Nektar Therapeutics (NKTR) Q3 2019 Earnings Report, Transcript and Summary

Ladies and gentlemen, thank you for standing by. And welcome to the Nektar Therapeutics Third Quarter 2019 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speaker’s presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today's conference may be recorded. [Operator Instructions] I would now like to conference over to your speaker today Ms. Jennifer Ruddock, Head of Investor Relations. Ma'am you may begin.

Thank you, Crystal. Good afternoon, everyone and thank you for joining us today. With us are Howard Robin, our President and CEO; Gil Labrucherie our COO and CFO; and Dr. Jonathan Zalevsky our Head of R&D. On today’s call, we expect to make forward-looking statements regarding our business including clinical trials results, timing and plans for future clinical trials, timing and plans for future clinical data presentations at medical meetings; the therapeutic potential of our drug candidates; outcomes and plans for help authority regulatory actions and decisions; financial guidance and certain other statements regarding the future of our business. Because forward-looking statements relate to the future, they are subject to inherent uncertainties and risks that are difficult to predict and many of which are outside of our control. Important risks and uncertainties are set forth in the Form 8-K filed today and the Form 10-Q that we filed on August 8th, 2019 which is available at sec.gov. We undertake no obligation to update any of these forward-looking statements whether as a result of new information, future developments, or otherwise. A webcast of this call will be available on the IR page of Nektar’s website at nektar.com. With that, I will hand the call over to our President and CEO, Howard Robin, Howard?

