our next question comes from the line of Pau Demia from Lattenburg-Talman. Please go ahead.
spk07: Good afternoon, team. Thank you for taking my questions and providing helpful updates. I have Three questions on the rhizocyclic, and if I have time, I'll ask one more on our DEP program. My first question has two portions. First one is, how many patients are we expecting to see data from the safety portion of the study? And the second part of the question is following up on Edward's question. When do we expect to see any efficacy data? And given your comments, Steve, on the PFS versus response rates, When would you envision the data would mature to show any clinical activity on the PFS?
spk22: I'll give Victor a rest and take the second part of your question first, if I may, I hope. So without a control arm, you know, we can, you know, the PFS, I'm going to say palbo and letrozole and breast cancer, is 8.3 months. But we're not going to wait 8.3 months to see what the PFS will be as part of this phase one study. The purpose of the phase one is to just clearly establish what the recommended phase two dose should be and thus what the dose for our registration trial ultimately will be. And if our PFS is 12 months or 8 months or 10 months, whatever it may be, it's very hard to interpret that without a control army in this patient population. So the goal is really to just determine what the dose of neurazocycline will be in combination with letrozole for a registration trial, which clearly will have a control arm and thus be able to compare the combination of Neuronacyclin plus Netrizole's PFS to watch the control arm that the FDA will tell us that they accept. So we really may see some efficacy data if there is a response. And again, these are not cytotoxic drugs, but sometimes you will see tumor shrinkage, but more likely, Not more likely, the registration trial will be determined by both PFS and overall survival rather than response table. And I don't remember the first part of your question at all. I don't know if I answered it. Would you like to repeat it?
spk07: This was helpful. The first part was the safety portion of the study. How many patients? What are we going to see? Are we going to see any target engagement and other analysis as well?
spk35: Okay, Victor, I think you've had enough of a rest, so can you take that, please?
spk36: Yes. The dose escalation portion is driven by, of course, the number of patients that we ultimately enroll. So that is a variable number and we give an approximation of where we might end up. The phase two portion is slated to enroll up to 30 patients in that phase two aid portion.
spk07: Thank you, Victor. My next question is on the safety profile. So having not much or not high impact diarrhea or neutrophilia is new. And the information that you mentioned, taking the one week off portion in the clinical setting is also new information. What are the steps you need to take to remove that one week portion off? What are the discussions like with the agency? How are you going to move forward with that part?
spk36: Well, first off, we are still to have our discussions with the agency. Right now, what we observe in our setting is that we are dosing continuously. And as long as that safety is supported for continuous dosing, our recommended Phase 2 dose will include continuously. and that would provide the basis of the discussions that we hold with the agency subsequently. So right now we are not doing the three weeks on, one week on that some of the CDK4-6 inhibitors have to do. We are dosing continuously.
spk07: I see. That's very helpful. Thank you. I'll keep my R-DEP question. I'll drop in the queue to be mindful of the others. Thank you so much for answering my question.
spk33: You're welcome.
spk07: Thank you.
spk33: Our next question comes from Joe at Guinness with HC Wainwright. Your line is now open.
spk30: Hi, this is Josh. I'm for Joe. Thank you for the update. I had a question about the enrollment and how that's looking and the number of patients for the phase two study for rigorous surgeon in the TKI resistant KRAS non small cell lung cancer.
spk26: Victor.
spk36: Yes, since the last update, we enrolled three more patients in that study. We are looking to have an update in terms of outcomes subsequently once we obtain a report from the investigator.
spk30: Thank you. The NARESA CYCLID trial on solid tumors, are you seeing any specific solid tumor indications, like more of a certain kind, or has it been pretty uniform across the solid tumors for the monotherapy trial?
spk36: We have enrolled a truly diverse set of patients with solid tumors. tumors, and so there isn't a particular pattern in the monotherapy that I can describe as standing out. Our initial patients tended to be more on the GI, gastrointestinal type of tumors, but there really isn't anything that stands out as being unique in terms of the patient population we're seeing.
spk30: All right. Thank you. Thank you again for the update.
spk25: You're welcome.
spk33: Our next question comes from the line of Robert E. Moyer from Noble Capital Markets. Your line is now open.
spk32: Since you're going to be doing an additional cohort in the neurazocyclic solid tumors, what is your projected start date for phase two at this point?
