Iovance Biotherapeutics Inc (IOVA) 2022 Q4 法說會逐字稿

Welcome to the Iovance Biotherapeutics Fourth Quarter and Full Year 2022 Financial Results and Corporate Update Conference Call. My name is Gigi, and I will be your operator for today's call. (Operator Instructions) Please note that this conference is being recorded.

I will now turn the call over to Sara Pellegrino, Senior Vice President, Investor Relations and Corporate Communications at Iovance. Sara, you may begin.

Thank you, operator. Good afternoon and thank you for joining us. Speaking on today's call, we have Dr. Fred Vogt, our Interim President and Chief Executive Officer; Dr. Igor Bilinsky, our Chief Operating Officer; Jim Ziegler, our Executive Vice President, Commercial; Dr. Friedrich Finckenstein, our Chief Medical Officer; and Jean-Marc Bellemin, our Chief Financial Officer; Dr. Raj Puri, our Executive Vice President, Regulatory Strategy and Translational Medicine is also available for Q&A session.

This afternoon, we issued a press release that can be found on our corporate website at iovance.com which includes the financial results for the 3 and 12 months ended on December 31st as well as recent corporate updates.

Before we start, I would like to remind everyone that statements made during this conference call will include forward-looking statements regarding Iovance's goals, business focus, business plans and transactions, pre-commercial activities, clinical trials and results, regulatory interaction, plans and strategies, research and preclinical activities, potential future applications of our technologies, manufacturing capabilities, regulatory feedback and guidance, payer interaction, licenses and collaborations, cash position and expense guidance and future updates. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties described from time-to-time in our SEC filings. Our results may differ materially from those projected during today's call. We undertake no obligation to publicly update any forward-looking statements.

With that, I will turn the call over to Fred.

Thank you, Sara, and good afternoon, everyone. I am pleased to highlight the positive milestones and significant progress at Iovance in 2022 and into the beginning of 2023. We are close to completing our biologics license application or BLA for our lead TIL therapy, lifileucel, in advanced melanoma before the end of this quarter. We are also preparing for commercialization, developing our robust immuno-oncology pipeline and integrating Proleukin upon the close of planned acquisition.

The BLA for lifileucel remains our #1 priority on behalf of patients with advanced melanoma who progress on or after anti-PD-1 therapy. This represents a significant unmet medical need given there are currently no FDA-approved treatment options in this setting. Feel very confident going into the BLA review process given the strength of our clinical data and unmet need as well as several positive interactions with feedback from the FDA during 2022. These included FDA alignment on the potency assay matrix last April and a successful pre-BLA meeting in July where the FDA provided favorable feedback on the clinical efficacy data from Cohorts 2 and 4 of our C-144-01 clinical trial, including duration of follow-up and that the clinical and safety data-set was sufficient for a BLA review.

In the fourth quarter, we also reached agreement with the FDA on our recently started TILVANCE-301 Phase 3 trial frontline advanced melanoma to serve as a registrational trial in that indication as well as a confirmatory study supporting full approval of lifileucel in postanti-PD-1 advanced melanoma. We expect TILVANCE-301 to be well underway at the time of potential approval and Friedrich will talk about additional details of the trial on today's call. Overall, the FDA continues to be engaged in supportive to look forward to continuing this level of collaboration in 2023.

We are also preparing to integrate Proleukin upon the close of our planned acquisition of this product. As a reminder, we announced last month that we have entered into a strategic transaction with clear agenda to acquire worldwide rights to Proleukin, an IL-2 product with currently approved indications. It is importantly also used to promote T cell activity following TIL infusions. We have a strong strategic fit and rationale for this transaction, which provides immediate and future revenue and full control of the IL-2 supply chain and logistics surrounding TIL therapy and, as expected, the lower clinical trial expenses and future cost of good for lifileucel.

In addition to lifileucel in melanoma, we are building a deep and diverse TIL therapy pipeline in multiple cell tumor types that has the potential to create significant value for cancer patients as well as our shareholders. We are conducting 6 active clinical trials preparing to randomize patients in the frontline melanoma treatment setting in our first Phase 3 study and advancing several genetically modified TIL therapies, which Friedrich will also highlight on today's call.

