PDS Biotechnology Corp (PDSB) 2022 Q4 法說會逐字稿

Hello, and welcome to the PDS Biotechnology Fourth Quarter 2022 and Full Year Earnings Call and Conference Call. (Operator Instructions) As a reminder, this conference is being recorded. It's now my pleasure to turn the call over to Gabrielle DeGravina of CG Capital Investor Relations. Please go ahead.

Good morning, and welcome to PDS Biotechnology's Fourth Quarter and Year-End 2022 Earnings Conference Call and Audio Webcast. On the call from the company are Dr. Frank Bedu-Addo, Chief Executive Officer; Dr. Lauren B. Wood, Chief Medical Officer; and Matt Hill, Chief Financial Officer.

Earlier this morning, PDS Biotech issued a press release announcing financial results for the quarter and full year ended December 31, 2022. We encourage everyone to read the press release as well as PDS Biotech's report on Form 10-K, which will be filed with the SEC shortly. The company's press release is available on the PDS website at pdsbiotech.com.

In addition, this conference call is being webcast and will be archived on the company website for future reference.

Before we begin, we need to remind everyone that on today's call, the company will be making forward-looking statements regarding regulatory and product candidate development plans as well as research activities. Certain information in this presentation may include forward-looking statements, including within the meaning of Section 21E of the United States Securities Exchange Act of 1934 as amended in Section 27A of the United States Securities Act of 1933 as amended, concerning PDS Biotechnology Corporation and other matters.

These statements may discuss goals, intentions and expectations as to future plans, trends, events, results of operations or financial conditions or otherwise, based on current beliefs of the company's management as well as assumptions made by and information currently available to management. These statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted.

A description of these risks can be found in PDS Biotech's most recent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this conference call.

So to the extent required by applicable law or regulation, PDSB undertakes no obligation to update the forward-looking statements included today to reflect subsequent events or circumstances.

With that, I will hand the call over to Dr. Frank Bedu-Addo. Frank?

Thank you, Gabby, and thank you all for joining us on our year-end call today. We have made tremendous progress this past year, achieving several significant milestones as we continue to advance our oncology pipeline, most importantly, progressing closer towards a registrational trial for our lead candidate, PDS0101.

PDS0101 is a novel investigational human papillomavirus or HPV targeted immunotherapy that stimulates a potent targeted T cell attack against HPV-positive cancers. Our goal is to commercialize PDS0101 as rapidly as possible by performing a well-designed Phase III trial that maximizes our potential for both speed and success.

Therefore, our key priority in 2023 is to move forward efficiently with finalizing the development of PDS0101 for the treatment of HPV-positive head and neck cancer in immune checkpoint inhibitor or ICI-naive patients.

Before we move into the fourth quarter update, I would like to briefly mention the recent meetings we have had with the U.S. Food and Drug Administration, also known as the FDA. These meetings were held to discuss the registrational pathways for our 2 most advanced Phase II trials, VERSATILE-002 and the National Cancer Institute-led or NCI-led triple combination trial.

In both meetings, the FDA provided very useful guidance on key elements of both trial designs. Therefore, we will be transitioning into Phase III clinical development this year, informed by the ongoing and maturing data from VERSATILE-002. This randomized controlled Phase III trial will investigate PDS0101 in combination with KEYTRUDA versus KEYTRUDA alone in ICI-naive patients with recurrent or metastatic HPV 16 positive head and neck cancer. The Phase III trial will be called VERSATILE-003.

In parallel, we will continue activities necessary to progress the NCI-led triple combination of PDS0101, PDS0301, formerly known as M9241 or NHS IL-12 with an approved immune checkpoint inhibitor or ICI.

Let's now touch on the VERSATILE-002 Phase II trial update. The trial is investigating PDS0101 in combination with Merck's ICI KEYTRUDA, also known as pembrolizumab, in both ICI-naive and refractory patients.

Interim results presented at ASCO 2022 demonstrated promising efficacy and safety profiles for the combination.

Data from 17 patients with available imaging showed an objective response rate of 41%, which included confirmed and unconfirmed responses. At 9 months of follow-up, the overall survival rate was 87%. In the published KEYNOTE-048 study, the 9-month overall survival rate for KEYTRUDA monotherapy was approximately 60%.

We believe that the parameter of highest relevance to the FDA is the overall survival, as in many immunotherapies, improvements in objective response rate, or ORR, and progression-free survival, or PFS, have not translated to improved overall survival or OS.

It should be noted that in recurrent or metastatic head and neck cancer, where an FDA-approved drug has been shown to improve survival such as KEYTRUDA has, overall survival becomes the most important criteria by which the new drug or combination will be evaluated.

