Iovance Biotherapeutics, Inc. (IOVA) Earnings Call Transcript & Summary

So first and foremost for us at Barclays down in Miami, this is our last session for the conference. So thank you for everyone for attending and making this live event happen and for everyone who's been enthusiastic or the questions or the participation or your time, so much appreciated. It's the first event in a couple of years, and it feels like we're getting back to normal, which is fantastic.

So good to be in person.

Yes. Yes, exactly. So my name is Peter Lawson, and I'm the biotech analyst, or one of the biotech analysts at Barclays. I cover -- have the pleasure of covering our events. So up on the stage, I've got Jean-Marc Bellemin, CFO; and Madan Jagasia, SVP of Medical Affairs. We had dinner last night and that went very well, and I'm sure there's similar questions today from me, so I apologize for that and/or elaboration on the questions from last night. But I know you've got a couple of prepared slides to walk through and then...

Yes. No, just some maybe introductory remarks, and thank you, Peter, thank you for Barclays team for the invite. It's good to be in person, indeed, we agree. Let me start first by reminding everybody that we will be making forward-looking statements during our presentation today. So yes, let's talk about the brief overview of Iovance to start with. We are a late-stage immuno-oncology company. We aim to be the global leader in developing, innovating and delivering a TIL, or tumor infiltrating lymphocyte cell therapy for patients with cancers. We are preparing our first biologic license application, or BLA, for our lead product, TIL product lifileucel for metastatic melanoma patients who have progressed on anti-PD-1 therapy, which is clearly an unmet medical need. To date, we have treated more than 500 patients with TIL, Iovance TIL products, using our scalable, centralized and the proprietary 22-day manufacturing process, which we call Gen 2. We also have in the clinical setting an optimized manufacturing process, which is called Gen 3, which is only 16 days. And to talk about manufacturing, we have, last year, finalized the build-out of Iovance Cell Therapy Center, or ICTC, which is our manufacturing facility in Philadelphia in Navy Yard. So we have now 136,000 square foot facility. I think it's still the bigger in the world. Actually, where we are producing our batch for clinical supply, and we are ramping up to get ready for commercialization of our products later on. From a clinical standpoint, I mean, you have the slide on the screen, you can see we are quite busy. Madan will certainly comment more, but we have 6 active clinical trials, among 4 solid tumor in multiple indications. So we are evaluating TIL in monotherapy, but also TIL with anti-PD-1 in multiple indication across various patient population in melanoma, in lung, in cervical in head and neck. And actually 2021 was really a rich year for us. We presented -- 118 patients treated last year among 420 tumor 5 indications. So very richer for us, and we have demonstrated the potential of TIL in solid tumor. So this was really a great year. In terms of moving beyond even the clinical pipeline, thinking about our future approach for the platform and optimizing TIL therapy, we have just announced this week the NDA allowance to proceed for a genetically-modified TIL product, IOV4001, in which PD-1 is inactivated. We also have work being done to evaluate the IL-2 analog. And finally, we also worked to evaluate the proof-of-concept of a polyclonal T cell platform in blood cancer in a Phase I/II study in CLL/SLL. What else, from a commercial standpoint, I want to mention that we are getting ready for launching lifileucel in metastatic melanoma. So by targeting and training the authorized treatment centers, we have disclosed that we will have more than 40 sites ready at the time of launch. We will also, by securing patient access and reimbursement, and by developing a tool we call the Iovance Care, which is our quality system, COI/COC, so chain of identity, chain of cost system, which will be a tremendous resource for the patients and physicians when we launch the drug. And last, but not least, we have a strong balance sheet at the end of last year. We had $602 million of cash or cash equivalents, which will be sufficient to finance all our clinical program research program, commercial readiness, and we will have enough cash runway into 2024.

Perfect. I'd love to ask about, of course, the potency assay, but the conversations you're having with the FDA, how has that changed over the last year, 6 months? What's the tone been like? I know you can't talk about the individual components of that, but...

Yes, we cannot really comment about the back and forth we have with the FDA. But yes, I think, it's fair to say that we have an active dialogue with the FDA. We have multiple interaction. Again, we don't comment too much around the exact nature of the interaction. But we know that based on the feedback and the discussion we have with the FDA, we are still on track to submit our BLA by the first half of 2022. So that's the key and the key priority for us clearly in 2022.

Okay. And it seems like a year ago, or 1.5 years ago, there was a lot of education probably on both sides, yourself and the FDA. But does that -- has the quality of those conversations kind of increased over time?

