Alkermes plc (ALKS) Earnings Call Transcript & Summary

Greetings, and welcome to the Alkermes Conference Call. My name is Paul, and I will be the operator for today's call. [Operator Instructions] Please note that this conference is being recorded. I'll now turn the call over to Sandra Coombs, Vice -- Senior 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 development program for nemvaleukin alfa, our investigational agent in oncology. These data are being presented as poster presentations at the 2021 American Society of Clinical Oncology Annual Meeting. Please note that during today's call, we will reference slides that are available on the webcast. If you have not already done so, 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 the clinical development of nemvaleukin and the potential therapeutic value of nemvaleukin. These forward-looking statements are neither promises nor guarantees and are subject to a 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 redevelopment program. This data set will evolve as patient enrollment continues and as more patient data becomes available. And the data presented today may not be indicative of future data or final results from such ongoing trials, results of future clinical trials or real-world results. Now I will turn the call over to Craig Hopkinson, Chief Medical Officer at Alkermes.

Thank you, Sandy. Good afternoon, and thank you for joining us. Today, we are pleased to be sharing new data from the nemvaleukin clinical development program. With me today from Alkermes is Jessicca Rege, Vice President and Head of Oncology. We're delighted that following the prepared remarks, we'll be joined by our special guests, Dr. Valentina Boni and Dr. Omid Hamid for discussion related to the data set presented at ASCO today. Dr. Boni is the lead author of the ARTISTRY-1 poster and Medical Oncologist and Principal Investigator at START Madrid in Spain. Dr. Hamid is the lead author of the ARTISTRY-2 poster and Co-director of the Cutaneous Oncology, Director of Melanoma Therapeutics and Phase I Immune-oncology Program and Chief Translational Research and Immunotherapy at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate. But first, I'll turn the call over to Jessicca to take us through the data being presented on the nemvaleukin program. Jess?

