Patrick J. Mahaffy – President and Chief Executive Officer
Cory Kasimov – JPMorgan Chase & Co.
Clovis Oncology, Inc. (CLVS) JPMorgan Healthcare Conference Call January 13, 2014 6:30 PM ET
Cory Kasimov – JPMorgan Chase & Co.
All right. Good afternoon, everyone. All right. We’re on. Good afternoon. My name is Cory Kasimov. I’m the Senior Biotech Analyst at JPMorgan and it is my pleasure to introduce our next company, which is Clovis Oncology. Presenting for Clovis is the President and CEO, Pat Mahaffy and after Pat’s presentation there will be a breakout session down the hall to the left in the Olympic Room.
So with that, I’ll turn it over to Pat.
Patrick J. Mahaffy
Great. Thank you, Cory. Thank you all for attending today. So forward-looking statements that we all have to tell you that things change. So here we go. Investment highlights; we believe that 21st Century Oncology gives us both the opportunity and to some extent the obligation to try to select those patients more likely to benefit from a given therapy and we have three programs that are directed at subset populations where we think we can see superior results.
Two of those are wholly-owned programs. We own global rights to both 1686 and to rucaparib and those two will be the subject of, in one case, three registration studies beginning in this first half of 2014 and in the case of rucaparib one registration study beginning as well in the first half of 2014, in one case EGFR-driven lung cancer, case of rucaparib in mutant ovarian cancer. We are also acquired rights to a third program in November of 2013, a drug called lucitanib, which is directed at a subset population in patients with both breast cancer or with lung cancer.
We are a rapidly accelerating company. We had a good year in 2013. We obviously have a big year operationally in 2014. If all goes well we will submit our first NDA, in this case for 1686 before the end of the year 2015. We benefit from significant IP protection and we can afford to do what we’ve committed to do, which we think is in the best interest of each of these drugs because we ended the year with about $320 million worth of cash and with $120 million projected burn in 2014, we’ll still end 2014 with over $200 million.
1686 is our lead compound. It is a oral, selective covalent inhibitor EGFR mutations, which are relatively common in non-small cell lung cancer. This drug was designed to inhibit both the activating mutation to EGFR like a Tarceva or Iressa or afatinib, but also the primary resistance mutation to patients who benefited from those drugs called T790M. We do not inhibit at least in clinically relevant concentrations, wild type EGFR. So for the first time we can say we have a drug that inhibits EGFR, but does not cause the rash or diarrhea that plague the use of these first-generation agents.
We also know we have an active drug. We showed a 67% response rate in evaluable patients that were reported at the world lung meeting at 2013. I’ll spend a little more time on that today. This Phase 1/2 study that was from – continues, we do believe that we’ll pick a dose from that study in the next three or four weeks and allow us to initiate this broad registration program. We have a companion diagnostic collaboration with QIAGEN who allow us to select those patients who are T790M positive. We’ll initiate of course those registration studies as well as other studies this year and to reiterate this is a rare situation where a company of our size has maintained global rights to this drug.
Briefly by background for those of you who don’t know this base well, EGFR mutations occur in about 15% of Caucasians who develop lung cancer, but more like 30% to 35% of patients who are Asian. So the opportunity here in Japan and Asian territories is a little different than it often is for oncology drugs where the distribution is a foot line across these geographies. Importantly, for patients who benefit from Tarceva or Iressa, about 60% of them ultimately fail because of the emergence of resistance mutation called T790M. So very clearly our initial opportunity here is by targeting that second line population of T790M positive patients who failed one of those first TKIs, but our label expansion opportunity, a study of which will direct ourselves forward beginning this year is in the first-line setting for patients who have the initial or activating mutations of EGFR.
Our last clinical update for 1686 from this Phase 1/2 study was at Sydney at the end of October in 2013. The data showed, as I reported earlier, 67% resist response rate in evaluable T790M positive patients. This was with our first formulation, dosed at 900 milligrams twice daily. I’ll provide an update shortly on the PK and early tolerability data for our superior formulation, the hydrobromide salt formulation, but even with the over formulation we obviously had very good efficacy. We also showed a drug that was really well-tolerated. We did see some local GI toxicity that sometimes manifested itself in diarrhea, but we saw no instance at all of rash with this earlier formulation of 1686. We’ve announced now that our next clinical update for 1686 including efficacy experienced with the hydrobromide salt will be at a meeting in Geneva at the end of the March, the European Lung Cancer Conference.
This is waterfall plot that got investigators enthusiastic about what they’re seeing with this drug and it just shows that at this 900 milligram dose we saw very encouraging evidence of activity. We had only one failure who is a valuable patient and that patient actually had fairly poor PK. So it didn’t completely surprise us. Obviously this is a very active compound.
