Celcuity - Earnings Call - Q4 2024

Executive Summary

• Q4 EPS missed S&P Global consensus as OpEx accelerated into pivotal program execution; GAAP EPS was -$0.85 vs S&P “Primary EPS” consensus -$0.71 (miss $0.14), and non-GAAP EPS was -$0.75 vs S&P “EPS Normalized” consensus -$0.67 (miss $0.08). Management attributed higher spend to VIKTORIA-1, the mCRPC study, and VIKTORIA-2 start-up, with R&D up to $33.5M (+85% YoY) and total OpEx $36.4M (+85% YoY). S&P Global values marked with an asterisk; see disclaimer.
• Cash/short-term investments ended at ~$235.1M, with runway to fund current clinical development through 2026; Q4 operating cash burn rose to $27.8M from $20.6M in Q3 and $18.5M in Q4’23.
• 2025 is framed as “transformational”: VIKTORIA-1 PIK3CA wild-type topline now guided to Q2 2025 (narrowed), mutant cohort in Q4 2025; VIKTORIA-2 first patient remains Q2 2025; Phase 1b/2 mCRPC preliminary data in late Q2 2025.
• Regulatory path: management plans to request Real-Time Oncology Review (RTOR) post-WT readout and, if not granted, pursue Priority Review, aiming to compress timelines to an NDA submission within ~1–1.5 quarters after topline data.

What Went Well and What Went Wrong

• What Went Well

  • VIKTORIA-1 execution: PIK3CA wild-type cohort fully enrolled; WT topline guided for Q2 2025; mutant cohort topline Q4 2025.
  • Strategic positioning and tolerability: Company emphasized triplet blockade rationale and favorable discontinuation profile vs single-node PAM inhibitors; stomatitis prophylaxis expected to further reduce AEs in Phase 3.
  • Regulatory and launch readiness: Plan to seek RTOR and potentially Priority Review following WT topline; broad market access rationale favoring IV administration and medical benefit reimbursement category.

• What Went Wrong

  • Earnings miss driven by spend: GAAP EPS (-$0.85) and non-GAAP EPS (-$0.75) missed S&P Global consensus (-$0.71 Primary; -$0.67 Normalized), as R&D increased to $33.5M and total OpEx to $36.4M, reflecting Phase 3/Phase 1b/2 activity and VIKTORIA-2 commencement. S&P Global values marked with an asterisk; see disclaimer.
  • Cash burn inflected: Operating cash outflow rose to $27.8M in Q4 vs $20.6M in Q3 and $18.5M in Q4’23, reflecting program ramp and working capital timing.
  • Event-rate opacity: Management declined to detail event accrual status ahead of WT topline, maintaining only the quarter-level timing range, creating near-term uncertainty for traders.

Transcript

Operator (participant)

Good afternoon, ladies and gentlemen, and welcome to the Celcuity Q4 and Q4 2024 financial results webcast conference call. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. I would now like to turn the conference over to Apoorva Chaloori with ICR Healthcare. Please go ahead.

Apoorva Chaloori (Senior Associate of Life Sciences Investor Relations)

Thank you, Operator, and good afternoon to everyone on the call. Thank you for joining us to review Celcuity's Q4 and full year 2024 financial results and business update. Earlier today, Celcuity released financial results for the Q4 ending December 31st, 2024. The press release can be found on the Investor section of the website. Joining me on the call today are Brian Sullivan, Celcuity's Chief Executive Officer and Co-founder; Vicky Hahne, Chief Financial Officer; as well as Igor Gorbatchevsky, Chief Medical Officer, who will be available during Q&A. Before we begin, I would like to remind listeners that our comments today will include some forward-looking statements. These statements involve a number of risks and uncertainties, which are outlined in today's press release and in our reports and filings with the SEC. Actual events or results may differ materially from those projected in the forward-looking statements.

Such forward-looking statements and their implications involve known and unknown risks, uncertainties, and other factors that may cause actual results or performance to differ materially from those projected. On this call, we will also refer to non-GAAP financial measures. These non-GAAP measures are used by management to make strategic decisions, forecast future results, and evaluate the company's current performance. Management believes the presentation of these non-GAAP financial measures is useful for investors' understanding and assessment of the company's ongoing core operations and prospects for the future. You can find the table reconciling the non-GAAP financial measures to GAAP measures in today's press release. I would now like to turn the call over to Brian Sullivan, CEO of Celcuity. Please go ahead.

