Oncternal Therapeutics Inc (ONCT) 2022 Q2 法說會逐字稿

Greetings. Welcome to the Oncternal Therapeutics, Inc. Second Quarter 2022 Financial Results Call. (Operator Instructions) Please note that this conference is being recorded. I will now turn the conference over to your host, Rich Vincent, CFO. You may begin.

Thank you, Kyle. Good afternoon, everyone, and thank you for joining us today. Joining me on the call this afternoon are our President and CEO, Dr. James Breitmeyer; and our CMO, Dr. Salim Yazji.

Today's call includes a business update and discussion of our 2022 second quarter financial results, which will be followed by Q&A. Today's press release and a replay of today's call will be available on the Investor Relations section of Oncternal's website for at least the next 30 days. Our 10-Q for the second quarter of 2022 is also available today.

Please note that certain information discussed on today's call is covered under the safe harbor provisions of the Private Securities Litigation Reform Act. We will be making forward-looking statements during this call about future events such as our business and product development strategies; the timing of initiation of our preclinical and clinical studies; the potential for our ZILO-301 study to support a BLA submission, the timing of planned interim data updates and the timing of our regulatory filings and submissions, including our IND submission for ONCT-808.

Our actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with our business. These forward-looking statements should be considered in conjunction with and are qualified by the cautionary statements contained in today's press release and our SEC filings, including our Form 10-K for the full year ended December 31, 2021.

This call contains time-sensitive information that is accurate only as of the date of this live broadcast, August 9, 2022. We undertake no obligation to revise or update any forward-looking statements to reflect events or circumstances occurring after the date of this call.

With that, it is my pleasure to hand the call over to our CEO, Dr. Jim Breitmeyer.

Thank you, Rich, and good afternoon, everyone. At Oncternal, we are advancing a focused and robust product pipeline with clinical and preclinical product candidates that target cancers for patients with unmet medical needs. During the second quarter of 2022, we made significant progress across our entire pipeline, including an encouraging data update at ASCO from a Phase I/II study of zilovertamab plus ibrutinib in patients with MCL and CLL which set..

Richard, it looks like Dr. Breitmeyer disconnected.

(technical difficulty)

Okay. Could you try him back?

Yes. One moment.

Thank you.

I apologize, everybody. We've been experiencing technical problems on our home phone. So I was saying that we were especially encouraged by our interim data from patients with p53-mutated CLL that we presented at ASCO. This is a challenging population to treat with current standard of care BTK inhibitor monotherapy and the combination of zilovertamab plus ibrutinib showed very robust progression-free survival.

Also in support of our upcoming Phase III studies, ZILO-301, we entered into a clinical trial collaboration and supply agreement with Pharmacyclics and AbbVie company for their gracious donation of ibrutinib to support our global registrational program. This is an important milestone, which further validates the clinical value testing ibrutinib with zilovertamab.

Next, ONCT-808, our autologous CAR-T therapy product candidate targeting ROR1, also continued to advance and is on track for an IND filing this month. We are enjoying strong collaborations with our partners, which include the Dana-Farber Cancer Institute's cell manipulation core facility, along with Lentigen and Miltenyi Biotec.

On the allogeneic or off-the-shelf front, our research collaborations with Celularity and the Karolinska Institutet continue to generate encouraging data for our next-generation ROR1-based cell therapies.

Finally, ONCT-534, our lead candidate for the dual action androgen receptor inhibitor or DAARI program continued to advance toward an IND filing, and we expect to have pre-IND interactions with the FDA in the fourth quarter of this year. We are optimistic that ONCT-534 may be a differentiated and novel treatment alternative for patients with advanced prostate cancer as we believe it interacts with both the N-terminal and the ligand-binding domains of the androgen receptor, inhibiting a function and inducing its degradation.

Preclinical data have shown that ONCT-534 exerts antitumor activity in clinically relevant treatment-resistant prostate cancer models, including those with AR amplification, enzalutamide-resistant or expressing androgen receptor splice variants such as AR-V7, all of which represent significant medical unmet needs for patients with prostate cancer. This broad advancement of our pipeline has occurred against the backdrop of a focused exigent vigilant resource cash management approach.

Now let me turn the call over to Oncternal's CMO, Salim Yazji, to discuss our zilovertamab clinical data and Phase III plans in more detail.

