Good day and thank you for standing by and welcome to the Clovis Oncology Quarter One Conference Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today Ms. Anna Sussman. Please go ahead.
CLVS Clovis Oncology
Thank you, Polly. Good morning everyone. Welcome to the Clovis Oncology first quarter 2021 conference call. Thank you for joining us.
You've likely seen this morning's news release. If not, it's available on our website at Clovisoncology.com.
As a reminder, this conference call is being recorded and webcast. Remarks may be accessed live on our website during the call and will be available in our archive for the next several weeks. Today's agenda includes the following. Patrick Mahaffy, our President and CEO will review the highlights of today's corporate update and Rubraca commercial progress. Then Dr. Thomas Harding our Chief Scientific Officer will review the FAP-2286 program and targeted radionuclide therapy development program. Dr. Lindsey Rolfe, our Chief Medical Officer will discuss the anticipated clinical milestones for both Rubraca and lucitanib during 2021. And then Dan Muehl, our Chief Financial Officer will cover the quarter's financial results in greater detail. Pat will make a few closing remarks and then we'll open the call for Q&A during which time Pat, Dan, Tom, and Lindsey will be available to answer questions.
Before we begin, please note that during today's conference call we may make forward-looking statements within the meaning of the federal securities laws including statements concerning our financial outlook and expected business plans.
All of these statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements.
Our actual results could differ materially due to a number of factors including the extent and duration of the effects of the COVID-19 pandemic and the timing and extent of recovery from the COVID-19 pandemic. Please refer to our recent filings with the SEC for a full review of the risks and uncertainties associated with our business.
Forward-looking statements speak only as of the date on which they are made and Clovis undertakes no obligation to update or revise any forward-looking statements.
Additionally, please note that we'll be discussing cash burn a non-GAAP financial measure during today's conference call. Required disclosures related to this are in today's news release which can be found on our website.
Now, I'd like to turn the call over to Patrick Mahaffy.
Thanks Anna. Good morning. Welcome everybody. I appreciate taking the time today.
While the continuing headwinds from COVID-19 impacted Rubraca sales in the US and in Europe this quarter, we believe the effect of the pandemic on patient diagnoses, patient visits, and access to oncology practices which began in late March last year will lessen over the course of 2021. Sales in Q1 2021 were $38.1 million which were lower than both Q1 2020, our last pre-pandemic quarter and our best US sales quarter ever and also lower than Q4 2020. It is extremely important to note that the sequential decline that we experienced in Q1 2021 in the US is consistent with the minimal growth or decline for other approved PARP inhibitors indicated for ovarian cancer in the US, which is a result or appears to be a result of the ongoing impact of COVID-19.
We are hoping that Q2 2021 represents the beginning of a return to a more normal post-pandemic environment.
While it is encouraging that office visits at the end of 2020 had returned to pre-pandemic levels, office visits are only a leading indicator. The number of ovarian cancer diagnoses and de-bulking surgeries declined 15% or more during the fall and winter. The reduced number of ovarian cancer de-bulking surgeries and reduced administration of platinum-based chemotherapy had a continuing impact on the maintenance use of PARP inhibitors broadly and as a consequence, Rubraca specifically. We do anticipate that as patient visits begin to rise as diagnoses increase and the urgent need to more actively manage the often-fatal disease grows, the maintenance treatment of ovarian cancer patients will increase including the use of Rubraca for women with advanced disease.
In terms of advancing our pipeline, I'm extremely pleased to announce that we achieved an important milestone in our commitment to targeted radionuclide therapies.
With the FDA clearance of our INDs for FAP-2286 for treatment and imaging, which enables us to open for enrollment the LuMIERE Phase I/II trial this quarter.
In addition we anticipate announcing top line ATHENA data for the Rubraca monotherapy versus placebo arms in the first-line ovarian cancer maintenance treatment setting in the second half of this year. Efficacy data from the non-clear cell ovarian cancer Phase II cohort of the LIO lucitanib and Opdivo combination will be presented in a poster at ASCO in June. And while evidence of clinical activity has been observed, we do not believe that the efficacy data support further development in non-clear cell ovarian cancer. Enrollment continues in the other three expansion cohorts in gynecological cancers and we plan to provide an update on the endometrial cohort later this year, at a medical meeting.
