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BioMarin Pharmaceutical Inc. (NASDAQ:BMRN)

March 19, 2013 5:00 pm ET

Executives

Eugenia Shen

Jean-Jacques Bienaim - Chief Executive Officer and Director

Henry J. Fuchs - Chief Medical Officer and Executive Vice President

Analysts

Matthew W. Luchini - Piper Jaffray Companies, Research Division

Ying Huang - Barclays Capital, Research Division

Joshua Schimmer - Lazard Capital Markets LLC, Research Division

Blake C. Arnold - Robert W. Baird & Co. Incorporated, Research Division

Robyn Karnauskas - Deutsche Bank AG, Research Division

Michael J. Yee - RBC Capital Markets, LLC, Research Division

Yaron Werber - Citigroup Inc, Research Division

Philip Nadeau - Cowen and Company, LLC, Research Division

Matthew Harrison - UBS Investment Bank, Research Division

Kimberly Lee - Janney Montgomery Scott LLC, Research Division

Matthew J. Andrews - Wells Fargo Securities, LLC, Research Division

Tim Lugo - William Blair & Company L.L.C., Research Division

Joseph P. Schwartz - Leerink Swann LLC, Research Division

Stephen D. Willey - Stifel, Nicolaus & Co., Inc., Research Division

Operator

Good day, ladies and gentlemen, and welcome to BioMarin Pharmaceutical's BMN-701 Phase I/II Trial Results Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded.

I would now like to turn the conference over to Ms. Eugenia Shen of Investor Relations. Ma'am, you may begin.

Eugenia Shen

Thank you. On the call today is J.J. Bienaimé, BioMarin's CEO; Hank Fuchs, Chief Medical Officer; our special guest speaker, Dr. Barry Byrne, Professor of Pediatrics and Molecular Genetics & Microbiology and Director at the University of Florida Powell Center and Lead Investigator for POM-001; Robert Baffi, Executive Vice President of Technical Operations; and Dan Spiegelman, CFO.

This non-confidential presentation contains forward-looking statements about the business prospects of BioMarin Pharmaceutical, including expectations regarding BioMarin's financial performance, commercial products and potential future products in different areas of therapeutic research and development. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in BioMarin's filings with the Securities and Exchange Commission such as 10-Q, 10-K and 8-K reports.

I'd now like to turn the call over to J.J., BioMarin's CEO.

Jean-Jacques Bienaim

Thank you, Eugenia. Good afternoon, everyone. Thank you for taking the time today to get an update on BioMarin's development program for late-onset Pompe disease. As you know from our press release, we are very pleased to communicate the data from our 701 Phase I/II study, which is propelling us to progress BMN-701 forwards into the clinic.

We are privileged to be joined today on the call by Professor Barry Byrne from the University of Florida. Professor Byrne is the principal investigator in the 701 Phase I/II study. He specializes in pediatric cardiology, and he has committed his career to improving outcomes in patients with muscle disease, Pompe among them.

Hank will review the findings of our study in detail. And next, Dr. Byrne will place his finding in context. And Hank will come back to talk about next steps.

Briefly, we are pleased to observe absolute improvement over baseline in the 2 endurance and the 4 respiratory functions we measured with 701. We're particularly pleased to see meaningful improvements in 2 important parameters of respiratory muscle function namely, maximal inspiratory and maximal expiratory pressure; and in 1 parameter of improved endurance, the fraction of patients who had superior improvement in 6-minute walk testing. Clearly, they're important parameters in the management of Pompe patients, as they were also measured in the study, which led to the approval of the presently marketed enzyme, alglucosidase alfa. We are reassured that in other parameters, patients treated with BMN-701 appear to do about as well as patients reported doing in the registration study for the currently approved therapy.

Based on the results from this study, we plan to gain alignment with health authorities on requirement for registration and produce sufficient material to support necessary testing in patients and launching switching study, utilizing our improved manufacturing process by the end of the year.

I will now turn the call over to Hank and Professor Byrne for a few prepared comments, after which, we will be available to answer your questions.

Henry J. Fuchs

Thanks, J.J., and good afternoon, everyone. The goal of the Phase I/II study was to evaluate the safety of BMN-701, its pharmacokinetics and to explore its efficacy. Briefly, 3 cohorts of patients underwent sequential dose escalation, starting 3 patients at 5 milligrams per kilogram every other week, followed by enrollment of 3 patients at 10 milligrams per kilogram every other week. When the safety of that cohort's dose was assessed, an additional 16 patients received treatment with 20 milligrams per kilogram every other week. As this was a Phase I/II study, the primary endpoints consisted of safety and pharmacokinetics. Additionally, evaluations of efficacy parameters similar to those measured in LOTS, walk, forced vital capacity, maximum inspiratory pressure, maximum expiratory pressure and quantitative muscle testing, was undertaken. The predefined primary efficacy evaluation was changed from baseline to week 24 with the other efficacy measures, super-responders on walk, forced vital capacity, maximum voluntary ventilation, maximum expiratory pressure, maximum inspiratory pressure and quantitative muscle testing, all predefined the secondary efficacy measures. For the purpose of this discussion, I'll focus my comments on the 16 patients administered 20 milligrams per kilo per every other week for 24 weeks.

First, in regard to safety, the principal side effects of BMN-701 were infusion-associated reactions. One patient had temporary drug interruption and one patient discontinued drug due to infusion-associated reaction out of the total of 22 patients treated in the first 24 weeks. Infusion-associated hypoglycemia, an expected pharmacologic effect of BMN-701, occurred in 13 patients, one of whom experienced a grade 3 event. All such events occurred during or within 1 hour of infusion and were readily managed with either oral or IV glucose.

Detailed pharmacokinetic evaluation was undertaken, and systemic exposure to BMN-701 was found to be about tenfold lower than that described for alglucosidase alfa. 3 out of 16 or 19% of patients experienced substantial improvement in the 6-minute walk distance, defined as an increase of 75 meters or more in their baseline walk distance to week 24. Mean improvement for the 6-minute walk distance was approximately 22 meters for the 16 patients treated in the 20-milligram-per-kilo cohort.

