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Chelsea Therapeutics International Ltd. (NASDAQ:CHTP)

FDA Issues Complete Response Letter Regarding Northera's NDA

March 29, 2012 08:00 am ET

Executives

Kate McNeil - Director, IR

Dr. Simon Pedder - President & CEO

Bill Schwieterman - CMO

Nick Riehle - VP, Administration and CFO

Keith Schmidt - VP, Marketing and Sales

Analysts

Robyn Karnauskas - Deutsche Bank

Juan Sanchez - Ladenburg

Jonathon Eckard - Leerink Swann

Scott Henry - Roth Capital

Liana Moussatos - Wedbush Securities

Operator

Good day ladies and gentlemen and an welcome to the Chelsea Therapeutics March 29th conference call. At this time all participant lines are in a listen-only mode. Later we will conduct the question-and-answer session and instructions will be given at that time. (Operator Instructions). As a reminder this conference is being recorded. I would now like to turn the conference over to your host, Ms. Kate McNeil, please go ahead.

Kate McNeil

Thank you, operator. Good morning and thank you all for joining us to discuss our Northera new drug application for the treatment of symptomatic neurogenic orthostatic hypotension and the complete response letter received yesterday from the US Food and Drug Administration. Our press release regarding the FDA’s decision can be found on our website www.chelseatherapeutics.com. Joining me from Chelsea is Dr. Simon Pedder, President and Chief Executive Officer; Chief Financial Officer Mr. Nick Riehle; Chief Medical Officer Dr. Bill Schwieterman; Chief Scientific Officer Arthur Hewitt; VP of marketing and sales Mr. Keith Schmidt; and our Chief Operating Officer, Joe Oliveto.

Following formal remarks by Dr. Pedder, the conference call will be open for questions. Now before I turn the call over to Dr. Pedder, let me note that some of the remarks that you will hear today may contain forward-looking statements about the company's performance, actual future results might differ materially from those projected in the forward-looking statements. Additional information concerning these factors that could cause actual results to materially differ from those in these forward-looking statements contained in our SEC filings and periodic reports under the Securities and Exchange Act of 1934 as amended, copies of which are available on our website or may be requested directly from the company. And with that said I'll turn the call over to Dr. Pedder.

Dr. Simon Pedder

Thank you Kate and thanks to everybody for joining our call today. As we announced late yesterday, the US Food and Drug Administration has issued a complete response letter related to our new drug application for Northera also known as droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension or NOH. This morning we would like to take you through each of these issues identified in last night's press release and answer questions you may have regarding the complete response letter or our path forward. Before we get into detail of the agency's response I would like to remind everyone that while we have had the opportunity to review the letter in detail, we of course have not had the opportunity to follow up or speak to anyone at the FDA.

In that respect some of our discussion will involve speculation until we consult with the agency on their recommendations. While the complete response letter identified several requests and recommendations, the principle request and the one with the greatest impact for Chelsea was the request for an additional efficacy data to support the findings of our pivotal study, Study 301 and to demonstrate the durability of effect the over a two to three-month period. The complete response letter detailed the agency's guidelines for an approval based on a single persuasive study and highlighted that Study 301 was positive and achieved a typically persuasive outcome on the OHQ, Orthostatic Hypotension Questionnaire.

They further acknowledged that that their guidance is open to the possibility of a single study approval in indications which there is an unmet serious medical need. And that NOH as a condition which is still [awaiting] symptoms with limited treatment options could be a condition for which they will consider an approval based on the results of one study. The letter also states that 301 has many of the characteristics of a single adequate well-controlled study that could make it adequate to support effectiveness.

However the agency's review of the data concluded that there were some subgroups namely women, older patients, US patients and those with Parkinson demonstrated less persuasive results following treatment with Northera and I will note separately that a majority of 301 was conducted in Ex US and that a majority of the US patients participating in the study were through consultation.

They further indicated that these inconsistencies, the results of Study 303 and 303 undercuts the persuasiveness of 301. Finally the letter raised some concerns regarding what they determined to be a disproportionate large favorable effect of one site on the outcome of Study 301. While we would agree that these results impacted the outcome of the 301 our analysis shows that consistent treatment effect is seen across the positive majority of the participating sites and that adjusted for the overall number of participants, results of Study 301 excluding the site would have been persuasive.