Let me turn now to a Rubraca commercial update.
Our global net revenue for the first quarter of 2020 -- 2021 was $38.1 million, down 11% over the comparable prior year period. Dan will describe these results in greater detail.
As we have discussed previously, an additional effect of COVID-19 is the substantial acceleration of what was already a trend toward reduced in-person access to academic and community-based clinics by sales reps. We believe this reduced access to oncology practices will continue, even once the pandemic is ultimately under control, as practices increasingly preferred digital programming and communication that can be accessed, on their own time. We believe the commercial strategy we introduced last fall will enable us to meet these preferences, as the effects of COVID-19 lessen overtime. This strategy embraces a hybrid approach that elevates easily accessible digital programming, virtual communication and peer-to-peer interactions. In-person promotion is reduced. And those remaining in-person activities are much more targeted. We remain energized about our strategy, and believe that we are an early adopter of a trend that will be increasingly common for oncology marketers.
In fact, several companies across the industry have announced similar changes in recent months. We adopted this hybrid strategy, to better reach physicians the way they want to be reached, utilizing resources, customized to their practices with the goal of accelerating growth as the ongoing impact of the virus resolves overtime. Despite our lower sales in Q1 compared to Q4, we believe we maintained our U.S. market share given that our competitors also appeared to experience COVID-related impact on U.S. sales.
While this is not yet proof of the potential for our hybrid commercial model, we maintained our share in a difficult environment with a hybrid model and with a 30% reduction in SG&A, compared to Q1 2020. Not all of this reduction was specific to selling costs, but we clearly believe we have found a more cost-effective commercial model to address our physician customers in the U.S. Obviously, as we come out of COVID-19, we hope our model will also accelerate growth. With regard to the U.S. prostate indication, while still a modest contributor to U.S. revenues sales of Rubraca in the prostate indication were consistent with our sales in Q4 2020.
Turning to Europe, we are very pleased with our progress to-date, despite the COVID-19 lockdowns that remain in place in most countries. Sales of Rubraca were up significantly, compared to the first quarter of 2020.
As in the U.S., we believe that a more normal oncology practice will reemerge as Europe reopens.
We have a smaller commercial organization in Europe and have been utilizing virtual communication in each of our primary territories, as regulations allow.
While national regulations vary among European countries and as compared to the U.S., we are tailoring a hybrid digital strategy for each country to better reach our clinician prescribers.
As we explained previously, December 19th, 2020 was the earliest date, that an ANDA could have been filed for Rubraca. At that time generic entities had been permitted to file an ANDA for Rubraca with a Paragraph IV certification, asserting that one or more patents listed in the Orange Book for Rubraca are either not infringed, invalid or not enforceable.
We have not received any Paragraph IV certification notice letters and to our knowledge, no ANDA filings for rucaparib have been made to-date. Because rucaparib camsylate is considered a cytotoxic drug, the published FDA guidance requires any party seeking approval for a generic form of rucaparib to file a bio-IND and recommend showing bioequivalence in, I'm quoting here, female patients with a deleterious BRCA mutation, associated with advanced cancer who have been treated with two or more chemotherapies and are receiving a regimen of rucaparib camsylate. The guidance sets forth, additional criteria including the demonstration of bioequivalence to a 90% confidence level. Demonstrating bioequivalence with Rubraca would only be an initial step in the ANDA approval process. In a potential ANDA litigation, a generic challenger would also need to successfully challenge or design around Orange Book listed patents, some of which do not expire until 2035.
Now let me turn the call over to Dr. Thomas Harding, our Chief Scientific Officer to briefly discuss the FAP-2286 and targeted nucleotide therapeutic programs, topics of growing interest, as we are now moving into clinical development with FAP-2286. Tom?
Thanks, Pat. Hello. It's a pleasure to speak with you today.
As Pat mentioned, our enthusiasm continues to grow for our target radionuclide therapeutic program including our lead asset FAP-2286, which we expect to enter into clinical development in this quarter with our Phase I/II LuMIERE study. Targeted radionuclide therapy uses cancer targeted molecules to deliver radiation missing isotypes, specifically to tumors. These targeted molecules can be peptides antibodies or small molecules. When injected into a patient's bloodstream, the targeted molecule attaches to cancer cells, delivering high doses of radiation to the tumor, while sparing normal tissue.
