Alkermes plc (ALKS) Earnings Call Transcript & Summary

Greetings. Welcome to Alkermes ESMO Data Conference Call. My name is Rob and I'll be your operator for today's call. [Operator Instructions] Please note, this conference is being recorded. I will now turn the call over to Sandra Coombs, Vice President of Investor Relations. Sandy, you may begin.

Thank you, and welcome to the Alkermes plc conference call and webcast to discuss new clinical data and updates from our ongoing ARTISTRY-1 clinical trial of ALKS 4230, our investigational agent in oncology. These data are being presented as a mini oral presentation at the European Society for Medical Oncology 2020 Virtual Meeting. Please note that during today's call, we will reference slides that are available on the webcast. If you have not done so already, please go to the Investors section of our website, alkermes.com, to access the webcast player. A PDF of the slides will be made available on our website following the conclusion of this call. During this presentation, we will be making forward-looking statements based on our current expectations relating to, among other things, the clinical development of ALKS 4230 and the potential therapeutic value of ALKS 4230. These forward-looking statements are neither promises nor guarantees and are subject to a high degree of uncertainty and risk. Please see Slide 2 of the investor presentation accompanying this webcast, our press release issued this morning and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the statements provided on this call as a result of new information or future results or developments. Our prepared remarks today will include recent data from certain ongoing clinical trials in our ARTISTRY development program. This data set will evolve as patient enrollment continues and as more patient data becomes a available, and may not be indicative of future data or the final study results from such ongoing trials or results of future clinical trials. With me today are Craig Hopkinson, our Chief Medical Officer and Executive Vice President of Research and Development; and special guest, Dr. Ulka Vaishampayan, Professor of Internal Medicine, Division of Hematology and Oncology at the University of Michigan and Lead Investigator of the ARTISTRY-1 clinical trial. After the prepared remarks, we'll open the call for Q&A. Now I'd like to turn the call over to Craig.

