Takeda Pharmaceutical Company Limited (4502) Earnings Call Transcript & Summary

Good afternoon. Thank you very much for your participation in the conference call for seminar on oncology business and its oncology products and disease in Japan. My name Ayako Iwamuro from Takeda Investor Relations. Before starting, I'd like to remind everyone that we will be discussing forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those discussed today. The factors that could cause our actual results to differ materially are discussed in the most recent Form 20-F and in our other SEC filings. Please also refer to the important notice on Page 2 of the presentation. And now please let me introduce today's presenters and panel. Takafumi Horii, Head of Japan Oncology Business Unit; Dr. Kei Hiraoka, Medical Director; Dr. Jumpei Soeda, Head of Japan Medical Affairs; Dr. Akiko Kimura, Senior Medical Director; and Yukari Nishikata, Head of Oncology Therapeutic Area Unit. First, we'd like to start with the presentation. And after that, we will have a question-and-answer session. And today, we will take questions only from the conference call. [Operator Instructions] Now we'd like to start the presentation. Mr. Horii, the floor is yours.

Thank you very much. I am Horii of Japan Oncology Business Unit. First of all, let me briefly introduce myself. Since last January, I have been the head of Japanese Oncology Business Unit. So just 1 year has passed since I assumed this position. I joined Takeda in 2009. I was in the Corporate Strategic unit since 2009. And then in China, I was ahead of Strategy Unit, a local company in China, and I was the head of growing and emerging market in Singapore and then head of Taiwan local entity. And immediately before the current position, I was in charge of the Middle East and Africa, located in Dubai. I will be discussing about 3 new products of FY 2020. But before going to start the product presentations, I'd like to give you an overview of Oncology business in Japan. I would like to skip this page, and please move forward to the next page. First, I'd like to introduce our vision that all employees are cherished in the Oncology business, that is to research, develop manufacture and deliver innovative products to the patients worldwide as soon as possible to cure their diseases. Please go to the next page. Page 3 shows the 3 major points as we present the Japanese Oncology business. First is a diverse leadership team. Second is a pipeline to supporting the future growth. And third is our strength and our capability. Next page, please. The Global Oncology leadership team is introduced on this page. This organization is directly reporting to CEO, Christophe. And currently, the President is Teresa Bitetti. And including myself, in the U.S., Japan and EU main countries, we have each head reporting directly to the president. That is how the organization is structured. The point here is that, talking about Japan, other than oncology, we have other disease areas. But regarding oncology, we have this single business unit formed so that we'll be able to make a speedy decision-making. Therefore, agility is our focus. And out of many disease areas, innovation and market dynamics or competitive landscape change in oncology is quite tough and severe. Therefore, we have this organizational structure. Going to the next page, please. Page 5, you can see the diverse leadership team here in Japan. First of all, the first characteristic is that we are a diversified leadership team that we have created here in Japan. And as you can see here, for example, we have 5 female leaders included in the leadership team. And there are 7, including myself, they are working for Americas or in the emerging markets so they have experience in those markets. And everyone listed here, they are experienced in multiple areas and territories. So they have a very diversified perspective to be able to make diversified decisions. And this is a team that we have. And the second characteristic is that, as I will explain later, Soeda, the MD, is leading the medical and scientific field. They have a PhD. So they have expertise in those areas, and there are 3 of them with those expertise included in the team. And the other focus is that we have this diversified nature and we can respond to different issues to be able to provide the operation necessary, and that is utmost important for all of us. Next, I want to talk about the future growth for the markets. First of all, Page 6, on the left-hand side, you can see the Japanese market, the pharmaceutical market and you can see that the growth is expected to be flat. However, for oncology, towards calendar year '23, we are looking for 5.1% of growth. And on the right-hand side, these are the areas in which Takeda has products in. These are the areas in which we have the oncological pharmaceutical product in. And as you can see here, for hepatocellular carcinoma or gynecological cancer, towards CY23, we are looking for a growth rate of more than 10%. In those oncological areas, we believe that the unmet medical needs are quite high, and this is a reflection of that need. Next page, please. Page 7. As I have introduced earlier, looking at the Japanese Oncology Unit, which was established in 2015, this shows you the transition of Oncology in Japan. We started with ADCETRIS and Vectibix and we have had 3 products up to fiscal year 2020. However, 3 products were added in fiscal year 2020 and the number of indications have been added as well. Towards 2025, we will see an addition of more than 20 indications and we would like to accelerate the growth going forward. Next page, please. This Page 8 shows details of what I have been talking about so far. Please focus the red boxes. These are the global brands. These are under development globally and we are preparing for launches of these products. And the gray boxes, these products are under development as well. And today, we would like to focus on the 3 products on the left-hand side. Three presenters will present the details of these products. Not only the product groups, but every year, we are going to see new products or new indications being launched every year towards fiscal year '23 to '25. So that is the momentum that we are seeing in our pipeline at the moment. Next page, please. Page 9. This shows the capabilities of the Oncology business here in Japan. First of all, we have a track record on clinical development and medical affairs. As you can see on the left-hand side, the first is looking at global data so that we can have simultaneous applications or submissions. And that is something that Hiraoka will touch on later on ALUNBRIG. And the second and third bullet points, these shows that the ZEJULA or CABOMETYX, these products are included so that we are able to proceed with creative drug development so that we can achieve no drug lag between U.S. and Japan, for example. And on the right-hand side, you can see the track record on medical affairs here in Japan. We have Takeda-government-academia collaboration, and we have investigator-initiated studies. And CDx development is ongoing as well. And we have a new partnership agreement with National Cancer Center. For ADCETRIS with Nagoya Medical Center, with the investigator-initiated study, we were able to gain approval for pediatric indication. So 6 pediatric patients were administered ADCETRIS and that shows the most important philosophy of Takeda, patient-centric, and we are very proud of this achievement. Next page, please. Page 10. This talks about the commercial reputation of Takeda, and this is one of our specific capability that we are proud of. On the left-hand side, you can see this is done by a third-party. This is a ranking of the MR reputation and this is ranked by physicians. 16,000 people replied to this survey, and Takeda was ranked #1 when it comes to reputation of MRs. And on the right-hand side, you can see Japan Oncology business against the overall Japan oncology market and you can see the growth being compared. The total Japan oncology market grew at 6.6%. But in 2020, Takeda grew at 19.6%, so we were stronger by threefold. And after 2021, with the pipeline that I showed you earlier, we will offer those products to our patients, and we hope to be able to exceed the growth rates that we are seeing going forward. Next page, please. Now on Page 11, what we are looking at is about Vectibix and ADCETRIS growth in Japan. These are existing products. To the left first, Vectibix. It was launched in 2010, and it's been growing steadily. And in 2015, we had inauguration of Japan Oncology Business Unit, and ever since, it's been steadily growing. To the right, ADCETRIS, especially in the last 3 years, we were able to add several indications and it's enjoying very high-growth rate. Next page, please. So this is my last slide to explain to you third capability or strengths we have, which is about driving digital transformation. Since last year and the coronavirus pandemic situation, the environment has changed dramatically. That is the background of our activities. But as for digital transformation, Takeda started to work on that quite early on. And with the coronavirus pandemic, this initiative has been accelerated. To the left, you can see nurturing digital talents. We now have 43 digital leads in Japan Oncology Business Unit, in the head office and also across Japan. And including those 43 digital leads, around 80 employees have a national certificate called IT Passport and these are the people who lead in their respective team a variety of measures and activities. And to the right, we are looking at something that we have prepared since last year and we have started rolling out this, which is about omnichannel strategy. So what I'd like to tell you is that CRM system, which is to manage customers, and this is incorporated with AI. And using such technology in an optimal way, we try to deliver information to health care professionals. And such system has been in place already. Apart from that, from the medical and PV perspective, we have ePRO and also safety dashboard and real-world evidence. In those regards, we fully utilize digital tools to accelerate our activities going forward. Next page, please. So I have explained to you our capabilities. Let me summarize here. The first one on the left, this is about human resource investment. Compared to 2015, when we started in terms of medical affairs, we have increased the personnel by 3x, for commercial 2x. And the second point is about research from Japan. As I have already explained to you, medical affairs members are trying to cater to the needs of Japan and thereby conducting clinical research. And the number of such clinical research conducted has increased by 3.5x. And we deliver information to health care professionals and we have strength there as well, which is to enhance MR expertise. From April 2020, oncology disease areas have increased. So rather than having a geographic area focus, we have now shifted towards therapeutic area focus in order to further heighten the expertise on the part of MR. Next page, please. So this is my last slide. As I have explained already, our leadership team and our strong pipeline and our capabilities, we are going to tap into all of these to grow our Oncology business towards 2025 even further. We would like to accelerate our growth. And for that, we have purpose, we have vision and we have values. And we are going to celebrate our 240th anniversary this year in Takeda, and we have kept all of these intact. We will work in earnest for the sake of the oncology patients with passion. So I'd like to close my presentation. Thank you for your kind attention.