Our lead compound FAP-2286 license as part of our ongoing collaboration with 3B Pharmaceuticals is an investigational peptide type radionuclide therapy, which targets fibroblast activation protein or FAP. FAP is highly expressed on cancer associated fibroblasts or CAFs, which represent one of the most abundant cell components in tumors and are found in the majority of cancer types, potentially making it a suitable target across a wider range of solid tumors, including breast, lung, colorectal and pancreatic carcinomas. Cancer Associated Fibroblasts play a critical role in tumor initiation progression metastasis and therapeutic resistance.
For example, recent studies have demonstrated that FAP expressing CAFs exert a potent immunosuppressive activity that can promote tumor progression and compel resistance to immune-based therapies, such as PD-1 and PD-L1 blockade. In certain tumor types, such as sarcoma and mesothelioma, FAP may also be expressed on the tumor cells themselves in addition to the cancer associated fibroblasts. FAP-2286 consists of two functional elements.
First, a targeting peptide, that binds to FAP-expressing CAFs and tumor cells. And second, a site that can be used to attach radioactive isotopes. Depending on the specific radioactive isotope attached, FAP-2286 can be used for patient imaging and selection or therapeutic applications. In our Phase I/II LuMIERE study, FAP-2286 will be attached to the isotope Gallium-68 to allow positron emission, tomography or PET imaging in selection of patients for inclusion in the study.
For the therapeutic agent, FAP-2286 will be attached to the isotope Lutetium-177, an emitter of beta particle ionizing radiation that causes DNA damage and cell death. Non-clinical studies including animal models presented at ESMO last year, show that FAP-2286, can potently and selectively bind to FAP.
In addition, antitumor efficacy of FAP-2286 linked to lutetium was observed in FAP expression tumor models. We look forward to sharing additional preclinical and clinical data at future meetings. We submitted two IND applications for FAP-2286 for uses in imaging and therapeutic agents at the end of 2020 to support our LuMIERE study with expansion cohorts planned in multiple tumor types as part of a global development program.
We are pleased to announce that the INDs cleared following acceptance by the FDA of CMC data from the first of our clinical sites, each of which will effectively serve as real-time manufacturers for the imaging agent given extreme short half-life of Gallium-68. With FDA clearance of our IND, the LuMIERE study is expected to open for enrollment by the end of this quarter. The Phase I portion of the LuMIERE study will evaluate the safety of the FAP targeting investigational therapeutic agent and identify the recommended Phase II dose and schedule of Lutetium-177 labeled FAP-2286. Once the recommended Phase II dose is determined, Phase II expansion cohorts are planned in multiple different tumor types. FAP-2286 label with Gallium-68 will be utilized as an investigational imaging agent to identify patients with FAP positive tumors appropriate for treatment with the therapeutic agent.
In addition, studies of FAP-2286 linked to an alpha particle emitting radionuclide and combination studies with other oncology compounds are also being planned.
Given the role of FAP-expressing CAFs in mediating immunosuppression, combination with PD-1 and PD-L1 blockade will be a priority.
In addition to our own program, a separate investigator-sponsored imaging study with FAP-2286 is underway at UCSF to evaluate FAP expression in multiple tumor types and is currently enrolling patients. Results from this study along with preclinical data we are generating are expected to help inform selection of tumor types for our Phase II expansion cohorts.
In addition, we and 3B Pharmaceuticals are collaborating on the discovery program directed at three additional targets for targeted radionuclide therapeutic development to which we have global rights. With our achievements to date, we believe we have the opportunity to be a leader in the virgin cure targeted radiotherapy for the treatment of solid tumors and to be the first to clinically develop a peptide targeted radionuclide therapy targeting FAP.
We are also enthusiastic about the targets and the subject of our discovery collaboration and look forward to providing additional detail where appropriate. One last thing some exciting new data for the entire targeted radionuclide therapy field will be reported in a plenary session at ASCO in June. In March, Novartis announced that the Phase III VISION trial with PSMA-617 in approximately 1000 metastatic castrate-resistant prostate cancer patients had achieved both primary endpoints, including overall survival. We look forward to seeing the details from the study and believe it will offer a new treatment option for men with advanced prostate cancer and further validate targeted radiotherapy as an important new therapeutic class.
