Imunon Inc (IMNN) 2020 Q2 法說會逐字稿

Good morning. My name is Cassidy, and I will be your operator today. At this time, I would like to welcome you all to Celsion's 2020 Second Quarter Financial Results Conference Call. (Operator Instructions)

At this time, I would like to turn the call over to Kim Golodetz. Please go ahead.

Thank you, and good morning, everyone. This is Kim Golodetz with LHA. Welcome to Celsion Corporation's conference call to discuss its second quarter 2020 financial results. As has been Celsion's practice and as noted by the operator, prepared remarks will be followed by a question-and-answer period. Today's conference call will be archived, and the telephone replay will be available beginning later today through August 28, 2020. The webcast will be available for the next 90 days on Celsion's website.

During this call, management will be making forward-looking statements regarding Celsion's expectations and projections about future events. Generally, forward-looking statements can be identified by terminologies such as expects, anticipates, believes or other similar expressions. These statements are based on current expectations and are subject to a number of risks and uncertainties, including those set forth in the company's periodic filings with the Securities and Exchange Commission. No forward-looking statements can be guaranteed, and actual results may differ materially from such statements.

In particular, there is significant uncertainty about the duration and contemplated impact of the COVID-19 pandemic. This means results could change at any time, and the contemplated impact of COVID-19 on Celsion's operations, financial results and outlook is a best estimate based on the information for today's discussion. I also caution that the content of this conference call is accurate only as of the date of the live broadcast, August 14, 2020. Celsion undertakes no obligation to revise or update comments made during this call, except as required by law.

With that said, I'd like to turn the call over to Michael Tardugno, Celsion's Chairman, CEO and President. Michael?

Well thank you, Kim. Good morning, everyone. It's always my pleasure to speak with you, particularly now. Joining me today is Jeffrey Church, our Executive Vice President and Chief Financial Officer, who will provide a review of Celsion's recent financial results in a few minutes. Also on the call for the Q&A and dialing in remotely is Dr. Nicholas Borys, our Executive Vice President and Chief Medical Officer.

We reported a great deal of news during the second quarter and recent weeks for both of our lead programs with much of it focused on ThermoDox, our Phase III OPTIMA Study for the treatment of newly diagnosed hepatocellular carcinoma or also known as primary liver cancer because we recently held a conference call to address the unexpected results suggesting futility from the DMC's second preplanned interim efficacy analysis. I'll touch on where we are with the OPTIMA study and our analysis and some brief comments later in this call.

But first, I'd like to focus on the spate of positive news that we've announced regarding the development of GEN-1, our gene mediated immunotherapy now being evaluated in the OVATION 2 study. Having successfully completed a Phase I run in, OVATION 2 has entered Phase II and is now recruiting patients who have been newly diagnosed with advanced ovarian cancer. I'm pleased to report that we initiated the Phase II portion of this trial in July, fully 5 months ahead of the schedule that we announced earlier this year.

Our plans for OVATION 2 include an aggressive recruitment program with 10 investigator sites currently active, 5 imminently active and 10 more being activated over the next few months, we anticipate completing enrollment of approximately 105 patients over the next 12 months or so. Additionally, we are strongly considering replacing 50% of the control arm, that's about 25 patients, using a propensity matched population of control patients from other randomized ovarian cancer studies. This novel synthetic control arm approach will reduce trial costs as well as the time to complete the enrollment.

The value, however, of the synthetic control arm goes beyond cost and time. As many of you know, recruiting patients into a randomized study is concerning for patients, for the most part, who are joining the trial in order to receive the investigational drug. But with only a 50-50 chance of this outcome, the patients in the control arm can be quite disappointed.

Now I'd like to review the trial, OVATION 2. And this is particularly for those of you who are new to Celsion. OVATION 2 is a 2 arm, one-to-one randomized study, 80% powered to show a 33% improvement in progression-free survival. PFS is its primary endpoint. As you know, it's being conducted as an open-label study, so we'll be able to provide clinical updates as they become available throughout the course of treatment. These updates will include overall response rates according to RECIST and surgical resection scores. Both are secondary endpoints in the study and both are prognostics for overall survival. So we'll have a pretty good idea of GEN-1's treatment effect as the trial progresses.