spk22: Again, to give Victor a rest, I'll take that. That's a great question, Robert. If we see additional DLTs in 2023 at the 280 milligram cohort, we may be done. If not, Again, we may go into the first quarter to establish the recommended phase two dose. We can't meet with the agency until we know the dose of the registration trial because they will want to see the safety of that dose. So if we have to go into the first quarter of 24 to establish the recommended phase two dose and meet with the agency, we estimate that the registration trial would begin in first half 2024 in low-grade endometrial cancer.
spk32: Okay. And if there are no DLTs in the cohort to be added, would you add another second cohort in 2024?
spk22: It's always hard to predict these things, Robert. It depends on what we see regarding it. As Victor explained, we have a pharmacodynamic marker of In kinase marker, we already see engagement, and as we dose escalate, more engagement. We know we're engaging the kinase-involved stem cell proliferation. We see some mild neutropenia. It really depends. It also depends on the PK. Are we maxing out? As we dose escalate, is PK going up or is it staying at a maximum level? So there's no need to dose escalate. So all those things, as Victor alluded to, go into the decision. Are we done at 280? Meaning, do we have DLTs at 280, which means the recommended phase 2 dose would be 240? Are we seeing enough evidence that 280 is safe with target engagement with maximum PK to claim that 280 will be the recommended phase 2 dose? So it's easier to answer that question with data than it hypothetically, but I answered it to the best of my ability.
spk32: Okay, great.
spk26: Thank you very much.
spk33: Our next question comes from the line of James Malloy from Alliance Global Partners. The line is now open.
spk14: Hi, good afternoon. Thank you for taking my question. My question is on the Riga CERT-Tib, getting the orphan designation. I know that we discussed before some of the challenges on that. Can you walk through sort of the steps you have to take to get the rigor sort of orphan designation and how the clinical trial plan might look should you get that?
spk22: Sure. And Meena, as our R-DEV squamous cell expert and expert in rare diseases, would you like to take that question of how we introduce the concept of odd dead squamous cell to the orphan group at FDA?
spk26: Amina? Amina is calling in from the UK.
spk22: Perhaps the connection was lost, so I'll take that. if I may, I think the goal, this is clearly an orphan disease, right? There are 60 to 100 patients per year that develop R-DEV in the U.S. Once squamous cell develops, the patients, 50% of the patients die within two and a half years. So clearly this is an orphan disease. Our goal at the orphan group is to explain to FDA why this is different than what I'll call spontaneous squamous cell. For instance, sun-damaged squamous cell. And it's different because, one, our dead squamous cell develops in late teenage years, early 20s. Sun-damaged squamous cell develops in the elderly. Some damaged squamous cells have a very good prognosis, usually removed surgically, and that's the end of the therapy required. R-DEB squamous cell is a very aggressive disease, as I just mentioned. And the cynical known that differentiates spontaneous squamous cell from R-DEB squamous cell is the fact that squamous cell complicating R-DEB has a mutation of the collagen 7 gene, which spontaneous squamous cell does not have. So our goal at the orphan group is to explain why this disease, R-deb squamous cell, is different in common squamous cell, which in fact is not by their definition an orphan disease, but clearly R-deb squamous cell is, and our goal is to interact with the agency to explain in greater detail what I just said.
spk05: Apologies, my line dropped. Thank you for answering that.
spk41: I've got no further things to add apart from... Hello. We've also presented last month at the EADV meeting as a late-breaking abstract, and we'll be taking learnings from the initial patient experience and moving that into the clinical development registrational program as well, and into discussion. So in addition to the discussion we've mentioned about the orphan drug designation, we'll be also doing that. Apologies, my line dropped there.
spk22: But Mina did sound so much informed than I did, only based on accents in my view.
spk14: Thank you. Thank you very much for that. I guess the one follow-up question will be, is it more sort of a check various boxes, or do you have to go make a presentation and sort of pitch them on the disease, or is it just kind of a form to fill out? How does that sort of mechanically work?
spk22: We'll basically do it any way the orphan designation group wants us to, but hopefully it'll be a chance for an interaction with them. We think that's much more valuable. The FDA orphan group will make that call. We will request a face-to-face meeting. My understanding is they're doing most of these virtually, and they may just respond to a written call. briefing book on why we believe we deserve law enforcement information.
spk26: It's up to you. Thank you for taking the question.
spk33: I'm showing no further questions in the queue. Ladies and gentlemen, thank you for your participation in today's conference call. This concludes today's event. You may now disconnect.