Thank you, Craig. I'd like to start by expressing my appreciation to Dr. Boni and Dr. Hamid for joining us today and look forward to hearing their clinical perspective related to the nemvaleukin clinical data set. Nemvaleukin is a unique cytokine, designed to harness and validate the IL-2 pathway biology. And Alkermes has studied nemvaleukin properties extensively in the clinic. Nemvaleukin's design arises directly from the natural biology of IL-2 and its receptors, which we leverage to convert differentiated properties. By combining the native IL-2 and the IL-2 receptor alpha sequences, we engineered a stable fusion protein that is inherently active, does not require any metabolic or proteolytic conversion and does not degrade into native IL-2. This unique approach makes nemvaleukin highly selective for the intermediate affinity IL-2 receptor and have been shown to activate cancer fighting CD8 T cells and NK cells, both systemically and locally within the tumor microenvironment. We believe both of these compartments are important. Activation and expansion of effector cells in the periphery may be key in driving antitumor responses against poorly immunogenic tumors that lack CD8 T cells and NK cells in their microenvironment. Nemvaleukin selectivity for the intermediate affinity receptor resulted in only minimal expansion of immunosuppressive Tregs. This selectivity also prevented activation of vascular endothelial cells, which have been associated with severe toxicity, including vascular leak syndrome and hypotension. We believe that these features of nemvaleukin may widen the therapeutic window of high-dose IL-2 both from a safety and efficacy perspective. This design theory has supported in practice by the clinical responses we've seen thus far in the program. Nemvaleukin has demonstrated durable and deepening responses in a range of tumor types, both as a monotherapy in combination and -- in combination with pembrolizumab and checkpoint inhibitor-naive and checkpoint inhibitor-experienced patients. To our knowledge, no other IL-2 variant has demonstrated this diverse of activity. Our clinical program is tailored to address key unmet needs in the field as we focus on difficult-to-treat patient populations, including patients with checkpoint inhibitor-unapproved tumor types and in the post checkpoint inhibitor setting. The nemvaleukin development program is now progressing rapidly. In the past 12 months, we've achieved clinical proof-of-concept in 2 indications that we plan to advance into registrational trials. We've enrolled over 220 patients in the clinical development program and entered into a clinical trial and supply agreement with Merck for our planned Phase III study in platinum-resistant ovarian cancer. Additionally, we secured FDA orphan drug designation for mucosal melanoma. This progress has been made possible by a dedicated team of oncology specialist here at Alkermes and the tremendous support from our external investigators. Slide 7 provides a brief overview of the nemvaleukin clinical development program, including the 5 ongoing studies and 1 additional study that we plan to initiate later this year. ARTISTRY-1 and ARTISTRY-2 are the foundational studies of the clinical program. It's designed to establish nemvaleukin safety and tolerability profile, to identify the recommended Phase II dose for both intravenous and subcutaneous administration and also identify signals of antitumor activities. These are the studies that will focus the presentation on today. ARTISTRY-3 and ION study are evaluating treatment-emergent changes in the tumor microenvironment. This will provide a deeper understanding of IV nemvaleukin immunogenic activity. Data from ARTISTRY-1 and ARTISTRY-2 have informed the recently initiated ARTISTRY-6 study in melanoma in a planned Phase III study in platinum-resistant ovarian cancer that we plan to initiate later this year. Now let's focus on the ARTISTRY-1 data presented at ASCO today. Here is the ARTISTRY-1 trial design. The data shared at ASCO this year were from Part B, monotherapy dose expansion stage; and Part C, combination stage with pembrolizumab. Today, I will discuss ASCO poster response and safety data, which reflect data cut as of March 19, unless otherwise specified. I will also share updated information on some of the responses in the duration of treatment from a latter data cut of May 3. First, let's talk about the safety data. The safety profile that we've seen with ARTISTRY-1 is consistent with our design hypothesis. The most commonly reported adverse event with monotherapy IV treatment were chills, pyrexia, nausea and hypotension, which were most transient in nature and the majority of which were low in grade. IV nemvaleukin, given in combination with pembrolizumab, did not demonstrate any additive toxicity to that establish with pembrolizumab alone or require any additional dose modifications. Among more than 200 patients treated as of the safety data cut, the side effect profile across the monotherapy in combination cohorts was generally consistent with the anticipated side effects of cytokine administration. Now let's focus on Part B monotherapy stage of ARTISTRY-1. This was designed to assess IV nemvaleukin's single agent antitumor activity in 2 tumor types where high-dose IL-2 has demonstrated efficacy, melanoma and renal cell carcinoma. In contrast to the original studies evaluating high-dose IL-2, which were conducted over more than 20 years ago and before the discovery of checkpoint inhibitors and other targeted agents, all patients enrolled on the monotherapy stage of ARTISTRY-1 were previously treated with a checkpoint inhibitor and had to have progressed on that therapy. Patients were allowed to roll over from the monotherapy portion of the study to Part C combination with pembrolizumab at the investigator's discretion. Now let's look at the data presented at ASCO. Here is a swimmers plot that shows the overall responses and duration of treatment of patients enrolled in the melanoma monotherapy cohort. 