As a reminder, this program has received fast-track designation from the FDA. Following our FDA meeting in the third quarter of 2022, we initiated a tech transfer of the PDS0101 manufacturing process to our selected commercial manufacturer for the scale-up and production of PDS0101 for VERSATILE-003.

The transfer was successful and the Phase III clinical product was successfully completed this quarter. The final sections of the chemistry, manufacturing and control section also known as CMC of the amended IND are in progress.

Most importantly, we are gaining insight into the potential progression-free survival and overall survival data that continue to mature from VERSATILE-002. These PFS and overall survival data are critical to our ability to design the statistical portion of the Phase III clinical study.

The duration it has taken for us to begin to gain insight to these critical parameters and possible endpoints is highly encouraging, as it signifies that the majority of patients are staying alive and not rapidly progressing. As I mentioned, overall survival is the most important parameter by which the FDA typically prefers to confirm approval of oncology products.

We are hopeful, based upon previously presented and ongoing results, that we will be able to show improved PFS and OS with the PDS0101 KEYTRUDA combination.

We are also currently in communication with the European regulatory agencies and expect feedback on the VERSATILE-003 clinical protocol and CMC section in the second quarter of this year. If possible, we intend to also incorporate their comments into the final protocol design that will be submitted to the FDA and other country-specific agencies will review. We, therefore, expect to file an amended IND in the third quarter of this year, which should allow us to present the protocols to the investigational review boards or IRB for the various sites as we perform the process of site activation. Overall, these start-up activities typically take 4 to 6 months.

We are working towards the goal of opening up the trial in the fourth quarter of this year and expect the trial to be run at 90 to 100 global sites. There are a number of reasons why we have decided to progress the versatile 003 trial ahead of the triple combination. First of all, obtaining an approval for the PDS0101 product specifically simplifies our development of future combinations of other agents such as PDS0301 with PDS0101 from a regulatory perspective. IND-related activities are further progressed with this program due to the earlier FDA meeting and also the clear regulatory pathway for combination of an investigational agent with commercial approved product.

Importantly, we have fast track for this program and with our clinical design, having good potential for PDS0101 to become the first approved immunotherapy to address HPV-positive cancer. In parallel, we continue to aggressively work towards getting the triple combination to a similar position and will provide updates on progress in the future. So transitioning to updates on the NCI-led Phase II triple combination trial for patients with advanced HPV-positive cancers.

Last month, we announced a successful meeting with the FDA for the triple combination of PDS0101 and PDS0301 with an FDA-approved ICI for the treatment of recurrent or metastatic HPV16-positive ICI refractory head and neck cancer. Our ability to replace the investigational ICI with a commercial ICI simplifies the regulatory pathway to develop the triple combination. Our strategic decision to acquire the novel antibody conjugated IL-12 now PDS0301 has mitigated operational risk and potential hurdles in moving the program forward. It has also unencumbered the agent for broader use in our pipeline.

Importantly, by replacing the investigational ICI with a commercial ICI and acquiring PDS0301, we also simplified and clarified the future economics pertaining to the current and future commercial combinations of PDS0301 with our pipeline products or other products.

It is also important to note that the PDS0301 acquisition deal does not financially burden development of the product as very minimal payments are due ahead of successful commercialization. This agreement also includes the supply of the clinical PDS0301 product by Merck KGaA, Darmstadt Germany.

This partnership, as you can see, therefore maximizes the potential for development and financial success for both parties. We are extremely pleased with our partnership with Merck KGaA and with the updated survival outcome results we reported from the triple combination last quarter.

PDS Biotech has selected advanced ICI refractory HPV 16-positive head and neck cancer as the initial indication for which the triple combination will be developed. These patients have few options and no clear effective standard of care therapy despite the severity of the disease.

Survival data from the trial has been encouraging, and the triple combination therapy appears to be reasonably well tolerated with grade 3 adverse events reported in 43% of patients and grade 4 treatment-related adverse events reported in only 7% of patients.

In December, we reported expanded National Cancer Institute interim data that included 50 patients. Of those, 37 HPV 16-positive patients were evaluable and 29 out of the 37 patients had failed ICI treatment and were, therefore, ICI refractory.

Median overall survival was 21 months in the 29 ICI refractory patients who received the triple combination. Of note, the reported historical median overall survival in patients with HPV-positive ICI refractory disease and treated with an ICI is only 3 to 4 months. As we announced on February 27, after our FDA meeting, our trial of the triple combination will initially target ICI refractory HPV 16-positive head and neck cancer. The best published median overall survival data to date in ICI refractory head and neck cancer is 8.2 months.

The expanded data continued to demonstrate the durability and tolerability of the PDS0101-based triple combination therapy in advanced HPV-positive cancers, and it is exciting to see consistency in the data with each update.