The study design calls for GEN-1 to be combined with neoadjuvant chemotherapy. Neoadjuvant chemotherapy is the current standard for -- standard of care for advanced disease among patients whose cancer burden is judged too great to be immediately surgically removed without related complications. Treatment of patients will be compared to a control arm of neoadjuvant chemotherapy alone. Neoadjuvant chemotherapy is designed to shrink the tumors and dry them up. These are tumors that are accompanied with a great deal of ascites or related fluid to dry them up. The goal is to improve the surgical outcome, and the real goal here is for an R0 resection, that being a virtually complete removal of all disease with no disease found in the surgical margins.

Following this debulking surgery, the patient will undergo 3 cycles of adjuvant chemotherapy and up to 9 weekly cycles of GEN-1 treatments if the patient has been randomized to the treatment arm. Our goal with this overall GEN-1 treatment regimen is to recruit a high level of immune system activity over a 6-month period, the result being a delay in progression. That's our expectation because we know clearly that progression portends a poor prognosis.

Now again, for those of you who may be new, I'd like to review GEN-1 technology and mechanism. GEN-1 is engineered using our proprietary TheraPlas technology platform. TheraPlas is a nonviral nanoparticle gene delivery system that provides a means to transfect cells with DNA plasmids coded for proteins of therapeutic value. Unlike viral vectors, those that are traditionally used for delivering DNA placement, so unlike viral vectors that can only be administered once, TheraPlas is not subject to the neutralizing activity of the patient's immune system. So the beauty of this technology is that it does not carry the risk of viral vectors, and it can be administered over and over again, making it ideal for titrating cancer treatments and particularly immunotherapy. The course of multiple treatments are typically required for effective results.

The first drug on this TheraPlas platform is GEN-1. GEN-1 incorporates a DNA plasmid coded for the pro-inflammatory protein or cytokine, interleukin 12, or IL-12. GEN-1 is administered local regionally into a body cavity, such as the abdomen for advanced ovarian cancer treatment. It's confined local regional activity avoids the systemic toxicity associated with the use of recombinant IL-12. Systemic toxicity is the reason why IL-12 cannot be administered intravenously and is not in widespread use. Our approach invented by our scientists in our research center in Huntsville, Alabama, provides an elegant solution that significantly improved IL-12's activity at the site of the tumor while mitigating any toxicities. So following administration, cell transfection is accomplished, resulting in a safe, persistent, durable, local effective secretion of IL-12 for up to 1 week.

I'll just make one last note about IL-12. It was first recognized in the 1980s at the NIH laboratory of Dr. Steven Rosenberg. It was then recognized as a potent immune system modulator. And by recruiting a robust immune response, it was well known to be an effective means to fight malignancy. GEN-1 is our amazing solution to the decades-old safety problem. It has the potential to provide a very powerful cancer therapeutic.

So where do we stand with the program? And why are we so encouraged? During the second quarter, we announced that the DSMB in its final recommendation, unanimously supported proceeding to Phase II with a higher dose of 100 milligrams per meter square. DSMB concluded that GEN-1's safety profile is satisfactory and that patients can be treated with up to 17 weekly doses during a course of treatment of about 6 months. And no dose-limiting toxicities were detected during this period. The results so far have been based on small numbers, I'll admit, but impressive nonetheless.

Let me give you an example of the 15 patients treated in Phase I, 9 were treated with GEN-1 at a dose of 100 milligrams per meter squared plus neoadjuvant chemotherapy and 6 were treated with neoadjuvant chemotherapy alone. And while all 15 had successful resections of their tumors, 7 out of 9 patients or 78% in the GEN-1 treatment arm had an R0 resection, which indicates, as I said earlier, a microscopically margin negative resection in which no gross or microscopic tumor remains in the surgical margins. This compares favorably to the control arm, where 3 of 6 patients, or 50%, hit an R0 resection.