Let me provide you a little update on our experience thus far with the hydrobromide salt and this is the formulation that we will develop from now on clinically and we intend for it to be a successful or commercial formulation. We started dosing with the hydrobromide salt at the end of August, early September. We’ve now dosed four different doses, four different patient cohorts with the hydrobromide formulation. Our highest dose was 1,000 milligrams twice daily.
As we saw on the healthy volunteers and reported at ASCO, we have seen very consistently greater exposures with the hydrobromide salt and we’ve seen far less variability, much tighter PK with this formulation. The reason that’s so relevant is great variability can lead to either under-dosing or overdosing patients. Under-dosing leads to limited efficacy. Overdosing could extenuate or exaggerate a tox profile. We see a forward oncology drug delivered orally, a really pretty clean PK profile with limited variability. We also know this drug is better tolerated than the former formulation and in particular we don’t appear to be seeing some of those local GI toxicities that we sometimes saw with the freebase. The freebase was a relatively insoluble compound. We think we had relatively high amounts concentrated in the gut that could cause some local irritation. We just don’t see that with the freebase.
We also know our dose limiting toxicity. We have not reached a maximum tolerated dose and we likely won’t. Our PK is good and the efficacy is good that we won’t keep dose escalating. The dose limiting toxicity, the one DLT we did see at the highest dose was hyperglycemia. This is actually almost always asymptomatic to the patient. It shows up in lab reports, but the patient doesn’t feel. At the highest doses we did see some patient complaints, but by and large it’s dose-related. It’s asymptomatic and it’s easily managed by dose reduction or in a couple of cases with an oral hypoglycemic therapy. So you have to have a side effect in oncology. This is a pretty manageable one.
We also can report that we do not see any evidence of wild-type inhibition, no rash with the hydrobromide salt and about a 10% incidence of grade 1 only and transient diarrhea in patients treated with the hydrobromide salt. This is placebo like reminding you that these are advanced patients who are on their fourth or fifth line of therapy and they are going to report things. We just don’t see evidence of wild-type inhibition and we are not going to.
Let me describe for you our development program for this compound, a program we call the TIGER program, a third-generation inhibitor of mutant EGFR in lung cancer. You know that these are always going to tortured, but here’s how we got there in terms of getting the name. I’ll describe each of these. It’s a robust program. TIGER1 is the study in first-line patients, a comparative study against Tarceva. TIGER2 is a registration study, single-arm study in patients who have immediately failed TKI.
TIGER3 is looking at patients who are later lined who failed at least one, maybe two or more TKIs as well as chemotherapy. I won’t spend more time on it, but we’ve already identified a TIGER4 and a TIGER5. TIGER4 is looking at patients whose T790M status is determined through a plasma-based assay, which over time is going to be a far more patient friendly way to determine their T790M status. TIGER5 will ultimately be a randomized comparative study against chemo in a second line patient population. TIGER4 will begin in the second half of this year, TIGER5 next year.
TIGER1, so this is a Phase 2, 3 study compared to study against Tarceva in patients who are treatment naïve and have reported not with T790M, but with the activating mutations of EGFR. The Phase 2 portion will begin in the first half of this year. It will be in around 150 patients. It will seamlessly transition into the Phase 3 portion of the trial. The Phase 2 will be used to determine sizing of the Phase 3 portions. I can’t give you a trial size. If I was just modeling I would assume it would be 500, 600, even 700 patients. We just don’t know until we get some data from the Phase 2 portion.
Primary endpoint will be progression-free survival. Efficacy biomarkers are going to be used to complement our PFS analysis and see if we can predict PFS before fully emergence. We expect results from the Phase 2 portion of this in the first half of 2016 and data from the Phase 3 portion in 2017.
TIGER2 and TIGER3 are passed to an accelerated approval. TIGER2 is in patients who are T790M+ who have immediately failed their first PKI like a Tarceva or Iressa. They can be allowed one prior line of chemo. The way these treatments are treating the community setting at least in the United States as they tend to go immediately on chemo while they await for the termination of their EGFR status than if we go on a Tarceva most likely in the United States, so we’ll allow that. It’s a single arm study in about 125 patients. The study will begin again in the first half of this year. Primary endpoint is overall response rate. Secondary endpoint, there will be lot of others, but the most important is duration and results will be in the second half of 2015.
TIGER3 is looking at a somewhat different population that are clearly T790M+, but have failed at least one TKI, but could have failed two or even three TKIs and could have also failed chemotherapy, just a more advanced patient population. We didn’t want to blend these two patient populations in one trial because their response or duration of that response could be different, but we certainly do want to explore both of these populations. Everything about this trial, timelines, patient enrollment, endpoint mirrors TIGER2.