For pulmonary function, mean absolute improvement in forced vital capacity was 1.2% in absolute terms or 2% relative improvement from pre-treatment baseline to week 24. Mean absolute improvement in maximum voluntary ventilation was 2.9 liters per minute in absolute terms or a 4.3% relative improvement from pre-treatment baseline to week 24. Mean absolute improvement in maximal expiratory pressure was 5.1% of predicted in absolute terms or 14.1% relative improvement from pre-treatment baseline to week 24. Mean absolute improvement in maximal inspiratory pressure was 11% in absolute terms or 27% relative improvement from pre-treatment baseline to week 24. Quantitative muscle testing in arms and legs did not meaningfully improve during the study. Values remained within the substantial variability of the treatment -- pre-treatment values.

In aggregate, 13 of the 16 patients treated in the trial experienced a more than 10% net improvement in 1 or more domain of either 6-minute walk test, maximum inspiratory pressure or maximum expiratory pressure. Although it was a much smaller sample size, taken together, these data suggest an outcome that is, in some cases, similar to available therapy, mean walk and mean forced vital capacity improvement, but in other cases, meaningfully better, maximum inspiratory pressure and maximum expiratory pressure, as well as the percentage of patients who had a greater than 75-meter improvement in walk.

With that, it's my pleasure to turn over the call to Dr. Barry Byrne who'll place the study and the findings in context. Barry?

Barry Byrne

Thanks very much, Hank. I'm glad to be able to join you for -- to describe these results. And as you could imagine, the primary motivation for this program is really to improve outcome of patients who have a lot of ongoing functional limitations despite currently available therapy for Pompe.

While improvements in outcome are observed in a small fraction of patients with current therapy, most patients experienced a continuous decline in motor function and breathing ability. We see as the disease progresses, patients may notice fatigue and lethargy from sleep-disordered breathing that results from respiratory muscle weakness complicated especially by lying down. And inevitably, most patients worsen, oftentimes quite rapidly, in fact, requiring assisted ventilation initially by intermittent assistance or sometimes positive pressure devices. And further decline results in the need for continuous ventilatory systems. And ultimately, respiratory failure is the outcome.

So respiratory muscle failure is really the principal cause of early mortality in most patients. Therefore, really a rational approach, based on the biology of the BMN-701 fusion protein, was necessary. And relatively, little was known about what to expect from this treatment because improving delivery of enzyme to muscle by administration of higher doses is really -- has been difficult for reasons of safety and cost. So based on our previously published review of long-term outcome in Pompe patients, the most impressive finding to me of the 701 study is the improvement seen in maximal expiratory pressure and maximal inspiratory pressure.

In Pompe, like in many other muscle diseases, muscle function is -- dysfunction is found everywhere, especially in the respiratory system. And from our 2011 published study, shortness of breath after exercise was reported in the majority of patients, in about 2/3, and it's the most common symptom noted. Maximum expiratory pressure and the inspiratory pressures are direct measures of respiratory muscle function and are really important indicators of the drug's effectiveness in this setting of muscle weakness.

In other natural history studies of Pompe done by van der Beek and his colleagues, the average annual decline in MIP is a little over 3% and MEP declines by almost 4% per year. Against this background, in improvements -- improvements in MIP and MEP that BMN-701 patients demonstrated is a unique and important finding. If this is confirmed in larger studies, one would believe that improved muscle -- delivery of the enzyme leads to improved function of specific muscle groups. And specifically, improvement in respiratory muscle strength would represent a very important benefit to patient's function and potential longevity.

Of course, you cannot exclude a placebo effect in an open-labeled study. However, I don't really believe that findings from the current study are biased, since no measurable placebo effect was observed in prior pivotal studies of alglucosidase. And it's important also and reassuring to see that there was a greater benefit for patients treated at higher than lower doses.

Finally, it's striking that most patients had a substantial improvement from baseline of more than 10% in 1 or more parameters of function. It's clear from other treating physicians in Pompe patients that a drug with greater impact on ventilatory function would be of importance assuming the results can be confirmed in subsequent studies. So our team is really eager to continue studying BMN-701, and we'd very much like to collaborate with BioMarin in its further development.

And now, I'll hand it back to Hank to address the future plans.

Henry J. Fuchs

Thanks, Dr. Byrne. We certainly support Dr. Byrne's conclusion that further study of BMN-701 is indeed warranted. If such evaluations are successful, we would anticipate that registration of the product as an alternative therapy, providing improved outcome for Pompe patients, would be supported.

The next study we propose to conduct would be one whose objective is to characterize the outcomes of switching patients who are currently treated with alglucosidase alfa to BMN-701. Our preference in current plans, subject to discussion with regulatory authorities, is that the study consists of a single arm, with treatment at 20 milligrams per kilo administered every other week. The study duration will be 24 weeks. And all patients would continue in an extension phase, pending product approval. The primary outcome measure would be efficacy as measured by the respiratory parameter, maximum inspiratory pressure. The secondary objectives will include maximum expiratory pressure and 6-minute walk test, as well as safety.

Based on discussions with Pompe key opinion leaders who have reviewed these data, we believe there will be a broad interest to participate in the study.

In addition to completing an encouraging Phase II study, we've also made significant progress on the manufacturing front. We've evaluated our initial manufacturing process extensively and successfully scaled it to 12,000 liters of manufacturing. During the course of this scaling work, we observed process variability during both cell culture and purification steps of this process, resulting in inconsistent yields. In parallel, we developed an alternative producer cell and purification process and, over the last several months, have verified substantial improvement in process robustness and productivity. Confirmation of these results at full-scale manufacturer is being undertaken. We believe the improved robust process and productivity will lead to substantially improved yields and normalized cost of goods.