Thank you, Jennifer. Good afternoon everyone and thank you for joining us on today's call. Today, we will provide several updates on our programs in our clinical pipeline and update our financial guidance for 2019. I'll start with several updates on our pipeline programs. First NKTR-181 as you will recall the FDA had issued a general advice letter in July, which was sent to several sponsors including us. And the letter stated that at the time, the FDA would be postponing product-specific opioid analgesic advisory committee meetings. While we're pleased to report today that the FDA recently informed us that they are now moving forward to schedule product-specific advisory committee meetings again, and the agency also told us based upon this that they're actively working to schedule an advisory committee conference meeting for NKTR-181, which we currently expect will occur in the next several months. So we'll be able to announce the data once it is published in the date once it is published in the Federal register. We believe that NKTR-181 as the first new opioid molecule designed in decades has the potential to be a step forward and an important building block to help address the opioid crisis that plagues our country. We've recently published a significant number of manuscripts that detail the data supporting this program. This includes our human abuse potential study results and our long-term safety study results, which were published in the Pain Medicine Journal in September and July respectively, as well as our Phase 3 efficacy results that were published in June in the journal pain. We look forward to a scientific discussion at the Rescheduled advisory committee meeting and continue to collaborate with the FDA team. Our wholly-owned subsidiary in Inheris Biopharma is preparing to launch NKTR-181 upon its potential approval. As we head into 2020 Inheris is carefully gaiting its spending prior to the potential FDA approval and commercial launch of NKTR-181. We are in the process of finalizing a capital structure with one or more potential capital partners in order to support the launch and distribution activities for NKTR-181. Next I'd like to briefly update you on NKTR-358 and our IL-2 pathway agonist that specifically activates and expands T regulatory cells. Eli Lilly and Nektar have made great progress on this program over the last quarter and NKTR-358 is now in the clinic under evaluation in three separate autoimmune disease conditions. As Lilly stated on their recent quarterly results call, NKTR-358 is a potential first-in-class opportunity for a medicine that preferentially stimulates expansion of T regulatory cells. We are currently studying NKTR-358 in a Phase 1b multiple ascending dose study in lupus patients, which is expected to complete by the end of the year. We plan to submit data from this study at an upcoming medical meeting in 2020, where we then plans to start a Phase 2b dose-ranging study in lupus in the first half of 2020. While we also recently initiated Phase 1b studies in psoriasis and atopic dermatitis and they plan to add an additional Phase 2 autoimmune indication to the development program in 2020. As you know we presented our first-in-human single ascending dose study data at the June 2019 EULAR conference which demonstrated that NKTR-358 achieved robust expansion of T regulatory cells in a dose-dependent fashion without expansion of conventional T cells. We plan to present additional mechanistic and pharmacodynamic data from this study in healthy volunteers at the American College of Rheumatology meeting this weekend in Atlanta. Lilly and Nektar are very excited about NKTR-358 and its potential to become the first-in-class therapeutic for multiple autoimmune and inflammatory indications. Moving on to NKTR-255, our IL-15 agonist program. We are excited to report that we recently initiated our first-in-human clinical trial this quarter in patients with relapsed/refractory non-Hodgkin's lymphoma on multiple myeloma. This study will first evaluate the safety of NKTR-255 as a monotherapy and then expand to combine with targeted antibody drugs that work through an antibody-dependent cell-mediated cytotoxicity or ADCC mechanism. Jonathan will talk more about this trial in the program in a moment. As Nektar -- as IL-15 strongly promotes the expansion activation and survival of natural killer cells, we are excited about its potentials to successfully combine with many significant therapies that utilize the ADCC Mechanism. As you know we had a preclinical collaboration in place with Janssen for NKTR-255 and they are currently evaluating the agent in combination with several different therapies in their oncology portfolio. And we have our ongoing preclinical collaboration with Gilead for NKTR-255 in virology. Gilead is evaluating NKTR-255 in various nonhuman primate models with a number of agents in their antiviral portfolio. As an IL-15 agonist NKTR-255s prolifer effect on memory T cells and other immune cells make it potentially compelling mechanism to combine with antivirals. We expect to have our first preclinical data from these collaborations in 2020 and are pleased with the advancement of our IL-15 program. Now I'd like to move on to review our bempeg program. In the registrational trial program with BMS, we currently have three registrational studies ongoing in combination with nivo, one in first-line metastatic melanoma, one in first-line assist ineligible urothelial cancer, and one in first-line metastatic renal cell carcinoma. To reiterate from last quarter, with respect to the differences that we discovered in two of the 22 lots of bempeg produced to date, we have put into place a control strategy that ensures these variances will not occur again. The two lots were produced very early in development in neither of these two manufacturing lots have been used in any of the ongoing registrational trials. We and BMS are also working together to ensure a constant and comprehensive quality control is implemented for the commercial scale manufacturing for Bempeg. I know that many of you are highly interested in how we are progressing with our next steps with BMS. We're having ongoing discussions to finalize the balance of the joint development plan in the collaboration with BMS and BMS has reiterated to us that they are highly committed to developing bempeg and preparing for future commercialization so we can bring this new immuno-oncology mechanism to patients. We and BMS are currently focusing on five to six key registrational trials. This includes, the ongoing registrational trials in first-line metastatic melanoma, first-line system eligible urothelial cancer, and first-line metastatic renal cell carcinoma. The next set of trials with BMS include a strategy to develop bempeg with nivolumab in non-small cell lung cancer are currently being planned. Both companies are working collaboratively in order to finalize this joint development plan by the end of this year. In addition, our PROPEL study is now actively enrolling patients with first-line non-small cell lung cancer. This study is evaluating Bempeg with Merck's pembrolizumab. And as you know pembro has emerged as the standard of care with or without chemotherapy in first line non-small cell lung cancer across all PD-L1 expression populations. Jonathan will discuss more on the design of the study in a moment. We are pursuing additional indications outside of the BMS joint development plan in partnership with other collaborators. For example, we have several ongoing clinical collaborations of Bempeg in other indications. These collaborations include one with Pfizer in head and neck cancer with avelumab and prostate cancer with Avelumab and Talazoparib or Enzalutamide. One of the – one with vaccibody in combination with multiple checkpoint inhibitors and with vaccibody’s personalized neoantigen vaccines in head and neck cancer and another collaboration with Bioxcel Therapeutics in combination with Pfizer's avelumab with Bioxcel's DPP inhibitor in pancreatic cancer. Of course, both BMS and Nektar were very pleased that in August of this year the doublet of Bempeg plus Nivo was granted a breakthrough therapy designation in first-line metastatic melanoma on the basis of its unique profile and a high complete response rate as compared to standard of care. The potential of this doublet in this indication is significant, and there is a possibility to expand in other melanoma indications as well. Our Phase 3 trial in the first-line metastatic melanoma population is continuing to enroll and data for the first endpoint in this study ORR could be available as early as Q4 of next year. As you know in the cohort of patients with first-line metastatic melanoma from the PIVOT-02 study, we saw a significant depth of response with a large percentage of patients achieving 100% reduction of target lesions and complete responses. At SITC this coming weekend Dr. Adi Diab will present an update on the cohort of melanoma patients in the PIVOT-02 study at an 18-month follow-up. We're very excited about this presentation and will it include for the first time a presentation of PFS for this cohort. We will also host a webcast for investors and those of you who can’t attend SITC in person. The webcast will include a representation of the data from the oral presentation with Dr. Diab and this will be held on Sunday morning at 9:00 a.m. Eastern Time and we hope you'll join us for a view of that data. With that, I'd like to hand the call over to Jonathan for a brief clinical discussion.