In our earlier Phase I OVATION 1 study had a population of patients with the same inclusion criteria as the Phase I portion of the OVATION 2 study that I just spoke of. When we pool results from these 2 studies, the data suggests dose-dependent efficacy when combining GEN-1 with neoadjuvant chemotherapy. Though not statistically significant due to small numbers, these findings were reinforced with a significant improvement in progression-free survival when we compare study patients to a propensity score matched synthetic control arm of similar patients from prior studies. We talked about the synthetic control arm approach and the comparison that it can provide during our quarterly call in May.

And we reported, having done that, a hazard ratio of 0.53 or a doubling of time to progression. Small numbers again, but approaching statistical significance and particularly impressive when taking into account the supportive and previously published translational data. So tissue samples taken from our prior Phase I study, clearly demonstrating that GEN-1 is profoundly active in clinical data from our other Phase I experiences showing dose-dependent tumor responses. I think you can see with me, conclude with me the synthetic control arm comparison is very promising and a compelling basis from which to launch our Phase II trial.

I'd like to conclude on GEN-1 by saying that we are building a foundation for what could be a very important asset worldwide. Should GEN-1 continue to show efficacy that is being noted in our early work, I will -- I'd suggest that we have much to look forward to. Finally, I'll also note that we have received orphan drug designation from both the U.S. FDA and the European Medicines Agency, which, of course, enhances the value of GEN-1. In particular, orphan designation received from the EU earlier this year provides for 10 years market exclusivity. In the United States, similarly, orphan drug designation provides 7 years market exclusivity following NDA approval.

So before we turn to ThermoDox, I just want to reiterate what I said about our financials during our recent call and reassure you that we are taking appropriate steps to ensure that the company is well positioned regardless of the outcome of the OPTIMA study. As I said, we are -- we have begun to eliminate all nonessential ThermoDox expenses, including, unfortunately, some headcount reductions and expect to save some $8 million to $9 million over the next 18 months versus our budgets. Our plans will ensure that we have capital sufficient to complete enrollment of the OVATION study. We're looking forward to reporting periodically on this Phase II study as it progresses.

Now I'd like to turn to ThermoDox. We've -- a lot of work is going on at the company and through our advisers. We still do not have a complete picture, but we're working on it. Remember that ThermoDox is our heat sensitive liposomal formulation of doxorubicin for the treatment of primary liver cancer. In July, we reported that the independent data monitoring committee for the Phase III OPTIMA study recommended that the company should consider stopping the study, but they left the decision up to us.

This recommendation was made following the DMC's second preplanned interim safety and efficacy analysis. The DMC's analysis found that the prespecified boundary for stopping the trial for futility, that boundary is 0.900, that the futility boundary was crossed with an actual value of 0.903. However, the p-value of 0.524, essentially a flip of the coin, for this analysis provides a high level of uncertainty as to the actual hazard ratio value. Therefore, in an unusual and, I might say, an unprecedented step, the DMC left the final decision of whether to stop the study up to the company. As we've been reviewing the data, I'd say, in hindsight, there appears to be some wisdom to the DMC's recommendation but that -- yet the jury is still out.

Our review of the unblinded data is ongoing, and we recently provided an update disclosing that we will continue to follow patients for overall survival, noting that the unexpected and marginally cross-utility boundary suggested by the Kaplan-Meier analysis may be associated with a data maturity issue. While we also noted that 26 consecutive patient deaths represented exclusively in the second analysis, remember, this was the second interim analysis. Exclusively in second interim analysis, we have 26 consecutive deaths that behaved far differently from the balance of the patients who died as of that date. And that the number of treatment deaths compared in the treatment arm deaths compared to the control arm, more than doubled, completely reversing the favorable trend in the treatment arm seen before and after the cohort of 26 deaths.

Those 26 consecutive deaths occurred between September 2019 and March 2020. When we remove them from the data for the interim analysis, the outcome suggests the OPTIMA study's overall survival pattern is similar to this prospective HEAT Study subgroup, upon which the OPTIMA study is based at the approximate comparable time point.

