CytomX Therapeutics (NASDAQ:CTMX) Q4 2019 Earnings Call

0:01 Good day, ladies and gentlemen, and welcome to the CytoMix Therapeutics Fourth Quarter 2019 and Full Year Financials Conference Call. At this time, all participants are in a listen-only mode. As a reminder, this call may be recorded. I would now like to introduce your host for today's conference, Christopher Keenan, Vice President of Investor Relations. Chris, you may begin.

0:25 Thank you, Lee. Good afternoon, and thank you for joining us. Earlier today, we issued a press release that includes a summary of our recent progress in fourth quarter 2019 and full-year financial results. This press release and a recording of this call can be found under the Investors & News section of our website at sitomx.com. With me today are Sitomx President, Chief Executive Officer and Chairman, Dr. Sean McCarthy, Sitomx Chief Development Officer, Dr. Amy Peterson, and Sitomx Vice President of Finance, Robin Nifsund. During today's call, we will be making forward-looking statements. Because forward-looking statements relate to the future, they are subject to inherent uncertainties and risks that are difficult to predict, and many of which are outside of our control. Important risks and uncertainties are set forth in our most public recent filings with the SEC at SEC.gov, including our Form 10-K file today.

1:17 We undertake no obligation to update any forward-looking statements, whether as a result of new information, future developments, or otherwise. I would now like to turn the call over to Sean.

1:27 Great, thank you very much, Chris, and good afternoon, everyone. Thanks very much for joining us. It's a pleasure to be here to provide an update on our progress during the fourth quarter and throughout 2019. I'll begin with an overview and some recent highlights across the pipeline, and we'll then turn the call over to Amy to review our lead CX072 and CX2009 programs in more depth. Robin will then review our fourth quarter and fourth year financial update, and I'll wrap up with upcoming 2020 milestones before opening up the call for questions. At Cytomix, we see a major opportunity to more effectively target therapeutic antibodies into diseased tissue, generating new classes of anti-cancer therapies. We believe our unique pro-body therapeutic platform represents a fundamental advance and we are highly focused on the discovery and development of a broad clinical pipeline of novel drug candidates to make a meaningful difference in the treatment of cancer.

2:25 Our unique science offers the potential for new and highly effective anti-cancer therapies, including potentially best-in-class molecules against validated targets, first-in-class molecules against novel undruggable targets, and new combination therapies. ProBodies are fully recombinant antibody prodrugs comprised of a therapeutic antibody and a mask designed to block the binding of the antibody to its target until the mask is removed. Mask removal is achieved specifically and selectively within cancer tissue by certain disease-associated proteins called proteases. This allows us to localize antibody activity into cancer tissue, decreasing target engagement in normal tissues and broadening or, in fact, even creating a therapeutic window.

3:11 We have pioneered this new approach that we see as an important evolution of the therapeutic antibody field with broad potential to improve and optimize a range of antibody formats, including cancer immunotherapies, antibody drug conjugates, and T-cell engaging by specific antibodies. This is an exciting time for our company as our pipeline continues to mature, as our partnerships advance, and as our research engine continues to produce innovative new molecules. In total today, we have more than 20 programs at various stages of discovery and development within our proprietary pipeline and in collaboration with our partners. Since our first presentation of clinical data for our platform less than two years ago, we have now generated and presented a wealth of data to support clinical proof of concept for our technology, and our three most advanced programs have all recently progressed into focused phase two clinical studies.

4:02 We expect to provide several significant data updates throughout 2020. Earlier this week, we announced an important pipeline milestone in our foundational oncology collaboration with Bristol-Myers Squibb. The leading edge of this alliance is the anti-CTLA-4 probody BMS-986249. CTLA-4, the target of ipilimumab, is the prototypical checkpoint target, and blocking this mechanism has proven highly effective both as monotherapy and in combination with PD pathway inhibitors in the broad treatment of patients with melanoma and in many other cancer types. While a very important advance, ipilimumab can cause severe immune-related toxicities, creating a clear opportunity for a probody version of this agent to improve tolerability, increase duration of treatment, and potentially improve activity.

4:54 BMS and cytomics have previously presented preclinical proof of concept for CTLA-4 probodies at several major research conferences. and BMS has completed enrollment now in the Phase 1 clinical studies with BMS 986249, the results of which we expect to see presented this year. As we announced on Monday, BMS has now initiated a randomized Phase 2 expansion study evaluating the tolerability and activity of BMS 986249 plus the PD-1 inhibitor nivolumab versus nivolumab with or without ipilimumab in metastatic melanoma. The advancement of BMS-986249 into this study has triggered a milestone payment of $10 million to Cytomix from BMS.

