Nektar Therapeutics (NKTR) Earnings Call Transcript & Summary

Great. Good afternoon, everyone. My name is Jess Fye. And we're continuing the 40th JPMorgan Healthcare Conference today with Nektar. I'm joined by the company's CEO, Howard Robin, who's going to give a presentation on the business, and then we're going to go into some Q&A. [Operator Instructions] So with that, let me pass it over to Howard.

Well, okay. Thank you, Jessica, for inviting us again to speak at the conference. And it's an important kickoff for 2022. We very much appreciate being here today and to give an update on our company. Before I get started, I'm going to be making some forward-looking statements. So good afternoon to everyone that's joining us and thank you for joining us. As you know, Nektar is the leader in the development of medicines in the cytokine field. First, we work to harness multiple components of the IL-2 pathway with BEMPEG, which captures the immune-activating potential of IL-2. And second, with NKTR-255, which harnesses the IL-15 pathway and enables us to stimulate the immune system with NK cell proliferation and has a broad potential in liquid and solid tumors. Finally, with NKTR-358, we've taken a very different approach to the IL-2 pathway and are instead capturing the immune regulating potential of IL-2. So we took this important in versatile cytokine and engineered a new molecular design to help those with a broad range of autoimmune conditions. And in fact, if you look at the field here in cytokine development, there's really no doubt that Nektar is clearly the leader. As most of you already know, the trail that we blazed has spurred the creation of dozens of companies, who have copycatted our programs in the cytokine space. Many of these are preclinical companies that have gone to the public markets. And of course, these companies have achieved their billions of dollars in funding based upon the clinical data that Nektar generated with BEMPEG plus nivolumab. This clearly underscores the conviction within our industry around the incredible importance of IL-2 and other cytokines. Now with BEMPEG, we have a clear data set in first-line melanoma that led to a rare breakthrough therapy designation. And on top of that, we're far ahead of other IL-2 companies with frontline and adjuvant studies in melanoma and several other studies in frontline solid tumor settings. And this has allowed us to potentially secure several very large IO frontline indications where checkpoint inhibitors are widely used in selling billions of dollars. And the history of development of checkpoint inhibitors tells us how important a leadership position is and why being bold with clinical development can make a difference for a first-in-class mechanism like BEMPEG. We have a development strategy that will reap benefits for us with 6 registrational studies underway, the first of which is our Phase III study in metastatic melanoma, which combines BEMPEG with nivolumab and compares to nivolumab in this setting. We're extremely excited that we are so close to having the results from this very important Phase III study, which we expect in the next few months. So I'll start with BEMPEG and IL-2. Now let me tell you why we believe we're in a unique in this field as a full-length IL-2 molecule, which provides the right amount of receptor bias to activate cytotoxic T cells. To start, let me remind you of the history of the IL-2 pathway in cancer and why Nektar set out on this journey to make a new and accessible medicine from this important cytokine. So IL-2 at high doses received its approvals in both melanoma and renal cell carcinoma in the 1990s. And at that time, high-dose IL-2 was associated with complete responses, which were, in fact, durable for decades without a need for further therapy, but the usage of high-dose IL-2 was limited in practice. It turns out that only a small percentage of patients were strong enough to tolerate the severe toxicities of the high-dose IL-2 regimen. Its usage was limited by its functionality on the IL-2 receptors and a high-dose regimen given in a hospital was the only way to elicit the clinical benefit of IL-2. So even though it had great promise, it was not really an accessible medicine. So our goal when we started the development of BEMPEG, was to create a new and novel molecule that captured the positive attributes of IL-2 and also addressed the historical problems with high-dose IL-2. We have a technology platform that was well served to solve these problems, and we chose an approach that we believe is the best in class. Now what is so unique about BEMPEG? The IL-2 biological pathway has 3 receptor subunits, alpha, beta and gamma. What we've done with BEMPEG is really very novel. We preferentially signal to the beta-gamma portion of IL-2, which stimulates the growth of cytotoxic T cells. But we do this without overactivating the alpha receptor, which can lead to down regulation of the immune system. Now as the pioneers in the field, we could have easily designed an overly selective approach as other companies that have followed us have done. Some companies are using mutated forms of IL-2 that only bind to beta-gamma receptors and don't bind to alpha at all. Again, that would have been really easy for us to