Moreover, following the second interim analysis, there were 8 additional patient deaths reported in a 3:1 ratio of control arm to treatment arm patients, which further supports our concern for data maturity. So at this point, we are now at 168 deaths, and that calculates to a hazard ratio of 0.875. Or when I look at it and the statisticians would probably give me a little lecture on this, so with a hazard ratio of 0.875, given where we see the control arm, this is an improvement of about 8 months in time to death over the control arm. Not an insignificant amount.

While we also note that OPTIMA study sites in China and Vietnam, which enrolled over 30% of the patients in the trial, joined the study approximately 12 and 18 months, respectively, after the trial was initiated. The Kaplan-Meier curves for both geographies demonstrate a potential maturity issue when compared with the behavior of the HEAT study subgroup and the other OPTIMA study testing site regions. The China sites, in particular, show a negative Kaplan-Meier curve, yet a 56% improvement in the treatment arm over the control arm in the median time to death.

The Vietnam sites similarly show a marginal Kaplan-Meier benefit, if at all. We had a 45% improvement in the treatment arm in a median time to death. Now we believe that this dichotomy must be reconciled most probably with longer follow-up, but has to be done so before we can determine the study's direction.

While we are engaging experts in statistical analyses for clinical trials looking specifically for proportionality issues between the OPTIMA and the HEAT Study Kaplan-Meier projections, and we're conducting sensitivity tests that may provide insights related to the observations that I just mentioned. And finally, and very importantly, we have sent the clinical trial data, all of it, including CMC data to the National Institutes of Health for their independent analyses, including all CT scans that are being prepared. It takes a little bit of time so that the NIH can independently evaluate progression-free survival. I caution you, depending on the trends noted during the overall survival follow-up period, we may choose to discontinue the study at any time. At this point, however, I can tell you definitely -- I can't tell you definitely, I'm sorry, I can't tell you definitely what we plan to do. But I assure you that we will be transparent about our plans.

As I said in our August 7 press release, the trial outcome, as predicted by the second interim analysis, may not change. Fortunately, we may be faced with futility. And as I said, as unlikely as it may be, in the event that we see substantially beneficial clinical results while we continue to monitor patients, we will carefully review our options with FDA and, of course, the other 13 regulatory agencies around the world that have allowed the OPTIMA study to be conducted. The ongoing support from our research investigators and clinical advisers demand it.

Just want to say before I turn this over to Jeff that you can be sure that Celsion's fundamentals continue to be strong. Our OVATION 2 study is directed to a large patient population with unmet medical needs and poor prognosis. Our manufacturing strategy is solid. It's being built with redundancy, continue to execute our development programs with the utmost care. Our relationship with regulatory agencies, both in and outside the United States, continue to be exemplary and encouraging. And we have cash sufficient with smart spending and cash management and expect to deliver on our promises.

With those comments, I'll turn it over to Jeff. Jeff?

Thank you, Michael. Details of Celsion's second quarter 2020 financial results were included in the press release we issued this morning and in our Form 10-Q, which we filed today before the market opened.

As of June 30, 2020, Celsion's cash and short-term investments were $25.5 million, which includes net cash proceeds of $1.8 million from the sale of our unused New Jersey net operating losses, or NOLS. We fully anticipate that an additional $2 million of unused New Jersey NOLs will be sold in the second half of this year, and this will further increase our cash reserves on a non-dilutive basis. Bottom line, we believe we have sufficient capital resources to fund our operations into the fourth quarter of 2021.

We are currently evaluating our venture debt facility with Horizon, including retiring all or restructuring a portion of the loan. This will not impact our projected cash operating outlook. During the second quarter of 2020, net cash used for operating activities were $7.9 million. This compares to $10.2 million in the comparable prior year period, a 22.5% decrease.

With respect to future funding flexibility, we have a $75 million shelf registration statement on file with the SEC, with $45 million remaining. We also have a traditional aftermarket facility with JonesTrading that allows us to raise money opportunistically with no warrants and at a very low commission.

Turning now to our second quarter P&L. For the quarter ended June 30, 2020, including noncash expenses, Celsion reported a net loss of $5.3 million or $0.18 per share. This compares to a loss of $5.9 million or $0.29 per share for the quarter ended June 30, 2019. Operating expenses were down 14% from $5.7 million last year to $4.9 million in the current quarter. Research and development expenses were $3 million compared to $3.6 million a year ago. Our clinical development costs for the Phase III OPTIMA study were $600,000 in the second quarter of this year, down from $1.2 million last year, and that was due to the completion of the patient enrollment in August of 2018.