Now I'll turn the call over to Lindsey Rolfe to discuss the pipeline for Rubraca and lucitanib. Lindsey?
Thanks. Good morning. I'm glad to be here with you today to discuss the key trends and milestones expected for Rubraca and lucitanib in 2021. With Rubraca, we expect to announce top line clinical data from the ATHENA trial monotherapy arm in the second half of 2021, although exact timing is contingent upon the occurrence of the critical specified PFS events.
As a reminder, ATHENA is a Phase 3 1000-patient study in frontline newly diagnosed advanced ovarian cancer maintenance. With ATHENA, we believe we are uniquely positioned to evaluate Rubraca in terms of two independent outcomes monotherapy versus placebo in the first-line maintenance study. In the HRD population inclusive of BRCA and in the all-comers or intent-to-treat population as well as evaluating any potential advantage of the combination of Rubraca and Opdivo over Rubraca alone. We believe this study offers an opportunity to truly differentiate Rubraca in the first-line maintenance setting.
As I mentioned earlier, the ATHENA readouts are pending on the timing of data maturity driven by PFS events. Once top line results are available, we would plan to file an sNDA shortly thereafter. Continuing with near-term milestones for Rubraca, the LODESTAR study or pan our Phase 2 pan-tumor study to evaluate Rubraca in homologous recombination repair genes including BRCA across unit types continues to enroll patients. The study evaluates Rubraca in patients with recurrent solid tumors associated with a deleterious homologous recombination repair gene mutation. Based on our interactions with FDA, this study may be registration-enabling through a targeted gene and tumor-agnostic label. Pending data we could potentially file for approval in the US for this indication in the first half of 2022. The newest Phase 3 clinical trial for Rubraca is the CASPAR study being sponsored by the Alliance for Clinical Trials in Oncology, which is part of the National Cancer Institute. CASPAR is a Phase 3 study comparing Xtandi and Rubraca to Xtandi and placebo as a non-therapy in first-line mCRPC in an all-comers population. The approximately 1000-patient study will begin enrollment shortly following an amendment to remove the run-in onco-kinetic sub study which is no longer necessary following the successful completion of the Clovis sponsored Phase 1 ramp study evaluating the same combination.
Now I'll discuss lucitanib. Lucitanib is our investigational angiogenesis inhibitor, which inhibits vascular endothelial growth factor receptors one through three platelet derived growth factor receptors alpha and beta and fiber growth factor receptors one through three. The Clovis sponsored LIO-1 study is a Phase 1B/2 study evaluating lucitanib in combination with Opdivo in gynecologic cancers, which is currently enrolling patients into successive expansion cohorts. Interim data from the non-PSL ovarian cancer expansion cohort have been accepted as a poster presentation at ASCO.
While evidence of clinical activity has been observed, we believe the FAP data do not support further development in non-clear cell ovarian cancer. The L-3 cohort, non-clear cell endometrial cervical and clear cell ovarian/endometrial cancers, continue to enroll patients, and we plan to submit an abstract describing the endometrial cohort data to a medical meeting later this year.
Lastly, I'm pleased to report that on the development front, the effect of COVID-19 on our clinical trial enrollment remains minimal. And with that, I'll turn the call over to Dan to discuss first quarter financial results.
Thanks, Lindsey, and hello, everyone. We reported net product revenues for Rubraca of $38.1 million for Q1 2021, which included US net product revenues of $31.7 million, and ex-US net product revenues of $6.4 million. This includes comparable net revenues from our prostate indication in the US in Q1 2021 as seen in Q4 2020.
First quarter 2021, net revenues represent an 11% decrease compared to Q1 2020 in which we recorded net revenues of $42.6 million, including net product revenues in the US of $39.3 million and ex-US of $3.3 million.
As Pat mentioned, we believe we maintained US market share during the quarter, despite the decrease in revenues as each of the marketers of PARP inhibitors with ovarian cancer indications faced some COVID related impact in the US in Q1 2021 compared to Q4 2020. Gross to net adjustments totaled 25.6% globally in Q1 2021 compared to 25.6% in Q4 2020 the same as last quarter. This metric fluctuates quarter-to-quarter and it's difficult to estimate our future revenues, but a range in the mid to high 20% seems likely depending on the revenue and distribution mix for the US and Europe.