Yes. I think it's fair to say, and maybe Madan can even comment that over the last few months or even year, we had a lot of interaction in terms of education. We have the first class agent polyclonal drug. So there is a lot of education we did around the mechanism of action and the mode of detection of the TIL product with the FDA in order to find an alignment around what's the best potency assays that can go into the BLA.

Yes. I would add to that, that our collaboration with the FDA is really very collegial. I think the questions that we are getting from the FDA does show that they really understand the science behind the polyclonality of the TIL therapy. And none of the questions are unanticipated. Our scientists have been able to answer the questions in a very collegial and collaborative manner. So we're making excellent progress with the FDA.

But has there been a kind of an arc of improvement in those conversations where they understand it more and their better question is coming back or...

So we have disclosed probably. I mean the iteration has been -- we are getting more, I can say, granular question and the discussion and interaction with the FDA, which is a good sign in terms of the engagement of PAT and how we are progressing. And again, the fact we still are on track to file is certainly a sign of the good interaction.

Do you feel they want to approve the product or get the assays through, or is -- there's no sense of resistance there is more...?

I cannot really comment too much around that. What I can say is the FDA, I think also, like all of us are acknowledge the clinical data for metastatic melanoma, that's a fact.

Got you. And then there's no questions about the strength of the data. It's always...

Yes, always about how to define a potent versus a sub-potent product, that's what the discussion is about.

Yes. And this is this kind of arc that's happened within the FDA are going from transplanted to productization...

I think it's fair to say that the FDA is sticking to their guidance, right? But the guidance is that the potency assays should be aligned with the mechanism of action. So as the depth of understanding of the mechanism of action increases, your questions are getting really finessed and granular, which is really a good sign.

Do you think the FDA will either update ahead or after -- they have -- you've all learned a lot, and you've talked a lot in that space. So it's a very old regulation we've got 2012 or so?

2011.

Right. Yes. I think it just really depends. So I think as I said, the potency assay is sort of a continuum, right? You have to define the assay. You have to qualify it. You have to validate it. You present the specifications of that. But there -- all of that needs to be completed prior to the BLA or some components can happen during the BLA review process. I think it's an ongoing discussion.

Got you. I know inbound questions from me and the questions I ask, investors ask are very focused around the potency assay. But does that come up when you're -- internally when you're interviewing people, is that on people's minds to worry about the FDA?

I'm not doing all the interviews, but people are talking about patients, talking about the fantastic product for melanoma, but even being on melanoma. They are excited about the opportunity to launch also drugs. So I mean, we are getting a fantastic candidate to join the company with a lot of cell therapy experience. I mean I think people are already beyond the BLA submission itself and talking about how we get this drug to market.

Got you. Good. Is there any worry about the change in regulatory environment in Washington? Or is it -- there's clear rules that you have to abide by and those are the rules you have to stick with or...

We are following in the current regulation, plus hearing and sending to FDA feedback and answering all the questions. I mean that's what I can tell.

Got you. Okay. Is there -- when if you could kind of walk through the sequence of events of what we kind of see from you? Will there be a PDUFA date, PDUFA AdCom panel, what kind of communication are we going to get?

Yes. I mean AdCom, we don't know, and there was nothing related to that. What I can tell you is, of course, we will disclose the BLA submission when it will happen. There is a lot of -- you have to understand, there is a lot of work streams, which are happening in parallel currently in order to deliver on this BLA submission, which include, for example, the RIC readout of the Cohort 4 data, which will have to go into the package, some work needs to be done on the assays. So again, we always -- always said we will disclose to investors and to the public all material information that we should disclose at the right time. For sure, the BLA submission will be one of them.

Got you. And then it sounded like over the last 6 months, maybe 9 months that there's a chance you're innovating for this assay, so you've potentially pattern protected?

Yes. Thank you for asking that question. Yes, definitely, we said the way we have been innovating in terms of addressing the feedback from the FDA is quite impressive. So we, of course, are considering and we are patenting in the potency assays that we'll be using because this is clearly a competitive advantage. We are spending time to be collaborative with the FDA to solve these issues. So we want to remain competitive there and patent. And that's why we have not disclosed so much on the detail itself of the potency assays that we are discussing.

So you'd get a sign off from the FDA around the potency assay. And then what -- just file patents around the...

Everything is happening in parallel.

Okay. So you push the button. Okay. Got you. on the assay itself, that's going to be tissue independent?

That is correct. So the potency assay matrix will be agnostic of the tumor type. So that's the reason we've spent that much time. We didn't want to develop an assay that is just melanoma-specific and then basically repeat that entire thing for the other cancers that we have our eye on.

Okay. And remind us again, the -- for the filing in melanoma, you want Cohort 4 to read out, and that's going to be included?

Correct.

