Ladies and gentlemen, welcome to the Basilea Pharmaceutica's half-year results 2019 conference call and live webcast. I'm Sandra, the Chorus Call operator. I would like to remind you that all participants will be in listen-only mode and the conference is being recorded. The presentation will be followed by a Q&A session. You can register for question at any time by pressing star and one on your telephone. For operator assistance, please press star and zero. The conference must not be recorded for publication or broadcast. At this time, it's my pleasure to hand over to David Veitch, Chief Executive Officer. Please go ahead, sir.
Thank you. Hello, this is David Veitch, CEO of Basilea. I would like to welcome you all to our conference call and webcast reviewing our financial results and key achievements for the first half-year 2019, and also review our upcoming milestones and financial guidance for the full-year 2019. I would like to mention that this call contains forward-looking statements. This morning, we issued a press release and financial report on the results of the first half-year 2019. These documents are available on our website at basilea.com. Joining me today on the call are Adesh Kaul, our Chief Financial Officer, and Dr. Marc Engelhardt, our Chief Medical Officer. For those on the call who are less familiar with Basilea, we focus on the research, development, and commercialization of innovative medicines that address the medical challenges in the therapeutic areas of oncology and infectious diseases.
Basilea has a proven track record of progressing brands from research through clinical development to commercialization. We have successfully brought two anti-infective brands to the market, our antifungal Cresemba and ZEVTERA, our broad-spectrum antibiotic that also covers MRSA. We continue to make great progress establishing Cresemba and ZEVTERA as global brands. In the first half of 2019, we saw continued strong revenue growth, including a substantial increase in the revenue contributions from Cresemba and ZEVTERA. We also made significant progress in our clinical stage programs and have been able to strengthen our preclinical pipeline through in-licensing collaborations. I would like to provide a brief summary of the financial results and development milestones we've achieved. We significantly increased the revenue from Cresemba and ZEVTERA by 91% year-on-year to CHF 53 million, reflecting both the growth from the first launch markets, but also initial contributions from newly launched markets.
We improved our operating result for the first half-year 2019 by 35% compared to the same period last year. I am also pleased to report a half-year cash position of CHF 178 million, which provides us with the necessary flexibility to continue moving forward towards additional value inflection milestones in 2019 and beyond. We also made significant progress in our late-stage clinical development. We reported positive phase III top-line results for the TARGET study with ceftobiprole in skin infections. This is a major milestone towards bringing ceftobiprole to the important U.S. market. We also expanded our derazantinib clinical program. After reporting positive interim results from the phase II study in intrahepatic cholangiocarcinoma, we recently initiated the phase I/II study in patients with advanced urothelial cancer, in combination with Roche's immuno-oncology drug, TECENTRIQ, to broaden the therapeutic potential of derazantinib.
Adesh will now give you an update on our commercial progress and also present financial highlights for the half-year 2019, as well as our financial guidance for 2019. Marc will provide you with more detailed information on the progress of our clinical development programs. Lastly, I'll provide you with an outlook for the remainder of 2019 and beyond. I'll now hand over to Adesh.
Thank you, David. In the first half of 2019, we together with our partners, continued to make significant progress in the commercialization of our two hospital anti-infective brands, Cresemba and ZEVTERA. The most current public in-market sales numbers available for Cresemba show that in the 12-month period ending March 2019, the global in-market sales of Cresemba grew by 43% year-on-year to approximately $170 million . This impressive performance is driven by a continued strong sales uptake in the U.S. and early launch countries in Europe. Going forward, we expect growing contributions from new and recently launched markets, adding to the continued growth in the more established markets. In the U.S., Astellas reports Cresemba sales for January to June 2019 of $67 million . For its fiscal year 2019, from April 2019 to March 2020, Astellas guided for $143 million in Cresemba sales, representing an expected 20% growth year-on-year.
Cresemba sales are increasing in Europe, too. As reported in January, the strong sales performance in Europe triggered a CHF 5 million milestone payment from Pfizer. While there is significant growth potential from the existing markets, an important factor for maximizing the global value of our brands is to continue to expand the geographic reach. We are pleased with the progress that our partners have made in 2019 so far in this respect. In the first half-year 2019, Cresemba was launched in 14 additional countries. It is now marketed in 33 countries globally. ZEVTERA was launched in Jordan and has now been launched in a total of 17 countries. We expect further launches of ZEVTERA around the world over the coming months and years. Our partners are well on track to reach the goal of 40 launched countries for Cresemba by the end of 2019.
This would double the number of countries from the end of 2018. We anticipate this number of launch countries will increase to 60 by the end of 2021. Our license and distribution partnerships for both our marketed products now cover more than 100 countries worldwide. They play an important role in the execution of our global commercialization strategy and provide a strong basis for future revenue growth of our brands. Basilea participates in the commercial success of both Cresemba and ZEVTERA through royalties or a transfer price structure. In addition, we already realized around CHF 245 million in upfront and milestone payments and could receive up to CHF 1.1 billion in potential future regulatory and sales milestone payments from our partnerships. Turning now to ceftobiprole, our anti-MRSA broad-spectrum antibiotic, which is marketed in most countries under the brand name ZEVTERA.
Our key priority for ZEVTERA is to gain access to the U.S. market. MRSA remains an important healthcare issue, and resistance rates are still high. In the U.S., MRSA rates of 45% have been reported, which are among the highest in the world. The U.S. clearly is the most important country for the commercialization of MRSA-branded hospital antibiotics. For individual products, the value share may go up to 90%, as seen for daptomycin, which is a standard drug for the treatment of MRSA infections in the hospital, and also for ceftaroline, which is a patent-protected anti-MRSA cephalosporin hospital antibiotic. Marc will provide you with an update on the progress we have made towards a potential U.S. filing for ceftobiprole based on the positive results of the phase III TARGET study. Moving on to financials.