As European revenues increase in proportion to the US global GTN will increase correspondingly. Research and development expenses totaled $52.8 million for Q1 2021, down 23% compared to $68.2 million for the comparable period in 2020, primarily due to lower spending on Rubraca clinical trials.
We expect research and development expenses to be lower in the full year 2021 compared to the full year 2020. Selling, general and administrative expenses totaled $29.9 million for Q1 2021, down 30% compared to $42.6 million for the comparable period in 2020 with savings due to the COVID-19 situation globally, and overall cost reduction efforts. Further, we expect SG&A expenses to decrease in 2021 compared to 2020. We reported a net loss for Q1 of $66.3 million or $0.64 per share, compared to a net loss for the first quarter of 2020 of $99.3 million or $1.39 per share. Net loss for Q1 included share-based compensation expense of $4 million, compared to $13 million for the comparable period in 2020.
Turning now to a discussion of cash as of March 31, we had $190.9 million in cash and equivalents. And as of March 31, we had drawn approximately $113.6 million under the Sixth Street Partners LLC ATHENA clinical trial financing, and had up to $61.4 million available to draw under the agreement to fund expenses of the ATHENA trial. Based on the company's anticipated revenues spending available financing sources and existing cash and cash equivalents, we believe we have sufficient cash and cash equivalents to fund our operations into early 2023, including any cash repayment unless refinanced earlier of the remaining $64.4 million aggregate principal amount of the 2.5% convertible notes at the maturity in September 2021. Net cash used in operating activities was $61.9 million for Q1 2021, down from $82.5 million recorded in Q1 2020. Cash burn in Q1 2021 was $48.1 million, down 28% from $66.9 million in Q1 2020.
We have reduced our R&D and SG&A expenses considerably compared to prior years. Most recently, we reduced R&D and SG&A expense by $28.1 million and reduced net cash used in operating activities by 25% compared to Q1 2020.
We expect this trend of lower cash burn to continue through 2021.
Now, I'll turn it back to Pat.
Thanks, Dan. In summary, we're very enthusiastic about FAP-2286 and our targeted radionuclide therapeutic development program overall, and look forward to providing updates as LuMIERE opens for enrollment, and our programs continue to advance. We believe that targeted radionuclide therapy will become an extremely important component of anticancer therapy, and believe that our early commitment to this field has been validated by the recent Phase 3 VISION trial for PSMA-617 in metastatic castration-resistant prostate cancer which as Tom noted will be reported at ASCO in June. If anything, we believe FAP may be an even more important target given its presence in multiple solid tumors and we are pleased to be the first company to enter clinical development with an FAP targeted peptide targeted radionuclide therapeutic.
While the last 12 months of COVID headwinds have been challenging, we believe that we are well positioned as the effect of the pandemic lessons over time for several reasons. ATHENA data later this year, which we anticipate may ultimately support Rubraca's use in what will likely be its most important indication the first-line maintenance ovarian cancer setting which includes the largest patient population of women with advanced ovarian cancer following successful treatment with platinum-based chemotherapy. We believe that the hybrid approach incorporated into our US commercial strategy last fall best enables us to reach clinicians in the way they want to be reached and positions us well as the impact of COVID-19 on oncology practices lessens over time. We remain focused on disciplined cost control as Dan discussed and our cash burn will be lower in 2021 than 2020.
Finally, based on current revenue and expense forecasts, we believe we have sufficient resources to fund our operations into early 2023. With that, we'll be happy to answer any questions you may have.
[Operator Instructions] Your first question comes from the line of Cory Kasimov with JPMorgan. Gavin Scott JPMorgan
Hey. This is Gavin on for Cory. Thanks for taking our question.
Just quickly on the FAP program, clearly there's some interest there. I'm curious what your expectations are for patient accrual there. Do you expect physicians to be receptive of enrolling patients in the study? And just any color you can provide on your expectations? Thank you.
It's a standard Phase 1. But Lindsey maybe I'll let you answer that question with a little more detail.
Sure thanks Pat. Thanks, Gavin.