As we grow our organization to prepare for our first potential launch, we currently have more than 500 Iovance employees who have expertise in developing and commercializing oncology and cell and gene therapy products.

I look forward to addressing your questions later during this call and will now ask Igor to address manufacturing updates and preparations to supply commercial TIL therapies upon potential approval.

Thank you, Fred. Manufacturing is critical for any commercial launch particularly for autologous cell therapies. So our top priority is to prepare for commercial supply to meet patient needs, while continuing to scale-up our internal capabilities and staffing. We are focused on operational excellence and maintain a consistent TIL manufacturing success rate of more than 90% in more than 600 patients treated with Iovance TIL therapy to date. We are currently supplying clinical studies from iCTC, which is operating flex suites for clinical manufacturing and core Suites for BLA readiness activities in preparation for commercial manufacturing. We have done significant work to ensure that iCTC and our contract manufacturers facility are well-prepared for launch with many of current efforts focused on the FDA pre-approval inspections that we expect to occur during the BLA review process.

The iCTC is expected to supply most of the commercial TIL therapies upon approval with contract manufacturers to provide additional flexibility to optimally balance capacity and patient demand.

Beyond the initial launch of lifileucel, we are planning for future capacity needs, as we look to establish TIL as the next paradigm shifting class of cancer therapy. The iCTC is currently built, has annual capacity to supply TIL products for more than 2,000 patients with available shelf space that we can build out to supply products for more than 5,000 patients annually from this facility. Longer-term, by adding new facilities as well as streamlining and automating manufacturing processes, our vision is to build capacity for more than 10,000 patients annually. Our intellectual progress for IP is also critical component to support and protect our proprietary manufacturing processes and knowhow and to further solidify our global leadership in TIL therapy. We currently own at least 60 granted or allowed U.S. and international patents, including Gen 2 patent rights that are expected to provide exclusivity into 2038.

Extensive detail on Iovance [IP] is highlighted on our corporate website and within our annual report on Form 10-K. I would now like to hand the call to Jim Ziegler to highlight our commercial launch preparations.

Thank you, Igor. Throughout 2022 the commercial team made steady progress towards launch. With the ongoing BLA submission, our launch priorities include onboarding of our Authorized Treatment Centers or ATCs, securing appropriate access and achieving operational readiness. Our cross-functional teams continue to partner with and on-board ATCs to develop new workflows that are unique to TIL therapy while leveraging workflows within existing cell therapy service lines at the centers. Our ATC operations and regional account director teams have structured interactions to support an efficient ATC onboarding process and we have developed a training curriculum to ensure multidisciplinary teams can administer the lifileucel treatment regimen upon FDA approval. The timing and execution of key onboarding activities and training at each center are aligned to our regulatory timelines. We support each center in developing their TIL service line and we plan just-in-time training to ensure launch readiness.

Our reimbursement strategies are focused on securing coding, coverage and payment. Our market access team continues to engage the key national and regional payers. As we transition from the clinical trial to commercially approved setting, our goal is to ensure patients have appropriate and timely access to lifileucel. Our cross-functional team is also assessing our needs and capabilities and developing our implementation plan for Proleukin. We are also fortunate to have several cross-functional team members with prior Proleukin leadership experience for leading and developing our end-to-end integration processes. We are preparing for a smooth transfer and operational readiness for Proleukin upon the close of our planned acquisition.

We understand that launching an autologous cell therapy require sustained operational excellence and I want to acknowledge the critical thinking, problem solving and tireless efforts of our cross-functional team. Our team has set a high bar for themselves to ensure the highest-quality of operational excellence. We are well-positioned to scale our efforts to ensure our commercial launch readiness.

I will now pass the call to Friedrich Finckenstein, our Chief Medical Officer to highlight our clinical progress.