I will highlight some of the key financial figures that were published in today's press release and in more detail in the half-year report. I'd like to mention that all the figures I will refer to are in Swiss francs. The financials for the first half-year 2019 are characterized by a significant increase of the revenue contributions from our two marketed products, Cresemba and ZEVTERA. This increase more than offset the impact from the completion of the non-cash revenue recognition related to our former hand eczema brand, Toctino. Total revenue increased by 5%, from CHF 59.9 million to CHF 63.2 million. The increase was mainly driven by higher revenue contributions from Cresemba and ZEVTERA, which increased 91%, from CHF 27.7 million to CHF 52.9 million. Our total cost and operating expenses declined by 5%, from CHF 80.3 million to CHF 76.4 million.
The operating loss in the first half-year 2019 improved by 35%, from CHF 20.4 million to CHF 13.2 million. Net cash used in operating activities was reduced significantly by 25% to CHF 45.4 million, compared to CHF 60.4 million in the first half-year of 2018. This improvement is a result, on the one hand, of the significant increase in cash flow generated from Cresemba and ZEVTERA, and on the other hand, of Basilea's continued focus on managing its operating expenses by continuously optimizing its preclinical and clinical portfolio and targeting its investments into its R&D pipeline. As of June 30th 2019, Basilea's combined cash and short-term investments amounted to CHF 177.9 million. In the first half of 2019, we lost CHF 18.8 million in revenue from the non-cash deferred revenue recognition related to the Toctino transaction.
We were able to more than offset this decrease through a CHF 25.1 million increase in revenue contributions from the two marketed products, Cresemba and ZEVTERA. In addition, we reported CHF 3.2 million lower BARDA revenues in the first half of 2019. This decrease is a result of lower costs related to the completed ceftobiprole phase III skin infection study, resulting in lower reimbursements from BARDA in the first half-year 2019. Moving to expenses. Total cost and operating expenses decreased from CHF 80.3 million in 2018 to CHF 76.4 million in the first half-year 2019. The decrease is mainly driven by a CHF 7 million decrease in R&D expenses. Cost of products sold increased by CHF 2.9 million, largely reflecting increasing product deliveries to our partners. SG&A expenses remained basically flat. Coming now to our financial guidance for the full-year 2019.
Based on our key priorities for the second half of 2019, which David will outline shortly, we provide the following guidance for the full-year 2019. Total revenue is expected to amount to between CHF 128 million and CHF 133 million. This is at the lower end of our previous guidance because of the lower than previously anticipated BARDA reimbursement due to the lower than anticipated costs for the successfully completed phase III skin infection study with ceftobiprole. Most importantly, we anticipate continued significant revenue growth from Cresemba and ZEVTERA in the range of CHF 105 million to CHF 110 million for the full-year 2019, which is an anticipated increase of 28%-34% over 2018 and at the high end of our previous guidance.
For the full-year 2019, we expect operating expenses to remain at approximately the same level as 2018, leading to an anticipated operating loss of CHF 22 million-CHF 27 million, narrowing our previous guidance around the same midpoint. We anticipate net cash used for operating activities to further decrease in the second half of 2019 as compared to the first half-year, resulting in an anticipated net cash consumption of CHF 60 million-CHF 65 million for the full-year. I will now hand over to Marc for the clinical development update.
Thank you, Adesh. Let me continue further with our antibiotic ceftobiprole. We have just reported positive top-line results from the so-called TARGET study, a phase III study in patients with Acute Bacterial Skin and Skin Structure Infections, also known as ABSSSI. The TARGET study was a randomized double-blind phase III non-inferiority study and enrolled 679 patients. It was conducted at more than 30 clinical centers in the U.S. and Europe. Patients received either ceftobiprole given intravenously three times daily or the comparator regimen of twice-daily intravenous vancomycin plus aztreonam. Ceftobiprole met the pre-specified primary endpoint of early clinical response at 48- 72 hours after start of study drug administration in the intent-to-treat population. This is the key endpoint according to the FDA guidance for the U.S. and includes all randomized patients. To achieve this endpoint, the initial skin lesion size had to decrease by 20% or more from baseline.
Response rates were 91.3% with ceftobiprole versus 88.1% for the comparator. Ceftobiprole also met the pre-specified secondary endpoints of investigator-assessed clinical success at the test-of-cure visit 15- 22 days after randomization. This is the key endpoint for the EMA in Europe. In the ITT population, clinical success was shown in 90.1% versus 89%, and in the clinically evaluable or CE population in 97.9% versus 95.2%. The CE population is the subset of patients in the ITT population with no major protocol deviations. In the TARGET study, the CE population was approximately 85% of the ITT population. In summary, ceftobiprole was non-inferior to vancomycin plus aztreonam for the treatment of ABSSSI, and the key endpoints for the FDA and Europe were both met.
Success rates showed a trend in favor of ceftobiprole, and the lower bounds of the 95% confidence intervals were all well within the pre-specified non-inferiority margin of 10%. Positive results were consistent in an analysis by region for the U.S. and Europe. Ceftobiprole was well-tolerated in the TARGET study. The overall rates of drug-related adverse events were 20% for ceftobiprole and 18% for vancomycin plus aztreonam, and are similar between the two treatment groups. The most common drug-related adverse events in both treatment groups were nausea, diarrhea, and headache, and the safety profile of ceftobiprole in the TARGET study was consistent with the known safety profile from earlier studies. The successful TARGET study is a major milestone towards the filing in the U.S.