Thank you, Sandy, and good morning, everyone. I'm delighted to be on the call today to share important new ALKS 4230 data being presented at ESMO with the clinical and investor communities. Efficacy, safety and tolerability data from the ARTISTRY development program have been accumulating, both in the monotherapy and combination settings and now provide a clearer picture of ALKS 4230's potential clinical profile and utility. In addition to the data set being presented at ESMO in a mini oral presentation this morning, we will also provide an update on our ARTISTRY-1 monotherapy melanoma cohorts, including data on an additional response that occurred subsequent to our ESMO data cutoff. As outlined in the press release we issued this morning, with 2 partial responses already observed in the first 6 evaluable patients in the monotherapy melanoma cohorts, we have met the protocol-defined criteria to expand this cohort for further enrollment. We believe that this is an important indicator of ALKS 4230's monotherapy activity profile. This morning, I will begin with an introduction to ALKS 4230, followed by an overview of our clinical development program. Dr. Vaishampayan will then share clinical data from ARTISTRY-1 that were presented at ESMO, after which I will elaborate on the most recent monotherapy response data and discuss enrollment trends and next steps for the ALKS 4230 development program. ALKS 4230 owes its roots to PROLEUKIN or recombinant human IL-2, one of the first immunotherapies approved for metastatic melanoma and renal cell carcinoma that demonstrated complete and durable antitumor responses due to its activation of CD8+ T cells and natural killer cells associated with cancer-fighting immune responses. Broader adoption of the therapy has been limited by its tolerability profile, notably vascular leak syndrome and severe hypotension. ALKS 4230 was designed to retain the therapeutic benefits of recombinant human IL-2 by selectively activating antitumor effector cells while mitigating the IL-2-associated expansion of immunosuppressive regulatory T cells or Tregs and activation of vascular endothelial cells. 4230 is a stable fusion protein consisting of IL-2 and the alpha subunits of a high affinity IL-2 receptor. This allows ALKS 4230 to preferentially bind to the intermediate affinity IL-2 receptor located on CD8+ T cells and NK cells, shown here on the right. At the same time, it is sterically occluded from binding to the high affinity receptor, which has been associated with certain undesirable effects of IL-2. ALKS 4230 is administered as an inherently active drug, does not require any metabolic conversion and does not degrade to native IL-2. For a more detailed discussion on 4230's mechanism, I encourage you to refer to our SITC investor presentation from last year, available on our company website. Our design concept for 4230 has been validated in preclinical models, which showed the desired pharmacokinetic and pharmacodynamic cell expansion profile, superior antitumor efficacy compared to recombinant human IL-2 as monotherapy and enhanced antitumor activity in combination with a variety of immunotherapies including anti-PD-1, anti-CTLA-4 and the angiogenesis inhibitor, lucitanib. These data support further exploration of 4230's potential clinical utility as monotherapy and in combination with a variety of immunotherapies and other cancer treatments. The clinical development program for ALKS 4230 is progressing on multiple fronts. In our ARTISTRY development program, we have 2 ongoing Phase I/II studies as well as a recently initiated Phase II study. ARTISTRY-1, evaluating ALKs 4230 administered intravenously, is the most advanced in enrollment and the subject of today's data presentation. ARTISTRY-2 is our subcutaneous dosing study and is evaluating the safety, tolerability and efficacy of 4230 in both once-weekly and once-every-3-week dosing regimens. Both of these studies are evaluating ALKS 4230 as a monotherapy and in combination with pembrolizumab. We also recently announced the initiation of ARTISTRY-3, a Phase II study to further evaluate the clinical and immunologic activity of ALKS 4230 monotherapy on the tumor microenvironment in advanced solid tumors. Findings from this study may help us answer important mechanistic questions and identify the tumor types for which ALKS 4230 could offer the most clinical benefit. In addition, our Phase II ION study, being conducted in collaboration with the Fred Hutchinson Cancer Research Center, is ongoing. Today, we will focus on ARTISTRY-1. The intent of this study is to evaluate the antitumor efficacy, safety, tolerability and pharmacodynamic effects of ALKS 4230 in both monotherapy and combination settings. There are 3 parts to the study. Data from Part A, the ongoing monotherapy dose escalation phase, led us to the identification of the 6-microgram per kg per day dose as our recommended Phase II dose, or RP2D, last year. Part B is a monotherapy dose expansion phase evaluating ALKS 4230 at the RP2D in refractory melanoma and refractory renal cell carcinoma, which are the approved indications for recombinant human IL-2. Both of these tumor types, patients often have limited treatment options following disease progression on PD-1 therapy. Understanding the single-agent activity of ALKS 4230 is an important aspect of its clinical profile and will help inform the potential therapeutic contributions of 4230 in possible combinations. Today, Dr. Vaishampayan will review ARTISTRY-1 data as of the data cutoff of July 24, 2020, that is being presented at ESMO. As I mentioned earlier, since the time of that data cut, a subsequent partial response was observed in the monotherapy melanoma cohort. With this second partial response in that cohort, we achieved the protocol-defined response criteria for the Simon 2-stage design enrollment, which triggered expansion for the melamine cohort to enroll up to 41 patients. I will speak to this in more detail later on the call. I will also note that patients in the Part B monotherapy expansion stage are eligible to roll over into the Part C combination stage of the study at the investigators' discretion following 4 cycles in good standing or upon progressive disease. Turning to Part C of ARTISTRY-1. This part of the study is evaluating 2 biologically active doses of ALKS 4230 in combination of pembrolizumab in a variety of advanced solid tumor types. The 3-microgram per kg dose is being evaluated in PD-1 approved tumor types in both refractory and treatment-naive patients as well as certain PD-1 unapproved tumor types and a cohort of monotherapy rollover patients. These basket cohorts are designed to provide important signal-seeking information and help inform future development strategies. The 6-microgram per kg does of 4230 is also being studied in combination with pembro in dedicated Part C cohorts in melanoma, non-small cell lung cancer and head and neck squamous cell carcinoma. Antitumor response and duration response assessments are based on RECIST 1.1 criteria and investigator-assessed, immune-related response, or iRECIST criteria. Unless otherwise noted, the safety data for all cohorts and the efficacy data for the monotherapy cohorts are from the data cutoff date of July 24, while the efficacy data for the combination cohorts are from a data cutoff of August 7. As we have advanced through development of ALKS 4230, we've been accumulating evidence supporting our design hypothesis. In ARTISTRY-1, ALKS 4230 has shown dose-dependent, selective expansion of effector cell populations with negligible expansion of Tregs. Monotherapy efficacy activity with evidence of disease stabilization and partial responses in melanoma, which will be discussed by Dr. Vaishampayan shortly. We've also seen durable and deepening responses for 4230 in combination with pembro in both anti-PD-1 approved and unapproved tumor types. In the combination cohorts, we are seeing clinical benefit, including stable disease or partial responses in patients who entered the study with difficult-to-treat progressive disease. Certain of these patients have remained on treatment for more than 6 months with some remaining on treatment for more than a year. And we have seen a clinically manageable safety profile with the most frequently observed treatment-emergent adverse events consistent with the anticipated effects of immunotherapy and no incidents of vascular leak so far. Now to provide an update from our ARTISTRY-1 clinical trial from the ESMO Virtual Congress, I'm pleased to introduce the ARTISTRY-1 lead investigator, Dr. Ulka Vaishampayan. Dr. Vaishampayan is a professor of internal medicine within the division of hematology/oncology at the University of Michigan. Her research is primarily in translational drug development and early phase clinical trials in cancer with a focus on genitourinary malignancies. Welcome, Dr. Vaishampayan, and thank you for joining us today.