5:39 This is an important study that, if positive, has the potential to place the ipilimumab probody on a registrational path. Moreover, this work is a direct embodiment of exactly what we set out to do with our platform when it was first conceived of, and we are very excited about the potential for cancer patients. Additional recent progress within our foundational BMS alliance includes the initiation of the dose escalation phase of a Phase I-IIa clinical study for a second anti-CTLA-4 probody, BMS 986288, which is based on a modified version of ipilimumab. This second clinical probody program demonstrates BMS commitment to our technology platform as a way to potentially unlock additional value in the CTLA-4 mechanisms.

6:25 As these CTLA-4 programs progress through clinical development, potential regulatory approval, and commercialization, CytomX is eligible to receive certain milestone payments and royalties. And it's important to note that we also continue to work closely with BMS to initiate new discovery programs under this broad-based alliance. In addition to this progress with BMS, 2019 was a year of many achievements for CytomX within our wholly-owned lead programs. the anti-PDL1 probody CX072 and the anti-CD166 probody drug conjugate CX2009. We also advanced a very unique program in partnership with AbbVie, the CD71 targeting probody drug conjugate CX2029.

7:13 CX072 is a probody therapeutic directed against the validated immuno-oncology target PDL1. We believe that CX072 has the potential to become a differentiated foundation for combination anti-cancer therapies by increasing tolerability, achieving optimal dosing, and delivering increased anti-cancer activity to improve patient outcomes. We have shown previously that CX072 is active as a monotherapy in multiple tumor types and that the probody has the activity to be expected from a checkpoint inhibitor, providing the first clinical proof of concept for our unique platform. In the fourth quarter, we advanced CX072 into a Phase II clinical trial to further evaluate the activity and tolerability of CX072 plus ipilimumab in patients with relapsed or refractory melanoma.

8:02 Building on our encouraging Phase I-II data, this trial is evaluating CX072 in combination with the full labeled monotherapy dose and schedule of IPI with a goal of driving meaningful anti-cancer activity in this difficult-to-treat patient population. We believe this combination has the potential to become a best-in-class regimen not only for melanoma but potentially other cancer types. Initial data is anticipated from Stage 1 of the Phase 2 study during 2020. Now turning to our second wholly-owned drug candidate, CX2009, a pro-body drug conjugate designed to target the previously undruggable target CD166. CD166 is a unique tumor antigen that is expressed at high levels on most solid tumors, but that's also present on most normal tissues, ruling it out as a target for a typical antibody drug conjugate.

8:55 We're exploring the ability of a pro-body drug conjugate to unlock the potential of this target by focusing anti-cancer activity to tumor tissue and not normal cells. Based on encouraging phase one clinical data we reported last year, We initiated in Q4 2019 a Phase 2 expansion study of CX2009 monotherapy in patients with hormone receptor-positive HER2-negative breast cancer. This study was initiated in the fourth quarter. Amy will provide more context on this program in a few moments. Now, returning briefly to our collaborations, and specifically within our AbbVie Alliance, We continue to enroll patients in the dose escalation and refinement phase of the Proclaim CX2029 Phase 1-2 study, evaluating monotherapy CX2029, a first-in-class pro-body drug conjugate targeting CD71.

9:48 And this is in patients with solid tumors. This is a very novel and ambitious program. CD71's biological role is to function as what we call a professional internalizer as it moves iron from the extracellular space to intracellular compartments CD71 is, in fact, the gold standard internalizer used to assess ADC activity in vitro. Now, while an attractive target for payload delivery to cancer cells, it has remained undruggable, and, in fact, we have shown that an ADC to CD71 is lethally toxic in preclinical models. In partnership with AbbVie, we've created a pro-body drug conjugate, CX2029, in which a masked antibody to CD71 is conjugated to the cytotoxic payload, MMAE.

10:38 Dose escalation in the clinic was initiated in mid-2018 and is ongoing as we progress towards the selection of a recommended Phase II dose. We anticipate the presentation of initial data from this exploratory clinical work in 2020. Should the study progress to cohort expansions at the recommended phase 2 dose, we anticipate the presentation of proof of concept data in 2021. For this program, CytomX has responsibility to advance it through initial proof of concept whereupon, if successful, the program will transition to AbbVie for registrational studies and ultimate commercialization. CytomX retains profit split and certain co-commercialization rights for this asset. Before handing the call over to Amy for more detail on our lead programs, I'd like to spend a few moments on two earlier stage programs that are emerging as a potential second wave of IND candidates in our pipeline.

11:36 Starting with our collaboration with Immunogen, from whom in Q4 we obtained exclusive worldwide development and commercial rights to an EPCAM-targeting pro-body drug conjugate. This program was developed utilizing cytomix pro-body technology and Immunogen's drug conjugate technology under rose from our previous strategic collaboration between the parties. At the 2018 European Antibody Congress and also at AACR 2019, Immunogen presented encouraging preclinical data demonstrating that an EPCAM pro-body drug conjugate has potent activity in in vivo efficacy models as well as improved tolerability and exposure compared to an unmasked EPCAM antibody drug conjugate. CytomX now has full development control and commercial rights for this promising program.