spk16: Thank you. Hello. Thank you. Thank you. music music
spk33: Ladies and gentlemen, thank you for standing by. Welcome to Onconova Therapeutics third quarter 2023 financial results and business update conference call. At this time, all participants are in the listen only mode. Following management's prepared remarks, we will hold a question and answer session. To ask a question at that time, please press star followed by number one on your touchtone phone. If anyone has a difficulty hearing the conference, please press star zero for operator assistance. As a reminder, this call is being recorded today, November 14, 2023. At this time, I would like to turn the call over to Bruce Mantle of Lifestyle Advisors.
spk02: Thank you, operator, and welcome everyone to Anca Nova's third 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 www.onconova.com. Following my introduction, we will hear from Onconova's President and CEO, Dr. Steve Fruchman, Chief Medical Officer, Dr. Victor Moyo, and Chief Operating Officer and Chief Financial Officer, Mark Guerin. Ankanova's VP of Global Medical Affairs and Research and Development, Mina Arora, will also be available during a 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 Frothman.
spk22: Thanks, Bruce, and thanks to everyone who is joining us today for this call. I'll open by saying that Onconova has made excellent progress in the third quarter of 2023. During the call today, our Chief Medical Officer, Dr. Victor Moyo, and our Chief Operating Officer and Chief Financial Officer, Mark Gurin, and I will provide you with an update on our lead program, Neurasa Cycle. Review the data from our recent scientific presentation. outline our upcoming milestones, provide a brief update on the RegoCerta development program, summarize our third quarter financial results and outlook on our cash runway, and of course, importantly, open the call for your questions. As you know, our mission means to develop novel proprietary products for patients with hard-to-treat cancer and with an unmet medical need. Starting with our lead program, our internal efforts are dedicated to basic preparations for nirazacyclin, our proprietary multi-kinase inhibitor of CD8.6, as well as other components for cell growth and DNA synthesis. The CDK4-6 class of inhibitory drugs has changed the face of cancer care in several indications, particularly in hormone receptor positive to negative metastatic breast cancer. Mirazic cyclin, was designed by Ankanova scientists as a potent next generation entrance into this multi-billion dollar drug class. In addition to its multi-kinase activity, we believe Nerazociclib may be differentiated from the other approved CDK4-6 inhibitors because of the potential. for an improved tolerability profile, and based on our preclinical studies, improved efficacy as well. The ability to act on targets beyond CDK4 and 6 may lower the risk of drug resistance faced by other CDK4-6 inhibitors. Our expansive preclinical studies have helped to define Nerazacyclib's ability to impact on additional vital targets involved in cell signaling and cancer survival, including the proteins ARC5, also known as NUAC1, CSF1R, and BUB1. All important in how cancer establishes its presence sites of metastatic disease, as well as proliferation of the cancer cells. We have selected low-grade endometrial cancer to be our lead registration indication for Neurasocycline in combination with the hormone therapy Letrozole. We believe this is the right choice in endometrial cancer for two main reasons. Number one, the proposed registration or trial has a high technical and regulatory success, probability of success. Publication of positive studies with other CDK4 and 6 inhibitors and letrozole combinations and compendia data indicating off-label use support the potential for a high probability of technical success. These data and the lack of an approved label underscore the unmet medical need and support the potential for high regulatory success. The second reason is the initial data from our dose ranging studies suggest The Razocyclic has the potential to be safer than the other DDK4-6 approved inhibitors with a wide dosing window that supports an excellent therapeutic index. Note that during our call today, we may use the acronym ALGEEC to describe this indication in endometrial cancer. To be registrational trial ready, we plan to, one, complete the dose escalation segment of our phase one and two programs and define a recommended phase two dose or RP2D. Secondly, engage with the FDA on the pivotal trial design under construction. Number three, work with key external clinical experts on the design and conduct of this trial, including the Gynecologic Oncology Group, or GOG, and the European Network for Gynecologic Oncology Trials, or NGOT. Our plan is to conduct the registration trial as part of our ongoing collaboration with both of these very prestigious groups. We intend to provide more information on each of these steps over the next few quarters. As you know, there are three early stage studies underway in the neurazocyclic program, including monotherapy and combination trials. Given Neurazacycline's multi-kinase mechanism of action, we have conducted our dose escalation studies very carefully. While Victor will summarize the status of these studies based on the clinical and biological target engagement and the acceptable