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XenoPort, Inc. (NASDAQ:XNPT)

XenoPort XP23829 Clinical Trial Results Call

October 04, 2012 04:30 pm ET

Executives

Jackie Cossmon - Investor Relations

Ron Barrett - Chief Executive Officer and Director

Bill Harris - Senior Vice President of Finance and Chief Financial Officer

Analysts

Michael Yee - RBC Capital Markets

Brian Abrahams - Wells Fargo

David Amsellem - Piper Jaffray

Operator

Good afternoon. My name is Kirk, and I will be your conference operator today. At this time, I would like to welcome everyone to the XenoPort XP23829 Clinical Trial Results Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. (Operator Instructions). Thank you. Ms. Jackie Cossmon of XenoPort, you may begin your conference.

Jackie Cossmon

Thank you, Kirk. Good afternoon and thank you for joining us on the call. Here with me today are Ron Barrett, our Chief Executive Officer and Bill Harris, our Senior Vice President of Finance and Chief Financial Officer.

Before we begin our discussion of today's news, I would like to note that the information to be discussed on this conference call and webcast, including answers to questions asked during this call will include forward-looking statements that involve risks and uncertainties, including statements related to our current and future clinical development programs and the timing thereof, future clinical trials, potential advantages of our product candidates and the therapeutic and commercial potential of our product candidates. XenoPort can give no assurance with respect to these statements and we assume no obligation to update them.

For detailed information about the risks and uncertainties that could cause actual results to differ materially from those implied by or anticipated in these forward-looking statements, please refer to the Risk Factors section of our most recent SEC filings, including our discussion of the inherent risks of clinical trials and regulatory matters. This webcast is a copyright of XenoPort.

At this time, I would like to turn the presentation over to Ron.

Ron Barrett

Thanks, Jackie. By now you have seen our press release announcing preliminary results from the Phase 1 trial in healthy adults designed to assess the pharmacokinetics, safety and tolerability of single doses of four different formulations of XP23829, which I will refer to as 829.

We are obviously pleased with the results. However I want to remind everyone that this study was done with a low single dose of 829 and a small number of healthy subjects. More work is needed to fully characterize the pharmacokinetics and tolerability profile of 829, particularly relative to other fumaric acid ester-based products. The data from this first in human trial obviously support continued advancement of this program. I'll discuss our next steps after I review the data from the study.

The press release gives the basics of the study design, so I won't repeat it here. Our focus on the major results of the study. First, 829 was metabolized to monomethyl fumarate in humans the way we intended. Second, we created different MMF PK profiles using different formulations, so we believe we can potentially mimic FUMADERM or BG-12 PK profiles or create other MMF profiles. One of our formulations appears to be worthy of further evaluation for potential once a day dosing with the potential added benefit of minimal food effect. And third, we obtained some preliminary insight into the potential relationship between MMF pharmacokinetics and flushing.

So, taking these one at a time, the trial showed that 829 was metabolized in human similar to the way it was metabolized in animal species, we've used in our pre-clinical work. After dosing of 829 in humans, we observed MMF in blood while the levels of the IMTEC prodrug and the potential desmethyl-metabolite were below the detection limits. The promoiety in pharmacologically inactive molecule that is released in the enzymatic conversion of 829 to MMF was cleared rapidly with a half-life of around three hours.

The dose of 829 administered all subjects in the study was equivalent to 107 milligram equivalents of MMF, so why did we select this dose?

The reason is that it approximates the same number of MMF equivalence as are present in a single FUMADERM tablet or a single BG-12 capsule containing 120 milligrams of dimethyl-fumarate or DMF.

Like 829, DMF is a prodrug of MMF. In principle, one could compare our MMF exposures to data that have been published for these products. I am sure that some of you have going to want to do that. Let me tell you why you need to be careful. I'll start with a technical point about the way that we measure MMF and other analytes.

We use high sensitivity of [CIMA] aspect methods to simultaneous measure multiple analytes in whole blood samples. Some of the BG-12 PK studies that have been reported in posters determine MMF levels from plasma. There can be differences between levels measured in plasma and whole blood, so quantitative comparisons between studies should be done cautiously.