Moving on to the MD Anderson led IMMUNOCERV Phase II trial. This study is being performed in patients with locally advanced cervical cancer with large tumors over 5 centimeters in size. Remarkable clinical and biomarker data were presented at SITC 2022. 100% of patients treated with the combination of PDS0101 and standard of care chemoradiation therapy had a clinical response with tumor shrinkage greater than 60%. 89% or 8 of the 9 patients treated with the combination demonstrated a complete response, or CR, with no evidence of the disease on day 170.

These results are encouraging, and we look forward to updating you when additional data becomes available. The Mayo Clinic continue studying PDS0101 in early-stage premetastatic HPV 16-positive oral cancer in a Phase II trial. Patients continue to be recruited and treated, and we are hopeful that we'll see data before the end of this year.

As we've mentioned before, the Mayo Clinic study is an investigator-initiated trial, meaning we do not have control over its progress, enrollment and treatment or the timing around data readouts. However, our expectation is that steady investigators would present preliminary data when available at a medical congress.

Moving on to our broader oncology pipeline. Tech transfer for PDS0103 is in progress. Pending availability of manufacturing slots and all the activities associated with initiating VERSATILE-003, we are hoping to file the IND in the second half of this year.

We expect to file the IND for PDS0102 in 2024. Before I turn the call over to Lauren, I will reiterate that we plan to initiate the VERSATILE-003 Phase III trial by the fourth quarter of this year. We continue to make significant progress with the program.

Clinical manufacturing is complete. Late-stage CMC activities are ongoing as well as finalization of the clinical protocol, and we expect to file the amended IND in the third quarter.

I will now turn the call to Lauren to walk us through the clinical updates.

Thanks, Frank. I'd like to recap some of the exciting data we announced in the last several months. With respect to PDS0301 monotherapy, clinical research conducted by the NCI was recently published in the peer-reviewed journal International Immunopharmacology. The study assessed immune changes in relation to the dose level and dosing schedule of PDS0301.

This study also evaluated the correlate of several treatment-related immunologic changes with clinical responses. Researchers evaluated a subset of 23 patients with advanced cancers who participated in a Phase I clinical trial of PDS0301.

Patients receiving the higher dose of PDS0301 generated more robust immune responses. Importantly, stronger immune responses were seen at the higher dose level. These data highlight the immunological activity of PDS0301, which supports the immune response data seen to date in the NCI triple combination study.

The ability to increase IL-12's presence within the tumors and to limit its exposure in the circulating blood, constitutes a significant advancement in the development of cytokine-based immunotherapy. The research published by the NCI demonstrates the potential of PDS0301 as a tumor targeting IL-12 and its ability to stimulate immune activation and increase the frequency of immune responses that potentially overcome the immunosuppressive tumor microenvironment.

Published studies of biologically active doses of PDS0301 monotherapy were associated with greater than or equal to grade 3 treatment-related adverse events in 20% of patients, and all of these were transient.

One grade 4 treatment-related adverse event was observed and no grade 5 treatment-related adverse event occurred. This was published by Strauss and colleagues in 2019 in clinical cancer research. Importantly, these biologically active doses are associated with increases in specific immune cells and improved clinical outcomes.

Now moving on to our preclinical programs. Recently, data on both PDS0102 and PDS0103 were presented at the 2022 American Association for Cancer Research, also known as AACR, special conference on tumor immunology and immunotherapy.

The poster presentation highlighted the development of Versamune immune-based drug formulations containing multi-epitope peptide antigen sequences of the tumor-associated protein TARP, which is also known as T cell receptor gamma chain, alternate reading frame protein, as well as modified sequences of the Mucin-1 oncoprotein or MUC1.

The preclinical research prevented -- provided the foundation for the clinical development of PDS0102 as a potential treatment for TARP-associated acute myeloid leukemia, prostate and breast cancers and PDS0103 as a potential treatment for MUC1-associated breast, colon, lung, ovarian and other cancers.

Key findings for PDS0102 were high levels of CD8 killer T cell responses against multiple TARP antigens and predominant induction of multifunctional potent tumor T cells similar to what's been seen and observed with PDS0101.

Key findings for PDS0103 were, again, similar to PDS0101 and PDS0102. The induction of high levels of CD8 killer T multifunctional responses against multiple MUC1 antigens and effective targeting and killing of MUC1 positive targets in vitro.

We're pleased with the preclinical research to date for these compounds confirming their biologic activity. The manufacturer of PDS0102 antigens is complete and the scale up and manufacture PDS0103 clinical product is in progress. There's been wise discussion among immunologists and infectious disease experts regarding the ability to develop more effective and more broadly acting vaccines against various inductive agents.