12:23 Another promising preclinical program is our T-cell bispecific probody targeting EGFR and CD3. This program is partnered with Amgen with CytomX retaining development control and certain commercial rights. We're really excited about the prospects for the T-cell bispecific application of probodies to enable solid tumor targeting of this modality. Solid tumor targeting with unmasked T-cell bispecifics has been very challenging for the field due to narrow or non-existent therapeutic window. We anticipate advancing a lead clinical candidate for this program during 2020. So now let me turn the call over to Amy.

13:00 Thanks, Sean. I'm pleased to be here today to report on the great progress we continue to make with our lead wholly owned programs, CX072 and CX2009, including studies that set us up to answer important questions over the next one to two years. Let's begin with our lead program, CX072. As previously reported, patient enrollment is complete for the Part D expansion cohorts. Studying CX072 at the dose of 10 milligrams per kilogram administered intravenously every two weeks to patients with multiple tumor types and we expect to present a summary of our findings from these expansion cohorts this year. Data presented to date, most recently at ASCO 2019, showed that CX072 functions as a checkpoint inhibitor, demonstrating encouraging activity where one would expect to see it with such agents, including triple negative breast cancer, anal squamous cell carcinoma, and cutaneous squamous cell carcinoma.

14:01 CX072 tolerability appears favorable as well. and while numbers are too small to be clinically significant, trends towards lower rates of immune-mediated adverse events have been observed. Clinical pharmacokinetic and biopsy data has shown that the CX072 probody behaves as designed. That is, it remains masked in the circulation and becomes unmasked in tumor tissue, resulting in intratumoral saturation of the target and anti-tumor activity. These findings provide an important clinical proof concept for our platform and a strong rationale for differentiation of CX072 from other PD inhibitors and support combination strategies with other anti-cancer agents.

14:50 Given that combination therapy is likely to be required to make continued significant improvements in patient outcomes, we are focusing our efforts on CX072 combinations and in the immediate term, specifically on the combination of CX072 with ipilimumab. During our last quarterly update, I cited multiple clinical trials evaluating regimens involving a PD inhibitor plus a CTLA-4 inhibitor where significant reductions in dose intensity of either agent, although more commonly with the CTLA-4 inhibitor, have been required in order to maintain a tolerable safety profile for patients. There are multiple studies demonstrating dose-dependent anti-cancer activity from ipilimumab. To date, no one has been able to combine full doses of CTLA-4 inhibition with full doses of PD inhibition.

15:47 We are interested to determine the extent to which our pro-body platform can enable the combination of full-dose PD inhibition here in the form of CXO7-2 plus full-dose ipilimumab. Accordingly, in Q4 2019, we advanced into an open-label, non-randomized, multicenter, Simon 2 stage phase 2 trial of CX072 in combination with ipilimumab in patients with advanced melanoma who have previously progressed on a PD pathway inhibitor. In this Phase 2 trial, patients are receiving ipilimumab at its full approved monotherapy labeled dose and schedule of 3 mg per kg every 3 weeks for 4 cycles, plus CX072 at a fixed dose of 800 mg every 3 weeks for 4 cycles.

16:39 Upon completion of this combination, patients can receive continued treatment with 800 mg CX072 monotherapy administered intravenously every two weeks. The primary objective of this study is overall response rate, with the secondary objectives being safety, tolerability, and other markers of clinical activity, including progression-free and overall survival, as well as the duration of response in those patients achieving partial and or complete responses. Stage 1 of this trial aims to enroll up to 40 patients, and we hope to have initial data from this stage of the study in 2020. To summarize, there are now two important studies underway evaluating pro-bodies in patients with melanoma. Each study is designed to show how these novel combinations can improve tolerability and lead to better outcomes for patients.

17:32 There is a lot to learn from each study, most importantly the ability this platform offers to improve the risk-benefit from IO-based therapy in people with cancer. We're excited about these two studies and look forward to learning from each. I'd like to now turn attention to CX2009, our pro-body drug conjugate targeting CD166, an ADC with a pro-body mask. In the fourth quarter of 2019, we initiated an open-label non-randomized multicenter phase two study of CX2009 monotherapy in up to 40 patients with hormone receptor, ERPR, positive and HER2 negative breast cancer, This subtype of breast cancer remains a substantial area of unmet medical need.

18:20 And in this study, CX2009 is being administered intravenously at seven milligrams per kilogram every three weeks to this population. The initiation of this expansion study follows our presentation of encouraging dose escalation phase one data at AACR 2019. As you heard from Sean, CD166 is widely expressed both on tumor and normal tissue. precluding the development of a CD166 targeting antibody drug conjugate due to expected systemic toxicities. We have leveraged our probody technology to mitigate binding of CX2009 to normal tissue, thereby creating a therapeutic window for this novel target.