Costs associated with the OVATION 2 study increased modestly to about $200,000 in the second quarter. This compared to $100,000 in the same period last year. Other costs related to clinical supplies and regulatory support for both of our programs increased to $2.3 million in the current quarter from $2.2 million a year ago, and this was driven largely by planned manufacturing costs for the GEN-1 clinical supplies needed for our Phase II portion of the OVATION 2 study.

General and administrative expenses were $1.9 million in the second quarter of this year. That compared to $2.1 million for the same period in 2019. This 11% decrease was primarily attributable to lower professional fees. Other expenses included a noncash charge of $300,000 for the change in the valuation of the earn-out milestone liability for the GEN-1 ovarian product candidate. The company incurred interest expense of $300,000 during the second quarter of this year in connection with our venture debt facility with Horizon. This compares to $400,000 in the comparable prior year period. We anticipate that our net cash usage for the third quarter of 2020 will be approximately $3.5 million, and this is in line with our revised spending plans, which call for keeping operating expenses and cash utilization at approximately $15 million for the full year 2020. The cost of continuing to follow patients in the ThermoDox trial, the OPTIMA study, are minimal and are largely behind us.

In closing, we believe that further progress with GEN-1 in late-stage ovarian cancer with data to be reported periodically will provide additional opportunities for building shareholder value. I'd now like to turn the call back to Michael.

Well thank you, Jeff. As always, a very good summary of our financials. Well we appreciate that. So operator, we'd like to now open the call to questions.

(Operator Instructions) Our first question comes from Justin Kim of Oppenheimer & Company.

I just had a question on GEN-1. Could you just walk us through the improvements made to the manufacturing process? And any future plans to further refine the process?

That's a good question, Justin. We -- our strategy all along for all of our investigational products, including GEN-1, will include redundancy. Particularly now since the -- many of these contract manufacturing organizations, particularly those that are quite sophisticated, like the parenteral injectable drug manufacturing facilities, are being acquired and consolidated by venture capitalists creating somewhat of an oligopoly. And of course, in that environment, you always have to worry about supply and price.

So we've taken the initiative, as we've talked about earlier, to work aggressively, both inside the -- in the United States and outside with some Chinese-based manufacturers to reduce the cost of our major components of GEN-1. There are 2: the polymer that used as a transfection vector in the plasmid. And I can tell you with confidence the cost of our plasmid has been reduced by almost an order of magnitude, as a result of the work that we're doing to develop a competitive quality manufacturing system for the plasmid. So we're seeing costs come down, both with our current manufacturer, it's European-based, and the -- as a result of this work that we're doing to finalize the process for plasmid manufacturing outside the United States, in China.

We've taken the step again in a redundant approach to provide 2 sources for the polymer, again, one in China, one in the United States. Interestingly enough, competition works. The cost -- and by the way, we've been successful with the transfer to the Chinese who are using that polymer in current manufacturing for investigational product for the Phase II portion of the study. But interestingly enough, as I said, the competition works. And it looks like the U.S. manufacturer not only will reduce their cost, but they may be substantially lower than the Chinese-based manufacturing.

And finally, the third component is finishing its fill and finish in lyophilization. Again, a second manufacturer now has become our primary source of this product in China. Again, a high-quality manufacturer that currently ships product to the United States for commercial sale, recently expanding its facilities at some of the state-of-the-art facilities recently evaluated by the FDA and other regulatory agencies. And in an island, by the way, off of the cost of China, not even near or close to any of this COVID virus pandemic that's concentrated in China. Their cost of manufacturing is, again, almost an order of magnitude lower than the supplier that we've qualified in the United States.

So our goal here is to have a redundant system and competitive manufacturing, low cost, because you know that our treatment paradigm for GEN-1 requires a large volume of plasmid. One patient will receive up to 500 vials worth of product over the course of a 6-month period. So getting the costs down not only is important to the company's financials, but it's very, very important to ensuring that we have a commercially successful product.

