Amicus Therapeutics, Inc. (NASDAQ:FOLD)
Phase III Fabry Monotherapy Study Results Conference Call
August 20, 2014 08:00 AM ET
Daphne Quimi - Vice President, Finance
John Crowley - Chairman and Chief Executive Officer
Jay Barth - Chief Medical Officer
Chip Baird - Chief Financial Officer
Bradley Campbell - Chief Operating Officer
Jeff Castelli - Vice President and Program Management
Ritu Baral - Cowen and Company
Joseph Schwartz - Leerink Partners
Kim Lee - Janney Capital
Good day, ladies and gentlemen, and welcome to the Amicus Phase 3 Fabry monotherapy results conference call. At this time all participants are in a listen only mode. Later we will conduct a question-and-answer session and instructions will follow at that time. (Operator Instructions). As a reminder, this conference is being recorded. I will now turn the call over to your host, Daphne Quimi, Vice President, Finance. Please go ahead.
Good morning and thank you for joining our conference call. Speaking on today’s call we have John Crowley, our Chairman and Chief Executive Officer; Chip Baird, our Chief Financial Officer; Jay Barth, our Chief Medical Officer; Bradley Campbell, our Chief Operating Officer; and Jeff Castelli, our Vice President and Program Management.
Today’s prepared remarks coincide with the slide presentation that is now available on our corporate Web site at www.amicusrx.com. The slides are located in the Investor section under Events and Presentations right below the webcast link to today’s call.
On slide two, you will find the reference to our Safe Harbor. This conference call contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 relating to business, operations and financial conditions of Amicus, including but not limited to, preclinical and clinical development of Amicus’ candidate drug products, cash runway and the timing and reporting of results from clinical trials evaluating Amicus’ candidate drug products.
Words such as, but not limited to, look forward to, believe, expect, anticipate, estimate, intend, plan, would, should and could and similar expressions or words identify forward-looking statements.
Although, Amicus believes the expectations reflected in such forward-looking statements are based upon reasonable assumptions, there can be no assurance that its expectations will be realized.
Actual results could differ materially from those projected in Amicus’ forward-looking statements due to numerous known and unknown risks and uncertainties, including the Risk Factors described in our annual report on Form 10-K for the year ended December 31, 2013.
All forward-looking statements are qualified in their entirety by this cautionary statement and Amicus undertakes no obligation to revise or update this presentation to reflect events or circumstances after the date hereof.
At this time, it is my pleasure to turn the call over to John Crowley, Chairman and Chief Executive Officer of Amicus.
Great, thank you Daphne and good morning everybody. This is a call we’re certainly very happy to host. I am here with my senior team and we’re all gathered around our conference table at offices in Cranbury, New Jersey a table that we’ve spent much time around in the last few years, designing and executing these Fabry monotherapy studies and the second Phase 3 is a study that we’re very happy to present the top line data on today I’ll reference Slide 3. I’ll just make some very brief introductory and summary comments before I hand the conversation and presentation over principally to Jay Barth our Chief Medical Officer.
But let me just reiterate as you see on Slide 3 that Migalastat successfully met both co-primary end points of comparability to enzyme replacement therapy on both key measures of kidney functions. And as you will note there we see that Migalastat had a comparable effect to enzyme replacement therapy on patients kidney function and Jay will show the graph and take you through some specific data. But you’ll see by measures of both eGFR and mGFR, two different ways to look at kidney function in both cases we saw a 100% overlap in the 95 confidence interval from both measures of kidney functions between the ERT and Migalastat groups.
Importantly another confirmatory piece of evidence was an important biomarker of disease the levels of plasma lyso-Gb3. We’ve talked about this extensively, it’s been written about in the last several years. And the literature is a very important biomarker of Fabry disease. You will see the chart, it’s very, very compelling shortly that when patients switched and again this was an immediate switch from ERT to Migalastat that the levels of that biomarker remained low and stable in patients with amenable mutations again who switched from ERT to Migalastat. As we have seen in all previous studies Migalastat was generally safe and well tolerated, so very pleased with that.