19:05 Our Phase I dose escalation trial was designed to gain a comprehensive look at the safety profile of this novel drug candidate as well as assess exploratory markers supporting the hypothesis behind this platform. While not expected in a dose escalation study in a heavily pretreated and heterogeneous patient population, preliminary signs of single-agent anti-cancer activity were observed and presented at AACR 2019. As a reminder, the payload conjugated to CX2009 is DM4, a metanzine derivative. Based on work conducted by Immunogen, from whom we licensed the payload, the toxicities associated with DM4 are well documented and are predominantly ocular and or neuropathic in nature.

19:54 Payload toxicities typically define the MTD of drug conjugates, and it's important to note that we would expect this to be the same for pro-bodies as for antibodies, since in the pro-body, it is the antibody that is masked, not the payload. Our pro-body drug conjugate strategy is to drug undruggable targets by achieving the maximum tolerated dose of the payload, but without the serious on-target off-tumor toxicity. Specifically, with CD166, we are seeking to avoid on-target toxicities expected to occur in organs where CD166 is highly expressed, for example, in colon, pancreas, and lungs. and, indeed, we were able to escalate up to 10 milligrams per kilogram, a dose that, to our knowledge, has never been previously administered with any ADC.

20:54 As we did, as expected, observe payload toxicities, including keratitis and neuropathies. Taken together, these findings demonstrate clearly that our masking strategy was effective in protecting against on-target, off-tumor toxicities. And what was even more encouraging, as we reported at AACR in 2019, was that in patients who received more than or equal to four milligrams per kilogram of CX2009, 38% achieved tumor shrinkage, and 74% achieved stable disease or better at the time of the first on-treatment scan. Observed anti-cancer activity included seven unconfirmed partial responses in breast cancer, including HER2-negative hormone receptor positive breast cancer, ovarian cancer and head and neck cancer.

21:50 This risk-benefit profile compares well to early Phase I experience for other ADCs that have advanced into registrational studies and supports the further development of this asset. We anticipate announcing more complete data from the CX2009 Phase 1 dose escalation trial in 2020, and we anticipate initial data from the breast cancer Phase 2 expansion trial in 2021. We're also very interested in the potential of CX2009 plus CX072 combination. When we think about the types of therapies that have been most successfully combined with PD inhibitors, in terms of improvements in risk-benefit profiles, we can't ignore the improved outcomes that have been observed in combination with cytotoxic agents. Furthermore, there's growing evidence that PD inhibition can be successfully combined with ADCs. We therefore also plan to evaluate the tolerability of the combination of CX072 plus CX2009 to identify a combination dose and regimen to advance in indications where both agents have demonstrated single agent activity.

23:01 Turning to our organization, we continue to strengthen the development capabilities of the company and most recently announced the appointment of Dr. Allison Hanna to the role of Senior Vice President and Chief Medical Officer reporting directly into me. Allison joins my team with 30 years of relevant experience in clinical drug development and oncology and malignant hematology. Prior to joining us, she led her own consultancy where she advised pharmaceutical and biotechnology clinical teams, resulting in successful filing of over 40 regulatory applications for first-in-human clinical testing, while also playing significant roles in the broad marketing approvals of eight therapeutics, including extensive experience interacting with global health and regulatory authorities.

23:47 I've been fortunate to have worked with Allison during my time at Beijing and Medivation and look forward to her many contributions during this important time in the advancement of our pipeline at Cytomix. I will now turn the call over to Robin for a review of financials.

24:03 Thank you, Amy. I would like to review selected financial highlights for the year 2019. We ended the year with cash, cash equivalents, and investments totaling $296.1 million. compared to $436.1 million as of December 31, 2018. Our strong balance sheet allows us to comfortably fund operations into the second half of 2021 assuming no new collaborations and or financings. Research and development expenses were $132 million for the year compared to $104 million in the corresponding period in 2018. The increase was primarily attributable to additional costs related to our maturing pipeline, including personnel-related expenses.

24:50 In 2019, we incurred approximately $16 million of non-recurring charges related to the acquisition of technological know-how, license fees to UCSB associated with entering into the amendment with UCSB, and a license fee for the EPCAM program. General and administrative expenses were $37 million compared to $34 million in the corresponding period in 2018. Revenue for the year was $57.5 million compared to $59.5 million in the corresponding year. The decrease was primarily due to a $13.1 million decrease in revenue from AbbVie under the CD71 co-development and licensing agreement relating to the $21 million DPHIL, Stephanie Robertson, Danielle Olander-Moghadassian, due to the accelerated revenue recognition related to the cessation of research on certain targets under our agreement with Bristol Myers Squibb in the first quarter of 2019.