Thank you, Jim. Good afternoon. As Jim mentioned, we recently presented very encouraging data from our ongoing Phase I/II clinical trial of zilovertamab in combination with ibrutinib at the ASCO meeting in June. An overall response rate of 85% and a CR rate of 41% for patients with MCL treated with zilovertamab plus ibrutinib, which compares favorably to the historical overall response rate of 66% and a CR rate of 20% for ibrutinib monotherapy. Median PFS of 35.9 months for MCL patients with a mid-term follow-up of 15.1 months, which is also compared favorably to the historical PFS of 12.8 months for ibrutinib monotherapy. For patients with p53 mutation, the median PFS was 17.3 months, which is compared again favorably to historical ibrutinib median PFS of 4 months.

In patients with p53-mutated CLL, the landmark PFS of zilovertamab plus ibrutinib was 100% at 24 months and 100% at 30 months, which compares favorably to the historical ibrutinib monotherapy landmark PFS of around 68% and around 55% at 24 months and 30 months, respectively. As you may know, mutation in or loss of p53 protein is a well-known negative prognostic factor in many types of cancer, causing genomic instability and loss of tumor suppression.

The combination of zilovertamab continued to be well tolerated with the safety profile consistent with or slightly improved compared to historical data for ibrutinib monotherapy. For example, in patients with MCL, Grade 3 and 4 neutrophil decrease was documented in only 9.1% of the patients with the zilovertamab plus ibrutinib compared to 29% for ibrutinib alone from its registrational study.

In terms of upcoming Phase III study ZILO-301, we are on track to initiate the study later this quarter as we are currently completing key ramp-up activities, including site selection and IRB submissions. As a reminder, ZILO-301 will identify patients with relapsed refractory MCL who have only had stable disease or reached a partial response after receiving 4 months of ibrutinib monotherapy and will randomize them to receive either blinded zilovertamab or placebo plus ibrutinib.

This study may provide 2 potential approvals. First, an escalated approval based on overall response rate, ORR, plus duration of response, DOR. And second, a regular FDA approval based on progression-free survival of PFS, which is the primary endpoint. Additionally, we are planning to conduct ZILO-302, an open-label companion study of zilovertamab plus ibrutinib for patients who have progressive disease during the ibrutinib monotherapy run-in phase of the study of ZILO-301. And results of this study could potentially support an additional approval and indication expansion.

Regarding ONCT-808, the lead candidate for our autologous ROR1 targeting CAR-T program, we are on track to submit our IND later this month. In our initial Phase I study, we plan to enroll patients with relapsed refractory aggressive lymphomas, including patients who have failed CD19 CAR-T cell therapy.

I will turn the call over to our CFO, Rich Vincent, to review our financial results and upcoming milestones.

Thank you, Salim. Our revenue is derived from a California Institute for Regenerative Medicine, or CIRM, grant subaward and 2 research and development grants from the National Institute of Health or NIH. In October 2017, CIRM awarded an $18.3 million grant to researchers at the UC San Diego School of Medicine to advance our Phase I/II study, CIRM-0001. We have conducted a study in collaboration with UC San Diego and expect to receive $14.6 million in development milestones under research subawards throughout the award period, which was substantially completed from a revenue perspective in the first quarter of 2022.

In the third quarter of 2021, the NIH awarded the company 2 research and development grants for up to $2.2 million to support preclinical activities for the company's ONCT-534 and ONCT-216 programs. Our grant revenue for the second quarter ended June 30, 2022, was $0.2 million. Our total operating expenses for the second quarter ended June 30, 2022, was $12 million, including $1.7 million in noncash stock-based compensation expense. Research and development expenses totaled $8.8 million and general and administrative expenses totaled $3.2 million. Net loss for the second quarter was $11.7 million or a loss of $0.23 per share basic and diluted.

Cash flows from financing activities include our first use of the at-the-market program with Jefferies LLC as our sales agent. Through June 30, 2022, the company sold 2.7 million shares of common stock for net proceeds of $3.9 million. As of June 30, 2022, we had $78.9 million in cash and cash equivalents and no debt. We believe these funds will be sufficient to support our planned operating activities into the first half of 2024. We have and will continue to manage our cash and all other resources deliberately.

As of June 30, 2022, we had 52.2 million shares of common stock outstanding. To summarize our upcoming milestones for our zilovertamab program, we expect to initiate the global registrational Phase III study, ZILO-301, in September 2022 and provide an interim clinical data update from our Phase I/II study of zilovertamab plus ibrutinib in patients with MCL and CLL in the fourth quarter of 2022. For ONCT-808, our lead autologous ROR1 CAR-T cell therapy candidate, we plan to submit our first IND in August 2022. For ONCT-534, our lead DAARI product candidate, we expect to have pre-IND interactions with the U.S. FDA in the fourth quarter of 2022.

With that, I will turn the call back over to Jim.