Thanks Howard. Before I review the clinical study design for NKTR-255, I'd like to comment briefly on our PROPEL study, which is evaluating the combination of bempeg with Merck's pembrolizumab. PROPEL will evaluate different dose levels of bempeg with a single regimen of pembrolizumab. To ensure that we identify the proper recommended Phase 2 dose for the combination. Importantly, the bempeg drug supply now being used in PROPEL matches drug supply from the ongoing registrational studies. And from a global program perspective, this study design allows us to generate important data in first-line non-small cell lung cancer with the standard of care in non-small cell lung cancer pembrolizumab. With respect to the initiation of additional combination trials for bempeg, as Howard stated, Pfizer and Nektar have already begun to screen patients for the Phase 1b/2 study in head and neck cancer and castration-resistant prostate cancer. The study will evaluate various doublet and triplet combinations with bempeg and Pfizer and Merck’s Serono’s anti-PD-L1 agent of avelumab. Pfizer’s PARP inhibitor talazoparib and Pfizer and Astellas’ enzalutamide. We’re very excited to work with Pfizer on this because of the opportunity in these two solid tumor settings for bempeg, particularly in patients with PD-L1 negative tumors. We are also evaluating different indications that could be pursued with other collaborators in 2020. Now moving on to NKTR-255, our IL-15 receptor agonists. The first-in-human study, which recently initiated with the first patient dosed last month will evaluate the safety and dose schedule of NKTR-255 as a monotherapy and then expand into combination with antibodies that work through an ADCC mechanism such as daratumumab and rituximab. We plan to enroll patients with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma. The study is designed as a dose escalation and dose expansion study. The dose escalation phase of the study will evaluate the safety and tolerability of NKTR-255 as monotherapy in approximately 40 patients in order to establish a recommended Phase 2 dose for NKTR-255. The subsequent dose expansion phase of the study will enroll in two separate cohorts. The first cohort will enroll patients with relapsed salvage multiple myeloma or non-Hodgkin's lymphoma to evaluate NKTR-255 at the recommended Phase 2 doses of monotherapy. The second cohort will enroll patients with relapsed/refractory or salvage multiple myeloma or NHL to evaluate NKTR-255 at the recommended Phase 2 dose in combination with targeted antibodies including the anti-CD38 monoclonal antibody daratumumab as well as the anti-CD20 monoclonal antibody rituximab. The study will also evaluate pharmacokinetic and pharmacodynamic effects, anti-tumor activity and biomarker assessments in blood and tissue. IL-15 stimulates the production, activation survival and function of natural killer cells and we have introduced a robust biomarker program into this trial to provide a deep assessment of the NKTR-255 mechanism of action. Besides NK cells, we will also evaluate total and subpopulations of CD4 and CD8 Memory T cells to study the effect of NKTR-255 on their expansion, activation and survival. This biomarker rich early clinical development approach allows us to follow the science and the development and planning for NKTR-255. Now NKTR-255's unique ability to target the NK cell compartment provides us with an exciting opportunity in combination with targeted therapies. One of the big challenges in treating cancer patients with targeted monoclonal antibodies, such as rituximab, cetuximab or trastuzumab is that cancer patients can exhibit a deficiency in the key effector cells that execute the ADCC reaction specifically NK cells. There are examples of patients with reduced numbers of NK cells or non-functional NK cells that are unable to execute a factor function and thus limit the therapeutic potential of antibodies. In addition, NK cells are rate limiting. They tend to be consumed in the ADCC reaction which also further can limit the targeted therapy. We believe that by increasing the number and activity of NK cells. NKTR-255 has the potential to enhance the tumor fighting response particularly when administered with an ADCC antibody. For example, in non-human primates NKTR-255 could provide continuous NK cell expansion with each cycle of dosing. And we look forward to evaluating these same effects in patients. The broad utility of targeted antibody therapy coupled with the immune enhancing properties of NKTR 255 make this a very exciting combination and we are looking forward to the progression of this first-in-human clinical trial. In non-clinical studies NKTR-255 exhibited antitumor activity and substantially enhanced in vivo proliferation and activation of NK cells to provide sustained cytotoxic function. In the preclinical lymphoma model, where single agent daratumumab was ineffective, NKTR-255 treatment in combination with daratumumab increased NK cell numbers and activity in bone marrow tissue and enhanced ADCC mediated tumor cell clearance in the bone marrow compartment. As Howard stated earlier, we also have a preclinical collaboration with Janssen and they plan to combine NKTR-255 with multiple agents in their oncology portfolio in animal models of cancer. In addition, our Gilead program is advancing nicely and they are working with NKTR-255 in various nonhuman primate virology models. And this coming week at SITC, we will also present new preclinical data on NKTR-255. There will be two poster presentations. One will focus on the scientific differentiation of NKTR-255, which is able to bind insister trends to all forms of the IL-15 receptor complex. IL-15 or Alpha IL-2 or beta and IL-2 or gamma versus the competing pipelines which can only buy into the IL-2 or beta and IL two our gamma dimeric complex. The second poster will focus on ADCC applications for solid tumor-targeting monoclonal antibodies, including mouse tumor studies evaluating the combination of NKTR-255 with cetuximab and trastuzumab. We also look forward to presenting additional preclinical data from the NKTR-255 program at the ASH Meeting in December, including data evaluating NKTR-255 in combination with CD19 CAR T cells. We then expect additional preclinical data from one or both of our NKTR-255 collaborations in 2020 and expect to have the first data from the Phase I clinical study in the second half of 2020. In closing, we are very excited about the start of the first NKTR-255 clinical trial, as it not only represents our next clinical program with the cytokine therapy. But it has significant potential in oncology as well as virology. And with that, I will hand the call to Gil to update our financial guidance for 2019.