Hi, Craig. Thank you, Craig, and good morning, everyone. So today's topic of presentation is regarding the efficacy of ALKS 4230. So today, I will focus on new data from the Part B monotherapy cohort of patients who received the recommended Phase II dose of 6 microgram per kilo of ALKS 4230 and the Part C combination cohort of patients who received the 3 microgram per kilo dose of ALKS 4230 along with pembrolizumab. Shown here are the patient baseline characteristics for the data set being presented at ESMO. A total of 15 patients were enrolled in the monotherapy cohort and 67 patients were enrolled in the combination cohort with dose of 3 microgram per kilo. At the time of enrollment, all patients had rapidly progressive disease. All of these patients were pretreated with the majority having received multiple lines of prior therapy. This slide shows the safety data observed for these cohorts as of the July 24 cutoff date, unless otherwise noted. ALKS 4230 given in combination with pembrolizumab did not demonstrate any additive toxicity as compared to that established with pembrolizumab alone. The side effect profile across the monotherapy and combination cohorts was generally consistent with what one would expect to see with cytokine therapy such as fever, chills and low-grade hypotension. Importantly, no signs of vascular leak syndrome, the hallmark toxicity associated with high-dose IL-2, were observed. In the combination cohort, 2 deaths reported in patients with pancreas cancer. 1 death was due to the underlying cancer and assessed as unrelated to treatment with ALKS 4230. The other was due to inanition, or starvation, and assessed as related to both study drugs. No deaths were reported in the Part B monotherapy cohort. Turning to efficacy data. I'll first review the overall response data from the monotherapy expansion cohort. Efficacy data presented here are as of the cutoff date of July 24, 2020, unless otherwise noted. In this cohort, 15 patients, 6 with melanoma and 9 with renal cell carcinoma, received the 6 microgram per kilo dose of ALKS 4230. This swimmer's plot is showing the overall responses and the duration in those patients. At the time of data cut, out of the 5 evaluable melanoma patients who had received 1 or more scans, 3 patients had stable disease or better. Of these 3 patients, 1 had a confirmed partial response and remained on ALKS 4230 monotherapy as of September 1 and the other 2 demonstrated stable disease on at least 2 consecutive scans and have since rolled into Part C. Let's now take a closer look at the patient who had a confirmed partial response. This is a case study of a 66-year-old female who was diagnosed with metastatic urethral mucosal melanoma back in 2017. The patient completed 1 year of nivolumab in September 2018, followed by 1 year without any treatment. Her disease recurred in September 2019 and was progressive at the time of her enrollment into ARTISTRY-1 in October 2019. Within the first 2 cycles of ALKS 4230 monotherapy, this patient experienced stable disease and her tumor began to shrink. She achieved a partial response by week 20 of treatment and the deepening of the response was observed through week 39 of treatment. As of her July 27 scan, her tumor has reduced by 39%. Further, the patient's serum LDH, or lactate dehydrogenase, a known marker for treatment response in melanoma, normalized at week 5 and has remained within the normal range. This patient experienced grade 3 transient hypotension, which was managed with IV fluids. As of September 1, this patient remains on ALKS 4230 monotherapy for more than 11 months. I'll also pause here to point out that this patient experienced iritis, an inflammation of the eye, which is an immune-related serious adverse event. Immune-related adverse events like this are consistent with the anticipated effects of cytokine administration and may be a potential indicator of ALKS 4230's activity. Taking a step back, the early responses observed with ALKS 4230 as a monotherapy treatment are an important element of its potential clinical utility. Now we will shift our focus to the combination cohorts of ARTISTRY-1. Data presented from Part C are as of the cutoff date of August 7, 2020, unless otherwise noted. This swimmer's plot shown here shows all 67 patients, representing more than 10 different tumor types who received ALKS 4230 3 microgram per kilo in combination with pembrolizumab. Of the 67 patients, 52 had evaluable scans as of the data cut. Responses were observed in both the PD-1 approved treatment-naive cohort, shown here in red, and the PD-1 unapproved cohort, shown here in bright green. Patients in these cohorts were heavily pretreated and had progressive disease on entry to the study. Overall responses seen as of the cutoff date are indicated on this slide. Responses were seen in multiple tumor types, and I will speak to some of these cases in greater detail. First, let's look at the patients from the PD-1 unapproved cohort. So here is a waterfall plot of the best response by target lesion for the 35 evaluable patients from the PD-1 unapproved cohort. So these patients have malignancies, which -- for which PD-1 therapy is not approved. The area between the 2 gray horizontal lines indicate stable disease per RECIST criteria. As evidenced by the arrows, as of the data cutoff date of August 7, 2020, 8 patients continue on therapy with maturing data. Now let's focus specifically on the ovarian cancer patients from the PD-1 unapproved group. This swimmer's plot shows the 14 ovarian cancer patients enrolled in this cohort, 13 of whom were evaluable at the time of the data cut. These patients entered the study with progressive ovarian cancer and were generally heavily pretreated. Of these 13 evaluable patients, 9 patients showed stable disease on their first scan, as indicated by the orange boxes. Amongst these patients, 6 received a second scan by the data cutoff, and 5 of these 6 patients experienced stable disease or better during the course of the treatment with ALKS 4230 and pembro, including 1 patient who demonstrated a tumor burden reduction of 76%. All 5 of these patients received prior platinum-based chemotherapy and were assessed by the investigators to be platinum-resistant. Some had also received prior bevacizumab and/or a PARP inhibitor. Of these 5 patients, 3 patients, noted as OC 1, 2 and 3 on this slide, experienced clinical responses, including 1 confirmed complete response, 1 confirmed partial response and 1 unconfirmed partial