Good afternoon, and welcome to the Inovio Pharmaceuticals Fourth Quarter 2022 Financial Results Conference Call. [Operator Instructions] Please note, this event is being recorded. I would now like to turn the conference over to Thomas Hong, Manager of Investor Relations. Please go ahead..

Good afternoon, and thank you for joining the Inovio 2022 Fourth Quarter and Full Year Financial Results Conference Call. Joining me on today's call are Dr. Jacque Shea, President and CEO; and Dr. Michael Sumner, Chief Medical Officer; and Mr. Peter Kies, Chief Financial Officer.

We also have other members of Innovia's leadership here with us today, who will be part of our Q&A session. Today's call will review our corporate and financial information for the quarter and year ended December 31, 2022, as well as provide an update on our efforts to develop our DNA medicines platform.

Following prepared remarks, we will conduct a question-and-answer segment. During the call, we will be making forward-looking statements regarding future events and the future performance of the company.

These events relate to our business plans to develop Inovio's DNA medicines platform, which include clinical and regulatory developments and timing of clinical data readouts, along with capital resources and strategic matters. All of these statements are based on the beliefs and expectations of management as of today.

Actual events or results could differ materially. We refer you to the documents we file from time to time with the SEC which under the heading Risk Factors identify important factors that could cause actual results to differ materially from those expressed by the company verbally as well as statements made within this afternoon's press release.

This call is being webcast live, and a link can be found on our website, ir.inovio.com, and a replay will be made available shortly after this call is concluded. I will now turn the call over to Inovio's President and CEO, Dr. Jacque Shea..

Thank you, Thomas. Good afternoon, and thank you to everyone for joining today's call. In the past year, Inovio has taken measured and at times difficult steps to prioritize our pipeline to focus on our programs with the highest probability of clinical and regulatory success and strongest commercial potential.

Guided by our commitment to operational excellence and financial discipline, we are positioning Inovio to best advance our key clinical programs and realize the potential of DNA medicines for patients. In our press release today, we announced the top line results from our REVEAL 2 trial of VGX-3100 Later in the call, our Chief Medical Officer, Dr.

Mike Sumner, will provide a detailed summary of our clinical programs, but I'd like to take this opportunity to highlight some key points about the REVEAL 2 trial as well as our work on INO-3107 as a potential treatment for recurrent respiratory papillomatosis, or RRP, both of which are HPV-related diseases.

As you may recall, in April last year, we changed the primary endpoint of REVEAL 2 from an all participants population to an investigational biomarker selective population.

We made this decision based on our analysis of data from REVEAL 1 from which we have defined an investigational biomarker signature that may have the potential to identify those women more likely to respond to treatment with VGX-3100.

In REVEAL 2, VGX-3100 did not achieve statistical significance in the primary biomarker selective population for the endpoint of lesion regression and viral clearance. However, VGX-3100 did achieve statistical significance in the all participants' population.

The original primary population for the trial for the endpoint of lesion regression and viral clearance.

Furthermore, the REVEAL 2 or participants data and the combined data across REVEAL 1 and REVEAL 2 trials, build upon the considerable data package that we've now obtained over multiple clinical trials that indicate DNA medicines are potentially able to clear the HPV virus and regress HPV-related lesions.

It also strengthens our confidence in our other HPV-related programs, including INO-3107 for RRP, where we recently reported encouraging data from the first and second cohorts from a Phase 1/2 trial. RRP is a truly devastating disease that can be overwhelming in patients' lives.

And we believe INO-3107 in has the potential to help alleviate this burden and improve the quality of life for those suffering from this terrible disease. We are focused on advancing INO-3107 to the next stage of development, and I look forward to sharing updates on our progress with you in the coming months.

Moving on to our infectious disease portfolio. Last month, we announced positive results from a Phase 1b clinical trial evaluating INO-4201 as a booster vaccine candidate in healthy adult participants who have previously received a single injection of Ovivo, an FDA-approved vaccine for Ebola.

We believe this data supports our position that DNA medicines could be an important part of global medical countermeasures against infectious diseases, either as primary vaccines, or as boost us to existing vaccines. Infectious diseases like Ebola, remain an ever-present threat globally.

