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spk01: Good day and welcome to the Innovio Fourth Quarter 2020 Financial Results Conference Call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing star, then zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on a touch-tone phone. To withdraw your question, please press star, then two. Please note this event is being recorded. I would now like to turn the conference over to Ben Matone. Please go ahead.
spk10: Thank you, operator. Good afternoon, and thank you for joining the Inovio fourth quarter and year-end 2020 earnings conference call. On the call from the company are Dr. Joseph Kim, President and CEO, Mr. Peter Keyes, Chief Financial Officer, Dr. Jackie Say, Chief Operating Officer, Dr. Lermont Emo, Chief Scientific Officer, Dr. Kate Broderick, Senior Vice President of Research and Development, and Dr. Prakash Buyan, Senior Vice President of Clinical Development and Medical Lead for RevealOne, the company's Phase III clinical trial for cervical dysplasia. For today's call, we will review our corporate and financial information for the fourth quarter and full year ended December 31, 2020, as well as provide an update on our clinical program's progress, which includes our COVID-19 vaccine program and today's release regarding our Phase III clinical study for cervical dysplasia known as RevealOne. This call is being webcast live on our website, ir.innovio.com, and a replay will be made available. Following prepared remarks, we will be conducting a question and answer segment reserved for Equity Research Channel. During the course of this 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 integrated platform of DNA medicines, which include clinical and regulatory developments and timing of clinical data readouts, along with capital resources and strategic matters, as well as the impact of the COVID-19 pandemic on Inovio's business operations. All of these statements are based on the beliefs and expectations of management as of today. These statements involve certain assumptions, risks, and uncertainties that could cause actual results to differ materially. We assume no obligation to revise or update forward-looking statements, whether as a result of new information, future events, or otherwise. Investors should read carefully the risks and uncertainties described in today's press release as well as the risk factors included in today's 10-K filing with the SEC. I would now like to turn the call over to Inovio's president and CEO, Dr. Joseph Kipp.
spk04: Thank you, Ben, and good afternoon, everyone. We have a lot to discuss following this afternoon's Phase 3 BGX 3100 announcement, and I want to ensure we cover our other key programs and allow time for analyst questions. While we know that you are all eager to get updates about our COVID-19 vaccine program, I want to first spend some time on our latest announcement for Reveal-1 trial and what this means for both the HP therapeutic landscape and the Inovio platform validation. Later in the call, Dr. Prakash Buyan and Dr. Kate Broderick will discuss the latest developments in our HPV and COVID-19 vaccine programs. Also, our CFO, Peter Keys, will outline Inovio's strong financial position to support our deep pipeline, clinical development, and anticipated commercialization of multiple products over the next several years. What does today's news of Reveal One top-line data mean for the patients for Inovio? Today's data announcement represents a potential big step forward towards a therapeutic option for women who currently suffer from high-grade cervical dysplasia and who would like to avoid surgery, which is the current standard of care. The data demonstrated that in responders, three doses of VGX3100 resulted in regression of high-grade dysplasia and clearance of underlying HPV16 and or 18 virus. which caused the disease in the first place. Today also represents a giant milestone for the company. This afternoon's release on positive Reveal One efficacy data is the first phase three data reported by our company for Inovio's DNA medicine technology, further validating the company's platform technology that supports all of our therapeutic areas of focus. We are proud to advance the development of VGX3100 as the first DNA medicine to achieve efficacy endpoints in a phase three clinical trial. I am so thankful for all trial volunteers, study staff, and partners as well as Inovio team who are dedicated to bringing VGX3100 as a much needed non-surgical therapeutic option another step closer to commercialization especially in the face of a global pandemic. Before I turn it over to Dr. Buyen, who will discuss Reveal-1 data in greater depth, I do want to remind everyone that Reveal-1 is the first of two Phase III trials with VGX3100 for the treatment of cervical H-cell, and these trials are still ongoing. Reveal-1 subjects will continue to be followed for safety and durability of responses, for 18 months following the last administration of either VGX3100 or placebo with the trial completing later this year. Reveal 2 continues to enroll across eight countries, including the U.S. Both trials are designed to assess and confirm the safety, tolerability, and efficacy of VGX3100 in women 18 years of age or older who have histologically confirmed cervical dysplasia or H-cell. With an eye towards optimizing the commercial attractiveness of VGX3100, just last week, Inovio expanded its master collaboration agreement with Quiagen to co-develop a companion diagnostic based on RNA sequencing technology to help guide clinical decision-making for the use of VGX3100. The goal of this project is to develop a pretreatment RNA-based blood test for prospective VGX3100 patients to better identify the patients who are most likely to respond to VGX3100, which complements and raises the eventual commercial profile for VGX3100. This biomarker technology had previously been employed in a post-hoc assessment of VGX3100 phase 2b data by Novio, where it correctly predicted efficacy in 85% of VGX3100 3D subjects. We plan to have the companion diagnostic available prior to the licensure of VGX3100. With that, I would like now to turn the call over to Dr. Buyen, who will discuss today's release of Reveal-1 data. Prakash?