response. The other 2 patients, noted here as patients OC 4 and 5, achieved stable disease and had tumor shrinkage of 22% and 18%, respectively, as of the August 7 data cut and had remained on therapy for more than 14 weeks and 21 weeks, respectively. As of August 7, 4 of these 5 platinum-resistant ovarian cancer patients continue on therapy. Next, we will go into greater detail on 2 of these patients who are marked as OC 1 and OC 2 on the slide. Shown here are details for a 48-year-old female patient who enrolled in the study with a diagnosis of high-grade, progressive ovarian carcinoma, which was BRCA wild-type. She had received 5 prior lines of therapy. This patient initiated ALKS 4230 in combination with pembro in January 2019. At cycle 4, she demonstrated a partial response with a 60% decrease in target lesions, along with a complete normalization of her CA-125 levels, which is an established prognostic indicator in ovarian cancer. At cycle 10, the patient had a complete response with a 70% decrease in target lesions, which was then confirmed at cycle 12. Throughout her treatment period, the patient tolerated therapy well and did not experience any serious adverse events. As of August 7, the patient had a sustained complete response and remained on study. The next case is an 83-year-old female patient with ovarian cancer who was BRCA negative. She had received 2 prior lines of therapy and had progressive disease when she entered ARTISTRY-1 in February 2020. At cycle 2 of treatment, the patient demonstrated stable disease with a 6% decrease in target lesions. Her tumor continued to shrink with treatment, and at cycle 8, she had a 76% decrease in target lesions. As of the August 7 data cutoff, the patient had not experienced any serious events and remained on therapy. The other things that were noticed but are not quite reportable in the response rates were things like improvement in ascites, improvement of symptoms such as pain, which are pretty typical with metastatic ovarian cancer. So as we think about the treatment landscape for ovarian cancer, the standard of care for first-line treatment is multimodality, involving both surgery, platinum-based chemotherapy with or without bevacizumab and a PARP inhibitor for patients who are BRCA positive or mutation. It is important to note here that there are no anti-PD-1 treatment approved for ovarian cancer. Following front-line platinum-based chemotherapy, many patients may become platinum resistant, and their disease often progresses within 6 months after completion of therapy. Unfortunately, there are limited treatment options for patients with platinum-resistant ovarian cancer. Non-platinum chemotherapy has low response rates and is associated with shorter progression-free survivals. The median overall survival for platinum-resistant ovarian cancer is less than 12 months. Given the high unmet need for this patient population, I'm really encouraged by the responses seen so far in ovarian cancer with ALKS 4230 in combination with pembro. Now let's take a closer look at the responses we have seen in other tumor types. Clinical responses associated with significant tumor burden reduction were observed in 4 additional patients in Part C. This included 1 patient with triple-negative breast cancer, 1 patient with pancreas cancer and 2 patients with esophageal cancer. Also, as shown by the orange boxes on Slide 26, a number of these patients, all of whom entered the trial with progressive disease, experienced prolonged stable disease for 2 or more consecutive scans while on treatment with ALKS 4230 in combination with pembrolizumab. I'll now discuss the 2 esophageal responses. This case is a 54-year-old female patient who had adenocarcinoma of the gastroesophageal junction. This tumor type is anti-PD-1 approved, but this patient had not had prior checkpoint inhibitor therapy. She had received 4 prior lines of therapy, however, before entering the study in January 2020. At cycle 6, she had a confirmed partial response with a 43% decrease in target lesions. At cycle 8, her response deepened to a 48% decrease. The next case is an 82-year-old male patient with esophageal squamous cell carcinoma. Unlike the previous esophageal cancer patient, this patient's tumor type is not approved for treatment with anti-PD-1 therapies. He initiated ALKS 4230 combination with pembro in March 2020. At cycle 4, his target lesions had decreased by 23%, and at cycle 6, he had a partial response awaiting confirmation with a 36% decrease in target lesions. This patient experienced transient grade 3 treatment-related AEs, including neutropenia and lymphopenia, and no serious adverse events. As of August 7, the patient remains on study. So the responses we have seen with ALKS 4230 in combination with pembro in these non-ovarian tumor types are also very encouraging, with reductions in target lesions of up to 66% and patients continuing on ALKS 4230 therapy for up to 74 weeks as of the August 7 cutoff. These data support further clinical evaluation of ALKS 4230 in combination with pembro. Of note, the 66% reduction in tumor size was observed in a patient with triple-negative breast cancer. This patient's case was presented last year at the SITC conference, and she has continued on treatment for more than 1.5 years with a sustained and deepening response. It's important to note that these patients, except for the 1 pancreatic patient who unfortunately passed away, are doing well on treatment and remain in the study. So to summarize, these data provide encouraging evidence of antitumor efficacy for ALKS 4230 as both monotherapy and in combination with pembro, with a safety profile that's generally consistent with the anticipated effects of cytokine therapy, but with no reports of capillary leak syndrome, which is otherwise a hallmark toxicity of high-dose interleukin-2 treatment. The most frequently observed adverse events regardless of causality in both monotherapy and combination treatment, were transient fever and chills. In terms of efficacy, we saw durable and deepening responses to ALKS 4230 as monotherapy as in the melanoma. and in combination with pembro in a diverse set of difficult-to-treat tumor types. The data presented here provide new insights into the potential clinical value of ALKS 4230 as a novel treatment option in oncology, and I believe future research for its use as monotherapy and in combination with other therapies is certainly warranted. Thank you. And I will turn it back over to Dr. Hopkinson.