do, but we purposely didn't do that. Based on our scientific work, we concluded that it was very important to retain some small amount of transient binding to the alpha receptor, so you can enhance the priming of T cells in the lymph nodes. And that means that you get T cell proliferation and infiltration of those T cells into the tumor when the new tumor antigen is presented. And another important thing that we did is that we used the full length IL-2 molecule with no amino acid substitutions, rather than a mutated version to ensure that we did not see any tachyphylaxis on the receptor or issues that mutein can have over time in vivo. The other tremendous advantage of BEMPEG is that it's a prodrug. And because it's a prodrug, you don't have the risk of a cytokine storm that you may see with a nonprodrug approach. And of course, this is something you want to avoid in a medicine that could potentially be used in so many cancer patients. Lastly, and I think a very unique advantage of a prodrug is that this allows BEMPEG to be given on an antibody-like dosing schedule, in fact, once every 3 weeks. We're very pleased with this profile as our goal is to combine with checkpoint inhibitors where the dosing schedule can work easily together. And this gives BEMPEG ease of administration in an outpatient setting, which is critically important with a broad-based mechanism. So now let me show you the rationale for combination with a checkpoint inhibitor. The combination is really quite simple and elegant. We think of it like building the best racecar. We know that targeting the PD-1 pathway may strengthen the immune response by reactivating cytotoxic T cells that have been stopped by the expression of PD-1 -- PD-L1 and PD-1. We think of this as removing the brakes on the immune system. And this alone, of course, has proven to be very effective for many cancer patients, particularly those with high levels of PD-L1 expression. So we released the brakes by targeting PD-1 with a checkpoint inhibitor. Then, by preferentially targeting the IL-2 pathway to significantly increase the number of cytotoxic immune cells in the tumor microenvironment, we put our foot on the gas. And these new immune cells also upregulate PD-1 as we have shown in the clinic with patients treated with BEMPEG. The end result is that the 2 together, BEMPEG plus nivolumab, could potentially drive deeper and more durable responses in patients. So let me show you how this concept of releasing the brakes and hitting the gas on the immune system translates into clinical data. This is our Phase II data in patients with first-line Stage IV metastatic melanoma. And I think this is a very good indicator of the potential of BEMPEG in the importance of harnessing the IL-2 pathway. So if you look at these data, you'll see that 34% of the patients had a complete response to therapy. And for those patients who responded, 90% of them had a reduction of 100% in their target lesions. That's incredibly impressive. And this data is all centrally read, blinded radiology review and not investigator-assessed. So I think that's very important to note. And we believe this is why BEMPEG is so important, and it could have the potential to help patients get to deep and durable responses, certainly with the goal of any cancer therapy. The median reduction in target lesions was in excess of 78%, very notable when you look at historical single-agent nivolumab data, where the median depth of response was about 35%. And even with the ipi/nivo IO-doublet therapy, where the median depth of response is only about 52%. In addition, we had very sick patients with liver metastases who benefited. In fact, 5 of 10 patients with liver mets experienced complete responses from the doublet therapy, and these data led to a breakthrough therapy designation for BEMPEG plus nivo, which is very rare in any first-line treatment setting in solid tumors. And of course, as I said earlier, high dose IL-2 delivered complete responses in melanoma and was approved there. So we have actually seen with BEMPEG in Phase II study exactly what you'd expect to see when you combine the right IL-2 mechanism with a checkpoint inhibitor in melanoma patients. Now I'd like to show you our PFS curve in these patients. So shown here is the median PFS for this cohort in the Phase II study. And as you can see, it was 30.9 months. To remind you of the bars here, we have designed our Phase III study in first-line melanoma patients with nivo single-agent therapy as the comparator arm. And we have a very good idea of how nivo performs as a single agent in these patients. In CheckMate 067, we see about a 6-month PFS and in the relativity study, a 4-month PFS with nivo as a single agent. So this PFS curve shows the potential of what can happen when you release the brakes and hit the gas on the immune system at the same time. Shown here are the 6 registrational trials underway for BEMPEG. Three of these studies will have data readouts in the first part of this year. These are the melanoma, kidney cancer and bladder cancer trials. And in melanoma, where the results come first, we do have a breakthrough therapy designation, and this will enable us to file quickly once we have positive Phase III results. The broad program for BEMPEG covers