To sum up 1686, we’ve seen very encouraging activity in a targeted patient population. This drug is well tolerated with easily managed side effects. In fact the adverse events that occur on these drugs are largely asymptomatic and for sure we can say that we are now the first EGFR inhibitor that is achieving a dose without seeing wild type inhibition evidence like rash or diarrhea.
Straightforward companion diagnostic collaboration with QIAGEN will initiate not one, but three registration studies in the first half of 2014. So we’ve taken a very aggressive approach to both the second and first line development of this drug. We anticipate, if successful our first NDA submission before the end of 2015. We’re managing global studies to support global registrations. So this isn’t just about the U.S., but Europe as well as Asian territories and I will reiterate we own global rights to this drug.
We turn to rucaparib. Rucaparib, of course our potent oral inhibitor of both PARP-1 and PARP-2. To our knowledge it is the only PARP inhibitor and we know there are others that is the subject of a development program that seeks to develop it in an identified patient population, mostly likely to benefit from a PARP inhibitor. We’re going to talk about how we’re doing that in both the Phase 2 and Phase 3 in a moment.
We see numerous responses in our Phase 1 at multiple doses in patients with mutant BRCA ovarian, breast and pancreatic cancer. We selected now a Phase 2/3 dose of 600 milligrams twice daily, a nice collaboration with Foundation Medicine to identity patients more likely to benefit from this drug. We’ve initiated a Phase 2 study that looks prospectively at patients with DNA repair deficiencies in addition to BRCA and that will be applied to the Phase 3 that we’ve just recently begun to recruit and I anticipate we’ll enroll our first patient in sometime this month.
Again, data reported at scientific meetings for rucaparib isn’t very encouraging. We’ve seen objective responses in ovarian, breast and pancreatic cancer, patients with germline BRCA mutations. In ovarian we’ve seen about a 70% extended disease control rate in patients with germline BRCA. That’s really relevant to a drug whose registration trial’s endpoint is PFS. So disease control is a proxy for PFS. So it’s very encouraging to us. We also know this drug is really well tolerated. We’ve not had a single patient go off rucaparib due to treatment-related adverse effects and at the 600 milligram dose that we’ve chosen we know that four of the five patients with mutant, breast or ovarian cancer patient have shown an objective response. So very active, very well tolerated drug in the target population.
Let’s talk about that target population. So unlike 1686, which is a mutant specific drug that is looking at T790M mutations or deletion 19 mutations is an example of an activating mutation we are trying to inhibit PARP patients, trying to inhibit or identify patients most likely to benefit from a PARP inhibitor. Now we know and everyone knows now the patients with mutants of BRCA are mostly likely to benefit from a PARP inhibitor because they already have deficiencies in DNA repair that a PARP inhibitor extenuates and causes those tumor cells to go apoptotic and die. But it isn’t only patients with BRCA mutations who have deficiencies in DNA repair. About 25 other genes of ovarian cancer have been identified that also for a similar effect a deficiency in the ability of tumor cells to repair themselves once assaulted and therefore are also likely to be very impacted by a PARP inhibitor. These can include FANC gene families or RAD51 gene families. It’s a number of gene families that have been identified.
So we are in collaboration with Foundation, seeking to identify patients not just with BRCA mutations but these other gene mutations. This cluster of genes has been described as BRCAness meaning they behave similarly to BRCA and our belief is that with tumor sequencing we can identify these other patients and increase the patient population we’re addressing from the sort of 20% to 25% of women with ovarian cancer who have either somatic or germ-line mutations of BRCA to the 50% of women with ovarian cancer who have not just mutations of BRCA, but may otherwise have mutations these other genes associated with DNA repair deficiency. But we’re not trying to go all the way and say that just because you benefited from a platinum agent that you are going to benefit from a PARP inhibitor.
Platinums are widely un-discriminatory and they’re going to kill a lot of cells, not necessarily only the ones that could benefit from a PARP inhibitor. What we’re trying to do in our trials is identified that kind of Goldilocks population that is most likely to benefit from a PARP inhibitor beyond just mutations of BRCA. So the ARIEL program has two trials so far seeking to identify those patients, ARIEL2 is – it’s a trial looking at response rate in women with ovarian cancer with either BRCA mutations or just BRCAness signature.
ARIEL3 is our maintenance therapy a study in ovarian cancer post platinum response compared to placebo, again looking first to patients with mutations of BRCA, if successful somatic or germline, if successful we’ll look at this BRCAness signature that we already have identified and will be refined in the prospective ARIEL2 of the Phase 2 study. And finally in the event that everybody with a platinum did benefit from a PARP inhibitor where we capture that too in the step-down analysis we do in the Phase 3.