Thank you, Dr. Vaishampayan, for your review of the clinical data today and for your participation in the ARTISTRY-1 study. In addition to the review you just heard on ARTISTRY-1, as I mentioned at the start of the call, since the data cuts for the ESMO mini-oral presentation, an additional melanoma patient in the monotherapy cohort achieved a partial response, awaiting confirmation. This 74-year-old male patient with sinonasal mucosal melanoma had prior nivo treatment and had progressive disease at the time of enrollment into the ARTISTRY-1 study in June of 2020. At cycle 4 monotherapy treatment with ALKS 4230, this patient demonstrated a 39% tumor shrinkage. And as of September 1, he remained on treatment. Interestingly, both partial responses observed to date with ALKS 4230 monotherapy have been in patients with mucosal melanomas who have received prior PD-1 therapy. Mucosal melanoma is considered a particularly aggressive form of melanoma and is often not discovered until an advanced stage. Treatment options for this subtype of melanoma are very limited. The recruitment of subjects in the monotherapy stage of ARTISTRY-1 follows a Simon 2-stage study design, commonly used for Phase II studies in oncology for both practical and ethical considerations. The first stage was designed to enroll up to 21 patients in each of the melanoma and renal cell carcinoma cohorts. If protocol-defined response criteria are achieved in this first stage of 21 patients, the applicable cohort is expanded to recruit up to an additional 20 patients. With 2 partial responses observed among the first 6 evaluable patients in the monotherapy melanoma cohort, the protocol-defined response criteria for expansion of this cohort were achieved, and up to an additional 20 patients will now be enrolled in this cohort for a total of up to 41 patients. These data are consistent with our design hypothesis for ALKS 4230 and the known monotherapy activity of recombinant human IL-2 in melanoma. We're encouraged by this evidence of single-agent antitumor efficacy for ALKS 4230 and look forward to enrolling more patients to further evaluate ALKS 4230 as a monotherapy. Across the ARTISTRY development program, overall patient enrollment has been accelerating despite certain COVID-19-related disruptions. Since January, we've enrolled 103 patients across the program, doubling our total number of enrolled patients. We believe these enrollment trends are an important indicator of investigator enthusiasm around the program. In ARTISTRY-1 as of September 9, 2020, we've enrolled 38 patients in Part A, 26 patients in Part B and 91 patients in Part C, including full enrollment of the Part C PD-1 unapproved cohort. Following a delay related to COVID, our ex-U.S. sites have recently reopened and ready -- already contributing to enrollment, particularly in the Part B monotherapy cohorts. One of the most distinctive features of ALKS 4230 clinical program is the potential for subcutaneous dosing. ARTISTRY-2, our subcutaneous study, is ongoing in its dose escalation phase for both the week -- once-weekly and once-every-3-week dosing options. As of September 9, 2020, we had enrolled a total of 43 patients in the study. We believe that we are narrowing in on the recommended Phase II dose for subcu and hope to share updates from that study later this year. Taking a step back, we've made significant progress in this development program, both in terms of new data accumulation and patient recruitment. I'm particularly gratified by -- that the responses we are seeing are occurring in patients that have failed multiple lines of prior therapy and may have few remaining potential treatment options. Each response is meaningful and I'd like to express my sincere appreciation to the patients and investigators that have participated in the development program to date. We look forward to updating you on progress as the program continues.