The letter also emphasizes the agency's interest in data that adequately demonstrates the durability of the effect. As you'll recall this was also a significant discussion point, both in the agency's briefing document and subsequent advisory committee meeting where the panel ultimately concluded the potential treatment benefits coupled with a significant unmet medical need warranted approval of Northera and outweighed the need for additional study concerning durability prior to the approval ultimately recommending approval of our NDA.

Given the need to provide evidence of durability of effect, the agency suggested an additional data supporting the NDA should be from a study designed to demonstrate durability of effect over a 2 to 3 month period and recommended we consult with the agency on the specific study design elements including endpoint measures to be used in future trials. While the FDA did not make reference to the company's ongoing Study 306 we believe that data from this trial could potentially meet the criteria for clinical efficacy and durability of effect data identified in the Complete Response Letter.

As you'll recall, Study 306b is an ongoing 10-week double-blind placebo-controlled trial evaluating Northera in patients with symptomatic neurogenic OH associated with (inaudible). The primary endpoint for this trial is the reduction in the rates of fall per patient per week. However the study is also designed to assess the benefit of Northera in the treatment population using both OHSA Item 1 which measures dizziness, light headedness, feeling faint or feeling like you might blackout as well as the OHQ composite which is a more global assessment of symptomatic and functional benefits.

Since the letter was not specific with regard to the design of a longer confirmatory study, we will need to speak to the agency regarding the suitability of 306b to meet their request. This discussion will of course involve discussion regarding the primary endpoint and if that would be necessary or possible to a co-primary endpoint including both [fall] and either OHSA Item 1 or the OHQ or change in the endpoint altogether.

Until we have these discussions, it is difficult to speculate in great detail as what will be the final path forward or the time forward towards the possible approval. However preliminary estimates suggest that given our enrolment in 306b, the time required to prepare the result with submissions, we could potentially submit a major amendment to our NDA as early as first quarter of next year. Once we have designed our path forward with the agency we will of course look to update you with more vision at the timeline through submissions and potential approval.

Now, in addition to the clinical request made by the agency there were a number of additional requests and recommendations made in the complete response letter. For the most part these are not issues that will prevent approval or time-to-market. As we indicated in the press release, the agency would like to see additional bioequivalence work in order to approve the 300 milligram capsule. Just to clarify, our clinical trials were conducted using combinations of 100 milligrams and 200 milligram capsules.

Our interest in approving a 300 milligram capsule would simply be for ease of administration and we could certainly launch with only 100 and 200 milligram capsules. Of course, given that we will be working to complete clinical requirements for approval, conducting the necessary bioequivalence work to approve the 300 milligram capsule shouldn't be an issue and we anticipate this could be really accomplished prior to an FDA approval of Northera.

Finally, the complete response letter included draft recommendations regarding our labeling. I would like to emphasize that, we did not have an opportunity to engage in meaningful discussions with the agency regarding our label. So while these recommendations are informative they are not final and would not certainly be dependent on the final outcome of future studies and the collected datasets.

As we set forth in the press release, the agency recommendation, narrowing the scope of symptomatic benefits claim to emphasize dizziness, lightheadedness, feeling faint or feeling like you may black out, as the clinical benefits associated with Northera treatment. The only other item of note in the labeling recommendations was that the FDA at this time made a preliminary recommendation to include a black box warning related to supine hypertension. However, the letter indicates such a black box warning could be reconsidered a suitable data, demonstrating lack of severe hypotension, were provided.

As you may recall this topic came up during the advisory committee at a time which we explained that, in keeping up with the standard of care and clinical practice. Patients are advised to maintain a 30 degree head-up tilt in a more supine position. Panelists in the agency expressed interest in testing supine hypertension in patients, when they are in a fully prone position. Given the convincing nature of lack of severe supine hypotension, relative to placebo in our clinical trial, we would expect to see a similar lack of significant, severe, supine hypotension compared to the placebo in a fully prone position. We look forward to get a better understanding from the agency to the scope of the data they would be interested in seeing, in order to remove the potential black box warning from our draft label.