spk08: Thank you, Joseph, and good afternoon to everyone joining us on the call. As Joseph mentioned in his opening remarks, this afternoon we announced positive results from Reveal-1, which is our phase three pivotal trial. evaluating VGX3100 as an immunotherapy for the treatment of high-grade precancerous cervical 8-cell caused by HPV16 and or HPV18. Importantly, the company achieved the primary and secondary efficacy objectives amongst all evaluable subjects, MITT modified intention to treat population, which we reported this morning. These results are a significant step forward for women's health by potentially giving women a choice to treat cervical precancer without surgery, which can have known negative impacts upon reproductive health. The REVEAL-1 trial included women 18 years of age or older with HPV-16 and or HPV-18 driven cervical H-cell, but who were otherwise healthy. Participants received either VGX3100 or placebo at 0, 4, and 12 weeks, randomized at 2 to 1, and powered at 90% for the evaluation of the primary endpoint. The MITT analysis, as pre-specified in the trial protocol, includes all subjects who received at least one dose and had endpoint data. The primary endpoint of histopathologic regression of H-CIL combined with virologic clearance of HPV-16 and or HPV-18 at week 36 was met, showing the percentage of responders as 23.7%, 31 out of 131 in the treatment group, versus 11.3%, 7 out of 62 in the placebo group, respectively. resulting in a p-value of 0.022, with a difference in percentage regression of 12.4%, and a 95% confidence interval of 0.4 and 22.5, which was statistically significant. All secondary objectives were achieved, These were regression of cervical H-cell to normal tissue combined with HPV 16, HPV 18 viral clearance, regression of cervical H-cell alone, regression of cervical H-cell to normal tissue, and HPV 16, HPV 18 viral clearance alone. We also reported the intention to treat or ITT analysis which includes all trial participants irrespective of being dosed or having data, automatically considering those without evaluable data to be non-responders. The ITT analysis did not meet significance for the primary objective and one secondary objective on account of a disproportionate number of subjects with missing data in the VGX3100 group, which had seven, compared to one in the placebo group. Based on blinded aggregate data, the overall safety findings are consistent with previously reported trials and considered generally safe and well-tolerated, having undergone reviews by our external data safety monitoring board. Lastly, I want to remind everyone that in addition to the continued progress towards treating cervical dysplasia, we are also exploring the capabilities of VGX3100 towards treating vulvar and anal high-grade dysplasias. We plan to seek regulatory guidance on the pathway to develop VGX3100 to treat HPV-driven vulvar and anal H-cell. We are also seeking orphan designations for these indications. Before I turn the call back over to Joseph, I just want to thank our investigators, study participants, site personnel, and all involved in making this critical research possible. Thank you. Back to you, Joseph.
spk04: Thank you, Prakash, and to your team for amazing work on providing patients with an alternative therapeutic option to surgery. We look forward to the team's continued effort to bring VGX3100 to patients dealing with cervical precancer. Moving now to INO5401 and GBM. Inovio had a productive fourth quarter across all of our DNA medicines platform. In addition to the continued developments and advancements occurring within our HPV and COVID-19 programs, we presented encouraging results in a landmark combination trial for GBM at the Snow 2020 Annual Meeting last November. Along with our partner Regeneron, we are continuing to review INO5401 in combination with Semiplumab, branded as Leptayo, which is co-developed by Regeneron and Sanofi, with an emphasis on identifying patients who are most likely to benefit from this innovative combination immunotherapy approach. In particular, we will evaluate overall survival at 24 months, along with immunology work focused on the three specific antigens that make up INO5401. We also will update the median overall survival for methylated patients as this still has not been met. Additional work and analysis remain in close collaboration with our partner Regeneron, and we plan to share additional data this year. Now, turning to our COVID-19 vaccine program. I am extremely proud of the dedication and efforts of our Innovio team in contributing to the global efforts to combat COVID-19. And we are thankful for all the phase one and two trial participants and grateful for the continued support of our partners for all of our Innovate clinical trial and for their help in the ongoing fight against the pandemic. I know 4800's key differentiators are the safety and tolerability data, as well as its excellent thermal stability profile, making it possible to manufacture at scale and transport without frozen cold chain requirements. IN04800 also maintains the ability to be safely re-administered and is further differentiated by its ability to stimulate both CD4 and CD8 positive T cell responses along with generating antibody responses, as published in eClinical Medicine, a peer-reviewed open access journal published by The Lancet. In parallel to our extensive ongoing IN04800 work, we are co-developing a next-generation pan-COVID vaccine candidate, which is designed to provide protection against both known and unknown SARS-CoV-2 variants. Next, Dr. Kate Broderick will provide some important updates about INO4800, as well as to speak to the measures and work being done to address the new COVID variants that have become topical in the news. Kate?
