Hi, thank you all for being here today. Welcome to TD Cowen's 45th Annual Healthcare Conference. My name is Divya Rao. I'm on the biotech team here at TD Cowen. I'm happy to introduce Alan Auerbach, CEO, President, and Chairman of the Board of Puma Biotechnology. We're happy to leave a few minutes at the end if anyone has any questions from the audience. Thank you.
Good morning and welcome to the Puma Biotechnology presentation. Just a reminder, I'll be making forward-looking statements. On this slide, you can see the product pipeline for the company. Our drug, NERLYNX, also known as neratinib, is currently approved in the HER2-positive breast cancer space in two different spaces, which is the extended adjuvant and the metastatic. We also have the drug in an ongoing clinical trial in combination with trastuzumab deruxtecan, also known as Enhertu, in HER2-amplified and mutated solid tumors. We also have a second drug, alisertib, which we in-licensed a few years ago, which is an Aurora kinase A inhibitor. And we're testing that in three different tumor types: HR+, HER2-negative metastatic breast cancer, metastatic EGFR- mutant non-Small Cell Lung Cancer, and Small Cell Lung Cancer. To first talk about NERLYNX, which is our commercial product.
In the United States, we sell NERLYNX ourselves through our own sales force. Ex-U.S., we sell it through partners who sell the drug and then pay us a royalty. Here you can see our pharmacy and distribution network in the U.S. In the U.S., we sell it through two networks, which we refer to as our specialty pharmacy network and our specialty distribution network. Specialty pharmacy network is the one where there's a physical prescription written, and then the bottle is actually delivered to the patient. The specialty distribution is also called our in-office dispensing, which is where the bottle is given to the patient in the physician's office. We go through both of these channels. About 75% of the business goes through the specialty pharmacy, about 25% through the specialty distribution. On this slide, you can see our financial results.
As you can see, in the fourth quarter of 2024, we reported $54.4 million in revenue, which was an increase from the prior year, which was $53.2 million. Going quarter- over- quarter, the $54.4 million reported in Q4 was a decline from the $56.1 million in Q3. From a bottle perspective, in Q4 of 2024, we sold 2,964 bottles. That was an increase from the 2,881 in the prior year, and also an increase from Q3 of 2024, which was 2,723. The main side effect of NERLYNX is that the drug causes a GIAE, which is a Grade 3 diarrhea. This tends to happen in the first cycle that the patient is on the drug.
We found that by doing a dose escalation, starting with half a dose in the first week and then dose escalating up in that first cycle, tended to do a nice job of reducing the AE and making the drug much more manageable. We started to track the use of this drug commercially. You can see in Q3 of 2021 is when we first got this approved in our label, which is where you see the big jump in the use of it. In the fourth quarter of 2024, 74% of the scripts that were written used this dose escalation technique. As I mentioned earlier, we sell the drug in the U.S. ourselves, Ex-U.S.. We have partners who sell the drug and then pay us a royalty. On this slide, you can see the different partners that we have.
In Australia and Southeast Asia, our partner is Specialized Therapeutics. In Israel, it's Medison. In Canada, it's Knight Therapeutics. In Latin America, it's Pint Pharma. In Europe, China and the Middle East region, it's Pierre Fabre. In South Korea, it's Bixink . The market for NERLYNX and extended adjuvant HER2-positive breast cancer, there's about 28,000 patients in the U.S. who have early-stage HER2-positive breast cancer that are treated with adjuvant treatment. The current NCCN guidelines really focus on the use of NERLYNX in the higher-risk patients, which is defined as those who are the no pathological complete response to neoadjuvant treatment. It also further says those with HR+, because that's where the data looks stronger. There the market is about 6,000 patients. Ex-U.S., the drug, approaches a group of about 37,000 patients that have early-stage HER2-positive breast cancer.
It's only approved in the HR+ population there, which represents about 65%-70% of those patients. In terms of our financial guidance, on this slide, you can see our recent financial guidance we put out. For 2025, we're expecting U.S. NERLYNX revenues of $192 million-$198 million, royalty guidance of about $20 million-$24 million. We're looking for net income in the range of $23 million-$28 million for the year, and our gross-to-net of between 20.5%-21.5%. For Q1, we're looking for U.S. revenues of $41 million-$43 million, royalties of $1.5 million-$2 million, net income of a slight loss of $2 million, with a range of a slight loss of $2 million to break even, and a gross-to-net of 22.5%-23.5%. As I mentioned, NERLYNX's neratinib is also in a clinical trial in combination with an HER2, which is trastuzumab deruxtecan.