Thank you. Now I would like to present on brigatinib by Dr. Hiraoka.

Thank you very much. I am Hiraoka, I'd like to introduce brigatinib to you. This is the agenda of my presentation. First, I'd like to start with disease epidemiology information. Regarding the target disease of brigatinib, it is ALK+ NSCLC. First of all, talking about the lung cancer as a whole. Lung cancer is the leading cause of cancer death, and in Japan, the number of cases have been increasing. And of that, NSCLC accounts for about 80% to 90% of the total lung cancer, especially lung adenocarcinoma, that is the most frequent histological type that accounts for about 55%. And approximately 2% to 5% of the patients with NSCLC have a rearrangement in the ALK genes identified specifically for adenocarcinoma. Next page. ALK positive lung cancer characteristics. ALK+ NSCLC, that is caused by a mutation in the ALK, anaplastic lymphoma kinase, gene. So it is a unique subset of lung cancer. Histologically, adenocarcinoma is predominant and it is quite rare in other histological types. And the characteristics is that it affects younger people. The median age at diagnosis is 52 years old, and overall, in lung cancer, it is around 71. Therefore, we have many young people. And EGFR mutation is different from this one. There is no clear racial differences, and also it's unlikely to be associated with smoking. ALK+ NSCLC, the prognosis is still poor today. And in the end, the patient experiences progressive disease leading to death. And systematically, it spreads. And the mutation sites could be in multiple sites. Stage IV, that is the metastatic disease with a distant metastasis, and the median OS is approximately 6.8 years in the U.S. And at diagnosis, this rate is associated with the number of organs with tumors. And talking about overall NSCLC, the most common site of metastasis is the brain, bone, liver and the adrenal glands. And in the case of ALK+ patients, especially the brain metastasis is a high risk and that is a characteristic of ALK+ disease. And ALK+ NSCLC in Japan, in first line, mostly ALK inhibitors are used for treatment. And I am now showing you the Japanese lung cancer treatment guideline. First, NSCLC patients receive the test of driver gene mutations. And as a result, if those driver gene mutations are identified, then accordingly the TKI is recommended to be used. So if ALK+ is confirmed, then ALK inhibitors are recommended. So far in Japan and also in the U.S. and the European Unions, the approved agents specifically target ALK rearrangements include crizotinib, ceritinib and alectinib and lorlatinib and also our brigatinib. And currently, in Japan, with a patient with brain metastasis, here is the treatment path. If there is a brain metastasis, then depending upon the number of brain metastasis and also depending upon the systemic condition and also the control status of primary or other diseases, whether or not the surgery is indicated or radiation therapies, whatever it is indicated are selected and also pharmacotherapy follows. And if it is asymptomatic brain metastasis, then pharmacological therapy is recommended. Therefore, ALK+ asymptomatic brain-metastatic NSCLC, pharmacotherapy is the recommendation. Next is about brigatinib. I'd like to give you an overview and mode of action. This is historical developmental overview of brigatinib. And this brigatinib is approved for adult patients with ALK+ advanced metastatic NSCLC for first- and second-line setting in January 2021 in Japan. And regarding development history, first, in 2007, EML4-ALK. This is driver oncogene in NSCLC was identified. And after that, ALK inhibitors were developed. And in 2017, for the first time in the U.S., brigatinib was approved for post-crizotinib treatment. And then in EU, in 2018, the approval was granted. And in 2020, depending upon the results of the clinical trials in the U.S. and in EU, first-line approval was added. And in Japan, this year, 2021, first line and second line, regardless of those treatment lines, the approval was granted. Next is mode of action of brigatinib. It is designed to target ALK molecular alterations in NSCLC. It is a small molecule inhibitor. And as you can see here, 2 ALK proteins to the ATP-binding site of ALK, the brigatinib binds and exact activities. And potency and selectivity are the features of brigatinib. Especially in the nonclinical studies in cellular trials, testing and those animal models, those were demonstrated. And also using ALK+ brain tumor model in mice compared to crizotinib, brigatinib demonstrated a greater CNS activity, showing the inhibitory activities in the brain metastasis. And talking about ALK and other kinase, the nonclinical activities inhibiting activities of brigatinib. In preclinical studies, relating to this cancer, there are 289 kinases screened. And of them, brigatinib showed potent and selective inhibitory activities. On the top line of the right-hand side the chart, these are the kinase assay results confirming the ALK inhibitory activities. And then resistant ALK mutations, L1196M, C1156Y and G1202R. For those resistant ALK mutations, broadly, inhibitory activity is well shown by brigatinib. And out of 289 kinases, we conducted this activity testing and only in 8 kinases the strong inhibitory activity is well demonstrated. So it's highly selective. It includes ROS1, the other driver genes. And cellular assays showed the similar results. Next is about