Thank you, Jim. Today. I would like to summarize our TIL therapy pipeline and next generation technology. I'll begin with our multi-pronged strategy in advanced melanoma. Our ongoing rolling BLA submission for lifileucel and anti-PD-1 advanced melanoma is based on the results from our C-144-01 trial, the largest single clinical study ever conducted for TIL therapy in post-ICI melanoma. In the fourth quarter, we presented positive data from C-144-01 Cohort 2 and 4 to the medical communities for the first time at the Society for Immunotherapy of Cancer or SITC Annual Meeting last November and published results from this study in the Journal of Immunotherapy of Cancer or JITC in December. We are confident that the strength of the clinical data from 153 patients in the C-144-01 trial, including our pivotal Cohort 4 and supportive Cohort 2 support approval.

Following the recent posting of our Phase 3 TILVANCE-301 trial in frontline advanced melanoma on clinicaltrials.gov. I would like to highlight additional detail on the trial to date. We reached agreement with the FDA for TILVANCE-301 to serve as our registrational trials like [TILVANCE] and full approval of lifileucel in combination with pembrolizumab in frontline advanced melanoma as well as the confirmatory trial to support full approval of lifileucel in post anti-PD-1 advanced melanoma. Notably, we were very pleased that the FDA agreed to dual primary endpoints of blinded independent review committee or BIRC assist objective response rate for ORR and progression free survival or PFS. TILVANCE-301 also includes several secondary endpoints such as overall survival and duration of response.

In terms of trial design, we plan to randomize 670 patients who are naive to therapy in maybe advanced setting equally to either lifileucel in combination with pembrolizumab in the experimental arm, or pembrolizumab monotherapy under control arm. We are including an appropriate number of global trade such as many large U.S. and European cancer centers and numerous other countries what we expect from enrollment.

In the control arm, patients will have the option to receive TIL monotherapy confirm disease progression verified by the IRC. Additional information on trial design, outcome measures and then eligibility criteria are available on clinicaltrials.gov.

Our confidence in the success of TILVANCE-301 is based on results from Cohort 1A in our IOV-com-202 trial of lifileucel in combination with pembrolizumab in ICI naive advanced melanoma. In addition to prior data at the NCI for TIL monotherapy in anti-PD-1 naive melanoma generated in the pre-ICI era. We look forward to advancing our frontline melanoma strategy throughout 2023, including site activation and patient randomization in TILVANCE-301.

As Fred mentioned, TILVANCE-301 is expected to be well underway at this time of potential BLA approval for lifileucel post anti-PD-1 advanced melanoma. We continue to execute on our non-small cell lung cancer or NSCLC private line at Iovance with 6 cohorts across 3 Iovance studies to investigate multiple treatment regimens in various populations at various stages from disease.

We recently shared topline initial data from Cohort 3A of the IOV-com-202 trial, which we highlighted in the press release, investor conference call last month. Based on the initial Cohort 3A positive results in patients with advanced NSCLC who are naive to ICI treatment, particularly within the treatment naive and post-chemotherapy subsets. We plan to meet with FDA in 2023 to discuss the data and the potential registration path for lifileucel in frontline advanced NSCLC patients. Enrollment to Cohort 3A is ongoing and we plan to present detailed and updated results at a medical meeting this year. Al right IOV-LUN-202 trial is investigating LN-145 monotherapy in patients who have received prior anti-PD-1 and chemotherapy in combination or sequentially and includes an option for pre-progression tumor harvest. We enrolled patients throughout 2022 and expect to continue enrollment this year.

Moving to cervical cancer, enrollment is underway in our expanded Cohort 2 in the ongoing C-145-04 trial in patients who have progressed after chemotherapy and anti-PD-1 therapy. As a reminder Cohort 2 is intended to be pivotal to support regulatory submissions following dialog and feedback from the FDA and we look forward to continuing Cohort 2 enrollment during the year.

We are excited about our next-generation TIL therapy. We are developing several genetically modified TIL therapies that utilize the gene editing TALEN technology licensed from Cellectis to optimize TIL therapy by inactivating immune checkpoint proteins that inhibit anti-tumor response. IOV-4001 is our first genetically modified PD-1 inactivated TIL therapy candidate. In this third quarter of last year, we treated the first patient with IOV-4001 in our first in-human IOV-GM1-201 trial in patients with previously treated advanced melanoma or NSCLC. Additional programs using the TALEN technology are expected to enter clinical development in 2024, including genetically modified TIL therapy with multiple inactivated immune checkpoint target.