We are not aware of any published PK data on a single-dose of the BG-12 capsule containing 120 milligrams of DMF. Since we don't know that MMF exposure after BG-12 is dose proportional, simple downward extrapolation for published data at higher doses could be misleading. However, there is a published study for MMF PK whole blood after a single dose of FUMADERM containing 120 milligrams in DMF.

The references leech skins at our bridged trial of clinical pharmacology 2004, 58 page 429 if some of you want to look that up, however until we do direct comparative PK studies with FUMADERM and BG-12 at the same dose with the same subject with the same analytical method, we think this data in this publication is the best information with which to compare our results.

The second takeaway from our study was that the PK profile of MMF in the blood after 829 dosing was altered using different formulation technologies. As mentioned in the press release, one of the 829 formulations which I'll refer to as Formulation 1, was designed to suppress the release of 829 while in the stomach, and then immediately release the drug upon reaching the small intestine.

The other three formulations were designed to delay and then slowly release 829. Formulation 1 was intended to perform similar to FUMADERM and BG 12. When dosed in fasted state, Formulation 1 produced the PK profile for MMF in blood that appears to be similar to the published data for single dose of FUMADERM. Generally subject to a delayed, but sharp peak of MMF windows fasted. Also, consistent with the data reported for FUMADERM, the maximal MMF concentrations after dosing Formulation 1 were lower and more variable when dosed with food.

The other three formulations were intended to produce more sustained exposures to MMF. They all did so, but one of them which I'll refer to as Formulation 2 stood out as producing the largest MMF exposure. The total MMF exposure was similar to that of Formulation 1, but with a lower maximal MMF concentration and a longer duration of exposure. Importantly, the presence of food has minimal effect on the total exposure in the pharmacokinetic profile of MMF.

We obviously need to do more work to establish the relationship between pharmacokinetics and the efficacy in treating multiple sclerosis and/or psoriasis, but we believe that the PK profile of Formulation 2 supports further evaluation of this formulation for once-a-day dosing.

Last, we learned from the trial that the PK profile of MMF probably plays a role in flushing. Flushing and feeling hot were the only adverse events reported in more than one subject and more frequently in 829 and placebo. Both of these adverse events were expected since MMF is thought to be responsible. These side effects occur more frequently for Formulation 1 and for the other three formulations suggesting that the Cmax or the rate of change of MMF levels rather than AUC, they trigger these adverse events.

Until we study higher doses, we don't know for sure whether Formulation 2 would have reduced flushing at therapeutic MMF exposures, but we believe today's data is a good start in exploring this potential benefit of Formulation 2.

Gastrointestinal events such as diarrhea, nausea, abdominal pain and discomfort vomiting and gastritis have been reported in the trials of BG-12, and are of obvious interest for 829. However, given the low single dose of 829 used in this trial, we wouldn't have necessarily expected the CGI side effects even if 829 were equivalent to BG-12. Only one subject reported abdominal pain when Formulation 1 was dosed both, fed and fasted. No subjects in any cohort reported any of the GI adverse events associated with BG-12 other than this one subject.

So, what's next? We are actively gearing up this for our two new studies early next year. The first will be a dose escalation multiple dose Phase 1 trial in healthy subjects designed to establish the safety tolerability in PK of 829. We may take both, formulations 1 and 2, into the study. The second study would be a drug metabolism disposition study done with radiolabeled 829 in healthy subjects. We plan to do the study with two versions of radiolabel 829 one with the label on the fumarate and one within the label in the promoiety. We have completed similar studies in rats.

The goal of the study would be to fully characterizing quantitate the metabolites of 829, and how they are eliminated from the body. In addition to addressing an important question on the human metabolism of 829, we believe this will be useful information for planning further animal tox studies. In summary, we're happy to report that the first human trial of 829 better expectations and answered the key question if 829 can deliver MMF into the systemic circulation.

