Inovio Pharmaceuticals, Inc. (INO) Q4 2020 Earnings Report, Transcript and Summary

Good day and welcome to the Inovio Fourth Quarter 2020 Financial Results Conference Call. All participants will be in a listen-only mode. [Operator Instructions] After today’s presentation, there’ll be an opportunity to ask questions. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to Ben Matone. Please go ahead.

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 Kies, Chief Financial Officer; Dr. Jackie Shea, Chief Operating Officer; Dr. Laurent Humeau, Chief Scientific Officer; Dr. Kate Broderick, Senior Vice President of Research and Development; and Dr. Prakash Bhuyan, Senior Vice President of Clinical Development and Medical Lead for REVEAL 1, the company’s Phase 3 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 programs progress, which includes our COVID-19 vaccine program and today’s release regarding our Phase 3 clinical study for cervical dysplasia known as REVEAL 1. This call is being webcast live on our website, ir.inovio.com, and a replay will be made available. Following prepared remarks, we will be conducting a question-and-answer segment reserved for equity research analysts. 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 and 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 Kim.

Thank you, Ben, and good afternoon, everyone. We have a lot to discuss following this afternoon’s Phase 3 VGX-3100 announcement. And I want to ensure we cover our other key programs and allow time for endless 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 HPV therapeutic landscape and the Inovio platform validation. Later in the call, Dr. Prakash Bhuyan and Dr. Kate Broderick will discuss the latest developments in our HPV and COVID-19 vaccine programs. Also our CFO, Peter Kies 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 1 top 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 VGX-3100 resulted in regression of high-grade dysplasia and clearance of underlying HPV-16 and/or 18 virus, which caused these in the first place. Today also represents a giant milestone for the company. This afternoon’s release on positive REVEAL 1 efficacy data is the first Phase 3 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 VGX-3100 as the first DNA medicine to achieve efficacy endpoints in a Phase 3 clinical trial. I am so thankful for all trial volunteers, study staff and partners, as well as Inovio team who are dedicated to bringing in VGX-3100 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. Bhuyan, who will discuss REVEAL 1 data in greater depths, I do want to remind everyone that REVEAL 1 is the first of two Phase 3 trials with VGX-3100 for the treatment of cervical HSIL, 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 VGX-3100 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 VGX-3100 in women 18 years of age or older, who have histologically confirmed cervical dysplasia or HSIL. So with an eye towards optimizing the commercial attractiveness of VGX-3100, just last week, Inovio expanded its master collaboration agreement with QIAGEN to co-develop a companion diagnostic based on RNA sequencing technology to help guide clinical decision-making for the use of VGX-3100. The goal of this project is to develop a pre-treatment RNA based blood tests for prospective VGX-3100 patients to better identify the patients who would most likely to respond to VGX-3100, which compliments and raises the eventual commercial profile for VGX-3100. This biomarker technology had previously been employed in a post-hoc assessment of VGX-3100 Phase 2b data by Inovio, where it correctly predicted efficacy in 85% of VGX-3100 to the subjects. We plan to have the companion diagnostic available prior to the licensure of VGX-3100. With that, I would like now to turn the call over to Dr. Bhuyan, who will discuss today’s release of REVEAL 1 data. Prakash?

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 3 pivotal trial evaluating VGX-3100 as an immunotherapy for the treatment of high-grade pre-cancerous cervical HSIL caused by HPV-16 and/or HPV-18. Importantly, the company achieved the primary and secondary efficacy objectives amongst all the valuable 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 pre-cancer 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 HSIL, but who were otherwise healthy. Participants received either VGX-3100 or placebo at 0, 4 and 12 weeks randomized at 2:1 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 histopathological regression of HSIL 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 HSIL to normal tissue combined with HPV-16, HPV-18 viral clearance, regression of cervical HSIL alone, regression of cervical HSIL 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 a valuable 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 VGX-3100 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 VGX-3100 towards treating vulvar and anal high-grade dysplasias. We plan to seek regulatory guidance on the pathway to develop VGX-3100 to treat HPV-driven vulvar and anal HSIL. 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.