both adjuvant and first-line solid tumor settings and positions BEMPEG in the most significant tumor types where checkpoint inhibitors are used today. Current sales of checkpoint inhibitors in these tumor types are over $6 billion, so a very significant opportunity for BEMPEG. Now with that, I'd like to shift gears now and discuss our next large cytokine program in development, our IL-15 agonist NKTR-255. NKTR-255 causes the proliferation of natural killer cells and also expands CD8+ T cells and memory cells. NKTR-255 has the potential to combine with both ADCC antibodies and CAR-T cell therapies. And I'd like to show you how this works. So if you think about it, one of the problems associated with ADCC antibodies, RITUXAN, Erbitux, DARZALEX. And they are all fantastic drugs, but they deplete NK cells. And as they deplete NK cells, they stop working. And we believe if you can combine a drug that proliferates NK cells with these antibodies, you should have a profound effect. And I'm going to talk about what we're doing in the clinic in a moment. We also believe we have an important opportunity in the area of cell therapy. We know that CAR-T therapies can be effective for some patients, but this benefit may only last for a relatively short period of time. An interesting observation is that for patients who do have durable responses with CAR-T, we see increased levels of IL-15. So by adding IL-15 to CAR T, the theory is that you should be able to drive a much better duration of response. In this context, we think of NKTR-255 serving as a cell therapy potentiator. Now let me show you our development plan for this novel molecule. First, we're pursuing a clinical study in liquid tumors in relapsed/refractory patients with multiple myeloma and NHL, specifically B-cell lymphomas. We've largely completed our monotherapy work. And in this study, and we'll be expanding to combine with RITUXAN and DARZALEX in the second part of this study. We have a collaboration with Janssen for supply of DARZALEX for this portion of the study. Second, we have a trial underway in head and neck cancer and colorectal cancer. And this study is combining NKTR-255 with Erbitux or cetuximab in these relapsed solid tumor settings. As you know, cetuximab has a very low response rate around 10% or so. So these highly refractory patients and we hope to improve upon that with the addition of NKTR-255. And finally, in 2021, we entered into an exciting new collaboration for NKTR-255 with Merck KGaA and Pfizer to combine it with avelumab in their approved indication in bladder cancer. This is a Phase II comparative study that is being run by Merck KGaA, and we're very excited about the opportunity here. And I'll show you what we've seen in the clinic with NKTR-255 so far. So with NKTR-255, we really have an agent here that can be used in both liquid and solid tumors. And we now know that we are increasing NK cell levels in a meaningful way. We've also have an approach, which can allow us to build a dose regimen in combination with these antibodies. In our early dose escalation work, we have observed a consistent increase of natural killer cells as well as CD8+ T cells across multiple tumor types, including multiple myeloma, non-Hodgkin's Lymphoma, colorectal cancer and head and neck cancer. We see up to a ninefold increase in NK cells and our pharmacokinetic profile is highly predictable, allowing us to dose NKTR-255 every 3 weeks or every 4 weeks. Importantly, we see increases in NK cells, even in the toughest patients including multiple myeloma patients with compromised bone marrow, and this is a very important attribute of NKTR-255. So we believe this novel IL-15 agent has an optimal PK profile and optimal PD profile. And this should allow NKTR-255 to be given as a monotherapy and in combination with targeted antibodies. Now I'd like to briefly share with you some interesting data on the CAR-T front, that we presented at the recent ASH Congress. So this is patient data analyzed by our colleagues at the Fred Hutchinson Cancer Center, and this chart shows patients with highly relapsed and refractory NHL and multiple myeloma, enrolled in the NKTR-255 study, who also had CAR-T as one of their prior therapies before entering the study. Three of these patients were well over a year past their CAR-T infusion. That's very important. All of them had minimal levels of detectable CAR-T at baseline prior to entering the NKTR-255 clinical study. And what we saw in all 4 of these patients with detectable CAR-T at baseline was a substantial increase in these cells after treatment with NKTR-255. Again, this is important. This was seen in patients where it had been more than a year since they had their CAR-T infusion. We think this reinforces our conviction that there is an important role for NKTR-255 as a CAR-T potentiator. So our next steps in the clinic will be to evaluate dosing of NKTR-255 shortly after CAR-T infusion to see if we can generate even more durable responses for patients. Now I'll switch gears now and move to our work in autoimmune disease with NKTR-358. So here's NKTR-358, and it really is the polar opposite of BEMPEG's mechanism. Instead of stimulating T cells, cytotoxic T cells, NKTR-358 is designed to induce regulatory T cells. Now this is