Importantly, the second phase III study in Staphylococcus aureus bacteremia of bloodstream infections, a study called ERADICATE, is well on track and is expected to deliver top-line results as planned in the second half of 2021. The phase III program for ceftobiprole is funded up to approximately 70% by the Biomedical Advanced Research and Development Authority of BARDA, which is part of the U.S. Department of Health and Human Services. This allows us to advance the development of ceftobiprole for the U.S. market in a cost-effective way. If the bacteremia study is also positive, Basilea plans to submit a new drug application to the U.S. FDA. Ceftobiprole is designated a qualified infectious disease product by the FDA for these indications. If approved, ceftobiprole will be eligible to receive 10 years of market exclusivity in the U.S. from the date of approval. Moving on to oncology.
Our lead oncology drug candidate is derazantinib, which we in-licensed in 2018 from the U.S. company ArQule. Derazantinib is a targeted orally available small molecule inhibitor of the fibroblast growth factor receptor, or FGFR, family of kinases, with the strongest inhibition seen with FGFR1, 2, and 3. Derazantinib also inhibits the colony-stimulating factor 1 receptor kinase, or CSF1R kinase, which has been identified as an important target in the modulation of the tumor immune microenvironment, and this supports combination studies of derazantinib with immune checkpoint inhibitors. In January 2019, we reported encouraging interim results from the registrational phase II study called FIDES-01 in the second-line treatment of FGFR2 fusion-positive iCCA. The FIDES-01 study is expected to report top-line results in mid-2020 in iCCA patients with FGFR2 fusions. This could potentially allow for accelerated approval in the U.S. in iCCA.
We have furthermore expanded the FIDES-01 study in June with a new cohort of iCCA patients with FGFR2 gene mutations or amplifications in their tumors. Through this new cohort, we intend to further define the full therapeutic potential of derazantinib in patients with iCCA. As mentioned earlier, derazantinib also inhibits the colony-stimulating factor 1 receptor, or CSF1R kinase, which is involved in the regulation of tumor-associated macrophages and immune response in cancer. Preclinical data has shown that tumor macrophage modulation through CSF1R blockade renders tumors more responsive to T-cell checkpoint immunotherapy, including approaches targeting PD-L1 and PD-1. CSF1R kinase inhibition may thereby improve the susceptibility of tumors to immunotherapy. Additionally, in urothelial cancer, patients with low PD-L1 expression, which has been associated with reduced responses to immunotherapy, show frequent FGFR genomic abnormalities. Derazantinib combined with PD-L1 inhibitors may address several oncogenic mechanisms and provide a new therapeutic paradigm.
The inhibition of CSF1R by derazantinib seems to be a unique feature for derazantinib compared to other FGFR inhibitors, this is supported by chemical structure analysis, which show that derazantinib fits better into the CSF1R binding pocket than other FGFR inhibitors, such as erdafitinib. The CSF1R inhibition may be important in the treatment of urothelial cancer may have a broader utility to support combination studies in other cancer types. We have recently started a phase II study with derazantinib as monotherapy and in combination with ROS PD-L1 blocking immune checkpoint inhibitor atezolizumab, TECENTRIQ, in a biomarker-driven multi-cohort clinical study in patients with advanced urothelial cancer. The name of the new study is FIDES-02. FGFR aberrations play an important role in many other cancers beyond iCCA or urothelial cancer, including gastric, breast, and lung cancers.
We are currently conducting significant preclinical translational work, this is being done in order to identify and prioritize further indications and patient populations which may benefit from treatment with derazantinib as a single agent or in combination with other cancer therapies. Moving now to our tumor checkpoint controller, BAL101553. We continued our activities in the field of glioblastoma, the most common and aggressive form of primary malignant brain tumors, and also an area of high unmet medical need with very few treatment options available. We are currently conducting three clinical study with BAL101553 in this indication. In Switzerland, a phase II-A expansion study in patients with recurrent glioblastoma is ongoing using weekly four-day hour infusions. A separate arm in this study also includes patients with platinum-resistant ovarian cancer. This study is anticipated to complete enrollment around year-end 2019.
In the U.K., the phase I dose escalation study is ongoing in patients with recurrent or progressive glioblastoma using daily oral administration of BAL101553. The study is close to completion with the aim to define the maximum tolerated dose. Finally, a phase I study is ongoing in the U.S. in patients with newly diagnosed glioblastoma using oral BAL101553 in combination with radiotherapy. This study is conducted in collaboration with the Adult Brain Tumor Consortium, ABTC, which is funded by the U.S. National Cancer Institute. Enrollment into this study could be completed by mid-2020. For BAL101553, we had previously identified a potential response-predictive biomarker called end-binding protein 1, or EB1, based on comprehensive preclinical studies in glioblastoma models.
In the ongoing clinical phase I study with daily oral dosing of BAL101553 in patients with recurrent glioblastoma, we have seen an exceptional durable response. With a patient who's ongoing for more than 15 months in the study, and shows an approximately 70% area reduction of the GBM tumor. The GBM tissue investigations performed in this study showed a strong EB1 expression in the GBM tissue of this responding patient, while non-responding patients did not show this pattern of strong EB1 expression. We are therefore assessing the potential utility of EB1 to support a biomarker-driven clinical program in GBM, and potentially other cancer types, and the use of BAL101553 as a targeted therapy in patients whose tumors show high EB1 expression. Moving on to our third oncology drug candidate, the pan-RAF kinase inhibitor, BAL3833.
As previously reported, the first-in-human phase I dose-escalation study with the oral formulation of BAL3833 in patients with solid tumors was completed without defining a maximum tolerated dose. The oral formulation explored in this study did not achieve consistent drug levels in patients. Based on the observed pharmacokinetics in the phase I clinical study, we do not intend to move forward in clinical development with this formulation. However, preclinical activities are ongoing to see if there are alternative ways forward with reformulated drug candidates. Finally, Basilea has entered into licensing and research collaborations for preclinical compounds in its strategic focus areas of oncology and infectious diseases. Thus, we are strengthening our pipeline to provide potential clinical assets for the future. I will now turn over to David.