18 of these patients had cutaneous melanoma, 6 had metastatic melanoma and the remaining patients had other subtypes of melanoma. All patients had prior checkpoint inhibitors and other lines of treatment, as noted by the parenthesis on the y-axis. Out of the 30 evaluable patients, we had at least -- that had at least one scan, 21 demonstrated stable disease. As of the March 19 data cut, partial responses were observed in both mucosal and cutaneous melanoma. An additional cutaneous melanoma response was observed following this data cut in the patient identified with the green arrow on this slide. I'll provide additional details on the responses in the next slide. In the top lane, you'll see 1 patient with a durable and deepening partial response, who has been on treatment for more than 1.5 years. However, the majority of the patients enrolled had been on study less than 3 months, at such time, the status still remains immature. Out of the 30 evaluable patients, 24 patients continue on study, as noted by the orange arrows and circles, including 11 patients who remain on IV nemvaleukin monotherapy. Several additional patients have recently initiated treatment are -- and are awaiting their first post baseline scan. Here is a more detailed summary of all of the responses we've seen in monotherapy melanoma cohort. With updated data through May 3, including 2 partial responses in mucosal melanoma and 2 in cutaneous melanoma. In each of these cases, the partial responses were initially observed between cycle 4 and cycle 6 of treatment. The first response in mucosal melanoma is the patient with the durable and deepening response with a maximum target lesion reduction of 44%. This patient has been on therapy more than 79 weeks and continues to do well. We also observed an unconfirmed partial response in another patient with mucosal melanoma that subsequently had progressed on the next scan and has now discontinued treatment. Turning to the cutaneous melanoma. The patient outlined in the third row of the table demonstrates a partial response with a 44% tumor reduction on monotherapy. This patient also subsequently progressed and rolled over onto the combination therapy. As I mentioned, a second cutaneous melanoma partial response, marked by the double asterisk here had a partial response with a 35% reduction in the target lesion and is now awaiting confirmation of that response. We are encouraged by this early activity we are seeing in the monotherapy melanoma cohort and look forward to further exploring nemvaleukin's activity in melanoma in the recently initiated ARTISTRY-6 study. Now let's look at the monotherapy renal cell carcinoma cohort. This swimmers plot shows the overall responses in duration of treatment of patients enrolled in the renal cell carcinoma monotherapy cohort. Of the 20 evaluable patients who had more than 1 post baseline scan, 2 achieved a partial response, of which 1 is awaiting confirmation of that response. Stable disease was observed in 10 of the evaluable patients. On this slide, the 2 partial responses are highlighted by the arrows. The partial response shown in the second lane from the stop -- top is still awaiting confirmation. The second partial response marked by the green arrow, was recently confirmed subsequent to the March 19 data cutoff. Overall, out of the 20 evaluable patients, 12 continue on study, including 6 patients who remain on monotherapy. On this slide, we see the same 2 partial responses in renal cell carcinoma with updated data as of May 3. The patient detailed in the first row has been on therapy for 38 weeks. Partial response was first observed at cycle 6 with a 31% target lesion reduction. This patient remains stable, and we are still awaiting confirmation. The second patient's partial response was first observed at cycle 4, with a 48% reduction in target lesion. This partial response was recently confirmed. Both of these patients continue on therapy as of May 3. We initially chose to evaluate IV nemvaleukin's monotherapy activity in renal cell carcinoma due to the high-dose IL-2's proven efficacy in this tumor type. The treatment landscape in this tumor type has evolved significantly since the approval of high-dose IL-2, with now the approval of checkpoint inhibitors and tyrosine kinase inhibitor. Given the competitive landscape, we've decided not to pursue the additional development in renal cell carcinoma. Nevertheless, seeing antitumor activity in this cohort is an important indication of IV nemvaleukin's monotherapy activity. Now let's talk about the combination part of ARTISTRY-1. The Part C cohort of ARTISTRY-1, we are evaluating IV nemvaleukin in combination of pembrolizumab in a variety of advanced solid tumor types. We recently completed enrollment in these cohorts, and this slide reflects final patient numbers. The study includes dedicated cohorts of PD-1 approved and unapproved tumor types and select indication specific cohorts. In addition, there is a dedicated cohort for those patients who are eligible to roll over from the monotherapy arm upon disease progression or at the investigator's discretion. Now as you see on Slide 17 is the summary of all responses we've seen in the cohort evaluating PD-1 unapproved tumor types, data cut as of May 3. We are particularly encouraged by the responses seen in platinum-resistant ovarian cancer patients. Among the 14 evaluable patients with ovarian cancer, we've observed 1 complete response and 3 partial responses, 1 of which is unconfirmed, and 6 patients had stable disease. All 4 other responders are platinum-resistant ovarian cancer patients. The patient with the complete response has been on therapy for more than 2 years and had maintained that complete response, even following recent discontinuation of pembrolizumab in transitioning on to monotherapy IV nemvaleukin at cycle 35 in February of 2021. Two of the patients with partial responses have been on combination therapy for more than a year. We are encouraged by the deepening and durable responses seen in the platinum-resistant ovarian cancer patients, and plan to build upon these results in the upcoming ARTISTRY-7 trial. In this cohort, we're also excited to see some initial responses in pancreatic cancer and squamous cell esophageal carcinoma, 2 additional difficult-to-treat tumor types. On this slide here is a waterfall plot that we presented on the ASCO poster of the best responses by target lesions of the 36 evaluable patients from the PD-1 unapproved cohort. The area between the 2 gray horizontal lines indicate stable disease of target lesions per RECIST criteria. 25 of the 36 patients showed stable disease of target lesions, and 13 of the 36 patients experienced tumor shrinkage. Six of these patients remain on therapy as marked by the arrows and the data continues to mature. Now let's look at the responses of the PD-1 approved tumor types in the tumor-specific cohorts as of the May 3 data cut. Within this set of patients, we have seen broad activity across 11 tumor types. In particular, we're encouraged by the responses observed in patients with cervical cancer. Of 4 evaluable patients, 2 have achieved a partial response, 1 of which is awaiting confirmation. Based on the responses we've seen in cervical and the platinum-resistant ovarian cancer, we believe IV nemvaleukin may have a particular utility in gynecologic cancers. We're also excited to see responses for the combination in multiple other tumor types, including, but not limited to, bladder, breast, colorectal, head and neck and lung cancer patients. These emerging data in a range of tumor type with varying levels of activity in responses to checkpoint inhibitors, support the broad utility of IP nemvaleukin in combination with pembrolizumab. Given our particular interest in mucosal melanoma, I'll also highlight that we observed a partial response in combination with pembro and a CPI naive who achieved a 100% reduction in target lesion and has been on therapy for 38 weeks. The waterfall plot shown here on Slide 20 shows the best response of target lesions for the 36 evaluable patients in the PD-1-approved cohort, including both PD-1 pretreated and treatment-naive patients. Overall, 29 of the 36 patients showed stable disease of target lesion. 