overall safety we are observing, we have decided to dose escalate to at least one more dosing cohort to fully evaluate the safety profile of Nuraziciclib and achieve the optimal recommended phase two dose. As a result of the phase one, two program, Nuraziciclib may continue into the first quarter of 2024. We believe this is very good news for the program because it underscores the potential for Neurazociclib to have a differentiated safety profile and a wide therapeutic index. Changing gears, I would like to touch briefly on our second program, that is Regocertib. As you know, in keeping with our focus on capital efficiency, We have been exploring the clinical utility of RegoCertib through a series of signal-finding, investigator-sponsored trials focused on solid tumor indications driven by RegoCertib's impact on one of two mechanisms. The first is the PLK1 pathway involved in scramus ocrossanoma complicating recessive dystrophic epidermolysis pilosa, and the second mutated KRAS protein seen in KRAS mutated non-small cell lung cancer in combination with checkpoint inhibitors. As outlined in our second quarter call, we are focused on mapping out a registration study plan for the ultra-rare indication of RdEB-associated squamous cell carcinoma. that we would define that as RDEB associated SCC in this call. We selected this to be the lead registration or indication based on the very impressive clinical responses we have seen to date in previously refractory patients and with the significant unmet medical need for this desperate patient population. As you know, we had a Type B meeting with the FDA in June. Based on this meeting and feedback from the agency, and as outlined in our second quarter call, we intend to develop a protocol for a registration or trial following interactions with the rare disease group at FDA in pursuit of an orphan designation for RdBev-associated squamous cells. We plan to provide an update on next steps in the first half of 2024. Looking ahead to the rest of this year and into 2024, we are focusing on achieving the following milestone. In the RASA cycle, we intend to, one, continue the dose escalation segment of the Phase 1-2 program, which may bring us into the first quarter of 2024, so we can add at least one more dosing cohort to this study. Number two, provide a readout on neurotic cycle safety and pharmacology in the first half of 2024, once we have completed the dose escalation studies. Number three, provide an update on our registration trial readiness over the next couple of quarters, including the definition of the recommended phase two dose, our engagement with the FDA and the pivotal trial design, and obtaining rare disease indication, orphan disease indication, and our work with internal, external clinical experts, including the GOG and NDI. Achievement of these milestones will also enable us to establish a solid foundation to expand the program to include other indications, such as breast cancer and ovarian cancer. For rego certum, As I just noted, in the first half of 2024, we continue to plan to provide an update on the next steps to obtain orphan drug designation and for the registration program. Before I hand the call over, I would like to warmly congratulate Victor, formerly taking on the role of Chief Medical Officer, and warmly welcome Nina Arroyo as Vice President of Global Medical Affairs Research and Development. Victor and I previously worked together at J&J, where he was instrumental in getting approval for some of the most revolutionary and impactful drugs in both supportive care and hematology oncology. Both of them are accomplished experts in their fields and bring significant and wide depth of experience in drug development. I believe Victor's extensive track record as a clinical researcher in drug development in oncology and MENA's unique medical affairs expertise in rare diseases and oncology will be instrumental to the company's success as we prepare the clinical plan and regulatory strategy for New Azacyclib and Regocertib. Now, I would like to turn the call over to Victor to provide some more details on the Narazacyclib program. Victor?
spk36: Thank you, Steve, and good afternoon, everyone. Today, I'd like to provide you with an update on the Narazacyclib Phase 1-2 program and touch briefly on our recent and upcoming medical meeting presentations. Starting with Narasacyclib, as you may recall, there are three studies in the Phase I-II program in advanced solid tumors in patients. There's a Phase I monotherapy dose escalation study underway with our partner, Hanex, in China. is a phase one monotherapy dose escalation study underway at three centers in the U.S. A phase one, two combination dose escalation and dose expansion study, which is underway at six centers in the United States. This study is evaluating the combination of increasing narazacyclic doses and a fixed 2.5 milligram per day dose of the widely prescribed anti-estrogen agent letrozole. This study has been conducted in patients with LBG and other gynecological tumors who are undergoing second and third line treatment. As of November 13, 2023, we have dosed about 30 patients across the entire Phase I-II program. In the U.S. Phase I monotherapy study, we are dosing patients in the seventh cohort at 280 milligrams per day, In the phase one, two combination study, we are starting the second cohort at 200 