CytomX Therapeutics, Inc. (CTMX) Earnings Call Transcript & Summary

Good morning, everyone. This session is for CytomX. My name is Ash Verma, and I'm part of the [ Smith Capitec and Spec Pharma ] team here at Bank of America. And CytomX is a clinical stage biotech company with a focus on cancer immunotherapy. And with me today is Sean McCarthy, Chairman, President and CEO of CytomX. Over to you, Sean.

Great. Thank you very much, Ash, and good morning, everyone. Thanks for joining us today. It's a pleasure to be here to provide an update on our recent progress and future directions at CytomX. So moving to Slide 2, our forward-looking statements. I want to remind you that over the next 30 minutes or so, I will be making certain forward-looking statements, and I refer you to our safe harbor statement. Now this has been a very busy year for us at CytomX. We've had many achievements so far this year. And abstracts were, of course, released yesterday for several presentations at ASCO. During this presentation, I will briefly review the key data presented in the abstracts in the context of each of my program updates. Our ASCO updates do span our full clinical pipeline, and they will provide an integrated view of the progress we're making in, firstly, advancing our understanding of our core Probody technology and secondly, in progressing our lead programs from Phase I into Phase II studies, where we believe the full potential of these assets has the potential to be demonstrated. Now there is a lot to digest across the multiple abstracts that came out last night, and I know many of you have questions. We will be holding an analyst and investor briefing on Friday, May 29, once the full ASCO presentations have been released in, of course, the virtual ASCO 2020 format. So moving to Slide 3. Company highlights. So we are a clinical-stage company advancing first-in-class and best-in-class cancer treatments with a very unique technology platform, we call Probody Therapeutics. We are the leader in this field. We've really pioneered this field of conditional activation of therapeutic antibodies with a very broad platform and discovery engine. We have presented over the last couple of years, additional clinical proof-of-concept for this idea, initially with a PD-L1 Probody. And we're now very busy advancing the pipeline from Phase I into Phase II. We are advancing potential first-in-class programs against previously undruggable targets, including Probody drug conjugates to novel antigens, CD166 and CD71. We're also advancing best-in-class programs against validated targets, principally in the immunotherapy space, PD-L1 and CTLA-4. We have, over the years, formed a number of major partnerships, which have been and continue to be very successful with BMS at the Amgen and most recently with Astellas. This and our -- these partnerships and our equity-based financings have put us in a very strong cash position. We just reported end of Q1 cash of $248 million. And that does not include an additional $130 million of cash received in milestone and upfront payments in Q1; earned in Q1 and received in Q2. So a strong balance sheet and cash position to advance the pipeline. Slide 4. Reimagining therapeutic antibodies for the treatment of cancer. So we all know, of course, antibodies are a very successful class of therapeutics. Our particular approach is to leverage Probody technology to localize target binding to tumor tissue and decrease binding in normal tissues. In doing so, to maintain antibody potency but reduce on target side effects. And the main opportunity with this platform is to enable new targets and new formats such as Probody drug conjugates, T cell bispecifics. And this technology, which we have pioneered, and as I mentioned, we are very clearly the leader in this field, really is built on a deep knowledge of tumor microenvironment biology, innovative [ intuitive ] engineering, deep IP and, of course, a deep understanding of protease biology given that protease activity in tumor tissue is what releases the mask from antibodies, from Probodies, allowing their binding selectively within tumor tissue. Moving to Slide 5. Our pipeline. So we have developed a broad and deep pipeline over the last several years, and it is advancing across multiple stages of development. We've seen strong progress in both our wholly owned and partnered programs over the last several years. I just want to briefly summarize the pipeline here, and I'll review each of the programs in some detail as we go through the presentation. The lead program in the pipeline is CX-2009. This is a CD166 targeting Probody drug conjugate. We have advanced this program into a Phase II expansion in hormone receptor positive HER2-negative breast cancer. We initiated that study towards the end of last year. The CX-072 program is our PD-L1 Probody, we did actually stop a study earlier this year of CX-072 in combination with ipilimumab in relapsed/refractory melanoma. That decision was taken for a number of strategic considerations. CX-072 does continue as an active program at the company, notably in combination with our internal assets, and we are preparing to start a combination study of CX-072 with CX-2009 in an indication, I'll come to a bit later in my