Thank you, Prakash, and to your team, for an amazing work on providing patients with an alternative therapeutic option to surgery. We look forward to the team’s continued effort to bring VGX-3100 to patients dealing with cervical pre-cancer. Moving now to INO-5401 in GBM. We had a productive fourth quarter across all of our DNA medicines platform. In addition to the continued developments and events occurring within our HPV and COVID-19 programs, we presented encouraging results in the landmark combination trial for GBM at the Snow 2020 Annual Meeting last November. Along with our partner Regeneron, we are continuing to review INO-5401 in combination with some cemiplimab branded as Libtayo, which is co-developed by Regeneron and Sanofi with an emphasis on identifying patients who are most likely to benefit from this INNOVATE 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 INO-5401. 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 Inovio team in contributing to the global efforts to combat COVID-19. And we are thankful for all the Phase 1 and 2 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. INO-4800’s key differentiators are the safety and tolerability data, as well as its excellent thermo stability profile, making it possible to manufacture at scale and transport without frozen cold chain requirements. INO-4800 also maintains the ability to be safely re-administered and is further differentiated by its ability to stimulate both CD4 and CD8 T cell responses along with generating antibody responses as published in EClinicalMedicine, a peer-reviewed, open access journal published by The Lancet. In parallel to our extensive ongoing INO-4800 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 INO-4800, 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?

Thank you, Joseph. Firstly, I’d like to see 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 CELLECTRA, 3PSP smart device, production of doses, and the procurement of CELLECTRA 2000 devices. As we stated in this afternoons’ earning press release, we continue to be focused on and we’ll complete the Phase 2 segment of our Phase 2/3 INNOVATE trial of INO-4800 early second quarter. As a reminder, there is a dose finalization component, selection of the doses based on week six immunogenicity and week eight safety data. Our Phase 2 segment is designed to evaluate safety, tolerability and immunogenicity of INO-4800 in a two dose regime, either one or two milligrams in a 3:1 randomization to receive either INO-4800 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 old, 51 to 64 year olds and 65 and older for the part for the subsequent Phase 3 efficacy evaluation. Additionally, we are also completing review of the interim expanded Phase 1 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 3 portion of INNOVATE clinical trial, which remains a partial clinical hold at this time due to the FDA’s remaining question related to the CELLECTRA 2000 device that will be used to deliver INO-4800. 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 an Inovio’s ex-U.S. activities and Inovio’s collaborators are advancing the clinical testing of INO-4800 in a Phase 2 setting. Advaccine with Inovio entered into an exclusive collaboration and license agreement for INO-4800 in greater China, is conducting a 640 subject Phase 2 clinical trial of INO-4800. And the International Vaccine Institute in South Korea is also in Phase 2a segment of its Phase 1/2a trial of INO-4800. We expect that the data from these two trials will be available later this year. In compliment to our INO-4800 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 INO-4800 foresees no boosting for those who have already received doses of INO-4800. 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 1 trial on our nonhuman primate studies. Given our overall safety profile and Inovio’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 Inovio’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, Inovio has been able to provide a third booster with INO-4800 in 93 out of 120 subjects from our Phase 1 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 1 trial of INO-4800. We look forward to sharing their immune response data with you in the second quarter. Inovio was also being diligent in the manufacturing side of INO-4800 development. We continue to build our global manufacturing consortium, which includes Thermo Fisher Scientic, Richter-Helm BioLogics and Ology Biosciences to ensure the ability to meet global demand. In the fourth quarter, we added Kaneka Eurogentec to the consortium. Inovio was 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 agrees, which would be used both by the CELLECTRA 2000 and the CELLECTRA 3PSP devices. Next, and at the top of mind for many at the moment, I’ll speak to the potential advantages 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 Inovio’s DNA vaccine technology is the ability to respond to emerging infectious diseases through rapid vaccine construct design and manufacture. As an example, INO-4800 was rapidly designed following the receipt of the Wuhan SARS-CoV-2 viral sequence from China. In addition, the optimization process of Inovio DNA medicines confers the ability to potentially deliver cross-strain presentation and pan-variant coverage mitigating the risk of the currently circulating strain variant, as well as potentially the new mutant strains that could appear. We have previously demonstrated the functional capability of this technology. Inovio’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 streams of the H1N1 and H3N2 influenza viruses since 1918, demonstrating complete protection against heterologous lethal challenges. Inovio has also been closely monitoring the development and evolution of COVID-19 mutations with a particular focus on the UK, South African and Brazilian variant, 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. And we’ll be always taking a two-pronged approach to the emerging crisis caused by the new variants. With INO-4800, we are currently testing the impact that these new strains have on the immunogenicity profile of the vaccine through doing an assessment of neutralizing antibodies in both wide and pseudo virus assay, as well as assessing the impact of the generating T-cell responses on these variants. In addition to the ongoing INO-4800 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 strain, 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 INO-4800. And with that I’ll hand back to Joseph.