One key area of research is the development of novel strategies to elicit CD4 T cells, also known as T helper cells, that can be much more broadly effective in providing protection against infection. An important advantage of CD4 T cells is their ability to be less susceptible to viral mutation.

Two important preclinical studies utilizing the Infectimune platform were published in February 2023 in the peer-reviewed journal viruses. New research performed in the laboratory of preeminent CD4 T cell researcher, Dr.Andrea Sant at the University of Rochester Center for Vaccine Biology and Immunology study Infectimune and demonstrated the technology's potency in eliciting CD4 T cells.

The study is focused on comparing Infectimune-induced immune responses following primary vaccination against influenza with the new responses induced by leading commercial vaccine adjuvant. This study concluded that Infectimune dramatically enhance CD4 T cell responses relative to 2 leading approved vaccine technologies that we're evaluating in the study.

The second publication in viruses from Dr. Siva Gandhapudi and Jerry Woodward from the University of Kentucky College of Medicine, demonstrated the ability of Infectimune with protein viral antigens to generate a broad and protective immune response against viruses including multiple strains of influenza.

Infectimune was tested in animal models of influenza. The investigational universal flu vaccine, PDS0202 demonstrated induction of T cell and neutralizing antibodies against multiple strains of influenza.

T cell responses were also generated against nonmutating regions of the flu virus. Importantly, PDS0202 completely protected animals from lethal challenges with influenza viruses. These consistent preclinical results among the 2 studies are promising, and we continue discussions with NIAID regarding clinical funding for our universal flu vaccine.

We will keep you posted as we move discussions forward. To summarize where we are today, first, with our Versamune based oncology programs. We are highly encouraged by the consistency and the clinical response and survival data we see coming from the VERSATILE-002, IMMUNOCERV and triple combination trial.

The Phase II biomarker study results reported by both the NCI and MD Anderson at FITC 2022 demonstrated induction of the right type of potent tumor-infiltrating multifunctional killer T cells in the right quantity, which correlated with clinical responses in both cases.

With our Infectimune-based infectious disease programs, we are similarly excited about the potential, especially considering the 2 studies independently reported in the journal viruses last month.

Both studies demonstrate unique potential of Infectimune not only to induce CD8 T cells, but also to induce multifunctional CD4 T cells that are more broadly reactive and potentially less susceptible to viral mutations while also inducing broadly reactive neutralizing antibodies.

At this time, I'd like to turn the call over to Matt to review our financial summary. Matt?

Thank you, Lauren. We had an extraordinary year at PDS Biotech. As we move the business forward, our financial strategy continues to seek to mitigate financial risk while supporting our overall commercial strategy.

Our goal remains to select the most promising combinations and indications and rapidly progress into registrational trials. We are excited to prepare our lead candidate PDS0101 for a registrational trial. We currently estimate our Phase III VERSATILE-003 trial will cost approximately $60 million, which is part of our operational budget and projections.

Now let's take a look at our summary financials for the year ended December 31, 2022. Net loss for the year ended December 31, 2022, was approximately $40.9 million or $1.43 per basic and diluted share compared to a net loss of approximately $16.9 million or $0.66 per basic and diluted share for the year ended December 31, 2021.

The higher net loss was primarily due to personnel costs, clinical research and quality and manufacturing costs and the cost to license of our PDS0301 asset.

Research and development expenses for the year ended December 31, 2022, increased to approximately $29.4 million compared to approximately $11.3 million for the year ended December 31, 2021. The increase of $18.1 million (sic) [18.2 million] was primarily attributable to an increase in personnel costs of $2.3 million, clinical costs of $2.3 million, manufacturing costs of $3.6 million and $10 million for the rights to PDS0301 for Merck KGaA, Darmstadt Germany. Of the $10 million, $5 million was in cash and the balance in shares of our common stock.

General and administrative expenses for the year ended December 31, 2022, increased to approximately $12.2 million compared to approximately $10.2 million for the year ended December 31, 2021.

The $2 million increase was primarily attributable to an increase in personnel costs of $1.3 million and professional fees of $0.7 million. Total operating expenses for the year ended December 31, 2022, were approximately $41.7 million compared to total operating expenses of approximately $21.4 million for the year ended December 31, 2021.

Loss per basic and diluted share for the year ended December 31, 2022, was $1.43 as compared to a loss of $0.66 per basically diluted share for the year ended December 31, 2021. This increase in loss per share can be primarily attributed to the investment in R&D and $10 million recorded to in-licensed PDS0301, which was all expensed in the fourth quarter and accounts for approximately $0.35 of loss per basic and diluted share.