spk00: Thank you, Joseph. Firstly, I'd like to say how grateful we are to have the continued support from the Department of Defense for both directly funding the company's Phase 2-3 Innovate clinical trial as well as the DOD's funding of the large-scale manufacture of our proprietary Selectra 3PSP smart device, production of doses, and the procurement of Selectra 2000 devices. As we stated in this afternoon's earning press release, we continue to be focused on and will complete the Phase 2 segment of our Phase 2-3 Innovate trial of INO4800 early second quarter. As a reminder, there is a dose finalization component. Selection of the dose is based on week six immunogenicity and week eight safety data. Our phase two segment is designed to evaluate safety, tolerability, and immunogenicity of INO4800 in a two-dose regime, either one or two milligrams, in a three to one randomization to receive either INO4800 or placebo for each dose to confirm the most appropriate dose for each of three age groups with high risk of infection. That's 18 to 50 year olds, 51 to 64 year olds, and 65 and older for the subsequent phase three efficacy evaluation. Additionally, we are also completing review of the interim expanded phase one safety and immunogenicity data in 120 subjects and that included those older subjects 51 to 64 years of age, and elderly subjects 65 and older. We are also actively preparing for the start of the phase three portion of an EVATE clinical trial, which remains a partial clinical hold at this time due to the FDA's remaining questions related to the Selectra 2000 device that will be used to deliver INO4800. We are continuing to work closely with the FDA to address all remaining device questions and plan to resolve them concurrently by the time we obtain the Phase 2 results in the second quarter and prior to the start of the Phase 3 segment of the trial. Moving to Inovio's ex-US activities, Inovio's collaborators are advancing the clinical testing of INO4800 in a Phase 2 setting. with whom Inovio entered into an exclusive collaboration and license agreement for INO4800 in Greater China, is conducting a 640-subject Phase 2 clinical trial of INO4800. And the International Vaccine Institute in South Korea is also in a Phase 2A segment of its Phase 1-2A trial of INO4800. We expect that the data from these two trials will be available later this year. In complement to our INO4800 clinical trial efforts, Inovio is also advancing work to assess the potential usage of our candidate as a seasonal booster. And why is this important? Well, the WHO recently stated that COVID-19 could likely become an endemic disease. It is therefore important to consider the potential use of INO4800 for seasonal boosting for those who have already received doses of INO4800. If successful, this could extend protections against the COVID-19 virus as it becomes endemic. We believe the booster may offer the ability to stimulate both CD4 and CD8 T cell responses, along with augmenting the antibody responses, which we have already demonstrated in our phase one trial and our non-human primate studies. Given our overall safety profile, Anovio's DNA vaccines may have the potential to serve as a safe and effective booster. We also plan to further evaluate the capabilities and the potential to boost other vaccines using Anovio's COVID DNA vaccines. We believe this ability to repeatedly boost is a very significant long-term differentiator for our DNA platform. In this regard, Anovio has been able to provide a third booster with IN04800 in 93 out of 120 subjects from our phase one clinical study. The subjects received their booster doses six to 10 months post the second vaccination. To date, the safety and tolerability data has been consistent with what we observed from our platform data and from our phase one trial of INO4800. We look forward to sharing the immune response data with you in the second quarter. Inovio has also been diligent in the manufacturing side of INO4800 development. We continue to build our global manufacturing consortium, which includes Thermo Fisher Scientific, Richter Helm Biologic, and Ology Biosciences. to ensure the ability to meet global demand. In the fourth quarter, we added Kanaka EuroGentech to the consortium. Inovio is also in active discussions with additional manufacturers to join the consortium. We have also brought on several contract manufacturers to produce global supply of single use and raise, which would be used both by the Selectra 2000 and the Selectra 3P SP devices. Next, and at the top of mind for many at the moment, I'll speak to the potential advances that our DNA-based vaccine technology may provide in addressing the threat of current and future variant strains of SARS-CoV-2. One of the hallmarks of Anobio's DNA vaccine technology is the ability to respond to emerging infectious diseases through rapid vaccine construct design and manufacture. As an example, INO4800 was rapidly designed following the receipt of the Wuhan SARS-CoV-2 viral sequence from China. In addition, the optimization process of Inovio's DNA medicines confers the ability to potentially deliver cross-strain presentation and pan-variant coverage, mitigating the risk of the currently circulating strain variants, as well as potentially the new mutant strains that could appear. We have previously demonstrated the functional capability of this technology. Anovio's Syncon vaccine design approach uses the company's proprietary algorithm to combine multiple existing strain sequences together to generate a synthetic mosaic design. We used this approach and applied it to influenza in multiple preclinical studies and generated broadly protective antibody responses against the most deadly strains of the H1N1 and H3N2 influenza viruses since 1918, demonstrating complete protection against heterologous lethal challenges. Anovia has also been closely monitoring the development and evolution of COVID-19 mutations, with a particular focus on the UK, South African, and Brazilian variants. With incidences of these variants on the rise globally, And with the UK variant expected to be the dominant strain in the United States this month, this has been an area of high priority for our COVID-19 vaccine team. Inovio is taking a two-pronged approach to the emerging crisis caused by the new variants. With INO4800, we are currently testing the impact that these new strains have on the immunogenicity profile of the vaccine through an assessment of neutralizing antibodies in both lives and pseudovirus assays, as well as assessing the impact of the generated T cell responses on these variants. In addition to the ongoing IN04800 work, we are also developing a next generation pan-COVID vaccine candidate using our proprietary AI-driven Syncon gene sequence algorithm to create a synthetic SARS-CoV-2 genetic design. The pan-COVID candidate is designed to provide protection against the UK, South African and Brazilian strains, as well as potentially the currently unknown SARS-CoV-2 variants. I should also note that the pan-COVID vaccine candidate is expected to share a similar safety and thermal stability profile to INO4800. And with that, I'll hand back to Joseph.