That said, as you are well aware Midodrine has a similar black box warning, though ultimately this is not a significant competitive disadvantage. None of the recommended label changes included discussions around the black box warning, meaningful change or meaningful change apart from pricing or potential market opportunity for Northera. We look forward at the appropriate time to continuing discussions with the agency regarding a potential label for Northera.

Finally, with respect to the complete response later from the agency, I would like to point out that beyond continuing to provide complete safety data as our clinical program progresses, the letter did not identify any outstanding safety concerns related to our NDA submission. We think this is particularly significant in the light of the briefing document issued by the agency before the advisory panel meeting and the emphasis in those documents on safety and are pleased that the data presented during the panel meeting appears to have mitigated these initial concerns related to our submission.

Before I open up the call for questions, I would like to take a minute to share our gratitude for physicians, nurses, study coordinators who conducted our clinical trial and especially the patients, who participated in medical science to help bring this drug to market by participating in our extensive clinical program to-date.

In closing, I would like to emphasize our faith in Northera remains strong as ever. The testimony we have heard from patients regarding the profound effects, they’ve experienced participating in our clinical trials is among the most moving I’ve had the privilege to hear.

Though yesterday’s response from the agency was indeed a setback, we’re committed to doing our best to help those that continue to suffer from symptomatic neurogenic OH, patients who have been waiting for long treatment options to help alleviate their mediated symptoms. We recognize that Northera may meet an unmet significant need for those patients and continue to look forward to bring in this product to these patients.

Now, I would like to turn the call over to questions. Operator?

Question-and-Answer Session

Operator

Thank you. (Operator Instructions) Our first question is from Robyn Karnauskas of Deutsche Bank. Your question please?

Robyn Karnauskas - Deutsche Bank

Good morning. So I guess my first question is regarding supine hypertension. Are you collecting, I think if I remember correctly, in the briefing document they highlighted the fact that you did not collect fully supine, blood pressure measurements. So I am just wondering in the 306 study, are you testing fully supine blood pressure and if not, would you have to do an additional trial? Could you do one in a very short period of time to sort of show that this chart does not have higher supine blood pressure?

Dr. Simon Pedder

Well, thanks for the question, Robyn. First of all, no, we’re not looking into 306 for patients to be flat. The rationale for that we discussed with investigator. Investigators would never tell a patient to lie flat, who have this disease. I think the important thing here is, regardless of the 30 degrees, this is why there is a placebo component in all trials five to do a comparator and the differences we expect out of 30 degrees between placebo and active would be the same difference that we would expect between placebo and active, if they will look flat at zero degrees. That being the case, I don’t think we need to do a trial, a specific trial to do that. I think that we could design something appropriately, to show what the differences may be, that would be informative to the FDA, but of course we really can’t finalize anything until we have a discussion with the agency and the rationale, why that we think the difference between placebo and active, that 30 is representative of what would be seen if they lie completely flat.

Robyn Karnauskas - Deutsche Bank

Okay. That’s helpful. Then on the FDA discussion, I guess the first question, what is typical timing of having a conversation with the FDA and or how could it help the investors get that color? Then I guess you mentioned that maybe 306 might be able to be sufficient to satisfy the requirement but the full trial is the primary end point and I know mentioned it may be in your core program. Do you think the fact that falls in the end point would be a hurdle for using 306 to support the FDA’s questions?

Dr. Simon Pedder

When it comes to timing for the FDA, I think it is normally about 60 days. Bill is in the room, so he can just comment.

Bill Schwieterman

Yeah I mean this variable it is difficult to predict, because those lie between class and between divisions, Simon is right, it is usually within 60 days you get it, sometimes sooner, sometimes later.

Dr. Simon Pedder

And now, your question about 306, we are obviously looking at both right now as plan that to be part of supplemental NDA. But we are also looking at the OHQ, so we’ll have all of the individual items of the OHQ in the competitive score. And we’re going to have a meeting with the agency to discuss this very point and that will obviously be a main agenda point during the meeting.

Robyn Karnauskas - Deutsche Bank

And then cash, you’ve mentioned if you were to launch, you can get through probably till early 2013, I think our math suggested you could probably go into second quarter 2013; maybe give us some sense of how you plan to conserve cash to ensure that we can make it through I guess at least the fourth quarter fall data and beyond what is your plan for cash?

Dr. Simon Pedder

I’ll hand that over to Nick.