the clinical trials and data of brigatinib. Page 27, please. These are main clinical trials with brigatinib. Regarding first-line first. This is a global study, ALTA-1L study, that is in ALK+ NSCLC treatment-naive patients. This is a Phase III study and it met primary endpoint in July 2018. Talking about the second and subsequent lines of therapies. In Japan, we have a Study 2001. It is called J-ALTA study. And this is a Phase II study in Japanese patients with the patient ALK inhibitor pretreatment histories. So it is second line, and we met the primary endpoint June 2020. And global, we have ALTA studies. After crizotinib, the second lines -- secondary treatment. And also as an ongoing study, we have ALTA 2 study. Alectinib or ceritinib treatment-resistant patient are the target patients and this is a single-arm Phase II study. And ALTA 3, that's also ongoing. This is post-crizotinib treatment. And brigatinib and alectinib are compared in this Phase III study. This is also ongoing. Next page, please. So I want to talk about ALTA-1L study. This is done in 20 countries. This is open-label, multicenter, randomized, international Phase III trial. And in the study, brigatinib was compared to crizotinib and we looked at the PFS. And the median for crizotinib, it was 11 months, but brigatinib, it was 24 months. And the hazard ratio came to 0.49. So long-term efficacy was demonstrated. Page 29, please. And in the ALTA-1L study, brigatinib compared against crizotinib for brain metastasis, we were able to see a significant improvement in PFS. As I have mentioned earlier, ALK+ NSCLC compared to other driver cancer, the brain metastasis is often seen. And at the time of treatment with patients with brain metastasis, we looked at the PFS, intracranial PFS. And 2 years before -- after study, for crizotinib, it was 15%, but brigatinib, it was 48%. And looking at the median of the PFS, crizotinib, it was 5.6 months. But brigatinib, it was 24 months with hazard ratio of 0.31. So we were able to see extension of the PFS period with brigatinib. And this is ALTA-1L looking at safety on Page 30. Looking at the TEAEs, in the brigatinib arm, so these are with some of the test -- lab test results. And with the brigatinib arm, 12%, and crizotinib, 9%, they had to discontinue treatment due to AEs, but no treatment-related death occurred in either arm. Page 31, please. This is looking at the J-ALTA targeting Japanese patient. This is single-arm, multicenter, Phase II, open-label study and it is called J-ALTA study. And in this study, this is a second line and whether having crizotinib prior or not, this is post-alectinib. So we were looking at any -- and we was able to see PFS and ORR. ORR was 31%. So this is a disease control rate of 79%. And PFS median value was 7.3 months. And alectinib-resistant -- or refractory patients with brain metastases was also looked at, and brigatinib demonstrated intracranial objective responses of 25%. Page 32, please. This is J-ALTA study. This is looking at the treatment-emergent adverse events at primary analysis. So any discontinuation, only 4 out of 72, so 6%. The median dose intensity was 170 milligrams per day, and ILD/pneumonitis was seen in 6 patients. And most ILD/pneumonitis cases improved after brigatinib discontinuation with or without steroid treatment. Page 33, please. This is ongoing clinical trials in Japan. Dependent or nonclinical trials are being conducted by investigator-initiated trials, and they are ongoing. There are 3 trials, which will start in 2021. And I'd like to introduce you to 2 representative studies. On the left, this is a ROS1 arrangement (sic) [ rearrangement ] positive brigatinib basket study in patients with advanced solid tumors. This ROS1 rearrangement, as I mentioned earlier, it is different from of ALK mutation and this is a driver mutation for lung cancer, and activation was also seen. And this is a focus on that. And on the right-hand side, you can see EGFR C797S, so this is a mutation with that for NSCLC patients. And EGFR mutation-resistant, this is the focus of this study. And panitumumab and brigatinib, so this is combination of both drugs. Panitumumab was developed here in Japan by Takeda. This is EGFR antibody for colon cancer at the moment. So this is in combination with panitumumab. Page 34, please. Now I want to talk about the product positioning here in Japan. Page 35, please. As you can see for ALK+ NSCLC patients, this is a progressive disease that is associated with poor survival rates and the unmet need is high for patients in Japan. So Takeda's brigatinib offers a new option with unique profile of selectivity and safety. It is going to be a new treatment option for NSCLC patients. In preclinical studies, brigatinib was found to be a potent and selective inhibitor. And when it comes to safety, dose reductions were mainly due to lab abnormalities in the clinical studies. No treatment-related deaths occurred in the studies for ALTA-1L and J-ALTA, and with brigatinib, this is another characteristic that we can focus on. This has a compelling efficacy in patients with brain metastasis. Brigatinib significantly improved PFS in patients with baseline brain metastasis against crizotinib. So this was a statistically significant result that we had achieved. And in January, it was launched and approved, and we will bring to -- prepare to launch here in Japan in the quarter 1 of fiscal year '21. That is all. Thank you very much.