Lysosomal delivery of BMN-701 is mediated through the insulin-like growth factor-2 portion of the molecule and, therefore, delivery to the lysosome is not dependent on the level of glycosylation. The original manufacturing process produced a material glycosylation did, however, make it vulnerable to clearance via the unrelated asialoglycoprotein receptor.

We have now conducted several studies that have evaluated the analytical and in vivo characteristics of the material produced with the revised manufacturing process, measuring parameters that are sensitive to key properties of the molecule that would drive efficacy, such as diaphragmatic glycogen clearance and systemic exposure. Based on the results in these -- observed in these studies, we're hopeful that even greater improvements in outcome will be observed after treatment with more properly sialylated glycosylated protein, leading to a reduction in non-target-related plasma clearance.

Material produced at full scale will be available in the fourth quarter this year, assuming a successful manufacturing campaign as we get set to begin this quarter. We're therefore encouraged that we'll have a substantial -- we'll have substantially completed development and evolution of the manufacturing process prior to Phase III, thus, reducing further risks of the program.

We believe that the switching study I described earlier will be an integral and potentially the central element of our registration package. We base this belief on evaluation of the regulatory approval pathways for Elelyso and Vpriv. The regulatory history of these compounds is important as they represent the most recent examples of an enzyme replacement therapy seeking approval in a market where one already exists. Some important lessons can be taken. Specifically, both new drugs were evaluated in approximately 100 total patients. While those programs also included comparative trials, the Elelyso program did not include a comparison to the marketed compound. For both Elelyso and Vpriv, the switching study was deemed important to support registration by documenting stability of patients and safety. It is of course important to point out that our expectation is that we will improve outcomes. Of course, we plan to discuss our plans with national health authorities to gain agreement prior to commencing our next study.

In summary, we're excited by the findings of our first study of BMN-701 in previously untreated Pompe patients. We note improvements in walking for some patients, substantial improvements in muscle -- respiratory muscle strength and improvements in 1 or more domains of health in nearly all patients. Safety of BMN-701 appears to be similar to other enzyme replacement therapies.

We will progress the development of BMN-701, utilizing our improved manufacturing process to address an underserved population with substantial need for improved therapy. We will conclude our manufacturing and regulatory planning activities this summer, with an aim to initiate our pivotal clinical trial program toward the end of the year.

And with that, we'll take calls from participants. Operator?

Question-and-Answer Session

Operator

[Operator Instructions] Our first question comes from Ian Somaiya from Piper Jaffray.

Matthew W. Luchini - Piper Jaffray Companies, Research Division

It's Matthew on for Ian. Just was wondering, looking at the -- the average 6-minute walk distance. I was just wondering if you could provide some color on if there's anything unique about those patients who did, particularly, I guess, less well, such that the average 6-minute walk change was actually -- looks to be a little bit lower than what we saw in LOTS?

Henry J. Fuchs

Yes. So the number of the average 6-minute walk change is indeed numerically smaller as you point out. There's quite a bit of variability in the 6-minute walk test. What was striking to us was that there were 3 patients who had really quite substantial improvement in walking. And of course, the big finding of the study was the great improvements in respiratory muscle strength. And while we don't know exactly why respiratory muscle strength is a more sensitive measure, it is nonetheless an incredibly important measure for patients for the reasons that Dr. Byrne outlined.

Matthew W. Luchini - Piper Jaffray Companies, Research Division

Sure. And I guess if I could maybe try to sneak in a related question to that. Is there any correlation, I guess, that those who were super-responders in the walking portion, did they do particularly well in the pulmonary? Is that something you guys have looked at yet?

Henry J. Fuchs

We've looked at that a little bit. As I said at the -- in my comments, 13 out of 16 patients had a clinically meaningful improvement in 1 or more domains. There were such substantial improvements in the respiratory muscle strength that we're not able to separate out whether the group of super walkers was the group that had the super respiratory muscle strength gain. It really is a very large, consistent robust improvement in respiratory muscle strength.

Operator

Our next question comes from Ying Huang from Barclays.

Ying Huang - Barclays Capital, Research Division

So first of all, Hank, can you talk about the median improvement in 6-minute walk test? Because that gives us a little color in terms of how the deterioration of 6-minute walk distance looks like? And then secondly, also for Professor Byrne here, how clinical relevant is this endpoint called the MIP or maximal inspiratory pressure here? If you -- because we're very familiar with the 6-minute walk test as a measure of the lung flow as well. So if you can provide any color, that'd be very helpful. And then lastly, how confident are you guys in your ability to replicate results from the Phase I/II trial using the new manufacturing process?

Henry J. Fuchs

Okay. So 3 questions, and I'll start with the first one. And then we can -- and then Barry will do the relevance and then we'll come back. I'll come back and do the replication. So I actually don't know the median numbers off the top of my head. Our expectation here is, is that both mean and median respiratory muscle strength is really substantially improved compared to current therapy. Our mean improvements are nearly double. Almost all patients had an improvement. Almost all patients had a greater than 10% relative improvement from their baseline in terms of respiratory muscle strength. So we really have very dramatic improvements in respiratory muscle strength. And, Barry, do you want to comment on the relevance of respiratory muscle strength?

Barry Byrne

Sure. So as in many conditions where there's generalized weakness, the maximal expiratory pressure is an important determinant of the ability to cough and clear respiratory secretions, which, in the absence of that, leads to respiratory infections and overall decline in respiratory function. The inspiratory pressure is an important indicator of how well patients can maintain spontaneous alveolar ventilation and so, a direct measure really of strength of the respiratory system, both from the diaphragm and the extra-diaphragmatic muscle. So together, they're really critical parts of maintaining overall respiratory function, both for clearance of secretions and for maintaining adequate clearance of CO2. So -- and that does have a big impact, I think, overall on patients' health because -- and in fact, ultimately, influences their functioning in the general muscle atrophy because in the absence of that normal pulmonary function, they develop fatigue. And fatigue, overall, would affect their performance on walk test and, in fact, their quality of life.

