Traws Pharma Inc (TRAW) 2021 Q2 法說會逐字稿

Ladies and gentlemen, thank you for standing by. Welcome to the Onconova Therapeutics Second Quarter 2021 Financial Results and Business Update Conference Call. (Operator Instructions) As a reminder, this call is being recorded today, August 12, 2021.

At this time, I would like to turn the call over to Avi Oler, Senior Vice President of Corporate Development and General Counsel. Please go ahead.

Thank you. Good afternoon, everyone, and welcome to Onconova's Second Quarter 2021 Financial Results and Business Update Conference Call. Earlier this afternoon, we issued a press release reporting our quarterly financial results and business progress. If you have not seen this press release, it is available in the Investors & Media section of our website at www.onconova.com.

On today's call, Dr. Steven Fruchtman, our President and CEO, will give a high-level overview on our recent progress and future outlook, and then Dr. Mark Gelder, our recently appointed a Chief Medical Officer, will introduce himself and provide a more detailed update on our clinical and scientific progress over the past few months. Finally, Mark Guerin, our Chief Financial Officer, will then review our second quarter financial results, and we'll move to the Q&A portion of the call.

Before we begin, I'd like to remind everyone that statements made during this conference call by management 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, it is my pleasure to turn the call over to Steve.

Thank you, Avi. Good afternoon, everyone, and thank you for joining us. As the COVID-19 pandemic continues to progress in the regions of our country and the world, we hope you and your loved ones are remaining safe. As has been the case throughout the pandemic, we remain committed to successfully navigating any challenges that may be posed to execute on our clinical and corporate objectives. Thanks to the talent and dedication of our employees, partners and investigators, we recently wrapped up a highly productive quarter and have achieved both clinical and corporate milestones since our last earnings call.

In our lead program, evaluating ON 123300, or simply called 123, we began dosing patients in our U.S. Phase I trial evaluating an everyday continuous dosing schedule. As a reminder, 123 is a novel multikinase inhibitor targeting CDK4 and 6 and additional kinases involved in tumor genesis, including ARK5, which is reported to be involved in cancer cell survival and the mechanisms of how cancer cells metastasize.

I'll let Dr. Mark Gelder speak in more detail about our 123 clinical development program and the importance of this Phase I study in a few minutes, but we'll say now that the trial is continuing to advance, and we remain on track to determine the recommended Phase II dose of 123 by the first half of next year. The recommended Phase II dose will be determined based on data from this clinical trial in the U.S. as well as the ongoing Phase I trial in China, evaluating there a 3 weeks on, 1 week off dosing schedule of 123. Both administration schemes under study are based on the 2 different dosing schemes of the FDA-approved CDK4/6 inhibitors in hormone receptor positive HER2-negative metastatic breast cancer.

Outside our lead program, we also saw a substantial progress in investigator-initiated programs, evaluating rigosertib in various indications. In the Phase I/II trial of rigosertib, in combination with a checkpoint inhibitor, nivolumab, all 3 dose-escalation cohorts defined in the current protocol have been completed without the maximum tolerated dose of oral rigosertib having been reached. Based on this positive finding regarding safety, a protocol amendment is being to allow for the evaluation of increased doses of rigosertib in combination with nivolumab. Preliminary data from the trial to date have also shown evidence of the combination's anticancer activity in the trial's challenging patient population. These preliminary data will be presented at the upcoming Third Annual RAS-Targeted Drug Development Summit taking place from September 21 through the 23 of 2021.

Support for this ongoing trial of rigosertib and nivolumab in lung cancer comes from preclinical studies demonstrating rigosertib's ability to reverse the immunosuppressive tumor microenvironment that frequently hampers the efficacy of checkpoint inhibitors. These studies were recently featured in a peer-reviewed publication from Vanderbilt University in the journal, Molecular Cancer. The published results provide a strong scientific rationale for combining rigosertib with checkpoint inhibitors. And based on these findings, an additional investigator-initiated trial designed to evaluate a rigosertib-checkpoint inhibitor combination in melanoma is undergoing final protocol evaluation.