Thank you very much. Now we'd like to have Soeda to present on niraparib.

I am Soeda, Head of Japan Medical Affairs. I'd like to introduce to you niraparib. We have indication approved for ovarian cancer in Japan. Page 37, please. This is my agenda. First, disease epidemiology information of ovarian cancer, overview and mode of action of niraparib and clinical trials and data and product positioning. In this order, I would like to present. Page 38. So in cancer, lung cancer, gastric cancer and colorectal cancer, you may be familiar with these cancer types. You may not be familiar, though, with ovarian cancer. But this is an important cancer for women. Oftentimes, at diagnosis, they are already at Stage III, which is advanced stage. In 2020, around 13,400 women will be diagnosed with ovarian cancer. And the median age at diagnosis is 63 years old. So these is relatively speaking a younger population, those people who are still taking care of their children or they may be still in working-age group. So this is a very difficult condition for women. And in 2021 (sic) [ 2020 ], it is estimated 4,700 deaths are expected from this ovarian cancer. Next page, please. So this is about clinical presentation and workup and diagnosis of ovarian cancer. As for screening, we have the fecal test for colorectal cancer. We may have endoscopy for gastric cancer. But there is nothing recommended as for screening of ovarian cancer. It's quite difficult to detect. So when it's found out, it is already advanced stage, like Stage III or IV. The most common symptoms are bloating or pelvic or abdominal pain or pressure or urinary symptoms such as urgency or frequency. Those symptoms may be there for patients or ovarian cancer may be found in checkups. And there is diagnostic imaging or sometimes a biopsy to determine whether it is benign or malignant. And eventually, surgical operation is an oftentime option for those patients. This is looking at survival stage at diagnosis and recurrence. For advanced ovarian cancer patients, 85% of the women with advanced disease will recur after first-line therapy. 70% to 95% is the recurrence rate for Stage III and IV. And once recurred, first line, second line, third line, fourth line, fifth line, these lines subsequently are conducted, but worsening interval gets shorter and shorter. And for 5 -- fifth-line therapy or sixth-line therapy, the median PFS is very short at around 4 months. So recurrent ovarian cancer is treatable, but it is very difficult to cure. Next, please. This is looking at ovarian cancer treatment. This is a general chart. So as I said, ovarian cancer, first treatment option is surgery or adjuvant therapy, which is a preoperational one. And that will be followed by first-line, second-line and third-line oftentimes chemotherapy based on platinum drugs are used. And when responding, they will have the same kind of treatment repeated for the second- or the third-line treatment. And if they do not respond very well, they may use other chemotherapies. It's very important to prolong the time to the next recurrence. That is very important. This why a second-line therapy has been developed, chemotherapy plus bevacizumab. And after the first line, bevacizumab can be used for maintenance or PARP inhibitors can be used for maintenance after the first-line therapy. So such maintenance therapies have been developed and they are actually used in clinical practice. Next is about niraparib overview and mode of action. Page 43, please. So this drug is for ovarian cancer. This is maintenance therapy after first line and this is in platinum-sensitive relapsed ovarian cancer, and this is a treatment of homologous recombination deficient platinum-sensitive relapsed ovarian cancer. As such, it was approved on September 25, 2020. This is a mode of action. Niraparib is highly selective PARP1/2 inhibitor to selectively cure a subset of cancer cells with deficiency in DNA repair pathways. And dosage and administration, this is once-a-day orally taken drug for maintenance therapy, which means those women may be working while having treatment, and because this is once-daily oral drug, this is quite a convenient formulation. And body weight and platelet count can be used to adjust the dosage. Next, 44, please. So this is looking at mechanism of action of PARP inhibitors in general. So as I said, PARP inhibitors inhibit the enzyme that repair the DNA rearrangement. BRCA was the indication that was developed for the first time. And HRD may be there for such patients. This is another enzyme that is inhibited to repair DNA. So these are very 2 important enzymes for repair of DNA and they can be inhibited with PARP inhibitors. So if homologous there is function for repair or rearrangement, therefore, PARP inhibitor -- inhibition effect is quite mild. And for those cancer cells, there is a fair activity of PARP inhibitors. However, for HRD also, for those patients themselves, PARP inhibitors were found to be efficacious. To the right, as you can see, in ovarian cancer, a serous type PARP inhibitors are said to be most efficacious for BRCA repair capability patient, accounting for 20% to 22%. And as for HRD patients, PARP inhibitors can cover up to 50% of the patients. Page 45, please. Next, this is about PARP inhibitors and niraparib, how is it different from other PARP inhibitors. There are 3, niraparib, olaparib, rucaparib, and talazoparib. There are 4 approved by FDA. And the characteristics of niraparib are here, and this is preclinical data. Niraparib has high invasion or Vd, volume of distribution for cancer cells, which means that this is highly efficaciously delivered to cancer cells and there is high concentration of niraparib in cancer cells and it is not metabolized by the enzyme of cancer cells. So no relevant drug-drug interaction is there. And the half-life is 48 hours to 51 hours. So that's why it makes it possible to have once-daily dosing with or without food. Among all 4 drugs approved by FDA, niraparib has quite high cytotoxicity. And talazoparib is #1 in that regard. But after that, niraparib has quite high cytotoxicity. 