Turning Point Therapeutics Inc (TPTX) 2021 Q1 法說會逐字稿

Thank you all for standing by, and welcome to the Turning Point Therapeutics First Quarter 2021 Conference Call. All lines have been placed in listening only mode until the question-and-answer session of today's conference. (Operator Instructions)

I'll now hand the call over to your host Jim Mazzola. Sir, you may begin.

Okay. Thank you, Jesse, and good afternoon, everyone. Following the market close today, we filed our Form 10-Q, issued an 8-K and issued a news release with a summary of our results for the first quarter of 2021. We also updated our investor presentation, and you may find these documents posted on the investor pages of tptherapeutics.com. Leading our call today will be Turning Point's President and Chief Executive Officer, Dr. Athena Countouriotis, who will provide an overview and update of our business results as well as a review of our financials. We will take questions following our prepared remarks and will be joined by Dr. Mohammad Hirmand, our Chief Medical Officer.

Mohammad is in a separate location for today's call, so please bear with us as we manage your questions across both sites. Before Athena begins, I want to remind you that during this conference call, we will be making forward-looking statements. The company's actual results may differ materially from those expressed in or indicated by such forward-looking statements. For a description of risk factors associated with investing in Turning Point Therapeutics, please refer to our recent filings with the Securities and Exchange Commission. Now let me turn the update over to Athena.

Thank you, Jim, and good afternoon to everyone joining us on today's call. For anyone new to our story, just 2 years ago, turning point had approximately 50 employees, had just completed our initial public offering and had one clinical-stage asset and one ongoing Phase I study. Now 2 years later, we have approximately 170 employees. We are advancing 4 clinical-stage assets with our lead asset repotrectinib with 5 regulatory designations, including brachytherapy designation. And this year, we plan to start our sixth and seventh clinical study of our drug candidates. I am so proud of the tremendous progress our growing team has continued to make as we work to accomplish the many important milestones we have outlined for 2021.

Overall, we continue to advance our 4 clinical-stage next-generation tyrosine kinase inhibitors that target genetic drivers of cancer. In addition, we are investing in a discovery engine with the goal of establishing a pipeline for long-term growth. The progress and investments we have made are all directed towards advancing our vision to be the leader in precision oncology. I will start with our lead program, repotrectinib, which is a next generation, ROS1 and TRK TKI, with greater than 90 folds higher preclinical potency than crizotinib and greater than 50 folds higher preclinical potency than entrectinib against wild-type ROS1. Repotrectinib is currently being studied in our ongoing registrational Phase II portion of TRIDENT-1 in patients with ROS1 positive advanced non-small cell lung cancer and NTRK+ advanced solid tumors.

We recently completed a Type B meeting with the FDA based on repotrectinib being granted breakthrough therapy designation for the treatment of patients with ROS1+ TKI naive metastatic non-small cell lung cancer. The purpose of the meeting was to discuss potential next steps as it relates to clinical, manufacturing and companion diagnostic development of repotrectinib, with a focus on the TKI-naive ROS1 positive patient cohort within the TRIDENT-1 study. The overall feedback from the meeting was generally supportive. Based on the FDA feedback, we now plan to discuss the top line blinded independent center review results with the FDA when responders have been followed for at least 6 months past onset of response. This is new guidance, and we believe it to be positive.

We plan to provide further guidance on the registration path for the ROS1+ TKI naive patient population upon completion of the next FDA meeting, which we anticipate having during the first quarter of 2022. Turning now to enrollment in the TRIDENT-1 study. We continue to enroll across all patient cohorts and anticipate reaching our target of 50 patients with TKI-naive ROS1+ non-small cell lung cancer pulled from the Phase I and Phase II portions of the study this quarter. It remains our goal to provide an enrollment and clinical data update from the Phase II portion of TRIDENT-1 in the second half of the year. Repotrectinib is also being studied in the Phase I/II CARE study in pediatric and young adult patients with advanced solid tumors harboring ALK, ROS1 or entrect alterations. We continue to enroll patients in this trial, which is one of our 5 ongoing clinical studies.

We are now planning to share initial data from this study in the second half of this year. In addition to our development of repotrectinib in the TRIDENT-1 and the Phase I/II CARE study, we are pleased to have within the past months, achieved both our third and fourth IND clearance within the past 2 years. And as it relates to our first company-sponsored combination study, our team continues to make progress towards the planned initiation of the first cohort of our multi-arm TRIDENT-2 combination study in mid-2021. This planned Phase Ib/II study in KRAS mutant solid tumors is based on repotrectinib's preclinical inhibition of JAK2 SRC and FAK, which is believed to suppress STAT3 and AKT signaling, known mechanisms of oncogenic resistance.