This is in patients that are HER2-amplified or HER2-mutated and open to all solid tumors. We are expecting to see interim data from this trial in the first half of 2025. I'll move now to our drug, alisertib, which is our pipeline asset that we recently brought in. This we are testing in breast cancer and Small Cell Lung Cancer. Alisertib is an oral drug that has an Aurora kinase A inhibitor. It has previously shown both single-agent and combinatorial clinical activity in a number of tumor types, including hormone receptor positive metastatic breast cancer, triple-negative breast cancer, Small Cell Lung Cancer, and head and neck cancer. It was also very widely tested in a number of hematological malignancies. Prior to us licensing the drug, we licensed this from Takeda. It was tested in about 1,300 patients across 22 trials.
We have a very well-characterized safety database for the drug. From a mechanistic perspective, there is a synthetic lethality between Aurora kinase A and RB1. More specifically, in tumors that have a loss-of-function mutation in RB1, this leads to a hyperactivated primed spindle assembly checkpoint. When this happens, you get an increase in Aurora kinase A, so it makes these targetable by an Aurora kinase A inhibitor. Preclinically, we have seen activity of alisertib in tumors that are RB1 loss-of-function mutations. Also, Aurora kinase A and c-Myc tend to co-regulate one another, as you can see on the slide. Specifically, when you see a tumor that is c-Myc upregulated, it also has Aurora kinase A upregulation. Again, we have seen preclinical activity of alisertib in tumors that are c-Myc amplified. To now move to the clinical development of the drug in breast cancer.
Previously, alisertib was tested in a monotherapy trial in a number of solid tumors. As you can see on the slide, this included hormone receptor positive, HER2-negative breast cancer, which is outlined in the box. In this trial, there were 26 patients tested, and the response rate was 23% with a PFS of 7.9 months. On this slide, you can see the waterfall plot. In that trial, the drug was tested in triple-negative breast, HR+, HER2-negative breast, and HER2-positive breast. You can see on this slide, the waterfall plot, the triple negative is in red, the HR+, HER2-negative is in blue, and the HER2-positive is in green. From a side effect perspective, alisertib is a cell cycle inhibitor. The side effects we would expect would be the ones associated with the cell cycle, so specifically the cytopenias.
As you can see on this slide, the main side effect seen with the drug was a Grade 3, 4 neutropenia. There was also a trial that was completed by the Translational Breast Cancer Research Consortium Group, known as TBCRC041. This trial tested alisertib plus fulvestrant versus alisertib alone in patients who had previously been treated with fulvestrant. In the trial, as you can see, the response rate of alisertib alone was 19.6% with a PFS of 5.6 months. In the alisertib plus fulvestrant, it was 20% with a PFS of 5.4 months. Again, from the side effect perspective, the main side effect you tend to see with the drug due to the cell cycle inhibition is the Grade 3, 4 neutropenia. As you can see on the slide, that is what we are seeing in this trial.
Alisertib was also tested in a randomized trial, which was a paclitaxel plus alisertib versus paclitaxel alone. In this study, patients were randomized to receive either the combination of paclitaxel plus alisertib or single-agent paclitaxel, and the primary endpoint was PFS. As you can see from the Kaplan-Meier curve on the right, the median PFS in the alisertib arm was 10.2 months. In the alisertib alone, 7.1 months. That resulted in a hazard ratio of 0.56 with a p-value of 0.005. The median OS in the trial was 26.3 months for the paclitaxel alisertib arm, 25.1 for the paclitaxel alone, and that was a hazard ratio of 0.89 with a p-value of 0.61.
Very interestingly, in the trial, when they looked at the subgroup of patients that were previously treated with CDK4/6 inhibitors, which is the standard of care in the U.S. and other countries, there was a much greater PFS benefit seen. This was 13.9 months for alisertib plus paclitaxel versus 5.6 months for paclitaxel alone with a hazard ratio of 0.58. There is preclinical data that shows that in patients who have palbociclib resistance, palbociclib being one of the main CDK4/6 inhibitors used, there is both an RB1 loss-of-function mutation as well as c-Myc upregulation. This could support why we're seeing this better activity of alisertib in this patient population. We currently have an ongoing study known as ALISCA- Breast1 , which is a phase II dose optimization trial. This is to satisfy Project Optimus with the FDA.