We also announced today for the first time that we’ll initiate a Phase 2 study that could be in fact if successful an accelerated registration study in patients with BRCA mutations with pancreatic cancer. We know that germline and somatic mutations of BRCA occur on the order of 15% of patients with pancreatic cancer. We’ve seen good evidence of activity although in a small in the rucaparib Phase 1 study there is every biological rationale to explore this further into Phase 2. It will be a single arm study in around 100 patients who failed chemotherapy, but if we saw very encouraging response rate we believe that has the potential to be the basis of an accelerated approval.
Let me turn to lucitanib. Lucitanib is a drug that we acquired through the acquisition of an Italian company called EOS in November of 2013. Lucitanib is a drug that is directed at patients with aberrant FGF, is clearly an FGF inhibitor. We also know that it inhibits VEGF and PDGF and the thesis here is although we’re using – we’re identifying patients based on aberrant FGF. We think that the reason this drug is showing the kind of responses it’s shown beyond that it ever been seen with an FGF targeted therapy is that it’s sort of angiogenesis inhibitor and by doing so we get the benefit of inhibiting PDGF, VEGF as well as FGF and we cover that in the impact on the tumor is kind of self-evident.
Through the acquisition of EOS, we gain exclusive rights to the drug in the United States and in Japan. They had already partnered European and other rest of world rights with Servier. The benefit to us however is Servier will fund the first approximately $110 million of the R&D program. So it has some real benefit to us. This drug will continue to be the subject of development by Servier and by us, but initially on Servier’s committed R&D funds.
Then we have three Phase 2 monotherapy studies that are underway in the case won by Servier where we’ll start in the next few months in lung cancer and breast cancer that we are sponsoring. This is a summary of the data that got us very enthusiastic about this drug. It showed about a 50% response rate in heavily pretreated patients with FGF-aberrations in breast cancer. Not only was the response rate good, but to show a median PFS of about 9.5 months in a patient population who already endured six or so prior lines of therapy was to watch them to our investigators, very encouraging early evidence of activity for this drug.
No drug is without side effects. Lucitanib clearly has some. The primary side effect here is related almost certainly to its inhibition of VEGF. As you know VEGF inhibitors almost always have hypertension. We did see a reasonable amount of grade 3 hypertension. I don’t want to minimize it, but I will point out the grade 3 hypertension is sort of 160 over 100. So that’s not great news, but it’s not a terrifying number to report. So this is well managed. It can be well managed particularly with ACE inhibitors. So it’s not the easiest drug in the world to take, but it’s by and large reasonably tolerated.
And it addresses patients with two of the most common forms of cancer. Our focus is going to be on breast cancer where about 60,000 of the annual patients a year report with FGF-aberrant breast cancer or in squamous non-small lung cancer where about 20,000 patients every year report with FGF-aberrant lung cancer. We have two Phase 2 trials that are planned or have begun in breast cancer. The first is sponsored by really a cooperative group of sponsored – initially by Servier, three cohorts of patients who are ER+, looking at two different forms of FGF-aberrant breast cancer as well as looking at a broader population of FGF wild-type, just looking at the activity of this drug in a non-selective population.
We will start a complementary study to that looking again at two forms of FGF-aberrant breast cancer, the two most common. We’ll also evaluate dose. The Servier dose is 15 milligrams daily. We will do about half of our patients at 15 milligrams that will compare it as well and a dose that hasn’t been adequately explored, which is 10 milligrams daily. The goal really is to find out if we get similar efficacy in reduction and side effects. And so this study is to build U.S. experience, but also to explore dose a little further before we initiate a Phase 3 in breast. We’ll also initiate a sponsored study in squamous non-small cell lung cancer again in FGF-aberrant patients. That study really should be seen as a proof of concept study that will begin in sort of mid-ish 2014.
So let me close with milestones. It is a really important year for us in terms of execution and operational engagement. For 1686 we’ll identify the dose in the next several weeks and then initiate the expansion cohorts in the second and third-line setting initiate TIGER2 and TIGER3 as well as TIGER1 in the first half of this year. Also in the first half we’ll initiate a Phase 1 study complementary to the U.S. European study in Japan. For rucaparib, we’ll continue to enroll patients in the ARIEL Phase 2 study that we started in October and we’ll initiate as well the Phase 3 and the Phase 2 study in pancreatic. From lucitanib we’ll initiate both the two studies that I’ve described and hope to enter before too long, probably in the second half of the year into a diagnostic partnership for FGF-aberrations.
And with that, I want to thank you for your time and attention and go [indiscernible]. Thank you.
[No Q&A session for this event]
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