In addition, we are studying rigosertib in a very rare tragic and invariably fatal condition called recessive dystrophic epidermolysis bullosa complicated by squamous cell carcinoma of the skin. There are no curative therapies for these patients and more recently, the standard of care for squamous cell carcinoma has been immuno-oncology agents, which in this setting have yielded disappointing results, because this disease is caused by loss of collagen 7, which anchors our skin cells in place and due to the lack of collagen 7, the skin denudes. And over time, most patients develop squamous cell carcinoma in their early 20s with overexpression of Polo-like Kinase 1. Based on drug screens for inhibitors of Polo-like Kinase 1, rigosertib was found to be the most potent inhibitor of polo-like kinase 1. An investigator-initiated study was started with a world's expert in this ultra-rare disease in Austria with a second site soon to be opened in the United Kingdom. The first patient has been dosed at the site in Austria, and we look forward to entering additional patients on this study and giving you follow-up.

Alongside our clinical and scientific accomplishments, we have also achieved a notable corporate milestone during the second quarter by having Dr. Mark Gelder join Onconova as our Chief Medical Officer. As Mark will tell you that himself in a few moments, our ability to recruit such a well-qualified and highly talented individual was due in part to the strength of our assets and the momentum we've generated in our clinical programs.

So with that, I'll now hand the call over to Dr. Gelder to provide you with some more detail on our programs and our overarching clinical development strategy. Mark?

So thanks, Steve, and thanks to all who are listening as well for joining us here today. For those of you on the call who don't yet know me, I joined Onconova as the company's Chief Medical Officer in the middle of June of this year. I am trained as an academic GYN oncologist and have more than 35 years of experience in drug development in hematology and oncology as well as medical affairs and medical marketing. I also have a fair degree of expertise in the development of kinase inhibitors as cancer therapeutics. One of the primary drivers behind my decision to join Onconova was indeed the potential I saw in the company's pipeline and, in particular, 123's clear differentiation compared to currently approved CDK4/6 inhibitors. 123's ability to simultaneously inhibit both the cell cycle and cellular metabolism through CDK and ARK5, respectively, positions it as a compelling approach for treating cancer patients that are refractory or have become resistant to current CDK4/6 inhibitors. I was also highly impressed by preclinical data showing that 123 exhibits superior CDK4 inhibition and improved on-target toxicity compared to palbociclib, which is currently the most widely prescribed CDK4/6 inhibitor.

123's potent kinase inhibition profile and [absolutely improved] safety profile based on mouse models with less neutropenia observed when directly compared to an approved CDK4/6 inhibitor may provide single-agent efficacy and facilitate continuous daily dose. This would be a significant development since palbociclib and another improved CDK 4/6 inhibitor, ribociclib, are prescribed in combination with an anti-estrogen in a 3 weeks on, 1 week off treatment schedule due to a lack of single-agent activity and issues of tolerability, including side effects related to neutropenia. We believe that continuous daily dose combined with 123's ability to potently inhibit CDK4/6 and other kinases may lead to improved efficacy compared to other approved CDK4/6 inhibitors.

Of note, to date, based on enrollment of the first 3 cohorts in the Phase I study in China, i.e., 40, 80 and 120 milligrams PO daily days 1 through 21, grade 3 or worse neutropenia has not been reported. As Steve mentioned, we are currently evaluating continuous daily dosing of 123 monotherapy in our ongoing Phase I study in the United States. We are pleased to have dosed the study's first patient this past quarter and have since completed dosing of the trial's first cohort, i.e., 40 milligrams PO daily. Following review of the safety data from the first cohort, the Safety Monitoring Committee approved moving to the second dosing cohort at 80 milligrams PO every day continuous dosing, and we are now enrolling patients in this cohort in the U.S. As a reminder, this trial is expected to include 3 U.S. sites and seeks to enroll patients with advanced cancers, including, but not limited to, hormone receptor positive HER2-negative metastatic breast cancer who are refractory to or have progressed on one of the currently approved CDK4/6 inhibitors.