Thank you, Craig and Dr. Vaishampayan. We'll now open the call for Q&A. Please note that Dr. Vaishampayan has a hard stop at 9:30, so we'll try to get to as many questions before then, but appreciate you limiting yourself to 1 question at a time. Rob?

[Operator Instructions] Our first question today comes from the line of Brandon Folkes with Cantor Fitzgerald.

Congratulations on the data. My one question, maybe just -- we've been getting a few questions this morning related to how do you think about 4230's potential contribution to the ovarian responses. So if you could just elaborate on that, that will be fantastic.

Dr. Vaishampayan, would you like to opine on that first?

Yes. I think given the current treatment landscape, these are -- the tumors where we are seeing responses are the ones where -- it's sort of significant that the usual immune checkpoint inhibitors have not shown efficacy like ovarian cancer. So that makes -- on that background, it makes it even more important type of response to see in these so-called refractory tumors to immune therapy. So that I would point out is one of the big things we notice on this study. And then the other one is, of course, even with the monotherapy in melanoma, which is so-called an immune response tumor where patients had been pretreated with immune checkpoint inhibitor, we are still seeing responses. So again, those would be the main highlights of the promise of this agent.

Yes. And Brandon, maybe just adding from my perspective. We're particularly excited that we are demonstrating monotherapy efficacy, especially in -- as Ulka said in mucosal melanoma, which is normally a pretty aggressive form of melanoma. And then secondly, I would agree with Ulka that in terms of the pembro unapproved tumor types, these are tumors that you wouldn't normally expect to see a robust response with an agent like pembro. And so we're particularly excited about the trends that we're seeing, for example, in the ovarian and the esophageal patients there.

Great. And congratulations again.

The next question is from the line of Vamil Divan with Mizuho.

I guess maybe for both of you also, but maybe more for Dr. Vaishampayan first. Just in terms of -- there's obviously other IL-2s in development, and we're getting questions on that as well. So how do we sort of look at this IL-2 substitute as [ cross draw ] comparisons of what we've seen from the other IL-2s versus what we're seeing from 4230, both in terms of efficacy, but maybe also in terms of the safety? You mentioned that the way that's been developed is to try to minimize similar side effects. If you can just talk about what are you seeing in your patients a little more on the tolerability side beyond the comments you made on the serious side effects?