Henry J. Fuchs

And then the final component of your question was on -- I think it was on replication of the manufacturing process. And with that, the proof is in the pudding. And I mentioned that we will begin our campaign shortly. But I would say that we think we have a good handle on the production process in terms of the original material and the new producer line in process. And we eagerly await the outcome of that -- those experiments.

Jean-Jacques Bienaim

But, Hank, I think the question, if I'm not mistaken, was related to whether we're confident that the new material and material with the improved process will result in clinical efficacy that's equivalent to the current process. I would just start, and maybe you can elaborate, Hank. But we have done extensive pre-clinical analysis of the new process versus the old process. And actually, we even compare the 2 in the transgenic Pompe mouse model in terms of ability of the 2 products to clear glycogen from different cells. And I think the new process, the improved process was at least as good in basically all muscle cells and actually apparently better in diaphragmatic muscle cells, which is very important in the respiratory function. I mean is that correct, Hank?

Henry J. Fuchs

That is absolutely correct. J.J., as usual, knows the data just as well as everybody else. And so, thanks for clarifying the question. And we compared the materials produced by the original process and cell to the more recently produced material. And we demonstrated in pre-clinical species, both improved [indiscernible] exposure correcting that abnormally fast clearance by the asialoglycoprotein receptor I mentioned. And we also demonstrated that translated to superior glycogen clearance, and we did that under conditions in which exposure was intentionally suboptimal, i.e., at lower doses to really -- to draw out whether there were differences in the new versus old. And to our pleasure, the outcome of those comparisons was that the new is at least as good and, in some case, better. And 1 case in which the new material is better than diaphragmatic glycogen clearance. And so that is very reassuring, because the diaphragm is such an important part of the respiratory muscle system.

Operator

Our next question comes from Josh Schimmer from Lazard Capital.

Joshua Schimmer - Lazard Capital Markets LLC, Research Division

Just wondering if there's any evidence that respiratory muscles have higher levels of type 1 muscle fiber compared to other muscles? Or is there any evidence of greater M6P receptor distribution on the sole surface of the respiratory muscles that might explain kind of a differentiated design in this data set?

Barry Byrne

Thanks for the question, Josh. The receptor density is -- particularly, as it relates to uptake of the fusion protein, is not known. But there is a greater propensity towards slow-twitch fibers, which may be better transduced by the fusion product. So that would be a rational explanation of why there is some improvement in those fiber types.

Henry J. Fuchs

And when we were talking about before, Barry and I were talking about this, is that deconditioning happens relatively quickly in the respiratory muscle. So they behave differently than skeletal muscles, and we may be, with a new pharmacological agent, probing the way in which they are different pharmacologically in a very profound and different way.

Operator

And our next question comes from Salveen Richter from Canaccord.

Unknown Analyst

Peter Goldsmith [ph] on the line for Salveen. Maybe this is a question for Dr. Byrne. But what will you be looking to, if you're deciding whether to switch a patient from Myozyme and Lumizyme to a new product?

Barry Byrne

It's a good question. And I think many of the treating physicians, and certainly the patient community, when they realized that they may have plateaued or only slowed their rate of decline and in both skeletal muscle function and respiratory muscle function would be eager to get further benefits from such a study. So those are the principal criteria. And if you reflect on the LOTS study, it's actually -- at least related to the forced vital capacity, the principal change was a reduction and decline and not, in fact, an improvement from baseline in any of those patients. So as they age, and there's the natural decline in that parameter with age to begin with, and it's certainly accelerated by the underlying disease, they -- patients, in general, I think, would be eager for new opportunities that would prevent their ultimate decline in ventilatory function.

Unknown Analyst

Great. And then maybe just a quick follow-up. I was wondering if you could talk at all about the dosing you use and why -- what's preventing you from going to a higher dose; if it's cost or side effects or what?

Henry J. Fuchs

Well, in general, I think the clinical experience, and Barry can certainly weigh in on this, is as you go to higher doses, there's more infusion-associated reactions and they're therapeutically problematic. I think Dr. Byrne can talk a lot about the infantile experience, where, in some cases, you're desperate and you have to. But it's always a bit of a hairy adventure on this one I had.

Barry Byrne

Yes. That was actually directly addressed in the pivotal studies of Myozyme. And then there was really no difference in the primary outcome of ventilator-free survival and only an increase in the number of IARs at the higher dose. Part of the rationale, I think, for the increased potency of the current molecule is that the -- all molecules are able to bind to the receptor as opposed to the fraction that contain -- are properly phosporylated on mannose. So there's a built-in increased potency of this design of this compound. So it shouldn't necessarily require a higher dose. And we're kind of reassured that there was a dose effect in the current study and an opportunity to actually look at the group of the low- and mid-dosed cohorts that can now increase to the high dose, which hasn't been done yet.

Operator

Our next question comes from Chris Raymond from Robert Baird.

Blake C. Arnold - Robert W. Baird & Co. Incorporated, Research Division

This is Blake calling in for Chris. I'm sorry if I may have missed this. But could you clarify, did the 1-patient discontinuation, did that occur at the 20-mg-per-kg dose? And then also, I'm not sure if you have this information with you. But how many patients in the Lumizyme LOTS trial discontinued due to infusion-related reactions?

Henry J. Fuchs

Yes. It was the 1 patient at the 20 -- the 1 patient who discontinued was at the 20-mg-per-kilo dose. And I don't have the number of discontinuers from the LOTS trial off the top of my head, although I think everyone's clinical impression, and, Barry, you might want to comment because you have the most clinical experience with this, is similar.

Barry Byrne

Yes. And I don't know about those who officially discontinued during that study or during the extension phase of that study. But I am aware of patients on commercial product who are discontinued from therapy because of infusion-associated reactions. And the -- it's not clear what the national or international experience is in terms of the frequency of that; those are not reported centrally for the commercial material. But it's -- probably, my guess would be it's in and around the same proportion. It's not common, but it is -- it's been observed.