46, please. Next, I'd like to talk about clinical trials and data, 3 pivotal trials for the approval of niraparib. Page 47, please. First, this is a Phase III trial, NOVA trial. So these patients who had a complete or partial response to platinum-based therapy, ovarian cancer or fallopian tube cancer or primary peritoneal cancer, these were the patients enrolled in this trial. So BRC (sic) [ BRCA ] mutation status-positive patients who are there, but there were non-BRCA mutation patients as well. This was a confirmatory prospective study for the first time conducted as such. And BRCA mutation, if there is no mutation, HRD, which is also a conditional marker where PARP inhibitors are set to work very well, there was analysis for this subset of the patient as well. And this a result of the NOVA study. Niraparib in all patient populations significantly improved their PFS. And in BRCA-mutated patients, that most expected subpopulation of the efficacy and also non-BRCA mutation, but HRD-positive and non-BRCA mutation overall without HRD positivities, especially PFS, was significantly improved in all such subpopulations of the patients. Next is about adverse events in NOVA study. PARP inhibitors selectively works on tumor cells. And this is anticancer drugs, therefore, it has AEs. Especially Grade 3 and over, placebo is 4.5% but the niraparib had 64.5% of AEs. However, only 14.7% led to discontinuation of the dosing. So I think it is manageable. And especially in niraparib, what characteristics is thrombocytopenia and hypertension. And anemia, neutropenia, fatigues, those are also observed. But these are also common, in general, in PARP inhibitors. Page 50, please. Next is about the QUADRA study. QUADRA study is in late line, especially the fourth and the subsequent treatment lines, and broadly, niraparib's efficacies was verified and it is a once-daily oral administration, and we conducted evaluation. Primary endpoints, 3 or 4 previous chemotherapy regimens. After that, having a platinum sensitivity and also platinum treatment-naive patients. That efficacy was primary endpoint. And here are the results. The ORR, 28%, so we met the primary endpoint. Especially in the later-line therapies, the generally used chemotherapies show 10% to 20% of the ORR. Therefore, we believe that this is a clinically significant rate. And this is the safety profile in QUADRA studies. As we also saw in NOVA studies, we had the information and QUADRA studies result were similar to those. And there patients who had to have dose interruption or reductions. However, only 21% of the patient withdrew from the study. Next is the PRIMA study. And this is for newly diagnosed, first-line maintenance therapy. Again, it is once-daily, the oral administration. Concerning the patient population, BRCA and HRD, regardless of those, platinum-based first-line therapy was given. And if a patient was responding to that, especially in Stage III or IV, the high risk of progressive disease, those were the target patients. Especially Stage III, if there is any remaining tumors, then that patient was actually enrolled. And we had 2:1 randomization, and we had niraparib arm and a placebo arm. And the platelet counts and the body weights, using those, doses as were adjusted. And that way, the protocol of PRIMA was modified to verify those adjustment. Here are the results in PRIMA study, HRD PFS. This is the populations most likely niraparib will work. And as a result, niraparib, in the newly diagnosed HRD advanced ovarian cancer, 57% of the PFS was observed. And the PFS number of months was about double of the placebo or 21.9 months vis-a-vis 10.4 months in placebo arm. Next is the PFS in overall population. In PRIMA study, niraparib in total populations, 38%, the death or progression of disease risk was decreased. So HRD, that is a population that PARP inhibitors would work mostly. And including non-HRD patient, this is the hazard ratio we obtained and that was 0.62, and it has quite significant results obtained in the overall populations. And next is the results of analysis of PFS in biomarker subgroups: with HRD, without HRD and with and without BRCA mutations. And in any of those subgroups, any of those analysis, niraparib significantly improved PFS. So as you saw, in PRIMA studies, HRD testing -- the testing itself was implemented. However, regardless of the status of HRD, in all subgroups benefit was demonstrated. Next is PRIMA study safety overview. Regarding TEAEs, it is mostly similar to all PARP inhibitors. And any AEs leading to treatment discontinuations, that's same as the previous studies of niraparib. And also dose adjustment was conducted due to the body weight and the platelet count and only 4.3% led to treatment discontinuation. And also death was observed but it's determined to be nontreatment-related. Next is product positioning. Page 59, please. In Japan, this is niraparib positioning. NOVA study showed significant clinical benefit in BRCA-mutated and non-BRCA-muted population in maintenance therapy for platinum-sensitive recurrent ovarian cancer. And the QUADRA study showed clinical meaningful benefit in fourth-line or later platinum-sensitive, HRD-positive population beyond BRCA mutation. And PRIMA study showed a clinical meaningful benefit across all biomarker groups. It was oral maintenance therapy. Presently, niraparib is the only PARP inhibitor with data showing benefit in the HR-proficient ovarian cancer. Thank you very much.

Next product. The last product is cabozantinib and Ms. Kimura will present.