Yes. So I think in comparison with high-dose IL2, which I did for many years for kidney cancer and melanoma, I think this one, there's a big difference in the toxicity profile. So there are patients typically that I would not even have considered to be candidates for high-dose IL-2 because of the cardiopulmonary risk, which really that kind of screening has not been an issue for ALKS 4230 because all we've seen is some pretty -- right after the infusion, sort of fever, chills for a couple of hours, which are pretty easily controlled, frankly, with whatever, Tylenol, antipyretics, NSAIDs, et cetera. And for the most part, even the hypotension was not really a big noticed side effect. And definitely, it wasn't symptomatic in most people except this 1 patient who had grade 3 hypotension, and we had to sort of give extra IV fluids. So I think in comparison to high-dose IL-2, clearly the toxicity profile stands out as being remarkably easy to tolerate. The other cytokine-type therapies, I mean, I think they are still under investigation, but from what I've seen, there is some significant capillary leak syndrome reported for some of them. So I think there is a little bit across the landscape of different therapies still being evaluated. But I really view this as significantly well tolerated agent.

Yes. And from that perspective, I would say, from a mechanistic perspective, we really are delivering on our original design intent for this compound where we're seeing significant expansion of NK and CD8-positive T cells, little to no Treg expansion and no signs of vascular leak. So that is the one aspect that I think we're pretty optimistic about. I think, secondly, we have taken the time to really explore monotherapy. And we're particularly gratified at the responses we're starting to see in difficult-to-treat melanoma patients. And then the last aspect which I think is truly differentiating is that we are exploring a subcutaneous administration program for 4230 in the ARTISTRY-2 program. So I think those are some of the areas that we're optimistic will differentiate 4230 versus other agents.

Okay. And Craig, maybe just one quick follow up, if I could. On the -- we saw some major responses from some patients, others not responding. Just curious, is there anything you're doing on the biomarker side to try and figure out which patient may be more or less likely to respond?

Yes. We've got a pretty robust biomarker program that we're investing in. And a lot of the studies that -- as we're initiating, we've been expanding on that translational medicine platform, and we will be sharing data as the data emerge over time at congresses in the future.

The next question is from the line of Paul Matteis with Stifel.

This is Alex on for Paul. Just one quick one here. I'm curious, related to ARTISTRY-2 and the subcu dosing, how confident are you that you could potentially dose this in an outpatient setting or out-of-the-office? How could you manage events like the grade 3 hypotension or other cytokine treatment-related event?

Yes. I mean I think at this point in time, we believe that our safety profile is pretty predictable. We've only seen 1 case of grade 3 hypertension, and that was managed with IV fluids in the clinic setting. I think it's important to ensure that patients are pretreated with fluids. We've got a standard regimen that we follow to ensure that the hypotension is manageable. And thus far, in the subcu program, we haven't seen any pronounced evidence of anything more than grade 2 hypotension. So we're pretty confident that it's manageable.

Yes. I mean I would agree with Craig that the time line even after the IVs is pretty predictable in the next couple of hours, typically, if they're going to have any symptoms assessed when they occur. And we typically tended to monitor patients for that long -- right in the clinic if they're doing the outpatient dosing. So the subcu, like we said, so far, we haven't run into problems, but it's still an ongoing trial.

The next question comes from the line of Umer Raffat with Evercore.

A couple, if I may. First, if you could remind us whether we've seen monotherapy responses with Nektar and other IL-2 constructs. I think that's shown some in renal, but I just wanted to check if we've seen that in melanoma also. Second, it would be really helpful just to understand how you guys are thinking about possible pivotal program, perhaps both in melanoma and in ovarian. So is there some sort of large expansion cohort that could be potentially pivotal in melanoma monotherapy? And also if there's some sort of randomized trial that you have in mind that you want to initiate in ovarian?

Yes. Sure. Thanks for those questions. So in terms of monotherapy efficacy in melanoma, I'm unaware of any monotherapy responses in the Nektar program. But I'm probably not the qualified person to find on their data. But I don't recall any monotherapy responses there. We are particularly excited about the prospects of the ovarian cohorts. Obviously, we're seeing a pretty good response rate within that ovarian cohort. And at this point in time, we're sort of prioritizing indications and figuring out which pivotal programs to move forward that will really give us the best chance of accelerating the program and putting a registration program in place. And that obviously includes the ovarian cohort and obviously, the melanoma cohorts based on the monotherapy responses we're seeing.