We are currently in discussions with our collaborators and also potential partners regarding the next development steps for INO-4201. In addition to the progress on the clinical front, we have been working to strengthen our financial position.

Peter will provide the details, but our emphasis on pipeline prioritization operational excellence and financial discipline has allowed us to reduce our cash burn substantially since last year. Given these efforts, our cash runway is expected to take us into the first quarter of 2025.

Financial prudence will continue to be an area of high importance at Inovio and underpin our decision-making process going forward. With that, I'd like to turn the call over to Mike to provide a more detailed update on our clinical pipeline and recent highlights.

Mike?.

Thank you very much, Jacque, and greetings, everyone. I'd like to start today by talking about VGX-3100 and sharing some more detailed insights on the REVEAL 2 results we announced today in our financial press release.

Our Phase III program for VGX-3100 includes REVEAL 1 and REVEAL 2, 2 trials evaluating the efficacy, safety, tolerability and immunogenicity of VGX-3100 to treat HPV-16/18 associated cervical high-grade squamous intraepithelial lesions or HSIL.

Both trials included a 3-dose treatment regimen and used regression of cervical lesions along with clearance of the virus as the primary endpoint. In REVEAL 1, the endpoint was evaluated against all participants in the clinical trial.

But in the second quarter of 2022, we amended the REVEAL 2 trial to focus on investigational biomarker selected population.

As Jacque described, we made this decision based on our analysis of data from REVEAL 1, in which we had defined an investigational biomarker signature that may have the potential to identify those women more likely to respond to treatment with VGX-3100.

Due to that amendment, we publicly announced that REVEAL 2 was no longer deemed to be a pivotal trial and would not lead to a biologics license application for a biomarker selective population. Since the U.S. Food and Drug Administration had indicated that an additional trial or trials would be required.

As the next slide shows the results from REVEAL 1 in the all participant intent-to-treat population did not achieve statistical significance. However, a modified intent-to-treat population did indeed reach significance. Following the change of primary endpoint in REVEAL 2, the result in the biomarker population was also not statistically significant.

The percentage of participants meeting the primary endpoint was 28.6% or 6 out of the 21 participants in the treatment group versus zero out of the four in the placebo group. The next slide shows the two studies and two populations side by side in more detail.

We just discussed the REVEAL 2 biomarker results that you can see in the bottom right quadrant. However, the all participants group in REVEAL 2, shown in green in the top right quadrant did achieve statistical significance. The percentage of patients meeting the endpoint was 27.6% in the treatment group versus 8.7% in the placebo group.

In addition, the treatment effect we saw was higher than observed in REVEAL 1. While not shown on the slide, we also achieved statistical significance in the all participants population of REVEAL 2 for viral clearance with 37.3% in the treated group, achieving viral clearance versus 8.7% in the placebo group.

Given the importance of viral clearance in removing the underlying cause of the HPV-related diseases, this data may have positive implications for our other HPV-related programs. Next, we can look at the integrated results from both REVEAL 1 and 2.

Since these trials utilize the same endpoint, we performed an ad hoc integrated efficacy analysis of the results. This analysis showed that we achieved statistical significance in both the biomarker and in the all participant populations.

For the combined biomarker population, which consisted of 92 participants, 68 of which were in the treatment group and 24 in the placebo group, the percentage of participants meeting the endpoint was 54.4% in the treatment group versus 12.5% in the placebo group.

For the combined all participants population of 404 participants, 272 of which were in the treatment group and 132 in the placebo group. The percentage of participants meeting the endpoint was 25% in the treatment group versus 9.8% in the placebo group.

With respect to safety in the REVEAL 2 trial, there were no treatment-related serious adverse events, and most adverse events were considered to be mild to moderate. These results were consistent with what was observed in REVEAL 1. Inovio will continue to evaluate the results to determine the path forward for VGX-3100 in cervical HSIL.

And this combined data set will be supportive in future regulatory interactions. We also plan to submit the data for publication in a peer-reviewed journal later this year.

While disappointed that we did not meet the primary endpoint for REVEAL 2 in the biomarker population, I am encouraged by the data as it further indicates that DNA medicines may be particularly well suited to treat HPV-related diseases.