Earlier stage research in preclinical studies ensued additional approaches to increase TIL potency, including the selection of CD39/69 double negative TIL and enhancements such as Teva's cytokine. As part of our strategy to optimize the TIL treatment regimen, we also continue IND-enabling studies of our novel interleukin analog IOV-3001.

I am available during the question-and-answer session. For now I will hand the call over to Jean-Marc to discuss our fourth quarter and full year 2022 financial results.

Thank you, Friedrich. My comments will summarize our planned acquisition of Proleukin as well as higher level financial results from our fourth quarter and full-year ended on December 31, 2022. More details can be found in the subsequent press release as well as in our SEC filings.

Last month, we announced that we have entered into an agreement to acquire Proleukin from Clinigen. Terms of the agreement include an upfront payment of GBP167.7 million, with GBP41.7 million milestone payment upon first approval of Lifileucel in advanced melanoma and double-digit Proleukin global sales royalties from Iovance to Clinigen. The transaction will be financed with existing cash and is expected to close after all conditions are met, including regulatory approvals and clearance and other customary closing conditions.

As a late-stage oncology company approaching potential commercialization this year, we are also investing in launch preparations, internal manufacturing and pipeline activities. As of December 31, 2022, we held $478.3 million in cash, cash equivalents, investments and restricted cash compared to $602.1 million as of December 31, 2021.

Taking into account proceeds raised in 2023 from our at-the-market or ATM facility. Our unaudited cash position is approximately $670 million as of February 24, 2023, which include approximately $450 million in net proceeds raised through the ATM during the fourth quarter of 2022 and into the first quarter of '23.

This current and strengthened cash position is expected to fund our operating plan into the second half of 2024, including Proleukin acquisition, manufacturing activities, launch readiness and execution, planned clinical trial and pipeline advancements.

Transitioning to the financial results for the fourth quarter and full year ended on December 31, 2022. Our net loss for the fourth quarter 2022 was $105.3 million or $0.64 per share compared to net loss of $99.3 million or $0.63 per share for the fourth quarter of 2021. Net loss for the full year of 2022 was $395.9 million or $2.49 per share compared to net loss of $342.3 million or $2.23 per share for the full year of 2021. Research and development expenses were $80.6 million for the fourth quarter 2022, an increase of $5 million compared to $75.6 million for the fourth quarter of 2021.

Research and development expenses were $294.8 million for the full year of 2022, an increase of $35.8 million compared to $259.0 million for the full year 2021. The increase in research and development expenses in the fourth quarter and full year 2022 over the prior year periods were primarily attributable to cost associated with the growth of the internal research and development team, including stock-based compensation expense as well as facility-related expenses and internal research programs. This increased expenses were partially offset by lower clinical and manufacturing costs, driven by completion of enrollment in pivotal cost of our clinical trials.

General and administrative expenses were $26.5 million for the fourth quarter 2022, an increase of $2.7 million compared to $23.8 million for the fourth quarter 2021. General and administrative expenses were $104.1 million for the full year 2022, an increase of $20.4 million compared to $83.7 million for full year 2021. The increase in general and administrative expenses in the fourth quarter and full year 2022 compared to the prior year periods were primarily attributable to costs associated with the growth of internal general and administrative and commercial teams, including stock-based compensation expense, the buildout of the new corporate headquarter as well as pre-commercial activities. As of December 31, 2022, there were approximately 187.8 million common shares outstanding.

I will now hand the call back to the operator to kick-off the Q&A session.

(Operator Instructions) Our first question comes from the line of Peter Lawson from Barclays.

Fred, you sounded confident around the BLA submission by the end of 1Q. What needs to be done there, what's left?

Yes, Peter, we're really confident that we're going to get this done. We have essentially a lot of activities we talk about relating to the assay work, CMC work, validation work and stuff like that we are completing. We've talked about it before. It's relatively routine work, but it's very important that the FDA and that's kind of what we're getting done here so we can complete the rolling BLA submission.

And then I know sometimes off, but just on the launch of Lifileucel, are you expecting to see a bolus of patients on loans and kind of anyway you can kind of quantify that?