milligrams per day of narazacycline with 2.5 milligrams per day of letrozole and have identified patients who could enroll on the next cohort. Based on the data we have observed to date, we have three important initial observations. Number one, Narazacyclib is safe and well tolerated to date. I'd like to make two points about the emerging safety characteristics of Narazacyclib. First, based on the initial safety data, pharmacokinetic studies, it may be possible to dose Narazacyclib once daily without the need for time off during treatment. This is important because it may address the need for a three-week on and one-week off dosing strategy that is required for bone marrow recovery following treatment with the most commonly prescribed CDK4-6 inhibitors. We believe this is an important potential feature of Narazacyclib because the requirement for a three weeks on, one week off dosing strategy may also permit tumor cell proliferation in between dosing. Secondly, initial data from our dosing studies suggest that Narazacyclib may be able to avoid the difficult adverse event of diarrhea. We believe that these two distinctive characteristics may enable a wide dosing window that supports an excellent therapeutic index for Narasal cyclic. Number two, we're seeing target engagement based on the observation of grade one and two neutropenia in patients receiving a dose of at least 120 milligrams per day. Number three, we're seeing biological target engagement based on the results of the thymidine kinase assay at doses of 200 milligrams and above. As indicated by Steve, based on the good target engagement and overall safety that we are observing, we believe that it would be reasonable to dose escalate to at least one more dosing cohort in order to fully explore the safety profile of Narazacyclib and to enable us to achieve the optimal recommended Phase 2 dose. This will extend the Phase 1-2 program for Narazacyclib into the first quarter. I would like to echo Steve's comment that our decision to add at least one more dosing cohort to the dose escalation study is very good news for the program because it underscores the potential for narraza-cyclib to have a differentiated safety profile and wide therapeutic index. We expect to provide a readout on safety and pharmacology in the first half of 2024, once we've completed the dose escalation study. This approach will help define the optimal recommended phase two dose, and we believe it is also in keeping with the FDA guidance from Project Optimus for dose optimization prior to approval. Also in the third quarter, there were two medical meeting presentations related to our programs. This included presentation number one of clinical data affirming the potential for regocertib in RDEB-associated squamous cell carcinoma. which was made by our colleagues from the University Hospital in Salzburg, Austria, and Thomas Jefferson in Philadelphia. These data were presented as a late breaker at the European Academy of Dermatology and Venerology, or EADV. The second presentation of promising preclinical data in combination with the of narazacyclib in combination with ibrutinib in the treatment of sensitive and resistant metal cell lymphoma cell line was given at the European MCL or mental cell network lymphoma annual meeting. Each of these presentations underscore the biology and activity for Narazacyclib and Rigocetin. Looking ahead to December, we plan to present two additional preclinical abstracts. The first one is at San Antonio at the Breast Cancer Symposium, often called SABCS. One of our collaborators will present a poster titled Narazacyclib's differentiated targets and kinase inhibitory activity contribute to the enhanced inhibition of tumor growth in preclinical models. We have a second presentation at the American Society for Hematology, or ASH, where our collaborators will present a poster titled Narazacyclib, a differentiated CDK4-6 antagonist prolongs cell cycle arrest and metabolic reprogramming, enabling restoration of ibrutinib sensitivity in BTKI-resistant mental cell lymphoma. We will share more of these abstracts in the coming weeks. In closing, I am optimistic about our programs, our progress, and the outlook for regocytes and narazacyclib in 2024. For regocertib, the promising activity that we have observed in RDEB-associated squamous cell cancer is distinct and could address a critical medical need for this ultra-rare condition. These data show plus its unique activity on PLK1 and KRAS pathways make Rigocertib a very interesting anti-cancer agent. Now that we have better defined the indications where we believe we'll be more likely to be successful based on its mechanism of action and studying cancers where these targets can be engaged by Rigocertib. For Narazacyclib, CDK4-6 inhibitors have substantially changed the face of cancer for the better. There is consistent positive clinical data on the class in endometrial cancer. In addition to target engagement, our program is showing acceptable initial safety, which could give Narazacyclib a unique profile. Based on our expansive large preclinical studies, we have defined a multi-kinase profile that could result in differentiated activity and the potential for broader clinical utility. These features are the cornerstone of my enthusiasm and optimism for Narazacycline. With that, I'll conclude my portion of the call and hand it off to Mark.