And again patient disposition remains excellent, of the 48 subjects with the amendable mutations who completed this study, 46% or 96% of those patients elected to continue with the 12 month treatment extension and of those 46, 45 remain on Migalastat today as their only treatment for Fabry disease. Towards the end of the presentation Jay will highlight how many patients today take Migalastat monotherapy as their only treatment for Fabry disease, many of whom have switched from enzyme replacement therapy.
So again the top line findings are as good as we could have hoped for it confirms a lot of the work that’s been done in science, in clinical medicine here at Amicus and build on what are now the two largest Phase 3 studies ever conducted in Fabry disease, we’ll talk more about the regulatory paths forward but certainly a great day for Fabry patients.
With that let me turn the conversation over to Dr. Jay Barth.
Thank you. I am going to start on Slide 4, reviewing the study design of the Phase 3 study the ATTRACT study. All patients in this study had been on ERT treatment, at least for one year and in general for much longer than that. And patients at baseline were randomized to receive either Migalastat a 150 milligrams given orally every other day, or to remain on their ERT, over an 18 months treatment period. At randomization patients were stratified by sex and by proteinuria in order to maintain balance on these two important prognostic factors.
Measured GFR was tested four times during the study, baseline six and 12 and 18 months. And eGFR was measured more frequently eight times during this study. eGFR just to remind everyone is the commonly used measure in Fabry disease the renal function and what is almost exclusively reported in the literature for Fabry patients.
Moving to Slide 5; we had pre-specified in these statistical analysis plan that comparability between the two treatments Migalastat and ERT based on two criteria applied to both co-primary end points eGFR and mGFR. And these comparability criteria are; one, that the 95% confidence interval would overlap by at least 50% and that means it would be within 2.2 milliliters per minute per meter square per year for GFR. We had specified this analysis would be performed based on an ANCOVA model that would include the terms treatment, sex, age, baseline GFR and baseline proteinuria. And that for efficacy the data would be analyzed in patients with GLP HEK amenable mutations. And as turned out there were four patients out of the total number randomized who had non-amendable mutations.
Now turning to the results on Slide 6; we can see here on the left are the results for eGFR, on the right mGFR, that in both cases there is a close comparison of the means for Migalastat and ERT, Migalastat in blue and for ERT in red. For eGFR the difference of the means was plus 0.63 for mGFR minus 1.1 both well within the margin of 2.2 that was specified in the statistical analysis plan. And one can see also that there is a 100% overlap of the 95% confidence intervals in both cases, both for eGFR and for mGFR.
And this is reflected in next slide, Slide 7; showing that Migalastat successfully met both co-primary end points for comparability. The 95% confidence interval overlap exceeded the 50% in both cases, in fact it was a 100% and a difference of the means was within 2.2 and in fact it was much less than that in both cases, as I said 0.63 and minus 1.1.
These results clearly demonstrate the comparability of Migalastat and ERT in efficacy, in renal function.
Moving to Slide 8; we also analyzed the data in several ways including looking at the medians, which is the way of looking at the data and not effected by some of the outlier values. And you can see looking at the results for the medians that there were even smaller differences between the Migalastat and ERT arms ranging between minus 0.42 and plus 0.34. And this analysis confirms the results we saw in the primary analysis of the means.
We also on Slide 9; supporting the positive results that we saw in GFR looked at disease substrate plasma lyso-Gb3, which is an important biomarker in Fabry disease. You could see on the figure on the left in amenable patients that Migalastat in blue had the same effect as ERT in red in maintaining low levels of substrate of lyso-Gb3 over 18 months, there was no difference between the two treatments. And in fact the four non-amendable patients who happen to be in the study provided very valuable information on this biomarker.
You could see on the right, for the two patients who had non-amendable mutations who are on ERT maintained the same level of lyso-Gb3 as they had when they came into this study. In contrast two patients with non-amendable mutations who received Migalastat had substantial increases in the lyso-Gb3 that occurred by month six and continued to increase through month 18, clearly confirming the effective drug in amendable patients and showing how the GLP HEK assay clearly identifies patients who will or will not respond to Migalastat based on their amendability of their mutations.