a schematic of the novel biology that we're unlocking with NKTR-358. You could think about this conceptually as autoimmunity being the result of an imbalance of a patient's immune system with an excess of effector T cells and a deficiency of regulatory T cells. NKTR-358 is designed to fix this and bring the immune system back into balance. This means NKTR-358 really could be a novel resolution therapeutic for autoimmune disorders that doesn't cause broad-based immune suppression, which is a problem with current therapies. This important program is being developed with our partner, Eli Lilly. In fact, this is actually the slide that they recently showed at their Annual Investor Meeting in December. Now I'd like to show you a piece of data from our study of NKTR-358 as a single agent in lupus patients. Shown here is data from our multiple ascending dose study in lupus. And what we are really excited about is the signal we saw with the Class A ASCO results. This is a score that measures the skin manifestation of lupus. And when we look at patients that started with moderate skin scores of 4 or higher, we see a dose-dependent drop in these patients. Seven of the 18 patients, who were on the drug treatment arm, had score drops of 4 or more. So it's exciting to see that we can achieve this with only 3 doses of single agent NKTR-358. This data led to Lilly launching a Phase II study in lupus patients, which is underway. And in addition, Lilly recently announced incredibly encouraging data in atopic dermatitis for NKTR-358, and we'd like to share this with you now. So here's the data from a study Lilly conducted in patients with moderate to severe atopic dermatitis or eczema. And Lilly considers this to be a true proof of concept for NKTR-358 in this disease setting. Improvement of atopic dermatitis is easy to measure and has clear endpoints, and this has allowed Lilly to evaluate early efficacy in this setting. The clinical trial was 12 weeks of therapy with single agent NKTR-358 compared to placebo. And what Lilly also did was to follow these patients for quite a while after the last dose of NKTR-358. And at 12 weeks, we see really robust efficacy at the highest dose of NKTR-358, shown here in blue, with a very clear separation from placebo. This efficacy at 12 weeks is comparable to the current standard of care, DUPIXENT, at 16 weeks. But clearly, the most fascinating aspect of the study was that when we looked at patients 36 weeks after we stopped dosing NKTR-358 therapy, their skin scores remained very low and even dropped further. This has us and Lilly very excited about the potential for durability with NKTR-358. These data really underscore our hypothesis that if you increase the function of regulatory T cells that you might, in fact, see a durable clinical signal like we see here even after treatment ends. And these exciting data led to Lilly now planning a Phase II study in atopic dermatitis, which further expands their Phase II program for NKTR-358. Here are the Phase II studies in the NKTR-358 program. We have a 280-patient Phase II study in lupus underway, a second Phase II study in 200 patients with ulcerative colitis underway, a third Phase II study planned in atopic dermatitis and a fourth Phase II study in autoimmune disease expected to start this year. So we're really poised to have a steady stream of data coming from these Lilly studies over the next 12 to 18 months, and we're pleased with the thoughtful and comprehensive approach that they've taken with this molecule. To remind you, our agreement has significant double-digit royalties for sales of NKTR-358 along with the option to co-promote. And we're truly excited about how large the opportunity is for this potential resolution therapeutic. Now before I share our 2022 upcoming milestones with you, I want to show you our entire clinical pipeline. If you take a look at the therapeutic areas where we're working and the sheer breadth of our clinical programs, I'm very proud of how we built this strong pipeline from a platform of immune science and a leadership position in the field of cytokines. So here are our milestones for the next 18-month period for Nektar. We're ending 2021 with approximately $800 million in cash and equivalents. For BEMPEG, 2022 is a very big year, and we look forward with great excitement to the Phase III study results. For NKTR-255, the study with avelumab in bladder cancer will start in the first half of the year, and we should have continuing data from our studies in liquid and solid tumors. And lastly, for NKTR-358, we expect our partner, Lilly, to present data from multiple clinical studies over the next 12 to 18 months, and they will also initiate the next 2 Phase II studies of NKTR-358, 1 in atopic dermatitis and 1 in another new indication. So in summary, Nektar has an outstanding portfolio with a very long list of late-stage clinical studies that positions us with significant data readouts coming very soon. We have a very strong cash position and are highly confident in our business heading into 2022. I'm very excited about where we are today and what is ahead of us, and I'd like to thank all of you for listening. And with that, I'll end my presentation and hand it to Jessica to lead us in the Q&A session. Thank you.