spk40: Thanks very much, Victor, and good afternoon, everyone. Ancanova closed the third quarter of 2023 with cash and cash equivalents of $25.2 million, compared to $38.8 million as of December 31st, 2022. Based on our current projections, we believe our current cash position will be sufficient to fund our ongoing clinical trials and business operations into the third quarter of 2024. Research and development expenses for the third quarter of 2023 were $2.5 million, compared to $3.6 million for the same period in 2022. General and administrative expenses for the third quarter of 2023 were $2.7 million, and this compares with $2.1 million for the same period in 2022. Net loss for the third quarter of 2023 was $4.7 million or 23 cents per share on 21 million weighted average shares outstanding. This compares with a net loss for the third quarter of 2022 of 5.4 million or 26 cents per share on 20.9 million weighted average shares outstanding. The change in net loss for the third quarter of 2023 compared with the same period in 2022 was primarily a result of the timing of manufacturing batch production and clinical trial expenses, partially offset by higher general and administrative costs related to our AGM in the 2023 period. From a corporate development perspective, we continue to actively engage in a range of discussions related to partnering opportunities to support the progression of our programs. With my financial review complete, I'll now hand the call back to Steve for his concluding remarks.
spk26: Thank you, Mark.
spk22: In closing, we are enthusiastic about the excellent progress that has been made for both Narada Cycle and Regal Certum in the third quarter. We look forward to building on that progress as we wrap up 2023. and begin the new year. Looking ahead, we are focused on achieving the following milestones. For our differentiated multi-kinase inhibitor neurazocyclic, we intend to, one, present two abstracts at the December important medical meetings. Two, continue the dose escalation segment of the phase one, two program, which may bring us into the first quarter of 2024. Three, provide a readout on neurodiscipline safety and pharmacology for the first half of 2024. Four, provide an update on our phase three readiness over the next couple of quarters, including definition of our recommended phase two dose, our engagement with the FDA on the PIMP filtration trial design, and plans to work to continue our work with external clinical experts, including the Gynecological Oncology Group, GOG, and the European Network for Gynecological Oncology Trials, NGOT. Our plan is to conduct a registration trial as part of our ongoing collaboration with both of these groups. These milestones will provide a strong foundation for the next steps for nerazocycline and L-geek with added potential indications, including breast cancer, ovarian cancer, and mantle cell lymphoma. For regocertum, our program has utilized an investigative trial strategy with several solid two-minute indications underway. Our main effort here is to remain focused on RDEV-associated squamous cell carcinoma, and we continue to plan to provide an update on the next steps to obtain orphan drug designation and a registrational program in the first half of 2024. In closing, I want to recognize diligent and dedicated work of our management team, employees, partners, and investigators. And most important, as well as the brave and dedicated patients who participate in our clinical trials and the investment of the investment community for the support of Onconova and our very important work. We look forward to updating you when I'll continue to progress. With that, we'll begin today's question and answer session. Operator?
spk33: Ladies and gentlemen, if you wish to register for a question for today's question and answer session, you will need to press star, then the number one on your telephone. If your question has been answered and you wish to withdraw your request, you may do so by pressing the pound key. If you are using a speakerphone, please pick up your handset before entering your request. One moment, please, for the first question. Our first question comes from the line of Charles Xu from Guggenheim Parkers. Your line is now open.
spk09: Hi, everyone. This is Edward On for Charles Xu at Guggenheim. Maybe I have to start off with just a question on how the narizocyclib plus letrozole combination, how that trial is tracking, and maybe when we could see potential initial efficacy data. I think you talked about in the past for a data update at 4Q 2023, so I'm just wondering how you're thinking about that now.
spk26: Sure. Victor, would you like to take that?
spk36: Yes. Thank you for that question. Right now, we are still in the process of dose escalation. As both Steve and I mentioned, we are seeing a wider therapeutic index requiring us to go to patients to higher doses before we go into expansion mode. So this study will extend into 2024 as a result as well, along with the monotherapy study.
spk22: And just to add to what Victor said, I want to remind everybody that the approved CDK4-6 inhibitors were approved not on response, but a prolongation of progression-free survival and overall survival. The reason for that are CDK4-6 inhibitors are not cytotoxic drugs. They don't cause response. They prevent tumor proliferation, thus improvement, hopefully, in PFS and overall survival. which we anticipate seeing in our registration trial.
spk09: Great. And maybe just a follow-up question, if I can. On the monotherapy dose escalation, it sounds like you have both the neutropenia and the thiamidine kinase assay. I guess, how much room, at least on the PKPD characterization, do you think you have to keep escalating? Do you think you still have... sufficient room to gain efficacy by escalating further? How are you thinking about that?
spk36: Yes, ultimately, to make a decision of whether we've reached an optimal dose for the phase two, we would look at a combination of the safety and the PK characteristics as well as the pharmacodynamic studies. You do raise a good, you do point out that since we might not see the same degree of neutropenia and diarrhea as some of the other CD4K inhibitors, we will be focusing on data coming from the PK including the tolerability, of course, but as well as pharmacodynamics. We have had to expand the last couple of cohorts, and usually when you see that, it would suggest that we are close to reaching what might be really... the optimal dose or the maximum tolerated dose.