Operator

Our next question comes from Robyn Karnauskas from Deutsche Bank.

Robyn Karnauskas - Deutsche Bank AG, Research Division

I was just -- I guess first question around the fees for Q3 design, are you planning to wash out patients from Myozyme? Or are they patients that could have failed on Myozyme? And then, first the patients would be -- these be patients similar to what we saw on the LOTS trial? Or could there be patients maybe on a ventilator or -- what kind of patients could this enroll?

Barry Byrne

I can address that because I think there's an opportunity actually, particularly, in patients who have less end-stage disease that may have been in regions where there's non-availability of commercial product or have a long time period from diagnosis to beginning treatment. So the potential to enroll patients with slightly more potential for recovery is an important aspect of the switchover study. And your question also regarding discontinuation in prior therapy, we do know from a couple of different types of information that the duration of drug availability after dosing is actually probably less than the dosing interval. So a prolonged washout, if you will, won't actually be necessary in order to study specific drug effects. At least, it would really -- that probably would have to be decided in a discussion with the regulatory authorities.

Robyn Karnauskas - Deutsche Bank AG, Research Division

And, theoretically, did you show an improvement in the endpoint versus when the patient was on Myozyme? Are you going to collect the data from the Myozyme? Or would that really not be a comparison?

Barry Byrne

Their baseline would be assumed for beginning the new -- the BMN-701. So it would be baseline on BMN-701 versus the subsequent time point.

Henry J. Fuchs

I think the design intention is not necessarily to cause people to get worse off of alglucosidase and put them on 701, sort of to catch the bounce down and then the bounce up. So it'd really be to show that wherever you are on your plateau of current therapy, you get better from there.

Operator

Our next question comes from Michael Yee from RBC Capital Markets.

Michael J. Yee - RBC Capital Markets, LLC, Research Division

In terms of the plans next up, you said you're going to run the switching study, can you just clarify whether or not you will or will not run a naïve patient study head to head? I know you gave some examples with the prev [ph] et cetera. Can you just clarify that for me? And then in terms of the 6-minute walk curves and also the respiratory curves, what does it say for the curve and how fast is the onset? Are you reaching peak pretty quickly? Or are you continuing to go up as you go across the 6 months? Maybe you could describe that and whether you expect to see potentially better data over the long periods of time.

Henry J. Fuchs

Yes. We don't have a plan for an additional naïve patient study. We think we've, to a very large extent, created the data set that's material there. The bulk of the prevalent patient population is on a current therapy. And we think the question that's relevant for them is, can I do better? It's really a simple clinical question. And we don't have plans for a head-to-head study. And as I pointed out, recently a biosimilar got approved without a head-to-head study, and we think that if we can demonstrate a superior outcome from our drug, that will really settle the score. Obviously, this is all subject to a discussion with health authorities. And in terms of the improvement kinetic, we pretty much observed the improvement pretty quickly. There doesn't appear to be evidence that it continues to climb with further therapy, but I would reserve comment for it being the first study, relatively small sample size, want to gather more information about that.

Michael J. Yee - RBC Capital Markets, LLC, Research Division

Okay. And then just a follow-up then. For the physician then, if they're stable or declining, those are the types of patients you would be looking to switch, people on Myozyme and Lumizyme?

Henry J. Fuchs

Yes. It's I suppose a good question for Barry. I mean, there's not a lot of patients who are running around saying, "Wow, this is a life-transforming result" on the currently available therapy. So I think the bulk of the prevalent population would probably be viewed as qualifying. And again, to your earlier question about the kinetic, because the benefit is observed early, we would expect that people would potentially notice the effect rather quickly, and therefore, that might be further reinforcing mechanism.

Barry Byrne

Maybe it's worth commenting though that the -- in order to be in keeping with the current outcome measures, there would be an ambulatory population. There is, from my understanding, no intention to study nonambulatory, invasively ventilated patients, although that is a challenging patient population, a difficult one to assess for changes because of the influence of disuse atrophy both from being nonambulatory and from requiring chronic-assisted ventilation. So it may be important to know, too, that continued improvements or further improvements may be observed in patients who receive an exercise prescription or some specific rehabilitation intervention which has not been part of any study so far. So I'm not sure that we know really what the maximal response is in some of the domains that are being evaluated.

Operator

Our next question comes from Yaron Werber from Citi.

Yaron Werber - Citigroup Inc, Research Division

So, Hank, I just have a few questions if you don't mind. So if you look at the vendor big data, it looks like vital capacity is strongly correlated with MIP and MEP. So help us understand a little bit. You guys are showing better outcomes in MIP and MEP than Lumizyme but the VC really wasn't -- the vital capacity wasn't that different. And so I don't know if you can talk about that. And then separately, how -- what's the clinical validation for MIP that the FDA or EMEA will allow you to use that as a primary endpoint? Why not use forced vital capacity or some kind of a more sort of functional benefit as opposed to just a measurement?