We ended the year with approximately $73.8 million in cash, which is attributed to our continued prudent financial discipline and efficient execution of our ATM. Based on the company's available cash resources and cash flow projections, the company believes this balance is sufficient to fund the company, operations and research and development programs into the third quarter of 2024.

This concludes my portion of the call, and I'd like to turn the call over to the operator for our question-and-answer session. Operator?

(Operator Instructions) Our first question today is coming from Leland Gershell from Oppenheimer.

Congratulations on all the progress. Just a question for -- maybe for Lauren. As we look forward to the VERSATILE-003 trial, I know you're still collecting data from 002 with respect to informing the statistical considerations, but do you have a sense of the size of the enrollment of what 003 may look like?

Thanks for your questions, Leland. Go ahead, Frank.

Nothing, Lauren. Since Leland directed that question to you. I'll hand over to you.

Thank you for your question, Leland. The design and the total sample size of VERSATILE-003 will be informed by the VERSATILE-002 data that's maturing in the ICI-naive population. We are looking for consistencies and trends, and we anticipate that we will have additional updates to that data in the spring that will allow us to finalize the protocol and give us a sample size to conduct the trial as efficiently as possible.

Okay. And then just with regard to the triple combo study. You have yet to identify the ICI. You'll be using except that it will be a commercially available one. Are there -- is there any information you are awaiting to learn that will allow you to settle on the choice of that ICI or at least allow us the public to hear what that is?

That's an excellent question, and thank you for that, Leland. Well, in terms of the design of the triple combination study, we plan to leverage and also have maturing data from the ICI refractory population of VERSATILE-002.

As Frank iterated, overall survival, we know is going to be key to informing the design of that trial, and we would like to have maturing data from VERSATILE-002 in the ICI refractory population since that will be the focus of the triple combination study.

As you're aware, there are 2 immune checkpoint inhibitors that have approval in the head and neck recurrent metastatic disease indication, and we will be making that determination as we get more informed data on overall survival from ICI refractory patients.

Just to add a little bit to what Lauren said. As you know, there are 2 commercial checkpoint inhibitors that have been approved, right, KEYTRUDA and OPDIVO for head and neck cancer, so it's going to be 1 of those 2.

But also in terms of the strategy to design that trial, one of the things we want to do is to be prudent in getting all the information we need. So one of the reasons why we've seen the kind of data we've seen today in our clinical trials is that we were very systematic in our preclinical studies and making sure that we did all the necessary studies understand exactly how this technology is working, select the optimal conditions and go into the clinical trials. And based upon that, we've seen very consistent results from trial to trial.

That's the reason why we're running all these various Phase II clinical trials, right, to gain as much information as possible that can then inform design of these trials. And now since we are going to a commercial checkpoint inhibitor, with PDS0101, that's exactly what we are evaluating in the ICI refractory arm of VERSATILE-002.

And so really having some information on how that's performing could be very informative in terms of how we design the trial. So for example, assuming we design a 350-patient trial, but wait a few months later, and I understand exactly whether we're actually seeing improvements in overall survival potentially with the dual combination, maybe we end up starting a few months later, but with a much smaller design, that's a lot more efficient, which could then dramatically reduce our cost and speed to commercialization.

So we just want to make sure that we're doing what's in the best interest of all shareholders, making sure we get the information that we specifically designed the trials to provide and then based upon that information progress into final design of that trial.

Next question is coming from Louise Chen from Cantor Fitzgerald.

Congratulations on all the progress this quarter. So I wanted to ask you a little bit more on the Phase III VERSATILE-003 study and see if you could provide some more details, maybe broadly speaking, how you wanted to design that study versus a VERSATILE-002?

And then how is the result of 002 inform your thinking on the Phase III design for 003? And then secondly, are you expecting to present any new data at major medical oncology conferences or even for your virus you Infectimune platform this year? And if so, where would you see presenting those and what venues?

And then lastly, just thinking about OpEx for 2023, is the fourth quarter of 2022, a good starting point? We're thinking about how to build things and you're starting a major study. So curious how you think about the cadence of R&D expense in 2023?

Okay, Louise, thanks a lot for the question. I'll start and then hand over to Lauren to finish up. But in terms of the Phase III trial, you are correct, we are looking to get as much information as possible from the VERSATILE-002 trial. As I mentioned, overall survival is what we believe will be the key parameter that the FDA would want us to power the trial to really understand. But also what we want to do as we design the trial is also take information from VERSATILE-002, for example, what do our PFS numbers look like?

Do our PFS numbers increase -- in PFS in VERSATILE-002 correlate with increase in overall survival, for example? And those were some of the key parameters that we needed to get insight into because if that's the case, then we can design that with certain interim data points that may allow us to get data that we could then start discussing with the FDA sooner than later regarding a potential approval.