spk04: Thank you, Kate. I want to summarize the capabilities of Inovio's platform as related to the emerging variant crisis that Kate touched on. Our DNA vaccines platform has the potential to mitigate the risk of the new viral variants through three main mechanisms. One, rapid design and testing of new DNA-based vaccine candidates based on newly emerging sequencing data. Two, ability to generate broad immune response profile which are less susceptible to viral strain shifts. Three, ability to repeatedly boost with no anti-vector immunity or reactogenicity issues on an annual or semi-annual basis to provide participants with persistent and tailored protection. An additional two key characteristics of the platform are also important, thermal stability profile, Our vaccine does not need to be frozen during transport or storage, a critical element when considering the feasibility of global distribution, and characterizable and scalable. The highly characterizable nature of the vaccine enables timely scaling of manufacturing with multiple manufacturing facilities able to be utilized. With that, I will turn now the call over to our CFO, Peter Keyes. for a brief financial update. Peter?
spk07: Thank you, Joseph. Good afternoon, everyone. As Joseph mentioned, Anobio enters 2021 well positioned financially with total cash, cash equivalents, and short-term investments of $411.6 million as of December 31st, 2020. Additionally, in January 2021, The company closed an underwritten public offering of the company's common stock, resulting in net proceeds of $162.1 million. Our current cash position provides us with multiple years of cash runway. We also have continued financial support from the DoD for our pivotal phase two and three trials for Anovio 4800. Turning now to our quarterly financial results. Total revenue for the three months ended December 31st, 2020 was 5.6 million compared to 279,000 for the same period in 2019. The increase in revenue is primarily comprised of upfront and milestone payments of 5 million related to our license agreement with AdVaccine. Our net loss for the quarter ended December 31st, 2020 was 24.3 million or 14 cents per share basic and dilutive compared to a net loss of 37.7 million or 38 cents per share basic and dilutive for the quarter ended December 31st, 2019. Research and development expenses for the three months ended December 31st, 2020 were $26.3 million compared to $22 million for the same period in 2019. The increase in R&D expenses was primarily related to an increase in drug manufacturing and outside services related to INO, 4800, and an increase in engineering services related to our Selectra 3PSP device. These increases were offset by an increase in our contra research and development expense recorded from grant agreements, among other variances. Lastly, general and administrative expenses were $8.6 million for the three months ended December 31, 2020, versus $8.7 for the same period in 2019. As a reminder, you can find our full financial statements in this afternoon's press release, as well in the company's Form 10-K filed with the SEC. Back to you, Joseph.
spk04: Thanks, Peter. In closing, I want to thank the Innovio team for their tireless effort to support pandemic response and across our full DNA medicines platform. I recognize the heightened interests and concerns about the variant strains and their implications. I am pleased with the significant progress we continue to make on INO4800 as well as our ability to concurrently support exploration of a pan-COVID variant vaccine candidate designed to protect against existing variant strains as well as those yet to come. our ability to potentially serve as a safe and effective seasonal booster for those who have received INO4800, as well as those who have received other vaccines, would potentially offer extended protection as the virus evolves and becomes endemic. We look to sharing additional details about these concurrent efforts in the months ahead. With that, operator, Please open the lines for questions.
spk01: We will now begin the question and answer session. To ask a question, you may press star, then 1 on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star, then 2. At this time, we will pause momentarily to assemble our roster. The first question comes from Harthard Singh with Oppenheimer. Please go ahead.
spk12: Great. Thank you. Just a couple of quick questions and good work on all the progress, especially the trial today. Focusing on your, on INR4800, the COVID vaccine, Joe, if you can detail a little bit, you know, you've been working on the boosters, you know, patient population, gathering that data. You're also working on the mutations, assuming you start your phase three in the second quarter of this year, how could the clinical path forward look for, you know, additional getting boosters approved or the variant vaccines approved? And then secondly, you know, the Department of Defense funding for Innovate, in the press release you indicated you'll be getting funding from the department. Will that also entail a certain amount of vaccine doses that, you know, the U.S. government expects to get? from Inovio at a certain cost, for example, like other companies, you know, have had those agreements. Thank you for the questions.
spk04: Thanks, Sartaj. First question first. We're currently working through INO4800 development and our exploration of pan-COVID vaccine candidate in parallel. So we're marching along and executing our plans for phase two. and phase three part of the Innovate trial, which is funded through the DoD funding as mentioned. In terms of the pan-COVID-19 vaccine candidate, we're looking to move that along as rapidly as possible, leveraging our technology platform. The second part of your question was the funding from the DoD. Actually, we've been receiving multiple levels of funding. as it was covered in the prepared remarks. The first is a direct funding of our Phase 2 and Phase 3 Innovate trial. So that's directly funded through our CRO partner and coming from the DoD. And then there's a second level of funding that we have announced in June of last year. that involves the funding and completion of 3-PSP device, as well as some limited number of doses for the DOD, a few hundred thousand doses. And we could project that as we advance our program, those numbers can be increased potentially. So I hope that these answers are satisfactory, too.
spk12: Yeah, no, no, thank you, Joe. Just a quick follow-up. So, you know, the FDA has released some initial guidelines and correlates of protection to help, you know, companies that have vaccines against, you know, for example, a booster shot or a shot against variants. As the FDA broadens those guidelines out, do you foresee that helping you? You know, for example, if 4,800 gets approved, then you have follow-up vaccines falling quickly afterwards. using that correlates of protection guidance that FDA seems to be kind of arriving at. And thank you for all the questions.