We are also pleased that we identified a formulation that we can further evaluate for potential once a day dosing with minimal food effect. We also got an early look at the potential impact of PK profile on flushing. Overall, we believe this was a very successful first trial in humans and we look forward to further advancements in this program.

We'll now take your questions. Operator?

Question-and-Answer Session

Operator

(Operator Instructions). Your first question comes from the line of Michael Yee. Your line is open.

Michael Yee - RBC Capital Markets

Thanks, guys. Two questions. The first is you think that you're releasing 107 milligrams of MMF, and that's approximately equivalent to 120 milligrams of the BG-12 capsule, so can you state what the blood levels were in your whole blood sample even though you don't want us to compare to plasma, just so we have the numbers since you must have the numbers.

Then related to that in the next study that you're doing then should we assume that you'll get up to double, triple, quadruple the numbers you are doing or those you are doing here, so we can always compared to what we think is going on in BG-12, since they are at 240 BID?

Bill Harris

Yes. So, the answer to your second question is, absolutely. That's the intention of the study to push the exposures up to the therapeutic exposures of FUMADERM the BG-12, and maybe even beyond if it's well tolerated.

With regard to the PK parameters, I'll say that for the Formulation 1, Cmax for fasted is around 530. The mean value, 530 nanograms per milligrams, Fed, 370 nanograms per milligram. For the Formulation 2 as I mentioned the Cmax is lower, so for fasted it's 140 nanograms per milligram, and 220 in fed, but as I said the major difference here is that the AUCs for the Formulation 2 were similar to fed and fasted and the length of the exposure was extended with the Formulation 2 compared to Formulation 1. That's about all the detail I want to give here and I'll give you the same caveats I gave in the opening remarks that you have to compare apples-to-apples.

Michael Yee - RBC Capital Markets

Okay. Then when you're going to do this study, this multiple dosing, when do you think your data when is the next (Inaudible)?

Bill Harris

Still we have work to do here. We ought to update our investigators for sure with this data and finalize the protocol. We have to start to make arrangements for sites. We're hoping to get started early next year. It's not I particularly long study we would hope to have the results in the first half of next year.

Michael Yee - RBC Capital Markets

Okay. Thank you very much.

Operator

Your next question comes from the line of Brian Abrahams from Wells Fargo. Your line is open.

Brian Abrahams - Wells Fargo

Hi. Thanks very much for taking my question and congratulations on the nice early data. I am wondering at what point might you consider comparative PK or tolerability studies, again BG-12 and do those makes them to do, are there specific enough scale that you might be able to really clearly tease out differences and I had a follow-up.

Ron Barrett

Yes. That is a great question, and we are planning such studies, but they are all obviously dependent BG-12 being approved, but assuming that that's the case and it's approved at the end of this year, we think we would be in a position next year to do a comparative PK studies and also potentially comparative tolerability study, so we have been working on the design that utilizes specific instruments for assessing flushing and GI tolerability, and we think that the study could be done in healthy subjects.

I would point you to study that Biogen currently has ongoing in which they are slowly titrating and utilizing aspirin to try to address flushing and GI side effects, and they're doing that in healthy subjects. I think the duration may be up to eight, nine-week, so it seems that they believe that this type of assessment can be done in healthy subjects and we certainly have this in our thoughts with regard to planning. However as I said it is contingent upon the BG-12 being available.

Brian Abrahams - Wells Fargo

Great. Really I think this is a small study, but can you speak a little bit about the patient the patient and patient variability in MMF exposures? I know with BG-12 and FUMADERM, there's quite a bit of variability. I was wondering if you saw any less variability with of these formulations.

Ron Barrett

Well, one thing that was particularly noteworthy is the fasted versus fed for the CT1 that is for the Formulation 2. The mean values of both Cmax and AUC, and the shape of the curve were pretty similar fed versus fasted and the percent CV in those parameters was better than the Formulation 1, particularly fed. Formulation 1 look pretty good in the fasted conditions, but not unlike this published study with FUMADERM.