Henry J. Fuchs

Well, so let's start with the correlations. I mean, I think that the fact that things are generally correlated doesn't mean that the same correlations will hold under the influence of a treatment. A treatment can affect one parameter much more dramatically than another parameter, for example. And what we think is, of course, vital capacity for lung volumes in general were developed initially as measures in obstructive lung disease or in restrictive lung disease, as restrictive lung diseases meaning where there's, for example, chest wall deformity or loss of a lung or rib cage deformities. And historically, in our space, those -- that all started with the mucopolysaccharidosis which are scalded slazures [ph] in which there's both an obstructive component of the airways disease and its chest wall component of the airways disease that's not present in Pompe. And finally, I'd say about the respiratory muscle strength is measured by the pressures. I mean, Pompe's really known as a muscle disease, so it makes more sense to measure muscle strength than it does to measure lung volume because it's not a disease of lung volume, it's a disease of muscle strength. In terms of validation, the FDA and EMEA have quite a bit of guidance about new endpoints. And for the reasons that Dr. Byrne described, the role of respiratory muscle strength is relevant in almost all stages of the illness, from evidence of that being of 2/3 of patients have dyspnea on exertion, shortness of breath on exertion or inability to cough and clear secretions or, as the disease progresses, require assisted ventilation, either intermittently or, as disease progresses, continuously, followed by progressive disease. Now so we'll hope to characterize that more extensively in our regulatory submissions, and we may even need to do some additional de novo work to correlate changes in the pressures with changes in clinical outcomes or patient-reported outcomes. All of that's yet to be determined and subsequent to our further discussions with the health authorities. The nut of this though is, is that what's new here is a very large effect on respiratory muscle strength, which is so central to the problem of Pompe disease. And usually from that, the accessory pathways, the validations and whatnot follow pretty straightforwardly.

Yaron Werber - Citigroup Inc, Research Division

Great. If you need to, can you do a 6-minute walk as a primary if the FDA gives you pushback?

Henry J. Fuchs

Well, I think as a fall, fall, fallback, you can do it. We certainly demonstrated an improvement. But we think that, that underestimates the benefit. From what Dr. Byrne was saying earlier, skeletal muscles and respiratory muscles are different beats, and one may reawaken with rest the duration of the enzyme differently than the other. The skeletal muscles may be much more subject to long-term atrophy of disuse and makes a much longer time will require much more rehabilitation to reawaken. And in contrast, the respiratory is much more vitally in play. And what we've shown in the study is, is that, if you will, they reawaken on enzyme reconstitution much more rapidly. We want to develop a drug that's better for patients, and we think that the evidence that we've collected indicates there's a good possibility that improved delivery leads to a better outcome. That's a big event for patients.

Yaron Werber - Citigroup Inc, Research Division

I guess I'm just having conceptual issue with -- MIP just seems like a marker of muscle strength. That's not really a clinical parameter that physicians can really understand and relate to, and that a lot of times, regulators won't understand what's the clinical benefit. That's the 1 element that I'm trying to really understand better. Is there a better, maybe a forced respiratory volume or some kind of a validated lung marker to use?

Henry J. Fuchs

Yes, there's a similar debate into -- with the 6-minute walk test. It's an elicited laboratory measure. It's not something that you are immediately aware of in terms of how far you can walk in 6 minutes. And so -- and it's closer to the clinical reality of day-to-day living than, for example, a creatine kinase or another laboratory marker. So the FDA has been willing to accept 6-minute walk tests because of its proximity to relevant clinical outcomes. And likewise, we'll build a case that says respiratory muscle strength, as evidenced by the laboratory elicited test of maximum expiratory pressure, is immediately related to things that patients notice. And for the reasons that Dr. Byrne described, what a patient is knowledgeable about, the difficulty in breathing, the difficulty in clearing secretions, how well they have slept when their diaphragm is being pushed on by their organs, that will all become evident in the course of further trials.

Operator

Our next question comes from Phil Nadeau from Cowen and Company.

Philip Nadeau - Cowen and Company, LLC, Research Division

Just first, a couple of follow-ups in MIP and MEP and then one for Dr. Byrne. On MIP and MEP, could you give us some idea how variable these measures are as measures? So if you measure them in a patient today, tomorrow and the next day, do you get the exact same measurement? Or it is there a lot of intra-patient variability? And then, Hank, could you also talk a little bit more about the consistency on the effects among the treated patients here? You kind of touched on the issue, but can you just give us some figures that says how consistent this effect was versus how much of it was driven by super-responders?

Henry J. Fuchs

Yes. I mean, one, there are -- 2 halves of your question. There are testing criteria from the American Thoracic Society on the performance and reproducibility of respiratory muscle function testing. And we went to a great deal of effort of creating the clinical trial sites according to the American Thoracic Society's criteria for test performance to audit their performance of the test and to make sure that they were performing the tests in as reproducible a fashion as is expected by their professional organization. I think one way to gauge the consistency of effect to your second question is -- and I don't have this exactly off the top of my head, but I can tell you the lower 95% confidence interval of the 6-minute walk -- I'm sorry, of the MIP result is something like 3 standard deviations over 0, meaning everybody had or the vast majority of this population had a very substantial improvement in their maximal inspiratory pressure. I mentioned that in aggregate, 13 out of 16 patients had an improvement in 1 or more domains of function, respiratory muscle strength, inspiratory, expiratory or walking distance. So there was really a fairly large and fairly consistent effect of the drug.

Philip Nadeau - Cowen and Company, LLC, Research Division

Okay. And, Dr. Byrne, one for you. It does seem like there's more hypoglycemia here than you see with Myozyme, Lumizyme. How will that impact your treatment decision? How much harder does it make 701 to give than Myozyme or Lumizyme and how will your…

Barry Byrne

Really not at all because we just were cognizant of the fact that patients shouldn't be fasted overnight when they begin the infusion, which really just meant that for first morning infusions, that they needed to be fed. So it really didn’t require any special intervention other than management -- monitoring and management with basically -- or feeding of oral snacks or glucose.

Henry J. Fuchs

And we observed that it got -- that the hypoglycemia abated with repeated administrations over the course of the 24 weeks of therapy, meaning that sites were getting onto the notion that Barry just described, which is more attention to the issue, less fasting overnight and it becomes much more readily manageable.

Philip Nadeau - Cowen and Company, LLC, Research Division

Okay. So of the instances that you had, were most of those in patients who had fasted overnight?

Henry J. Fuchs

Barry, do you want to comment about that?

Barry Byrne

We -- at least I can't speak to the other sites, but we did not have -- that was not -- that was more correlated with those that had early morning, beginning times of their treatment. And obviously, as there's more clinical applications of the strategy, patients ultimately will get home infusions. And then at whatever time of the day that works out, they would not be overnight fasted. So there's really no need for fasting and we'd advise against it. So I think in clinical practice, it won't be a problem.