We have also seen sustained progress in 123's other ongoing Phase I study, which is being conducted in China in collaboration with our partner, HanX Biopharmaceuticals. To date, the first 3 dosing cohorts in the Chinese trial have been accrued. Based on the data we have seen to date, 123 appears to be well tolerated as no dose-limiting toxicities have been observed. We expect findings from the ongoing trial in China to complement those from the U.S. trial I mentioned earlier, as the Chinese trial is dosing patients with 123 days 1 through 21 of a 28-day cycle. Based on the findings from these 2 studies, our aim is to establish the recommended dose and treatment regimen for future Phase II basket trial that will enroll patients with several different types of cancer that over-express the tyrosine kinases targeted by 123 in addition to CDK4 and 6.

Based on preclinical models, we have thus far identified at least 2 potential target indications for this future basket study. We plan to enroll approximately 36 hormone receptor positive HER2-negative metastatic breast cancer patients who are resistant to approved second-generation CDK4/6 inhibitors as well as patients diagnosed with advanced non-Hodgkin's lymphoma with a special interest in mantle cell lymphoma as well as studying indications with apparent clinical benefit demonstrated in the Phase I trial.

I should also point out that while the focus of the 123 program will be on CDK4/6 inhibitor-refractory patients, we do believe that there may be an opportunity to move to first-line therapy in the future given 123's best-in-class potential. Looking forward, we will continue to be guided by the results of clinical and preclinical studies as we finalize the design of our future basket trial. Based on the data we have seen to date, we are particularly excited about 123's potential to address unmet needs in hormone receptor positive HER2-negative breast cancer. We believe this indication also represents a large commercial opportunity as total worldwide sales of the 3 currently marketed CDK4/6 inhibitors exceeded $6 billion in 2019.

Shifting gears a bit, I would now like to discuss some progress being made with rigosertib, which is being advanced in multiple investigator-initiated program. Rigosertib is a RAS pathway modulator that has been shown to synergize with checkpoint inhibitors in preclinical studies. These studies were recently featured in a peer-reviewed publication out of Vanderbilt University. Data presented in the paper demonstrated the ability of rigosertib to reverse the immunosuppressive tumor microenvironment and promote the activation and tumor infiltration of anticancer immune cells by creating novel antigens such as CD40 to be expressed on the tumor cells. This is an important finding as immunosuppressive tumor microenvironment and the lack of immune cell infiltration often leads to checkpoint inhibitor resistance in patients.

When tested in combination with immune checkpoint blockade, rigosertib demonstrated synergistic anticancer activity and led to improved tumor growth inhibition and survival in a murine melanoma model that did not respond to immune checkpoint blockade alone or a clinically used combination of immune checkpoint blockade plus a BRAF and/or MEK inhibitor. These data demonstrate rigosertib's potential to address a critical unmet need by increasing the proportion of patients who respond to checkpoint inhibitor therapies. Based on these promising findings, an investigator-initiated study evaluating rigosertib in combination with the checkpoint inhibitor, pembrolizumab, more commonly known as KEYTRUDA, in patients with advanced malignant melanoma is currently under active review for finalization.

In addition to forming the basis for a potential melanoma trial, the recently published data also provides strong mechanistic support for the ongoing KRAS-mutated non-small cell lung cancer trial of rigosertib in combination with the checkpoint inhibitor, nivolumab, which is provided by Bristol-Myers Squibb and more commonly referred to as Opdivo. Through this trial, we are aiming to address a critical unmet need as KRAS mutations are the predominant genetic driver of non-small cell lung cancer, and there is currently a lack of effective treatment options for patients who fail to adequately respond to checkpoint inhibitor therapy. The objectives of this trial are to identify the recommended Phase II dose of this novel rigosertib-nivolumab doublet and to characterize its safety profile. Secondary objectives include the preliminary evaluation of efficacy via assessments of overall response rate, progression-free survival and overall survival.

