Welcome back to the 46th annual TD Cowen Health Care Conference. I'm Marc Frahm from the biotech team here at TD Cowen. In the next session, we're really pleased to have with us, Alan H. Auerbach, the CEO of Puma Biotech, to talk about their continued commercialization of NERLYNX, but also some pipeline updates that are gonna be coming in the next quarter or two.
Okay.
from Alisertib. With that, I'll hand it over to Alan.
Great. Thank you, Marc. Just a reminder, I'll be making forward-looking statements. On this slide, you can see our product pipeline. As Marc mentioned, we have our commercial drug neratinib, which is also known as NERLYNX, which is FDA approved in HER2-positive breast cancer, both in the extended adjuvant setting as well as in the metastatic setting. In the extended adjuvant setting, that's based on the phase III results of our ExteNET trial. In the metastatic setting, that's based on our phase III NALA study. We also have the drug alisertib, which is an Aurora kinase inhibitor that we have in two phase II trials. One is in HER2-positive, HER2-negative metastatic breast cancer, and the other one in small cell lung cancer. Those trials are referred to as ALISCA-Breast and ALISCA-Lung, respectively. First, to talk about our commercialization.
This is our current pharmacy and distribution network. As you can see, we have two channels that we sell the drug through. We refer to these as our specialty pharmacy and specialty distributor networks. In the specialty pharmacy, this is where there's a physical prescription that's written for the drug, and those are filled by the pharmacies you see on the screen. In the specialty distributor, this is where the drug is actually given to the patient in the physician's office or in the hospital. There you can see the distribution network that we have. We just recently reported our NERLYNX revenues for the fourth quarter of 2025. As you can see on the slide on the left, our net revenue was $59.9 million for NERLYNX in Q4 of 2025.
That compares favorably to the Q4 2024 of $54.4 million. Looking at that sequentially, on the right-hand side, Q4 2025 was $59.9 million. That compares favorably to Q3 2025, which was $51.9 million. Looking at that from a unit perspective, in Q4 2025, there was 3,298 bottles sold. That compares favorably to the Q4 2024 number of 2,964. Looking at that sequentially on the right-hand side, the 3,298 in Q4 2025 compares favorably to the 2,949 in Q3 2025. The main side effect of NERLYNX is that in the first cycle the patient is on it, there could be a grade 3/4 diarrhea.
This tends to be a first cycle effect, over time there's a tachyphylaxis of the mechanism, the incidence of it reduces. What we have found is that by doing a dose escalation, starting at a low dose and titrating up in the first month, it greatly reduces the side effect of the drug. We've been tracking the number of patients who start at this reduced dose as a way to track better tolerability. As you can see on the slide, this has been increasing over time, in Q4 of 2025, this was about 75% of the new patient starts. In the United States, we commercialize the drug ourselves. Outside the United States, we have partners who sell the drug for us. On the slide, you can see all the partnerships that we have.
This includes Specialised Therapeutics in Australia, and Southeast Asia, Medison in Israel, Canada, we have Knight, Latin America, our partner is Pint, in Europe, China, the Middle East, North and West Africa, South Africa and Turkey, our partner is Pierre Fabre, in South Korea, Bixink, and in Russia and the CIS, Er-Kim. The total market for NERLYNX in the extended adjuvant setting, it's about 28,300 patients in the U.S. who have early-stage HER2-positive breast cancer. About 6,000 of these are HR-positive early-stage patients who have no pathological complete response to neoadjuvant treatment, hence this high-risk disease. This is where the NCCN guidelines have us slated. Outside the U.S., there's about 37,000 patients in the EU with early-stage HER2-positive breast cancer. About 65%-70% of these have HR-positive disease.
In the United States, our label includes both HR-positive and HR-negative. In Europe, it is limited to just HR-positive patients. On this slide, you can see the financial guidance we have both for Q1 2026 and for full year 2026. For the full year, we're looking for revenues for NERLYNX of $194 million-$198 million, royalties of $20 million-$23 million, and we're not expecting any license revenue. That gives us total revenue for the year of $214 million-$221 million. For the year, we're expecting to be profitable with a net income of $10 million-$13 million and a gross to net somewhere in the range of 27.5% to 28.5%.