spk33: Our next question comes from the line of Paola Demir from Lattenburg-Talman. Please go ahead.
spk07: Good afternoon, team. Thank you for taking my questions and providing helpful updates. I have Three questions on the results, and if I have time, I'll ask one more on our DEP program. My first question has two portions. First one is, how many patients are we expecting to see data from the safety portion of the study? And the second part of the question is following up on Edward's question. When do we expect to see any efficacy data? And given your comments, Steve, on the PFS versus response rates, When would you envision the data would mature to show any clinical activity on the PFS?
spk22: I'll give Victor a rest and take the second part of your question first, if I may, I hope. So without a control arm, you know, we can, you know, the PFS, I'm going to say palbo and letrozole and breast cancer, is 8.3 months. But we're not going to wait 8.3 months to see what the PFS will be as part of this phase one study. The purpose of the phase one is to just clearly establish what the recommended phase two dose should be and thus what the dose for our registration trial ultimately will be. And if our PFS is 12 months or 8 months or 10 months, whatever it may be, it's very hard to interpret that without a control army in this patient population. So the goal is really to just determine what the dose of neurazocycline will be in combination with letrozole for a registration trial, which clearly will have a control arm and thus be able to compare the combination of Neuronocycline plus Netrizole's PFS to watch the control arm that the FDA will tell us that they accept. So we really may see some efficacy data if there is a response. And again, these are not cytotoxic drugs, but sometimes you will see tumor shrinkage, but more likely, Not more likely, the registration trial will be determined by both PFS and overall survival rather than response table. And I don't remember the first part of your question at all. I don't know if I answered it. Would you like to repeat it?
spk07: This was helpful. The first part was the safety portion of the study. How many patients? What are we going to see? Are we going to see any target engagement and other analysis as well?
spk22: Okay, Victor, I think you've had enough of a rest, so can you take that, please?
spk36: Yes. The dose escalation portion is driven by, of course, the number of patients that we ultimately enroll. So that is a variable number and we give an approximation of where we might end up. The phase two portion is slated to enroll up to 30 patients in that phase two aid portion.
spk07: Thank you, Victor. My next question is on the safety profile. So having not much or not high impact diarrhea or neutrophilia is new. And the information that you mentioned, taking the one week off portion in the clinical setting is also new information. What are the steps you need to take to remove that one week portion off? What are the discussions like with the agency? How are you going to move forward with that part?
spk36: Well, first off, we are still to have our discussions with the agency. Right now, what we observe in our setting is that we are dosing continuously. And as long as that safety is supported for continuous dosing, our recommended Phase 2 dose will include continuously. are dosing and that would provide the basis of the discussions that we hold with the agency subsequently. So right now we are not doing the three weeks on, one week on that some of the CDK4-6 inhibitors have to do. We are dosing continuously.
spk07: I see. That's very helpful. Thank you. I'll keep my R-DEP question. I'll drop in the queue to be mindful of the others. Thank you so much for answering my question.
spk24: You're welcome. Thank you.
spk33: Our next question comes from Joe at Guinness with HC Wainwright. Your line is now open.
spk30: Hi, this is Josh. I'm for Joe. Thank you for the update. I had a question about the enrollment and how that's looking and the number of patients for the phase two study for rigorous surgeon in the TKI resistant KRAS non small cell lung cancer.
spk26: Victor.
spk36: Yes, since the last update, we enrolled three more patients in that study. We are looking to have an update in terms of outcomes subsequently once we obtain a report from the investigator.
spk30: All right, thank you. The NARESA CYCLID trial on solid tumors, are you seeing any specific solid tumor indications, like more of a certain kind, or has it been pretty uniform across the solid tumors for the monotherapy trial?
spk36: We have enrolled a truly diverse set of patients with solid tumors. tumors, and so there isn't a particular pattern in the monotherapy that I can describe as standing out. Our initial patients tended to be more on the GI, gastrointestinal type of tumors, but there really isn't anything that stands out as being unique in terms of the patient population we're seeing.
spk30: Okay. All right. Thank you.
spk26: Thank you again for the update.
spk25: You're welcome.
spk33: Our next question comes from the line of Robert E. Moyer from Noble Capital Markets. Your line is now open.
spk32: Since you're going to be doing an additional cohort in the neurazocyclic solid tumors, what is your projected start date for phase two at this point?