Nick Riehle

Hi Robyn, as we discussed on the last couple of conference calls, the commercial team has made a real effort to constrain spending, I mean just as an example of this despite the positive outcome of the sales reps that we've been recruiting have been, was done so on a contingent basis, especially we’ve got no liabilities on pulling back those sort of expenses.

Accordingly, we will end March with over $50 million in cash and we are already taking steps necessary to quickly reduce the burn rate. Significantly, as Simon discussed earlier, we have looked at various scenarios for acquiring the data that the FDA is requesting and we are doing with cash on hand, that it is likely to be more than adequate to get out of such data and somewhat beyond that.

Robyn Karnauskas - Deutsche Bank

I guess lastly, with the delayed sort of approval, you know raises questions around IP and of course if you won’t get an OHS, you need to get orphan drug designation. But can you just remind us again like what are the options for patent expiration; I think your patent goes out to 2020 and then you might be able to get [high tracks] and then also the site competition for 306 in the US versus EU?

Dr. Simon Pedder

Well, that's one of the attractive feature of droxidopa Northera having off of that, is that when you are dependent on IP, everyday that you don’t get approved, you are losing value for your asset. With orphan status you get seven years from approval and so we would not be losing any of our timeline, we will get seven years of protection in the US upon approval. We get 10 years of protection in US and in Europe.

The other thing where we do now have IP around is our control release once-a-day, the droxidopa, but that kind of goes out to 2026. So from a protection viewpoint, we’re in really good shape. Of course with the once-a-day, that’s a whole different development program that we’re getting into in due new course, but our focused opportunity right now is getting the present formulation approved here in the US for NOH.

Robyn Karnauskas - Deutsche Bank

And the site competition of 306, US versus EU that was an issue that’s raised with the FDA?

Dr. Simon Pedder

Well, 306 is all done in the US. I would like to point out that the largest benefit in Study 302, to grow the efficacy of 302 were in the Parkinson patients in United States. If we combine 301 and 302 together, it really does show very similar outcome when it comes to geography, when it comes to disease and it’s a situation of you get very small numbers when you get into the subgroups. So we combined 301 and 302, it doesn’t differ from geography, doesn’t differ from the disease.

Operator

Thank you. Our next question is from Juan Sanchez of Ladenburg. Your question please.

Juan Sanchez - Ladenburg

If 306 be enrolling patients in the US in majority or not and if you can give us a recap of the safety finding of Study 306a?

Dr. Simon Pedder

Sure. 306 is all being recruited in the US and the safety from 306a was similar to what we previously reported for other trials and that’s basically no real difference from placebo.

Juan Sanchez - Ladenburg

And can you remind us, it was some derivative for physical significance, but in Item 1 where was the (inaudible) placebo in 306a?

Dr. Simon Pedder

Yeah, it range from one week, a unit difference of 1.5 to week eight; it was a delta difference of 0.9. So very similar kind of what we reported in 301.

Juan Sanchez - Ladenburg

On OHQ 1, that’s 1.5, right?

Dr. Simon Pedder

The OH showed a nice delta early, which we dictated overtime mostly to placebo increases by week eight.

Operator

Thank you. Our next question is from Jonathon Eckard of Leerink Swann. Your question please.

Jonathon Eckard - Leerink Swann

So with regards to 306, it is one of the larger trials that you have conducted. Is there any powering around some of the secondary endpoints such as OHSA Item 1? And then also that endpoint, if I am not mistaken has been positive on old trials with 302, which primarily use the different trial design. Can you talk a little bit about the differences in the trial design and how this item might be favorable in this coming trial?

Dr. Simon Pedder

Yeah, I will start off and I’ll let Bill and Art jump in if they want to add anything. You know, 306 is powered for a [falls] benefit and when we planned this study, this study was planned as part of the supplemental NDA.

That being said, the number of that powering for a falls benefit came out to 160 patients. 160 patients you will recall is the same number that we ended up recruiting for Study 301 which was powered for an OHQ benefit and there it will be same powering for OHQ as for Item 1, so that seems to be, 160 patients seems to be around the same ballpark as what we would need.

Clearly, we want to have a talk with the agency though and kind of talk about how we should look at 306 to conclude any kind of discussions with regards to the number of patients to be enrolled and finalize that with the agency before we talk to anybody else.