For Q1 2026, we're looking for $36 million-$39 million in revenue, $2 million-$3 million in royalties for total revenue of $38 million-$42 million. We're expecting a small net loss between $8 million and $10 million this quarter, and a gross to net of 29.5%-30.5%. We also have an ongoing study of neratinib in combination with Enhertu, also known as T-DXd. One of the important aspects of neratinib is that as an irreversible HER2 inhibitor, it internalizes the HER2 receptor, so when you combine it with an ADC, it ends up internalizing the receptor, hence internalizing the ADC, so we see synergy combining neratinib with an ADC. You can see the preclinical data on the left, which shows that combining neratinib with T-DXd, you get a synergy that occurs in the PDX64 model.
We have an ongoing dose escalation study of neratinib with T-DXd with a dose escalation seen on the slide on the right. The data on this was reported at the AACR meeting in 2025. Here you can see the waterfall plot, and as you can see, we are very pleased to see the tumor shrinkages that we saw. Importantly, we saw tumor shrinkages in a lot of tumor types when HER2 has not been shown to show a lot of activity, and that includes tumors like, you know, pancreatic cancer, ovarian, and some of the GI tumors. This trial is continuing, and we're expecting an update sometime this year on this. To move now to our investigational drug, alisertib, which we're testing both in breast cancer and small cell lung cancer. Alisertib is a drug that we in-licensed.
It was tested previously both in a single agent and in combination with other chemotherapy agents in hormone receptor-positive breast cancer, triple-negative breast, small cell lung, and head and neck cancer. It also showed single-agent activity in hematological malignancies, including peripheral T cell lymphoma and the non-Hodgkin's lymphoma. It's got a well-characterized safety profile, and prior to us licensing the drug, it was tested in 1,300 patients across 22 company-sponsored trials. As an Aurora kinase A inhibitor, it's known that there's a synthetic lethality between Aurora kinase A and RB1. More specifically, loss of function mutations in RB1 are events that can occur in both lung cancer and in HR-positive breast. RB1 tends to control the entry phase into the S phase of mitosis, so when you have a loss of function mutation, you get a hyperactivated set spindle assembly checkpoint.
When you have this hyperactivated spindle assembly checkpoint, you get an activation of Aurora kinase A, hence making it a target for an Aurora kinase A inhibitor. As you can see on the slide, when you decrease Aurora kinase A in this setting, you get mitotic arrest and apoptosis. It's also known that Aurora kinase A and c-Myc co-regulate each other, such that you get a transcriptional upregulation of each other which shows a positive feedback loop. As you can see on the slide, when you inhibit Aurora kinase A, you also end up inhibiting c-Myc, which changes the cell proliferation into apoptosis. Now to go into the development of alisertib in breast cancer. Prior to us licensing the drug, alisertib was tested in two studies as a monotherapy.
In this one, it was tested in a 21-day cycle, 50 mg twice a day for seven days, followed by a 14-day break. It was tested in hormone receptor-positive, HER2-negative, HER2-positive, and triple-negative breast. Focusing on hormone receptor-positive, HER2-negative, you'll see that previously a objective response rate of 23% and a PFS of 7.9 months was seen. Here you can see the waterfall plots. On the plot, the triple-negative patients are in the red, the HR-positive, HER2-negative in the blue, and the HER2-positive in the green. Focusing again on the HR-positive, HER2-negative, you can see that we saw very nice tumor shrinkage on the waterfall plots with a number of these patients showing tumor regressions.
This was the side effect profile seen in the trial. Being that the drug is a cell cycle inhibitor, the typical side effects you would expect would be the ones with the cell cycle, hence the cytopenias that one would see. In the trial, the main ones we saw were the neutropenia, the anemia, and the leukopenia. There was also a trial that was done of the drug known as TBCRC 041. This was a trial that tested alisertib alone or in combination with fulvestrant in patients who had previously failed fulvestrant. As you can see on the box on the right, the response rate to alisertib alone was 19.6%. To alisertib plus fulvestrant, 20.0%. The PFS to alisertib alone was 5.6 months, and the combination, 5.4 months.