Great. Thanks, Howard, for that presentation. We'll give it a second for your colleagues to join here. [Operator Instructions] I guess to start out, when the top line data from the melanoma Phase III trial reads out in the first part of 2022, what would you consider a win? And do the data from relatlimab plus nivolumab set a new bar?

Well, I think -- okay. Clearly, the measurement point is nivo. And I don't know that -- of course, everything that's new sets a new bar, but that isn't our comparison. And we're not making a person against a LAG-3. So I think you have to look at these studies individually, see how we compare against nivo. But clearly, what's really important to remember here is that the mechanism is well defined, well understood. The use of IL-2 is well documented and well elucidated. And therefore, I think conceptually, if we have a successful trial, and I'm hopeful that we do that, that should actually set a new bar and certainly in melanoma. And I think if you look at our PFS of 30.9 months, I obviously don't know what it's going to look like in the Phase III study, but that was an incredible number. And I don't think you have to make a comparison to the relative -- to the relativity study. I think you have to look at this as its own and it is a completely different mechanism, a completely unique approach, and it will be highly used. And I actually believe it can become the gold standard in melanoma.

Okay. Got a question on the portal here. This one saying it looks like the BEMPEG Phase III, I'm assuming this is about melanoma, because the rest of the question -- it looks like the BEMPEG Phase III took a bit longer to enroll than the LAG-3 Phase III. Do you know why?

Yes. Look, I think it's a very good question. And I -- and it certainly took longer than we would have liked, quite frankly. I think, believe it or not, the COVID shutdown had a major role in that. I believe -- we weren't enrolling patients for 6 or 8 months, because of the COVID shutdown. And I do think that we also wanted to make sure that we had the pharmacokinetic profile dialed in and fully tested before we kept enrolling patients. But I think one of the largest factors there was COVID, and it's definitely slowed down our trial and the trial for other companies as well.

Got it. What level of read-through, if any, do you think it's appropriate to make from the melanoma Phase III results to the other 2 pivotal readouts coming out in 2022, the RCC, OS interim and the UC study?

Well, look, I think clearly, IL-2 has a great history, even high-dose IL-2 has a great history in melanoma and renal cancer. So I would like to believe that if we see positive results in melanoma, we also will see positive results in renal cancer. However, there are 3 completely different tumor types and varying degrees of immune responsiveness. So it's hard to get that read through. Obviously, a positive study in melanoma bodes well for what we see in renal and bladder, but it's hard to make that call at this point.

Fair enough. Switching to RCC, how do you see the ORR data you generated in Phase I/II translating into a survival benefit in that Phase III trial? What's the -- is relative bogey here? And where could BEMPEG fit in the treatment paradigm? What other advantages could a BEMPEG nivo combo bring relative to the TKI PD-1 combos and other therapies, if that study is positive?

I guess I'll let Dimitry handle that question.

Thanks, Howard. We do recognize that the RCC landscape continues to evolve. Right now, there's nivolumab and ipilimumab combination and also the checkpoint plus TKIs. And that includes already pembrolizumab and avelumab and more recently, cabozantinib with nivolumab was added. There are 2 key points here. One is that the combination of BEMPEG plus nivolumab does offer another treatment option. The TKI can be used in multiple settings. It can be used in combination with the checkpoint inhibitor in the second line, but it can also be used as monotherapy treatment in that setting or in a later line setting. And if you talk to different physicians around the world, people are really taking advantage of different treatment options that are available right now. And it depends on the patient, it depends on the setting. There are physicians who prefer to use the IO doublet upfront in the first-line setting as it can induce a higher degree of complete responses, very long-lasting responses, and it gives patients time of treatment. But others like to use a TKI combination, and then you can also have the option of TKI in the first-line setting as monotherapy, which is still used a lot. Some of it is based on availability of other drugs or lack of availability, but there are definitely patients, for example, favorable risk patients with a low disease burden for whom this is a good option to give a monotherapy TKI upfront. Lastly, another benefit from the IO doublet upfront is without a TKI here, it does give patients and physicians an option when the disease recurs. That's something comforting, especially for patients to know there's something else down the line. So if you use the IO doubled upfront, the tumor remains naive to the VEGF TKI treatment, and it can be used in a later line setting. So I think the goal here is to introduce another treatment option for patients that potentially has all the qualities we've seen in our PIVOT-02 study and high CR rate and deep and durable responses. We do expect potentially to have a different safety profile as well than is offered right now with the checkpoint combination and TKIs or ipi/nivo. And depending on the efficacy, we believe there is really a different treatment option that we can offer. But of course, the Phase III data will need to confirm this, that this becomes a possibility. And then lastly, we do have a holistic approach. We have a TKI inclusive approach as well. Obviously, it's important, and we are building together with BMS upon the BEMPEG -- sorry, upon the nivo-cabo data by adding BEMPEG on top of this in a randomized Phase II trial.