So right now, for example, there has been recent guidance from the FDA in terms of how they would look at accelerated approvals and how they would look at single-controlled trials for accelerated and final approvals, right? So with all that information, part of the key things that we would want to do is as we finalize this design, get input from the other countries into the design, finalize the numbers but also give ourselves the opportunity to see data sooner than later.

And if positive, be able to start having discussions with the regulatory agencies. So that's one of the key reasons why we needed to reunderstand how our PFS numbers were beginning to look as well as overall survival and see if there was an improvement over published KEYTRUDA monotherapy data in terms of improvement in both sets of parameters. And so I'll hand over to Lauren to address the additional questions.

So in follow-up to Frank's comments, our intention, Louise, is to present updated data from VERSATILE-002 at scientific meetings. So we are targeting to present data potentially either at ASCO, ESMO and also potentially SITC related not only to the updated clinical outcomes in the ICI-naive population as it relates to PFS and overall survival, which, again, Frank noted, will inform our designer VERSATILE-003, but also confirmation and examination of the immunogenicity parameters that we are seeing in VERSATILE-002.

I think one of the most important things to come out last year was the demonstration that we see in patients, even in heavily treatment-experienced patients, the induction of these HPV 16-specific multifunctional potent CD8 killer T cells in patients. And we're looking to present that data from VERSATILE-002 as well during the course of 2022.

So yes, we will be presenting that data. I can't really comment regarding Infectimune presentations. The viruses publications were very, very impressive for us in terms of the ability to demonstrate broad antigen-specific CD4s and CD8 cells that indeed protected from lethal challenge.

And I think any scientific presentations during the rest of this year will be guided by additional preclinical studies that we may be pursuing with the goal of progressing our Infectimune-based platform to human clinical trials. And there was a third question that you had. Could you just repeat that for us?

Yes, it was a financial question. So I wanted to ask you, the OpEX for 2023, is fourth quarter 2022, a good base to build off of? And then with the start of this VERSATILE-003 by fourth quarter '23, how should we think about the cadence and R&D expense this coming year?

So Lauren, I think that would be a good one for Matt to take since its operation expenses. So Matt?

Sure. Thanks, Frank. Thanks, Louise. Appreciate your question. I think looking at Q4, you're started to see the step-up and increase in associated costs related to our trials, and that's going to continue into 2024. But I think if you take Obviously, in the fourth quarter numbers, we've got the $10 million that we spent with Merck KGaA. So after eliminating that, that's a good way to think about it. And so -- and also, obviously, we're going to have some additional R&D expenditures as well -- I'm sorry, general and administrative expenses as well.

Next question is coming from Kalpit Patel from B. Riley.

This is Andy Fleszar on for Kalpit. Congratulations on the progress. We know that you had a successful initial meeting with the FDA for the doublet. But is the agency requiring any more data to be submitted along with the final trial protocol? And when should we expect this protocol to be submitted?

Andy, thanks a lot for the question. But I think with the triple, as we mentioned, we are looking to get some additional data. Hopefully, that will inform how we design the statistical portion of that program. And also, one of the key things that we would want to do as the FDA would want to see -- I think one of the key things we mentioned a number of times is the contribution of agents.

We've talked about that quite a bit, right? And so pending what that information provides to us. We may be able to go in, in terms of looking at PDS-0301 and PDS -- and PDS0101 and PDS0301 in addition to the triple combination. We anticipate that, that may be possible. But again, that's something that we would have to discuss with the FDA. That's also important for us because if you recall, with the triple combination trial, there are 2 of the 3 agents which have been found to be critical in the clinical outcomes, PDS0101 and PDS-0301, right?

Both of those were found to be critical for those outcomes. And so part of what we may potentially do is the Simon 2-stage where we look at a small number of patients as a median to their bigger registrational trial. But again, those are things that we are looking waiting for information for to finalize that design.

We think based upon what we know today, we think it's going to be a smaller design than VERSATILE-003, but until we have all the information to design that trial, I probably wouldn't be able to provide too much detail into what you're asking, but these are some of the key things that we're looking at to come up with the most efficient design possible.

Sorry if I misspoke, but I was actually questioning the doublet study. If we see the (inaudible) more data before initiating that's right, yes, correct.

No, no, we don't require any more data before initiating that trial.

Okay. And do you have a sense of the time line of when that protocol will be submitted?

Yes. So right now, we're in discussions with the EU and the regulatory agencies from the other countries in order to get their feedback that we would then put into the final design that would then go to the FDA. And so we're anticipating that by the time we have all that information from those other countries that we've put into that protocol. So that's currently ongoing.