Again, focusing on the side effect profile, the main ones seen are the cytopenias one would expect for a cell cycle inhibitor, with neutropenia being the main one, that came out. There was also a randomized study done of alisertib, which was paclitaxel plus alisertib versus paclitaxel alone, again done in ER-positive, HER2 negative patients. As you can see on the Kaplan-Meier on the right, the median PFS was shown to be 10.2 months for alisertib plus paclitaxel versus 7.1 months for paclitaxel alone, with a hazard ratio of 0.56 and a P value of 0.005. As the box on the lower right shows, the median OS was 26.3 months for paclitaxel/alisertib and 25.1 months for paclitaxel alone.
Interestingly, in this trial, in the patients that had previously been treated with palbociclib, which is a CDK4/6 inhibitor, there was a slightly better PFS seen, a PFS of 13.9 months for the paclitaxel/alisertib arm versus 5.6 months for the paclitaxel alone. There is preclinical data that shows that palbociclib resistance is known to be seen in tumors with RB1 loss and with c-Myc upregulation. This has been shown in palbociclib-resistant HR-positive breast cancer lines. As previously shown, for an Aurora kinase A inhibitor, it would be expected to be active both in RB1 loss of function mutation tumors and those with c-Myc upregulation. This has led us to our ongoing study, which is the ALISCA-Breast1 trial.
This is a Phase II dose optimization trial looking also at biomarker evaluation in HR-positive, HER2-negative metastatic breast cancer. This was done in conjunction with the FDA Project Optimus. Here what we're testing is alisertib at doses of either 50, 40, or 30 mg BID on days one to three, eight to 10, and 15- 17 day dosing in combination with endocrine treatment. The endpoints we're looking for are the typical ones like response rate, PFS, et cetera. And specifically, we're also looking at the biomarkers known to be involved with Aurora kinase activity and known to be involved with ER-positive breast. To now move to the development in small cell lung cancer. Alisertib was previously tested in a trial as a single agent in patients with small cell lung cancer.
These were in patients who had undergone less than two previous cytotoxic regimens. As you can see on the slide part on the right, in chemotherapy-sensitive patients, a 19% response rate was seen with a PFS of 2.6 months. In chemotherapy refractory resistant, a 25% response rate was seen with a PFS of 1.7 months. Here you can see the waterfall plot from the trial. The chemotherapy-sensitive patients are in the light blue, the chemotherapy refractory resistant in the red. We're very happy to see very nice tumor regressions with this drug. From a safety perspective, very similar to what was seen in breast, the main side effects seen are the cytopenias one would expect for a cell cycle inhibitor. That includes the neutropenia, which was the most common, as well as the yeah, thrombocytopenia and leukopenia.
There was also a randomized study done of Alisertib in combination with paclitaxel versus paclitaxel plus placebo. This was done as a second-line small cell lung cancer trial. In the trial, the PFS was shown, as you can see on the slide in the lower left, the hazard ratio was 0.77 with a P value of 0.113. The original way this trial was done, the stratification factor used for determining whether they were sensitive or resistant was basically done on time from start of chemo. That is not the standard way that it is done. It's usually done from completion of chemotherapy. When they used that corrected definition, the hazard ratio went to 0.71 with a P value of 0.038.
You can see the OS on the right, and this is a hazard ratio of 0.87 with a corrected of 0.79. Very interesting in the trial, they did a retrospective biomarker evaluation. In this, in the patients with c-MYC expression, there was indeed a benefit seen with a median PFS of 4.64 for the paclitaxel alisertib arm, 2.27 for the paclitaxel placebo. That was a hazard ratio of 0.29. It was also seen that for tumors with a genetic alterations in the cell cycle genes, which included CDK6, RBL1, RBL2, and RB1, the majority of these were RB1 loss of function mutations, there was both a PFS benefit and an OS benefit seen.
Alisertib plus paclitaxel was 3.68-month PFS versus paclitaxel placebo, 1.8. OS, 7.2 months for the Alisertib paclitaxel arm versus 4.47 for the placebo paclitaxel with an OS hazard ratio of 0.427, P value of 0.00085. From the safety perspective, as we've seen in the breast cancer trial, the main side effects that are seen are those involved in cell cycle inhibitors. Again, the neutropenia and thrombocytopenia are the ones that tend to come out most frequently. This has led us to our trial, which we call ALISCA-Lung1 or ALLY-4201. We originally started this trial as a monotherapy trial testing 50 mg BID days one to seven on a 21-day cycle.