At AACR, we showed preclinical data of repotrectinib in combination with approved MEK inhibitor, trametinib, which was more effective than single agent treatment in patient-derived KRAS mutant G12D/V lung and G12D/V/R pancreatic cancer models. As we previously announced, the first cohort of the TRIDENT-2 study will examine the safety, tolerability, pharmacokinetics and any early signals of efficacy of repotrectinib in combination with trametinib in patients with KRAS mutant G12D advanced solid tumors. Next in our pipeline is TPX-0022, our MET, SRC and CSF1R inhibitor currently being studied in our ongoing Phase I SHIELD-1 study in patients with advanced solid tumors harboring genetic alterations in MET. MET-driven cancers represent a heterogeneous population across multiple tumor types, as was reflected in our early clinical data update last October.

While there are now 2 approved therapies for MET exon 14 skipping non-small cell lung cancer, we continue to believe we have the potential to expand the development of O22, including MET amplified non-small cell lung cancer, both as a single agent and in combinations, as well as in GI tumors. Additionally, we believe there is room for improvement in the exon 14 space, given the limited duration of response and safety profile of the 2 approved agents. As a reminder, our preliminary data update last year showed objective responses across several tumor types with a generally well-tolerated safety profile in a heavily pretreated patient population. The Phase I study continues to enroll patients, and we are on track with our goal to identify the recommended Phase II dose this quarter.

Once selected, we plan to proceed directly into the Phase I dose expansion in multiple patient cohorts. We anticipate sharing an additional clinical data update from the Phase I dose-finding portion of SHIELD-1 in the second half of this year. We have multiple updates anticipated in the second half of this year for O22, including a potential discussion with the FDA regarding our plans to modify the Shield one study into a registrational Phase I/II design. Initiation of the Phase II portion of the study pending FDA feedback; and finally, initiation of our combination study with an EGFR targeted therapy. Next in our pipeline is TPX-0046, our RET inhibitor, currently being studied in our ongoing Phase I/II SWORD-1 study in patients with advanced solid tumors determined to be RET fusion or mutation positive.

O46 is a compact TKI with preclinical potency against wild-type RET and multiple RET mutations. As a reminder, there are currently no approved targeted therapies for patients who have been treated with a prior selective RET-TKI. We believe this represents an unmet medical need and opportunity for O46 in addition to potential safety differentiation. We recently presented early clinical data for O46 and are encouraged by the emerging profile. TPX-0046 was generally well tolerated with preliminary data showing clinical activity in a heavily pretreated patient population. The Phase I dose-finding portion of SWORD-1 continues to enroll patients, and we continue to evaluate multiple doses and schedules to further characterize the pharmacokinetics, safety and efficacy profile of O46 before determining the recommended Phase II dose.

We have modified the Phase I protocol to include multiple dose expansion cohorts in both TKI-naive and less heavily pretreated TKI-pretreated patients. Next in our pipeline is TPX-0131, our ALK inhibitor, currently in the Phase I portion of the FORGE-1 study in patients with TKI-pretreated ALK+ non-small cell lung cancer. At AACR, we presented preclinical data demonstrating the potential for O131 to cross the blood-brain barrier. Additionally, we showed O131 has [sub animal or] potency against wild-type ALK and is more potent in comparison to approved ALK inhibitors against many clinically observed resistant mutations.

While there are several ALK inhibitors currently approved, we believe O131 could have great potential, initially in TKI-pretreated patients who often develop single or compound ALK mutations. LORBRENA or lorlatinib is the current standard of care in this setting. But given its limited potency against many resistant mutations and its known safety profile, we believe there is an opportunity for O131 to potentially differentiate based on efficacy and/or safety. Lastly, I want to highlight our growing discovery team. This is a core area of focus for us. And as a reminder, in the second half of this year, we plan to outline our research strategy, including our anticipated timeline to new drug candidates.

We are making progress in our programs and look forward to sharing more detail later this year. Now let me turn to our financial results. You will see in our press release and financial tables that we generated $25.2 million in revenue during the quarter, primarily related to the upfront payment from Zai Lab under our licensing agreement for O22 in Greater China. Operating expenses for the first quarter totaled $61.3 million compared to $62.6 million in the first quarter of 2020. Excluding a one-time noncash stock-based compensation charge in the first quarter of 2020, non-GAAP operating expenses increased by $30 million, driven by an $18.5 million increase in R&D expenses and an $11.5 million increase in G&A expenses.