Thank you, Kate. I want to summarize the capabilities of Inovio’s platform that’s related to the emerging variant crisis that Kate touched on. Our DNA vaccines platform has the potential to mitigate the risks 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 react to genicity issues on an annual or semi-annual basis to provide participants with persistent and tailor protection. And additional two key characteristics to 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 Kies for a brief financial update. Peter?

Thank you, Joseph. Good afternoon, everyone. As Joseph mentioned, Inovio enters 2021 well-positioned financially with total cash, cash equivalents and short-term investment of 411.6 million as of December 31, 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 2 and Phase 3 for Inovio 4800. Turning now to our quarterly financial results, total revenue for the three months ended December 31, 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 31, 2020 was 24.3 million or $0. 14 per share, basic and dilutive compared to a net loss of $37.7 million or $0.38 per share basic and dilutive for the quarter ended December 31, 2019. Research and development expenses for the three months ended December 31, 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 CELLECTRA 3PSP device, these increases were offset by an increase in our contract research and development expense recorded from grant agreement among other variances. Lastly, general and administrative expenses were 8.6 million for the three months ended December 31, 2020 versus 8.7 million 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.

Thanks Peter. In closing, I want to thank the Inovio team for their tireless efforts to support pandemic response across our full DNA medicines platform. I recognize the heightened interest and concerns about the variant strains and their implications. I am pleased with the significant progress we continue to make on INO-4,800 as well as our ability to concurrently support exploration of pan-COVID variant vaccine candidate designed to protect against existing variant strains as well as those yet to come. Equally, our ability to potentially serve as a safe and effective seasonal booster for those who have received INO-4800 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.

[Operator Instructions] The first question comes from Hartaj Singh with Oppenheimer. Please go ahead.

Great. Thank you. Just a couple of quick questions. And good work on all the progress especially the trial today. Focusing on your INO-4800 the COVID vaccine, Joe if you can detail a little bit, you’ve been working on the boosters, patient population gathered that data. You’re also working on the mutations. Assuming you start your Phase 3 in the second quarter of this year, how could the clinical path forward look for additional getting boosters approved or the variant vaccines approved? And then secondly, the Department of Defense funding for INNOVATE, in the press release you indicated you’ll be getting funding from the Department. Would that also entail a certain amount of vaccine doses that the U.S. government expects to get from Inovio at a certain cost, for example like other companies that had those agreements? Thank you for the questions.

Thanks, Hartaj. First question first, we’re currently working through INO-4800 development and our exploration of pan-COVID vaccine candidate in parallel. So we’re marching along and executing our plans for Phase 2 and Phase 3 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 from – 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 3PSP 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 these answers are satisfactory to you.

Yes, no, no, thank you, Joe. Just a quick follow-up. So the FDA has released some initial guidelines on correlates of protection to help companies that have vaccines against a boon, for example, a booster shot or a shot against variants. As the FDA broadens those guidelines out, do you foresee that helping you, for example, if 4800 gets approved, then you have follow-up vaccines following quickly afterwards using that correlates of protection guidance that FDA seems to be kind of arriving at. And thank you for all the questions.

Yes, 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 INO-4800 as well as our pan-COVID vaccine in the future.

Great. Thank you, Joe.

Great.

The next question comes from Gregory Renza with RBC Capital Markets. Please go ahead.

Hey, Joseph and team, thank you for taking my question today. Just on –

Hi, Greg.

Hey. Just on 4800, just wanted to get a better sense perhaps of the timelines and perhaps your best estimation how they potentially line up just with the Phase 2. Would that data be coming in second quarter? And 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 that 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.

Yes, thanks, Greg. We’re going to have a very busy second quarter as I think we have alluded to we expect the Phase 2 top line data to be available in the early part of the second quarter as well as a 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 3 portion in the later part of the second quarter this year.

Okay, got it. And then just turning to VGX-3100, just curious if you could provide some context on 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 2? And perhaps just to thinking more broadly about the differences between the modified intent to treat versus the intent to treat and on those subjects who were either discard or lost to follow up. Thank you again.

Yes, Greg. I’ll address the first part initially, and then I’ll ask Dr. Bhuyan to comment. Yes, I think the data is very significant for us, so first successfully met Phase 3 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 cause high-grade cervical dysplasia. Right now, the one true treatment option is surgery with potential to damage their cervical integrity and impact reproductive health. So I think this is a very important product for us for women’s health and all of these patients who are seeking for non-surgical option, not only to treat the disease, but also eradicate the virus that caused the disease from the cervix. So we couldn’t be any more excited about the data. Prakash, would you like to add anything else regarding Greg’s question?