That will probably be late Q2 or early Q3. So we anticipate that the final amended IND will be filed in Q3. And then once we get the FDA feedback, we'll then start activating the various investigational review boards IRBs for the various sites. We are hopeful that we will be able to convert a number of the sites, most of the sites we're working with today, into the VERSATILE-003 sites.

And so that -- those processes typically will take anywhere from 4 to 6 months. So with that timeline, what we are working towards and hopeful is that we will be able to get this trial up and running by Q4, right, considering all these other activities.

As I mentioned, the clinical manufacturing has been successfully completed already, right? So we are finalizing the later stage of the CMC section, right? So all those activities are progressing really successfully to date, right? So that's our timeline in terms of when we anticipate we'll file the IND and when we'll get the IRB approval, get the sites activated and get the trial initiated by Q4.

Next question is coming from James Molloy from Alliance Global Partners.

I had a quick question on the amended IND in the Phase III VERSATILE-003 trial, could you walk through the amendments to the IND, what exactly you're amending on there?

And then when -- what sort of breakpoint should we anticipate? I know the trial is going to take a little bit of time to run. Do you anticipate some interim looks at some point or in any way to guide to where sort of the next catalyst should be looking for once the trial is up and running a potential data coming out?

Well, James, thanks for the question. Well, we call it an amended IND, but if you're really updating your IND. The initial IND was filed for the Phase II trial, which was a single-arm trial. And now we're going into a controlled Phase III trial, right? So those updates have to be made. We have to update the manufacturing process.

We've now selected our commercial manufacturer. We've transferred the process. We're going to have to update the manufacturing process. As we update the manufacturing process for Phase III manufacturer of the peptides, those have to be updated in the CMC.

The manufacture of the R-DOTAP raw material for the Versamune that's also been scaled up to the Phase III. All those updates have to be made to the IND. And so that's why we call it the amended IND. It's really look at it as an updated IND with all the new information transitioning from the Phase II to the Phase III with a lot of those pertaining to what the commercial manufacturing and CMC package would look like, right? So that's really what we're doing there. James, does that answer your question?

It did, indeed. And then any thoughts on expectations for potential interim looks or data points here? Once the trial is up and running, what should we be thinking on timing potentially some data coming out?

Yes. So I think that's what we're looking at, for example, with PFS, right? So I think one of the key things we mentioned is whatever interim data points you come up with it would have to give some indication that you are prolonging overall survival. As I mentioned during the presentation, objective response rates, for example, haven't really correlated with overall survival in most immunotherapies.

So many of the immunotherapies that the FDA has been evaluating recently. And so one of the key reasons we are looking at the data for PFS and overall survival is that in VERSATILE-002 that do we see an improvement in PFS as well as overall survival?

And based upon that, that improvement, what's the delta between what we're seeing with our VERSATILE-002 versus what's reported in KEYNOTE-048 with KEYTRUDA monotherapy. And then based upon that delta for both the PFS and the overall survival that will inform us in determining how we designed the trial and what we could use as an interim data look.

And so that delta is really going to determine the statistics, right, in terms of what's the size of the patient population that we're going to need before we see PFS, if we have seen an increase in PFS, but very importantly, we would also want that to be associated with an increase in overall survival at least an indication that we improve in overall survival, right?

So -- and that's why those numbers were very important, and that's why we have to wait to get some clarity to those numbers before being able to design the trial. We are now waiting for the feedback from the various countries. And then that may cause us to tweak things a little bit before we finalize the design. But we are absolutely looking to design this trial to get some early looks to be able to go and have discussions with the FDA rather than waiting to go through the entire trial to completion of the trial before having discussions with the FDA. So we are looking specifically at that design in our design.

Excellent. And the final question would be on the triple combo. I know that you highlighted earlier how it's somewhat out of your hands with a partner running the trial. Can you walk through expectations or the current expectations for some of the data -- next data from this?

and then any -- I know 003 is clearly the focus here, but any thoughts on potentially a Phase III starting the triple combo at some point in the future?

Absolutely. I think with the triple combination, so the triple combination is not out of our hands, right? The NCI trial is essentially completed, right? So right now, what we've done is we have acquired the PDS0301. So really, it's now in our control, right, in terms of our partnership with Merck KGaA. They are providing us with the material redesigning the trial.

However, to complete design of that trial and to have an efficient trial, we are also looking at PDS0101 plus KEYTRUDA, which is a commercial checkpoint inhibitor in this exact patient population we're going to be treating, which is recurrent metastatic head and neck cancer.

And therefore, we anticipate that we should see this data sometime in Q3. That data, even though we're looking at PDS0101 in KEYTRUDA without IL-12, we know that IL-12 is critical in these checkpoint inhibitor refractory patients. So that data will not necessarily be essentially what we would anticipate seeing the Phase III trial, but it will be very informative.