And maybe switching to UC. Can you walk us through the treatment landscape for low PD-L1 expressing patients with cis-ineligible UC? What does BEMPEG plus nivo need to show to support a potential accelerated approval? And given the data from cis-eligible and ineligible patients showed a 48% ORR and 19% CR rate. Could we expect something higher?

So here also, we believe that new treatment options are needed for patients then and it's even more urgent in the setting of PD-L1 low status. We believe that the doublet of BEMPEG and nivo could offer patients here differentiated IO doublet approach with a potentially attractive safety and tolerability profile. As you're probably aware of this population of patients can be elderly and fragile. By definition, they're not eligible for cisplatin and some patients are not eligible for carboplatin therapy. So tolerability is also very, very important in this setting. And referring back to our PIVOT-02 data, if we can, let's say, drive the high CR rates than expected with a single agent checkpoint therapy and thus setting into, let's say, our larger data set, we could really have a differentiated option for PD-L1 low patients, specifically. Also, it's good to know the combination of a good response rate is something, of course, we're looking for, but the combination is also with the CR rate and long duration of responses. In the PIVOT-10 trial, we've set it up in a way that we analyze the data with a minimum follow-up of 18 months. So we really have a rich data set to show the durability of responses, which we think is very critical in this setting, which is another appealing point where patients can be off treatment for a while, and then they can still have access to that the ADC treatment in the second line and different therapies as well.

Moving to NKTR-255. Can you elaborate on why we didn't see dose-dependent increases in CD8+ T cells across multiple dose levels compared to the NK cell levels? Is that something you expected? And is it specifically related to the drug's mechanism?

JZ, perhaps you want to answer that question.

Sure. Jess, so definitely one of the important things about IL-15 biology is that it is the most important homeostatic cytokine that regulates NK cells. And it does that both from mature NK cells to ones that terminally differentiate, all the way down to the immature NK precursors even to some of the stem cells, that give rise to NK cell development. So you have a different degree of sensitivity across cell populations. And at least 1 of those reasons is believed to be due to the amount of the beta receptor on the different cell populations. There's a higher expressed on NK cells. And as you move through T cells, particularly to CD4 T cells, the levels drop. So you have very different amounts of sensitivity. And so it is reasonable that we saw that kind of plateauing on the CD8 compartment. Once we reach high enough dose levels, where we saturated target-mediated disposition and the PK is linear with dose. So this is something very reasonable. And in this study, we're dose-escalating, as you know, in the monotherapy trial, and we're going to be continuing to evaluate the doses looking at all the totality of evidence from all of the PK safety elements as well as the pharmacodynamic responses.

And you mentioned in the ASH poster that there were minimal changes in CD4 T regs observed. Can you walk us through those findings and why I believe IL-15 wouldn't impact T reg activation or function either directly or indirectly?

Yes. It's very similar to what I mentioned earlier. So the actual quantity of the IL-2 beta receptor, which is also known as CD122, is the critical determinant for IL-15 signaling when it binds to the dimeric beta-gamma complex. And so cell types that have the lowest amount of CD122 expression are actually CD4 T cells and also T regs. And so those cells have very, very little both binding and biological activation in response to IL-15 signaling. And this isn't just even the case for 255, we've known this for both native IL-15, and it's even the case with the other kinds of IL-15 molecules in development.