Increased expenses were attributable to the investments we made to develop our current pipeline as well as in earlier stage discovery and personnel. We continue to expect expenses will increase during the year as we execute across now 5 clinical trials, initiate 2 additional new clinical trials and make investments in our discovery efforts. Net cash used during the quarter totaled $15.7 million, with the revenue we generated from the Zai Lab agreement partially offsetting cash used. Cash, cash equivalents and marketable securities at March 31 totaled approximately $1.1 billion. We continue to project our current cash funds current operations into 2024.

To close, I will summarize our goals for the rest of the year beginning this quarter with a key anticipated milestone of reaching our target enrollment of 50 patients with TKI-naive ROS1+ non-small cell lung cancer pools in the Phase I and Phase II portions of the TRIDENT-1 study. Moving on to midyear, we expect to initiate the first cohort of our TRIDENT-2 combination study. And in the second half, we anticipate providing 3 clinical data updates, including from the ongoing TRIDENT-1 and SHIELD-1 studies and initial data from the ongoing Phase I/II pediatric CARE study.

Additionally, we anticipate providing an enrollment update from the TRIDENT-1 study, initiating the Phase II portion of the SHIELD-1 study pending FDA feedback and initiating the SHIELD-2 combination study. Last, we also plan on outlining our research strategy, including our anticipated timeline to development candidates. With that update, we are now ready to take your questions. Before we do, I want to close by thanking our great and growing Turning Point team for all they have accomplished so far this year. Operator, you may now open the line for questions.

(Operator Instructions) Our first question is from the line of Michael Schmidt of Guggenheim Securities.

This is Charles Zhu on for Michael Schmidt. Congrats on the quarter, especially with the feedback from the FDA. But regarding that meeting and the potential registration path forward for repo and ROS1 on lung cancer, correct me if I'm wrong, this actually sounds very similar to the old guidance from the early pre-ROZLYTREK days, which is great. I am wondering, however, how we should think about the potential efficacy benchmarks given ROZLYTREK's recent updates? And in what types of scenarios might the FDA request something like a 12-month follow-up or perhaps a randomized study?

Yes, sure. First of all, Charles, thanks for the questions and the comment. So let me start with we agree with you, and thank you for the congratulations comment. We do believe that feedback is positive. That said, the feedback was specifically that we should come back and request a meeting to discuss the top line data based on blinded independent central review. As you know, we've not unblinded that data yet, specifically for the cohort 1 patient population with a minimum of 6-month of follow-up since the last response.

Now just to your point about previous guidance, this is new guidance. Going back to our previous guidance to our end of Phase I meeting at the end of 2018, the prior guidance from the FDA, which was used as the guidance for the ROZLYTREK approval was a minimum of 12 months of follow-up to support standard approval. So again, this is new guidance. We are pleased with feedback. But again, this will be data dependent for a meeting that we're currently anticipating will be in Q1 of next year.

Got it. Makes sense and very helpful. I was also kind of wondering if you could help us level set expectations for the TPX-0022 update later this year relative to what was presented last year at the triple. And I guess as a related follow-up, given the diversity of MET alterations and potential ranges of copy number amplification, if you could provide some of your thoughts around potentially refining this population in expansion cohorts going forward?

Sure. So, as I said during the prepared remarks, we have 3 clinical trial updates we will give in the second half of the year. You're alluding to one from the SHIELD-1 study, which is our MET program. That study still remains in the dose-finding portion. If you remember, when we presented in the plenary session last fall, we had data at multiple cohorts, 40 milligrams, 80 milligrams and 120 milligrams. We have subsequently also done additional titration cohorts going from lower doses to higher doses or QD to BID dosing. So that information is what we're currently collecting. We anticipate that the update in the second half of the year will be coming from this dose-finding portion.

We don't have an estimate yet on the number of patients. We've not done a data set cut for this analysis yet. But that said, it will be a heterogeneous population to the point that you made. This will still be advanced solid tumor patients with MET alterations. And we have not refined down the gene copy number for MET amplification yet to your point. It is something we may consider in the future as we move into dose expansion, but we haven't done that yet during the dose-finding portion.

Next question is from the line of Paul Choi of Goldman Sachs.