Thank you Jonathan and good afternoon everyone. Today we issued our financial results for the quarter ended September 30, 2019. I will briefly review our updated 2019 financial guidance. Starting with our cash position, we now anticipate ending 2019 with approximately $1.6 billion of cash and investments. Our full year GAAP revenue guidance remains at between $100 million and $110 million for 2019. We now anticipate full year 2019 GAAP R&D expense will range between $430 million and $450 million, which includes approximately $65 million of non-cash depreciation and stock compensation expense. We project G&A expense for 2019 to be approximately $100 million, which includes approximately $45 million of non-cash depreciation and stock compensation expense. Our G&A expense forecast is lower than we originally estimated as a result of the FDA's delay in holding the NKTR-181 advisory committee meeting. As Howard stated earlier, we continue to carefully gate in Harris commercial readiness spending until a successful approval of NKTR-181 is achieved. We are in a very fortunate position with a strong balance sheet. As we develop our 2020 operating budget, we plan to be prudent in our capital allocation with the objective of getting bempeg approved as quickly as possible and advancing our pipeline with the resources on hand. And with that, I will open the call for questions. Operator? Question-and-Answer Session

Thank you. [Operator Instructions] And our first question comes from Chris Shibutani from Cowen. Your line is open.

Thank you very much. A question on PROPEL. You described that you're going to be doing several different doses. Can you remind us what those dose levels will be? And how that compares with the dose of bempeg that you've been using in the PIVOT studies? Secondly, as far as inclusion criteria for that PROPEL study will patients be able to receive chemotherapy as part of that regimen as well in this first-line setting?

Sure. Hey, Chris, this is JZ. So to the first question, you asked about the dose levels being evaluated in PROPEL. And so yeah, one of the things that we're doing is we will be evaluating if the dose level that we identified in combination with nivolumab, which was 0.006 mg/kg. If that's the same appropriate dose for a combination with pembrolizumab. And so in order to do that in the PROPEL study, we were going to open evaluating two dose levels. 0.006, the same dose level as with nivo and also a little bit of a higher dose level 0.008 mg/kg as well. And we're really looking to see if there is an opportunity or a need for example our necessity in order to define a different dose range with the different checkpoint inhibitor. And then in regards to the design of PROPEL. So really this study is designed to focus in on I-O doublet. And so in that case, short answer is, no, we'll not be treating patients with chemotherapy in addition to the doublet. But we will be evaluating the doublet of Bempeg plus pembrolizumab in three different PD-L1 expresser populations in the PD-L1 low less than 1% and in the PD-L1 intermediate and 1% to 49% and the PD-L1 high the greater than 50% in populations.

And then just to be clear we are after what I understood September 30 to have been kind of the demarcation line as far as the Bristol relationship. It did sound as if you were describing that there's ongoing discussions. But in particular for PROPEL with pembro which is obviously Merck's. Do they – can you provide us any clarity in terms of who's sort of commercialization rights et cetera? Is there anything formalized in terms of if this continues to develop successfully given that the first-line indication is really standard of care with pembro? Thanks.

Yeah. Thanks, Chris. This is Howard. Good question. Look, we're doing the PROPEL study and we've shifted the PROPEL study as JZ said principally to first line non-small cell lung cancer and we certainly have the right to do that under the agreement. In the final analysis though the marketability of this still rests with Nektar and BMS in other words the relationship between Nektar and BMS is such that we both jointly market bempeg and we keep 65% of the profits and they keep 35% of the profits. Now where we go with the combination with pembro, let's look at the data, let's see how important it looks. Let's see how important it looks to patients. Obviously if it's a very important compound a combination for patients with first-line non-small cell lung cancer we will bring it to those patients and we'll bring it to market. But it doesn't – it can't become Merck's product at that point. Obviously, bempeg stays with Nektar and BMS.

Thanks for the helpful clarification. I will get back in the queue.

Thank you. Our next question comes from Jessica Fye from JPMorgan. Your line is open.

Hey, guys. Good evening. Thanks for taking my questions. You mentioned the ORR data Phase 3 melanoma trial could come in the fourth quarter of 2020 would that be based on a subset of the total number of patients in the trial? And if so how many patients?

Yeah. Hey, Jessica this is JZ. So yes just to update you. So definitely, we've updated the clinicaltrials.gov posting for that trial and as it states in the second half of 2020. For example, as early as Q4 of 2020 is when the ORR endpoint from the melanoma study can be achieved and can be reported. We haven't indicated how many patients that is but it is a subset of the patients in the trial. And I will also remind you that this is a trial that BMS is operationalizing it. So we work very closely with BMS but the specific time lines and cadences under BMS's operationalization and very much is the update that they gave at ESMO was very current with the most recent information about that study.

Okay. So what's the latest expectation for the timing of the PFS readout for that trial?

So right now that's targeted for the middle of 2021.