presentation. In collaboration with BMS, we are advancing an anti-CTLA-4 Probody, BMS-986249. This has recently entered into a Phase II study in frontline melanoma. We have released last night in abstract form preliminary initial data from CX-2029, a CD71 targeting Probody drug conjugate. We have a second CTLA-4 program advancing with BMS, BMS-986288. This is based on a modified version of ipilimumab. That program is also in the clinic in a Phase I study. And I'll come back to some of the preclinical programs towards the end of the presentation. So the pipeline, both our wholly owned assets and in collaboration with our partners, has really continued to take great shape and advance from Phase I into Phase II over the course of the last 12 months. Turning to Slide 6. As I mentioned, we have a number of comprehensive updates coming up at ASCO on May 29, updates across 4 clinical-stage programs. These include Phase I -- updated Phase I and PK data for CX-2009, the first clinical data for CX-2029 targeting CD71, the first clinical data for BMS-986249 targeting CTLA-4 and updated Phase I/II data, together with PK and translational data for the PD-L1 Probody, CX-072. So I'd like to turn now to targeting undruggable targets with Probody drug conjugates, and let's move into Slide 8. So I want to spend a few moments describing the concept behind Probody drug conjugates. These are designed to be first-in-class drug candidates, addressing undruggable targets. And they're designed to deliver significant single-agent activity. The basic idea here is that we can address a novel class of antigens which are highly expressed on tumor tissue, but that have not been advanced into the clinic before because these targets are present at high levels on normal tissue. So the concept of the Probody, which allows tumor localization, is to allow localized activity of the Probody and the Probody drug conjugate by tumor activation by mask removal in the tumor by tumor-associated proteases, and in doing so in localizing the construct to tumor tissue to deliver a cytotoxic payload locally into tumor cells, but not in the periphery against normal cells. So the objective here of a Probody drug conjugate is to deliver therapeutic levels of payload without dose-limiting on target toxicities in normal tissues. So the PDC comprises an antibody, an antibody mask and the payload. And the mask removal by proteases in the tumor now allows the antibody to bind the target to internalize the payload and elicit its cytotoxic effect. I want to emphasize that in these constructs, the payload itself is not masked. So we still expect to see typical payload toxicities in our preclinical and clinical studies. And I'll come back to that in the course of my description of the programs. Thus far, we have advanced 2 Probody drug conjugates into the clinic, CX-2009 against CD166 and CX-2029 against CD71. So let's, first of all, discuss CX-2009, a Probody drug conjugate targeting CD166, otherwise known as ALCAM, and this is on Slide 9. So CD166 is a highly expressed tumor antigen. It's on multiple tumor types. It's broadly and homogeneously expressed on many different tumors. You can see here, for example, an IHC of breast cancer. It's also present in ovarian, head & neck and lung cancer, many solid tumors. But it's also present at high levels on most normal tissues, including the liver, lung, skin, the GI tract. So CD166 does not meet the rules of selection of a typical ADC target that actually breaks those rules by being present on normal tissues. So we've applied our Probody technology to make a proprietary anti-CD166 antibody. We engineered this into a Probody by masking it, and then we conjugated it to the immunogen payload DM4 via the cleavable linker SPDB. This is a microtubule inhibitor, which has been shown to be active against multiple tumors. And in fact, DM4 is the payload of the immunogen ovarian cancer folate receptor drug in Phase III. The expected payload related toxicities from DM4 include ocular toxicity, neutropenia and peripheral neuropathy. And with this payload, we expect to see clinical activity in the dose range of 4 [ mgs per kg ]and above based on the work of others. And going back several years, as we designed our first Probody drug conjugates, we were careful to select known payloads with known efficacy profiles and known toxicity profiles so that we could deconvolute our clinical data in the event we saw toxicity as to where that toxicity was coming from. So moving to Slide 10. This is just a summary of the updated Phase I data that will be presented at ASCO in a couple of weeks. And also, I want to speak to an emerging breast cancer strategy for our initial Phase II expansions, for CX-2009. We reported Phase I data, the initial Phase I data last year at AACR. The abstract for ASCO provides an update to that AACR presentation from last year. And the -- principally, the update on the dose escalation in advanced metastatic disease. Now dose escalation began at 0.25 milligrams per kilogram. And in the ASCO abstract, you can see that as of November 30, 2019, cutoff, 92 patients have been enrolled. We saw partial responses in 8 patients, 2 of which were confirmed, and these were both in hormone receptor positive HER2-negative breast