Brian Sullivan (CEO and Co-founder)

Thank you, Apoorva, and good afternoon, everyone. We appreciate your interest in Celcuity. Our team made significant progress executing our clinical development programs in 2024. We completed enrollment of the PIK3CA wild-type cohort in VIKTORIA-1, our phase III study evaluating gedatolisib plus fulvestrant with and without palbociclib as second-line treatment for patients with HR-positive, HER2-negative advanced breast cancer. We also completed selection of approximately 200 sites for VIKTORIA-2, our phase III study designed to evaluate gedatolisib in combination with fulvestrant and either ribociclib or palbociclib as first-line treatment for patients with HR-positive, HER2-negative, endocrine therapy resistant advanced breast cancer. Our phase I-B dose escalation portion of our study evaluating gedatolisib in combination with darolutamide for patients with metastatic castration-resistant prostate cancer is ongoing and remains on track to report preliminary data at the end of the second quarter of this year.

We reported overall survival data from our phase I-B study for treatment naive and CDK4/6 pretreated patients who received our phase III dosing schedule. In our view, each of these three programs has the potential to generate blockbuster levels of revenue. If these three programs ultimately result in regulatory approvals, we estimate that nearly 200,000 late-stage cancer patients globally would be eligible to be treated with gedatolisib. As a result of the progress we made in 2024, 2025 will be a transformational year for Celcuity, as we anticipate reporting several important clinical data readouts. For our VIKTORIA-1 clinical trial, we anticipate reporting top-line data for the PIK3CA wild-type cohort in the second quarter of 2025 and top-line data for the PIK3CA mutant-type cohort in the fourth quarter of 2025.

The primary endpoints for VIKTORIA-1 are progression-free survival, or PFS, per RECIST 1.1 criteria, as assessed by a blinded independent central review. The study is designed to independently evaluate a PIK3CA wild-type cohort and a PIK3CA mutant cohort. For the PIK3CA wild-type cohort, there are two primary endpoints that will be tested hierarchically, whereas the PIK3CA mutant patient cohort has a single primary endpoint. The primary analysis for each patient cohort is triggered upon reaching a predefined number of progression events. Patients we're evaluating in our VIKTORIA-1 study have HR-positive, HER2-negative advanced breast cancer whose disease progressed while on or after receiving treatment with a CDK4/6 inhibitor and an aromatase inhibitor. We recognize that the treatment landscape for these second or third-line patients is evolving, as a number of investigational therapies are under development.

Our view is that the underlying biological drivers of HR-positive, HER2-negative advanced breast cancer will ultimately determine which regimens become standard of care. Three interconnected signaling pathways, the estrogens, cyclin D1, CDK4/6, and PI3K/AKT/mTOR pathways, promote this disease. We believe that simultaneous blockade of all three of these pathways offers the best opportunity to optimize anti-tumor control. This suggests that a triplet that addresses these three disease drivers, whether in the first or second-line setting, may have a long-term advantage versus a doublet or monotherapy that addresses just one or two of these signaling pathways. Additionally, a triplet that could treat all patients, regardless of PIK3CA or ESR1 mutational status, would have an even greater advantage.

The current second-line treatment paradigm for HR-positive, HER2-negative patients with advanced breast cancer includes selective estrogen receptor degraders, or SERDs, like fulvestrant or elacestrant as single agents, or one of the three approved PAM inhibitors combined with endocrine therapy. However, each of the PAM inhibitors only targets a single PAM node, such as PI3K-alpha, AKT, or mTORC1, which is suboptimal because the uninhibited PAM nodes can induce compensatory resistance. In patients who've received prior treatment with a CDK4/6 inhibitor, none of these single-node PAM inhibitors have demonstrated efficacy in patients who have PIK3CA wild-type tumors, while only the PI3K-alpha and AKT inhibitor have reported benefit in patients with PIK3CA mutations. These results are consistent with the non-clinical data that shows these single-node inhibitors are three to four times less potent in breast cancer cells without PIK3CA mutations than in those with them.