Preliminary clinical efficacy and scientific correlates, such as the genotype of the various possible KRAS mutations and the immune status of the tumors, are also being investigated. I'm pleased to say that we continue to see steady progress in this study. The clinical data to date provide preliminary evidence of potential anticancer activity of the rigosertib-nivolumab combination and, as Steve mentioned earlier, show that the maximum tolerated dose of rigosertib in combination with nivolumab was not reached in the 3 cohorts of the trial's dose-escalation phase. That we have seen some preliminary evidence of anticancer activity as well as an acceptable safety profile is highly encouraging, particularly when you consider that patients enrolled in this trial have failed prior therapy with checkpoint inhibitors, cytotoxics, et cetera, making this an extremely challenging patient population. Based on these positive preliminary findings, a protocol amendment is currently being prepared that will allow for the evaluation of increased rigosertib doses in combination with the full dose of nivolumab recommended on its product label, i.e., 240 milligrams IV every 2 weeks.

In parallel, the trial continues to recruit patients as part of the expansion phase at the highest dose of oral rigosertib defined in the current protocol. Looking ahead, we expect preliminary data from the expansion cohort to be presented in late September and hope that the continued progression of this program will offer non-small cell lung cancer patients who have progressed following first-line therapy with a potential efficacious second-line treatment.

Moving on, I'd like to speak very briefly about the investigator-initiated trial evaluating rigosertib monotherapy in advanced squamous cell carcinoma associated with recessive, dystrophic epidermolysis bullosa. I'm pleased to say that this trial continues to progress as planned following the dosing of the first patient earlier in the second quarter. We look forward to its continued progress and hope that rigosertib will prove beneficial to this patient population who suffered with a tremendous unmet medical need.

Lastly, before handing the call off to Mark to talk about our financials, I'd like to emphasize that while we are very interested in the outcomes of the ongoing and potential investigator-initiated studies, we remain committed to preserving our primary focus and resources on our lead ON 123300 program.

And with that, I will now turn the call over to Mark Guerin for a discussion of our second quarter financial results. Mark?

Thanks, Mark, and good afternoon, everyone. I'll begin with a quick review of our second quarter expenses, and then I'll discuss our cash position and runway. Research and development expenses for the second quarter of 2021 were $1.9 million compared to $4.8 million for the second quarter of 2020. The decrease was primarily related to clinical development and consulting expenses related to our INSPIRE study in the 2020 period.

General and administrative expenses for the second quarter of 2021 were $2.9 million compared to $2.6 million for the second quarter of 2020. The increase here was primarily related to expenses for investor relations, proxy solicitation and fees related to our special meeting by proxy in the 2021 period.

We reported a net loss for the second quarter of 2021 of $4.2 million or $0.27 per share on 15.8 million weighted average shares outstanding. This compares with a net loss for the second quarter of 2020 of $7.4 million or $0.65 per share on 11.3 million weighted shares outstanding.

Cash and cash equivalents as of June 30, 2021, were $43.7 million compared to $19 million as of December 31, 2020. We believe that this cash position will be sufficient to fund our ongoing clinical trials and business operations for more than 18 months and through the achievement of significant milestones, including pursuing corporate development opportunities.

This completes my financial review. I'll now turn the call back to Steve.

Thank you very much, Mark. In summary, we have multiple key near-term milestones and value drivers ahead of us. One, the continued progression of our ON 123300 studies in the U.S. and China and the anticipated selection of a recommended Phase II dose in the first half of next year. Two, the presentation of preliminary data from the investigator-initiated Phase I/IIa study of the rigosertib-nivolumab combination therapy in refractory KRAS-mutated non-small cell lung cancer trial to be presented in late September. Three, finally, we continue to actively evaluate strategic licensing opportunities to enhance our product portfolio. As with all of our decisions, any decision we make on this front will be driven by science and the potential for clinical benefit in an indication with an unmet medical need.

So with that review of our clinical progress and our financial results, we'd like to open up the call now for questions. Operator?

(Operator Instructions) We have your first question from Dr. Etzer Darout with Guggenheim Securities.

Great. Congrats on the progress here. So the first question for me. Just wondered if you could provide any additional color on the ongoing China study for 123, maybe the types of patients being enrolled so far. And anything differentiating about the data beyond the lack of grade 3 plus neutropenia that you highlighted?

And then I guess secondly, anything further on the protocol amendment for rigosertib-nivolumab trial that's being prepared, maybe what doses may be explored? And any other changes that you may be making to the study design.