Maybe just starting with a follow-up on the MET question. Have you provided any more or gotten any more clarity on how you're thinking about which EGFR combination you'll focus on and which tumor types? And just as you kick off the Phase Ib portion of SHIELD-2 there, just what and how you'll communicate to the market on that?

Yes, happy to. We have discussed that it would be focusing within non-small cell lung cancer likely. The EGFR combination partner, though we have not yet discussed. And so that could be either an approved agent or utilizing an investigational agent through a collaboration. So that's the additional guidance we haven't provided, but remaining on track to initiate that trial in the second half of the year.

Okay. And then maybe circling back to TRIDENT-1 ahead of your planned FDA discussion early next year. Just with regard to sort of completion and telegraphing to the market, just the results from that frontline cohort. Any specific medical meetings that might provide a forum for that? Or just how are you thinking about that?

Yes. I mean, so as I said to Charles a moment ago, we're pleased with the FDA feedback. Of course, we're remaining on track to complete this cohort this quarter. And then per the FDA feedback, in addition to where we are with enrollment completion, we're looking at the first quarter of next year for the timing for that meeting. It would likely be our standard practice to discuss the results with the FDA first and then to submit the data set to a future medical forum. We have not yet determined which forum that would be, though, but obviously in 2022.

Next question is from the line of Matt Biegler of Oppenheimer.

Congrats on the regulatory update. It seems like duration of follow-up is still somewhat of a wildcard here, but have you gotten any sense from your recent Type B about the size of the safety database that the FDA would want to consider for approval?

Yes. I mean, first of all, interesting in that the way the duration of follow-up conversation has gone with the agency historically, if you go back, of course, they discussed with us a minimum of 12 months of follow-up to support approval. And then that was the precedent that was used for ROZLYTREK. As you know, this is a unique asset in the sense that it received breakthrough therapy designation in an indication where there are already 2 approved agents. And so with that, that led to this Type B meeting, and we're encouraged by the fact that the agency wants to review the data set with us with less follow-up.

So what I can't say yet is will that data set support registration. That, of course, will be data dependent, and we've never looked at the blinded independent central review data from the Phase II, but it is encouraging that the agency is willing to discuss with us less follow-up than the prior guidance. So with that said, I mean, that's kind of the first way I would address it. From a safety database perspective, we have general benchmarks from Mohammad's history of taking drugs to market, from my history of taking drugs to market, from our ongoing conversations with the agency.

And the way we built the TRIDENT-1 study, of course, supporting safety, not only just from the Phase II, but also the Phase I. We believe that we'll have a sufficient number of patients to support a safety profile. Now the specific numbers as to how many patients would be needed, that would be discussed during the review.

That makes sense. And maybe I can just follow up with a quick one on labeling and timelines. I appreciate the focus is obviously on ROS1, but any guidance or when you might be in a position to guide on when you might be able to discuss like label expansion opportunities for the entrect tumors?

So as you know, we have 2 cohorts within the TRIDENT-1 study now, right? So the naive cohort as well as the pretreated cohort. We've already received fast track designation for the TRK-pretreated cohort. We are now going to share our first data from our ongoing pediatric study that is enrolling TRK patients. So there will be more information coming, not only just from the Ped study, but also we talked about that we plan on doing a clinical data update in the second half of the year as it relates to the TRIDENT-1 study. I think to your specific question, when will TRK go into the label if our first indication is based on ROS1. I can't predict that yet. Of course, that will also be data dependent and in discussion with the agency. But clearly, we've been having ongoing discussions with the agency because we've already received fast track.

Congrats guys.

Next question is from the line of Zegbeh Jallah of ROTH Capital Partners.

I have a couple of different questions here. I think the first Athena is about the Type B meeting. I think ahead of the meeting had mentioned perhaps discussing with the FDA progress with your companion diagnostics. I was just wondering if you had any updates on that? And then how that's factoring into your timeline?

Yes. Thank you. And it's interesting, Zegbeh, I just realized you probably have more difficulty with pronunciation of your name than I do, and I obviously always have issues. So I feel for you there. The feedback, first let me go back to the conversations we've had with the agency over the last few years. And we had previously disclosed that we submitted for an investigational device exemption with CDRH, and that was cleared, and that's kind of a standard first step as it relates to companion diagnostic development.

We have already identified our partner for companion diagnostic development and we've been using our clinical trial assay in the study for prospective testing. So we've been doing quite a bit of work as it relates to the companion diagnostic. The discussion with the agency was really just in line with where we are today and what we need to do to support potential labeling in the future. And so that's what I would share as of now. But again, we've had ongoing discussion with the agency and particularly the CDRH group.