Now, this is in sharp contrast to the non-clinical and preliminary efficacy data we've reported for gedatolisib. In non-clinical studies evaluating breast cancer and prostate cancer cell lines, gedatolisib was found to be equally potent and cytotoxic in cell lines with and without PIK3CA or PTEN mutations, and at least 300x more potent, on average, in breast cancer cells than single-node PAM inhibitors. Now, consistent with these non-clinical results, the preliminary clinical endpoints we reported in our phase I-B breast cancer study that evaluated gedatolisib combined with palbociclib and either letrozole or fulvestrant was comparable in both treatment naive and second and third-line patients with and without PIK3CA mutations.

We think these results demonstrate that along with the CDK4/6 pathways, the PAM pathway plays an intrinsic role as a disease driver in HR-positive, HER2-negative advanced breast cancer that's independent of the presence of an activating mutation like PIK3CA. That's why we believe development of an optimized PAM inhibitor like gedatolisib that targets all Class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively blockade the PAM pathway represents one of the most important opportunities to improve the standard of care in HR-positive, HER2-negative advanced breast cancer. We think that gedatolisib's tolerability may also favor its potential positioning in a future treatment landscape. Gedatolisib's treatment-related discontinuation rate due to adverse events was only 4% in the phase I-B arm of the phase III intermittent dose schedule, which is comparable to the 6%-8% discontinuation rates for CDK4/6 plus fulvestrant regimens.

While we don't have head-to-head data, these results compare favorably to the treatment-related discontinuation rates reported in the phase III studies for alpelisib plus fulvestrant, where 26% of patients discontinued, and everolimus plus exemestane, where 24% of patients discontinued. The results for gedatolisib were especially encouraging, given that the phase I-B study did not include prophylactic therapy for stomatitis, the most common treatment-related adverse event for gedatolisib. Since we're prescribing stomatitis prophylaxis in our phase III trial, we would expect fewer stomatitis-related adverse events, which would further enhance geda's already promising tolerability. Now, of course, the foundation of geda's role in this treatment landscape will require the gedatolisib to be well tolerated and report a clinically meaningful full benefit measured in terms of the incremental improvement in both median PFS and the hazard ratio relative to standard of care.

Now, breast cancer KOLs and regulators generally consider an incremental improvement in median PFS of three months relative to its control to be clinically meaningful. The current median PFS benchmarks for patients pretreated with a CDK4/6 inhibitor, the patient population we're evaluating, are modest. Published reports from recent randomized trials of median progression-free survival for fulvestrant averaged 2.7 months in patients with ESR1 wild-type tumors and 3.8 months for oral SERDs in patients with ESR1 mutant tumors. The incremental median PFS benefit for patients with ESR1 mutations treated with an oral SERD was a 1.9-month difference. For patients with PIK3CA or AKT mutations, median PFS ranges from 5.5-7 months when treated with either an AKT or PI3K-alpha inhibitor, representing approximately 3.5 months of incremental median PFS benefit.

The rapid adoption and resulting annual run rate for each of these drugs, which is approximately $500 million and $600 million, respectively, illustrates the desire physicians have to switch to new therapies, even when the incremental clinical benefit to their patients is modest. Now, a potentially more important data point than incremental PFS benefit to consider in advanced breast cancer when assessing the clinical benefit of one therapeutic regimen relative to another is the hazard ratio. Now, this is because recent randomized studies evaluating therapies for patients with HR-positive, HER2-negative advanced breast cancer have enrolled widely heterogeneous patient populations. For instance, one study that evaluated an oral SERD conducted primary analysis that included first and second-line patients. The same study evaluated the combination of the oral SERD with a CDK4/6 inhibitor that included both patients who were CDK treatment naive and those who had received prior CDK4/6 therapy.

In another study evaluating an AKT inhibitor, the primary analysis included both patients who were CDK4/6 treatment naive and those who had received prior CDK4/6 therapy. Since physicians, rather, make different treatment decisions for patients depending on, among other factors, how many lines of therapy or which type of therapy they've received, results from these studies can be hard to interpret using absolute median PFS or incremental median PFS benefit alone. As a result, the top-line median PFS results from these studies don't provide sufficient clarity about the actual benefit the particular patient population may receive. Hazard ratio essentially factors out the differences in study populations and thus provides patients, physicians, rather, with an objective benchmark. We not only hope to report a hazard ratio that is statistically significant, but one that compares favorably to the hazard ratio reported for other therapies available for these second-line patients.