Thank you, Etzer. Dr. Gelder, would you like to take those 2 questions?

Sure, Steve. No, thank you. So the study with 123 in China, as we mentioned, we are currently enrolling the third cohort. So the first cohort was at 40 milligrams a day, days 1 through 21 of a 28-day cycle. Second was at 80. And this third cohort is at 120 milligrams. What I can tell you is that all 3 patients in the third cohort have been enrolled, the DLT period for the third patient has not yet been completed. And what the -- in terms of the tumor types that we're seeing, it's open to all solid tumors. They have seen a fair amount of -- well, they've seen a variety of different tumors, have seen breast cancer, have seen, I believe, colorectal cancer, have seen prostate cancer. So they're seeing the usual types of patients that you would expect in a Phase I trial that is open to all solid tumors.

In terms of the safety profile and what we're seeing, the tolerability so far seems to be very, very good. We have not seen any DLTs, and we have not seen any grade 3 or beyond neutropenia. We've seen a couple of patients who have had grade 1 or grade 2 neutropenia. The other side effects that we've seen have been low-grade fatigue, weakness, that sort of thing, but we have not seen anything to date that is a strike. Is there anything else I can tell you about the study in China?

No. Maybe if we could talk a little bit about the rigosertib protocol amendment and any changes there that you could kind of provide incremental color on?

Sure. So as you know, the rigosertib trial that's ongoing is -- and this is a combination study with rigosertib and nivolumab, it's in Stage 4 non-small cell lung cancer with KRAS mutations who have progressed on "standard of care." The original protocol called for 3 dose-escalation cohorts. And the first cohort was rigosertib 280 milligrams PO twice a day or BID. The second dosing cohort was 560 milligrams of rigosertib in the morning, 280-milligram mid-afternoon. And the third dosing cohort was 560 milligrams twice a day. And what I can tell you is that in the first and second cohort, there were no DLTs observed.

I should also mention that in all of these cohorts, in addition to the rigosertib, patients received nivolumab 240 milligrams IV every 2 weeks. In the first 2 cohorts, there were no DLTs observed. In the third dosing cohort, there was one DLT observed. It was grade 3 hyponatremia. As you know, hyponatremia is commonly observed in patients with non-small cell lung cancer, but has also been seen with rigosertib. And so based on a variety of data, I think appropriately, a decision was made that this was due to the rigosertib. But there was one DLT, an additional 3 patients were enrolled because it was a 3 plus 3 design, and there were no further DLTs observed. So the investigator went on and started enrolling 6 more patients at that dose level. And in -- because this is an ISS, an investigator-initiated study, the investigator really makes the decisions in terms of what he wants to do next in discussions with us and in discussions with the folks at Bristol-Myer because remember, Bristol-Myers Squibb providing the nivolumab. All of the parties concerned have said they would be interested in seeing further dose escalation.

So have we seen the protocol amendment yet? No, I have personally not seen a final copy of it in writing. That will be up to the PI of the study when he presents that to us. What do I anticipate? My suspicion is that this dose level 4 will probably be -- it will be an escalation of the rigosertib from 560 to 660, 760, probably 840 milligrams in the morning and 560 milligrams in the afternoon in combination with the nivolumab. And if he wants to go with dose level 5, that would then probably be 840 twice a day in combination with nivolumab. But again, I have not seen this yet. There have been some discussions, but I haven't seen it in writing. But do we anticipate that we are going to get an amendment for further dose escalations? Yes, we do. But Steven Fruchtman, did you have anything to add to that?

No Mark, thank you. Etzer, thank you. I think that is the anticipated based on the tablets that we are currently using is 280 milligrams, that's a 560 plus 280, that's how Mark came up with the 840 number. So probably next dose escalation will be 840 in the morning, 560 in the afternoon if there are no additional DLTs and the next will be probably 840 in the morning, 840 in the afternoon. We look forward to that amendment being completed.

We have your next question from Joe Pantginis with H.C. Wainwright.

This is Sara, on for Joe. My first question is, I'm just wondering how is the screening process currently going for your squamous cell carcinoma study in the recessive dystrophic epidermolysis patients. If you could just provide any color on how that process is being handled.