Correct. That is correct. Yes. So Cohort 4 is obviously the pivotal cohort. So that IRC read information would be part of the BLA submission.

Will we see Cohort 4 data before...

Our hope is that we would have a top line release of the data. I think, as Jean-Marc mentioned, it just really depends upon the sequence of events and how temporarily compressed or distant they are. But we hope to present the Cohort 4 data at a medical congress for sure.

Why is Cohort 4 so important?

So Cohort 4 is the pivotal cohort. It is a registration cohort. Cohort 2 is exactly similar to Cohort 4 in terms of key eligibility criteria, but that may be considered supportive for the BLA application.

Got you. Do you have to run kind of any confirmatory studies as well. At the same time, are they starting what's the time line around?

So we do have our RMAT designation. The decision whether we need a confirmatory study for "full approval," that's a decision that will be obviously discussed with the FDA. But there is a possibility that a confirmatory study may not be needed. I think just a reminder, we have extensive long-term follow-up on the Cohort 2 patients. So we have presented at ASCO21. The median follow-up at that time was 33.1 months. So that could be a potential avenue or the agency could ask for a confirmatory study and ask us to kind of go down that path as well.

Got you. Can you remind us how many assays that are in this matrix of assays and...

We've not publicly disclosed the number of tests that are in the matrix.

Okay. How many iterations are you on? Or is it just like an ongoing thing for the...

I wouldn't say that the assays themselves -- the tests themselves are not as iterative, but their qualification, validation and setting the specs that could sometimes be an iterative process.

And the matrix would end up generating an output number that you used to kind of select in or select out data?

That is -- that is a potential possibility.

Yes.

Okay. So there's kind of -- that's still being refined the algorithm for the asset?

Right. We've not publicly guided on that, whether the assay, the number of tests are all locked in? Or can there be a iteration of that?

Got you. Okay. Do you think the FDA is happy with the assays now and it's just looking down the assay itself? Or is there any risk that you have to go off and run a new assay? Develop a new assay?

I think we just need to repeat, I mean, we are on track to find for the first half of 2022, and that should answer your question.

Yes, sure.

Much appreciated.

And I guess the next thing is just like cervical cancer. I mean that's changed so much. And so this assay would be good for cervical cancer as well?

Yes. That is the hope, yes.

Would the assay prevent you from starting additional trials in any way or...?

No, not necessarily.

And then I guess the final question because it's come up before in prior conversations as well, but it could change the response rates for assay.

The assay could potentially change the response rate. So imagine a scenario where you have a benchmark of an assay and below that number "the product" there's a manufacturing failure, but a patient in that sort of swim lane could have been a responder, so the spec may change. So is that the reason I said it is an iterative process.

Got you. And so we should view this assay as a clear barrier of entry for competitors coming through?

Yes, I think so. I mean the discussion will have to happen. I mean it's all about the manufacturing process, also we need to gain the experience to be able to have the right potency assay. So there are clearly work needs to be done in for our competitors, yes.

Got you. And I think you've addressed it before, but there's no chance that you would be running out of any collected samples?

No. No. That's not an issue.

That's not? Perfect. And then cervical cancer. The landscape has changed. How quickly do you think you're in a position to potentially file or commercialize in...

As we've discussed, we've had interactions with the agency on cervical cancer. So as you mentioned, the landscape has changed. But fortunately, we have a cohort that is enrolled in post-PD-1 landscape. But we are discussing with the agency regarding what does the final cohort look like, what is the new benchmark out there because there are multiple second-line agents for cervical cancer, but none of them have specifically been tested in the post-PD-1 landscape. So we have to make some assumptions of what is expected as a benchmark. And what is the -- what is that number of the overall response rate that we have to target. And also keep in mind that when you're doing a single-arm Phase II study, the FDA does not look just at the ORR. They look at the complete data package. They look at the safety profile, the duration of response. It's sort of a collective data package with the FDA based their decision on.

Do you think TIL responses are any way dependent upon PD-1 expression levels or prior IO?

It's a good question. So I think if you look across all the public data that we have presented, whether it is cervical cancer, melanoma, head and neck or non-small cell lung cancer, I think a common theme is that the TIL response rate is not dependent upon the PD-L1 status of the tumor. It is likely that a high PD-L1 expressing tumor may have an enhanced efficacy, but it's not proven sort of statistically. So I think that's really the strength of the TIL regimen. We have shown in the context of melanoma, in the context of Cohort 2 that the cumulative prior duration of anti-PD-1 therapy is inversely associated with the duration of response. So it does not influence the response rate as such, but it influences the duration of response. And that's I think key to keep in mind. So our hope is that once we are in market for metastatic melanoma, if a patient has failed an anti-PD-1 therapy, they move on to lifileucel versus just recycling for the checkpoint inhibitors.