Jean-Jacques Bienaim

Actually, it's J.J. here. I've got, actually, a question to Dr. Byrne and maybe also to Hank to further answer the previous question regarding the clinical relevance of MIP and MEP. Isn't -- aren't MIP and MEP used to determine the need for ventilation support? I understand that if MIP is less negative than certain targets, it's a sign for a need for ventilation?

Barry Byrne

Yes, absolutely. No, it really is a clinically relevant outcome.

Henry J. Fuchs

And on a day-to-day basis, everybody's got their own sort of approach to managing these things. But it's not uncommon in the intensive care unit, for example, for the respiratory therapy test to walk around with a manometer while a patient is attempting to demonstrate whether they have recovered sufficiently to be taken off of the ventilator. And the respiratory technician, for example, will give the patient a trial off the ventilator measure pressures and see if the patient can maintain -- whether the patient has sufficient respiratory muscle strength to breathe independently. So in the intensive care unit, for example, these are quite commonly employed measures.

Operator

Our next question on the phone comes from Matthew Harrison from UBS.

Matthew Harrison - UBS Investment Bank, Research Division

Two more. I guess what I wanted to ask about was similar to some of the other questions on MEP and MIP. If you look at the LOTS data, right, so they had an 8% and a 12.5% improvement. And you sort of doubled those. But they were still fairly sizable improvement over what seems like declining patients without therapy. So I guess why hasn't this been a -- or maybe it has been in clinical discussions, but why hasn't this been a focus of Lumizyme treatment? And I guess just so we can understand what you perceive to be the functional benefit over and above what we saw from LOTS. And then a follow-up question on Phase III plans. Can you just confirm, so we should only expect you to run a Phase III switching study and no other Phase III studies?

Henry J. Fuchs

Yes. So on your first question, I'm not sure who doesn't make a big deal out of respiratory muscle strength. I mean, it was a prospective endpoint in the approval study for alglucosidase alfa. I think it was also -- it's been extensively studied. Just on this call, we've referenced Dr. Byrne's 517-patient or 511-patient natural history study, the van der Beek study. There's another study by Wilkie. There's a lot of natural history studies both looking at cohorts and longitudinal outcomes in Pompe's patients, quantifying respiratory muscle strength. And if you think some is good, then what we're talking about is more being better, the difference being that the improvements that have been previously observed are kind of in the same category as the improvements of the -- of walking in vital capacity, sort of improvements, but not outstanding improvements and nothing that delays the inexorable decline in lung function. And what we're observing, as you correctly point out, is about a doubling of the outcome by virtue of the historical contrast to the prior trial. So we think that given the importance of respiratory muscle strength in Pompe's disease, that twice as good is going to translate into further clinical benefit to patients. And as far as the full Phase III program, as I said on the -- in my prepared comments, the plan in preference is to conduct a switching study in addition to a naïve patient study that we've already completed. We believe that will be, if not the sole requirement for registration, 2 really important parts. As to what else we plan to do, and when we plan to do, I want to hold off until we have an opportunity to discuss with health authorities on what will be requirements for registration.

Matthew Harrison - UBS Investment Bank, Research Division

And can I just ask a follow-up? I mean, have you had any discussions with the regulators prior to this about MEP and MIP, therefore, other studies that you've done or when you were talking about the Phase I/II study?

Henry J. Fuchs

It's unprecedented. The answer is no because, as Barry mentioned during the call, no one had really done a systematic study of can we deliver more. It's not like you could readily deliver -- we think our enzyme's about 5x as potent in clearing glycogen from a Pompe knock-out mouse and more potent than being up-taken by the mannose-6-phosphate receptor. You can't give 5x as much as the currently available therapy. It's even twice as much as prohibitive in terms of side effects, as we talked about before. So no one really knew what to expect. And what we learned is, is that there was dramatic improvement in respiratory muscle strength, and that's to the good because respiratory muscle weakness is such a key part of the disease and now we will begin those conversations. But again, as I said earlier, where you can make a big difference in people, usually the validation in regulatory pathways follow pretty straightforwardly.

Jean-Jacques Bienaim

And going back to comments that Hank made earlier about the historical use of FVC, I think it's probably related to the fact that most -- and maybe Dr. Byrne can correct me here, but to the fact that most "pulmonary drugs" have been approved for obstructive pulmonary disease or restrictive pulmonary disease, asthma, CF, COPD. And I understand that FVC is a pretty good measurement or tool for these kind of diseases, but I don't think there are any or very few drugs approved today to improve respiratory muscle function. Actually, is there 1 that we know of?

Barry Byrne

No, not to my knowledge.

Jean-Jacques Bienaim

So that's the reason why we have to...

Henry J. Fuchs

Those that we're breaking new ground, but we think it's physiologically rational, and that's what's in front of us.

Operator

Our next question comes from Kim Lee from Janney Capital.

Kimberly Lee - Janney Montgomery Scott LLC, Research Division

Just a quick question on your assumptions for patient enrollment rate for this Phase II/III, and when could we possibly see data?

Henry J. Fuchs

Well, we expect enrollment to be relatively brisk. The treated population is -- there's a large number of previously identified prevalent patients, something like 1,500 patients on drug. And the general sense in talking to clinicians, I don't know if Barry wants to add anything there, is that the outcomes of current therapy are not judged to be superior, and people would be generally interested in trying something better. I don't know if you want to add anything.

Barry Byrne

No, I think that covers it.

Jean-Jacques Bienaim

And actually, to add, Hank has talked to a handful of key opinion leaders, including Dr. Byrne, and from what I heard from Hank, all of them are interested in participating in the next phase.

Operator

Our next question comes from Brian Abrahams from Wells Fargo.