As Pat said it's a standard Phase 1 trial with cohort-by-cohort enrollment.
So timeline wise we'd expect it to proceed in that fashion.
In terms of investigation enthusiasm, at each of the investigational sites, we're working with a nuclear medicine physician and one or more oncologists. And that maximizes the engagement and the appropriate expertise.
So I'm not expecting oncologists just to manage this whole new therapeutic modality. They're doing it hand-in-hand with in every case a very enthusiastic nuclear medicine partner.
Next question please.
And your next question comes from Ed White with H.C. Wainwright.
Good morning. Thanks for taking my questions.
Just to - as a follow-up on the FAPs to be more clear, could we see some Phase 1 data this year?
Ed, what we've said is that the Phase 1 will be continuing this year. It's more likely to be presented formally at a medical meeting next year. That being said, we've committed to providing updates on the program on these quarterly calls including if and when and as we see them initial evidence of clinical benefit.
So these calls will be a forum for an update on progress, but the formal presentation and scientific data will be probably sometime in the first half of next year.
Okay. Thanks, Pat. And I just want to get a little bit of clarity on the expenses. I know that you had said that costs will be down are expected to be down in 2021 versus 2020. But looking at the first quarter and thinking on a going forward on a sequential basis quarterly, are we looking at a new base now, or could we expect to see additional cuts going forward on a quarter-to-quarter basis?
Yeah. Thanks for the question.
As we've talked about in the past, we've had a declining slope of R&D spend primarily around the Rubraca trials, which are for the most part hopefully enrolled and going down the other side of the slope.
So there will be continued reductions really driven by that. And on the SG&A side we're -- we clearly expect to have lower SG&A for the year. And the rate of how that will proceed for the rest of this year, we haven't specifically disclosed. But part of that will get back to activities that we may or may not contemplate in the second half of the year related to the sales and marketing group. But clearly we're at a much lower level of spend than we were compared to last year.
Okay. Thanks Dan. And my last question if I may, Pat you had mentioned that you maintained share in the U.S. PARP market. Can you give us a little bit more color on what's going on in the U.S. PARP market? We had talked in the past about penetration being 40% to 45% in the second-line maintenance area and just want to get your thoughts on where it is now. And what if anything can be done to get the penetration of the market to grow the overall market? I know you've worked on it in the past, or is it just getting through the pandemic? Thanks.
So in terms of Q4 versus Q1, you heard our numbers today. Zejula was down 5% from Q4 to Q1. And actually that included a 5% price hike on January 1st, so they were effectively down 10%. Olaparib sales were effectively flat and they noted that any growth that the primary growth driver for them in the U.S. was in the prostate indication. At SGO there was a presentation on what's happening in real-world experience and utilization of PARP inhibitors in the maintenance setting and it remained at around 50%, Ed.
So while many physicians have adopted maintenance treatment in the second-line setting and to some extent in the first-line setting, either they're limiting it to a subset of populations who they think would benefit most, maybe it's BRCA, maybe it's HRD, maybe it's related to the patient's experience on platinum. We still see a number of physicians who or a percentage of the physician population that limit their use to -- of PARP inhibitors to a very small number of patients. And that's why we're at this 50% number that we as a community have tracked at for whatever it's been now three years.
In addition, a driver of the market's performance in Q1 was just the continuing effect of COVID-19 and the cumulative effect of COVID-19 on ovarian cancer de-bulking surgeries, on primary diagnosis and on a more limited use because of that of platinum-based chemotherapies, which are a precedent therapy for use of PARP maintenance. Office visits are back to normal.
I think that this is going to correct itself. Tragically many patients are going to be diagnosed with more advanced disease, which is going to create an urgency around care and so it's why I referenced in my prepared remarks that we think as COVID lessens that things will improve over the course of this year. But we did see that cumulative effect on the PARP market in Q1.
Okay. Thanks Pat for taking my question.
You bet. Thank you.
And your next question comes from the line of Paul Choi with Goldman Sachs.
Thanks. Good morning and thank you for taking our questions. Two pipeline questions for Lindsey if I may.