Okay. Great. Great. I guess then maybe just shifting gears. Could you talk a little bit about the OPTIMA continuation? And sort of is there a threshold of observation that might be meaningful? And what sort of time frame might be a better period to assess the potential for data maturity issues?

Yes. So we're looking at this on a number of fronts, and I hesitate to give you a date. I mean, the easiest answer would be just to continue to follow patients until we have a sufficient number that makes it very, very clear that this study is either going to result in a failed trial or there's a potential for a positive trial. The death rate in the study is -- will be the determiner for that. As it appears now, we could have an answer sometime in the fourth quarter if we only take that stuff. The other steps that we're taking and looking at some of the discontinuities that I pointed out earlier that could just immediately give us some hope that the -- this data maturity issue is very real and it's predictable on a statistical basis. If in that case, if we conclude that the sensitivity analysis has identified these discontinuities, yes, we may take the immediate step to begin to meet with the FDA to discuss the direction of the study. And then we'll, of course, we'll provide feedback to the investment community as soon as we know something from the agency. That's pretty much our strategy.

Okay. Got it. And maybe just a final question before I hop into the queue. On that point with conversations with regulators, have you had any initial conversations regarding the study? And just what the perception of a positive result might look like in light of the unblinding of the study?

Can repeat the first part of that?

Just initial feedback with regulators on sort of OPTIMA and the potential for a positive readout given the data has been unblinded.

Yes. So we have not had that conversation with the regulatory agencies. We'd like to know more. We'd like to have a little bit better understanding of some of these, as I'm going to call them, discontinuities. Like to understand them a little bit more and have a better idea of the trajectory of the trial before we meet with the agency.

Our next question comes from Kumar Raja of Brookline Capital Markets.

And with regard to the OPTIMA trial, the patients from China/Vietnam, what percentage of these patients make up the whole trial? And in terms of the 26 deaths that are different, how does that compare with 8 patients later on? How do you see that evolving?

Yes. So we can give you some good detail on both those questions. 37% of the patients enrolled in the study were enrolled by the Chinese and the Vietnamese investigators in about an equal amount. A few more patients from China than there were in Vietnam. And as I pointed out, there seems to be a dichotomy here between the median time to death -- compared to median time to death, and what the Kaplan-Meier curves are suggesting. I mean that leads us to believe that the data is quite immature for these 2 regions.

With regard to the 26 patients, we -- the study had been tracking, I think as we mentioned in an earlier press release, on a positive vein. The separation of the 2 arms appear to mirror what we had been seeing in the HEAT Study subgroup, the prospective subgroup of 285 patients. In the first interim analysis -- and we did as much as we could to compare the same time points, first interim analysis, we're looking at a hazard ratio of about 0.78. Subsequently, so that was at 128 deaths. I mean the next look is 160. So there are 32 patients enrolled, additional patients enrolled for the second interim analysis. Of those 32, 26 consecutive patients saw a complete reversal of the treatment arm versus the control arm. The vast majority, I believe, it was 17 out of 27 patients -- or 26 patients who had died had died in the treatment arm, the complete reverse. And it's in a confined time period.

And when you look at the Kaplan-Meier, I mean, it's just very hard to understand how that could happen. It's a phenomenon. I mean it may be maturity-related, but we're also looking at other causative factors. So when we take those 26 patients out of the analysis, for the most part, the Kaplan-Meier curves are very much on track with what we would have expected when we compare it to the HEAT Study subgroup Kaplan-Meier curves.

The last point I'll make in the -- subsequently, as I mentioned in my prepared remarks, subsequent to the interim analysis, there have been 8 more patient deaths reported and the -- those patients are in a ratio for every 1 treatment arm death, we have 3 control arm deaths, actually, taking the hazard ratio from what we had said earlier, 0.903 to 0.875.

So in terms of these 8 patients, what is the split, the geographic aspect, whether they are from China or Vietnam? And also in the future, even -- the expectation is that -- where these patients are from that's going to drive the differences?