As you can see, patients are randomized into one of three arms: 30 milligrams b.i.d. alisertib, 40 milligrams b.i.d. alisertib, or 50 milligrams b.i.d. alisertib in combination with one of the endocrine therapies shown on the slide. This is principally being done in patients who are CDK4/6 experienced in the recurrent or metastatic setting, and they can have up to one additional endocrine treatment before entering the trial. These are all chemotherapy naive patients, as that's where we're positioning the drug, because in the chemotherapy naive third-line hormone resistant population. We initiated this trial in the fourth quarter of 2024. As we mentioned on our recent earnings call, this trial is actually enrolling better than we expected, and we're expecting to have interim data from the trial later this year. To move now to the clinical development in Small Cell Lung Cancer.
This is a phase II trial of alisertib monotherapy in solid tumors that I mentioned earlier. In this trial, they enrolled patients who had undergone up to two previous cytotoxic regimens, and they were given alisertib as a monotherapy in a 21-day cycle, which was 50 milligrams b.i.d. for seven days, followed by a break of 14 days. There were 48 patients total in the trial. In Small Cell Lung Cancer, they tend to break this into chemotherapy sensitive or chemotherapy refractory or resistant. The trial enrolled 36 patients with chemotherapy sensitive, 12 patients with chemotherapy refractory or resistant. The efficacy that was seen in the trial was there was of the 36 patients who were chemotherapy sensitive, the response rate was 19% with a PFS of 2.6 months.
In the patients who were chemotherapy refractory or resistant, the response rate was 25% with a PFS of 1.7 months. On this slide, you can see the waterfall plot from that study. The chemotherapy sensitive patients are in the light blue. The chemotherapy refractory or resistant are in the red. Again, the side effect profile that was seen in the study was very similar to what we've seen previously. This being a cell cycle inhibitor, the main side effect seen is the Grade 3 neutropenia. Obviously, the other cytopenias like anemia and thrombocytopenia as well. There was a second trial done of alisertib in Small Cell Lung Cancer. This was a randomized study of paclitaxel plus alisertib versus paclitaxel plus placebo in second-line Small Cell Lung Cancer. Patients were randomized to receive either alisertib plus paclitaxel, alisertib being given at 40 milligrams b.i.d.
for three weeks on days 1 -3 , 8- 10, and 15 - 17, plus paclitaxel given at 60 mg per meter squared IV on days 1, 8, and 15, or a placebo plus paclitaxel given at 80 mg per meter squared on days 1, 8, and 15 in a 28-day cycle. The primary endpoint was PFS. In the intent to treat population, so initially when they enrolled the trial, they had done the categorization of sensitive versus resistant based on time from response. That is not the standard definition that is used in Small Cell Lung Cancer. It is usually from time from completion of chemotherapy. There were two analyses done. The primary, which uses the definition based on response, and then the corrected, which uses the definition that's more accepted, which is based on completion of chemotherapy.
In the intent to treat population, the hazard ratio was 0.77 with a p-value of 0.113. In the corrected, using the corrected definition, the hazard ratio was 0.71 with a p-value of 0.038. From an OS perspective, the OS, as you can see on the Kaplan-Meier on the right, was 0.87 with a p-value of 0.714. The corrected definition was a hazard ratio of 0.79 with a p-value of 0.209. They did a very in-depth biomarker analysis in the trial. In the study, they looked at patients with c-Myc expression and amplification. In the subgroup of patients that had c-Myc amplification, the PFS seen in the paclitaxel alisertib arm was 4.6 months. The paclitaxel placebo was 2.27 months. That was a hazard ratio of 0.29. As you can see from the confidence interval, that was indeed statistically significant.
As I mentioned, they also did a very extensive biomarker analysis. They also looked at patients that had any genetic alteration in the cell cycle. That included CDK6, RBL1, RBL2, and RB1 mutations. The large majority of these were RB1 mutations. The other ones had hits of like 1% or less. In the patients that had the mutations, as you can see on the Kaplan-Meier curve on the upper left, the hazard ratio was 0.395 with a p-value of 0.0003. That was a PFS of 3.68 months in the alisertib plus paclitaxel arm and 1.8 months in the placebo arm. The OS in the trial also showed statistical significance as the Kaplan-Meier curve on the upper right with a hazard ratio of 0.427 with a p-value of 0.00065, I believe that looks like.