If for example, we already seen improvement in the overall survival even without IL-12 in that patient population. That information then allows us to more efficiently design the statistical portion of that Phase III clinical trial, right? So those are the key pieces of information we're looking for.

We are also, at the same time, doing the work needed to identify the correct commercial manufacturer for that product as we take it over, right? So it's actually what we want to do, as we go into our Phase III clinical trials, is to make sure that it's going to be pretty much very similar to what the commercial product is going to look like in terms of the manufacturing, right?

That mitigates your risk significantly and speeds up going from your BLA to actually producing and selling your commercial product, right? So those are some of the key things that we did for VERSATILE-003, and we'd like to take the same approach with the triple combination to make that process much more efficient once we started from beginning to end.

So currently, we are prioritizing getting VERSATILE-003 up and running. But once that's happened, our then primary goal is also and primary focus would then be getting the triple combination also up and running.

Our key here is commercialization of PDS0101 and commercialization of PDS0101 plus PDS0301, right? So that's really the approach we're taking, just to make sure that we mitigate risk as much as possible and make sure that we can execute the most efficient trial possible.

(Operator Instructions) Our next question is coming from Robert LeBoyer from Noble Capital Markets.

Thank you for all the details you've given on the VERSATILE and the triple therapy trials. My question has to do with the MD Anderson and the Mayo Clinic data that's been coming out and whether you have plans to include those in trials or any milestones going forward or things to look forward to from those indications?

Thanks, Robert. Lauren, do you want to take this one first?

Yes. Thanks, Robert. So as Frank mentioned, both the MD Anderson-led IMMUNOCERV trial as well as the Mayo Clinic trial are investigator-initiated studies. So we don't have control over the accrual rates or actually the publication or presentation of scientific data from those trials. However, we do know that there has been significant interest and enrollment and accrual to the Mayo IIT trial. Just reminding everyone that this is using and investigating PDS0101 alone (inaudible) combination with KEYTRUDA prior to definitive curative surgical resection in individuals who are presenting for initial treatment of HPV 16 oropharyngeal cancer.

Our hope is that we will be hearing from investigators and that they'll be able to present some interim data hopefully this year regarding preliminary findings in this population. It's very important to us because the study is going to provide us insight into not only immunogenicity, tumor shrinkage prior to surgery, pathologic response in tissues, but also an important examination of the biomarker of circulating tumor HPV 16 DNA.

The IMMUNOCERV data from MD Anderson was on the first 9 subjects who had actually completed their day 170 evaluations. We know that there are additional patients from this study that have already undergone treatment, but were not at that time point to allow presentation of their data at the end of 2022. So we look forward to additional data as that matures from that study as well.

Lauren, do you want to add a little bit about the Mayo Clinic and how it could be translated into a potential randomized trial, that may also help?

Okay. So one of the things that we're very interested in is seeing whether or not we can impact differentiating outcomes for patients earlier in disease. And so we hope to see, in addition to whether or not we see tumor shrinkage and declines in circulating tumor DNA and whether or not those are predictive of disease recurrence, we would potentially design a randomized trial to look at PDS0101 alone versus PDS0101 in combination with KEYTRUDA in this neoadjuvant treatment setting.

Merck has published studies examining KEYTRUDA alone in the neoadjuvant treatment setting with some evidence of -- preliminary evidence of tumor shrinkage and minimal pathologic response, and we would hope to improve on that.

Right. Thanks a lot, Lauren. so Robert, really here with both of them, there is a significant commercial opportunity for both -- in both trials. And so the key here is really getting that basic information that will say, okay, yes, move forward.

And if yes, move forward, how do we design that controlled trial based upon the information that we received from both trials. So both provide us with a significant commercial opportunity that we are currently waiting for the data to make that next decision.

We've reached end of our question-and-answer session. I'd like to turn the floor back over to management for any further closing comments.

Thank you very much. Well, thank you very much for joining us today on our fourth quarter and full year ended earnings conference call. So while 2022 was a year of tremendous progress for both our clinical and preclinical development programs, 2023 is poised to be transformational for our platform technologies and PDS Biotech.

I will reiterate that our key goal this year is to prioritize rapid commercialization of PDS0101, first in the VERSATILE-003 study. We have selected and completed manufacturing of PDS0101 at our preferred commercial manufacturer for VERSATILE-003.

We will also progress activities needed to commercialize PDS0101 in combination with PDS0301. We will continue with activities necessary to progress PDS0103 to IND this year. And we also plan to continue progressing discussions with the NIAID towards hopefully getting PDS0202 for the universal flu into the clinic.

We thank you for your continued interest, and we will continue to update you as we advance through this exciting journey. Thank you very much.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.