Thank you, Rich. Oncternal has performed well in this historically challenging macro environment. We plan to continue to use our capital and resources efficiently as we advance our focused pipeline towards significant value inflection points that we believe will make a difference for patients suffering from hematologic malignancies and prostate cancer. We look forward to events later this quarter, especially the planned initiation of our global Phase III zilovertamab study and also submitting our ROR1 CAR-T IND application as well as advancing our DAARI program toward the clinic.

Thank you for joining us today, and we look forward to updating you over the year and at conferences. With that, I will turn things back to Kyle for the Q&A portion of this afternoon's call.

(Operator Instructions) Our first question is from Hartaj Singh with Oppenheimer.

Great. Thanks, everyone, for the update and the question. One is it's great to see all the programs moving ahead. Just on the interim update, Jim and team, looking at the p53-mutated CLL patients, you saw some pretty -- I would maybe even call it eye-opening data with the PFS at 36 months of 100%. I mean what are your thoughts on CLL? What are the sort of discussions you could have with regulatory authorities on that? Is it intriguing enough that you could run a trial just there on those p53-mutated patients? Are they easy to find in the clinical trial, put on clinical trials? Just any thought there.

And then secondly, can you just dig a little bit more into what your Phase I/II will look like with the ROR1, 808, the CAR-T? Is it a basket trial focused on patients with CD19, et cetera? If you can just kind of dig into that a little bit more.

Sure, Hartaj. And thank you for the good questions. And so I'll answer the first one. Salim can handle the second one. So we do believe that the very pleasantly surprising strong PFS results of 100% for patients with p53-mutated CLL is -- does represent an opportunity for a registration strategy. We believe that about 50% of patients with CLL carry one of these abnormalities, which can include both mutated p53 sequences, but also a deletion of the p53 gene or portions of the chromosome.

And so most patients are already tight for that. It's known to be a challenging characteristic for BTK inhibitor treatment. And so we think that it would be -- we think there is a potential there for an additional registration strategy. We are headed back to the bench to try to figure out what is going on between ROR1 and p53. We know there's got to be some interesting science there. So we hope to learn more about that in the near future.

And so that's your first question. And we'll let Salim talk about the Phase I study for 808 or CAR-T.

Yes. Thanks, Jim. Yes, Hartaj, I mean what we're trying to do here is to have an aggressive lymphoma in our dose escalation phase, which is specifically is going to be diffuse large B-cell lymphoma and MCL. Once we reach our recommended Phase II dose, we're going to expand in those 2 indications, and we may go into -- possibly into additional hematological indication.

Great. And just a quick follow-up. Jim, can you just put any kind of idea on the timing? You go back to bench, understand the science behind what's going on with the p53 abnormalities. And then when would you kind of go and talk to regulators? I mean is this sort of a 2023 event, maybe 2024? Just any thoughts there?

And Salim, just in terms of just the patients you're talking about, are there any limitations just from manufacturing the sites that you choose for the ROR1 CAR-T study?

So I think I can get both of those, Hartaj. And so we're -- first, you were asking about the manufacturing side of the CAR-T program. Is that right?

Yes, Jim. Yes.

Yes. Okay. And so we are -- we've got -- we're having a delightful collaboration with the cell processing facility at the Dana Farber, actually some -- involving some people who I've known for decades. And they've got -- they have a vast amount of experience with the prodigy cell processing system that we're using that we think is going to be groundbreaking in the cell therapy field with a really different manufacturing model.

And so we're working out all the logistics right now, but we think it's going to be pretty straightforward to get the patient cells to Boston. And then their CAR-T product is frozen and can be transported back for infusion with -- in both ends of the supply chain are pretty straightforward.

And then I think timing-wise, we're -- as you know, we are being very careful with our cash reserves right now. And so the -- we won't be opening a CLL study this year certainly or probably not next year, but we're hoping to have some science to talk about really as soon as we can generate it. I will say that a new indication that could be game-changing for 50% of CLL patients is something that some strategic pharmaceutical companies are interested in.

Next question is from Carl Byrnes with Northland Capital Markets.

Congratulations on all your progress. My questions on p53 mutation were answered, so I'll move on to a couple of others. I'm wondering if you have any visibility into the time line of data from the Phase Ib investigator-sponsored trial at UCSD in prostate cancer. And then also considering the IND submission in August for 808, would you expect the time line for first dose patient to be in the September-ish area?

So for the -- I'll start on the -- in the investigator-sponsored study, we really don't have any control over the rate of enrollment or availability of data. So I can't -- we know as much as you do, Carl, and usually know more than we do. But I'll let Salim comment on the second question.