The OS was 7.2 months in the alisertib arm, 4.47 months in the placebo arm. From a side effect perspective, similar to what we've seen previously, the main ones that came out were the cytopenias with neutropenia and anemia and thrombocytopenia being the main ones. We currently have an ongoing phase II trial. We call this ALISCA- Lung 1 or also the 4201 study. This is a study of single agent alisertib 50 milligrams b.i.d. on days 1- 7 every 28 days. The trial was started in the first quarter of 2024, and we'll have additional interim data on this later in 2025. We're doing a very extensive biomarker analysis in this trial based on the previous data. What we're doing is kind of a real-time biomarker analysis.
As we see increased activity in certain biomarkers, we're going to be enriching the enrollment in the trial so that we can get a better hit on those biomarkers. We mentioned on a recent conference call that this is exactly what we would be doing because we were noticing that patients with increased c-Myc copy numbers and overexpression, we were getting better activity. That tends to be in Small Cell Lung Cancer, something that occurs as a mechanism of response and resistance to treatment. In more patients who've been more heavily pretreated, you're likely to see a higher enrichment of this biomarker. As we mentioned on our call recently, we're going to be opening the trial to not just patients who've had one or two prior lines of therapy, but even more to try to enrich more for this biomarker.
From an IP perspective for NERLYNX, the composition matter patent is issued, and that expires in 2030. That was extended in November 2021 by Hatch-Waxman. We also have use in the treatment of cancer patents issued that expire in 2025. There are two polymorph patents issued. They expire in 2028. There is a combination with capecitabine that expires in 2031, and then a use in extended adjuvant that also expires in 2030. For alisertib, our composition of matter patent is issued and expires in 2029. Our use in the treatment of proliferative disorders in 2032. The use in the treatment of Small Cell Lung Cancer expires in 2033, and the use in the treatment of breast cancer expires in 2034. All of these patent expirations do not include Hatch-Waxman exclusivity, which can extend the patents for up to five years.
We also have IP in a related area, which is in the EGFR T790M mutation area. These are issued claims in Europe, Asia, Australia, and in the United States, which are for an irreversible EGFR inhibitor for treating cancer with a T790M mutation, as well as those for lung cancer and non-Small Cell Lung Cancer. We actually had litigation against AstraZeneca regarding this. We went to trial on this, and we got awarded $107 million in damages for the infringement in May of 2024. The judge later ruled that the patent was invalid for lack of enablement in August of 2024, and we filed an appeal on this in September 2024. In terms of the expected milestones for the company, we're looking to present interim data from our trial of neratinib plus in HER2, known as trastuzumab deruxtecan.
This is a trial being run by the NCI. That will be sometime in the first half of 2025. We will have interim data from the ALISCA-Breast1 trial, which is our phase II trial of alisertib in combination with endocrine treatment in patients with chemotherapy-naive, HER2-negative hormone receptor-positive breast cancer, and that will be sometime in 2025. We will also have additional interim data from the ALISCA-Lung trial, which is the phase II of alisertib in the treatment of extensive stage Small Cell Lung Cancer, and that will also be sometime in 2025. From a management perspective, I act as the CEO and President of the company. Jeff Ludwig is our Chief Commercial Officer. He has prior experience from Eli Lilly, Astellas, and Amgen. Maximo Nougues is our Chief Financial Officer. He has prior experience from Getinge, Boston Scientific, and Clorox.
Doug Hunt is our Chief Regulatory Officer, and he previously worked at Amgen as well as Baxter Healthcare and Amgen. From the board of directors, we're very pleased to have a board that comprises both, or I should say, all-inclusive of commercial, financial, clinical, and regulatory experience. That includes Alessandra Cesano, who's the Chief Medical Officer of ESSA, and you can see her experience on the slide. Allison Dorval, who's currently the CFO of Verve, and you can see her experience as well. Mike Miller, who was formerly the Executive Vice President of Commercial for Jazz, and he was also the VP of sales and marketing for Genentech and specifically for the cancer business. Jay Moyes, who used to be the CFO of Sera Prognostics and was the former CFO of Myriad Genetics.