These results also give us additional confidence as we advance INO-3107 at handed up for the treatment of RRP into the next stage of development, which brings me to the recently announced data for INO-3107.

As a reminder, INO-3107 is a DNA immunotherapy composed of two plasmids, one encoding for HPV 6 and 11, E6 and E7 and the second INO-9112, a plasmid encoding for human interleukin-12 as an adjuvant to boost the immune response.

This DNA medicine candidate was evaluated in an open-label multi-center trial to assess its safety, tolerability, immunogenicity and efficacy in patients with HPV 6 and/or HPV 11 associated RRP. There were two cohorts for this trial. Enrollment into the trial required a minimum of two surgeries in the year prior to treatment.

In both cohorts, patients received four doses of INO-3107 on day zero and weeks three, six and nine. Surgery was performed once in the two weeks prior to the first dose in order to establish a disease baseline, but any surgery performed following day 0 including during the dosing window was counted against efficacy.

Last month, we reported positive preliminary results from the second cohort of 11 patients. who were administered INO-3107 using the exploratory side port needle.

The data from the second cohort achieved statistical significance based on the clinical endpoint of a reduction in the number of surgical interventions, echoing data from the first cohort announced in October of 2022.

In particular, in the second cohort, we saw a median decrease of 3 surgical interventions, 10 of the 11 patients or 91% saw a reduction in surgical interventions in the year following treatment. Of those 10 patients, 4 required no surgical intervention during the 52-week trial period.

In the year prior to treatment, these 11 patients had between 2 and 8 surgical interventions with a median of 5. Treatment induced cellular responses against both HPV 6 and HPV 11, inducing both activated CD4 and activated lytic CD8 T cells.

T cell responses were also observed at week 52, which was 43 weeks after final treatment with INO-3107, indicating a persistent cellular memory response. As we mentioned previously, we believe this memory response could be a key factor in the treatment of chronic viral diseases such as RRP.

As we have seen with our other DNA medicines, INO-3107 was well tolerated in both the first and second cohorts with all participants completing the treatment course. Treatment-emergent adverse events observed in the trial were generally low grade with injection site pain and fatigue being the most commonly reported AEs.

When the data from both cohorts is combined, it shows that 81% or 26 of the 32 participants saw a reduction in the number of surgical interventions compared to the previous year.

We found these results incredibly important, not just because they show the potential of our platform, but more importantly, because of the potential impact, INO-3107 can have on patients suffering from RRP. For instance, the two photos on this slide show the change in the airway of one of the patients in our trial from before and after treatment.

This patient had required frequent surgeries in the year prior to the trial. But as you can see on the right, there was marked improvement in the disease, which meant from a clinical management perspective that this patient required no surgeries following treatment.

In this next slide, you can see the impact of INO-3107 in on a patient with much more significant disease. The improvement here is tremendous. And while some residual disease is visible on the right side of the airway, this patient did not need any surgery after day 0 through the completion of the 52-week trial.

We have heard from patients and investigators that any reduction in surgery, even on less surgery would be life-changing for patients, who often have to schedule their entire lives around surgical procedures to control their disease. Our Phase 1/2 results are an indication of the positive impact INO-3107 could potentially have for the RRP community.

We are currently in discussions with the regulatory agencies to discuss the next steps for this program and determine the most expeditious path to bring the potential benefits of this treatment to RRP patients in need. We continue to have discussions with KOLs in U.S.

and Europe as we plan to advance to the next clinical development stage with the goal of recruiting globally for the next trial. We are also excited to be presenting our Phase 1/2 trial data at the American Broncho-Esophageal Association at COSM in May of this year.

We look forward to providing additional details about our data at this important conference. Now I'd like to turn to updates on a few other product candidates mentioned in today's press release. INO-3112 is our candidate for the treatment of HPV-related cancers. As you may recall, the asset was returned to us in 2021 from AstraZeneca.

Updated results have recently been published in clinical cancer research which included an improved overall response rate, or ORR, from a Phase 1b/2a trial, evaluating the safety and tolerability and antitumor activity and immunogenicity of INO-3112 when used in combination with durvalumab, a PD-L1 checkpoint inhibitor.

