ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA)
Jefferies 2014 Global Healthcare Conference
June 4, 2014 02:30 PM ET
Tim Clackson - President of Research and Development and CSO
Eun Yang - Jefferies
Good afternoon. This is Eun Yang, a biotech analyst with Jefferies. So, next presenting company is ARIAD Pharmaceuticals. ARIAD is a cancer -- largely, primarily focused on cancer and has one product on the market Iclusig, and then second product entering Phase 3 shortly. So fresh, coming out of the fresh, out of ASCO fresher Tim Clackson is the one representing from ARIAD Pharmaceuticals. And Tim is the President of Research & Development at ARIAD. Tim?
Thank you Eun, it’s a pleasure to be here and to give you -- yes a very fresh update on the data that we presented at ASCO. More generally on the progress that ARIAD is making across our various different programs. Before I start, I’d like to remind you that some of the statements I’ll be making are subject to risks and uncertainties and you can read our regular SEC filings for details on those risks.
At ARIAD, our major focus for this year has been and will be to build and rebuild confidence in Iclusig, our lead product for CML and Philadelphia positive ALL. The drug is indicated in the U.S. and Europe and approved for patients with resistant or intolerant CML and Philadelphia positive ALL. And following the review of safety information and temporary suspension last year, the drug is now back on the market in the US and the relaunch has proved to be strong in the last few months.
We’re also in the middle of process of roll out of pricing and reimbursement in Europe and with an ongoing review process due to complete later this year, that should then lead to the completion of several other pricing and reimbursement events in different European countries.
We are on track for filing of a JNDA in Japan next year and that we anticipate would lead to approval in Japan and there are filings ongoing in other markets as well.
Another part of the news this year has been the lifting of partial clinical holds which were placed on Iclusig development late last year, most recently including our GIST trial, gastro intestinal stromal tumors and I’ll be able to give you an exciting update on the latest data from that trial later in the presentation. And that leads in turn to new indications potentially for Iclusig down the line.
Overall our approach and our strategy is to rebuild the value of Iclusig -- value of ARIAD through improving and reinforcing a benefit risk ratio for Iclusig, for -- by emphasizing the advantages that we believe 113 has as a highly potent and competitive ALK inhibitor for lung cancer and then by moving on our pipeline, including the nomination of another development candidate from our internal discovery efforts by the end of this year.
So first let me turn to Iclusig, as a general update on Iclusig -- first in CML and Philadelphia positive ALL. There's a strong U.S. commercial opportunity for Iclusig now that we are back on the market. The eligible population under the revised U.S. label and the prescribing information is approximately 1,300 new patients annually. So that is the incident, largely incident patient population. And by virtue of having a more streamlined patient population that are currently eligible for the drug, we've been also able to streamline our distribution process and that allows us to have a very good insight and visibility into the individual patients and physicians who are writing and taking Iclusig.
In this re-launch we have maintained our pricing strategy and that is to have a modest price premium, compared to the existing second generation agents and that translates to an annual cost of approximately $125,000. In addition to this pricing approach we continue to have a very comprehensive payment assistance program, including just a $10 co-pay.
Our early progress in the re-launch which began at the beginning of this year has been good and strong. An important aspect was converting those patients who had been on single patient INDs during the marketing suspension back on to commercial drug. At the time of relabeling and re-launch of the drug, we had approximately 300 patients who had been receiving Iclusig through the single patient IND process and through the first quarter we were able to successfully convert to commercial drug about 210 of those. The remaining patients were either those who had come to the end of that quarter therapy by virtue of having advanced disease primarily or who were not eligible for commercial drug and therefore receive free drug through our assistance program.
The distribution of IND patients was as you on the screen and was including both third line and fourth line as well as some legacy second line patients, most of those patients were chronic phase patients and only 25% of those had the T315-I mutation. So by no means is this a patient population that is skewed towards that particularly resistant mutation that is refractory to all other therapies. In addition to the patients who moved over from a single patient IND we had a substantial number of patients who became Iclusig patients de novo, and so at the end of the first quarter, we had greater than 300 patients now in our prescribing base.
An important on going focus in 2014 is to grow and maximize the opportunity that we have for Iclusig in Europe. We are currently marketing and selling the drug in Germany, the UK, France, Austria, Switzerland outside the EU, the Netherlands, Norway, and Sweden. And we have modest commercial operations in many centers but not all of those centers in the EU that in a cost effective manner allow us to reach those countries and those territories. On-going at the moment is under the edges of pharmacovigilance review committee of the EMEA is an article 20 referral procedure, which is if you like a deep dive into the updated efficacy and safety information for Iclusig with a view to optimizing the labelling information and recommendations for use. This process is underway and we expect the conclusion of the current round of that process in July.