An additional factor, which we think may ultimately accrue to gedatolisib's advantage, particularly in the community physician setting, is the fact that gedatolisib is an infused therapy administered in office. This perspective has been reflected in the feedback we're receiving from oncologists, both key opinion leaders and community physicians, and market access stakeholders in conjunction with our preliminary market research. Of particular note is the encouraging feedback received regarding gedatolisib's IV route of administration. Physicians can monitor and manage patient compliance more effectively than they can with oral therapies, and this is relevant, particularly for oral therapies that induce unpleasant side effects. With these therapies, patient compliance can often be a challenge. This preliminary research does suggest an IV administration will not be a barrier to utilization of gedatolisib, and in fact, may be an important advantage.

Additionally, in-office administered therapies such as gedatolisib fall into the medical benefit category, which has a more streamlined reimbursement process than orally administered drugs, which fall into the pharmacy benefit category. Our market research suggests that this fact has several implications for oncologists, patients, and our company. First, oncologists view IV-administered drugs favorably, allowing them to recover additional costs associated with treating their patients in office. Second, oncologists have more autonomy to select therapies they believe will benefit their patient. Third, the payer management process is less burdensome to navigate. Finally, patients typically incur lower out-of-pocket costs with an infused therapy, which is an important consideration for most patients. For pharmaceutical companies, payer contracting is less common and results in fewer price discounts.

In a real-world setting, patient convenience is only a meaningful consideration for IV-administered drugs when the efficacy and safety profile of the alternative drugs are comparable, or when a patient lives a significant distance from a treatment site. Otherwise, based on our market research, a well-tolerated therapy that offers a clinically meaningful benefit is preferred by oncologists relative to one that offers less efficacy but is more convenient. The fact that the most widely prescribed oncology drugs are administered in office reinforces this point. For instance, in breast cancer, Herceptin, Perjeta, Keytruda, and Enhertu each recorded multi-billion-dollar peak revenues while treating smaller patient populations than the potential populations we seek to address with gedatolisib and our two current breast cancer clinical trials.

If gedatolisib ultimately does receive FDA approval for both the PIK3CA wild-type and mutant populations, we estimate the peak revenue potential for the second-line indication could exceed $2 billion with just 40% market penetration. Now, turning to our first-line breast cancer program, we've completed the selection of the clinical sites that will participate in our VIKTORIA-2 study. Approximately 200 sites across North America, Europe, Latin America, and Asia-Pacific are in process now of being activated. We're very pleased with the level of interest our current VIKTORIA-1 sites expressed in participating in this study, and we continue to expect to enroll our first patient in the second quarter of 2025.

VIKTORIA-2 study is a global phase III open-label, randomized clinical trial evaluating the efficacy and safety of gedatolisib in combination with fulvestrant plus investigator's choice of either ribociclib or palbociclib as a first-line treatment for patients with HR-positive, HER2-negative advanced breast cancer who are endocrine therapy resistant. Approximately 638 patients will be assigned to a cohort based on their PIK3CA mutation status. Clinical trial endpoints are progression-free survival per RECIST 1.1 criteria, as assessed by blinded independent central review. The primary PFS endpoint for each of the two cohorts will be evaluated independently. Prior to the initiation of the phase III portion of the trial, a safety run-in study will be conducted in 12-36 patients to assess the safety profile of gedatolisib in combination with ribociclib and fulvestrant.

We estimate that 15,000-20,000 patients with endocrine therapy resistant advanced breast cancer are diagnosed each year in the U.S. alone. Since this population does not overlap with the patient population we are evaluating in our VIKTORIA-1 study, an approval to treat these patients would increase the size of the addressable U.S. market potential for gedatolisib by up to $3 billion. Turning now to our prostate cancer program, we remain on track with our phase I-B trial that is evaluating the safety and tolerability of gedatolisib in combination with darolutamide in patients who have metastatic castration-resistant prostate cancer. The underlying biology of prostate cancer has a lot of similarities to ER-positive breast cancer. Both are hormonally-driven tumor types, and both involve the PAM pathway.

While the development of PAM inhibitors in breast cancer is further advanced than in prostate cancer, there's significant non-clinical evidence and emerging clinical data that suggests simultaneous inhibition of both the AR and PAM pathway may be more efficacious than treatment with an AR inhibitor alone. We expect to report out preliminary data from the phase I-B dose escalation portion of the study towards the end of the second quarter of this year. Since we're at an earlier phase in this program, our focus is optimizing the dose and schedule for this tumor type and drug combination. The data set will include approximately 36 patients, half of whom will have received a 120 mg dose of geda, the other half a 180 mg dose. Each are administered on a three-week-on-one-week-off schedule.