Sure. So I’ll just add that a good efficacy outcome is really the achievement of the primary endpoint. And so really we’re excited to have achieved that in all the valuable subjects for the REVEAL 1 trial. And looking back at Phase 2, we also achieved the primary and secondary efficacy objectives in that trial. So having now met that in both that trial as well as now a pivotal Phase 3 trial gives us really a great step forward. And we went into in the prepared remarks some of the descriptions of the MITT all the valuable subjects’ analysis and the ITT analysis. And so we – 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 2, but also for Phase 3.

That’s great. Thanks, Prakash. Thanks, Joseph.

Thank you.

The next question comes from Stephen Willey with Stifel. Please go ahead.

Yes, good afternoon. Thanks for taking the questions.

Hi, Steve.

Hey, Joseph. So maybe just to clarify then, I just want to make sure that the modified intent to treat was the pre-specified primary endpoint of REVEAL 1 and is also of REVEAL 2.

Yes, both modified intent to treat – yes, Prakash, why don’t you take that?

Yes. 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 those – all three of those analyses are pre-specified in the trial protocol.

Are they co-primaries or are they – is there’s some kind of hierarchy involved in terms of how they’re statistically assessed?

Well, they’re assessed in total. So they actually stand – they stand together. And so the evaluation is really done with all of the analyses one has complete data. So it isn’t really that the primary is based – in any one of them, the primary is evaluated under all three analysis condition.

Okay.

But the MITT, specifically the MITT evaluates under having subjects who had data.

Okay. And I know that the patients are being followed to demonstrate durability of response. And I guess, do we know from the Phase 2 data what that durability of response will look 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?

So we did actually publish a manuscript last year on the durability data from the Phase 2 cohort, and that did follow subjects 18 months after their last administration. And what it showed was that for the women who responded to VGX-3100, 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 with the trial out to week 88 to get that information.

Okay. That’s very helpful. And 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 plan to biomarker utilization?

So we did put that and Joseph touched on it in our prepared remarks, and we put some of that informational so 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 VGX-3100. And in Phase 2 we actually observed 85%. And we’re working with, as Joseph mentioned earlier, post partnership with QIAGEN to develop that.

Okay. 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?

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?

Yes. No, I think you were pretty comprehensive. We look forward to confirming lot of that information and bring those out in the coming year.

Okay. And I guess just lastly, sorry. Would the biomarker also be used for the anal and vulvar trials as well?

So we haven’t made that determination yet, but I think our first step is really to look with QIAGEN at our lead indication, which is the cervical dysplasia indication. But you’re touching on an important question and I think as we continue to develop the biomarker, we hope to give more of that information as we go along.

Great. Thanks for taking the questions.

Great. Thank you, Steve.

The next question comes from Aydin Huseynov with Benchmark. Please go ahead.

Hi, good afternoon.

Hi, Aydin.

Congratulations with – hi, Joe, the quarter with VGX-3100. And thanks for taking the questions. So the first one I have about INO-4800. So you mentioned about pan-COVID vaccine candidates from known and potential unknown SARS-CoV-2 variants. Would you need another Phase 1 trial for these potential vaccine candidates? And how difficult for other companies would be to create pan-COVID candidates and how differentiated is this for Inovio?

Yes. Very briefly – yes, 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, INO-4800 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 make progress.

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 that specific subpopulation?

Yes. So first of all, this was a Phase 1 subjects. 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 4800, the fact I think is quite interesting itself. The duration was – 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 1. 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 we’re excited, but it’s confirming the safety of our boosting of INO-4800 and the potential to expand and augment the immune responses to INO-4800.

All right, appreciate that. Thanks a lot. And another one I have on VGX-3100, just want to confirm the timing of the expected result for REVEAL 2, because it seems like it is being run in parallel. And also for companion diagnostic, would you think that given even without companion diagnostic they would have been approved by the FDA, if you had similar results for REVEAL 2? And companion diagnostic is more for adoption purposes. Just one…

Yes. Second question first, Aydin. We’ve been working with QIAGEN and internally to develop a biomarker for VGX-3100 for last several years since the Phase 2 results. And we think that’s a significant step towards really raising the commercial attractiveness of VGX-3100 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, 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.

Okay. Thank you very much. Congrats again on the quarter.

Thank you, Aydin.