So the GFR clinical data is supported by the biomarker data with lyso-Gb3. We also saw in the study in Slide 10, a favorable safety profile for Migalastat as has been seen throughout its development. This table shows the common adverse events those occurring at least 10% frequency. And as you can see there was no increased incident of adverse events for Migalastat compared to ERT. And in fact the number of common adverse events at least 10% were greater for ERT than Migalastat.
This favorable safety profile will be a factor that will figure well into the benefit risk assessment that regulators will take when reviewing the data for Migalastat.
And in fact moving to Slide 11; there is extensive experience with Migalastat over the years in a large of patients. 143 patients Fabry disease have taken Migalastat, some for more than eight years. And 96% of patients have chosen to continue on Migalastat when offered an extension study. At this time there are 97 patients who are taking Migalastat as their only specific therapy for Fabry disease.
With all the data that we have now from the Phase 3 studies as well as this extensive experience over the years. Moving to Slide 12; we’re pursuing the fastest path to approval in all regions. We’ve started work on a centralized procedure in Europe for an MAA submission and in fact had an EMA pre-submission meeting planned for the fourth quarter of this year. Now the MAA will be based primarily on comparability to ERT which was demonstrated in study 012 with supported data from the other Phase 3 studies, study 011 as well as the other clinical data that we have collected over time. And we’re also moving ahead in the U.S., we’ll be presenting into FDA the totality of the data and that includes the two Phase 3 studies as well as long-term data from all the extension studies, and we’re very much looking forward to these regulatory interactions both in Europe and in the U.S.
Thank you for the overview and summary Jay that was terrific. So again we’re very pleased with where the data has come out where we think this is a terrific day for people living with Fabry disease, who for sometime have needed to have a potential new therapy in for their physicians in their arsenal of drugs to treat this devastating and fatal genetic disorder. Again this is a very novel mechanism of action, small molecule pharmacological chaperone. We think that this is also an excellent use of personalized medicine and we think we now have and verified by this further study that we can predict with nearly 100% certainty, patients with those amendable mutations for whom Migalastat monotherapy would be the appropriate and only treatment for their Fabry disease over the course of their life time.
So to Jay’s point something we’re going to move forward with very rapidly, this is a market with over a billion dollars in enzyme replacement therapy sales and thousands of patients on those drugs, we intend to move forward as Jay indicated in the U.S. and in the EU and other jurisdictions to move this drug to patients as rapidly as we possibly can. And in the meantime to the other half or so of the Fabry market for whom this drug we don’t think will be a benefit. Those with a non-amendable mutations, we intend to move very rapidly with our next generation enzyme replacement therapy as you are all aware of, that combines our proprietary ERT with Migalastat co-formulated as a next generation ERT.
So our vision is that over the next several years patients and physicians will have the option to take an Amicus therapy even monotherapy for those with amendable mutations were in next generation enzyme replacement for those with non-amendable.
So that’s our vision, we’ve got a lot of work ahead of us, this is certainly a great day for patients and we’re happy to take your questions.
Thank you. (Operator Instructions). Our first question comes from Ritu Baral with Cowen.
Ritu Baral - Cowen and Company
I've got just a couple questions. One, can you just take us through the placebo dropout? You've got 21 patients in the safety analysis and 18, I believe in the efficacy. Can you take us through the reasons for the dropouts and the timing?
I think you referenced placebo, I think you meant the ERT arm Ritu?
Ritu Baral - Cowen and Company
Jay if you just want to speak to the drop outs in the ERT?
I think we can start with the overall population; there were 60 patients who randomized into the study. Three patients who randomized to the ERT arm dropped out before they received the dose of the medication, presumably because they decided not to continue into the study once they know they were going to receive ERT. And after that the population that we focused on for efficacy were those with the GLP HEK amendable mutations. And as I mentioned there were four patients who are randomized, who based on the clinical trial HEK assay, who turned out in the validated GLP assay not to have amendable mutations. So there were four patients excluded from the efficacy analysis for that reason.