cancer. And these patients were treated at doses between 4 and 10 milligrams per kilogram. We also saw 21 patients with stable disease and dose-dependent ocular toxicities, which were observed with the payload. This was an expected toxicity, particularly at the higher doses. We have demonstrated now that the dose-dependent ocular toxicity can be mitigated by ocular prophylaxis by eyedrops essentially up to doses of 7 mgs per kg. We have selected 7 mgs per kg a [key] 3-week dosing as our recommended Phase II dose. We have initiated an expansion cohort with the goal of enrolling 40 patients in hormone receptor positive HER2-negative breast cancer. We did initiate that towards the end of last year. That enrollment is currently paused as we announced previously, due to COVID-19. We are actively monitoring the situation and hope to get that study up and running as soon as possible. We also plan to initiate in the second half of this year, a combination of the PD-L1 Probody, CX-072 with CX-2009 in triple-negative breast cancer. And this is an interesting opportunity for us. We've seen clear evidence of single-agent activity in triple negative, which we presented previously for CX-072 also for CX-2009, and we think this is a venue and an opportunity to combine these 2 agents. We know that checkpoint inhibitors can combine well with active lead drug conjugates. And we'll be kicking that study off again in the second half of this year, pending further resolution of the COVID-19 situation. So we look forward to presenting a full update on this on this data as described in the abstract at ASCO on May 29. So I'd like to move now to our second Probody drug conjugate, CX-2029, targeting CD71 or the transferrin receptor. And I'm now on Slide 11. So CD71 is a cell surface protein, the transferrin receptor. It's a transmembrane glycoprotein that is known to efficiently -- functions to efficiently internalize iron bound transferrin. It's highly expressed on malignant cells. This has been known for decades. It's been thought of as a very high potential target for cancer therapy for a very long time. And in fact, many different modalities have been shown to be internalized by CD71, but no one's has success moving this into the clinic to actually demonstrate anti-cancer activity. We really like this target because it cycles so fast off of the cell surface. It has the potential to deliver antibody-drug conjugates into the cell, deliver a payload into the cancer cell in a very efficient way. So in many ways, we refer to it as a professional internalizer. Because, however, CD71's presence on many healthy tissues that have a high iron requirement, dividing cells, certain erythrocyte precursors. This is considered to be an undruggable target with traditional antibody drug conjugate technology, but it does have enormous potential because it's present on so many solid tumors and certain hematologic malignancies at high levels. So for a few years now, we have been working to ask whether we can open a therapeutic window for CD71 and demonstrate tolerability and clinical activity in drug conjugate form for CD71 targeting Probody drug conjugate. The construct that we've advanced into the clinic is, again, it's a masked antibody to CD71. And in this case, conjugated to the cytotoxic payload MMAE by the VC linker. So VC MMAE, which is, by the way, the same linker and payload as ADCETRIS. So turning to Slide 12. I want to spend some time taking a little bit of a deep dive into the preclinical science on CD71 and CX-2029. And the next 2 slides are taken from a presentation we gave at World ADC in London in early March. So first of all, the design of the Probody and the preclinical efficacy, and then I'm going to speak to the preclinical talks. So first of all, on the left-hand side of Slide 12, this is data that shows the masking of the antibody. You can see that the masking shifts the binding affinity of the antibody significantly. Because we block the binding of the antibody to its target. This data also shows that in vitro, we can remove the mask within vitro protease treatment, regaining the full binding potency of the antibody. This is the typical profile for a Probody, and it's also noted here that this antibody is nicely cross reactive between human and cyno, which has allowed us to do some very important cynotoxicity studies that I'll show you on the next slide. The right-hand panels show the broad preclinical efficacy of this molecule, CX-2029 in multiple tumor types, solid tumors and also in DLBCL. And these doses that are considered therapeutic and developable doses of the agent from an efficacy standpoint. So broad-based activity in tumor models. And as you can see, 71% of the cell line drive models that were tested showed regressions or stasis and in high expressing models, 83% of those responded. So broad activity, as we would expect, given the high level of expression of this target on many different solid tumors. So moving now to Slide 13 and the Cyno tox data. So this is a little bit of a complicated table, but the main point is that we did a head-to-head comparison of the antibody drug conjugate against the Probody drug conjugate to ask the question, to what extent, based on the preclinical efficacy that we've seen, to