The ORR was updated from 22.2% to 27.6%, which meant the number of both complete responses and partial responses increased from 3 to 4. We believe the results from our HPV program to date supports the reevaluation of INO-3112. Therefore, we are currently evaluating the next development steps and also potential collaborators to move INO-3112 forward.

Turning to INO-5401. Last year at ASCO, we announced additional overall survival data from our trial of evaluating INO-5401 in combination with the PD-1 inhibitor, Libtayo. We are in discussions with Regeneron regarding the next steps for this program.

Given the tolerability and immunogenicity profile when combined with the survival data we believe this asset should continue to be investigated, and we plan to provide additional updates in the coming months.

On the infectious disease front, we also announced positive results from our early phase clinical trial evaluating INO-4201 as a boost to vaccine in healthy adult participants who had previously received a single injection of Ovivo, the only FDA-approved vaccine for Ebola.

As you heard from Jacque earlier, we believe DNA medicines have an important role to play as part of global medical countermeasures against infectious diseases. We are currently in discussions with collaborators and potential partners and we'll seek regulatory input regarding what next steps we need to take to move this product forward.

We will hopefully be able to provide a further update in the second half of this year. As you can see, we've been busy, and we have a lot of exciting work ahead. We believe our DNA medicines are well suited as therapeutics for chronic viral conditions.

Attributes of DNA medicines such as durable T cell responses, a well-tolerated profile, ability to readminister and the lack of antivector response could play an important role in the treatment for HPV-related diseases. We are truly excited about taking our pipeline to the next stage of development.

I'll now turn the call over to our CFO, Peter Kies, for our 2022 fourth quarter and full year financial summary.

Peter?.

Thank you, Michael. We finished the fourth quarter of 2022 with $253 million in cash, cash equivalents and short-term investments compared to $401.3 million as of December 31, 2021. As of December 31, 2022, Inovio had 253.1 million common shares outstanding and 271 million common shares outstanding on a fully diluted basis.

Our total revenue was $125,000 and $10.3 million for the quarter and year ended December 31, 2022, compared to $839,000 and $1.8 million for the same period in 2021, respectively. The year-over-year increase in revenue resulted from the fulfillment of obligations under our contract with the U.S. Department of Defense.

Total operating expenses were $56.1 million and $277.8 million for the quarter and year ended December 31, 2022 compared to $106.3 million and $303 million for the same period in 2021.

Our net loss for the quarter and year ended December 31, 2022, was $54.5 million or $0.22 per share basic and dilutive, and $279.8 million or $1.17 per share basic and dilutive, respectively, compared to a net loss of $106.9 million or $0.50 per share basic and dilutive, and $303.7 million or $1.45 per share basic and dilutive for the quarter and year ended December 31, 2021.

Research and development expenses for the quarter and year-end December 31, 2022, were $42.1 million and $187.7 million compared to $92.3 million and $249.2 million, respectively, for the same period in 2021.

The year-over-year decrease in R&D expenses was primarily related to lower drug manufacturing, outside services and clinical expenses related to INO-4800 and VGX-3100.

And also nonrecurring expenses related to the acquisition and installation of manufacturing equipment for INO-4800 during 2021, as well as lower engineering services and expenses related to our selective 3PSP device array automation project.

These decreases were offset by $29.2 million, lower contra research and development expenses recorded from grant agreements. General and administrative expenses were $14 million and $90.2 million for the quarter and year ended December 31, 2022 versus $14 million and $53.8 million, respectively, for the same periods in 2021.

The year-over-year increase in G&A expenses was primarily due to a $14 million noncash expense related to the settlement of Inovio's securities class action litigation, including issuance of common stock as part of the settlement and other related litigation costs as well as $6.9 million in onetime severance expenses.

Looking forward, our projected cash runway into first quarter 2025 includes a cash burn estimate of approximately $32 million for the first quarter of 2023. These projections do not include any funds that may be raised through our existing at-the-market program or other capital-raising activities.

As a reminder, you can find our full financial statements in this afternoon's press release as well as in our Form 10-K filed with the SEC. And with that, I'll turn it back to Jacque..

Thanks, Peter. I'd now like to open up the call to answer any questions you might have.

Operator?.

[Operator Instructions] Our first question today comes from Hartaj Singh with Oppenheimer..