Ritu Baral - Cowen and Company
It's not in the slides, but since you did do GFRs at least every six months, how does the time course of the GFRs look over the 18 months? Is it something that shows you sort of rapid of any sort of variability within the six and 12 month timeframe?
When looking at the mGFR because it was measured four times, there is fluctuation in some cases from one-time point to the next. But the way we analyzed this was a slope analysis that took into account each of these time points, and then smoothed out these differences to arrive at one value which has been value for the slope. There was differences between patients of course, but overall I think the fluctuation and variability occurred as we expected with mGFR that’s the nature of the test. And so the with eGFR, there were also more measurements done at the eGFR. So we saw as we expected less variability in eGFR, that’s reflected in smaller confidence intervals that you can see on the slide for the eGFR compared to the mGFR.
So I think the results were pretty much as we expected them for eGFR and mGFR in comparing the two as ways of measuring the renal function in Fabry disease.
And to be clear Ritu any fluctuations or flexibility we’re seeing in both the Migalastat group and the ERT group. And again I think to Jay’s point on measured GFR that’s part of the inherent variability of that testing measure.
Ritu Baral - Cowen and Company
Last question; did you check these patients for either antibodies to ERT or neutralizing antibodies to ERT?
No that wasn’t part of this study.
Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open.
Joseph Schwartz - Leerink Partners
I was wondering if you could tell us do you think that the regulators are okay with your per protocol MITT analysis, or do you think that they might require an ITT analysis? And how does the data look on that basis? I could reason where it would be even stronger or maybe not as strong if you exclude the patients that were not in that ERT arm ultimately.
We have pre-specified in the statistical analysis plan that the MITT population would be the efficacy population. And the main difference between the ITT and the MITT are the four patients who did not have amendable mutations. And I think the regulators will accept that fact. That based on the validated GLP assay, these four patients will not be included in the MITT, certainly the lyso-Gb3 data supports the fact that these patients were not respond to Migalastat. So I don’t think the MITT population will be an issue with the regulators who are looking at the efficacy data.
Joseph Schwartz - Leerink Partners
Then can you just give us some timeline of what we should expect with regards to next steps with the FDA and EMA?
I think with the EMA, we’ve already begun the submission and the centralized procedure is already underway. So I think we have a very clear path in Europe. So that will continue through this year into the first part of next year. We would lead with the regulatory strategy outside the United States. We do intend to meet here in the fourth quarter with the FDA and present to them what they ask for, which is the results from both Phase 3 studies. And again I think with a very compelling data set and positive Phase 3 studies in both cases I am very hopeful that the risk benefit analysis will weigh very heavily in the favor of Migalastat as a new treatment option here in the United States for Fabry patient.
(Operator Instructions). Our next question comes from Kim Lee with Janney Capital. Your line is open.
Kim Lee - Janney Capital
Just a follow-up on timelines here. Assuming best case scenario with the FDA and your talks go well, can you remind us what's the earliest timeframe you could get this drug approved in the US and what would be the considerations to do so?
I think as our operations for submission, pre-submissions and meetings occur in the second half of this year, perhaps into very early 2015. I think you could look for filings shortly thereafter, and I don’t want to give specific guidance but we still need to have those discussions, if you have any further color, go ahead.
I think it’s difficult at this point to give the exact timeframe because it does depend on how the discussions go with the FDA but we’d be looking to submit next year and the review process will take as long as FDA decides it needs to take into 2016, but it’s hard to be more specific at this point till we engage them further.
I am showing no further questions at this time. I will now turn the call back over to John Crowley, CEO for closing remarks.
Thank you all for listening and thanks for the great questions. We’re going to get back to work here and continue to do all the work necessary to move Migalastat forward toward approval while also advancing all of our programs and our pipeline and we’re very excited about. So let’s stay tuned. Thank you, have a great day.
Thank you ladies and gentlemen that does conclude today conference. You may all disconnect and everyone have a great day.
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