I'm from Oncology Therapeutic Area Unit for Japan & Asia and Oncology Clinical Science. My name is Akiko Kimura, I'm the Senior Medical Director. I want to present to you about cabozantinib today. First, I would like to explain the mode of action and product information and talk about the development overall. Page 62, please. This is MOA of cabozantinib. Please look at the left-hand side. With cabozantinib, it has activation of TKI receptors, VEGFR and MET and AXL. And cabozantinib targets receptors that contribute to the left-hand side and important functions of cancer progression, proliferation, survival, migration and invasion and relations to VEGFR TKI. In the treatment of malignant diseases, important to jointly inhibit signaling pathways important to the cancer cells. Cabozantinib, the only compound that simultaneously inhibit those. And recently, it has come to be known that receptors targeted by cabozantinib is related to immunity. In the systems using the cell lines and mouse models, we evaluated the combination of cabozantinib and the immune checkpoint inhibitors. And it showed that it has the killing ability of T cells against tumor cells and lower the function and numbers of cells that suppress immunity. And compared to monotherapy, they showed higher anti-tumor response in combination. So based on these immunological mechanisms, a number of trials looking at evaluating combination therapies are ongoing. Please look at Page 63. So this is a clinical development of cabozantinib. On the lower hand, you can see the development overseas in U.S. and Europe, and on the top, you can see development here in Japan. So this was created by Exelixis' share in the U.S. And it has wide-ranging indications, and development was ongoing for many different indications. And when we look at overseas, in the U.S., it was approved for progressive, metastatic medullary thyroid cancer in capsule form in 2012. And then approval for advanced renal cell carcinoma for patients who have received prior anti-angiogenic therapy in the U.S. was approved in 2016. And in January this year, in 2021, approval for patients with advanced renal cell carcinoma as a first-line treatment in combination with nivolumab was approved. Other than the U.S., in EU and other regions, it is approved very widely. And when we look at development here in Japan, in 2017, we started collaboration with Exelixis. And in 2020, we had many different developmental activities. In March, received approval to manufacture and market cabozantinib for the indication of unresectable metastatic renal cell carcinoma and began multiple clinical trials to evaluate this as combo with other drugs. And the nivolumab combination therapy that I talked about earlier for naive RCC, we did a filing in October. And in November, received approval for partial change to the manufacturing and marketing approval for the indication of unresectable hepatocellular carcinoma. Page 64, please. Today, we were able to get approval for renal cell cancer, so I'd like to introduce you to the disease epidemiology information. Page 65, please. This is looking at renal carcinoma, and this is a Japanese data. You can see renal carcinoma, and this is a malignant tumor arising in the renal parenchyma, including cancer, sarcoma and lymphoma. Many of them come from epithelial cell. However, we can separate it from epithelial to mesenchymal. And if there are mesenchymal tumor, we can say that epidemiological data can be gained. And when it comes to renal cancer, we have about 20,000 here in Japan as a number of patients, and 90% are renal cell cancer, and many of them are karyotype. And cabozantinib is efficacious against that type of histological cancer. Page 66, please. This slide looks at the renal cell carcinoma. Renal cell carcinoma is often asymptomatic, and symptoms by metastases are often detected incidentally. When it comes to the therapy and diagnosis, we look at the risk classification and also the whole status of the patients to make the diagnosis. Different from other metastatic carcinoma, resectable surgery is recommended. And if not, therapy is provided with medications, and antitumor drugs is often used in combination. When we talk about risk classification, with renal cell carcinoma, this is looking at the prognosis of the carcinoma. We look at low, medium and also high risks. And we have the clinical study data and the status of the patient and the period from diagnosis to treatment. And these are the classifications used to diagnose patients. And Page 67. This is looking at the clinical staging of renal cell carcinoma here in Japan. On the left-hand side, stage 4, 14% of the patients falls under stage 4, and these are the targets for cabozantinib. And on the right-hand side, you can see a graph showing the survival rate by staging by kidney cancer. And you can see from 1 to 3 stages, compared to those stages, at stage 4, you can see that the survival rate is extremely low. And Page 68, please. This is from 2020, and this is a treatment modality of renal cell carcinoma here in Japan. On the left-hand side, you can see from stage 1 to stage 3, surgical resection is the main therapy provided. But on the right-hand side, for metastatic treatment modality distribution, you can see that holistic treatment is provided, or systemic therapy is provided. And on the bottom right, you can see the top 3 metastatic systemic regimens. These are the medications that were approved by 2020. And as I said at the beginning, cabozantinib data is not included here, but the treatment option is wide-ranging. However, as I showed you earlier, for metastatic patients, the treatment efficacy is not seen. Page 69, please. After that, after this slide, I will talk about the clinical trials, their outcomes data and life cycle management and also clinical development plan for the future. Page 70, please. This is talking about the efficacy arising from the METEOR study. This was done overseas. This is a Phase III study VEGF receptor TKI group, and this was after the second line. Japan did not participate in the study. And when it comes to the efficacy outcome, cabozantinib, everolimus is a medication that is targeted here. But we looked at PFS, progression-free survival; and OS, overall survival; and ORR, objective response rate. And you can see that cabozantinib showed a significant improvement against other medications. And we had subgroups, and in each of the subgroups, we had seen that cabozantinib's clinical benefit was indicated. And upon the result of the study, for RCC, this was approved as standard of care for after second line overseas. Page 71, please. This is a METEOR study. This is a safety data, and on the right-hand side, you can see the AE profile. And because the medication used is different, so the AE profile is different. However, dose adjustments and support therapy was given, and AEs were controlled. So discontinuation due to AEs were similar in both arms. Now Page 72, please. So this is looking at CABOSUN study efficacy data. This was conducted overseas. This is untreated RCC patient study. Cabozantinib was compared to sunitinib. This was a Phase II trial. And risk classification, this included immediate and poor-risk patients included. And