[Operator Instructions] The next question comes from Charles Duncan with Cantor Fitzgerald. Please go ahead.

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 the 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?

Yes, thank you. I’ll briefly address and then ask Dr. Bhuyan to comment as well. So it’s important and thanks for reiterating that Charles, both in our Phase 3 REVEAL 1 and our Phase 2b trial. There were both large 167 in Phase 2 and little over 200 in Phase 3 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 3 was not designed to be compared to Phase 2b, but I will ask Prakash to comment on this little further. Prakash?

Sure. So yes, 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 we’re on track to actually beat the enrollment rate that we had observed in Phase 2. And we were really, I think 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, but 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 global – a much more expansive global footprint. So, 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. So 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.

Okay. I guess inherently 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 was – I was happy to see this 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 compounding 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?

Well, the two samples really do stand independently. And the key result is really the ability to meet the primary endpoint, which were 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.

Okay. That’s fair. And then if I can hop over to INO-4800 in terms of next steps, I’m sorry if I missed this one 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 I guess infection rates and then case rates being able to provide even Phase 3 data yet in 2021?

Yes, thanks Charles. As I said, we expect to have the completed data from Phase 2 studies in the early part of second quarter and we’ll submit to the FDA to start the Phase 3. So our goal is to start the Phase 3 trials in the latter part of second quarter of this year. Now, the UA 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 U.S. 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 3 trial. And we’re looking to accelerate all of these efforts to make sure that we can get to our efficacy data of INO-4800 as soon as possible. And then in parallel, we are also working to test what’s the variant’s impact on INO-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 Africa 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.

Last 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?

Yes, absolutely. And we covered 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 1 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 boosts across the timeframe of about two years in the clinical trials, without any anti-vector response or any stunting of the immune response from INO-5401. And we’ve seen similar impacts from other vaccines and 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 Inovio’s vaccine program.

Thank you for taking my questions, Joe.

Great. Thank you, Charles.

The next question comes from Yi Chen with H.C. Wainwright. Please go ahead.

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 read out and how does that variability – how should we expect that variability to transfer – to translate to commercial prospects of the drug?

Yes, let me just quickly address that. Number one, that’s why you call it variability, but we call this right design that’s why we have a placebo control 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 the Phase 2b study. And we’re very optimistic that same thing will continue in REVEAL 2. And in terms of the commercial attractiveness, that’s why we’re also adding the biomarker portion to increase the overall efficacy, absolute efficacy of VGX-3100 by focusing, helping the clinicians and all of us focused on the right patient population, who have the best chance of being helped by VGX-3100 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 QIAGEN, so a lot more data to come in the coming year.

Got it. And the 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?

But, I think certainly one-dose regimen has lot of attractiveness. But as I mentioned before, I think the one-dose regimen is a fool school, in that you would likely, almost every KOL is predicting that as we deal with this COVID, SARS-CoV-2 virus as an endemic stage, and as we look at the mid-term 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 boost. 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 they’re not really amenable because of the entire vector response. There may be concerns about formulations in messenger RNA delivery that may increase the severity and the frequency of adverse events to reach 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 the different insert and without any tolerability or safety issues. And we look forward to demonstrating that with our booster study from INO-4800, 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 INO-4800 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.

Got it. Thank you.

Next question comes from Chris Raymond with Piper Sandler. Please go ahead.

Hey, thanks. 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 and 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, 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?

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 a three different methods. But Prakash would you like to comment on that question?

Yes. I’ll just add, so 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.

Just to quickly add Chris to what Prakash said, the only difference between MITT and ITT is eight subjects whose endpoint data was not available at week 36. And there were confounding break – the breakdown of seven of those missing end points in the trio group versus the one in the placebo group that was very skewed and unbalanced. So that occurring in REVEAL 2 I think is highly unlikely, as the trial is 2:1 randomized. So, if you look at the stats, only difference, the only reason we’re talking about this is because of those unbalanced missing data points.

Right. Okay. Thank you. And then maybe just follow-up on INO-4800, 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 the March as the goal to respond to the FDA. And now 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 any specifics as to what’s causing that pushback, since it’s just kind of half, it seems like it just really happened very recently.

It’s – we have 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 we would provide a comprehensive package for the FDA including all of the device related and their responses. So we are on track to do that in the early part of second quarter now.

Okay. All right. Thanks very much, guys.

Yes. Thank you.

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

Yes. Thank you very much everyone. Have a great evening.

The conference is now concluded. Thank you for attending today’s presentation. You may now disconnect.