Bill Schwieterman

And the only thing I’ll add to that Jon, its Bill that 302 was a withdrawal study and because of the punitive carryover of FDA that might be minimized and in fact will probably explain some of the findings of very sensitive endpoints. 306 as you recall, 301 is an induction design study and in addition to that there are other advantages on 306 which is why Art and I designed it that way to avoid that carryover effect of that open label filtration period as well. Through the patients in 306 does not in the drug and that helps you with the power; obviously we have to discuss with the agency how all of that plays out in terms of overall power and design and we think that those are advantages.

Operator

Thank you, our next question is from Scott Henry of Roth Capital.

Scott Henry - Roth Capital

I guess my question is more discussion oriented, but from my perspective it seems there has been somewhat of a pattern of trying to change trial and trying to meet the FDA requirements with something slightly different than they are asking for. At some point do you think it is necessary to start from scratch, to design a trial in line with specifically what they are asking for and delivering it, I mean how do you think about that versus trying to take a different trial in fitting that into the box they are looking for?

Dr. Simon Pedder

Yes well I would approach that to say that you know we are kind of really pioneering the space. The only other experience is obviously with Midodrine and you know there were seven trials with Midodrine. I think the FDA is still waiting hopefully for the next two to show symptomatic benefit. We have demonstrated symptomatic benefit, we have demonstrated symptomatic benefit in the larger studies that’s reported in this population, I think that's a huge win for us. You know Dr. Temple said clearly it's a big win and in our previous discussions with the leadership at the FDA they have been very upfront about the fact that this is a hard to see study and that no one has reported symptomatic benefit.

Even when we showed them the data from 302, they highlighted the fact that you know there is clear symptomatic benefit albeit not in the primary as we expect to and you know we learned an incredible lot from these studies, we are going to learn an incredible lot from Study 306. 306 obviously we are putting forward as a second in trial that could lead to approval and in this indication, but I think we are going to learn a tremendous lot about what the benefit is involved, what the benefit is in Parkinson’s of these patients so that may be above and beyond NOH.

So this is what clinical trials should be. Clinical trials should be a learning experience. Unfortunately we are not bringing the (inaudible) to market using the HCR-20 as the primary outcome. This is a market where there is no benefit demonstrated in a clinical trial before we came along, it's a learning experience for us. I am sure it's a learning experience for the FDA and the best way forward is for us to get down to the agency and talk about the way forward and once we do that, we will be very upfront and open about what we and the agency have agreed as the best way forward.

Scott Henry - Roth Capital

Okay and obviously you are going to meet with the FDA and find out specifically what they are looking for. In the scenario that 306 does not fit that requirement, could you talk about what the time and the cost of a new trial would be?

Dr. Simon Pedder

You know that’s something that we have haven't really explored at all. I mean clearly we have a lot of faith in the Study 306, we think it’s a very good design and still outlines the rationale for why it was designed so. We have seen the data from 306a, you know it does indicate efficacies especially with looking at dizziness and the safety again was beyond approach. So you know we obviously are right now planning on completing 306b and obviously having significant discussions with the agency about how that would be suitable to lead to an approval because I think it's no doubt that this drug works in the patient population.

Scott Henry - Roth Capital

Yes it does appear to work. Then I guess asking that question in a couple of different ways and hopefully I have my 300 numbers correct, but trial 301, how long did that trial take to complete and what was the approximate total cost?

Dr. Simon Pedder

It's approximately 2 years, total cost for it you know I'm guessing $20 million and $25 million in the ballpark, we can't give you specifics and that’s with the general.

Scott Henry - Roth Capital

Yes that is more than good enough.

Bill Schwieterman

And that too was that it was being done largely concurrently with the 302 study and so some of the costs were somewhat overlapping.

Scott Henry - Roth Capital

And then you know another question for you, if the FDA did, again if they didn't think 306 was sufficient, would you anticipate that you would want to run another trial, I would expect you would because the drug appears to work, but I just wanted to get your thoughts on that?

