Greetings, and welcome to the Alkermes Conference Call. My name is Paul, and I will be the operator for today's call. At this time, all participants are in a listen only mode. A brief question and answer session will follow the formal presentation. Please note that this conference is being recorded.
I'll now turn the call over to Sandra Coombs, Senior Vice President of Investor Relations. Sandra, 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 nembleukin 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, 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 nemvelukin and the potential therapeutic value of nembilukin. 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 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 are 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 nimbleukin clinical development program. With me today from Alkermes is Jessica Rege, Vice President and Head of Oncology. We're delighted that following the prepared remarks, will be joined by special guests, Doctor.
Valentina Bani and Doctor. Omid Hamid for discussion related to the data set presented at ASCO today. Doctor. Bahni is the lead author of the Artistry 1 poster and medical oncologist and principal investigator at Starc Madrid in Spain. Doctor.
Hamid is the lead author of the ARTISTRY II poster and co director of the cutaneous oncology, director Melanoma Therapeutics and Phase 1 Immuno Oncology Program and Chief of Translational Research and Immunotherapy at the Angeles Clinic and Research Institute, a Cedars Sinai Affiliate. But first, I'll turn the call over to Jessica to take us through the data being presented on the nembleukin program. Jess?
Thank you, Craig. I'd like to start by expressing my appreciation to Doctor. Bonnie and Doctor. Hamid for joining us today and look forward to hearing their clinical perspectives related to the nimbleukin clinical data set. Nimbleukin is a unique cytokine designed to harness and validate the IL-two pathway biology and Alkermes has studied nimbleukin's properties extensively in the clinic.
Nimbleukin's design arises directly from the natural biology of IL-two and its receptors, which we leverage to confer differentiated properties. By combining the native IL-two and the IL-two 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-two. This unique approach makes nimbleukin highly selective for the intermediate affinity IL-two 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.
A 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 nimvelukin may widen the therapeutic window of high dose IL-two, 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. Nimbleukin has demonstrated durable and deepening responses in a range of tumor types, both as a monotherapy in combination and in combination with pembrolizumab in checkpoint inhibitor naive and checkpoint inhibitor experienced patients. To our knowledge, no other IL-two variant has demonstrated this diverse of activity.
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 nimbleukin 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 3 study in platinum resistant ovarian cancer. Additionally, we secured FDA orphan drug designation mucosal melanoma.
This progress has been made possible by a dedicated team of oncology specialists here at Alkermes and the tremendous support from our external investigators. Slide 7 provides a brief overview of the nimbleukin clinical development program, including the 5 ongoing studies and one 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 nimblukin safety and tolerability profile identify the recommended Phase 2 dose for both intravenous and subcutaneous administration and also identify signals of anti tumor activities. These are the studies that we'll 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 nimbleukin immuno genomics activity. Data from ARTISTRY I and ARTISTRY II have informed the recently initiated ARTISTRY VI study and a planned Phase 3 study in platinum resistant ovarian cancer that we plan to initiate later this year. Now, let's focus on the ARTISTRY-one data presented at ASCO today. Here is the ARTISTRY-one trial design.
The data shared at ASCO this year were from Part B monotherapy dose expansion stage and Part C combination stage with timbrelizumab. 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 and the duration of treatment from a ladder 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 nimvelukin given in combination with pembrolizumab did not demonstrate any additive toxicity to that established 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 Now, let's focus on Part B monotherapy stage of ARTISTRY-1. This was designed to assess IV nimvelu can single agent anti tumor activity and 2 tumor types where high dose IL-two has demonstrated efficacy, melanoma and renal cell carcinoma. In contrast to the original studies evaluating high dose IL-two, 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 swimmer's 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 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 a year and a half.
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 nimvelukin monotherapy. Several additional patients have recently initiated treatment 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 3rd 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 nimvoleukin's activity in melanoma in the recently initiated ARTISTRY-six study. Now, let's look at the monotherapy renal cell carcinoma cohort.
This swimmer's plot shows the overall responses and 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 one is awaiting confirmation of that response. Stable disease was observed in 10 of the evaluable patients. On this slide, the two partial responses are highlighted by the arrows. The partial response shown in the second lane from the 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 two 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 nimvelukin's monotherapy activity in renal cell carcinoma due to the high dose IL-two due to the high dose IL-two's proven efficacy in this tumor type. The treatment landscape in this tumor type has evolved significantly since the approval of high dose IL-two, with now the approval of checkpoint inhibitors and tyrosine kinase inhibitors.