spk04: Yeah, absolutely. I think that's a positive development provided by the FDA. And we expect these guidances to evolve as the landscape evolves with the concerns of the variants. So we expect to leverage all of these helpful guidances as we develop both INO4800 as well as our pan-COVID vaccine in the future.
spk12: Great. Thank you, Joe. Great.
spk01: The next question comes from Gregory Rinza with RBC Capital Markets. Please go ahead.
spk11: Hey, Joseph and team. Thank you for taking my question today. Joseph, just on 4800, just wanted to get a better sense perhaps of of the timelines and perhaps to your best estimation how they potentially line up. Just with the Phase 2, would that data be coming second quarter? And, you know, as we think about the Phase 3 up and running, I'm just curious the timeline on the FDA reply, just had a sense that it may have been in March, but maybe on recent disclosures, it might be looking more like a May event. So any clarity on how we should think about things lining up there would be great. Thank you very much.
spk04: Yeah, thanks, Greg. We're going to have a very busy second quarter. As I think we have alluded to, we expect phase two top line data to be available in the early part of the second quarter, as well as the completion of all of the device-related submission to be available by that time. So all of these submissions will be filed with the FDA at the same time. And once everything is filed, they have up to 30 days to concur with our plan or not. And we are very hopeful that we can do that this time, allowing us to move forward with the phase three portion in the later part of the second quarter this year.
spk11: Okay, got it. And then just turning to VGX 3100, just curious if you could provide some context and your thoughts on that significance of the 12.4% difference there, how you think about these results comparing to the previous studies in the Phase II, and perhaps just thinking more broadly about the differences between the modified intent-to-treat versus the intent-to-treat and on those subjects who either disconned or lost a follow-up. Thank you again.
spk04: That's great. I'll address the first part initially and then I'll ask Dr. Buyan to comment. Yes, I think the data is very significant for us. It's our first successfully met phase three trial data. And in terms of our meeting all the primary and secondary endpoints with regards to the HPV treatment, we're very excited about that and looking forward to executing the REVEAL-2 trial with the confirmatory data for this important product. We're really looking forward to bringing this product out as a first non-surgical treatment for these women who are suffering from HPV-caused high-grade cervical dysplasia Right now, the one true treatment option is surgery with potential to damage their cervical integrity and impact their reproductive health. So I think this is a very important product for us, for women's health, and all these patients who are seeking for non-surgical options not only to treat the disease, but also eradicate the virus that caused the disease from the cervix. We couldn't be any more excited about the data. Prakash, would you like to add anything else regarding Greg's question?
spk08: Sure. I'll just add that a good efficacy outcome is really the achievement of the primary endpoint. Really we're excited to have achieved that in all the valuable subjects for the REVEAL-1 trial. And looking back at phase two, we also achieved the primary and secondary efficacy objectives in that trial. So having now met that in both that trial as well now a pivotal phase three trial gives us really a great step forward. And, you know, we went into, in the prepared remarks, some of the descriptions of the MITT all-available subjects analysis and the ITT analysis. And so we, you know, the reasons really for the differences were the endpoint data that were missing and included as subjects who were considered non-responders in the ITT analysis. And so we provided both really for completeness, but we're really excited in terms of what we've seen now, not just for phase two, but also for phase three.
spk11: That's great. Thanks, Prakash. Thanks, Joseph.
spk05: Thank you.
spk01: The next question comes from Steve and Lily with Stiefel. Please go ahead.
spk06: Yeah, good afternoon. Thanks for taking the questions, Joseph. So maybe just to clarify then is, and I just want to make sure that the modified intent to treat was the pre-specified primary endpoint of reveal one and is also of reveal two.
spk04: Yeah, both modified intent to treat. Yeah, Prakash, why don't you take that?
spk08: Yeah, so both the modified intention to treat and the ITT are analyses that are pre-specified. We're also going to be doing a protocol analysis once we have complete data. So all three of those analyses are pre-specified in the trial protocol.
spk06: Are they co-primaries or is there some kind of hierarchy involved in terms of how they're statistically assessed?
spk08: Well, they're assessed in total, so they actually stand together, and so the evaluation is really done with all of the analyses once one has complete data. So it isn't really that the primary is based you know, in any one of them, the primary is evaluated under all three analysis conditions.
spk06: Okay.
spk08: But the MITT, specifically the MITT evaluates under having subjects who had data.
spk06: Okay. And I know that the patients are being followed to demonstrate durability of response, and I guess, Do we know from the phase two data what that durability of response looked like 18 months following last administration? And I guess has there been any kind of regulatory dialogue around what that durability needs to look like?
spk08: So we did actually publish a manuscript last year on the durability data from the phase two cohort. And that did follow subjects 18 months after their last administration. And what it showed was that for the women who responded to VGX3100 that there were no breakthroughs in terms of recurrence of viral infection and that their pap smears remained improved. And so there were no sort of regression from that. And that was very encouraging looking out 18 months. As far as the second part of your question, actually the reason why this trial goes out to week 88 is actually to provide that durability information. And we'll be continuing the trial out to week 88 to get that information.
spk06: Okay. That's very helpful. I guess maybe just lastly on 3100, I think, have you talked about what proportion of the treatment eligible patient population would be eligible, I guess, under this planned biomarker utilization?