16 of 36 patients experienced tumor shrinkage. Overall, 15 patients continue on therapy, as noted by the arrows. Many of these patients with tumor shrinkage remain on treatment today. The tumor types of patients who continue on therapy include cervical, bladder, lung, endometrial, hepatocellular and colorectal cancers. Now if we take a step back, we've learned a great deal about the IV nemvaleukin profile and antitumor activity in the signal-seeking study, both as a monotherapy and in combination with pembrolizumab. The accumulating data from this study have helped to inform the next stage of development, including the recently initiated ARTISTRY-6 study in melanoma and a planned Phase III study in platinum-resistant ovarian cancer in combination with pembrolizumab. As we look back at our first response in November of 2019, the program has advanced significantly to reach the stage of development. We believe the emerging signals of antitumor activity of the IV nemvaleukin in combination with pembrolizumab in a diverse range of tumors with high unmet need support IV nemvaleukin's broad potential clinical activity across multiple tumor types. Now I'll focus my attention on the ARTISTRY-2 data presented at ASCO. ARTISTRY-2 is our subcutaneous dosing study. We recently identified 3 mgs dosed weekly as the recommended Phase II dose for subcutaneous nemvaleukin and initiated the Phase II efficacy expansion portion of the study. First, let's look at the safety data that supported the selection of the recommended Phase II dose for the subcutaneous administration. Recall that we tested both weekly and q 3 weekly dosing. Both 3 mg q weekly and 6 mgs q 3 weekly demonstrated a safety profile consistent with the anticipated cytokine treatment-related adverse events. We selected 3 mg weekly as our recommended Phase II dose based on the totality of data from the dose escalation phase of the study, which included pharmacokinetic, pharmacodynamic, safety and antitumor activity. Overall, at the recommended safety dose, the safety profile of subcu nemvaleukin was largely consistent with its mechanism of actions and the safety profile of IV nemvaleukin. The common AEs across all doses, regardless of causality, were fatigue, fever, nausea and injection site reaction. There were no treatment-related discontinuations or deaths. Now if we move on to the pharmacokinetic and pharmacodynamic data collected in the subcutaneous dose escalation portion. The systemic exposure of subcutaneous nemvaleukin increased with increasing doses accompanied by a transient elevation of interferon-gamma and IL-6 concentration. Interestingly, when we compare to the 6-microgram IV dose, the 3-milligram dose of subcutaneous nemvaleukin induced higher levels of interferon-gamma, a cytokine that has been associated with antitumor efficacy in clinical studies and a lower transient upregulation of IL-6 concentrations. The pharmacodynamic data for subcutaneous nemvaleukin were consistent with nemvaleukin's mechanism of action, showing a threefold increase in CD8 T cells and a 16-fold increase in NK cells, which were similar to or greater than that, that was observed in recommended Phase II dose of IV nemvaleukin and low-level nondose-dependent expansion of regulatory T cells. Importantly, the expansion of NK cells with the 3 mg subcutaneous dose exceeded that seen with the IV dosing. Several studies have shown the significance of NK cell expansion and the ability of such cells to induce direct tumor killing. Antidrug antibodies were observed in a subset of patients treated with subcutaneous nemvaleukin in the dose escalation portion. The presence of ADAs did not appear to have a clinically meaningful effect on the pharmacokinetic, the pharmacodynamics or the safety of nemvaleukin. We will continue to evaluate ADAs as we collect more data in the subcutaneous program. Of the 57 patients enrolled in the dose escalation, where one or more on-treatment scan, including on patients that received subtherapeutic doses, 31 patients had stable disease on the first scan. Among the 37 patients with 2 or more treatment scans, 17 had stable disease on 2 or more consecutive scans. Now I will share some updates on the first objective response observed in the Phase II expansion stage of ARTISTRY-2 that we initially discussed at our recent Investor Day. This is a 69-year-old female and have platinum-resistant ovarian cancer with high-grade serous histology. We previously reported data up to cycle 2 of treatment when the patient had achieved a partial response awaiting confirmation with approximately a 50% reduction in target lesions. Today, I'm happy to report that subsequent to the March 19 data cut, this patient continued to experience tumor shrinkage and has achieved a confirmation of the partial response at cycle 5 with a 53% reduction in target lesions. In parallel, her CA-125 levels have normalized with a 99% reduction from baseline. And as of the May 3, she continues to remain on therapy. Now if we take a step back, we're pleased to see the progress that we've made on the subcutaneous program and are continuing to explore subcutaneous nemvaleukin's efficacy, safety and PK/PD profile. We expect to advance patient enrollment in the expansion cohorts throughout the remainder of the year and look forward to sharing additional data at future medical meetings. So to summarize, nemvaleukin is a unique cytokine design to harness the validated IL-2 pathway biology. Nemvaleukin is accumulating in clinical data set that differentiates it from other IL-2 variants in development. It has demonstrated antitumor activity in high unmet need populations in a range of tumor types, including as a monotherapy and checkpoint-experienced patients with renal cell or melanoma and in combination of pembrolizumab in a broad range of tumor types in both checkpoint inhibitor-naive and checkpoint inhibitor-experienced patients. The development program has accelerated significantly over the past year. The studies that we plan to begin this year with intravenous nemvaleukin, including the already initiated ARTISTRY-6 study in melanoma, and a planned Phase III study in platinum-resistant ovarian cancer, are designed to support potential registration, pending the magnitude and durability of responses and the safety observed in those studies. We look forward to sharing additional data from the clinical development programs at future meetings. Now with that, I would like to welcome Dr. Valentina Boni and Dr. Omid Hamid to discuss, and I'll turn it back to Sandy.