what extent can we show that masking actually can improve the tolerability of engaging CD71 in Cynomolgus monkeys. As you can see in the title, CX-2029 was tolerated at 10x higher doses than CD71 than the CD71 ADC in these monkey studies. So that's very encouraging that we can through masking, get to higher doses, decrease toxicity. It's noteworthy that the principal toxicity is observed in the monkey models were hematologic. This was expected. As I said, with the DM4 payload for the CD166 program, the principal expected toxicity there of the payload, of the unmasked payload is ocular tox, which we can manage. In this case, the principal toxicity is hematologic tox, which is known to be the principal toxicity of the MMAE payload. And you can see that it's really heme tox that underpins the lethal toxicity of the antibody drug conjugate in monkeys. Whereas the Probody drug conjugate is well tolerated at doses of 10x higher 6 mgs per kg. The -- just a quick comment on the nature of this heme tox. The -- as I said, MMAE is known to induce hematologic tox. We do also know that CD71 is on erythrocyte precursors. So at the higher doses here of the Probody drug conjugate, we can't rule out at this point that at some level that there is some binding at a low level to CD71 at the higher doses here that might be expected. And that could be contributing to the toxicity at the higher levels. But it does show, regardless, this data shows us that the Probody drug conjugate is tolerated at therapeutic and indeed potentially super therapeutic doses regardless of the principal toxicities that we observe. So a very encouraging set of data on the preclinical side from the efficacy and the safety, essentially showing that at efficacious doses this PDC is tolerated in monkey studies. So that data, of course, encouraged us to file our IND and move into the clinic. And I'd like to move now to Slide 14, titled Phase I dose escalation data for CX-2029 to be presented at ASCO 2020. So I should say this program is partnered with AbbVie. CytomX is developing the program through clinical proof-of-concept in expansion cohorts. After a clinical proof-of-concept, the program will go back to AbbVie for late-stage clinical development, potential registration and commercialization. CytomX retains certain U.S. commercial rights as part of a global co-development relationship that starts with the initiation of Phase III studies. In March of this year, we announced achievement of a $40 million milestone from AbbVie for reaching pre-specified dose escalation criteria. The main goal of dose escalation was, of course, to find a dose for Phase II for expansion cohorts. And given the pharmacology of this target and indeed, the unique pharmacology of the Probody drug conjugate itself, yet this is not a trivial achievement. People have been trying to drug this target for a long time, and we've made substantial progress we believe in these early clinical studies. These data will be the subject of an oral presentation at ASCO to be delivered by Dr. Melissa Johnson on May 29. Key points from the abstracts that was published last night. So first of all, the starting dose was 0.1 mg per kg. That's lower than the dose we began with CD 166. Given the nature of this target, we decided to start at an even lower dose and do a careful thoughtful dose escalation. As of November 30, 2019, 34 patients have been enrolled into dose escalation, again, beginning at 0.1 mg per kg. The pharmacokinetic data shows that Probody masking was efficiently maintained in circulation with the Probody remaining 94% intact after a single dose. The safety in the clinic as of this data cutoff, it largely tracked what we've seen in the preclinical models. The principal grade 3+ treatment-related adverse events for anemia and neutropenia, as we expected, consistent with preclinical observations. We also saw infusion related reactions, low-grade in many patients, but low-grade and manageable and principally on the first dose. And we have observed evidence of preliminary clinical activity. We have a confirmed partial response from early dose escalation in a patient with squamous non-small cell cancer and 9 patients with stable disease. The -- so these preliminary data show that, number one, we can achieve therapeutic doses of this agent in cancer patients. And two, that CX-2029 is clinically active. Clearly, we have more work to do, but this is encouraging, and additional data will be presented at ASCO in a couple of weeks from an April 2020 data cutoff. So in terms of what to expect at ASCO from the April cutoff, we will have additional patients at the higher end of the dose escalation range. We will describe the dose levels and the cohorts with dose escalation in some detail. Together with our understanding of dose response and the recommended Phase II dose, together with indications for Phase II expansions and how the Phase I data support these decisions. Moving now to Slide 15 and into our potentially best-in-class programs against immunotherapy targets. So starting with CTLA-4. We've been in the clinic for a while now, or BMS has been in the clinic for a while with a Probody version of ipilimumab. The objective here, of course, is to enable a potentially safer and more