spk08: So we did put that, you know, and Joseph touched on it in our prepared remarks. and we put some of that information also in our press release today. But we are really aiming for a biomarker that would have a very high level of predictability in terms of identifying women who are likely to respond to VGX3100. And in phase two, we actually observed 85% And we're working with, as Joseph mentioned earlier, a close partnership with QIAGEN to develop that. Okay.
spk06: So it's effective in predicting response in 85% of patients, and it could be used in all treatment-eligible patients, I guess. I'm just trying to figure out that if you were to apply what the biomarker is telling you about response to the 3100 eligible patient population, what would that haircut look like in terms of treatment eligible patients based on biomarker criteria?
spk08: I think as we continue to develop the biomarker with QIAGEN, we'll have more information on the specific characteristics and performance of the biomarker, so I think it's something that I would say you should look forward to as we go through the rest of the year. Joseph, is there anything you would add to that?
spk04: Yeah, no, I think you were pretty comprehensive. We look forward to confirming a lot of that information and bring those out in the coming year.
spk06: Okay. And I guess just lastly, sorry, would you... Would the biomarker also be used for the anal and vulvar trials as well?
spk08: So we haven't made that determination yet, but I think our first step is really to look, you know, with Kyogen at our lead indication, which is the cervical dysplasia indication. But, you know, you're touching on an important question, and I think as we continue to develop the biomarker, we hope to you know, give more of that information as we go along. Great. Thanks for taking the questions.
spk04: Great. Thank you, Steve.
spk01: The next question comes from Aiden Huzinov with Benchmark. Please go ahead.
spk13: Hi. Good afternoon. Hi, Aiden. Congratulations with the VJX 3100 and thanks for taking the questions. So the first one I have about INO4800. So you mentioned about pan-COVID vaccine candidates, you know, for known and potential unknown SARS-CoV-2 variants. Would you need another phase one trial for this potential vaccine candidate? And how difficult for other companies would it be to create pan-COVID candidates? And how differentiated is this for in all the others?
spk04: Yeah, very briefly, yeah, we think so, but based on some of the earlier guidances from the FDA regarding the variants for the vaccine developers, and also based on our overall safety profile of our platform and our COVID-9-04800 thus far, we think we can move quite rapidly. in the development of that program. But more information will be given. We just started that process, so we'll share with the street as we make progress.
spk13: Okay. And for the third booster, I think you mentioned 93 patients got the third booster in the Phase 2 trial, and could you specify what was the time lag after the second dose, and would you expect increase in efficacy in that specific subpopulation?
spk04: Yeah, so first of all, this was a Phase 1 subject. We had a total of 120, total pool of maximum 120 people from Phase 1. And amazingly, 93 out of 120 signed up to be boosted with 4,800. The fact, I think, is quite interesting itself. The shortest duration from the last vaccination was six months. The longest was around 10 months. So I think we can see, first of all, really Good information about the safety and tolerability of our boosting, number one. And so far it's consistent to our first two doses that we had seen in phase one. And then we're hopeful that we can show the expansion of antibody responses as well as CD4 and CD8 T cell responses. Those data are getting processed as the samples come in. from the booster study and we should have that available in our very productive second quarter of this year. So, you know, what we're excited about is confirming the safety of our boosting of INO4800 and the potential to expand and augment the immune responses to INO4800.
spk13: All right, appreciate that. Thanks a lot. And another one I have on VEGX3100, just want to confirm the timing of the expected results for review two, because it seems like it is being run in parallel. And also for companion diagnostic, would you think that given, even without companion diagnostic that would have been approved by the FDA if you had similar results for review two, and compounded diagnostic is more for adoption purposes. Just one.
spk04: Second question first, Aidan. We've been working with QIJEN and internally to develop a biomarker for VTGX3100 for the last several years, since the phase two results. And we think that's a significant step towards really raising the commercial attractiveness of VGX3100 during launch and post-launch. Being able to target the patients who would most benefit from our immunotherapy, I think it provides additional boost, pardon my pun, into the commercial attractiveness of this immunotherapy. The first part of the question, you know, Reveal 2 enrollment was hampered throughout last year, and we're still trying to recover from that, from the global COVID pandemic, just like many of the other companies' large trials. So we haven't provided the guidance on when we will finish. But once we have a more solid visibility, we will share with the street. Now, what I can tell you is due to the incredible hard work by our team, we're pretty much back to the pre-pandemic levels of early last year in terms of the recruitment. So I think we're beginning of the strong track back for Reveal 2 enrollment during a global COVID pandemic.
spk13: Okay. Thank you very much. Congrats again with the quarter.
spk04: Thank you.
spk01: Just a quick reminder to limit yourself to one question and one follow-up. The next question comes from Charles Duncan with Cantor Fitzgerald. Please go ahead.
spk03: Hi, Joe. Thanks for taking my questions, and congratulations on the progress, particularly the release of the 3100 Reveal 1 results today. That was a nice surprise. I guess I'm wondering, when you consider Reveal 1 and the enrollment of patients in that trial versus, say, the Phase 2 experience, how would you compare and contrast those two clinical trial samples?