We instituted a prophylactic GCSF with this in an effort to reduce the neutropenia that was seen as a single agent. We've publicly announced on this as we were quite pleased to see a very dramatic reduction in the neutropenia with the drug, which led us to amend the trial to dose increase to 60 mg BID. On our most recent earnings call, we also mentioned the fact that we are seeing much better tolerability than we expected at 60 mg, and we'll be looking to escalate this to 70 mg. We're doing a parallel development of this trial with a biomarker strategy, with the idea being to look at the initial drug activity, see whether or not we see better evidence of activity in biomarkers that are associated with Aurora kinase activity, and then focus the enrollment on that biomarker subgroup.
By doing this, we think we may have a path for a accelerated approval in that biomarker-defined population. From an IP perspective, for NERLYNX, our marketed drug, the composition of matter patent is issued, and that expires in 2030. It was extended by the United States Patent and Trademark Office in November 2021 per Hatch-Waxman. We also have use patents for the treatment of cancer that are issued that go out to 2025. There's two polymorph patents going out to 2028, a combination with capecitabine patent going out to 2031, and a use in extended adjuvant breast going out to 2030.
For alisertib, the composition of matter patent goes out to 2029, use in proliferative disorders out to 2032, use in small cell lung out to 2033, and use in the treatment of breast to 2034. We are also filing additional patents as we get clinical data in an effort to try to extend this IP life. We also have IP on a related area, which is the EGFR T790M area, specifically with claims for a pharmaceutical composition that comprises an irreversible EGFR inhibitor for treating cancer with a T790M mutation. We had filed a patent infringement lawsuit against AstraZeneca, and a jury trial found that our patents were valid and were indeed infringed by AstraZeneca, and awarded us $107.5 million in damages.
The judge ruled that the patent was invalid for lack of enablement and adequate written description, and that was in August of 2024. We filed an appeal in September 2024, we're waiting for that to go through the system. In terms of our expected milestones, we expect to report interim data from the ALISCA-Breast1 trial, which is our dose-optimized trial of Alisertib, both at 30, 40, and 50 mg in combination with endocrine therapy in patients with chemotherapy-naive, HER2-negative, hormone receptor-positive metastatic breast cancer. We're expecting that sometime in the second quarter of 2026. We'll also get interim data from the ALISCA-Lung1 trial, which is our monotherapy study of Alisertib in the treatment of extensive-stage small cell lung cancer, again, 2026.
We expect then to have full data from the ALISCA-Breast1, which is again the dose-ranging study of alisertib in combination with endocrine in patients with chemotherapy-naive, HER2-negative, hormone receptor-positive metastatic breast cancer in the fourth quarter of this year. From a management perspective, I act as the CEO and President of the company. Maximo F. Nougues is our Chief Financial Officer. Doug Hunt acts as our Interim Chief Scientific Officer, but also our Head of Regulatory, Medical Affairs, and Pharmacovigilance. Heather Blaber is our Senior Vice President of Marketing, and Roger Storms is our Senior Vice President of Sales. In terms of the board, we're very pleased to have a board that comprises all aspects of the company in terms of both the commercial, the clinical, the finance, and the regulatory. As you can see, the members of the board on the slide.
This includes Alexandra Sasano, Allison Dorval, Mike Miller, Jay Moyes, Adrian Senderowicz, Brian Stuglik, and Troy Wilson. From a financial perspective, we currently trade on the Nasdaq under the ticker PBYI. Our cash and cash equivalents at the end of December was $97.5 million. Our net income in the fourth quarter of the year was $13.4 million, with cash earned of $3.1 million. There were two private placements done in 2022. One was to me and Athyrium Capital, the other one to me directly. Our shares issued and outstanding is 50.9 million. Other than those placements to me and Athyrium in 2022, we have not done a public offering since 2016.
Just to close with our company highlights, NERLYNX is the first HER2-directed drug approved by the FDA for the extended adjuvant treatment of early-stage HER2-positive breast cancer in patients who've received prior trastuzumab. It's also the first HER2 tyrosine kinase inhibitor that's approved both in the early-stage and metastatic HER2-positive breast cancer. We retain the full U.S. commercial rights to the drug. We've seen for our development stage drug, Alisertib, clinical activity that's been demonstrated in phase two trials in HR-positive, HER2-negative breast, triple-negative breast, and small cell lung cancer, and the potential for a very novel biomarker-directed commercial opportunity with Alisertib, which differentiates us from the other drugs that are currently being tested. I wanna thank everyone for attending and thank Cowen for inviting us to the conference.