Okay. And when you guys are talking about the registrational trials for Bempeg and nivo including melanoma urothelial and RCC, are you guys still looking at that 100 patient second-line non-small cell cohort as being potentially registrational? And what's the timing for that data?

Yeah. So this arm and pivot is still enrolling. And as you point out, it's focused on enrolling the relapsed patient populations. So, specifically these are patients that have relapsed following pembro plus chemo combination. And this is a first-line combination. And as Howard stated, we're currently planning a potential strategy with BMS. And in totality that includes non-small cell lung cancer. And we'll be able to update you and everyone on the overall strategy for lung cancer when we complete that process.

Okay. Got it. I know Bristol's has had some recent updates with their lung trials and you mentioned that you are hoping to have the kind of collaboration the new registrational trials hammered out by year-end. Does that give you enough time to kind of incorporate the relatively recent news on the kind of Bristol I-O front?

Yeah, Jessica. Well, we did say that we will -- we are getting close to finalizing what the new set of clinical trials look like the additional clinical trials. I did say we have that completed by the end of the year. And that's an assurance I have from BMS and we're working actively on that. I think that whatever data we have now will be included in that process. And I'm fairly confident now that we'll be adding to the study to the three studies that we're currently running and at the end of the year or at the JPMorgan conference, we'll certainly be talking about the new clinical trial set in that collaboration. But remember it's still in the final analysis, it's still an incredibly impressive and important collaboration in that five or six registrational trials combined with an enormous economic commitment from BMS is very important to us.

Okay. Got it. Maybe just last one on RCC and when we couldn't exceed data. I think you had talked about maybe that coming as an I-O. When should we expect the next look at the PIVOT data in first-line RCC?

Yeah. Hey. Hello, Jessica, this is JZ. So in the context of that data when we looked at all of it, it became clear to us that presenting it in the context of a publication was a much more appropriate way to present that data because it allows us to cover the context of all of the changes in the manufacturing batches that were used in PIVOT-02. So you can expect to see next year our upcoming publications that you'll see in peer-reviewed manuscripts. and that will cover that data as well.

Okay. Got it. Thank you.

Okay.

Thank you. Our next question comes from Tyler Van Buren from Piper Jaffray. Your line is open. Q – Tyler Van Buren: Hey, guys. Good afternoon. Can you provide updated thoughts on timing for the bladder and RCC registrational trials?

Sorry. Tyler, do you mind repeating the question again? Q – Tyler Van Buren: Yeah, just updated thoughts on timing for the bladder and RCC registrational trials, when we should get the initial top line data?

Yeah, absolutely. So for the bladder clinical study mid-2021 is an update on when we could see top line data. This is a study that utilizes ORR and the DOR the duration of response as the two components. And then for RCC it would be the year after in either the very end of 2021 and 2022.

Okay. I guess just across melanoma and bladder and RCC and the registrational trials we're clearly experiencing some delays here. So could you guys just help put that in context is enrollment just taking a little bit longer than anticipated? Or how should we think about it?

Yeah. So as some of those studies started there was a little bit of a slower rate of initiating the sites. This is a little bit slower than what we'd like to see. But now we're starting to see the studies that have now hit the large majority of the sites already open. So take for example in the case of melanoma now almost all of the sites are open and enrolling patients. And it's essentially enrolling at scale at this time. So you'll see these studies now all move and pick up.

Okay. That's helpful context. And just a final question is with the three registration ongoing plus lung that's 4. So with five or six or potentially one or two more registrational trials I guess, can you guys just help us think about the potential different indications that would make sense for those one or two or what you guys are currently thinking about at the moment?

Yeah. Look we – as we said, we have the bladder the melanoma and the renal running. I think we will also – as I said we're also working actively with BMS to design a long non-small cell lung cancer program. And I think in the context of the three trials that are running I think you'll see some additional trials. Clearly, in melanoma where we have breakthrough designation because of the results we've had to date that I think are quite impressive. I think we're likely to see increases in studies there as well as ladder and renal. And these are the most immuno sensitive tumor types. And I think that's of course where we have the largest chance for success. And these are also a fairly large market opportunity especially in melanoma and it gives – it certainly gives BMS the opportunities that dominate the melanoma space for the foreseeable future. So we're pretty excited about those programs. And remember we do have do have a number of other programs that we're running with the companies as I talked about head and neck and prostate with Pfizer. So – and there'll probably be more. There'll probably be other collaborations that we put together in the near future with other companies. So I think you'll see a pretty broad portfolio of opportunities with Bempeg.

Great. Thanks for taking the question.

Thank you. Our next question comes from Difei Yang from Mizuho. Your line is open. Please check that you line is not on mute.

Hey, sorry guys. I was on mute. This is Alex for Difei. Thank you for taking the question. Just coming back to the bladder indication are you still considering a trial in muscle-invasive bladder cancer?

This is JZ. Yes indeed we are considering that trial. So as you know the pivot 10 is in the accelerated approval kind of opportunity. And so definitely a confirmatory study is necessary right in order to support that. And muscle-invasive bladder cancer is indeed the study that we are considering to fulfill that role.