Yes, Jim, do you want to take that one?

Sure. Given our experience in dialoging with the KOLs at many of these sites and even our clinical trial experience, there is a high unmet need. And this translates into a number of patients who are in need of therapy after checkpoint inhibitor. So we are expecting a bolus of patients at launch given that high unmet need.

And Peter, we do run an EAP program in order to stay in close contact with the sites, so that we're making sure that we have a good feel for what's out there, having care for patients as FDA wants to do.

Our next question comes from the line of Mark Breidenbach from Oppenheimer.

Two quick ones from me. First, I'm wondering if you can just comment on remaining barriers before you can begin recruitment into the TILVANCE-301 study? And then I'm also wondering aside from the Cohort 3A lung data that Friedrich mentioned, are there plans for additional clinical data presentations in 2023?

Friedrich, do you want to talk a little bit about the startup activities for 301, and you can probably talk about little bit about the potential for lung data later this year too, if you want.

Sure, happy to. Thanks for the question. So we have spoken about being in start-up on TILVANCE-301. So that basically means submission of the protocol to -- to sites reviews, at sites -- site start-up, site initiation and then start-up enrollment. There are no specific additional hurdles that would be kind of like one hurdle that would apply to all sites. It's now really activities at individual sites and much of that work is basically going on in parallel and will continue as we are adding a meaningful number of sites both in the U.S. as well as ex-U.S., Europe and beyond Europe to the sites available to the trial. So really no specific hurdles of site startup activities at individual site. Does that make sense?

Sure. I guess I'm trying to get a sense for when you would expect the first patient to be enrolled.

Yes, we haven't guided to when exactly the first patient will be enrolled. What we have said though is that we expect enrollment to be well underway at the time of approval of the relapsed, refractory, indication and I think that's the main point here.

Yes, Mark, we would certainly -- if when we do randomized the first patient.

Got it. And then with respect to other clinical presentations, besides the Cohort 3A lung data?

Yes. I mean I can cover that one. We have additional lung studies running right now, including IOV-202 study which could potentially read out this year. Plus, we've already put out just a few weeks ago the 3A data and we do want to get to a medical conference and drawing that data little bit more deeply. So that'll be, I think a very important presentation for the company when that comes.

Okay, but all the presentations will be in long is what you're implying?

No, not necessarily. I think you were just asking about long.

There is no for all other indications as well.

Yes, there's other -- well, I cannot say for sure, we're going to do, but we've got a pretty fit pipeline and there could be other presentations and other indications for sure.

Our next question comes from the line of Tyler Van Buren from Cowen.

It's Tara. So I guess staying on the same topic of the lung data, so I know that when you just closed a few weeks ago or back in January, that it was too early to comment on response, duration, but what do you kind of expect to see when the full results are presented? And then how are your discussions with the FDA going following that positive feedback that you received on 202. Is there anything new to report there since January?

I assume you mean the IOV-lun-202 study.

Yes.

Yes, that's one where we're engaging with discussions with FDA. I don't have any updates for you on that right now. On 3A we are, like we said when we release the data, the durability is something we're going to watch closely and it will certainly be part of our medical meeting presentation on that. I can't really say much more about that ahead of time, that's obviously important thing to, to the content of the medical presentation we do it, but we are very comfortable that what we're seeing, should support a potential registrational trial like the one we described in January. And we do -- we do -- we're doing our best to get back to FDA with that proposal as soon as we can.

Our next question comes from the line of Michael Yee from Jefferies.

This is Dina on for Michael. Given that you guys are reiterated the BLA submission for Q1, I just kind of wanted to get a better sense on -- I know you guys spoke about it slightly, but just if you can add any additional color unlike the progress you've made since the last update and what are just remaining gating factors to getting that BLA submitted. And also if you had any further interactions with the FDA since that last update as well and based on the commentary that you guys have had with them, is there any color that you can share on a potential AdCom or priority review that'd be helpful.

No, we haven't had any additional interactions with them. We do expect that priority review for this and we'll know more about an AdCom at some point, we've spoken before about whether an AdCom is likely here, it's possible we may not get an AdCom, because it is familiar with T-Cell therapies at this point, where I just talked about that a few times with on calls like this.