Thank you, Marc. In summary, we are on track with the execution of our strategy in terms of both significantly growing our revenues and advancing our R&D portfolio. We have already achieved the majority of the development goals we set for 2019. For this second half of the year, there are two additional milestones for BAL101553. As Marc indicated, we anticipate to complete enrollment into the phase I study with the oral formulation in patients with recurrent glioblastoma, and we also expect to complete the phase II-A study with 48-hour infusion in patients with ovarian cancer and glioblastoma. Operationally, we will continue to focus on increasing our cash-generating revenues from both our marketed brands, Cresemba and ZEVTERA. We will advance the derazantinib registrational phase II study in intrahepatic cholangiocarcinoma and the phase I/II study in urothelial cancer towards data readouts in 2020.
We will progress the phase III study with ceftobiprole in Staphylococcus aureus bacteremia towards top-line results in the second half of 2021. Finally, we will continue to explore opportunities to selectively expand our clinical and preclinical oncology portfolio through both in-licensing and internal development. We will now open the line for your questions.
We will now begin the question and answer session. Anyone who wishes to ask a question may press star and one on the touchtone telephone. You will hear a tone to confirm that you have entered a queue. If you wish to remove yourself from the question queue, you may press star and two. Participants are requested to use only handsets while asking a question. Please note, only three questions may be asked in a row, then the line will be open to others. You can get back in the line again for any follow-up questions. Anyone who has a question may press star and one at this time. The first question comes from Louise Chen from Cantor. Please go ahead.
Hi. Thanks for taking my questions here, and congratulations on the quarter. My first question is the primary mechanistic advantage and disadvantages of the FGFR mechanism for the treatment of cancer, and what makes derazantinib safe and different from the other ones that are on the market or in development. Second question I had is back on derazantinib again. What other new indications will you pursue? Looks like you've already moved here on two, and I know there are others in the wings here, so anything on that front will be helpful. Last one here is on BAL101553, for the treatment of glioblastoma. Is there any interest in combination therapy with this product? Thank you.
Okay. Thank you, Louise. Actually, given the questions you've asked, I'll ask Marc. Could you start off with the FGFR mechanism in cancer, the comment on any different indications we might be looking at. Actually, they're probably all for you initially, and then 101553, the combination potential. Maybe Marc, you could.
Yes. As I've understood, the first question was about the mechanistics of the anti-cancer effect in FGFR genomically altered tumors, and the differentiation of derazantinib. I think today we know that at least two tumor types really have, where FGFR is a strong oncogenic driver, which is iCCA and urothelial cancer, where several FGFR inhibitors have shown significant and really substantial therapeutic benefit. There are other indications that are currently being explored. Some companies do basket study, others look at indication. We have done a lot of translational work and also feel confident to expand our reach in terms of cancer indications beyond urothelial and iCCA, and we will update on these plans later in the year. In terms of the differentiations, we believe when looking at the various FGFR inhibitor in clinical development, that there is differentiation between these compounds on their kinase inhibition profile.
One of the points we've made during our presentation is that derazantinib also inhibits CSF1R, which may be quite important in the combination therapy with immunotherapy agents. We also see differences in the safety profile of the various compounds. There are some compounds which cause a higher rate of ophthalmic events, including retinal events. There's difference in nail toxicity and hand-foot syndrome, and this may all impact the ability to combine these compounds clinically. In short, the two really established indications currently is iCCA and urothelial cancer. There are additional indication that we are in the process of moving into at least one other indication based on the substantive preclinical work. The differentiation is really about pharmacology, kinase inhibition profile, and safety profile.
The 101553 combination potential?
It's certainly there. We have frequent data that have looked at combination with radiotherapy. Remember, we are conducting a study in the U.S. with the ABTC in newly diagnosed glioblastoma in combination with radiotherapy, and the support by the ABTC that we obtained was really based on the preclinical data in combination with radiotherapy. We also have studies with triple combinations, including temozolomide, which are very promising. In addition, we have several preclinical studies combining with Herceptin or Avastin that may become relevant when we talk about GBM. As said, this would be future plans. At the moment, we are looking into the combination with radiotherapy, and as we've indicated during the presentation, we're looking into strong EB1-expressing tumors and may use this as a potential enrichment biomarker for future clinical programs.
Okay, thank you.
Next question comes from Bob Pooler from valuationLAB. Please go ahead.
Good afternoon, gentlemen. Congratulations with the excellent first half results and also the positive top-line TARGET results there. Mine's three questions, if I may. First, on Cresemba. At the moment, most of the sales are generated in the U.S. Do you expect with the global rollout that Europe and the rest of the world will overtake that and become more than the U.S. going forward? Second question is on ZEVTERA. With the TARGET results in the pocket, do you expect to start negotiations commercialization rights in the U.S., or are you still going to wait for ERADICATE results there? The third question on derazantinib. What is the expected trial duration of this FIDES-02 trial in urothelial cancer, and could you indicate what kind of peak sales you're envisaging for this indication? Thank you.
Okay. Thanks, Bob. I'll kick off with the sales of Cresemba, and then I'll hand over to Adesh and Marc for the other questions. Yes, you're correct. If you look at the sales now, and you can look at this from the IQVIA sales that Adesh alluded to, the $170 million of 12-month sales to the end of March, that more than half of them are from the U.S. That's largely because of the fact that the market access in the U.S. is quick, but also the U.S., you may remember the FDA approval was before the EMA approval. We launched in the U.S., or Astellas launched in the U.S. in March, April 2015, whereas it wasn't really launched Cresemba until 2016 in Europe.