First, just with regard to your commentary on LODESTAR, could you please elaborate just on what FDA feedback has been that gives you confidence that the trial could be registration enabling? Is this something that you had in minute post recent FDA update or readings? And then second on the LIO-1 update and the decision to not proceed in non-clear cell ovarian, can you comment whether the MTD dose was reached for that particular cohort and that particular reason, or was it just underwhelming efficacy? Thank you very much.
Thanks Paul for the questions.
For LODESTAR, as you know, there's plenty of precedent now for approvals in pan-tumor genetically defined indications. But of course, we have discussed our development plan in person with FDA and designed the LODESTAR study taking their feedback into account.
So that gives us confidence that we're on the right track there.
For LIO-1 in the non-clear cell ovarian comport, we -- this was underwhelming efficacy. The dosing was just as we expected.
You'll recall that we had the possibility built in for patients to escalate the dose if they got through the first cohort without significant adverse effects. And we saw the proportion of patients in both just as we anticipated. The adverse event profile was also just as we anticipated.
So, right dose unsuitable tumor type probably, I think is the answer. And of course, the other three independent cohorts in unconnected tumor types are continuing as planned. Thanks for the questions.
And your next question comes from the line of Andrew Berens with SVB Leerink.
Hi, thanks. I was wondering if you guys could give some more color on the LODESTAR program. How much do you think the tumor-agnostic indication would expand the addressable market? And what's the status of the other PARP inhibitors in this indication? And then, I have a question about your cash flow after that.
The largest population of BRCA-mutated patients is in ovarian cancer, in breast cancer and in prostate cancer.
So, I think it will have an effect if approved. And obviously, we think the opportunity to bring targeted therapy to other indications where they maybe effective, is what we're here to do. I would actually focus everybody's attention, however, on two trials that are going to be markedly larger in opportunity for us. That's ATHENA, which will read out prior to any data from LODESTAR and TRITON3, which will at the latest fully enroll in the first quarter early second quarter of next year and we'll definitely have data next year. And those are far bigger indications for us than LODESTAR. We're enthusiastic about LODESTAR obviously, directing the trial consistent with FDA interactions and pleased to be doing it, but the two big drivers for us over the next year or 18 months are ATHENA and TRITON3. And you had another question?
Yes. And just on that what is the status of the other PARP inhibitors in a tumor-agnostic indication before I ask the cash runway question?
They're not as forthcoming on those programs as we are or as TESARO used to be.
So, it's hard to know exactly what their status are. Others are running either monotherapy trials -- I believe Pfizer is running a combo trial with an IO agent as well.
So, as ever in the PARP class there is likely to be competition.
Okay. Thanks. And then, just on the cash runway, I'd just like to get some more clarity, because I don't see how it stretches to 2023. Did you guys say that includes repaying the 2021 note? Based on our numbers, I just don't see even if you back rein in expenses further and back out ATHENA you could stretch $190 million to $23 million.
Yes. Andy, this is Dan.
So, there's a few components to that obviously.
So from a revenue point of view, we have a range of outcomes that we plan for. And we're effectively in those ranges. And as you saw although we're having some struggles in the US at the moment the European sales continue to do well and we're feeling pretty good about that. And we do hope for improvement as the year goes on with the COVID situation. And on the expense side, you can see we pretty dramatically reduced expenses and we have continued to that over the last year or so.
So, that is a large contributor to that as well. It does include repaying the 2021 so $64 million. But we also keep in mind have the $61 million left coming in on the ATHENA financing.
So it's really $190 million plus the $61 million is the way to look at it over that timeframe so it's more like $250 million. And we do have expense levers that we have that help us to get there so we have obviously looked at it pretty carefully. It's an important disclosure so we're -- that's where we are.
Okay thank you very much for the color. Appreciate it.
Your next question comes from the line of Joe Catanzaro with Piper Sandler.
Hey guys. Thanks for taking my question. Maybe one first on LIO and Lindsey I think you kind of alluded to this, but does the signal you've seen in non-clear cell ovarian provide any readthrough to the other cohorts? And then relatedly I know we've seen data for Lenvatinib plus Pembro in ovarian cancer, but don't specifically recall if they've broken out clear cell versus non-clear cell.
Just wondering if you have any insight into that?
Thanks Joe for the question.
I think all cohorts really are independent. The only commonality is that their tumors all affect women. Molecularly really non-clear cell ovarian is not similar to the other types of tumors that we're studying. I've blanked on the second part of the question. What was it again? Sorry.