effective anti CTLA-4 therapy. The Probody is called BMS-986249. Preclinical data has been presented previously, Phase I dose escalation is complete. BMS has advanced into a 5-arm randomized Phase II study in frontline metastatic melanoma, and they're also evaluating, as I mentioned earlier, an additional Probody against the modified version of ipilimumab, which is in a Phase I study as well. So 2 CTLA-4 Probodies in the clinic. The ASCO presentation, the poster last night -- published last night shows that the overall data from Phase I dose escalation is consistent with the Probody mechanism of action. They've evaluated really some very high levels -- dose levels of the Probody, including, for example, showing that, at the combination of 249 and neither has a manageable safety profile. And as an example, the [ Q 8-week] dosing of effectively 20 mgs per kg of IPI Probody that shows a 9% incidence of Grade 3/4 treatment related adverse events. No new safety signals reported and a clear evidence from Phase I that this agent can be administered at higher doses than IPI. And additional details will be presented in the poster at ASCO. Moving to CX-072, we have shown previously that integrated data across this program validates the probody approach in terms of masking and circulation, anti-tumor activity, unmasking in the tumor, it shows us a lot about our platform and the -- moving to Slide 19, the update at ASCO will speak to long-term treatment and durability of CX-072 in patients treated in multiple tumor types in Phase II expansions, where we've enrolled about 15 patients in multiple tumor types, and we look forward to providing the full update at ASCO. And I want to spend the last couple of minutes now talking about another exciting application of our technology, which is targeting undruggable targets with T cell bispecifics, which is, we think, a very exciting future application of our technology and that we're exploring internally and in 2 partnerships. We have a partnership with Amgen described on Slide 21. We recently announced the advancement of CX-904, which is an EGFR CD3 binding bispecific in Probody form designed to open a therapeutic window for EGFR, against -- in this particular format. This format has the potential to turn immunologically cold tumors into hot tumors, and we're excited to now be moving CX-904 into IND-enabling studies with Amgen, an important milestone. The first Probody T cell bispecific to move towards the clinic. Also on this technology, Slide 22, we announced recently a major new collaboration with Astellas in the T cell bispecific therapeutic space. We received $80 million in upfront -- and upfront payments. This is an alliance that will target initially up to 4 tumor antigens again, with CD3 bispecifics. And it really builds on a number of years of very exciting basic research that we've done here at the company in showing how Probody technology can open a therapeutic window for this particular format, and we are very excited to have Astellas as our new partner, our newest partner. Turning now just to wrap up on the pipeline. Slide 23. So again, broad-based progress across our pipeline, multiple assets moving from Phase I to Phase II comprehensive updates at ASCO, an integrated update that we will cover in our conference call on May 29. We also have a second wave of programs now moving towards the clinic, the CX-904 program, an EpCAM Probody drug conjugate, which we recently reacquired full rights from Immunogen and a number of other preclinical programs in T cell bispecifics, both ourselves with Astellas and with Amgen. And so again, very strong progress. The company is well financed to advance its pipeline. Wrapping up on Slide 24, really a significant number of key achievements from the company this year, a number of key milestones achieved. Our partnerships are moving forward very well. Milestones in BMS, AbbVie and new alliance with Astellas, a milestone with Amgen, significant additions to our team with the addition of Carlos as our CFO; Amy as our Chief Development Officer; Alison Hannah is our Chief Medical Officer; and in terms of future milestones, of course, we're coming up on important updates at ASCO on May 29. And future readouts from the pipeline will include a readout from the breast cancer Phase II expansion cohort for CX-2009, and hormone receptor positive HER2-negative breast cancer, the initiation of the Phase II study for the combination of 2009 with CX-072. The readout from the CX-2029 Phase II expansions. Also from the randomized Phase II study that BMS is running for the ipilimumab Probody in frontline melanoma and the advancement of CX-904, the EGFR CD3 program into Phase I. So thank you all for your time today. I hope you agree, we've made terrific progress in recent months at the company. We look forward to seeing you all virtually at ASCO in a couple of weeks. We also hope you are all keeping safe and well under the present circumstances. So thank you very much for your time today.

Great. Thanks, Sean, for your time today. It seems like an exciting time for the company, and we look forward to all the updates that you outlined. With that, operator, we can close the call. Thanks everyone.

Hey, thank you very much, everybody. Bye-bye.

Goodbye.