Okay. Great. Thank you.

Our next question comes from George Farmer from BMO Capital Markets. Your line is open.

Hi. This is Gobind Singh on for George Farmer. Thanks for taking our questions. So I guess the first one I have is for bempeg. Can you tell us a little bit the PFS data, I think you guys confirmed is going to be presented at SITC. Can you give us an idea of how we should be thinking about the overall survival data?

Sure. So yes, so the new data that we'll be presenting at SITC will be the PFS for the melanoma first-line cohort in PIVOT-02. OS is obviously something that we track, but it really is something that would be out much more into the future. So that's something that in a future update there could be something that we update, but really it's too early to focus on that. So, focusing on PFS at this time.

Okay. And…

Well, I'll just sort of add that one of the really sort of interesting components since you asked about overall survival is at ASCO this year right that you've provided data from a meta-analysis where they looked at different treatment therapies for melanoma and they looked at the depth of response. And then they compare the depth of response to long-term survival essentially to overall survival. And what they did find is that patients that had a 75% tumor shrinkage or better including a complete response and particularly from treatment from an I-O agent like a checkpoint inhibitor or a checkpoint combo, they really had the most improvement in their overall survival reaching extremely high survival over periods of time. So, that the depth of response was very positively correlated. This is something that of course we see in our melanoma data as well. We see 34% of patients with a complete response and a large number of patients reaching 75% or greater tumor shrinkage. So we're very, very excited about that data. And we also had the opportunity to present that data to the FDA. And it really was one of the big reasons the complete response rate and the depth of response that led to the breakthrough therapy designation that we were awarded in first-line melanoma for the combination of bempeg plus nivo. So all of these factors are coming together and they look very, very promising and encouraging for the combination and especially for the patients.

Thank you. That's a very helpful color. And with another on DenTeK. With RCC specifically it's a very competitive landscape is constantly evolving. How do you guys see DenTeK sitting in that overall treatment landscape?

Yeah. It's a really good question. And certainly the results with axitinib that have been presented lately both with Merck's KEYTRUDA as well as Pfizer's avelumab are very important to the landscape. So for us it's very important to also consider what the addition of a TKI can bring to the doublet of bempeg plus a checkpoint like nivolumab. So that's something that we're looking into. Now we have an overall holistic strategy. And in that strategy you'd like to see both TKI Inclusive as well as a TKI sparing set of combinations, because not all patients will be able to take TKIs whether they're in single or in combination form. So our strategy working closely with BMS will explore all of that space where bempeg can add to multiple combinations in that tumor type.

Okay. And then just my last question for -- just going on to 358 now. With -- there's a couple of other compounds there I think earlier in development, but we're just trying to get a feeling of how your compound is differentiated from a lot of the other compounds that are also following the footsteps that you guys are creating here? And maybe like why is Eli Lilly and you guys -- what was the rationale for going after like psoriasis and atopic dermatitis and lupus where there's a couple of other diseases that we can think of that would also be a good set. If there was any reason for that that would be helpful too. Thanks.

Sure. So firstly with regards to differentiation. So one of the features of NKTR-358 is that as you know our approach at Nektar is we use our polymer conjugation core competency to modify the properties of the biologic. We do that without the need for mutagenesis. Our introduction of any amino acid substitutions into the molecule. Now when you consider the competing molecules. Now when you consider – the computing for molecules for example Amgen has one. Roche has one. Celgene have one. They all have very, very similar amino acid mutations where they've reduced the binding to the beta receptor. In some cases, they've even increased the binding to the alpha receptor in order to sort of guide the molecule to have a certain kind of a receptor-binding profile at the T reg. And then, they also all use an FC extension strategy. Or in the case of Roche and Immunoglobulin that dimerizes the IL-2. We're able to achieve all of the things that we need to achieve in a completely differentiated manner. Ours is the only molecule compared to that bunch that has no amino acid mutations. And with our polymer we have a very, very long half-life. And we've already demonstrated not only in non-human primates, but now also in healthy volunteers that we're able to get the right kind of T reg elevation the right duration of Treg expansion and the persistence of T regs in the blood. Following just a single administration of NKTR-358 in the healthy volunteer study. And as Howard mentioned, we also will be concluding the end of this year our Phase Ib MAD study. There we gave the drug multiple cycles into patients with lupus and we were able to also follow the Treg expansion in all of those other pharmacodynamic endpoints. So we really have a unique way of differentiating from the pipelines. And it's very much akin to the kind of differentiation that we have with bempeg relative to those pipelines as well. Now specifically, in the context of indications the T reg targeting mechanism has very broad application as you can imagine since these cells are involved in maintaining peripheral tolerance against pretty much any kind of T cell-mediated autoimmune or cell reactivity trigger. And so you can apply that broadly to dermatological diseases to systemic autoimmune diseases like lupus or rheumatoid arthritis. And even to diseases that have a central component like MS. So what we've done is we work closely with Lilly to prioritize some of the different biological features that some of these indications share in common like some of them have some common pathologies. Some of them have a certain kind of mode of inflammation that's unique to that either tissue type or that kind of autoimmune disease and so we've bind them into groups and buckets. And that's why we focused on those indications. So in the case of lupus specifically this is a case where there's a well-known IL-2 dysfunction. Lupus patients have reduced levels of T regs and the TRx is they do have a non or low functioning – they're lowly suppressive. And a lot of times they have an expansion of TH17 cells that are negatively sort of negative ratio the TRx go down and the TH17 cells go up. So that's a disease where you have a rationale for IL-2 and we've also seen low dose IL 2 have a level of efficacy in that disease. And in the case of the derm diseases there are – again there are multiple examples where we know that Tregs can impact the skin compartment whether that's in the setting of atopic dermatitis or psoriasis. And then what you'll see next year is additional indications that Lilly and Nektar will be adding in our partnership. So you'll be seeing those roll themselves out throughout the end of the year and there'll be new indications different than the three I just mentioned.