Thank you, Jess. Before we open the call more broadly for Q&A, I'd like to invite Dr. Boni and Dr. Hamid to share their perspective on the data presented today on the nemvaleukin program. Dr. Boni, if I can start with you. The START Oncology works with a lot of early phase drugs, what are your overall impressions of nemvaleukin efficacy and safety data?

Thank you for this question. Well, we have seen preliminary activity in a broad spectrum tumor type, including the tumor not approved or typically responsible to checkpoint inhibitors and in patients already treated with anti-PD-1 and PD-L1 therapy. We have seen responses also in platinum-resistant ovarian cancer. This is a very difficult disease because with limited treatment options for patients and worse outcomes. Therefore, to my -- by my point of view, these data are very encouraging. And the course, we need further confirmation. But my impression is that we have seen several responses in ovarian cancers are interesting and, of course, are very encouraging at this point. Regarding safety profiling of nemvaleukin, the nemvaleukin demonstrated to be very well tolerated. There are some side effects. The majority of which are, in general, transient and easily manageable and the grade I, grade II. So also in the clinic, we are very comfortable with this type of treatment at this point.

That was very helpful. Dr. Hamid, would you share your perspectives on the importance of monotherapy activity, particularly in the CPI-experienced population?

Sure. I think it's very difficult to express how important this is where multiple other combinatorials with checkpoint inhibitors have failed to show any benefit, and that's been linked possibly to their lack of efficacy as a monotherapy. With this drug, with nemvaleukin, we've seen single-agent activity that not only is seen in checkpoint inhibitor refractory patients, but it's durable and, in some patients, deep. It mimics what we've known with interleukin-2, but it follows the science of improving this type of therapy by minimizing toxicity and not just that scientifically decreasing the Treg effects and the VEGF effects of this treatment.

Thank you. Dr. Boni, would you share your perspective on the response activity across the various tumor types we've seen in ARTISTRY-1? And maybe give -- how should investors think about the range of tumor types? And what that means for nemvaleukin's ultimate potential clinical utility?