With respect to the work and little bit more color on the work, it's, like I said earlier, it's largely validation activities leading to some of the CMC stuff that we do that's part of our filings. I can tell you the bulk of the work for the BLA is done and submitted. So we're in the homestretch now and we're just completing some of these key tasks and it takes a lot of effort from the company. We have a lot of people who are working very hard to get this done. And really, it's not the kind of thing we're, it's extremely tactical in nature, would be very difficult to the communicate with the Street on this, but it's basically a lot of additional CMC validation activities, like we've spoken that before.

Our next question comes from the line of Ben Burnett from Stifel.

I wanted to just ask about the launch preparations for Lifileucel. Can you remind us just how many melanoma treatment centers in the U.S., do you have already sort of onboarded were in, you feel that you're sufficiently trained all the necessary stakeholders at a particular clinical site. So like how many clinical sites have be onboarded as for all of your clinical trial activities to date.

Let me track that.

Go ahead, Jim.

Great. The onboarding process is exactly that, it's a process. We have engaged in a number of key types across the country to ensure that we have sufficient geographic coverage as well as access. I won't give you the specific numbers, but what we have stated in the past is based upon our own assessment looking at analogs like CAR-Ts, we know that there is a heavy concentration of care at these top centers in the CAR-T market, about 10 centers drive about 50% of all the treated patients, and the top 40 about 80% of all the treated patients. So we're focused on getting the right sites up in our targeted and up ready for a launch. We want to train them in the final phases of launch. If we train them too soon, there could be staff turnover, there could be the recency, so what we're really doing is lining everyone up now and as soon as we have the BLA acceptance, BLA filing and acceptance, then we'll start to really accelerate that final onboarding process.

Okay, understood. That makes sense and then I wanted to ask just another question about the timing of data from this year's CRC program, in particular the expanded CRC program in the post-chemo, post pembro setting. I guess number one, do you have line-of-sight as to when we could get data? And then have you said how many additional patients needed to be enrolled there to kind of support BLA in that setting?

I think Ben you're not talking about colorectal, you're talking about non-small cell lung, right? So I assume you won't take so long, you got cut off there.

Sorry, ovarian cancer. My apologies, I said the wrong indication.

Yes, we don't have an ovarian indication at Iovance right now. Although, it's certainly something we're very interested in. We've explored through IFPs.

Okay, my bad. I mistook that for a different program.

So many earnings calls today.

One moment for our next question. Our next question comes from the line of Reni Benjamin from JMP Securities.

I guess just to start-off, maybe for Friedrich. The PD-1 selected TIL studies, the PBL therapy in the PD-1 inactivated pills, can you give us a sense as to how those studies are progressing and kind of off Mark's question, do you think this is something that we might see some initial data for at the end of this year. I guess that will be question number one. Question number two would be the Proleukin revenues are supposed to be I think near term or are imminent right like once the deal is done. Can you just, I think you talked about in the past, but can you just remind us what sort of near-term revenues you expect from Proleukin this year.

Yes. I only take the first one, then I'll have Jean-Marc cover the revenues, we can't give you guidance on revenues Reni, but we can tell you historically, what revenues have been for that product. And you can figure out how look when particularly upon launch of Lifileucel. For the PD1 selected and PD1 knockout, the PD1 select program, both both of those programs are running and we could be putting data on, I will note this year at some point. PD1 knockout in particular is of high interest to us. That's why it's on the highlights of our portfolio because that particularly in lung and melanoma should, we think give us additional efficacy. So we're very excited about that. That's one that when we have data will be putting it out pretty quickly. PD1 selected something we've been running for a while and at some point we'll discuss that further.

Jean-Marc, you want to cover the revenue.

Yes, thank you, Fried, and thank you for the question. I mean, as Fried mentioned, we are not giving any kind of revenue guidance. First of all, we need to close the deal first, and then we can talk and be more specific about the potential in the future. What we have publicly communicated is the revenue that was generated by Clinigen, which probably came in the past, and we were mentioning 2021 was close to GBP30 million or $35 million. So that's the only indication that we were giving in terms of fast revenues.