We're comparing both the landmark PFS at six months and the safety profile of these two arms to each other and historical control data for second-line metastatic castration-resistant prostate cancer patients who are retreated with an androgen receptor inhibitor. Finally, we're very excited to report last December encouraging preliminary overall survival data from both first-line and second-line advanced breast cancer patients from our phase I-B study that evaluated gedatolisib in combination with palbociclib and endocrine therapy. For the phase I, rather, the first-line patients, median overall survival was 77 months, which compares favorably to published phase III data for palbociclib plus letrozole. For the second-line cohort, median overall survival was about 34 months, which compares favorably to recently published OS data results for fulvestrant. Of course, you have to be careful making cross-trial comparisons, especially since ours was just a single-arm study.

Certainly, we view the data as very encouraging. With that, I'll now turn the call over to Vicky Hahne to review our financial results.

Vicky Hahne (CFO)

Thank you, Brian, and good afternoon, everyone. I'll provide a brief overview of our financial results for the fourth quarter and full year 2024, and I invite you to review our 10-K, which will be filed later today for a more detailed discussion. Our fourth quarter net loss was $36.7 million, or $0.85 per share, compared to $18.8 million net loss, or $0.65 per share for the fourth quarter of 2023. Net loss for the full year 2024 was $111.8 million, or $2.83 per share, compared to $63.8 million net loss, or $2.69 per share for the same period in 2023. Because these quarterly and full-year net losses include significant non-cash items, including stock-based compensation and non-cash interest, we also included in our press release non-GAAP adjusted net loss for the quarter and the full year ending December 31st, 2024.

Our non-GAAP adjusted net loss was $32.3 million, or $0.75 per share for the fourth quarter of 2024, compared to non-GAAP adjusted net loss of $17.6 million, or $0.61 per share for the fourth quarter of 2023. Non-GAAP adjusted net loss for the full year 2024 was $101.9 million, or $2.58 per share, compared to non-GAAP adjusted net loss of $57.8 million, or $2.44 per share for the full year 2023. Research and development expenses were $33.5 million for the fourth quarter of 2024, compared to $18.1 million for the fourth quarter of 2023. R&D expenses for the full year of 2024 were $104.2 million, compared to $60.6 million for the prior year.

Of the approximately $43.6 million increase in R&D expenses year-over-year, $30.7 million was related to ongoing activities supporting the VIKTORIA-1 phase III trial and the phase I-B/II prostate trial, along with the commencement of the VIKTORIA-2 phase III trial. The remaining $12.9 million increase in R&D expenses is related to increased employee and consulting expenses. General and administrative expenses were $3 million for the fourth quarter of 2024, compared to $1.6 million for the same period in 2023. G&A expenses for the full year of 2024 were $9.1 million, compared to $5.6 million for the prior year. Of the approximately $3.4 million increase in G&A expenses, $2.6 million was related to increased employee-related expenses, and $0.8 million was related to professional fees, expanding infrastructure, and other administrative expenses.

Net cash used in operating activities for the fourth quarter of 2024 was $27.8 million, compared to $18.5 million for the fourth quarter of 2023. This was a result of non-GAAP adjusted net loss of approximately $32.3 million, offset by approximately $4.5 million of working capital changes. Net cash used in operating activities for the full year 2024 was $83.5 million, compared to $53.8 million for the full year 2023. This was a result of non-GAAP adjusted net loss of approximately $101.9 million, offset by working capital changes of approximately $18.4 million. We ended the year with approximately $235.1 million of cash, cash equivalents, and short-term investments, compared to $180.6 million on December 31st, 2023. The increase of $54.5 million in cash, cash equivalents, and short-term investments was a result of several financing activities that occurred in fiscal 2024 and yielded net proceeds of $138.4 million.

The $138.4 million was partially offset by year-to-date operating cash used of $83.5 million and capital equipment purchases of $0.3 million. I will now hand the call back to Brian.

Brian Sullivan (CEO and Co-founder)

Thank you, Vicky. Operator, could you please open the call for questions?