Yes, Carl, can you please report -- repeat your second question, please?

Yes. This is with respect to 808. Considering the IND is going to be filed in August, would it be safe to assume or would your expectation be the first patient dose would be in the September time frame or whatever time frame you would expect?

Well, I mean as you know, we're going to submit the IND end of August, and it will probably be 30 days hold-on period from the FDA. So before we get the green light, there's no questions from the FDA that's probably going to put us until end of September, beginning of October.

And I think with regard to the patients, I mean once we get the IRB approval, and it may take some time, it's going to be all ready to go. But we are hoping to have our patients hopefully by -- before the end of this year.

Our next question is from Robert Burns with H.C Wainwright.

Just 2, if I may. So I know that you're going to be pursuing CD19 patients who have received prior CD19 targeted therapy for the hematology for your ROR1 targeted CAR-T. I was just curious whether you're also thinking about solid tumors given the expression of ROR1 and solid tumors express lung stomach cancer?

And then my second question, with your financial guidance for your operational run rate, does that take into account clinical trials for both 808 and your lead DAARI asset?

So I'll answer the first question, and then we'll have Rich talk to you about the cash runway. So yes, we are -- we're very interested in extending our cellular immunotherapy program into patients with solid tumors. As you know very well, the current generation of CAR-T, even though they work so very well in liquid tumors, have had a hard time overcoming the immunosuppressive microenvironment of solid tumors.

And so I think that most people in the field feel like we do, that you're going to need some additional success factor to get somewhere with the solid tumors, like checkpoint inhibition or TGF beta suppression, something -- those are the sort of things that people are looking at.

And so we're keeping our eyes open for potential add-on therapy to the CAR-T that would open up the solid tumor field. We could treat some solid tumor patients, kind of a basket trial without that technology, but we think that it would be more likely to succeed with additional tech.

And Rich, on the runway question?

Sure. So overall, our model or spend forecast does include what we've discussed today as our upcoming milestones, and it also includes the initial studies for both ONCT-808 and ONCT-534 in this time horizon.

Rich and I have always been very thrifty and we're going to stay that way.

Our next question is from Kumar Raja with Brookline Capital Markets.

Congratulations on the progress. With regard to ONCT-808, what are your expectations in terms of the starting dose? And how soon do you think you can get to the recommended Phase II dose?

Yes, Kumar, and thank you for the question. We're going to start at a dose of 1 x 10 to the sixth T cells per kilogram of ideal body weight, and that is a -- that's a starting dose that FDA already agreed we could use in pre-IND discussions. And we think then that we can get to a recommended dose with 3, maybe 4, but just a few dose levels. We think we'll be able to get there pretty quickly.

Okay. And you will have enough cells from like a single manufacturing run to do all these dose escalations?

Yes, we're getting -- with healthy donor, Leukopaks, we're getting massive numbers of CAR-T cells with very high expression levels. And so we can make -- we appear to be able to make more CAR-T cells than we're going to need.

Okay. And with regard to the clinical agreement with the Pharmacyclics supplement of ibrutinib, how much involvement will they have in the clinical trials? And what kind of expectations are built from Oncternal for this?

So it's -- we're having -- we're enjoying a really good working relationships with the Pharmacyclics and AbbVie clinical team. They have provided some very helpful advice in terms of the study design and some elements. Their experience with ibrutinib is very valuable here. And so they have -- we -- if we make changes in the protocol, we would welcome their assistance with any modifications that we make. And -- but I think to be clear, they don't have any commercial rights to the product gained from this relationship.

Okay. Finally, with regard to 534 following the pre-IND interactions with the FDA, what do you think would be the timing of IND filing for that?

So Salim, I'll take this one because of the preclinical question. There's an interesting COVID-related thing going on right now. And you may have heard this from some of the other companies that you follow, but there is a worldwide shortage of Beagle dogs for preclinical toxicology work. And it's going to take some time for -- believe it or not, for the dog supply to catch up with the demand, and that's the species that everybody uses for tox studies.

And so we're in a little bit of a holding pattern right now for the timing of finishing our tox work. We're confident that we'll have an IND next year, but we're not guiding to a date at this point.

We have reached the end of the question-and-answer session. And I will now turn the call over to CEO, Jim Breitmeyer, for closing remarks.

So thank you, everybody, for joining us today. We were pleased to pass along our significant progress and delighted to be able to interact with such good questions with those who are following the company. And so with that, thank you, and good day to everyone.

This concludes today's conference, and you may disconnect your lines at this time. Thank you for your participation.