The U.S. got off to a strong start, and it's growing still nicely, but it's a significant part of the sales. Ultimately, to come back to the other part of your question, ultimately, if you look at voriconazole, which I guess you could say is the best benchmark for us in terms of the previous gold standard for invasive aspergillosis. voriconazole global sales at peak were about 25% in the U.S. Actually, unlike what Adesh was commenting on for ZEVTERA, where we believe the U.S. is clearly the most important market for Cresemba, ultimately at peak, if we mirrored voriconazole, then the U.S. would be about a quarter of the global sales. Obviously, for us to materialize that and for that to happen, we need to launch in all the other major markets of the world, which we're currently planning to do.
That gives you an indication of ultimately, the U.S., if it was to follow the voriconazole pattern, should be around the 25% of global sales. Whereas at the moment, it's significantly more than that because of the reasons I've said. That's a comment on Cresemba. Maybe, Adesh, you could take the ZEVTERA commercialization strategy.
Sure. As you already implied, Bob, in your question, our preferred option for the commercialization of ZEVTERA in the U.S. will be partnering. Absolutely confirmed. We are constantly, as you know from our past discussions, in discussions with potential partners. As part of our strategy, we will also discuss the positive TARGET study results with partners. We're not necessarily in a rush because, from a registration perspective, the driving factor or the timing is driven by the bacteremia study readout, which will be in the second half of 2021. For us, it will be important rather to find the right partner that will allow us in the right financial structure to optimize the value of the asset rather than rushing into a partnership.
Marc, do you want to comment on the FIDES-02 trial duration?
Yes. This is a study that will have several sub-study or cohorts in different therapeutic setting, including second-line post-chemotherapy, post-immunotherapy patients, also first-line platinum-ineligible. We have a cohort in patients who had progressed on prior FGFR inhibitors to see how derazantinib works in that setting. The entire study will, if we run all cohorts, including follow-up, will go for approximately three years. We expect in the next 12-18 months to have readouts from the ongoing cohort. This will be a staggered approach with a staggered set of readouts. The total trial duration is probably about three years. The final point was around the peak sales potential of derazantinib in the urothelial cancer indication.
As for other products, I'll take that question, Bob. As for other products, other indications will not really provide peak sales estimates. I think it is safe to say that urothelial cancer represents a significant market opportunity. It's the sixth most frequent cancer type in the U.S.. There are about 80,000 new cases reported in the U.S. on an annual basis. Of those, about 20% have an advanced disease or metastatic disease. Within that population, I think there is some variance about estimates how many are FGFR positive. I would guess somewhere in the range of 20% is a safe bet. We're talking about 3,000 new cases in the U.S. alone on an annual basis. If you take sort of the G7 countries, you would take that number probably to close to 8,000 cases per year.
That should give you some indication. I think the peak sales at the end will then depend on the clinical benefit provided in this patient population, the duration of response, how long are they being treated, and then ultimately the pricing, which is also then a function of the clinical benefit that we'll be seeing out of the clinical trial. Therefore, there is sort of some guesswork that you would have to do.
Well, very clear, very describing the market there. Thank you for answering the question.
The next question comes from Victor Floc'h from Bryan, Garnie r. Please go ahead.
Hi, guys. Thanks a lot for taking my question and congrats on the results. Actually, I have two questions about BAL101 553. First one, I was wondering if you have any epidemiological data regarding the frequency of the EB1 expression in patient with glioblastoma. Second question, when are you expecting to present results from the phase II-A study? Thank you.
Okay. Thank you. Marc, I guess they're yours.
Yeah. I'll start with the second question. We'll report results from the phase II-A study with the 48-hour infusion towards the end of the year. The other question about the EB1 epidemiology, that's currently something we are looking into. There is not much published on this topic, and it also depends on the methodology of the staining method. We believe that from what we have stained so far in the clinical trial, that this is not a very frequent condition which supports that this could be quite something specific and targeted. This doesn't have a massive abundance. We've been staining a couple of samples from the clinical trials asset, which points into the direction this is quite specific. These are very good conditions to run a biomarker enrichment design, because it could be quite a very specific biomarker for BAL101553.
Just to reinforce what Marc said, it's a very good question, and it's clearly one of the key questions we're asking at the moment, and we're trying to find the answer to that and do the analysis to understand what is the epidemiology of the EB1 incidence in GBM, and for that matter, other tumor types.
Correct. To also understand whether there's a genomic underlying pattern for a strong EB1 expression. We're not looking at this purely from a staining epidemiology, but we'd also like trying to understand the underlying genomic patterns of it.
Okay, got it. Thank you, guys.
Next question comes from Brigitte de Lima with goetzpartners securities. Please go ahead.
Good afternoon. I'd like to ask three questions on the anti-infectives portfolio. The first one would be on Cresemba. Can you remind me if you expect Cresemba to be launched in the APAC region this year? Specifically, I'm wondering if that would trigger a milestone payment as well. The other two questions on ceftobiprole. Can you remind me if it was ever on the cards to file the skin infection in Europe as a label expansion, given the data is so strong? Maybe you've discussed this in the past, but I was just wondering if you thought the competitive environment is conducive to adding another antibiotic to skin infections. The third question would be on this recent initiative announced in July, where the NHS will test a subscription service for anti-infectives. We've been seeing this coming.
The FDA talked about this, it seems to be happening now. To what extent might you be involved? Is ZEVTERA potentially one of the antibiotics that could be trialed? Have you heard anything about other health systems, other countries planning to do something similar in the near future? I'll stop here.
Okay. Thank you, Brigitte. In terms of Cresemba and the APAC launches, Adesh, do you want to comment on that point?