26:20 With that, I will turn the call back over to Sean.

26:23 Great. Thanks, Robyn. So, in closing, let me briefly review our anticipated 2020 milestones. For CX072, our PD-L1 probody, we anticipate presentation of final monotherapy data for the expansion arms in multiple selected tumor types, building on our ASCO 2019 presentations of last year. We also, for the CX072-IPI combination in relapsed refractory melanoma, we anticipate initial data from Stage 1 of the ongoing Phase 2 study. CX2009, our CD166 targeting pro-body drug conjugate, we anticipate presentation of updated phase one dose escalation and dose ranging data that support the dose and indication selection for the ongoing phase two study you've heard about today. And then for CX2029, our CD71 pro-body drug conjugate, we anticipate initial data from the phase one dose escalation portion of the phase one two study with additional proof of concept data from expansion cohorts targeted for 2021, assuming that the program transitions to that stage.

27:37 Also, and as I mentioned earlier on in my remarks, we do anticipate that BMS will present the phase one data for the IPI ProBody BMS 986249 sometime this year and that of course would be the data that has supported the announcement that we made this week regarding their entry into the randomized phase 2 study of the IPI ProBody that we're all very very excited about. So thanks everyone for taking some time to join us today. It's obviously been a turbulent day out there in the markets but we're very pleased with the broad progress we've made at Cytomix last year and continuing into this year both with our Very unique technology platform and also with our advancing and deepening clinical pipeline and all of us on the Cytovix team are excited for an eventful 2020 ahead. So I think with that, we'll turn the call back to Chris for Q&A.

28:36 Lee, I think we're ready to open the call for questions. Certainly. Ladies and gentlemen, if you have a question at this time, please press star and then the number one key on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, press the pound key. We'll pause for just a moment. Your first question is from Christopher Mirai from Nomura InstantNet. Your line is now open.

29:05 Oh, hi. Thanks for taking the question and congrats on all the progress. I was wondering if you could touch upon the CD166-2009 ProBody program. I guess you updated us on the path forward there, including HER2-negative, HR-positive breast cancer, and that would constitute your expansion cohort in the Phase 2. Could you maybe elaborate a little bit on a potential path to approval that could emerge from that and how that might look? Is there a go-no-go decision that you're looking for? And then how might this fit into the evolving treatment paradigm here? Obviously, other therapies are looking for approval in this setting as well.

29:54 Thank you.

29:56 Sure. Hi, thanks, Christopher. This is Amy. Thanks for your question. Yeah, so this study, just to recap, is the first part of the study will evaluate 40 patients with hormone receptor-positive HER2-negative breast cancer. While we can't disclose the details around the eligibility criteria, what I can say is we have taken a sharp eye to that to ensure that the patient population is one that would be something that we can take forward to global health authorities should we see hectivity commensurate with taking the molecule forward. And it is in patients who have received hormonal-based therapy. We recognize that Other treatments are emerging, and we always have an eye to that. But at this point in time, I can't really divulge further details around specifics of the eligibility criteria.

30:51 Okay, then. And just to follow up, perhaps the expansion component of the trial, I assume, would not be registration-directed. At what point does Zytomix make a go-no-go decision on this and run out a phase three and even the population that you may be selecting in this expansion cohort? Thank you.

31:15 Sure. Thanks for the follow-on. So, you're right. With 40 patients, that's not registrational. However, depending on what we see and depending on our discussions with health authorities, it could potentially lead to something that is registrational. if we have the right sample size, if that answers the question.

31:39 Yep, and then just the go-no-go on data here, what do you want to see in those 40 patients? And I'll jump back in the queue. Thank you.

31:45 I think, Chris, as I mentioned, our goal there is to have initial data on this first 40 patients in 2021, and obviously we'll take a look at that data and decide the path forward. Your next question is from Mohit Bansal from Citi. Your line is now open. Hi, this is James on for Mohit. It looks like Bristol now has 986-288 and 986-249 in trials. Can you remind us how these two CTLA-4s differ and any insight on BMS's strategy to explore both?

32:25 Yeah, hi, James. Absolutely. So 249 is the ProBody version of IPI itself. And I think as we've laid out, that's the program that's being advanced into the randomized phase two study. And that was the first ProBody targeting CTLA-4 that we made with BMS in this alliance. 288 is, as we said, a modified version of IPI that is designed to be more active than the parental antibody. I'm expecting them to probably say a bit more about this program this year as the new leadership within BMS get their arms around these programs. So we're not at liberty to say too much about it, but we've made a pro body version of that modified IPI and that has now also gone into phase one dose escalation. So as I said in my prepared remarks, The press release mentions that the EGFR T-cell bispecific with Amgen is going to be advancing in 2020.