Yes, sure. So we have seen activity in both nemvaleukin monotherapy and in combination group with the pembrolizumab. In Part B, we have explored the nemvaleukin monotherapy, and we reported the patient in a cutaneous, mucosal and renal cell carcinoma. Regarding -- I think that it's particularly remarkable, the responses that we have achieved in mucosal melanoma, mucosal subtype is, in general, a tumor type in which response rate to checkpoint immunotherapy is lower than a more common cutaneous disease. And 2 out of the 6 melanoma patients are resistant also to anti-PD-1 therapy, and we reported the response in this group. So I think that in this tumor type, particularly also in mucosal, it is very remarkable response, and it could be important to explore further the activity in this subgroup of patients in which we have an unmet medical need. Regarding the combination part, we have seen activity in ovarian carcinoma patients, platinum resistant. I think that also in this tumor type, we have already seen that anti-PD1 and the PD-L1 therapy demonstrated the limited efficacy in this group of patients. And here, we have seen some response, 4 out of the 14 evaluable patients with heavily treated ovarian cancer achieved the response. And one of these was complete response, and all of this patient was platinum resistant. So I think that also in this group of patient, it is particularly interesting response. I think also that the response that we have seen even in broad range of tumor type, including the tumor type in which the activity of immunotherapy is, in general, low and [ such as ] for example, pancreatic tumor type. So I think that this type of activity is of particular interest.

Great. Thank you. That was very helpful. Dr. Hamid, given your experience in melanoma, what are your impressions on the responses and data observed thus far with nemvaleukin both in cutaneous and in mucosal melanomas?

Well, I think, again, it's important to look at the past where we've known that interleukin-2 has a role in the treatment of melanoma. The toxicity and patient performance status has dictated who can and who cannot get this drug. Now with nemvaleukin, not only are we seeing that we can give it to a broad range of melanoma types. So Dr. Boni said before, mucosal melanoma, lower response rate, poor prognosis, lower progression-free survival with checkpoint inhibition and signal agent and in combination. We're now bringing another drug that can give us some response and possibly work synergistically with checkpoints and others. We're also showing the ability to give this drug in an outpatient setting without significant morbidity or mortality. Few people remember the mortality with high-dose IL-2. And not only that, that we've seen durable deep responses in these patients and in patients who failed prior checkpoint. So this is -- it checks off what you need in melanoma. What's interesting here is that we also have an ability to develop a drug that can be given in multiple different ways, not just intravenously, but subcutaneously and therefore, that could benefit the patients in time in office, need for back and forth, et cetera.

Yes. Maybe we can build on that. Can you share your perspectives on the pharmacodynamic profile that you've seen with subcu nemvaleukin in ARTISTRY-2 and maybe speak to the importance of the CD8 T cells and NK cells?

Well, look, it's easily set up that you want to see in single agent, you want to see what we have shown here, a proof of the principle, that you're increasing CD8 T cells. That's what we've always talked about, making a cold tumor hot. You're bringing in NK cells that are important in the tumor micro environment, and you're decreasing T regulatory cells. That's absolutely important. And then more striking is where we've seen that pharmacokinetic and pharmacodynamic data within IV is similar to subcu. So here, you are not losing efficacy by moving into a different route of administration.

Wonderful. Thanks. And this will be my last question before we open it up for broader Q&A. Dr. Boni. I'm curious about your -- in your clinical experience, is there a patient profile that you identify as particularly well suited for nemvaleukin?

Well, we have successfully treated several patients, including elderly patients, patients with high tumor burden at the beginning of treatment and also with involvement of liver with liver metastases. So one of our mucosal melanoma patient that was naive of the therapy, he had a nice tumor burden at the beginning of the treatment, and he achieved the partial response in a very short time frame. And we documented also complete metabolic response in these patients and durable response. This patient was with mucosal melanoma patient and high tumor burden. In another hand, for example, in renal carcinoma patient, who have already failed other type of TKIs and anti-PD1, we also have documented response. So by my point of view, the activity of the drug, we've also seen in several tumor types different profiling of the disease. And therefore, it is difficult to so far to identify a unique profile of a patient more suitable of nemvaleukin treatment.

Wonderful. Thank you. Paul, we'll now open up the call for Q&A for either the Alkermes team or for Dr. Boni and Dr. Hamid. Would you please pool for questions?

[Operator Instructions] Our first question will come from Jason Gerberry with Bank of America.

So I guess first one for me is where do you see essentially the best opportunity, what you know today for 4230 in a large established tumor market? I appreciate the commentary about RCC and the competitive dynamics there, but mucosal melanoma and PROC are somewhat niche. And then my second question, just looking at Slide 20 and the waterfall plot, it looks like majority of the patients seeing that 30% threshold for response are PD-1 naive. So just kind of what gives you confidence that the benefit is coming from 4230 and not the checkpoint inhibitor?