cabozantinib compared to sunitinib, cabozantinib improved PFS and ORR. And in subgroup analysis by risk classification and bone metastases and in the subgroups with over 20 subjects per treatment arm, cabozantinib showed consistently favorable PFS and ORR. And this -- with this study, cabozantinib became one of the treatment options for first-line treatment of RCC. And in the United States, regardless of the treatment line, cabozantinib has been approved. Page 73, please. This is looking at safety data of CABOSUN study. To the right, we are looking at AE profile. Just like METEOR trial, we have different mode of action drugs. Therefore, the profile is different. But more or less, these AEs were managed with supportive care or dose modifications. Discontinuation due to AEs was comparable between the 2 arms. Page 75 (sic) [ Page 74 ], please. This is another study called C2001 study. This study, we introduced other overseas studies where we did not take part from Japan. So we had a Japan single monotherapy trial in Japan, and we had a bridging with METEOR trial to see cabozantinib's efficacy and safety in RCC in Japan. So METEOR trial and C2001 trials were combined for evaluation. And just like in non-Japanese patients, cabozantinib was able to demonstrate comparable ORR. So in Japanese, just like in non-Japanese, we could expect efficacy of cabozantinib for second-line and later. And the risk stratification and also the number of previous treatment and numbers and lung metastases, we have subgroups analysis for that. And cabozantinib showed comparable ORR in those subgroups with more than 10 subjects, just like in the overall population. And as for first-line treatment, we have not conducted a study here in Japan. But if you put together the data of METEOR trial and CABOSUN trial, we could say that cabozantinib can also expect to show efficacy for any lines of treatment. And with that judgment, now with regardless of line of treatment, we think we can expect efficacy from cabozantinib for the Japanese patient as well. Next page, please. This is about safety data of C2001 study. In this study, if you look at the profile of AEs, this is comparable to that of the METEOR study. So the results are similar to the results of non-Japanese. So Japanese and non-Japanese, there was a slightly different AE profile. But all of these adverse events were well-managed with supportive care and dose modifications. And discontinuations due to AEs were 5.7%, and the cabozantinib arm of METEOR study discontinuation due to AEs were 13%. So actually, such discontinuation was lower in this Japanese study. So CABOSUN trial, METEOR trial and C2001 trial, if we judge from all 3 trials, we can say that we can expect safety as well as efficacy of cabozantinib in the Japanese population as well. And based on this trial, we are submitting in Japan as well. And for the indication in Japan, this will be regardless of treatment of line. And also, as for the guidelines, cabozantinib is recommended for all 3 treatment lines, starting from first to the third line. This is about CheckMate -9ER study looking at the efficacy data. This study for first-line RCC patients, we are comparing nivolumab plus cabozantinib compared with sunitinib. This is a Phase III global trial, and we took part in this trial from Japan. As you can see from this data, this is looking at efficacy of the overall population, and this is untreated patients, advanced and metastatic RCC patients. And PFS and OS and ORR, in terms of all these endpoints, this combination had an improvement. Baseline risk and bone metastases and other were used for stratification, and we were able to show consistently the clinical benefit of the combination. And for advanced and metastatic untreated RCC, this combination can become a standard of care for patients with advanced or metastatic untreated RCC. Page 77, please. So this is once again, CheckMate -9ER study, and we are now looking at safety data. So just as we introduced in other clinical trials, we have different drugs. Therefore, the safety profile is slightly different between the 2 arms. But with dose modifications and through supportive care, more or less, those AEs were manageable. And discontinuations due to AEs were also comparable between the 2 arms. Next, Page 78, please. So I have been talking about clinical development for RCC so far. Now I'd like to turn to other indications. At the top of the slide, we are looking at monotherapy cabozantinib trial, and this is for HCC. Overseas, CELESTIAL study Phase III trial has been conducted, and this was a comparison against placebo. Cabozantinib monotherapy was evaluated against placebo in this trial. And based on the results of this trial, approval was obtained overseas. Japan did not take part in this study. So just like for renal cell carcinoma, we conducted a monotherapy single-arm trial in Japan. This was a Phase II trial. And putting together with the data from CELESTIAL study, we were able to get an approval for the same indication. And at the bottom, we are looking at the development plan with the combination with atezolizumab. So CONTACT-01, -02 and -03 trials, global Phase III studies are there. We are taking part from Japan as well. And indications are non-small cell lung cancer and the castration-resistant prostate cancer and advanced renal cell carcinoma, respectively, for these 3 trials. Page 79, please. Finally, I'd like to talk about product positioning of cabozantinib in Japan. So Page 80, please, now. So talking about the positioning in Japan, we have developed some indications here, RCC, HCC. And right now, we have a clinical trial for non-small cell lung cancer and also for CRPC. And those indications and diseases have just limited number of treatment options, and efficacy is also limited. This means there are high unmet medical needs. That's why we decided to conduct clinical trials. VEGF receptor, MET and AXL, all are inhibited at the same time. In that regard, cabozantinib is unique. That is why it can become a new treatment option. And on top of monotherapy of cabozantinib, when it's combined with immune checkpoint inhibitors, we can even broaden indications and target populations. As for RCC, especially for first-line treatment, monotherapy and also combination with nivolumab, we have developed this compound for both indications. But for the first line, as I explained, with the mode of action of cabozantinib compared to monotherapy administration combination with nivolumab, efficacy can be -- higher efficacy can be expected. But it may not be for all the patients. For instance, if patients have autoimmune diseases, nivolumab may not be administered. Therefore, monotherapy versus combination therapy, we have developed both. And I think there is significance in that. And we have ongoing studies in combination with atezolizumab, and we expect to see further additions of indications. Talking about launch projections, for RCC combination with nivolumab untreated patients, now right now, this is under review, and approval is expected in December 2021. And as for combination with atezolizumab, 2024 is the expected date for all these indications. That's all from me for cabozantinib. Thank you for your attention.