Got it. Okay. And just one final one. This really just has to do with mainly the CEO search. Is that still going, Fried? Are you dying to move your interim status to something more permanent -- and I'll throw it out there, Christi Shaw has left Kite Gilead. Is someone close to that name joining anytime soon? That's it for us.

I can't say specifics like that, but the search is ongoing and no, it won't be me. So at some point, we'll be able to talk more about that. And the Board is definitely interested in finding somebody who knows.

Our next question comes from the line of Mara Goldstein from Mizuho Group.

Great. I just have a quick follow-up on Proleukin and I respect you're not giving guidance, but I'm just curious around your expectations about working capital and how the ATM figures into that as you onboard that product. And then secondarily, can you speak to the TILVANCE trial? And how we should think about the primary endpoint in terms of the delta improvement looking for given the number of patients in the trial? And secondarily, the presence of the crossover arm does -- how do you account for pressure on the OS secondary endpoint there?

Yes. Maybe Jean-Marc, do you want to take the first part of that and Friedrich the second part?

Yes, sure. Yes, I'm trying to try to think about the best way to answer your question. So I think our goal is to integrate Proleukin in a way that we will keep it as a profitable activity. Again, it will be separate in a way from last wholesale. So we will have TIL cell Proleukin outside of our own usage. So the -- currently, I will Proleukin is profitable, and we intend to do the same in the future after integration. I'm not too much concerned around working capital as itself because, again, we're not talking about large amount. We will not carry a lot of amount of inventory and everything should be pretty much managed correctly. So no concern on that. ATM-related, I mean we've commented about the activity that we've just done. And I think what's the most important there is to keep in mind, we have enough cash, including the acquisition of Proleukin into the second half of 2024.

And then the TILVANCE questions.

Yes, sure. Thanks for the question. Friedrich here. So I think that was a 2-part question, Madam was about what -- how do you think about deltas that we're trying to achieve in the context of the study design and the sample size and the second question was about crossover.

So the first question, just, I mean I'm just stating the obvious, the design of the study is a randomized, comparative study right. So we're not shooting for specific delta to an existing benchmark. We're shooting for a difference or a hazard ratio between the 2 arm. What you usually do when you design a study like that, we do look at the best available information about what you might be expecting in your control arm and then you're powering in order to be able to get the difference or the hazard ratio. It's a little different from how we would have done this and/or are doing it in our single-ARM design.

The information that we're pulling in for that is pretty straightforward. It's available information on what you're seeing in the frontline population of patients treated with pembrolizumab monotherapy and the information is available in the USPIS for pembro or/and publication. So that's probably as much as I can say here. The confidence here comes from our knowledge of what we're currently seeing in, in our COM-202 Cohort 1A, where the response rate is 66.7% with our last update and that would compare to something that's in the low 30% for pembrolizumab monotherapy. So that gives you an idea around the ORR.

The crossover, so yes, obviously, the crossovers are something that you have to keep in mind, as you're thinking about an overall survival endpoint, but that is exactly the reason why overall survival is not a primary endpoint yet. It's very typical to in that situation then go with non-overall survival endpoint and we are particularly happy about having gotten agreement of being able to use ORR and PFS is dual endpoint in our discussion with the FDA and that's exactly the reason for it. The value of the crossover arm in this case is outweighing potential impact on the overall survival secondary endpoints.

Our next question comes from the line of Kelsey Goodwin from Guggenheim Partners.

I guess, first regarding manufacturing. I guess, how do you think about kind of initial launch capacity and then the timing for step-up, if we're kind of thinking about it similarly to what we've been seeing with the autologous CAR-T therapies. Maybe just a bit more granular than kind of the Phase 1, Phase 2 that you lay out for the iCTC. And then secondly, maybe just a quick one, are you able to provide any more color on your plans for potentially expanding into Europe for melanoma.