Given the competitive landscape, we've decided not to pursue the additional development in renal cell carcinoma. Nevertheless, seeing anti tumor activity in this cohort is an important indication of IV nimvelukin monotherapy activity. Now let's talk about the combination part of ARTISTRY-one. The Part C cohort of ARTISTRY-one, we are evaluating IV nimvelu can 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-one approved and unapproved tumor types and select indication specific cohorts. In addition, there is a dedicated cohort for those patients who are eligible to rollover from the monotherapy arm upon disease progression or at the investigator's discretion. Now, as you see on Slide 17, it's a summary of all responses we've seen in the cohort evaluating PD-one unapproved tumor types data cut as of May 3. We are particularly encouraged by the responses seen in the platinum and 3 partial responses, one of which is unconfirmed, and 6 patients had stable disease. All 4 of the responders are platinum resistant ovarian cancer patients.
The patient with the complete response has been on therapy for more than 2 years and has maintained that complete response. Even following recent discontinuation of pembrolizumab and transitioning onto monotherapy IV nimvelukin at cycle 35 in February of 2021. 2 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-one unapproved cohort. The area between the 2 gray horizontal lines indicate stable disease of target lesions paresis criteria. 25 of the 36 patients showed stable disease of target lesions and 13 of the 36 patients experienced tumor shrinkage. 6 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-one approved tumor types in the tumor specific cohorts as of the May 3rd 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, one of which is awaiting confirmation. Based on the responses we've seen in cervical and the platinum resistant ovarian cancer, we believe IV nimbilukin 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 data in a range of tumor types with varying levels of activity in responses to checkpoint inhibitors support the broad utility of IV nimbilukin 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 in 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-one approved cohort, including both PD-one pretreated and treatment naive patients. Overall, 29 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 nimvelukins profile and antitumor activity in this 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 3 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 this stage of development.
We believe the emerging signals of anti tumor activity of the IV nimvelukin in combination with pembrolizumab in a diverse range of tumors with high unmet need support IV nimbleukin's broad potential clinical activity across multiple tumor types. Now, I'll focus my attention on the ARTISTRY II data presented at ASCO. ARTISTRY II is our subcutaneous dosing study. We recently identified 3 mgs dosed weekly as the recommended Phase II dose for subcutaneous nimvelu can and initiated the Phase 2 efficacy expansion portion of the study. First, let's look at the safety data that supported the selection of the recommended Phase 2 dose for the subcutaneous mid administration.
Recall that we tested both weekly and Q3 weekly dosing. Both 3 mg qweekly and 6 mgs q3 weekly demonstrated a safety profile consistent with the anticipated cytokine treatment related adverse events. We selected 3 mid weekly as a recommended Phase 2 dose based on the totality of data from the dose escalation phase of the study, which included pharmacokinetic, pharmacodynamics, safety and anti tumor activity. Overall, at the recommended Phase 2 dose, the safety profile of subcu nimvelukin was largely consistent with its mechanism of action and the safety profile of IV nimvelukin. The most common AEs across all doses regardless of causality were fatigue, fever, nausea and injection site reactions.
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 nimbleukin increased with increasing doses accompanied by a transient elevation of interferon gamma and IL-six concentration. Interestingly, when we compare to the 6 microgram IV dose, the 3 milligram dose of subcutaneous nimbleukin induced higher levels of interferon gamma, a cytokine that has been associated with anti tumor efficacy in clinical studies and a lower transient upregulation of IL-six concentrations. The pharmacodynamic data for subcutaneous nimvelukin were consistent with nimvelukin's mechanism of showing a 3 fold 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 the recommended Phase 2 dose of IV nemvelukin and low level non dose dependent expansion of regulatory T cells.