spk22: Again, to give Victor a rest, I'll take that. That's a great question, Robert. If we see additional DLTs in 2023 at the 280 milligram cohort, we may be done. If not, Again, we may go into the first quarter to establish the recommended phase two dose. We can't meet with the agency until we know the dose of the registration trial because they will want to see the safety of that dose. So we have to go into the first quarter of 24 to establish the recommended phase two dose and meet with the agency. We estimate that the registration trial would begin in first half 2024 in low-grade endometrial cancer.
spk32: Okay. And if there are no DLTs in the cohort to be added, would you add another second cohort in 2024?
spk22: It's always hard to predict these things, Robert. It depends on what we see regarding it. As Victor explained, we have a pharmacodynamic marker of In kinase marker, we already see engagement, and as we dose escalate, more engagement. We know we're engaging the kinase-involved stem cell proliferation. We see some mild neutropenia. It really depends. It also depends on the PK. Are we maxing out? As we dose escalate, is PK going up or is it staying at a maximum level? So there's no need to dose escalate. So all those things, as Victor alluded to, go into the decision. Are we done at 280? Meaning, do we have DLTs at 280, which means the recommended phase 2 dose would be 240? Are we seeing enough evidence that 280 is safe with target engagement with maximum PK to claim that 280 will be the recommended phase 2 dose? So it's easier to answer that question with data than it hypothetically, but I answered it to the best of my ability.
spk26: Okay, great. Thank you very much.
spk33: Our next question comes from the line of James Molloy from Alliance Global Partners. The line is now open.
spk14: Hi, good afternoon. Thank you for taking my question. My question is on the Riga Certib, getting the orphan designation. I know that we discussed before some of the challenges on that. Can you walk through sort of the steps you have to take to get the rigor sort of orphan designation and how the clinical trial plan might look should you get that?
spk22: Sure. And Meena, as our R-DEV squamous cell expert and expert in rare diseases, would you like to take that question of how we introduced the concept of odd dead squamous cell to the orphan group at FDA?
spk26: Amina? Amina's calling in from the UK.
spk22: Perhaps the connection was lost, so I'll take that. if I may, I think the goal, this is clearly an orphan disease, right? There are 60 to 100 patients per year that develop R-DEV in the U.S. Once squamous cell develops, the patients, 50% of the patients die within two and a half years. So clearly this is an orphan disease. Our goal at the orphan group is to explain to FDA why this is different than what I'll call spontaneous squamous cell. For instance, sun-damaged squamous cell. And it's different because, one, our dead squamous cell develops in late teenage years, early 20s. Sun-damaged squamous cell develops in the elderly. Some damaged squamous cells have a very good prognosis, usually removed surgically, and that's the end of the therapy required. R-DEB squamous cell is a very aggressive disease, as I just mentioned. And the cynical known that differentiates spontaneous squamous cell from R-DEB squamous cell is the fact that squamous cell complicating R-DEB has a mutation of the collagen 7 gene, which spontaneous squamous cell does not have. So our goal at the orphan group is to explain why this disease, R-deb squamous cell, is different in common squamous cell, which in fact is not by their definition an orphan disease, but clearly R-deb squamous cell is, and our goal is to interact with the agency to explain in greater detail what I just said.
spk05: Apologies, my line dropped. Thank you for answering that.
spk41: I've got no further things to add apart from... Hello. We've also presented last month at the EADB meeting as a late-breaking abstract, and we'll be taking learnings from the initial patient experience and moving that into the clinical development registrational program as well, and into discussion. So in addition to the discussion we've mentioned about the orphan drug designation, We'll be also doing that. Apologies, my line dropped there.
spk22: The meeting did sound so much informed than I did, only based on accents in my view.
spk14: Thank you. Thank you very much for that. I guess the one follow-up question will be, is it more sort of a check various boxes, or do you have to go make a presentation and sort of pitch them on the disease, or is it just kind of a form to fill out? How does that sort of mechanically work?
spk22: We'll basically do it any way the orphan designation group wants us to, but hopefully it'll be a chance for an interaction with them. We think that's much more valuable. The FDA orphan group will make that call. We will request a face-to-face meeting. My understanding is they're doing most of these virtually, and they may just respond to a written call. Briefing book on why we believe we deserve what?
spk33: It's up to you Thank you taking the question I'm sure you know further questions in the queue ladies and gentlemen Thank you for your participation and for today's conference call this concludes the base event you may now disconnect
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