So pricing and reimbursement is an on-going activity throughout this year as I mentioned many of the countries that we would market in the U.S. in the EU already have pricing and reimbursement and sales on-going, others will kick in either midyear as shown here or towards the end of the year for other countries aligned in part with the finalization of the PRAC process. So how are we going to be advancing clinical development and what’s important with Iclusig, the single most important priority we have is to improve the benefit risk ratio of Iclusig to emphasize and drive home the benefits of the drug and mitigate as much as possible the vascular occlusive and other events that we have seen with higher doses of Iclusig in our on-going clinical trials.
The very important aspect to this is to gain a better understanding of the nature of these vaso-occlusive events and we’ll gain in the part through continued follow-up of clinical trials. As an example at ASCO this week, we were able to announce and present with our investigators a further follow up of the Phase I and PACE Phase II trials that continue to show these time points that reductions in dose in the face of adverse event leads to largely continuation of response. There are very few patients who have dose reductions and lose their response. And we’ll be able to continue following these patients to understand whether dose reductions also lead to stabilization or reduction in the rate of vascular occlusive events.
Another way to understand these events is to very carefully follow patients who are receiving commercial product and one of our commitments is to conduct pharmacovigilance studies to reach out into marketplace and understand how patients are doing efficacy and safety and also the concomitant medications that they’re taking. We will also have science dedicated towards understanding the mechanism of these events our ambition from the scientific point of view is to own the vascular occlusion signal and to carefully evaluate from a scientific point of view how we can use that knowledge to mitigate these effects.
From a practical point of view, we are actively interested in potential interventions that could reduce vascular occlusion, but we need to be careful for example the use of baby aspirin maybe a problem in patients sudden through the disease naturally prone to bleeding. And so in many cases, this is a patient to patient decision and we are suggesting guidelines but certainly not mandating a particular treatment. It’s also important we have learnt to manage underlying cardiovascular and other diseased states. We know that there are some risk factors that appear to predispose to vascular occlusive events, notably hypertension of baseline and the existence of uncontrolled or other diabetes. And so management of these diseases is an important aspect of optimizing the use of Iclusig.
Most importantly perhaps we are interested in actively evaluating lower starting doses of Iclusig, I mentioned that we were able to show in the PACE trial that the starting dose of 45 milligrams can be associated with lower event rates when you analyse patients who had dose reductions to 30 or 15 milligrams, but we do not have data yet for patients who started at that dose and we will be running a randomized trail starting later this year to actively investigate the efficacy and safety of such dosing regiments.
This will allow us in turn to optimize a dose, which we anticipate maybe a lower dose and that will allow us in turn to consider what the possibilities might be for moving Iclusig back into earlier lines of therapy.
Outside of leukemias, there are number of opportunity for Iclusig in other tumour types that stem from its ability to inhibit other kinases. At ASCO this year we were able for the first time to describe activity and the first results in gastrointestinal stromal tumours or GIST. GIST is a disease that has an annual instance in the U.S. of around 4,500. Most cases are caused by activation of a particular receptor tyrosine kinase called KIT by point mutations.
Standard of care involves first line imatinib, but many patients on imatinib fail often because of point mutations that cause resistance. And then there are subsequent therapies which are in general inadequate in stabilizing the disease for meaningful periods of time. We have had an on-going Phase II trial in patients with TKI resistant GIST. At ASCO we described the results from the first 35 patients in this trial, and the time on trial profile is shown on this slide, what you can see is a substantial proportion of patients, despite the fact that these are very late stage patients have remained on drug, and in many cases gaining a clear clinical benefit for six months or longer. In this late stage patient population, true objective responses, especially in GIST which is complex to measure are not generally expected. The goal is really to stabilize the disease and that’s captured in a clinical benefit response end point that includes stable disease.
In the most responsive cohort that we saw, the code, the so called Excellent 11, positive cohort we saw a 50% clinical benefit response rate. Coupled with the duration that I showed you on the previous slide, that is a very promising early finding that we see as emphasizing proof of concept for the use of ponatinib in the resistant GIST patients. Importantly the median survival in these patients so far has not yet been reached and the median PSS appears to be around seven months, a very respectable number given the nature of this patient population.
Generally the safety profile of Iclusig in GIST was analogous of that in leukemic patients with a notable exception that myelosuppression as expected in this non-leukemic population was much lower. So overall, we see this early data set as defining a clear path forward for Iclusig in further development in resistant GIST and we are currently debating internally and with the drivers, the potential path that could result in pivotal trial testing.
Beyond GIST, we’re exploring a whole series of other potential applications of Iclusig, in other tumour types or in aspects of CML and Philadelphia positive ALL that are not entirely covered by our current indication. And listed on this slide and the next slide are trails which are either underway or will shortly be underway to allow us to explore in a comprehensive manner, potential additional indications. Each of these represents an additional potential value driver for Iclusig in the near medium and long term.