When you dose with food, the variability goes up substantially, and so that's all I can say without showing you the actual data itself. We hope to abstract deadlines for AAN is next week. We are hoping to submit this and have it presented at AAN next year, and which I believe is in March.

Brian Abrahams - Wells Fargo

Great. One last question and I'll hop back in the queue. Are there any additional tweaks need to make to the formulations, particularly Formulation 2 and will you try looking at Formulation 3 and 4, perhaps with higher doses or are those kind of on hold now?

Ron Barrett

Yes. We just got this data. We're still digesting it. We haven't made final plans. We think it's certainly reasonable to take two formulations into the next study whether we do more than that, I think, remains to be seen. For the next study, we don't believe we need to do any additional tweaks of these formulations. Once we get to steady state at a higher probable therapeutic dose, we may want to make some modifications, but that remains to be determined. Certainly getting started to the next couple of studies, we think these formulations are suitable.

Brian Abrahams - Wells Fargo

Great. Well, congratulations again.

Ron Barrett

Thank you.

Operator

Your next question comes from the line of David Amsellem from Piper Jaffray. Your line is open.

David Amsellem - Piper Jaffray

Thanks. Just a quick one. Any possibility that there could be a 505(b)(2) pathway for the product, and then maybe talk about what kind of dialogue you have had with the FDA on that realizing it's very early, but you any light that you can shed there would be helpful. Thanks.

Ron Barrett

Yes. It's a very interesting question. There is no real precedent for a 505(b)(2) this type of situation. The situation being that BG-12 being approved and then we referencing the safety and efficacy of BG-12. There's logic to it from a regulatory law perspective, because EMF and 829 are prodrugs of MMF, and we had talked to regulatory experts outside the agency and they believe that there is a rationale there.

We did have a pre-IND meeting earlier this year with the FDA, and we did raise this and their initial response was well, it's not really, you can't engage in a full discussion of that, because the reference listed drug is not approved yet BG-12 is not approved yet, but just in principal, they didn't reject the notion outright but I think there are some challenges here both, from the standpoint of are we going to have different pharmacokinetics, and what would be if we do. We know that in our other situations or other programs, we've had to do at least one study to demonstrate that those different pharmacokinetics still maintaining the efficacy of the parent drug.

Then there's issues related to regulatory exclusivity that come into play with a 505(b)(2) assuming BG-12 gets five years of new chemical entity regulatory exclusivity, so I think it's still an open question. We are very much interested in that and one thing I want to say is that that the plan we have in place for next year is the multiple dose study, the radiolabeled study, the comparative PK study perhaps the comparative tolerability study in healthy subjects, is really agnostic with regard to what the development path or the indication is. This is work that we want to do to build an understanding of the value of the product independence of the plan.

Going forward from there, obviously, you got to pick an indication. You got to pick a regulatory strategy and so on, but we don't need to know that today.

David Amsellem - Piper Jaffray

Okay. That's helpful. One last question if I may. How far would you want to take this on your own before looking at a partnership and I suppose that's dependent in part on what indication you know you pick, but now any latest thoughts there?

Ron Barrett

Yes. I would say that we are open to discussions at anytime here. We have been having discussions. It's really around do we share common view on the value and the strategy for the program with the partners. And, look, there's no again the round effects that there are some questions and in some peoples' minds about when will a generic BG-12 be on the market and what type of profile you with need to have in an environment in which there is generic BG-12, so these are all kind of questions that we hope to address in our discussions with them, but one of the reasons why we did the financing in July was to give us the ability to continue to invest in this program. We are excited about today's results and I would say that there we will have independent tracks going on, partnering discussions and continued execution of the plan that I have described.

David Amsellem - Piper Jaffray

Okay. Thanks.

Operator

(Operator Instructions). Your next question comes from the line of David Friedman from Morgan Stanley. Your line is open.

David Friedman - Morgan Stanley

Hi. Thanks for taking the question. Just two ones real quick. The first is, were there any other metabolites measured in any relevant concentration besides the desmethyl-metabolite?