Can you talk a little bit more about the additional cohorts you plan to pursue in the Phase I study with NKTR-255 and maybe include time lines and the overall development strategy in multiple myeloma and NHL? Where do you think the product could be most effectively utilized based on the data you have so far?

Yes. So this -- the 255 first-in-human heme trial, it's currently testing monotherapy, and it continues to enroll heavily pretreated non-Hodgkin lymphoma as well as multiple myeloma patients, and it even includes patients that have had prior CAR-T therapies. And then Howard showed you an example of 4 of the -- such patients where NKTR-255 could increase CAR-T levels. In addition, as it continues, we will be evaluating patients in the combination of NKTR-255 plus rituximab in the NHL setting and also NKTR-255 with DARZALEX FASPRO in patients with multiple myeloma. And all of these are based on the hypothesis that NK cell expansion is crucial for the activity of antibodies to function through an ADCC or antibody-dependent cellular cytotoxicity mechanism of action. So we believe that these doublets will initiate in the second quarter of this year, and we'll be in a position to identify the recommended Phase II dose around that time, as we start those expansion cohorts. And the strategy for these patient population includes also offering alternative treatment options post CAR-T or bispecifics as outcomes there are really poor and very, very short-lived. In addition, at ASH, we also presented the preliminary data post CAR-T, which is essential. And we're also paying attention now to options of combining NKTR-255 with CAR-T cell therapy. The example that Howard mentioned showed a big delay between administration of CAR-T and NKTR-255. This was really done in kind of a first-in-human safety setting. But obviously, our intention is to have the administration with 255 much more contemporaneous to the CAR-T transplant, essentially in a kind of like a combination setting, where NKTR-255 can substantially increase the persistence, the functional activity that we call this term, stemness and the overall activity of a CAR-T transplant in patients.

Maybe shifting to NKTR-358. In the Phase Ib data in moderate to severe atopic derm, you showed a 70% maximum improvement in EC score at 12 weeks with a higher dose. How does that compare to other approved products if we account for the maybe placebo-adjusted response?

Sure. Well, so one of the things that's important is that the data there the standard of care is set by DARZALEX -- sorry, excuse me, DUPIXENT, apologies. Dupilumab is the antibody, too many Ds for antibody names. And so this is an antibody that showed approximately 60% reduction in 1 study and about 65% reduction in the other Phase III study. And they treated for a 16-week period. And placebo in these trials usually hovers in the 20% to 30% range. It's just typical of dermal trials. And so that's kind of the benchmark. And obviously, this has led to a very, very effective drug for Sanofi that's already greater than $1 billion blockbuster drug, and they're expanding it to additional indications. What was so notable for our results with NKTR-358 is obviously, the activity is right in line with 12 weeks, as you can see from the data presented by Lilly. It's between 60% and 70% EC reduction. But then with time the score is improved even further. And that happened post cessation of treatment. So one of the things that were asked of the Lilly presenters at their Shareholder Day was, if you treated longer, do you think you could even improve on the overall peak of efficacy relative to that minus 60% week 12? And that's certainly something that's very interesting to be tested in the upcoming Phase IIb that Lilly talked about. And then the other really important and substantially differentiating feature, right, is the durability of the response was maintained for 6 months after the drug was stopped dosing. Now we -- in a sense, we saw those activities in our preclinical studies. So we saw, for example, in mice that we treated with NKTR-358, we could basically train their immune system to no longer be inflammatory in response to repeated challenge with an inflammatory antigen. And so in a mouse, that's an okay result. Certainly seeing this result in patients with moderate to severe atopic dermatitis, maintaining 6 months of essentially disease control after treatment is very, very exciting and consistent with what we think a T reg mechanism can bring to these kinds of diseases.

Okay. Great. Well, we are out of time here. The last minute, I'll just work in this last one. Any chance you can narrow down the timing for the Phase III melanoma study within the -- I think the slide up there says early 2022?

Yes, that question certainly would come up. Look, as I said in my presentation, it will be within the next few months. Obviously, I can't give specific guidance on that. But it will be coming in the next few months. And I think it's listed in ClinicalTrials.gov as April, and let's see how that evolves. But we're excited about it. And it should be a dramatic benefit for Nektar. That's what we're hoping. So thank you for doing this, Jessica. I appreciate it.

Great. Thank you, guys. Thanks, everyone, for listening in.

Thanks.

Thanks.