That's perfect. And I'm sorry just one more quick question. Just piggybacking off of Chris' earlier question with the 0.008 milligrams per kilogram dose with Bempeg, can you remind us what the safety profile was with that? And then I'll go back in the queue. Thank you.

Yes. Sure. In the monotherapy study, we dosed up to 0.009 mg per kg. We also dosed to 0.012 mg for taking patient. So we -- the dose 0.08 is definitely within our window of the safety profile. And if you actually would like to also see the detailed safety information. We recently published our monotherapy excel manuscripts in cancer discovery. And that has a full details of all of the AE profiles across these dose levels including 009 and the 012 dose levels.

Thank you. Our next question comes from Andy Hsieh from William Blair. Your line is open.

Great. Thanks for taking my question. So two for JZ. In terms of the Phase 1 255 study. For the monotherapy arm, is it there just for comparative purposes? Or if there is a specific immunology question they're asking specifically in the CAR-T refractory patient population?

Yes. So it is one -- so one of the things we'd like to know is the kinds of immunological changes that we expect to see with NKTR-255 across the NK cell and the subset of the T cell compartments is able to be seen both in NHL patients that had many lines of prior treatment, because we're essentially looking at like third line very late-stage kind of salvage patients. So really, want to make sure that we can induce the immunological changes in those as well. And then in the case that they for example might have been CAR-T refractory. There's also an opportunity to sort of study that kind of an immune system in the setting of again a patient that has really failed a lot of prior therapies.

Okay. And just to follow up on the 50 poster. I think you did a head-to-head comparison 255 versus IL-15 super agonist. So we're just curious about your thoughts and potential clinical implications there?

Yes. Well I think if you're interested in that question I think you'll be very interested in this poster. So what the poster does is it takes two different forms of the IL-15 super agonist sort of families. And there's basically two different kinds that I know you know of. There are all of the molecules where the IL-15 receptor alpha is in complex with IL-15 and that's usually in an EPC kind of background. So that's very similar to like the altor molecule that newest has Xencor's molecule is very similar to that for example. So there's a whole range of molecules that are that kind of complex. And then there's the Sushi domain right which is just that small 65 amino acid fragment of the alpha receptor bound and complex to the IL-15. Both of those are being developed by numerous companies. And they both share the binding mode that they're unable to interact with IL-15 receptor alpha in the body. They can only bind to the dimeric beta gamma IL-2 subset or the dimeric receptor. Now in contrast in a poster we take those two molecules as exemplars and we compare them to NKTR-255 and NKTR-255 is really a lot more like IL-15 in the sense that a combined to IL-15 receptor alpha anywhere it exists in the body. So, wherever it's unoccupied, and then secondly it can participate in cell cell-mediated signaling interactions. And that's the kind of trans, presentation or trans binding mode that the other agents that are complex to the receptor are unable to interact in. And so we take those exemplars through six different kinds of biological test systems setting everything from receptor, internalization pathway activity, the assessment of stat versus ERC versus AKT pathways PI3-kinase pathways all the things that assess what you'd consider for a full or partial agonism across the pathway as well as assessing cell cell-mediated contact and assessing multiple cell populations. It is a very interesting kind of scientific work and it really profiles the difference between these two classes of molecules and it shows a lot of really surprising differences. So it should be a I think a poster you might enjoy very much. And certainly after it's presented we'll be happy to send it to you.

Great. Thanks. I appreciate the very detailed answer. Just two quick ones if you don't mind any updates in terms of timing when are you going to hear from the 262 program. And also for the pivotal studies ongoing are you planning on utilizing the real-time oncology review pathway?