And then for the TRIDENT-2 study, I was just wondering if you're going to be [reaching] for specific tumor types? And are you planning to pursue some kind of (inaudible) as you're thinking about designing the study?

The TRIDENT-2 study. So where we're starting right now is obviously with trametinib in G12D advanced solid tumors. And we've said that this is a multi-cohort or a multi-arm trial. So there may be other KRAS-driven indications or obviously others outside of G12D. You know we've already done data with AMG510. And so whether we would add a G12C arm in the future is something that we just haven't disclosed yet. But for right now, the focus is on initiating the trial. We're very happy that the IND cleared in combination so far with trametinib.

And then just the last one here regarding the pediatric CARE study. As you're thinking about our model updates, just want to know, in terms of patient identification, is it similar to (inaudible) ? Are there any nuances that we should take into account?

So the one thing I would say about the pediatric trial, remembering that this is still a relatively rare indication. But unfortunately, for many children that are diagnosed, either with entrect-driven tumors, ALK-driven tumors or even very rare ROS1 fibrosarcoma, we have had a heterogeneous group that has enrolled. And so we're encouraged to share the first initial data from that study, and that's all we're ready to say today, but that will come in the second half of the year.

Next question is from the line of Silvan Tuerkcan of JMP Securities.

Congrats on all the progress and the Type B meeting. I have a question, maybe a big picture about your KRAS and specifically KRAS G12D strategy in the face of that has some preclinical KRAS G12D inhibitors. How can we think about the data that we may get? And what could be the strategy going forward? Were you then maybe switch partnering with those specific inhibitors? Or would there always be a MET inhibitor or triplets? Or how would that look like?

At this point, given the IND just cleared and we're looking forward to initiation of the trial, I think it's a little early to say where we'd be going in the future. If we stay on the doublet, stay within that inhibitor or go to a triple TKI regimen. But I will say that our preclinical data that we've shown consistently over the last 1.5 years at multiple medical conferences, supports the rationale based on a synergistic effect to combine the 2 agents. And so that's where we're going to start. The strongest depth of the data set is in G12D. And so that is where we're focusing first. And then again, as we add more arms, hopefully, to this trial, you'll see where we're additionally going to go with potentially other doublets.

Great. And with respect to the MET inhibition, TPX-0022, there will be a Phase II dose, if I understood correctly, in the second quarter, will you communicate that? Or will we find out in your data update in the second half of the year?

We've talked about that. I mean we're evaluating, obviously, knowing that we want to define the dose this quarter. So we're evaluating where we are with pharmacokinetics as well as ongoing safety. And this is an area where Mohammad's team is incredibly focused. The likely scenario is we'll move right into dose expansion cohorts, as we've outlined in the prepared remarks, and then to potentially discuss our recommended Phase II dose on our next quarterly call.

Last question is from the line of Arlinda Lee of Canaccord.

Congrats on the regulatory discussions. I have a couple of questions. One, on the TRIDENT-2 combination, you just announced that IND has been cleared for the first combination. Can you talk about what constitutes an interesting combination for you for additional combinations? And how many of these might you undertake?

Well so, first of all, thank you, Arlinda, for the comments about the regulatory discussions. As it relates to TRIDENT-2, at this point, we're focused on initiating the trial with trametinib. That's the design that went to the agency to support IND clearance. Future cohorts, again, without saying too much, as you've seen, we've shown data with 2 MEK inhibitors, both trametinib as well as Verastem-6766 agent. And then we've also showed data with AMG510. We have publicly said that we've also compiled more data with other G12C inhibitors.

I will say this is one of the strengths of Siegfried and his entire group that has been growing tremendously on the translational front as well as cancer biology front, really looking at the science to dictate where we should go in these combinations. And so to some extent, I would just say how we are going to determine where we go next, we'll absolutely be based on the preclinical data. And at this point, Arlinda, that's probably all I'll say until we start moving the trial towards patient dosing and then adding additional cohorts.

Thanks, operator. Are there any other questions?

No further questions.

Okay. Well, first of all, thank you, again, for everybody who's dialed in today for your interest and support of our team and for Turning Point Therapeutics as a whole. I hope you and your families continue to stay well. And operator, you may now close the call. Thank you very much.

And that concludes today's conference. Thank you all for participating. You may now disconnect.