spk04: Yeah, thank you. I'll briefly address and then ask Dr. Buyan to comment as well. So, you know, it's important, and thanks for reiterating that, Charles, is both in our Phase 3 Reveal 1, and our Phase IIb trial, there were both large 167 in Phase II and a little over 200 in Phase III trials. In both trials, we met all of the primary and the secondary endpoints based on the modified intention to treat statistical analysis. Now, these two trials were not designed to be cross-compared. But I'm going to ask, statistically, they were not designed. Phase III was not designed to be compared to 2B. But I will ask Prakash to comment on this a little further. Prakash?
spk08: Sure. So, yeah, your question is really about the enrollment of Phase 2 and then what we observed in the enrollment of Phase 3. And what we did in Phase 3 was we expanded our geography considerably. We actually were enrolling in five continents. We actually... pre-pandemic were on track to actually beat the enrollment rate that we had observed in Phase 2. And we were really, really, I think, you know, in a different world at that point. And then, of course, with the pandemic, really, we had to pivot and try to work with our trial sites as best as we could to address their local challenges. and their patient level challenges. And we're still, I think, in the middle of that struggle. So it's really, in that sense, in order to compare the enrollment characteristics of the two trials, I would say They were similar, if not actually better enrollment that we were starting to observe, which was really encouraging in terms of a much more expansive global footprint. But now we're dealing, of course, with a different situation, which is to make sure that our trial staff and their patients are all safe. in terms of how they participate in our trials. But I'm encouraged by what we've seen. We've not lost sight of what we need to do and really I think more and more trial sites have really been engaged. They've never lost their engagement and the fact is that that this disease, it simply does not go away. It hasn't gone away. And so we're simply not going to stop trying. And I'm hopeful that as the pandemic improves, we'll actually be able to get back to that rate.
spk03: Okay. I guess inherent in my question, I know that it's tough to compare across trials, but Inherent my question is when you consider the results of the Phase 2b versus the Reveal 1 results, which I was happy to see the statistical significance, it just seems like the effect size were a little bit more modest than in Phase 2b. And that's not uncommon, but I'm wondering if there are particular confounding variables that you're looking at to help explain the differences, or do you think that really one sample doesn't necessarily reflect the broader population?
spk08: Well, the two samples really do stand independently, and the key result is really the ability to meet the primary endpoint, which we're met. And as we go through the trial, once we have completed Reveal 1 and fully unblinded the trial, we'll be looking at the complete data set. to be able to understand the population characteristics better.
spk03: Okay, that's fair. And then if I can hop over to 4800 in terms of next steps. I'm sorry if I missed this. It was presented before. But in terms of this year being able to complete Phase 2b and then Phase 3, how do you feel about the current, you know, I guess, infection rates and then case rates? being able to provide even phase three data yet in 21.
spk04: Yeah, thanks, Chas. As I said, we expect to have the completed data from phase two studies in the early part of second quarter and will submit to the FDA to start the phase three. So our goal is to start the phase three trials in the latter part of second quarter this year. Now, the EUA vaccines are getting rolled out, and there's a couple of landscape changes. That's one, and then the advent of the new variants really dominating. For instance, the UK variant should be the dominant variant in the US by later this month. So within these landscape changes, One thing we're doing, as it was alluded to during the prepared remarks, is we're looking to look both in the U.S. and ex-U.S. to execute our Phase III trial. And we're looking to accelerate all of these efforts to make sure that we can get to our efficacy data of INO4800 as soon as possible. And then, in parallel, You know, we are also working to test what's the variant's impact on 4800 immunogenicity, as well as to leverage our Syncon technology to come up with the next generation pan COVID vaccine that could address the UK and South African and Brazilian variants directly. but also have the broad protection ability to protect against the future variants. Because otherwise you're just playing catch up. And as we have utilized this and honed this technology against influenza and HIV and other rapidly changing viruses, we're very confident that we have a strong technology to go after these ever-changing variants with the new program. And we plan to develop both concurrently, and we're very excited about just the fact that our technology would allow us to do that.
spk03: Let's question Joe, and this may be a total fire, and I apologize if it seems like it, but it's not meant to be. My question is What do you think about using your technology platform as a follow-up or booster to other vaccines? And I guess any in particular you think that that may be effective or additive in terms of efficacy without increasing tolerability issues? Is it possible that your platform could serve well as a booster?
spk04: Yeah, absolutely. And we cover some of those potential in the prepared remarks. And in fact, one of the reasons why we're doing a booster study in between six to 10 months of the last vaccination in our phase one cohorts is to demonstrate the safety and tolerability of that and the ability to boost the immune response as a booster. Now, of course, we've published a lot of papers around DNA vaccines from Inovio to serve as a booster to other vaccines like the viral vectors and maybe even messenger RNA. Quickly, we know we can tolerably deliver, such as in our GBM study, our patients receive half a dozen to a dozen boost across the timeframe of about two years in the clinical trials without any anti-vector response or any stunting of the immune response from INO5401. And we've seen similar impacts from other vaccines that we've been testing in Ebola and HIV and others. So we're very confident that this may be a very strong and potential long-term upside for NWO's vaccine program.
spk03: Thank you for taking my questions, Joe.
spk04: Great. Thank you, Charles.
spk01: The next question comes from Yi Chen with HCVainright. Please go ahead.
spk02: Hi. Thank you for taking my question. First question, just to follow up on the variability between the number of responders for the primary endpoint. between the Reveal 1 study and the Phase 2 study. So should we expect similar variability in the Reveal 2 readout? And how does that variability... I mean, how should we expect that variability transferred to... translate to commercial prospects of the drug?