Ron Barrett

So, there are other metabolites that we've seen in animals that we are measuring and we don't have all of those data yet. But, to-date they all are low or undetectable except for metabolites related to the promoiety. So, the pro-moiety is present. We think it's an innocuous molecule based on all of our animal tox work, it is metabolized. It's [dated and we can detect] metabolite of the prodrug, but we haven't completed all of the metabolite work at this point.

David Amsellem - Piper Jaffray

Okay. Thanks. Then the second question is, you mentioned the Biogen study in healthy volunteers that they do indeed show that dose titration can remove much of the sort of GI side effects and flushing. How do you guys see yourselves being able to differentiate the drug? Is it something other than that? Is there an efficacy argument given the different PK that you mentioned here?

Ron Barrett

Well, I don't necessarily jump to the conclusion if they are going to solve the problem. There has been quite a lot of work with FUMADERM for instance using slow titration and it hasn't really provided that much benefit. And as you can see from our resulting, even with a relatively low dose, we get flushing with the Formulation 1, so we will see what their study brings, but I think you are raising an interesting question that we've talked about in the past. This PK variability, to what extent is that contributing to differential efficacy amongst patients. The doses that are selected for BG-12, that's in some way the compromise, because of the high variability. It's a higher dose that may be causing side effects in some people in order to get the bottom of the curve to a therapeutic level. We don't know the answers to those questions.

The other thing I would say is, again, we don't know the answers yet, but this Formulation 2 that we have, certainly extends the MMF exposure or length of time than the Formulation 1, which we think is emulating BG-12 or FUMADERM, and so if we can get the once a day dosing, obviously, that comes with better compliance. There's lot of data that suggests that that's the case. And, for a degenerative disease and a progressive disease like multiple sclerosis compliances obviously an issue. Now that's just in MS.

Psoriasis, other indications that we're potentially interest in, the dynamics are different. So, I hope that I addressed your question.

David Amsellem - Piper Jaffray

Yes. You have. Thanks. And then just one last question is, I guess is just around the metabolite. Are there any other different ones from what you get from MMF itself?

Ron Barrett

Yes. There is the promoiety, right? That's the different from EMF, and the promoiety is a very simple molecule. It's been well-characterized in our animal tox studies. We've now seen and it's produced in humans. It's cleared rapidly, I said, about a about a three-hour half life. I mentioned that it's, [gluked date] which is also a kind of detoxification solution that evolutions come up with, so we don't anticipate any issues introduced by the novel metabolites that are created by 829.

David Amsellem - Piper Jaffray

Okay. Then just one last thing was, in terms of you sort of, I think, looked at safety in terms of AUC versus Cmax here. Given that MMF or BG-12, we don't really know exactly how it works in MS. Is there any sense that Cmax versus AUC is more or less relevant on the efficacy side versus the safety side? That's my last question I promise.

Ron Barrett

Yes. That's a terrific question, and I think that a lot of us want to know the answer to that question. All I'll say is, we have the tools to do it, because we now have a formulation in Formulation 2 that spreads the AUC out of a length of time and avoids the peak in the way that the Formulation 1 or FUMADERM or BG-12 has, and so we are anxious to get the answer to that question.

It's not easy to discern what's actually going on with BG-12 from the mean PK data that the Biogen has published, but we would really like to is the individual PK data to see whether there's pulses two or three pulses, sharp pulses throughout the day or whether with two or three dosing, there's is more of a spread AUC over the course of the day, in which case for the potential once a day formulation we have would be potentially already validated. So, that's the data that we want to generate on our own next year when BG-12 is available.

David Amsellem - Piper Jaffray

Great. Thanks a lot.

Ron Barrett

You're welcome.

Operator

We have no further questions at this time. I'll turn the call back over to the presenters.

Ron Barrett

Well, thank you all for listening this afternoon. We look forward to further advancing this program and providing updates in the future. We think we've gotten off to a great start and thanks for attending and have a good day.

Operator

This concludes today's conference call. You may now disconnect.

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