Operator (participant)

Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. Should you have a question, please press the star followed by the number one on your touchstone phone. You will hear a prompt that your hand has been raised. Should you wish to decline from the polling process, please press the star followed by the number two. If you are using a speakerphone, please lift the handset before pressing any keys. One moment, please, for your first question. Your first question comes from Maury Raycroft with Jefferies. Please go ahead.

Maury Raycroft (Equity Research Analyst)

Hi, thanks for taking my questions and congrats on the progress.

Brian Sullivan (CEO and Co-founder)

Thanks.

Maury Raycroft (Equity Research Analyst)

Just wondering if you can provide an update on the current status of the event rate for VIKTORIA-1, and are you expecting to achieve the required number of events any day now, or is there still some time left before reaching the final milestone to trigger the readout?

Brian Sullivan (CEO and Co-founder)

At this stage, we're not commenting on any of the specifics related to achieving our ability to report top-line data. Right now, we're just providing guidance on when we believe we'll have the top-line data available.

Maury Raycroft (Equity Research Analyst)

Got it. Okay. Wondering if you can talk more about your plans following the second quarter readout. When do you expect to file the NDA, and what are your thoughts on whether you would get priority review?

Brian Sullivan (CEO and Co-founder)

Sure. We would hope to initiate an RTOR, a real-time oncology review request, soon after we have our top-line data. FDA has to approve that request. Otherwise, if they do not approve that, we would seek to get a priority review. We think either of those programs would shorten the overall review time substantially. We think because we have breakthrough status that we certainly would get good consideration of those requests. For instance, if we have our RTOR status granted, we would begin submitting within months of receiving that approval and with the completion of the overall package within a quarter or quarter and a half after we get our top-line data.

Maury Raycroft (Equity Research Analyst)

Got it. That's helpful. Okay. Thanks for taking my questions. I'll hop back into the queue.

Brian Sullivan (CEO and Co-founder)

You're welcome.

Operator (participant)

Thank you. The next question comes from Brad Canino with Stifel. Please go ahead.

Brad Canino (Equity Research Analyst)

Hey, afternoon. Thanks for the questions, Brian. First, could you just discuss what you're currently thinking about the extent of the data you would plan to share in the 2Q top-line and then how timelines might look for a medical meeting presentation?

Brian Sullivan (CEO and Co-founder)

Sure. We would expect to present median PFS data for each of the three arms in the wild-type cohort, as well as corresponding hazard ratios for the two primary analyses, and then follow that up with a complete presentation or fuller presentation of the data at the corresponding next available major medical meeting. We're not really providing a specific estimate of which medical meeting that would be.

Brad Canino (Equity Research Analyst)

Yeah, that makes sense. Separately, have you heard any feedback from investigators as you're working on site startup for the front-line triplet about the dear doctor letter sent by Roche for inavolisib about the life-threatening ketoacidosis? What do you think this might mean for the opportunity in the mutant population where there is a bit of overlap with the inavolisib label? Thank you.

Brian Sullivan (CEO and Co-founder)

I'm not going to comment on Roche's situation. As far as feedback from investigators, I think PI3K-alpha inhibitors, as I think most of you know, have been known to induce high levels of hyperglycemia. In the case of the inavolisib drug, it was only evaluated in patients who would be generally considered to be metabolically healthy. They were not prediabetic or did not have type 2 diabetes. The label itself, though, did not restrict the population to that category of patients, while it did require pretty intense monitoring of glucose in the early cycles of treatment. What that means is that drug requires a fair amount of scrutiny to prescribe. I think the feedback we've received from investigators is that that imposes a burden on them to provide extra management of these patients, as well as on the patients, because they have to self-administer glucose testing.

That drug right now is only approved to treat patients who are endocrine treatment resistant in the front-line setting. It really does not overlap with our second-line indication at all. It overlaps with our VIKTORIA-2 first-line population. I think net-net for us, if we are able to report favorable data and if we are able to present safety data comparable to what we have reported in our early phase studies, we have the potential to have a significant advantage because we would, if all goes according to plan, have the opportunity to treat patients independent of their status at PIK3CA and independent of their metabolic status. We would really only be restricted from treating patients who have uncontrolled type 1 diabetes. The easier it is for patients' doctors to administer drugs, the less potential requirement for patients to self-monitor.