And why is that for the exposure to PD-L1 or PD-1 and the inverse relationship?

Yes, it's a good question. Scientifically, we don't know, but it is very likely that prolonged exposure to anti-PD-1 really immuno-edits or sculpts the tumor in such a way that the tumor microenvironment is much more harsher and less therapies are likely to work subsequent to that. But again, it's -- again, we've seen this observation only in the context of Cohort 2 so far. So we really need a larger end to sort of generalize this. Now biologically, we know that if a patient has seen anti-PD-1, recycling anti-PD-1 does not help. In melanoma, there's a small body of literature that it may add efficacy. But in non-small cell lung cancer, the standard of care is never to recycle a JAK1 inhibitor because it has no efficacy.

Got you. How varied are the TILs in, say, melanoma versus cervical cancer? How many do know how the best way to characterize it by the clonal copy number?

Absolutely. So we actually had -- we've published data as a poster in 2020, and we had data at SITC as well. So let me talk about the SITC data. In the context of non-small cell lung cancer, we looked at the clonal diversity, the entropy index and the number of unique CDR3 clones in non-small cell lung cancer and compared it to the previous published data for melanoma and cervical. And then at a high level, there is no dissimilarities over there. So the TIL product, at a high level, looks very similar across tumor types.

Great. Just going back to cervical cancer and kind of the post-PD-1. How many patients would you -- would that be separate cohort? How many patients would you need to see in the post-PD-L1 setting?

So again, those are discussions that are ongoing with the agency to kind of get final agreement on what that cohort size needs to look like.

Got you. But you could potentially file a mixture of PD-1 exposed PD-1...

We've not disclosed that exact strategy. But I think, in general, the agency likes to see a homogeneity in the cohort.

Got you. How early do you think TIL therapy could be used?

Yes, it's a great question. So I think in the context of melanoma, right? The NCI recently published a paper what they've shown in 196 patients that -- metastatic melanoma, checkpoint naive patients, they had a ORR, I believe, of 56%, with an excellent progression-free survival. We also have data when we combine TIL plus pembro , we had data at SITC, the denominator was 10 patients, the ORR was north of 60% with a CR rate of 30%. So in melanoma, I think there is sound scientific rationale to move this therapy into the frontline setting, ideally in combination with an anti-PD-1 strategy.

Got you. Maybe in the last 90 seconds I could just touch upon lung. And just like what would the registrational trial look like for you? And what's the best trial to either focus on? And what do you think yields the best results?

Absolutely. So at SITC, we showed data in late-line lung cancer in 28 patients. Our ORR was 21.4%. The goal of that study was to demonstrate safety, feasibility, which we did. We definitely saw a signal. The duration of response, obviously, we want to see more sort of clinically meaningful DOR. So we have a multipronged strategy. Our main study is LUN-202, where we are using single-agent TIL therapy in a solid second line setting where patients have failed frontline chemotherapy plus IO. That study needs to read out. That's activated at more than 30 sites currently and is actively accruing. We have multiple other strategies going on in lung. Cohort 3a, we are combining TIL plus pembro in checkpoint naive lung cancer patients, and Cohort 3c, if a patient has failed checkpoint monotherapy. We are asking the question, giving a dose of a checkpoint inhibitor prior to tumor resection, does that increase the TIL infiltrate in the tumor so that when we surgically excise it, do we get a better product? And as you may have seen in our press release just a couple of days ago, we've got IOV-4001, which is a PD-1 knockout TIL. We are -- we are basically exploring that in non-small cell lung cancer, advanced patients with an unmet need. So we have multiple strategies going on in lung, but our main focus is really on LUN-202, which is second line.

And how should we think about how difficult it is to biopsy in the lung, and how addressable that population is?

Yes. Absolutely.

And is it getting better that you can get more out of less?

Absolutely. So that's exactly what we learned from Cohort 3b, right? We had a lot of skeptics about can the lung cancer patients be biopsied? And the answer was yes. In fact, in Cohort 3b, more than 60% of the anatomic resections, lung was the site of resection. So clearly, these patients can get resected. They can bounce back from their surgical comorbidities in time to get lymphodepletion. There was also questions about can a lung cancer patient tolerate high-dose IL-2. And the answer is yes. In fact, the median dose that they could get was 5 out of the 6 planned doses, which is very similar to what we've seen in melanoma and cervical cancer.

Thank you so much. We are going through time. So...

Thank you.

Thank you.

Thank you so much. Looking forward to filing.

Thank you. Thank you.

Thank you.