33:29 Can you highlight what sort of developments have been made and if we'll be seeing any preclinical data this year? We've presented some preclinical data previously, as you may have seen in poster form. So the basic concept and the basic proof of concept behind EGFR CD3 has been presented. What we've been doing with Amgen for the last couple of years is really working through the detailed protein engineering and molecular biology of how to optimize that format. And there's As I'm sure you know, there's a lot to that.

34:23 There's a lot of different formats to sort through, a lot of geometry to get right in terms of the activity of the two arms of this type of bispecific. And all I can say is that we've made good progress, and we do expect to move towards lead clinical candidate stage over the course of this year with Amgen. One other note is, as I mentioned, we do at Cytomix, much like in the AbbVie Alliance, we retain... Development Control for this program through proof of concept. So we'll be filing the IND once we get to the point of having a clinical candidate that we agree to move forward with our partner. Fantastic. Thank you for taking the questions. Thank you. Your next question is from Terrence Flint from Goldman Sachs, your line is now open.

35:11 Hi, this is Holly on for Terrance. Thanks so much for taking the question. Two for us. One, so as we look towards the data from Stage 1 of the Phase 2 study of CX072, which is especially later this year, what do you need to see in order to move that program into Stage 2 of the Phase 2 study? Secondly, on CXA2009, beyond the breast cancer indication that you outlined, what other tumor types might be appropriate for this treatment, considering the risk-benefit profile that's demonstrated thus far? Thanks.

35:43 Thanks for the questions, Holly. I'll be happy to turn those over to Amy.

35:46 Okay, great. So, as far as the Stage 1 of the Phase 2 study for CXA072, what we would need to see to move forward, I don't think we're actually giving guidance on What sort of response rates we would need to see. However, I will say that from the data that is available in the public domain, response rates have been around the 20s and in some cases using immune resist as high as 45%. And we are well aware of those and looking to see where we benchmark to that. For CD166 program, additional indications, as I sort of alluded to in the transcript, we saw monotherapy activity with patients in head and neck, triple negative breast cancer, hormone receptor positive HER2 negative breast cancer. And in the 2019 presentation, there are other indications where tumor volume reductions were observed, for example, in ovarian cancer.

36:52 and what we might think about then are moving forward into those indications where we at least observe activity with our agent. But at this point in time, we're focusing on the hormone receptor positive HER2 negative breast cancer population, which you probably know very well is about 60% of all of patients with breast cancer. And at this point in time, there is no ADC approved in this particular indication. And then when it comes to CX2009 in combination with 072, what I alluded to in the transcript is we would look to indications where either have had single agent activity and think about bringing the combination forward in those indications. But we haven't disclosed what those indications are yet.

37:46 Lee, I think we're ready for the next question. Thank you. Your next question is from Terence Flynn. Oh, it's from Mary Goldstein from Mizuho, your line is now open.

37:57 Great. Thanks so much for taking the question. Thanks for the additional color on the 2029 program. I just had a question with respect to the biomarker arm in that study and if you can provide a little bit more insight into that and when you might have that information. And as well, Given the novelty of this particular target, how should we think about it in terms of the focus of tumor types, even though I certainly respect it's a solid tumor study? And then secondarily, I know you've spoken to Bristol having data on the 249 program sometime this year. Do you have any particular insight as to what venue that might be?

38:46 Hey, Mara. Thanks for the questions. Take the second question first. Can't comment on that, unfortunately. They're working that through, but appreciate the question. Regarding 2029, so our guidance at this point, so this is a big idea, this target. It's a very exciting target, and As I've said before, what we're doing is a pretty careful, thoughtful dose escalation with a target that, as we've demonstrated preclinically, if you don't mask it, is actually extraordinarily toxic, in fact lethal. So we're taking it carefully to learn about this molecule in patients. And what we're working towards presenting this year is initial safety data from phase one dose escalation.

39:42 The Biomarker biopsy data would come from a little later in the study as we move to not quite into expansion stage, but the upper range of the dose escalation. So probably no biomarker data this year. Okay. Thank you. Your next question is from Robert Burns from HC Wing, right? Your line is now open.

40:14 Hi guys, thanks for taking my questions. So I just want to circle back on the CX072 plus Yurovoi Phase 2 study. So considering that Idara Pharmaceuticals is currently running a Phase 3 for their acid IMO2125 plus Yurovoi versus Yurovoi in anti-PD1 or L1 refractory melanoma patients after achieving a 24% objective response rate in their Phase 2, could you comment about the sort of efficacy benchmark you believe you would have to hit in your Phase 2 trial? for CX072 plus Yu-Waye in order for your Phase 2 trial to potentially be registrational in nature. And then I have one follow-up after.

40:55 Yeah, hi, Robert. Great question. And, yeah, we've obviously noted that data, and I'll hand over to Amy.