Importantly, the expansion of NK cells with a 3 mg subcutaneous dose exceeded that seen with IV dosing. Several studies have shown the significance of NK cell expansion and the ability of such cells to induce direct tumor killing. Anti drug antibodies were observed in a subset of patients treated with subcutaneous nimvelukin in the dose escalation portion. The presence of ADA did not appear to have a clinically meaningful effect on the pharmacokinetics, the pharmacodynamics or the safety of nimbleukin. 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 1 or more on treatment scans, including on patients that received sub therapeutic 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 2 expansion stage of ARTISTRY II that we initially discussed at our recent Investor Day. This is a 69 year old female and has 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 CA125 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 nimbleukin's efficacy, safety and PKPD 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, nimvelukin is a unique cytokine designed to harness the validated IL-two pathway nimbleukin is accumulating in clinical data set that differentiates it from other IL-two variants in development. It has demonstrated anti tumor activity in high unmet need populations in a range of tumor types, including as a monotherapy and check point experienced patients with renal cell or melanoma and in combination with 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 nimvelukin including the already initiated ARTIS 3 6 study in melanoma and a planned Phase 3 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 Doctor. Valentina Boney and Doctor. Omid Hamid to discuss and I'll turn it back to Sandy.
Thank you, Jess. Before we open the call more broadly for Q and A, I'd like to invite Doctor. Bunney and Doctor. Hamid to share their perspectives on the data presented today on the Nembhalukin program. Doctor.
Bunny, if I can start with you, the START oncology works with a lot of early phase drugs. What are your overall impressions of the nembleukin efficacy and safety data?
Thank you for this question. Well, we have seen a preliminary activity in a broader spectrum tumor type, including the tumor not approved or typically responsive to checkpoint inhibitors and in patient already is also in platinum resistant ovarian cancer. This is a very difficult treatment disease because with limited treatment options for patient and worse outcomes. Therefore, to my by my point of view, these data are very encouraging. And of course, we need the further confirmation, but my impression is that we have seen several response in ovarian cancers are impressive and, of course, are very encouraging at this point.
Regarding safety profiling of Nimbaledin, the Nimbaledin 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 1, grade 2. So also in the clinic, we are very comfortable with this type of treatment at this point.
Thanks. That was very helpful. Doctor. 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 nemvelukin, 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-two, 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. Doctor. Bunney, 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 Nembolukin's ultimate potential clinical utility?
Yes, sure. So we have seen activity in both a nonvallicinomonal therapy and in combination group with the pembrolizumab. In Part B, we have explored nimbalikin as monotherapy, and we reported the patient in 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 sex point immunotherapy is lower than a more common cutaneous disease.
And 2 out of the 6 melanoma patients are resistant also to RTPD-one therapy, and we reported the response in this group. So I think that in these tumor type, in particularly, also in mucosal, it is a very remarkable response. And it could be important to further the activity in this subgroup of patient in which we have an unmet medical need. Regarding the combination path, we have seen activity in ovarian carcinoma patient, platinum resistant. I think that also in this tumor type, we have already seen that anti PD-one and the PD L1 therapy demonstrated the limited efficacy in this group of patients.
And here, we have seen some response for out of the 14 evaluable patient patients with heavily predicted ovarian cancer achieved the response, and one of these was complete response and all of these patients were platinum resistant. So I think that all in this group of the patient, it is particularly interesting the response. I think also that the response that we have seen is in a broad range of tumor type, including 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 particularly interest.
Great. Thank you. That was very helpful. Doctor. Hamed, given your experience in melanoma, what are your impressions on the responses and data observed thus far with nemvelukin 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-two has a role in the treatment of melanoma. The toxicity in patient performance status has dictated who can and who cannot get this drug. Now with nimbleukin, not only are we seeing that we can give it to a broad range of melanoma types. So, Doctor. Boni said before, mucosal melanoma, lower response rate, poor prognosis, lower progression free survival with checkpoint inhibition in single 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-two. And not only 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 and in time in office, need for back and forth, etcetera. Yes.
Maybe we can build on that. Can you share your perspectives on the pharmacodynamic profile that you've seen with subcu nembleukin in ARTISTRY-two 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, the 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 microenvironment and you're decreasing T Health, 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 and A. Doctor. Bunny, I'm curious about your clinic in your clinical experience.
Is there a patient profile that you identify as particularly well suited for nembleukin?
Well, we have successfully treated several patients, including elderly patient, a patient with high tumor burden at the beginning of the treatment and also with involvement of liver metastasis. So one of our mucosal melanoma patient that was naive of therapy, he had a nice tumor burden at the beginning of the treatment And he achieved partial response in a very short time frame. And we documented also complete metabolic response in these patient and the 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 TKI and anti PD-one, we also have documented the response.