Great. And thanks for a couple of questions, just quick ones. One is you had mentioned that you had learned a lot from the trial REVEAL 1 and REVEAL 2 in the various biomarker-selected patient population. And I imagine you're learning more going forward as you look at that data.

Can you just help us understand how that helps you the RRP trial, other trials that you're looking at with other projects? That's number one, how it's going to help you with all comers and patient population? And then I just got a quick follow-up after..

Thanks, Hartaj, nice to hear from you. So I'll kick off and sort of provide some top-level comments and then I'm going to hand over to Mike to comment in more detail.

So I think the really encouraging thing that we've seen from REVEAL 1 and REVEAL 2 and from the earlier Phase II trial for VGX-3100 and that we've also seen across the anal indication for VGX-3100 and now with RRP, is our ability really to be able to see viral clearance and lesion regression.

And I think that's a common factor that we're seeing across all of those different indications. And whilst we did not reach statistical significance in the biomarker selected population, we did reach statistical significance against tissue against tissue regression and viral clearance in the all-comers population in REVEAL 2.

And I think this is really important data. And I think it really strengthens our belief and our conviction that DNA medicines are really particularly well suited to addressing HPV-related diseases. And with that, I'll hand it over to Mike to make some more specific comments.

Mike?.

Thank you, Jacque, and nice to speak to you again. I think, obviously, Jacque hit on all the main points. I think -- and as you rightly said at the start, we obviously do have more work to understand the biomarker population. We only really got the data in our hands about a week ago. So it's very early for us to start examining that.

I think for me, personally, I mean, as Jacque said, I mean, the fact we are able with a 3 treatment regimen to clear 36% of patients of their virus, which really is the foundation of the disease in the HPV-related disorders is particularly promising. And I think also when you think about our RRP product, we also include IL-12 as an adjuvant.

So we're hoping. And as you saw, we actually do have greater efficacy. We're able to get 81% of subjects have less surgeries than the previous year. So I think you just put all the entirety of the data we've seen across our programs. I mean we're just confident, I think, now that we can treat HPV-related diseases..

And then just a follow-up on that, which is that as you're going -- you've got your lead program HSIL, now RRP, GBM with Regeneron, what other preclinical targets are you looking at? I guess, as these learnings are kind of coming into effect in Inovio, is -- are you getting sort of better able -- better visibility into the kind of preclinical targets you want to go after, bringing to the clinic so that you have greater certainty with kind of platform technology you have at DNA medicines?.

I mean that's a really interesting question. And I would say we remain focused on advancing our DNA medicine candidates that have the greatest scientific promise, clear regulatory path and strongest commercial potential.

And that's really underpinned by our desire to bring to market innovative life-saving DNA medicines for the benefit of patients globally as quickly as possible. With our platform, we're able to do many different things. I mean we have candidates across infectious disease, HPV-related disease, immuno-oncology.

We also have programs in early clinical development in terms of DNA-delivered monoclonal antibodies and then some further earlier preclinical work. But I think what we're really seeing now with our DNA medicines is our ability to potentially treat HPV-related diseases.

I think it's going to be very interesting to see how that may translate to other chronic viral diseases. And I think we're also very excited to see what we can do in the immuno-oncology space, both in HPV-related cancers, but also in some other cancers more broadly.

So I think the past few years, we've had a lot of data readouts, a lot of encouraging data. And we're really digging down and analyzing that data to see what it tells us and to really narrow down and focus on where do we really think the best opportunities are for DNA medicines to get potentially life-saving products to patients more quickly.

So I hope that....

The next question is from Gregory Renza with RBC Capital Markets..

It's Anish on for Greg. Just a quick one for me here.

How should we think about the prioritization of your pipeline programs and the relative investment in each?.

So first of all, as I mentioned in my previous response, we're really focused on advancing our DNA medicine candidates where we think we have the greatest scientific promise, the strongest commercial potential and a clear regulatory pathway going forward as well.

So that's really what we're looking at as we assess and evaluate these different opportunities. We've had quite a lot of data over the recent months. We're in the process at the moment, as I said, was really sitting down, going through that data and really prioritizing how we're going to move our candidates, boards and in what order.

And we'll be providing some further updates on that over the coming months..