Obviously, the lower the risk of severe adverse events that could require hospitalization are all what everyone is looking for in a cancer drug. We think we have a good potential opportunity to deliver that. Potentially, based on what you've just told me, it would contrast with the situation with the Roche drug.

Brad Canino (Equity Research Analyst)

Great. Thanks again.

Brian Sullivan (CEO and Co-founder)

You're welcome.

Operator (participant)

Thank you. The next question comes from Oliver McCammon with LifeSci Capital. Please go ahead.

Oliver McCammon (Biotech Equity Research Analyst)

Hi. Thanks for the update and for taking my question. We've seen a number of readouts in advanced HR-positive breast cancer over the past few months. Can you just remind us of how closely we should be looking at patient baseline characteristics like measurable disease and treatment experience in some of these reference studies as we think about contextualizing these upcoming PIK3CA wild-type data? Thanks again.

Brian Sullivan (CEO and Co-founder)

Sure. No, that's a great question. The more heterogeneous the population that a study enrolls, the harder it can be to interpret the data. I discussed this a bit in my remarks. I think you've seen in some early phase studies in this setting, inclusion of patients who have non-measurable disease as an example, which makes it very difficult to assess a population that includes a significant proportion of patients of that type to those who are evaluating patients with measurable disease because of the impact it can have on progression-free survival and potentially tilting upward the median results. In the setting in registrational studies, I think we've seen some studies evaluate, as I alluded to earlier, multiple patient groups.

It makes it hard to interpret those results because the doctors need to understand what the data is for the patient that they're treating and whether that patient is a second-line patient that's received prior CDK or a first-line patient who may be endocrine treatment resistant. You may have different treatment options for them or different competitive or different alternatives that may have different relative benefits depending on a patient's profile. All of that said, I think the doctors will be paying very strict attention to the results within a patient population. The best way to do that, certainly they'll be looking at the median PFS and whatever the incremental benefit is for patients. Just as important will be the hazard ratio because it really does allow you to more objectively compare results.

I mean, obviously, you can't do head-to-head comparisons to every drug in the landscape. The hazard ratio does allow you to essentially net out some of these factors which make it hard to interpret absolute PFS numbers or absolute incremental PFS. Again, it's always important to look at who's being treated in a study because of the impact that can have on the results and the relevance when you're comparing it to other studies. There are ways to try to get a bead on how one drug is performing for patients relative to another drug by using the hazard ratio. Oliver?

Operator (participant)

Oliver?

Brian Sullivan (CEO and Co-founder)

I guess he didn't like my answer.

Oliver McCammon (Biotech Equity Research Analyst)

No. Great answer. Thanks again for taking my question.

Brian Sullivan (CEO and Co-founder)

Okay. You're welcome.

Operator (participant)

All right. Thank you. The next question comes from Tara Bancroft with TD Cowen. Please go ahead.

Frances Dovell (Biotech Equity Research Associate)

Hello. This is Frances Dovell on for Tara Bancroft. You mentioned the second-line plus opportunity could reach $2 billion. Can you elaborate regarding the assumptions that go into that number? A quick follow-up after that, do you expect to go into a quiet period ahead of the top-line data next quarter?

Brian Sullivan (CEO and Co-founder)

Regarding the second-line opportunity, we estimate, and these estimates are based on third-party data that's available, that there are roughly between 30,000 and 35,000 women who are treated in the second-line setting after they've progressed on a CDK4/6 inhibitor. The pricing for drugs today in this that are proprietary treating these patients ranges up between, I would say, $15,000-$20,000. That would be a price assumption to use for estimating the market. You can use anywhere between 5-12 months. You have to do sensitivity analysis to estimate then the corresponding served market potential. From there, you can make an assumption about the penetration rate, how many of the patients will potentially retreat versus those who are offering competitive or alternative therapies. Net-net, we estimate the served market potential for our drug would be about $5 billion.

Obviously, we're not going to get all of that, but we think it's not unreasonable to certainly shoot for, let's say, 40% penetration if our data is favorable. That might be a goal of ours. That translates to a $2 billion potential revenue opportunity for us. I think your second question, just remind me, Tara person.

Frances Dovell (Biotech Equity Research Associate)

Yes. It was just if you expect to go into a quiet period ahead of the top-line data next quarter.

Brian Sullivan (CEO and Co-founder)

We would, that is to be determined.

Frances Dovell (Biotech Equity Research Associate)

Wonderful. Thank you so much.