Among the most exciting applications I think are acute myeloid leukaemia, where we already know the drug is active based on analysis of a small cohort in our original U.S. phase I study. And non-small cell lung cancer, where two subsets of disease driven either by RET or by FGF receptor mutations are expected, based or predicted based on preclinical activity to potentially be susceptible to Iclusig treatment and all of those hypothesis are now being tested clinically.
So, let me now turn the rest of the presentation to talk about AP26113, 113 is our highly potent oral ALK inhibitor to inhibit the ALK positive sub-population of non-small cell lung cancer. We had a substantial data update on this program at ASCO and I am showing you one of the most important take home slides from that presentation. It is the waterfall plot that shows our activity in now a group of more than 50 ALK positive lung cancer patients. Some of these patients had never received crizotinib and therefore were crizotinib-naïve, most of them had received crizotinib and a handful had also received additional ALK inhibitors. I think you can see just from the visual impact of the waterfall plot that we have a very deep and consistent trend of high activity in this patient population with essentially every patient showing some kind of tumour shrinkage, many patients showing a profound tumour shrinkage and with the durations being quite substantial.
Most patients with or excuse me all patients with naïve disease had a response including one patient with a complete response, so that’s six out of six responding patients. In the subset of patients who have just seen and failed on crizotinib, the overall response rate was 69% as you can see here and many of those responses were of quite substantial duration ranging up to 14.7 months. The median PFS was almost 11 months but again in that context of this late stage disease and already failure of the main and only frontline targeted therapy, we believe is a substantial indication of clinical benefit.
A very important aspect of the activity of 113 is there is activity in the CNS; more than 50% of patients who fail therapy with crizotinib do so with the presence of brain metastasis. So, addressing the problem and ideally in the future preventing the problem of brain metastasis is a key therapeutic target and desired outcome.
In our dataset of the 13 patients we examined who had active brain metastasis; nine of those had regression of those metastasis that were untreated or progressing. We believe this is a clinically meaningful result and an important subset of these patients and adds to the general sense of the efficacy of the drug. We spent some time understanding carefully the safety and tolerability of 113 at different doses. The dose escalation trial evaluated doses on a once daily oral range all the way up from 30 to 300 milligrams and we now understand that doses of 90 milligrams or higher are able to achieve clinical levels which we predict will overcome all crizotinib resistant ALK mutations. We had substantial efficacy data at both 90 and 180 milligram dose levels. In our earlier studies, we saw a phenomenon of early pulmonary syndromes including dyspnea and hypoxia which we wish to understand and ideally ameliorate with dosing.
These were typically findings that we saw in the first one to two days of dosing and the data we presented at ASCO showed that by using one of two approaches either flat dosing at 90 milligrams continuously or week of 90 milligram dosing followed by escalation to a 180 permanently substantially reduced the rate of this pulmonary observation and of the patients that we treated with 90 to 180 dosing approach of which they were 28, none of them now show this syndrome. So, we believe we substantially reduce the rate. This allows us to move confidently into the trial which is now underway, a pivotal trial to test the activity of 113 in crizotinib-resistant ALK positive patients. The design of the trial is shown on this slide and we have elected to run a two arm randomized trial although a non-comparative trial to evaluate both of those dosing approaches to maximize our opportunity to have a productive dose or perhaps two doses that we can move forward with commercially.
So, patients on this trial which we call the ALTA trial will be enrolled globally, 220 patients will be targeted. All patients will receive 90 milligrams for the first week then they will be randomized either to stay at 90 or to have escalate to 180 and we'll follow patients for the primary endpoint of objective response rate.
So in closing the ARIAD story today involves a number of novel molecules, all of which have emerged from our internal discovery and development engine that represent different stages in the ARIAD story and its evolution. Our legacy programs with deforolimus and AP1903 have been or are in the hands of partners who are developing them for separate indications in or outside of oncology where deforolimus will become an ARIAD asset again at the end of this year.
The current generation of products which are wholly-owned include Iclusig, ponatinib and 113 both of which are moving ahead in various arms of clinical testing and of course Iclusig is approved in its initial indication in the U.S. and Europe. And then beyond that as I mentioned at the beginning of the presentation, at the end of this year we anticipate the nomination of a new clinical candidate an oral small-molecule that inhibits oncogenic TKI that we believe will be very differentiated and that would become the next molecule to move into the clinic from the ARIAD engine.
So, overall we believe by combining our internal discovery, accelerated development and then our own dedicated commercialization infrastructure in the U.S. and the EU that we can continue to build shareholder value across the entire spectrum of drug discovery. Thank you.
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