Yes. So it could be a regional issue. Maybe that's what you're getting to. It also may be a time-dependent issue. This may be a phenomenon that we're seeing as a function of a period of time, during which these patients were being treated or followed. So it may be regional, it may be time-dependent. We don't know. I mean, that's some of the sensitivity work that we have to yet complete. As far as where the 8 patients come from, I don't know off the top of my head. Do you have that?

They were primarily from the China and Southeast Asia area.

Okay. And in terms of GEN-1, what kind of protocol deviations do you expect due to the COVID-19? And have you got any...

Yes. So I believe Dr. Borys is on the phone. And we can -- we've been very careful about this COVID issue. And Nick, are you in a position to be able to answer that question, please?

Yes. Thank you. In terms of COVID-19 impact on the OVATION 2 study, we've been discussing this quite extensively with all of our investigators and our lead investigators. They are aggressively seeing a lot of patients that meet our study criteria. They're anxious to get into the study. And the way we're designing moving forward with COVID is that we are going to be following ASCO guidelines for treating patients during this COVID period, testing them for COVID and taking COVID precautions throughout. So I do not see any major protocol deviations. There might be challenges. There may be occasional visits being missed. But the impact on the endpoints I would expect to be minimal.

Okay. And in terms of the NIH analysis, what kind of -- what is the expectation from this analysis by the NIH?

So the NIH, Kumar, had a -- took a different look at the data than was published by the company. Recall, our look at the subgroup was confined to those patients who had more than 45 minutes of heating time. NIH conducted a side-by-side analysis looking at the entire -- excuse me, intent-to-treat population for patients, single-agent patients, those are the ones that could measure the heating time with precision. And they developed an algorithm that shows the relationship between longer heating time and survival. So what we expect from the NIH, since we do have this concern for data maturity, is to plug this data into their model and to -- and by the way, the -- I'm sorry, I missed a very important point here. They were evaluating heating time as a function of tumor volume.

And so we want them to plug it into the model, they may have to make some modifications. But our expectation is that this model will either confirm for us that we should wait, that there may be a data maturity issue. Or it could confirm that the futility analysis has a high potential of being correct. So that's really what we're expecting from the NIH. We also separately are looking for PFS. We'd like to know in their model, looking at PFS, whether or not the PFS that we are currently seeing from the investigator-reported events is accurate. And I think Nick, again, if you're still on the phone, please, can you address the use of the radiology in evaluating patients in the overall study by the NIH?

Yes. As Michael has stated, NIH's particular interest was to take a different view of the data, a different slice, meaning they did a volume-based analysis. So as Michael said, the first question is going to be -- is for them to reproduce the same analysis that they did in the HEAT Study and apply it to the OPTIMA study. And we'll see whether the curves are similar or different, and that will help us determine whether there's any kind of anomalies to be seen there. And then going from there, we'll look at investigator rate at PFS versus central lab rate at PFS that will be done by the NIH to see if there's any significant differences to what we're expecting. So the data will be a treasure trove of how to really take a good look at the OPTIMA data and compare it to what we learned in the HEAT study.

Our next question comes from [Mitch Landgraf], a private investor.

As a cancer patient advocate and Celsion investor, I want to appreciate and commend efforts of the company to work with all of the regulatory bodies, however possible, to hopefully bring this drug to market. We know as a fact that it's safe. We also know as a fact from the HEAT Study and from patient and investigator anecdotals that it works.

And I would hope that these various countries would want a drug like that, a treatment or a novel treatment like this available to their constituencies and their patients. My question is probably more for Dr. Borys. Seeing this anomalous data from those 26 patients, totally different than our entire experience with ThermoDox to date, and seeing that its time period is from December to March and that it was in Southeast Asia, obviously, it leads one to question whether COVID-19 had an effect.

And I was wondering if there's any thoughts as a possible causality that the hypothermia itself, the radio frequency ablation or the interaction of an anthracycline on the immune system possibly is having some interplay in the treatment arm with COVID-19 and whether the company does know or not whether any of those patients were positive or possibly perished because of -- or partially because of complications of COVID-19.

That's a great question. I'll turn that over to Dr. Borys. Thank you, Nick -- Mitch.