So by my point of view, the activity of the drug was 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 nyombalic in treatment.
Wonderful. Thank you. Paul, we'll now open up the call for Q and A for either the Alkermes team or for Doctor. Bunyan and Doctor. Hamed.
Would you please poll for questions?
No problem. Thank you. We will now be conducting a question and answer session. Our first question will come from Jason Gerberry with Bank of America. Please proceed with your question.
Hey, guys. Thanks for taking my questions. So I guess first one for me is, where do you see potentially the best opportunity what you know today for 4,230 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 in the waterfall plot, it looks like majority of the patients hitting that 30% threshold for response are PD-one naive.
So just kind of what gives you confidence that the benefit is coming from 4,230 and not checkpoint inhibitor?
Thanks. Jeff, do you want to start off with the first question about the opportunity? And then maybe we can ask Doctor. 1 of the thought leaders to pine in on the contribution
of nembleukin. Sure. Thanks for the question. So I think as it relates to wanting to have a broad tumor type, one of our focuses right now, of course, is to get this drug to the patients as soon as we can as we continue to watch the data mature and open up the opportunities that we're seeing. As you've seen, we plan to focus with mucosal melanoma and monotherapy and CPI experience as well as the platinum resistant ovarian cancer.
But seeing responses in cutaneous as well as some of our other responses in cervical and other broad utility in a multitude of tumor types, development program.
And Doctor. Buney, did you want to opine on nembleukin's contribution for some of those PD-one treatment naive patients in the Part C combination stage of ARTISTRY-1?
Well, yes, I think that, of course, in a patient with PD-one, PD L1 naive and in the combination part, it is more difficult to say which is the drug that is working better. I mean, we have already documented in the monotherapy part that nonvoluting is active and it is activating the T cells into the macro environment. So I think that likely we have the contribution of the 2 drugs in order to improve the efficacy also of pembrolizumab and nimbalekin is likely to increase the activity of the T cell infiltrating the tumor. So I think that we have seen in this part of a combination with approved tumor type response And it is remarkable based on also the previous activity in the monotherapy. And I think that another point to remark that in the combination part, for example, with CTLA inhibitors such as ipilimumab, we in general see a synergistic effect, more response, but with the cost of more facilities.
Here, in this combination, we don't have seen a remarkable increase of the toxicity because the toxicity profile is and the treatment related adverse events frequency is very similar in both parts, the monotherapy and in the combination. So I think that both of these things are remarkable to have a combination that it is also safe without an increase of toxicities is important at this point.
Got it. Thank you.
You're welcome.
Our next question comes from Umer Raffat with Evercore ISI. Please proceed with your question.
Hi, thanks so much for taking my questions. I had 3, if I may. Perhaps first one for the KOLs on the line. Do you think given the clinical activity and the monotherapy activity difference we're seeing between the IV and subcu program, do you think that the subcu nemalukin is being under dosed? I'd be very curious how you think about that.
Secondly, on back on the IV, I want to touch up on the melanoma and RCC separately. 1st on melanoma, the patient would be unconfirmed PR, cutaneous melanoma with 4 prior lines. I would have thought they would have had their follow-up scan by now to be able to confirm it. So I just wanted to understand the status there. And also I was a little puzzled by the decision to roll over that patient over to PD-one combo considering there's a finite data set that exists with monotherapy activity to understand duration of response.
So just wanted to understand the thought process there. And then finally in RCC, again, the new response reported as of March, I would have thought we could have had a confirmation by now. I just wanted to understand if follow-up scan happened. Thank you very much.
I will leave those questions about the decisions made by my colleagues and follow-up scans to the Alkermes people. But what I will tell you is that it's very difficult to evaluate response rates as it relates to different subsets of patients and different subgroups of patients. So what we're really seeing is PK and PD that's equivalent. So I wouldn't you really can't say that there's decreased efficacy. The second thing that I would say to you is that I would agree that if someone is responding to a single agent, you'd want to see the duration of response.
But at times, what's the way the trials are written and the decisions are made by the primary investigator. Clearly, what we're seeing in melanoma is that you can have a single agent that has a response and at times, even with checkpoint progression, keeping that checkpoint on can increase your response rate and your durability. And at ASCO 21, there's some data to show that, but we've seen that with the data of switching to anti CTLA-four and anti PD-one versus anti CTLA-four alone upon PD-one progression. So those are decisions that are made. In relation to the drug itself, I think what we're showing here is a tolerable drug that has shown in early trials, responses that are durable amongst the subset of patients that have low response rates or low durations of response.