Thank you very much. Now we'd like to take questions. [Operator Instructions]

[Operator Instructions]

This is Yamaguchi speaking. Can you hear me?

Yes, we can.

I have 2 questions. My first question may not be directly relevant to R&D. But -- well, you gave us 3 product presentations. And talking about the global revenue, I think you gave us a rough guidance, but in Japan, well, of course, it depends on indications. But could you give me some rough images, if you can disclose of expected peak revenue for each product over those 3? And ALUNBRIG, niraparib and cabozantinib, they are existing products in the market, and you are launching those. In the case of ALUNBRIG, the ALECENSA and [indiscernible] and LYNPARZA, those were available for each. And what are the differentiation points compared to those existing drugs? I'd like to ask you to highlight any major single point of differentiation of each.

First, about the peak sales. This is Iwamuro of IR. I'd like to discuss this. Concerning ALUNBRIG, global revenue, $800 million to $1 billion. That's the disclosed number. And ZEJULA and CABOMETYX, it is only the right for us to sell and market in Japan. So we don't disclose individual peak sales for these 2 products. I apologize for that. And differentiation points for each product, I'd like to have the answers given from each person in charge. Thank you, Yamaguchi-san. First about brigatinib, Hiraoka would like to explain.

As you asked the question in Japan, alectinib is mostly the standard of care. And under such environment, still ALK+ NSCLC has poor prognosis. Especially with brain metastases, there is no sufficiently effective treatment available. And brigatinib showed treatment efficacy with data in patients with brain metastases. And also there is a resistant mutation of ALK, and also it's in nonclinical. Brigatinib demonstrated broad efficacy. Therefore, I believe that we'll be able to contribute to a wider population of patients.

Next, niraparib, I would like to talk about data, Soeda speaking, especially in the first-line maintenance therapy, niraparib as monotherapy or [indiscernible]. And regardless of the biomarkers, this is the only PARP inhibitor indicated with approval, and in late-line therapies, this is the only approved PARP inhibitor. Therefore, that's a differentiation from olaparib.

Next is about cabozantinib, I'd like to explain. I am Kimura. Cabozantinib and the lenvatinib is a comparison you mentioned. And concerning RCC, lenvatinib is approved for the first line but cabozantinib in the second and later lines. Therefore, treatment lines are different. So it is easy for us to demarcate. And concerning RCC, cabozantinib and nivolumab, we have already filed for approval. That's a regimen we submitted. And also the lenvatinib and pembrolizumab combination in the same lines, that's also studied right now. They would compete directly. And looking at the study design, it is compared to sunitinib. So it looks similar. However, looking into more details about the target population, their demographies are different. Therefore, we cannot simply compare. And cabozantinib and nivolumab combination, as I mentioned in my presentation, PFS, OS and ORR, in all those 3 efficacy endpoints, the significant benefit was shown. And also patient with metastases without any differences from overall population, efficacy was demonstrated. And also, I didn't touch it today, regarding QoL compared to sunitinib, the very nice benefit was also demonstrated in our study. And therefore, I believe that, to the patients and also to the attending doctors, this could be a very good treatment option.

This is Hashiguchi from Daiwa Securities. I have three questions. The first question, for each drug, the characteristics of Japanese markets can be considered, and it will be different positioning from the U.S. market. If there are some points that you can emphasize, please, mention. In the U.S., the positioning may be established with approval. But here in Japan, can we expect it to be approved and used in the similar manner here in Japan? The patient characteristics and the doctors' options and that is available and how they decide on which medication to be used, if it is different from the U.S., please let us know. And brigatinib, the ALTA 3 study was introduced. After the results become available, what is the impact on sales? What can we expect? In the first line, alectinib has a very high share in the market. And the clinical question is, after alectinib failure, how will it be used in the second line? I think that is the mostly important point that we need to consider. So crizotinib failure patients, what is the outcome going to be? What kind of impact will it have on the second-line options? Or in the first line, if brigatinib is going to be an option, crizotinib failure results, how is the decision made whether to choose brigatinib or alectinib? That is my question. And Page 8, please. This is talking about the pipeline of the Japanese oncology business and relugolix is not included. This is for prostate cancer. In Asia, including Japan, I think Takeda is working on this drug. So can you talk about that drug as well?

So for each of the drugs, how it will be used differently from the U.S. market and the differences in the trend will be explained by each of the presenters.

Thank you very much for your question. First, I want to talk about brigatinib. This is Hiraoka speaking. When it comes to brigatinib, as for the approval and indication for first line and second line, it is simultaneous here in Japan and U.S. And when it comes to treatment, alectinib is across the SOC, standard of care. So I don't think there is a major difference. However, when we look at the first line and the second line, brigatinib is being used widely, and we hope that it will expand.

I want to talk about niraparib. So the difference between Japan and U.S., I don't think there is a major difference. But ovarian cancer, rucaparib is being approved. And late-line treatment, olaparib and rucaparib is used in the third line for mutated patients for BRCA. And in the U.S., there are many PARP inhibitors available in the market. But here in Japan, we are competing against olaparib and also niraparib.

I want to talk about cabozantinib. When it comes to the indications, there were several indications that I introduced to. But here in the U.S. and Japanese market, I don't think there is a major difference. When it comes to RCC and also HCC, we were conducting trials in Japan following the trials in the U.S. for approval. But the 3 CONTACT studies that I mentioned, Japan participated in the global collaborative study, and we will be included in the development with overseas markets. So I don't think there is much of a difference between the U.S. and Japan.

Thank you very much. Hiraoka-san, can you talk about ALTA 2 study, please?

No, I think it was a question on ALTA 3, ALTA 3 study. So Page 27, please. So this ALTA 3 study for crizotinib, if there was a resistance to ALK treatment. So second line, alectinib and also brigatinib, this was a comparison study in the Phase III. And second-line ALK drugs, the randomized study was not conducted so far. So this data is very interesting when it comes to such a study. But this study itself is looking at brigatinib and alectinib. This is looking at the superiority against it in the second line. And the other target is the ALTA study was conducted before. And this was 2-arm study, and this was done on a reconfirmation basis. And the results of this study will show whether it is efficacious in the first line. And at the moment, we cannot give you any comments as to the results that will come in the future. The ALTA 3 study data is going to come in the -- in 2021. The interim data will be available in 2021, but the time line may change in the future.