Hi, Brigitte. The regulatory process in many countries outside of Europe and the U.S. is not as clearly defined timing-wise, so it's difficult to point to anything that is equivalent to a PDUFA date, so it's hard to say when exactly we would see launches in the APAC region. What is important is that our partner for the region, Pfizer, has made submissions in really a number of countries in the APAC region, and therefore we are expecting to really see a launch in the very near future in the first countries in that region. With regard to milestones, what I would say is that the milestones in our transaction with Pfizer are predominantly sales milestones.
Just to add one thing. Adesh commented on Pfizer being our partner for APAC. It depends if you call it in the definition, but Japan is not with Pfizer. Japan is with another partner, Asahi Kasei, and we previously explained that it's on track, and we're carrying out phase III. Our partner, Asahi Kasei, is carrying out a phase III study in Japan with regard to a potential filing in Japan for Cresemba. That's just in addition to what Adesh said with regard to the rest of Asia- Pac.
Thank you, David. In that collaboration, because that's more like a license agreement that we have, you would actually see regulatory and development milestones as well.
Okay. The comment about the skin with the strength of the TARGET data, would we file it?
I can take that as well. From a positioning perspective, just to be clear, for the U.S., we believe that the bacteremia study will be really the differentiator. However, as you pointed out correctly, the TARGET data is actually quite positive. Given just the number of patients with skin infections, we believe that even in the skin indication, there may be an interesting market opportunity. That's generally speaking, with regard to the U.S. strategy. Outside of the U.S., we are evaluating with our partners on a more or less country-by-country basis on the best strategy to leverage the data. There are considerations on the one hand of what kind of incremental sales would you be creating. On the other hand, you have to take into consideration what would be market access considerations, post-regulatory requirements that you may have, and so on.
That's really very individual from country to country, and we're in discussions with our partners. What we can do in any event is we can, of course, leverage and our partner can leverage the data in appropriate medical communication in the territories. We anticipate to publish the data, and as such, it will be available through the appropriate channels in the markets.
Yeah. Your comment about the U.K. policy initiative on antibiotics and have other countries come up with, or thinking of coming up with other similar initiatives? I'll try and say this very briefly because it's quite a big topic, of the so-called sort of pull incentives that the antibiotic manufacturers are looking for from policy changes in terms of stimulating a sort of greater commercial return for antibiotics. The two that we're aware of that have been sort of announced are the U.K. one that you mentioned in July. There was also a U.S. policy initiative mentioned in August. Both are trying to deal with this issue of trying to separate the commercial return from the volume usage of the products and try and make it more financially viable for companies bringing out new antibiotics. The U.K. one, we are working with our partner.
We obviously have a commercial stage partner in the U.K., Correvio, and we are working with our partner and exploring the potential for ZEVTERA to be included in, initially a pilot phase. The U.K. have announced that there's two compounds that would be in the pilot phase of their initiative. It's probably just worth saying whether or not we are included or not in the pilot phase, the U.K. commercial potential for ZEVTERA is very small because of MRSA rates and looking at the analogs for MRSA hospital antibiotics in the U.K. The U.S. becoming a more friendly, if you want to put it like that, environment for antibiotics is much more important for the reasons that Adesh said, the potential of MRSA agents in the U.S.
Therefore, the U.S. policy initiative that was mentioned in August, and there are other ones currently going through Congress that could potentially equally add to a more favorable commercial environment for antibiotics in the U.S. They're much more meaningful for us. Actually, to the question of are there other countries like France or Germany or anywhere else, other countries might be taking part in discussions, but we haven't as yet seen any results of those policy announcements that have come out of the U.K. and U.S. I hope that, in essence, attempts to answer your question, Brigitte.
Yes. Thank you. Very helpful. Go back in the queue. Thanks.
Thank you.
The next question comes from Brian White, Cantor Fitzgerald. Please go ahead.
Yes. Good afternoon. I was wondering just on Well, a couple of questions on derazantinib and the urothelial cancer indication, also another one on the study itself. Just thinking about the recent positive results for the TECENTRIQ, IMvigor130 in urothelial cancer. I know that there was no indication of response by PD-L1 type, I wondered if there was a risk that this might resolve some of the concerns that the regulators have with the use of checkpoint inhibition in urothelial cancer. As an adjunct to that question, I presume that you're measuring PD-L1 status in the FIDES-02 study as well. The final question is that this is an open-label study, I presume you are able to feed some interesting data as and when you have it. Thank you.
Yes. It's an open label study. We are seeing the data as they emerge. For the other question, I think the TECENTRIQ data is in combination with chemotherapy. It's not a targeted treatment for FGFR alterations. What we're seeing in urothelial cancer is that in the PD-L1 low part of the urothelial cancers, there is a nested enrichment of FGFR alteration. That's what we're primarily targeting and trying to see whether we can leverage the potential synergy of derazantinib and atezolizumab based on the CSF1R inhibiting properties of derazantinib. We feel that this has quite a limited impact on any potential patient pool being accessible to derazantinib because we're really looking specifically at this combination of PD-L1 low and FGFR alteration, and this was not the scope of the TECENTRIQ study. We are looking in every patient at the beginning at their PD-L1 status.
Okay, thank you.
The next question comes from Paul Verbraeken, Research Partners. Please go ahead.
Yes. Hello, gentlemen. Two questions, if I may. The first one about Cresemba in Europe. When do you expect Pfizer to take over manufacturing, and is it going to be a gradual process per country, or will it take place in one stroke? The second about BARDA. BARDA revenues went down following the phase III expenses, I guess. Should we, going forward, keep around this level, or do you think the BARDA revenues are going to go down any further going forward? That's it. Thanks.
Thanks, Paul. Thanks for your questions. Adesh, you.