It was whether Lenvatinib plus Pembro has broken out their ovarian cancer data based on non-clear cell versus clear cell.
I'm pretty sure that they didn't include clear cell cancer patients in their cohort and it was mainly high-grade serious population.
Got it. Then if I could just ask a follow-up. I'm wondering if you could elaborate a little bit on what you saw in 4Q of last year around Rubraca dynamics that contribute to a relatively strong quarter then that you didn't see this quarter?
I'll take that. We've tried to figure that out and I think the primary thing we saw is that in Q4 new patient starts combined with continuing therapy from patients enrolled as early as the end of the prior year and in Q1, allowed us to kind of continue with a good sales performance. And in fact we didn't see a number of patients fall out of therapy and our average duration of use actually continued to go up some. In Q1 some of those patients fell off and were not adequately, I'll say replaced with newly diagnosed patients eligible for second line maintenance. for the reasons I described the fall off the reduction in debulking surgeries platinum-based chemo and overall diagnoses. We believe that dynamic will change over the remainder of this year particularly as inpatient visits office visits have gone back to normal. And obviously this is a tragically difficult disease to treat, but when it's not treated because of concerns about COVID or other things it doesn't stop growing and it doesn't stop occurring.
And so patients are going to be diagnosed, they're going to be requiring therapies and they're going to get back into the maintenance use of PARP inhibitors including Rubraca.
So as diagnoses increase, new patient starts will increase and that will be the driver of sales over the remainder of this year.
For the class not just for us.
Okay. Thanks for taking my question.
And your final question comes from the line of Tazeen Ahmad with Bank of America.
Hi, good morning. Thanks for taking my question. Pat, I just wanted to get some color on your thoughts about, what kind of off target things might you expect to see with 2286? And then, as it relates to the ATHENA study, assuming that you do have the positive beta come in, what would be the next steps to filings for the sNDA and when would you expect to actually have that new label add? Thank you.
So with regard to FAP-2286, we have a limited amount of data.
As you may recall from the 10 or 11 patients that we imaged and treated on compassionate use in Germany, and we did not see off target accumulation in any tumor type.
Sorry, in any situ type. And we're pleased that we didn't.
We also didn't see anything in animal models that caused us any concern. Obviously, with any new drug, it can be hard to predict, what a side effect might be. And if there would be off target accumulation, the two areas, I think we would be most focused on, would be the potential for myelosuppression, true of any DNA damaging agent. And the second is, because of the way, each of the -- each of PSMA-617 Lutathera and our agent all peptides are eliminated, we will see some accumulation in the kidney. And the question is, whether that has any acute or chronic impact. It has not for Lutathera or PSMA-617 at least to our knowledge. We'll get an update on the entirety of PSMA-617 in a month or so. But there's nothing in our data that caused us to be thinking, oh man we're really worried about something. When we did see the original scans from the 10 or 11 patients in Germany, because of the known off-target accumulation in the salivary glands of PSMA-617, all this looked at the salivary glands and of course we didn't see any accumulation there. It's very specific to PSMA-617.
So, we're optimistic. Obviously, it's a Phase 1 study that we'll start at a low dose, so if a signal emerges, we'll see it. Lindsey, anything you would add to that?
No, that was excellent.
And then what was -- oh the timing.
So the timing of the ATHENA data as Lindsey noted will be driven by when we achieve a specified number of PFS events. I would suggest that, when we see those data and announce those data, we'd be about three months from filing an sNDA. And then, the FDA would have up to six months to review it.
So, think of an approval on or around -- well a potential approval on or around nine months from when we announce topline data.
So hopefully, we'll be well into COVID recovery by then.
I believe strongly.
I think all of us do that we will be and hope so fervently for all sorts of reasons.
Okay. Thank you, Pat.
Thanks, Tazeen. Anna?
Thanks everyone. Thank you for your interest in Clovis today.
If you have any follow-up questions, please call me at 303-625-5022 or Breanna at 303-625-5023. This call can be accessed via a replay of our webcast at clovisoncology.com beginning in about an hour and will be available for 30 days. Again, we appreciate your interest and time and thank you and have a good day.
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