Great. And just to follow up, just the second part of my question there.

Is there sort of a difference in the relative investment of time and capital into each of your programs, just given the prudent approach you've been taking to resource allocation?.

Yes. So when we're looking across our pipeline, obviously, we're considering what the regulatory paths are, what the next steps are, likely costs, time lines, et cetera. And we're really allocating our resources across the different programs, dependent on that.

So I think as Mike mentioned, we're going to be sitting down and figuring out the path forward for RRP. We're currently in discussions with the regulators as to the next steps there. And then we'll may be banking announcements about that program over the coming months. For VGX-3100 as well as he mentioned, this is very recent data.

We really need to dig down into the figure out what we can learn from this and how we might want to proceed going forward. We also have other indications for this product candidate as well that we need to take into consideration..

The next question is from Geoff Meacham with Bank of America..

This is Charlie Young on for Geoff. So I guess I have kind of two part questions. First is, I'm wondering whether you can provide details in terms of why the biomarkers have been tested in this trial for REVEAL 2.

And maybe one appetite is, is the reason why we're not seeing a statistic here due to the fact that the number of patients enrolled were relatively small. So is the trial on the power? And that's the reason why we're going to see a statistic in the biomarkers to like the patients? And I have a follow-up after this..

I think those are interesting questions. So as you may recollect from the call, the biomarker-selected population was selected using our investigational biomarker. I'm going to hand it over to Mike now to provide some further details as to how we selected that biomarker and what the potential implications might be going forward.

Mike?.

Yes. So at present, we have not disclosed what our biomarker signal was. And we'll do that, I think, in context of a full analysis of both what we saw on REVEAL 1 as well as what we saw in REVEAL 2, as without the sort of full detailed sort of population and the other impacts that can affect treatment efficacy.

I think it would just be a little premature for us to talk about that at the moment. I mean to your comment around power, I mean, obviously, we did expect a higher number of subjects to have the biomarker based on what we saw in REVEAL 1. But really, it wasn't a powering issue with the study.

I mean we genuinely saw a lower efficacy rate from the biomarker selective population.

So that's what really makes us want to dig into the data and understand what went on in that biomarker population so that we can come back and tell people what really happened, and we're just not at the stage to do that at the moment, but we will be doing that work..

Yes. And if I can just add to that, Mike. I mean, we should remember that these were trials that were not enrolled on the basis of the biomarker. The biomarker was applied retrospectively. And we have developed or defined the biomarker signature based on what we had seen in REVEAL 1.

And I think this was part of the reason why in discussions with the FDA, it became clear that REVEAL 2 would need to be exploratory for that biomarker selective population..

And maybe just a follow-up on a different question. Can you -- so you mentioned in the press release that the cash run rate into first quarter of 2025.

Can you just provide some details on the assumptions in terms of your program? And how would the -- I guess, the next steps in terms of development for RRP and maybe the GBM will impact that cash runway? Thank you..

I'll take that..

Thanks, Peter..

So what you're seeing is the wind down -- there'll be a few wind down costs from our COVID program, but you're seeing the expenses shifting over into the RRP programs. and the slight increase in the GBM programs. We still have money going into our annual programs. and then an increase in 5PSP and 3PSP developments to get those to commercial ready.

Right now, probably one of the lead programs is the RP and that does anticipate that we get the Phase 3 trial started upon regulatory approval from the FDA to be able to move forward toward the end of the year, third quarter, beginning of fourth quarter. And we will cover the majority of those Phase 3 costs..

The next question is from Roger Song with Jefferies. Please go ahead..

Great. Thank you for taking the question. Maybe a few ones for the detail. First, for the REVEAL trial, I think you mentioned the biomarker patient seems to be lower, the number of the patients seem to be lower than expected.

So just curious what is the expected percentage of the biomarker-driven population will look like in a general population and also given you now have the data set from both trials, any thoughts around how to improve upon the market strategy? I have a follow-up after that. Thank you..

Okay. Thanks, Roger. I'm going to hand those questions over to Mike.

Mike?.

Yes. So as we presented during the presentation, -- when you look at the REVEAL 1 population, the biomarker from an efficacy level was at 65.9%. And in terms of frequency within the 201 patients in the trial, it actually accounted for 33% of those patients.