Thanks, Paul. On your question about the Pfizer deferred revenues. Actually, as a matter of fact, you may have seen the footnote in our halfway report that we're expecting the complete remaining portion of the upfront payment to be recognized within the next 12 months. That, in essence, correlates with the timeframe anticipated for Pfizer assuming responsibility for manufacturing. That will happen in the course of 2020, or is anticipated as of today, in the course of 2020. Having said that, it is gradual in the sense not country by country, but step by step, because as you may know, manufacturing is like a multistep process. It starts with starting materials, API, drug product, secondary packaging, and so on. This is a gradual process, stepwise, but not country-wise. I hope this answers your question on the Pfizer manufacturing handover.
The second question about BARDA is, it is hard to really define in advance on a six-month period how much exactly will get reimbursed by BARDA, because the mechanism is simply that we are incurring costs and then we're being reimbursed for the costs. The costs correlate or are driven by the progress that we're making on the studies, including the geographic mix, how many sites are active, and so on and so forth. Generally speaking, we wouldn't expect that portion to go down because with the SAB study, which is continuing, we're still expanding on the number of sites being included in the study. We expect some ramp-up in the costs related to SAB in order to ensure that we have then the study completed and the top-line results available as announced in the second half of 2021.
Overall, I would think that the safest assumption is about flat going forward, and then with a winding down starting in the first half of 2021, and then with the remainder in the second half of 2022.
Okay, very clear. Thank you.
Thank you.
The next question comes from Sean Conroy from Edison. Please go ahead, sir.
Hi there. Thanks for taking my questions. Just going to start with a couple on Cresemba. How do you see pricing strategies evolving as Pfizer looks to launch in additional markets? Can you provide any more guidance on how the sales milestones, which are based on cumulative sales, how they're staggered? I've got another question about derazantinib afterwards.
Okay. Thank you, Sean, for the question. In terms of the pricing strategies and the evolution of the pricing strategies, obviously we don't get involved in detailed pricing discussions with our partners. What I would say is that the pricing, it has been usually benchmarked, the isavuconazole Cresemba launch price is usually benchmarked at the original VFEND and branded price definitely in the U.S. and across Europe. Obviously based on the fact that the data was superior in terms of safety in the pivotal invasive aspergillosis study and the fact that in the mucormycosis indication, the key drug that's really used there, apart from isavuconazole, that's active is liposomal amphotericin B, which is highly priced. Even though it's off patent, it's still highly priced in the market.
Actually that supports us having a good fair price for Cresemba, like I say, at a sort of similar level to the original VFEND and branded price. This is sort of like what we've noticed is the pricing across the globe so far. In terms of also has that affected the uptake, I think the answer to that is no. You can see that from the in-market sales, that the $170 million and 12-month sales to the end of March that we referred to earlier. That's in an environment where generic voriconazole is obviously, as you would usually expect with a generic pricing, is coming down all the time. I think it's clear to say that the physicians see the benefit of isavuconazole, so it hasn't precluded the uptake that we've seen so far of isavuconazole.
In terms of the pricing strategy, that's probably what I'd comment on. In terms of the Pfizer sales milestone and how that works and when they're hit. Adesh, do you want to comment on that?
You may have seen in our press release that we announced that the Pfizer milestones work on cumulative sales from the start of our agreement. They're set up in a way that they're triggered on average every 12-18 months. Given that they're on cumulative sales, the individual milestones are sort of lower. You can think about them as being more frequent, coming every 12-18 months, but being lower than what you would be expecting on an annual sales basis or with Astellas, for instance.
Okay, brilliant. That's good. Thank you for that.
Just as a reminder, the total for both territories together is still CHF 645 million in milestones that are outstanding from Pfizer. That's for the APAC region and for Europe.
Okay, thank you for that. If I could just ask one question about derazantinib. How do the development milestones and royalties that ArQule are eligible for, how do they vary as you expand the clinical development beyond iCCA?
That's a very good question. Again, as a reminder, the milestones, they are total milestones of CHF 326 million. They are predominantly sales milestones, which are not indication-specific, but also relating to the sales level that you'll be seeing for derazantinib. When it comes to the pre-sales or pre-commercialization milestones, they are largely separated by indication, but then also by territories. That's sort of the level of granularity that we can give. They are predominantly really sales milestones. If you think about the split, certainly it's more than 50% that is towards sales milestones.
Brilliant. Thank you for that, Adesh.
We have a follow-up question from Brigitte de Lima from goetzpartners securities. Please go ahead, madam.
Hi. I'd like to ask two housekeeping questions, if I may. The first one is on back going to Cresemba, the licensing deal and the deferred portion recognized. Adesh, as you mentioned, quite a lot was already recognized in H1. My numbers tell me it was around CHF 16 million. Maybe you can comment on that. The question is more, should we see a similar amount in the second half and then the balance next year? Or should we assume a smaller amount in the second half and then a bigger balance next year? The second question is relating to the total cost associated with the clinical trials for derazantinib. Just wondering if you can give us a very, very rough estimate of how much the UC trial, the phase II, may cost.
Okay. That's a simple question, but will take a little bit time to explain. Yeah, you're right. Maybe I start with the different buckets of deferred revenues. Pfizer. Pfizer, indeed, if you do a back calculation, you will conclude that we recognized CHF 15.7 million in deferred revenues in the first half of 2019. The portion that we will be recognizing over the next 12 months is, as I alluded to in my response to Paul, would be the remaining CHF 36.7 million. That's the current portion of deferred revenues that is still sort of outstanding. How this will split between the second half of 2019 and the first half of 2020 remains to be seen, because that correlates at the end of the day with the product deliveries to Pfizer. That's not on a linear basis based on end market sales.