So we're talking about ovarian cancer where the response rates are in the 10 to the teens and they're short lived. Finding a drug that works as single agent, low toxicity and can be combined is rare. And I would state that, there have been other drugs that have shown less and have already moved on to Phase 3 trials and I support and I applaud the decisions made here to take some of this data and look at small subsets of patients as they are doing in the melanoma subset in ARTISTRY 6?
Thank you, Doctor. Hamid. So I'll address the couple of questions as it related to the monotherapy. So in relation to the cutaneous melanoma patients, I think there was a question on why was the decision to move the patient that was responding over to the combination. That patient had a partial response at the subsequent scan, as I noted in the presentation, head of aggression.
And per our protocol, they are allowed to move over into the combination portion of the trial. So that's the first unconfirmed response. And then
And maybe just to add to that, you'll recall that previously when we discussed this particular portion of the protocol, we felt it was ethical to allow patients to roll over as combination therapy, and also afford the patient an opportunity to demonstrate a response in combination. So that was the thought process behind it.
Yes. Thank you, Craig. And I'll say the second cutaneous melanoma, that's actually a new response. And so that patient still remains on therapy and we are awaiting confirmation. So that subsequent scan should be forthcoming.
And then I think as we talked about the renal cell patient that we talked about with the partial response, they have had additional subsequent scans as noted on the slide. It actually is the nuances in RECIST is all around the tumor shrinkage. It is teetering on the window between a 30% and a 29% reduction and that's why you saw the subsequent scan. So we're still awaiting that confirmation of PR and that patient still remains on monotherapy.
And then just to maybe add to the discussion on our recommended Phase 2 dose for subcu. I mean, the thought process there was really based on a sort of a combination assessment of tolerability and safety together with the pharmacodynamic profile. Obviously, we look at it very closely at the CD8 T cell expansion as well as NK cell expansion. I wanted to ensure that we didn't see expansion of Treg cells there. And then lastly, we looked also at efficacy and really a disease stabilization in patients as it relates to the subcu.
And that's really how we got to the recommended Phase 2 dose.
Thank you, guys.
Thanks, Omar.
Thank you. Our next question comes from Terence Flynn with Goldman Sachs. Please proceed with your question.
Hi. Thanks for taking the question. Maybe 2 for me. In ARTISTRY 1 in the combo arm, I was just wondering if you guys have collected any data on PD L1 expression levels and if there's any correlation with activity there. And then I was wondering if you can provide the rate of ADAs.
I know you mentioned it, but just curious what the rate was? And again, if there's any kind of dose response on that front? Thank you. Yes,
probably seen in the Artistry II poster, we did see antidrug antibodies against the nimbleukin in a subset of patients treated with the subcu nembleukin. The prevalence of ADA did not was not related to dose or dosing frequency either in the sort of Q7 or Q21 day cohort. And the presence of ADAs didn't appear to have any clinically meaningful effect on the pharmacokinetics or the pharmacodynamics or the safety profile of nembleukin. Obviously, we continue to monitor ADAs in the program.
And as it relates to the PD L1 expression question, so when we think about in the PD-one unapproved tumor types, first of all, I should say the PD-one status was not collected on all of the patients within the trial. It wasn't required for enrollment. But we do talk with our investigators and work with the data at all times. And so in the unapproved cohort, we do have some patients, but the majority do not have PD L1 status because of course it's unapproved and not typically done. In the PD-one approved cohorts, we do again have patients that are responding with PD L1 negative and positive in the subset of patients in which we do have some data.
But again, it wasn't a requirement in order to enroll in the trial nor is it a requirement for us to collect that on all of the patients.
All right. Paul, would you like to pull for questions one more time? I think that might be it for today. And we only have a couple more minutes left anyway.
Sure.
I think that's all we have. Again, I'd like to really thank Doctor. Bani and Doctor. Ahmed for joining us on the call today to share their perspective. If there's any remaining questions on the data set, please don't hesitate to reach out to the Investor Relations team at Alkermes, and we look forward to continuing the conversation.
So thanks, everyone, and have a great weekend.