So obviously, when you come on to the REVEAL 2 population, there was a difference that we need to investigate there. And so there was a second -- so yes, so in terms of how to improve, I mean, I think that goes back to my previous answer. We need to dig into the data and see what what's going on in the REVEAL 2 data set.

But when you think about -- I mean, as Jacque mentioned, it was an investigational biomarker the team only had the REVEAL 1 population to work on. They now have double the amount of data to look for the appropriate signature.

So I think there's a lot more the team can do to really delve into a biomarker signature and see where that leads us once we've got our hands on more data..

Got it. Yes, that makes sense. And then so for RRP, can you just remind us what is the criteria for the patient to do surgery given that one of the key endpoints and how consistent the criteria across size and investigation as you want to do a global trial for the later stage development? Thank you..

Yes. That's a really good question, Roger. And if you recollect for our Phase 1/2 study, we were actually using multiple sites across the U.S. and we've been working and talking closely with KOLs and other investigators as to how we might expand the study to Europe.

But I'm going to ask Mike to comment on the criteria for surgery and how variable the disease can be..

Yes. So when you look at the sort of surgical intervention in the current trial, we didn't really specify when and how the patients could receive surgery. It was ultimately a decision between the patient and the treating clinician. As you can imagine, one of the things because surgery is a key indicator of efficacy.

We will need to try and standardize that as we move toward a registration trial. And that is going to be one of the discussions that we have with the regulatory bodies. But at present, we're not in a position that we can disclose what criteria we're thinking about. But it is an important aspect of how we design the next trial..

And if I can just add in here. What we're hearing from patients, what we're hearing from investigators is -- they really are looking for an improvement and a reduction in number of surgeries. That's the major impact on patients' lives, and that's really the thing that will move the needle for patients.

So more work to do, more discussions to be had, but we really are focused on surgery..

Next question is from Yi Chen with H.C. Wainwright. Please go ahead..

Thank you for taking my questions.

First question is the biomarker you're utilizing in REVEAL 2 and REVEAL 1, is that the only biomarker available? Or there are some other candidate biomarkers?.

Yes, Yi. That's a really important question. So I'm going to hand over to Mike to talk a bit about our biomarker strategy..

So I always feel bad because I can't give too much information about this. The biomarker signature that we used as the primary biomarker to select the population was not the only biomarker that we looked at -- so we will actually have more data in the database. But again, we haven't disclosed that level of detail at the moment, I'm afraid..

I think what we can say though is we're working with our partner, QIAGEN, to develop these biomarkers. And this data is very new. It's very recent for us and we're going to need to dig down into it and hopefully, come back to you with some further updates over the coming months..

Got it.

Did the FDA say that future trials have to use a biomarker?.

I don't believe they stipulated that. That was our decision after we saw the data from REVEAL 1 in terms of our proposal to them.

I mean, what they did say that by switching to the biomarker population, it became a more exploratory study, and we would have had to do or we will have to do one or two more trials before we could file for a BLA in that investigator in the biomarker investigational population..

Okay. Got it. And did the does the fact that the combined data set for both the biomarker selected population and the amortization population but sell the statistical significance.

Does that mean I mean the biomarker really doesn't add much to the final results?.

I guess it depends what you mean by it doesn't add much. But I mean, clearly, the efficacy rate in the biomarker-selected population in the combined group was, I believe, 54%. So I mean there was a significantly increased efficacy seen in that population. So I mean, there was clearly an indication of a predictive nature of that biomarker..

This concludes our question-and-answer session. I would like to turn the conference back over to Jacque Shea for any closing remarks..

Thank you for your questions and to everyone joining us today. To summarize, as you've heard on the call today, -- in the past year, we've taken measured steps to prioritize our pipeline and focus our efforts on the programs with the highest probability of clinical and regulatory success and strongest commercial potential.

These steps are underpinned by our commitment to operational excellence and financial discipline and our belief in the potential of DNA medicines to improve the lives of patients.

We're excited about our plans to advance our key programs, such as INO-3107 to the next stage of clinical development and look forward to providing you with updates on our progress in the coming quarters. With that, thank you again for your attention, and have a great evening, everyone..