Mark?

Yes. So again, this is a investigator-initiated study that is currently open in Austria. What I can tell you is that a second site in the U.K. we anticipate will be opening in the near future. But the exact timing of that, I can't tell you for certain today. Additionally, a very similar study but separate ISS in this same population will open here in the United States shortly. And the screening is -- I mean, I can go through the screening criteria, inclusion-exclusion criteria, et cetera, for you. But the -- this is a population of patient with this very unfortunate disease who have developed biopsy-proven squamous cell carcinomas and who have been refractory to standard of care. And as you may or may not be aware, multiple different therapies have been tried over the ages for these patients, none of them to date have been very successful because of the fact that they have large areas of skin that are denuded, cytotoxic therapy is very risky in this population because of the fibrosis in webs, in the esophagus and limited ability to swallow pills and take things orally. Many of these patients have to receive medications intravenously. And the checkpoint inhibitors have not proven to be very effective in this population.

There are no large series with the checkpoint inhibitors in these populations. There are just some isolated case reports. But in talking with the investigator, the results have generally been somewhat discouraging. So they are very hopeful based on the preclinical work that they have done and the PLK1 over-expression seen in many, if not most or all of these tumors, they are very hopeful that they will see some activity with rigosertib. I'm not sure (inaudible) inclusion-exclusion criteria I can. But this is a very, very rare disease.

I think the answer to your question is when a patient is identified, they'll be put on the study. These are very rare patients, as Mark was saying, nothing works. Actually, it's proud -- but I shouldn't say this, but I will. Anybody wants to go on a weight loss program after eating, you can view pictures of these patients, it's very tragic. We hope to be able to help them.

Okay. Yes. That's really helpful. And then I had one quick follow-up question. You kind of touched on this briefly before, but regarding your 123 program, what's your communication strategy for the study in China? Do you have a certain number of patients that you'd want enrolled first before like fully disclosing your data set? Or can early responses in limited numbers also be shared? Or what's your -- yes, what's the strategy for this program in general?

Yes, sure. I'll take that one. So we have standing joint development meetings between Onconova and HanX to make sure that all the data, both for the U.S. patients, we review that data with them and we review the data put on the 123 protocol in China. My approach, my vote, I will do this as a consensus, is probably to wait for the recommended Phase II dose to be determined and then at a major medical meeting to present the data from the Phase I and to do it that way as opposed if we get a response to -- just to announce it, we probably would prefer completing the study, seeing what patients because as Mark -- Dr. Gelder said, we have diverse patient population. It's all -- there's many different cancer indications. So we probably will do it -- reveal the data at a major medical meeting.

We have your next question from Dr. Robert LeBoyer with NOBLE Capital.

I just had a quick question about the second cohort in the 123300 trial, if you could just discuss how many patients and what the timing of that data would be? You mentioned selection of dose in the second half, but if there's any data presentation or any other details you can give that would be helpful.

So I'll take that one as well. So the second cohort, as Mark said, is 80 -- I'm just making sure you're asking about ON 123300. So the second cohort was treated at 80 milligrams 3 out of 4 weeks. And that's the only thing we revealed in the public domain so far. And as I already said, rather than doing it per cohort, the third cohort has already been fully accrued, but we anticipate revealing the data from the entire study at a major medical meeting when we -- following reaching the recommended Phase II dose.

Okay. Great. And did you mention when the trial with rigosertib and KEYTRUDA might start accruing patients?

That trial, the protocol is being finalized. It needs the usual IRB approval. So once the protocol is finalized, which I -- we expect quite soon, it will be submitted to the IRB, the Vanderbilt IRB. I don't know if they meet every 2 weeks, every month. So following IRB approval, I think we look forward to the initiation of patients being put on to the protocol. It's hard to predict precisely. I would guess in the next few months as a guess.

I'm showing no further questions at this time. I'd like to turn it back to Steve Fruchtman for any closing remarks.

Thank you, everybody, for participating on today's update call. We look forward to executing on our business plan and to keep you appraised of all of our progress. We appreciate your continued interest in our programs. Thank you again, and have a great evening.

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