Thank you for that question. Let me just basically say that all possibilities are being evaluated right now. Certainly, COVID was an important consideration during the study and as we were collecting data. And we were always keeping a careful watch on that to make sure there wasn't much of an impact. And we are reviewing the causes of death for these patients, and we're interviewing the investigators to see if they could give us more insight into that. So your points are well taken, and we have been considering all possibilities with this data.

(Operator Instructions) Our next question comes from [Judson Porter], a shareholder.

A couple of questions. First, to ask you for a statistical projection. If the balance of the deaths continued to the end of the study to be 3:1, as the recent 8 deaths have been, what hazard ratio would that produce?

I don't know that we can give you that number off -- that exact number off the top of our heads. But if it continues at this rate, I believe we would be looking at a successful trial, Judson.

Okay. Secondly is a question of clarification. In the very careful language that points out the dichotomy between the second 26 grouping of deaths and the experience of percentage improvement in overall survival, are the overall survival numbers presented in the press release from OPTIMA, from HEAT, from both combined? Or will you present that going over 50% increase in overall survival in China or Vietnam and over 40% in the other?

Got it. Got it. Got it. So I don't know -- what you're referring to is this apparent dichotomy. When we talk about a 50% improvement, actually, it's a 56% improvement in the treatment arm compared to the control arm in the median time to death. That comes from the OPTIMA study, those patients that were treated in China. So we take all of the Chinese patients, we plot them on a Kaplan-Meier curve, it goes through that very complex algorithm, we see the -- actually a negative result where the treatment arm crosses the control arm pretty early on in a small number of patients but still concerning nonetheless.

And then when we look at each of the patient's median time to death -- or time to death, and we take the median, there's a contradiction for the median time to death improved by 56% in spite of this Kaplan-Meier curve that shows a negative result. So those are specific -- to answer your question specifically, those comparisons, the Kaplan-Meier curve, and the overall survival median are coming from the OPTIMA study in those regions, in Vietnam and in China.

That's very encouraging to hear. One more question, and I know this is speculative, and you may have already hinted at it. If in the end, when the study is complete, you wound up with a hazard ratio of 78, 0.78 instead of 0.75, which is success, that's still a very substantial [approval] of survival, and there's no other treatment. Is it reasonable to assume that your discussions with the various approval arms would still consider that to be successful enough to go to market?

So this is a question that we kind of debate quite a bit. So the n is very important here, Judson. You can have a hazard ratio that looks very good but not statistically significant because you don't have enough number of patients to have a confidence of a p equal to 0.05. So those are the 2 interplaying factors here. But to your point, if we see 0.78 or maybe even something closer to 0.8, I think given what we've seen in the treatment arm -- I mean, in the control arm, median time to death so far is approaching 60 months, then we will be demonstrating a very substantial improvement in the median time to death with ThermoDox.

And we believe that this deserves a discussion with the FDA. We may not be well received. And we may have to have a discussion with the -- and with an ODAC committee in that regard. But we do believe that the magnitude of effect, that's really what we're talking about, that the magnitude effect is very, very important in the consideration of whether or not ThermoDox should be a commercial product, particularly given the product safety profile. We know that ThermoDox has been administered now to well over 700 patients. And the safety profile for this drug is quite manageable, quite manageable.

At this time, we have no further questions in queue. And I'd like to turn it back to today's presenters.

Thank you very much, operator. And for all of you who are on the call, we certainly appreciate your support and your attention and your interest in the company. As you can see, we're going through some -- a challenging time. However, I want to point out that GEN-1 has a great potential in ovarian cancer. Please, as you're thinking about the company, don't dismiss that by any means. And as we continue to evaluate the OPTIMA data, as I said earlier, we will be very transparent with our analysis and where we -- what we expect to do as a result of that analysis. So we are continuing to be driven by our commitment to these therapeutics. We know that there is a great potential to make a difference for patients and clinicians and their families of cancer patients. We are committed to that. Thank you very much for your time, and we look forward to keeping you appraised of our progress. Thank you.

Thank you, ladies and gentlemen. This concludes today's teleconference. You may now disconnect.