That's sort of, not maybe the perfect answer, but gives you some indication. We've of course included our assumptions in our, this is included in our guidance, in essence, for the second half. The other deferred revenues that you're seeing are a little bit easier because they are largely on a linear basis. If you look at our deferred revenues related to the Asahi transaction, they are CHF 1.3 million on an annual basis, CHF 0.6 million per year. Gosun is CHF 0.6 million on an annual basis, so CHF 0.3 million on a six-month period. Then, in essence, you'll be looking at about CHF 1 million for our distribution agreements on an ongoing basis. For Astellas, there are deferred revenues of around CHF 5.4 million in the first half of 2019, that's also more or less on a linear basis.
Until next year, we will be recognizing CHF 8.4 million for Astellas. Did this answer your question?
Yes, the first bit. I was specifically interested in the Pfizer one because the others are quite straightforward, but the Pfizer one did surprise me a little bit. I thought it'd be recognized over the next three years. It was quite a big chunk this year, but your answer perfectly explains it with the whole manufacturing process. Thank you.
Okay.
Marc, do you want to get the one about the cost of the?
Yeah, sure. Brigitte, as a framework, if you take everything together, what a study costs and you basically bring this down on per patient cost, in general, these type of studies cost in a range of CHF 50,000-CHF 100,000 per patient. This depends on the geographic mix, how many patients are included in each cohort, the duration. As we have a clinical supply agreement with Roche related to TECENTRIQ, one could assume that the average cost per patient over the entire study are rather in the lower to mid-range of this estimate of CHF 50,000-CHF 100,000. To then make a number really depends on how many patients will be ultimately enrolled in this study because we've set this up as a series of different cohorts which are performed in two stages.
You start with a Stage 1, and if that Stage 1 is successful, then the Stage 2 follows, and usually the size in terms of patient numbers, Stage 1 to Stage 2 is roughly on average of 1% to 2%. Basically, a higher cost will also imply that the study is successful in a way. That's how these studies are de-risked.
That's very helpful. Thank you.
Thank you.
As a reminder, if you wish to register for questions, please press star and one on your telephone. The next question comes from Ram Selvaraju, H.C. Wainwright. Please go ahead.
Thanks very much for taking my question. Firstly, with respect to ceftobiprole, within the context of the United States, I wanted to know if you could comment on the advantages that ceftobiprole specifically might have as an IV-administered antibiotic within the U.S. market environment, which historically has proven somewhat problematic for novel antibiotics that are administered intravenously.
Yeah. Thanks, Ram. Marc, do you want to take that about the potential advantages of ceftobiprole?
Yes. There's a couple of advantages that will certainly play out for the Staph aureus bacteremia indication. I think there, the differentiation of ceftobiprole is easier than for the ABSSSI indication. There's also some differentiation. I think the SAB differentiation is quite straightforward. The first thing is, if you compare it to, there are only very few drugs that cover MRSA and MSSA at the same time. This includes basically only vancomycin, which is considered to be not ideal from a safety perspective, but also has a weak activity for MSSA. At the outset of patients being treated, physicians usually don't know what they're dealing with. Daptomycin is the other. Daptomycin has several limitations.
First, it isn't effective in pulmonary infections. These patients often present in an ICU, at least with a rule-out diagnosis of a pulmonary infection. Ceftobiprole is approved for pneumonia in Europe, it's clearly active in the lung, whilst daptomycin is inactivated in the alveolar, that's the problem on the pulmonary side. Also, people are looking for cephalosporins traditionally are drugs that are preferred by physicians in a setting of a Staph aureus bacteremia. They are bactericidal, rapidly active. With daptomycin, what's been reported is a kind of MIC creep of the staphylococci. Whilst patients are on treatment, they can develop resistance. That's really not been described much with ceftobiprole, the last point is that ceftobiprole covers the gram-negative spectrum compared to both daptomycin, vancomycin.
Any patient with a suspected polymicrobial infection, including, for example, gram-negative pathogens, would be far better off with an initial empirical treatment with ceftobiprole. These are, in summary, the differentiation points for SAB, some of which also apply for ABSSSI. As I said, the profile of ceftobiprole is certainly much stronger in the competitive landscape in the SAB indication.
Thank you very much for that clarification. Wanted to ask about what you expect the length of the regimen to be in the ABSSSI and bacteremia settings once potentially ceftobiprole is approved in the U.S. If you have some thoughts on that, please.
In the study, usually the regular time of treatment is 5-10 days for ABSSSI, and it's going to be four to six weeks for the SAB indication.
Okay, great. Just one question on darolutamid, please. If you could comment on specifically the potential of darolutamid in the breast cancer context, also if you expect over the course of the next couple of years any incremental clinical data to be generated by the other entity that holds some rights to darolutamid in China, Sinovant, and if you think that might potentially be incrementally beneficial as you continue to work on darolutamid. Thank you.
Maybe I start with the breast. There have been a few studies now with other FGFR inhibitor in FGFR-amplified breast cancer populations, relatively small studies. We are also in the process of looking at this preclinically and then make a decision whether we move forward in breast or in another indication. As I said, we are quite advanced with our plans, and we'll provide more information during the course of 2019.
Ram, we can't give direction on exactly which indications we're moving into, but as Marc said, we actually are planning on giving guidance later this year on our next steps in terms of, as Marc said, following a lot of the preclinical translational work we're doing, where we go next. We can't actually specifically answer your question. In terms of the partner for darolutamid in the geography that we don't cover, yes, Sinovant covers Greater China, and clearly any data we generate and any data they generate is available for both parties to be aware of. Actually, any additional data they create on top of what we create can only be beneficial, I would imagine.
Thank you very much.
For any further question, please press star and one on your telephone. Star and one. Gentlemen, so far we have no more questions.
Okay. Thank you all very much. Thank you for your interest in Basilea, and enjoy the rest of your day.
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