Brian Sullivan (CEO and Co-founder)

You're welcome.

Operator (participant)

Thank you. The next question comes from Gil Blum from Needham & Company. Please go ahead.

Gil Blum (Senior Biotech Analyst)

Hi, Brian. Thanks for taking our question. Maybe a bit to the side here. Recent reports for degraders have been a little bit, shall we say, disappointing, but activity has been seen specifically in ESR1 mutant population. Now, yes, I completely understand it's a different mechanism, but do you think the VIKTORIA study has sufficient power to see an effect in that population to see if there's some overlap there? Just wondering here. Thanks.

Brian Sullivan (CEO and Co-founder)

Sure. We think we haven't published this data because the sample size is relatively small, but we did not see in our preliminary phase 1b data differences in activity associated with ESR1 status. We would hope to eventually report results that isolates activity between ESR1 mutant and wild-type patients. Obviously, the most important mutation relative to our drug is status of PIK3CA.

Gil Blum (Senior Biotech Analyst)

Maybe in a similar vein, as it relates to patient activity towards prior CDK4/6, is this something we're also going to break out at that scientific meeting?

Brian Sullivan (CEO and Co-founder)

As far as which particular CDK4/6 patients had previously?

Gil Blum (Senior Biotech Analyst)

If it was active in those patients, basically, they were.

Brian Sullivan (CEO and Co-founder)

Sure. We'll roll out data probably on a rolling basis. I mean, typically, you have a more narrow presentation of data maybe at the first meeting, and then you follow on with additional details at later meetings. We'll kind of follow. I would expect that we would follow that pattern.

Gil Blum (Senior Biotech Analyst)

Thank you, Brian.

Brian Sullivan (CEO and Co-founder)

You're welcome.

Operator (participant)

Thank you. The next question comes from Chase Knickerbocker with Craig-Hallum Capital Group. Please go ahead.

Chase Knickerbocker (Senior Equity Research Analyst of Healthcare)

Good afternoon. Thanks for taking the questions. Brian, actually, maybe one on the prostate study, being that that's two key data as well. Can you walk us through kind of the moving pieces and kind of the bar that you have there for either doing some more early to mid-stage clinical work rather than moving the drug in prostate into later stage, more robust studies?

Brian Sullivan (CEO and Co-founder)

Sure. The population that we're evaluating will have progressed on a prior androgen receptor inhibitor, the next generation version of those drugs. If they're retreated with a different androgen receptor inhibitor in the second-line setting, data suggests that they'll get in the 5-5.5 month median PFS benefit. We would be comparing ourselves to that. Since we don't have a head-to-head, we establish our primary endpoint using landmark PFS at six months as the primary endpoint for that study. We would compare statistically whether we identify a difference between what our PFS rate at six months is relative to historical controls. One consideration for us, since we're at a much earlier stage in development of this drug in light of the FDA's increased focus on dose optimization, is that that's what we have to make sure we get right.

We will look at the data and make decisions accordingly. Obviously, one of the big components will be safety. If safety data is great, you have flexibility potentially in your dosing. Those are all questions that we'll be addressing as we review our data.

Chase Knickerbocker (Senior Equity Research Analyst of Healthcare)

Got it. Thanks, Brian. Maybe, Vicky, as we think about kind of R&D over 2025, a couple of moving pieces, obviously, with some studies wrapping up and some studies starting. Is annualizing Q4 kind of the right way to think about 2025, or just maybe what you budgeted for R&D in 2025, some general thoughts?

Vicky Hahne (CFO)

Yeah. I think looking at the R&D component, obviously, anticipating any type of additional commercial activities, if we do, that number would increase. In terms of kind of the R&D and G&A spend, Q4 is a relevant peg. I mean, we will continue to increase some kind of pre-launch activities, 10% or so.

Chase Knickerbocker (Senior Equity Research Analyst of Healthcare)

Great. Thanks, guys.

Operator (participant)

Thank you. There are no further questions at this time. I will now turn the call over to Brian Sullivan, the Chief Executive Officer and Co-founder. Please go ahead, sir.

Brian Sullivan (CEO and Co-founder)

Thanks again for participating in our call today, for your ongoing support. We'll be participating in the Needham Conference and Stifel's virtual oncology day in April and look forward to hopefully interacting with some of you there. Goodbye.

Operator (participant)

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.