Sure so starting with 262, we're still dose escalating in that protocol. And so as we continue to dose escalate. We're still dosing up until we find our recommended Phase 2 dose and then that will move into an expansion cohort that will basically evaluate the co-administration of 262 along with Bempeg as a doublet or in a triplet with NKTR-262 with Bempeg as well as nivolumab. And so we expect that we should be able to give an update on the program again next year. It's been roughly a year since the last time we gave an update in February of 2019 of this year at ASCO site. It was the last time we gave an update. So you can expect to see an update of that program next year and then regarding the oncology sort of the registrational trials. So we kind of gave you the sort of the cadence of the updates in the earlier question. So the earliest study that we expect to provide data would be around the fourth quarter 2020. That could come from the – that will come from the melanoma clinical trial. So that is an opportunity to potentially move into an early approval process. And that's assuming that we reach that interim analysis successfully, so very much as we've stated before as you know.

So what I meant was the real-time oncology review by the FDA. So basically what that program allows for is basically as the data matures you basically share that within real-time and therefore you basically get a very abbreviated review time. Just wondering if you guys are kind of thinking?

Yeah. Sorry, I misunderstood your question. Yes. So we already have breakthrough therapy right designation for example in first line melanoma. And so yeah, we're taking every opportunity to leverage the fastest possible review process that we can with the division. So, all of the components are in play. And as you know the breakthrough Therapy designation is very powerful. It allows us additional touch points with the FDA and it really allows us to move much more quickly through the agency.

Got it. Great. Thank you very much.

Thank you. [Operator Instructions] And our next question comes from Daina Graybosch from SVB Leerink. Your line is open.

Hi. Thank you for the question. A couple of quick ones and a couple of longer ones. I didn't hear anything about triple-negative breast cancer. I wonder if you guys can talk about any plans for taking that forward as well as when you might see some of the non-small cell lung data from PIVOT-02 and PROPEL will be next year or later than that?

Yeah. With regard to triple-negative breast cancer, it's certainly something we're still discussing with BMS. And we're deciding how we want to approach these new clinical -- these additional clinical programs. I can tell you that the data that we have so far a PIVOT was very impressive. And I think we believe that it should be developed in triple-negative breast cancer and we'll see how that evolves into the expansion of the new trials that we put together with BMS. And in any case if it doesn't go in that direction. I think it's highly likely that we move it into the clinic with another partner. JZ, do you want to answer the last part of question?

Absolutely. So, yeah, so in regards to the first-line non-small cell lung cancer cohort and PIVOT, so, stated as we did state in our last conference call. The enrollment in this cohort has been slower than it was anticipated. But there were a number of patients who were enrolled more recently in the second and third quarters. Overall the early data we're observing in the few patients in the first-line non-small cell lung cancer sub-cohorts support the bempeg mechanism of action and its potential benefit in the below 50% PD-L1 expressers as well as the PD-L1 negative baseline patients and we reported that same kind of effect in other tumor types as well. For example, where we've seen PD-L1 conversion in bladder cancer and so forth. In the greater than 50% PD-L1 expression sub-cohort, we haven't seen the same benefit and we're trying to understand this observation in light of the manufacturing issues. When we examined the depth of tumor reduction by lots, there is some early evidence that patients are benefiting more when they started on lots one and three. We are enrolling additional patients in these cohorts and those patients are starting treatment with bempeg lots that are not lots two and five. And as a result overall of the current immaturity of the data and the desire to continue to assess drug lot references, yeah, we did withdraw the abstract from the ESMO meeting as you know. We want the data to mature more fully and then we'll make a decision on when where to present this data in the future.

Got it. Thank you. Now maybe a more theoretical question on NKTR-255. You mentioned the combination of daratumumab, which I think you know and many of us know that daratumumab actually knocks down NK cells targeting CD38 on the NK cells themselves. Does combining NKTR-255 help counteract that? Are you just getting more cells and then dara knocks it down? How are you thinking about that interaction when deciding to combine daratumumab versus other monoclonal antibodies that don't harm in CSOs.

Yes. That's a great question Daina. And one of the reasons why we're looking at both rituximab and daratumumab right in this early study. And it's precisely for this very reason. They kind of addressed two different questions. So because CD38 is expressed on NK cells. And you know there are CD38 positive MC38 negative NK cells and they do have some different roles. And you can see differences in the repletion right following dara and multiple myeloma patients' right that's been published. So, one of the things that we'd like to address in that combination is precisely that effect is, we can help sort of replenish the NK cell compartment and we can help it in two ways. One is, we would prevent the dara direct targeting and also by sort of replenishing the cell populations. But in addition, we can also help the dara mediated ADCC because again there would be more NK cells. So, it is very much a component of why we want to evaluate those two liquid tumor-targeting ADCC antibodies to really address that kind of difference between their biologies and address the effect of 255 on NK cells in those two different kinds of depletion modes.

Great. Thank you. That’s all from me.

Thank you. And that does conclude our question-and-answer session for today's conference. I'd now like to turn the call back over to Howard Robin for any closing remarks.

Well, thank you everyone for joining us on today's call. And of course, I'd like to thank all of our employees for their hard work this past quarter. And most importantly, we look forward to seeing many of you at the Citi conference this weekend. So thank you very much.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect. Everyone have a wonderful day.