Yes, let me take the last one and, and then Igor can give you some more color on the manufacturing. Yes, Europe is something we're very interested in. We haven't publicly spoken much about Europe, but we are active there. Obviously, our trials have been run there and we continue to run them there and TILVANCE-301 is going to get have a significant European presence. We are engaged with the European regulators and I think you'll hear more from us in 2023 on that. But that is an important market we think for melanoma as well as other markets around the world, where we have a highest since rate of melanoma. You got the one answer for the manufacturing question.

Happy to Kelsey, thanks for the question. So as I mentioned earlier, we have the build to capacity because the facilities built can support more than 2,000 patients per year, and we're now hiring the manufacturing team to meet the demand that we anticipate at launch. We're not sharing the exact demand numbers, but as Jim mentioned, actually in response to an earlier question, we expect maybe a bolus. So we've taken that into consideration as we're planning, planning the initial launch capacity. Beyond that we can continue hiring the staff as-needed and then also build-out the shelf-space that we have within the existing iCTC facility that can bring us to over 5,000 patients per year. To increase the capacity step wise, there is a process similar across cell therapies similar to CAR-T that requires capacity demo submissions to the agency and we're planning those as well.

Our next question comes from the line of Asthika Goonewardene from Truist.

This is Karina in for Asthika. My question is for TILVANCE-301 study. How long it will take for you to finish recruitment? And given that the study is open-label, do you plan to report interim data? And if so, at what point?

Friedrich, do you want to take that.

Yes, so the prediction of, projection of accomplishing the analysis is hard particularly when you are in the early nearly phases of start-up. I think we will better understand that once we're in and make progress on enrollment and in-site activations. Also keep in mind that ultimately these endpoints, particularly PFS endpoint are event-driven and a true and exact projection has never really truly, truly possible because of that. So stay posted on that.

Repeat the second question about -- oh, yes, you were saying that this is an open-label study? It's actually not. It's a blinded study, so meaning we are blinded to the treatment assignment as you would in any other study design, the assessments are done by a blinded independent radiology committee. So there's probably no update in between other than a final decision is being made by the DMC.

And also I have another question. You said that you do not expect to get REMS in best of the case.

Yes, we don't see any reason why we will get a REMS. The TIL treatment regimen, Cy Flu and IL2 don't have a REMS today. So -- and TILs don't really carry any safety issues themselves. So we don't see -- we don't have the issues that you see with some of the CAR-Ts that triggered the REMS in those cases.

Our next question comes from the line of Madhu Kumar from Goldman Sachs.

This is Rob on for Madhu. Just how should we think about the timing of data from cervical cancer cohort and then on genetically edited TIL project products, what are you guys thinking in terms of accuracy, really like where do you expect to be better?

Yes, genetically edited TIL products, to take that one first, that combined (technical difficulty) with the TIL product. So we're hoping to get something that would look like additive efficacy between the 2, the 2 modes, the TIL response and then the blockade of the inhibitory mechanism directly within the cell now. And then as we add additional immune checkpoint targets to our gene editing, we can hopefully add on top of that too. So that's the basic theory behind it. We're testing that now in humans, and we'll know more about how that works. It's similar in many respects to how you see a lot of people developing bispecific antibodies right now that blockade PD1 and something else. I mean, this is the kind of thing that we want to do within the cell. And so, the first -- the PD1 knockout is the first one. That's in humans right now. We'll have more updates on that for you later on this year. Cervical, we just restarted enrollment in that study and that's a pivotal study. We intend it to be a pivotal study. And so we don't have an update for you today on that. The post PD1 cervical population is large enough to we think we can enroll that reasonably well, but we'll know more later this year on that.

Thank you. At this time, I would now like to turn the conference back to Fred Vogt for closing remarks.

Thank you again for joining the Iovance Biotherapeutics Fourth Quarter and Full Year 2022 Financial Results Conference Call. We've had an exciting start to 2023 with Proleukin agreement and new clinical data, and we look forward to completing the BLA this quarter and delivering on our regulatory commercial manufacturing, pipeline activities and milestones throughout the year. I'm grateful for the patients, physicians and regulators as well as our employees and cross-functional teams who have worked in close collaboration to advance our mission to be the global leader in TIL therapy, but also like to thank our shareholders and covering analyst for their support. Please feel free to reach out any time our Investor Relations team for any follow-up. Thank you.