41:00 Okay, great. Right, so as far as what we would need to see in the Phase 2 single-arm study, what we would need to see to make it registrational in and of itself, It's hard to pinpoint. Obviously, they went forward with Phase 3 with a response rate of 24%, and we're encouraged certainly by that. And so for a registrational standalone, we're probably looking at something upwards of 24%, right? However, if we do see that, it certainly gives us – to move forward into larger randomized studies as they did. And we'll see what happens with their data, which I think we're expecting in 2022 from the phase three.

41:52 Okay. Thank you for that. And then one more from me. So I'm curious as to how you see that sort of indication, the anti-PD-1 refractory melanoma patient setting evolving over time when we consider some of the assets and combinations where we see moving into that space.

42:09 Thanks. Let me make sure I understand your question. So it's how does the anti-PD-1 refractory patient population evolve as other agents are moving into the space?

42:24 Yeah, I'm sort of curious as to how you see that sort of treatment pattern sort of evolve considering all the data we're seeing from multiple different assets. Just from a landscape perspective, your thoughts on it.

42:40 Yeah, I guess first, nothing's yet approved. And so while there might be a lot of people dabbling in this space and testing in this space, I think until we have approvals, the space is open. And I guess I'm not quite sure what additional

43:02 I was just going to add that we've moved into this patient population in large part, of course, because of the substantial unmet medical need. That could shift over time, right, if some of these other approaches are Thank you very much. advantages over others because we know, for example, the depth and durability of response that can be afforded with this still the only IO-IO combination that's been approved can be very impressive and very meaningful for patients.

44:01 And so I think we'll just have to see how it unfolds. We haven't, as you well know, we haven't committed at this stage to a large randomized study. We wanted to take it one step at a time. And we'll closely monitor the field and see how it unfolds. Awesome. Thanks, guys. Your next question is from Edzer Deroth from Guggenheim. Your line is now open.

44:29 Great. Thanks for taking the question. Just a couple of questions for me. First, on CX2009, just wondered if you could talk a little bit about the population that the study is going into, the hormone receptor-positive HER2 breast and many more. Thank you very much.

45:19 Let me answer the second question first, and thanks very much for the questions. And I'm sure Amy would be happy to take the second on the 2009 patient population. So, you know, obviously, BMS has made a pretty substantial commitment to the melanoma, the randomized melanoma study. Can't comment on what their thoughts might be in terms of other indications, but as we've said, with our combination of O72 plus IFI, we do see opportunities beyond melanoma that we could potentially move into, and the team, Amy and Alison and the team, are very actively working those through. So no specific update at this point, but we certainly see additional opportunity on our side.

46:05 Great. And then I'll address your first question, which was, I think, trying to better understand what response rate we might be benchmarking to in this patient population given the competitive landscape. So I can't give guidance on what response rate we're benchmarking to. It's known that hormone receptor-positive HER2-negative breast cancer responses are not as easy to have with chemotherapy or with other agents, which doesn't mean that these patients aren't getting benefits. So we will be looking at a couple of things in addition to response rates. Clinical benefit rate, for example, at 24 weeks is often used to assess whether or not the drug is doing anything.

46:57 and when it comes to other drugs moving in the area, there are certainly drugs moving in and there are drugs moving out and CDK4-6 inhibitors, for example, are possibly moving to adjuvant spaces. Sacituzumab, we're interested to see what ultimately happens with that, but we don't anticipate that data for quite some time. So I can't give you a number.

47:23 That's fair, thank you. Your next question is from . Your line is now open.

47:34 Hi, guys. Thanks for taking my questions. Maybe I guess one more, Sean, on the refractory melanoma trial. I think on this call you talked about a 20 to 24% ORR is a good benchmark. Have you positioned that if we look at, you know, the 14% ORR that was presented by FDA, I think they published this data in Lancet in 2017 in about 2,500 patients that fail PD-1 but continue to be treated with PD-1 post-progression. So essentially, you're getting a 14% ORR on PD-1 after they progress. So do you think a 20% to 24% ORR in that population with the combo would be a differentiator?

48:25 Thanks.

48:27 Yeah, hi, Darren. Good question. I want to be clear, though. I mean, we're not guiding to a... I don't think we did specifically guide to a 20% to 24% response rate on this call. I think what we said is when we look at the... And by the way, that data that you cite is, of course, interesting in terms of continued PD therapy in failures. But what we're saying... Let me try and be as clear about this as I can be, is that if we look at the published evidence or the publicly available evidence for how patients who have been pre-treated, treated previously with a PD inhibitor, how they fare on a PD-CTLA-4 combination, those response rates are in the 20% to 40% range. And the landscape is shifting, as Robert asked and others have asked, right, with other combinations in this patient setting. So the bar is is probably getting higher, not lower.

49:28 So we'll do the best we can do, and we're obviously looking for the best response rate we can get, but we're not specifically guiding to 20 to 24, just to be clear. We have to do better.