Adrian Senderowicz, who was the former Chief Medical Officer of Constellation and previously worked at a number of companies and also worked at the FDA in their oncology drug product division. Brian Stuglik, who was the CEO of Verastem, and then also was the Chief Marketing Officer for Lilly. Troy Wilson, who is the President and CEO currently of Kura Oncology and has been with a number of companies, as you can see on the slide as well. From a financial perspective, we currently trade on the NASDAQ under the ticker PBYI. Our cash and cash equivalents at the end of the year was $101 million. Our net income was $19.3 million in the fourth quarter of 2024. That $19.3 million included a non-cash deferred income tax benefit of $7.1 million. Our cash earned in the fourth quarter was $4.3 million. We did two private placements.
The company has not raised money publicly since 2016. We did do two private placements, which was basically to me in March of 2022. We did $3.5 million shares to me and Athyrium Capital, who is our debt holder. In December 2022, did 568,000 shares to me. Our total issued and outstanding is $49.6 million. I can just close with the company highlights. NERLYNX is the first HER2-positive directed drug approved by the FDA for the extended adjuvant treatment of early stage HER2-positive breast cancer in patients who receive prior trastuzumab. It is also the first HER2-directed tyrosine kinase inhibitor approved both in the early stage and metastatic breast settings. We retain the full U.S. commercial rights to NERLYNX.
For alisertib, we have clinical activity that's been demonstrated in previous phase II trials, both in HR+, HER2-negative breast cancer, triple-negative breast cancer, and Small Cell Lung Cancer. We've got the potential with alisertib for a very novel biomarker-directed commercial opportunity compared to the other drugs that are currently in development in those tumor types. I would like to thank everyone for coming and thank TD Cowen for allowing us to present. We've got some extra time, so I'm happy to take any questions that anyone has.
I'll ask two questions if that's okay.
Of course.
The first one.
Just whisper your name.
Test, test.
There you go.
Thank you. One question on the financials. You obviously in your last earnings call gave 2025 revenue guidance, which for at least for NERLYNX calls for somewhat flattish year-over-year growth. Can you walk through some of the assumptions that you made when looking, when kind of generating that revenue guidance? I have another question as well.
In terms of revenue guidance, as we said on the call, we're looking kind of flattish to slightly down in terms of demand. With that and then the price increase, that's where you're getting the range from. Drug is in year seven of its launch. Obviously, without new data, et cetera, kind of challenging to try to impact that and grow that. That's one of the reasons you've seen us kind of cut our commercial budget from that perspective is seven years into the launch, the drug was approved in mid-2017. Challenging to try to inflect that. We're just being pragmatic and responsible with the shareholders' money. On the net income side of things, where a lot of that is coming from is we originally had, when we first launched NERLYNX, we took out $150 million in debt.
This is straight debt, so it's paid out over time. It's not a convert. We've been paying that down every quarter. Now we're down to about $60 million in debt. That includes this year, includes about, I think it's $11 million a quarter in interest expense. That obviously hits our net income line as well.
That's helpful. Then from an alisertib perspective, you have a couple of updates coming in 2025. I guess starting with the metastatic breast cancer combo trial, any color on one, I guess the venue, are you looking for kind of a press release similar to or in conjunction with earnings, kind of similar to what you did with Small Cell? Also the scope of the update. Again, would it be similar to kind of what you presented with Small Cell?
We have a steering committee for this, so they would obviously have a say in where this would be presented, when, et cetera. I have to defer and wait for that feedback. The trial is enrolling a lot better than we expected it to. I mean, we're really getting wonderful feedback from the breast cancer community on this. I've been surprised how often you often at medical conferences, they'll do these dinners for community oncologists, and they'll talk about all the drugs on the market, all the ones in development. I am surprised how often I'm seeing alisertib mentioned that we're not doing this, the docs are. It'll be on a slide of, here's everything in phase III, phase II we're excited about. Right there in phase II, they always mention it. We've really gotten wonderful support from the breast cancer community.
A lot of that deals with the prior use of the drug, the prior trials, and the work that was done by TBCRC, the Translational Breast Cancer Research Consortium. What a great group of doctors. They have been very, very, very supportive. I expect we will have a strong double-digit number of patients to be able to talk about probably in each arm of the trial. What that will consist of, I would have to just wait to see what that looks like.
That's helpful. Thank you.
Great. Thank you.