Thanks, Alan. We have a few minutes if anybody wants to ask a question. I'll maybe throw something in for Alan.
Sure.
Just so the mic picks up for the webcast. Alan, you mentioned the, those Alisertib updates.
Mm-hmm.
That are coming over the next year. Just maybe want to first frame kinda what you think of as the bar that is meaningful data, which I think you touched on a bit with some of the background data. Importantly also, what are, you know, if you hit those bars, what are the next steps on the side on either side? You know, are these places where a single arm approval is potentially on the table where you could expand? Or?
Yeah.
Is this a place where you need to follow up with randomized data sets?
Yeah. The question is, you know, what's the bar, and then what else is needed for approval? On the approval side of things, you know, I think you've definitely seen the FDA leaning against single arm approvals and more toward randomized studies. In ER-positive breast cancer, I'm not aware of the FDA ever approving a drug in a single-arm study, that's obviously gonna require a randomized. In small cell lung cancer, I have seen them do single-arm approvals, but usually, they want the randomized trial up and running and fully enrolled at the time. That's what I would assume would be characteristic there. We are very interested in biomarker-directed approach in both of these settings. You know, we've certainly seen that on the retrospective analysis for small cell lung cancer.
Haven't yet seen that in ER-positive breast. We'll get that data shortly and see where that goes. I think the PFS we've seen so far of 5 and a half months for alisertib in kind of this 3rd line setting, right, which was in the prior, TBCRC 41 trial. You know, I think that's competitive. I think we would... You know, if we can find a biomarker where it goes higher to, say, like, you know, six, seven, or eight months, I think that'd be much more, you know, competitive, if you will. What the randomized trial looks like is obviously a discussion with the FDA.
I mean, what we've typically seen done, in other situations, like some of the, you know, biomarker-directed, like PIK3CA or, you know, ESR1, you know, has been the investigational drug against endocrine or the investigational drug in combination with endocrine against placebo endocrine, right? You saw that for the PIK3CAs and I think some things like that. I would assume something in that general genre is something on the table. That's what I would assume. Again, we wait to see the data and see what the path takes us. I think in small cell lung, you know, I think we'd be looking for a much later, you know, more of a, you know, second, third line. A lot of them are moving more toward the first. Not sure that's really where we wanna go.
I think we're more looking at the second line, third lines, and things like that. I think, you know, in the second line setting, second, third line, I would say most of the drugs you've seen, like Lurbinectedin, et cetera, have had like a PFS of four months. I think that's an appropriate part to look at.
Maybe on those next steps, just is that something that you can kind of sustain with the You know, there is a cash balance and there is NERLYNX you know, is somewhat profitable. Is that something you can sustain with the business, or would you need to do some sort of either partnership, equity?
Yep
you know, something to help support kind of next steps?
Yeah. I'm very happy you asked that question. This year will be our fourth official year of profitability. I think in 2022, we were flat zero, so if you want to call that profitability, you can. We have said on every call it is very important for us to stay net income positive. It's nice to be in control of your own destiny, but it's also nice to be able to tell shareholders you don't need to raise money, and we haven't had to do that since 2016, in a public equity setting. I think that we are, again, you know, our financials, I've said what they were for the year.
Importantly, we have debt that we took out when we launched the drug, and then we paid off some of that, refinanced some of that. Our last two debt payments, it's a straight... It's not a convert. It's straight debt payments where you pay a certain amount every quarter. We have two more payments to make, and then we will be a debt-free company. It's public information. We pay about $11 million a quarter in debt payments. Take our net income, add on $11 million a quarter, that gives us a heck of a lot of cash flow to be able to put forward, you know, into our clinical trials.
If we need to stagger them so we can put one forward instead of the other or space them out, so we can stay net income positive, I'm totally okay doing that because I know that we have a fiscal responsibility to the shareholders, and I take that very seriously.
Any other questions from the group? All right. Maybe with that, we'll cut it off there.
Great.
Thanks a lot, Alan, for joining.
Thank you again for having us present.