49:39 Okay, that's helpful. And then on the EpiCAM, can you just talk about, you know, this is a target that's also expressed on normal cells, and Can you just talk a little bit about what you're seeing in the animal data and whether that will correlate in terms of off-target toxicity?

49:55 The question is on EPCAM. Yeah, so we're really interested in this target. And, you know, Immunogen has been for some time, as you know. And it just – the program became available in the context of Immunogen's strategic reprioritization last year. So we were able to – negotiate to bring it back into cytomics. So the target, it's been thought of for a very long time as a very good cancer target. It's actually a reasonably well-validated target in that there is data out there, there's Phase II data for a fusion protein, an Epcam-targeting fusion protein, which actually is a different kind of a toxin.

50:40 It's a a recombinant toxin fusion that is quite effective in phase two. So we know this target can work. The preclinical data has shown that the, and again Immunogen has presented this, that the ADC is quite toxic. It induces a range of toxicities including in the skin. The probody is protected in that regard and yet the probody retains the anti-cancer activity of the underlying ADC, just like our pro-body drug conjugates do. So it's an interesting and exciting program. We've just brought it back into the company, so we're in the process of evaluating the data to decide what our timeline is going to be for moving that program forward.

51:30 But we think it's a really interesting molecule.

51:33 I'll just clarify the indications where it is clinically validated. It's in bladder cancer, and they moved into a pivotal study. Additionally, EPCAM as a naked antibody is used for the treatment of ascites and ovarian cancer in certain regions of the world. So there are two clinically validated areas where EPCAM has demonstrated activity resulting in it. continued progress forward to registration studies or approval.

52:06 Great. Okay. Thank you. Your next question is from Joe Catanzaro from Piper Sandler. Your line is up.

52:16 Hey, guys. Thanks for taking the questions. Those are a couple of quick ones from me. Would you be able to say how many patients enrolled into the dose-ranging portion of the 2009 Phase I study and whether we should expect that cohort of patients to be less heavily pretreated than six or seven prior lines of therapy for the initial dose escalation cohort.

52:42 Hey, Sean, just let me make sure I understand the question. So you're asking about the phase one study enrollment, right?

52:51 So yeah, so like the dose optimization that you had done in implementing the prophylactic measures for ocular toxicity.

52:59 Right, yeah, so again, our goal is to present a pretty comprehensive update on all of that work sometime this year. What I can say is that the patient population really throughout the work that we did that led to the selection of dose and indication was all done in pretty late-stage patients. And so now, as we're moving into the Phase 2 expansion, the team has revised the are enrollment criteria and is working hard to tighten up that patient population relative to the phase one. So I don't want to comment on specific numbers at this point, but it should become clearer as the year goes on.

53:45 Okay, got it. And then maybe following up along those lines, and I was kind of asked earlier, but With phase one dose escalation and optimization complete, what triggers the expansion of additional cohorts beyond the initial hormone receptor positive cohort that you just kicked off?

54:05 Yeah, no one thing, really. I think it could be additional data. It could be thinking about priorities across the portfolio. of course it would be data that we've already seen from the phase one so something that we're looking at in real time and particularly Amy and Allison now that they're here and firmly on board are looking at very closely.

54:28 Okay, great. That's all I have. Thanks for taking my questions.

54:31 You bet. Your next question is from Varun Kumar from Cantor Fitzgerald. Your line is now open.

54:41 Hey, good evening everyone and thanks for taking the questions. First on CX2029, I understand the toxin used in this one is MMAE versus DM4 being used in 2009. Can you provide some context as how should we think about some of the MMAE-related talks when we see the first data and some of the off-target talks we should expect from the initial data?

55:11 Well, thanks for the question, Varun. If I could paraphrase your question to some extent, it might be, would we expect to see ocular toxicities with MMAE? The answer there is that we probably wouldn't expect it based on the wealth of clinical experience with that payload. Ocular toxicity is a particular Thanks, Sean. And just maybe one question on 0-7-2 combo.

56:06 Any color on inclusion criteria being used based on prior ear voice therapy in the patient?

56:16 When you say the 072 combo, you're referring to the ipilimumab combo. And we are not allowing prior CTLA for exposure.

56:30 Okay, so all the enrolled patients will be CTLA for naive in the enrolled cohort. Correct. Okay, great. Thank you, Sean, and thank you, Amy.

56:43 You're welcome. So we're reaching the top of the hour, and I don't see any more questions. I'm going to turn the call back over to Sean.

56:50 Yeah, great. Thanks, Chris. Well, once again, 2019 was a very big year for the company, very important advancements across the pipeline, and we think we're off to a great start in 2020. So thanks for your time, and we'll talk to you next time. Ladies and gentlemen, this concludes today's conference. Thank you for your participation and have a wonderful day. You may all disconnect.

57:14 Goodbye.