Matthew J. Andrews - Wells Fargo Securities, LLC, Research Division

This is Matthew calling in for Brian. In the past, you've discussed the potential for 701 to have a superior profile to Lumizyme. Is that still the goal from the labeling perspective? And if so, how do you hope to demonstrate this in your current clinical program?

Henry J. Fuchs

Well, I think that the observation that a patient who is stable on current therapy who gets better on 701, that will lead to its labeling and its superiority, therefore, will be relatively self-evident. Because we don't necessarily plan to compare directly head to head to achieve that objective, we don't know exactly how the label will read. But I think that's a logical conclusion to draw from a trial that had that kind of outcome.

Operator

Our next question comes from Tim Lugo from William Blair.

Tim Lugo - William Blair & Company L.L.C., Research Division

You might have mentioned this earlier. I came on a little late. Are you enrolled -- are you following these Phase I/II patients? And shall we see 36- as well as 48-week data updated throughout the year? And also, are you going to be requiring biopsies at all in the Phase II/III? And if so, why or why not?

Henry J. Fuchs

We'll continue to follow the patients. All the way up through registration, they're going to represent the patients who have had the drug for the longest. As to when and whether and when we'll update, I think that's -- I don't know the answer to that sitting here. And the second part of your question was...

Tim Lugo - William Blair & Company L.L.C., Research Division

Biopsies in the Phase II/III?

Henry J. Fuchs

There's quite of bit of intellectual and academic interest in biopsies. Barry presented data from the only paired biopsy samples that were taken from this study at the World Conference in Orlando. And as to making it mandatory, I think that would be a bit of a stretch. That might be an impediment to the conduct of the trial. But there's certainly a lot of interest. I don't know, Barry, if you want to add anything about muscle biopsy?

Barry Byrne

Yes. I think we did learn some things about how to facilitate small-needle biopsies that would be not a big end burden to the patients. I think many patients who underwent several open muscle biopsies even to achieve their diagnosis are reluctant to repeat that experience. But if the information can be gained from a less-invasive procedure that is equivalent to, in fact, a risk profile of blood drawing, then maybe more patients would participate. And I think it would be informative.

Operator

Our next question comes from Joseph Schwartz from Leerink Swann.

Joseph P. Schwartz - Leerink Swann LLC, Research Division

I wanted to ask about antibodies since they can be a real problem for Pompe patients. Did you notice any patterns of antibody generation such as being any less among the super-responders or more against the -- amongst the patients with infusion reactions? Was there an increase in the tighters over time? And how do you expect the drug to perform differently in a switching study where patients may enter with antibodies to Myozyme and Lumizyme?

Henry J. Fuchs

Yes. So the general answer to your question is it's early and we haven't completed all of the evaluations of all the antibodies and all of the correlations and it's relatively a small number of patients. Our expectation is that we'll observe antibodies in all patients, and our further expectation is that it's going to be very difficult to correlate the presence or absence of antibodies or the tighter of antibodies with clinical outcomes that's been generally distorted with enzyme replacement therapies. And I don't expect the story to be radically different here.

Joseph P. Schwartz - Leerink Swann LLC, Research Division

Okay, great. And then what kinds of inclusion criteria parameters are you thinking about for the Phase II/III switching study? Do you think that you might just attract the toughest cases unless you intend to enrich the enrollment otherwise?

Henry J. Fuchs

I think they're all tough cases. I think, as Barry said, you could think about the nonambulatory or the extensively progressed group as maybe too far along to include in the main trial. What we ended up doing, and this we might end up being a similar template, is if you try to replace the main switching study and the sort of central prevalent population and maybe we end up with ancillary studies and a more early and a more later group of patients, but I think it's a little bit premature to get into the design of the program as opposed to talking about what the specific study that's going to be the proof of the pudding for registration.

Operator

Our next question comes from Stephen Willey from Stifel.

Stephen D. Willey - Stifel, Nicolaus & Co., Inc., Research Division

Just a quick follow-up on the biopsies; so there was no additional data collected within the 20-mg cohort group, is that correct?

Henry J. Fuchs

No additional biopsy data, that's correct.

Stephen D. Willey - Stifel, Nicolaus & Co., Inc., Research Division

And then I know that one of the patients that was charted out at WORLD was in the 20-mg cohort and I think showed kind of a 3x to 4x reduction in glycogen clearance over the course of 24 weeks. I'm just wondering if you noticed that, that was corresponding to any of the dramatic increases you saw in a 6-minute walk test?

Barry Byrne

Yes, we didn't compare -- those were all done blinded. So we actually only included the dosing cohort just for clarity. But there was no correlation with the functional data yet. That work can be done in the future.

Henry J. Fuchs

Great testament to our investigators, by the way, to maintain their objectivity by not looking at the results and trying to make these correlations to avoid the introduction of bias; it's part of what gives us a lot of confidence about the trial.

Operator

This concludes our question-and-answer session. I would like to hand the conference over to Mr. Bienaim for any closing remarks.

Jean-Jacques Bienaim

So thank you. So in summary, as you can tell, we are pleased to provide this update on our BMN-701 program and for Pompe disease today. So we have surpassed our internal goal criteria for the Phase I/II trial, and we look forward to proceeding to the next phase of development.

Taking a step back, we believe that we are uniquely positioned for another transformative year at BioMarin. And we are generating over $0.5 billion in revenues from our commercial portfolio, and we are working toward our fifth product approval by the end of this year. We expect the BLA for Vimizim to be filed in the U.S. by end of the month or very soon thereafter. And we're on track for filing the market application authorization in the E.U. also for Vimizim by the end of April. And we have recently obtained accelerated assessment designation for Vimizim in Europe. Vimizim has the ability to double our revenue and bring the company to the next phase of maturity, including reaching sustained and substantial profitability.

I want to thank you for your continued support, and we look forward to keeping you updated on our progress. Goodbye.

Operator

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may all disconnect, and have a wonderful day.

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