spk04: Yeah, let me just quickly address that. Number one, you know, that's why We call it variability, but we call this right design. That's why we have a placebo-controlled and randomized double-blinded design to make sure that we can account for any variability within the trial. And we think the REVEAL-1 worked as we designed. as did the Phase IIb study, and we're very optimistic that same thing will continue in Reveal 2. And in terms of the commercial attractiveness, you know, that's why we're also adding the biomarker portion to increase the overall efficacy, absolute efficacy of VGX3100 by focusing, helping the clinicians and all of us focus on the right patient population who have the best chance of being helped by PGX3100 treatment. So we're on the right track and we're certainly excited with our Reveal 1 data and the progress we're making with Reveal 2, not to mention the progress we're making in the biomarker development with our partner QIGEN. So a lot more data to come in the coming year.
spk02: Got it. And a second question. So considering that Johnson & Johnson's COVID-19 vaccine is about to enter the market, Do you think a large portion of the population would prefer a one-dose regimen? And do you think that your next generation COVID-19 vaccine could have a one-dose regimen instead of two?
spk04: Well, you know, I think certainly one-dose regimen has a lot of attractiveness. But as I mentioned before, I think the one-dose regimen is a fool's goal. in that you would likely, almost every KOL is predicting that as we deal with this SARS-CoV-2 virus as an endemic stage, and as we look at the midterm and the long term of this virus, we're not going to eradicate the virus from the earth. It's going to be with us for many years. So likely there will be additional boosts. So really what the initial administration does, I think, is less of an importance than what you do in the long term. Now, that being said, of course, one could be better than two. But I think it's really the overall efficacy and safety. And then one thing to be concerned about is the potential tolerability of each boost. Some platforms are not set up to be used as a booster, like the viral vector platforms. You know, they're not really amenable because of the anti-vector response. There may be concerns about formulations in messenger RNA delivery that may increase the severity and frequency of adverse events after each dosing. but we'll need to track more data from the field in that regard. One thing I can tell you is what we have seen with Inovio's vaccines is we can boost almost forever. As I mentioned in our cancer vaccine trials, patients receive up to half a dozen to a dozen doses of our vaccine, same DNA with a different insert. and without any tolerability or safety issues. And we have, we look forward to demonstrating that with our booster study from INO4800, but we've seen and have published around our Ebola and HIV vaccine clinical studies in the past. So we have a strong confidence that INO4800 And our overall COVID vaccines based on our platform could be used as a booster both for our vaccine certainly and then potentially for other vaccines as well.
spk02: Got it. Thank you.
spk01: The next question comes from Chris Raymond with Piper Sandler. Please go ahead.
spk09: Hey, thanks for squeezing me in here at the end. Two questions. So it's first on VGX 3100. I know others have asked around Reveal 1 in the readout, but I don't think I really understand which population is used for the primary endpoint. And I apologize. I'm getting this question from a few investors. So I know all three, you know, ITT, modified ITT, and per protocol were pre-specified. But can you just say with clarity, Joseph, Did the FDA agree that it's just the modified ITT that can serve as the primary endpoint and that ITT is not part of the analysis, or is there some sort of statistical hierarchy?
spk04: Well, no. We plan to present all three, MITT, ITT, and PER protocol as well. And those were all specified, so you can think of that as three different methods But Prakash, would you like to comment on that question?
spk08: Yeah. I'll just add that, you know, so the, our expectation is that the FDA will review everything, of course. And so they will review, as Joseph said, all three analyses that were pre-specified in the trial protocol. And they'll also be reviewing the data from our Reveal 2 trial. And so it really is a comprehensive review of everything. The reason we put the MITT and ITT results in was really just to be complete and show you all of the data in terms of what was analyzed.
spk04: So just to quickly add, Chris, to what Prakash said the only difference between MITT and ITT is 8 subjects whose endpoint data was not available at week 36 and they were confounding the breakdown of 7 of those missing endpoints in the TRIA group versus the one in the placebo group as it, you know, that was very skewed and unbalanced. So, you know, that occurring in Reveal 2, I think, is highly unlikely as the trial is 2 to 1 randomized. So, you know, if you look at the stats, only difference, and that's only the only way, only reason we're talking about this is because of those unbalanced missing data points.
spk09: Right, okay. Thank you. And then maybe just a follow-up then. I know 4,800. So just on the response time to the FDA, I was just looking back at your January prospectus, and that was, I think, about five weeks ago. You guys were still guiding to March as the goal to respond to the FDA. And I know on this call now you're saying it's May, or at least in your regulatory filings you said it's May. So can you maybe provide, you know, any specifics as to what's causing that pushback? Since it just kind of seems like it just really happened very recently.
spk04: Well, it's, you know, we've been guiding by end of March or early second quarter, I believe beginning of this year as well. It's just compiling all of the data and even from the data from our booster studies which would provide a comprehensive package for the FDA, including all of the device-related and other responses. So, you know, we are on track to do that in the early part of second quarter now. Okay.
spk09: All right. Thanks very much, guys.
spk04: Yep. Thank you.
spk01: This concludes our question and answer session. I would like to turn the conference back over to Joseph Kim for any closing remarks.
spk04: Thank you very much, everyone. Have a great evening.
spk01: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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