Dr. Simon Pedder

Well you know I think part of the discussion we will have with the agency would be that you know if 306 did not work to take something that we don't think has happened, but if 306 did not work, what other additional trial would they buy into based on what they have learned and based on what we have learned going through the process and you know I think that we would take our collective education and design additional trial because clearly this is a drug that works. We have a lot of patients who have demanded access to this drug that we have made available in long-term extensions or compassionate release and I think you heard the story from many patients and caregivers that the advisory committee of the benefit, certainly when we show the buckets of responses that are 2,3,4, 5 unit improvements whether or not it's the dizziness or the OHQ as a composite score clearly identifies that a significant number of patients have a very robust benefit to this drug. The FDA would understand that and I think the FDA wants to work with us to make sure that we get that drug to them in a short time as possible.

Operator

Thank you. (Operator Instructions). Our next question is from Liana Moussatos of Wedbush Securities.

Liana Moussatos - Wedbush Securities

Just following up a little bit on Robyn’s question about the positioning of the patient in 306b versus what was mentioned in the Complete Response Letter, can you go through that again like 30 degree head-tilt versus laying prone and then the other question I have is when will you request the meeting with the FDA?

Dr. Simon Pedder

I will take the last question first and that is immediately we will request a meeting with the FDA. When it comes to the head tilt you know how the standard of care for people who treat these patients is to measure supine hypertension, a (inaudible) table at about 30 degree inline, that’s the standard of care. So that's what we did, that allows the comparison between active and placebo in a relatively supine position which all investigators say that’s the way that they do it. You know to really make these patients becomes supine and get high blood pressure is questionable, that’s why the access in the field report that a better comparison would be would be appropriate at 30 degree tilt.

Operator

Our next question is from Jonathan Eckard with Leerink Swann.

Jonathon Eckard - Leerink Swann

I was just going to have as maybe Bill if you could talk about some of the aspects Midodrine profile according to their label and other kind of key differences that you see in your falls profile, not try and tell you to predict the label through that or a [label] with that, that would be differentiating if both drugs had a block box warning initially.

Bill Schwieterman

That's an interesting question John, because they’re not natural to midodrine’s label but they have a black box for supine hypertension, we intend to cover the key back. I’d like to mention that FDA is offering us the possibility of not having that supine hypertension if we have discussions with them being in the flat position for [drug intake]. That’s that's a real advantage. As you know, the midodrine study is quite a bit smaller than what FDA is asking us to do an ARM program and I am not sure why that is, but I think we are going to have discussions with them about what they need to know. Certainly our own way forward would involve according to this communication with FDA, longer-term studies that they want to see out to 8 to 10 weeks. I don't think that might have been keeping currently that they would have that data at all. So there's a couple of differentiating factors right there. The possibility for us going in there with the supine hypertension, which we've always said to take advantage, now we are going to have a much larger and a much longer dataset than the midodrine data have. I think that's an advantage but Keith why don't you chime in here.

Keith Schmidt

Sure. With regard to the black box warning between the two labels, I mean Simon mentioned that the FDA’s comments were that that black box warning that they put in the draft right now could come out, if we can demonstrate that there's a lower incidence and we frankly have already done that with our clinical trial today. We showed a much lower incidence of supine hypertension at the 180 millimeters in mercury for sure and at the 200, even more so, because the label, if you look at midodrine’s label it talks about patients with supine hypertension in the 22% to 25% dose range. The other thing that’s in their black box warning is the admonition to physicians that the product has never shown any symptomatic benefits and so it’s a product out there has a real problem in the terms of benefits to risk ratio, why would you risk supine hypertension if the product really doesn't show any benefit to the patient.

So that’s the issue, the safety arm with their black box. I am pretty confident that with the data that we can generate that, we will be able convince to the FDA that our product is safe, it doesn’t have the nearly the incidence of supine hypotension. And I would add to that, that the FDA also noted in our letter that they were removing the RIMS requirement. So that there is no risk mitigation strategy required because they didn’t see the benefit. They didn’t see the risk of the product of wanting a RIMS program. So keep that in the back of your mind as well.

The other difference between frankly midodrine and Droxidopa has to do with alpha agonist adverse events and that is the part that drives the frail and elderly patients’ berserk. Because it causes the numbness, the tingling in the scalp, the needle prick sensation, it’s the kind of thing that really makes it difficult for the patient to comply. The other thing, as you know, alpha agonists have the same products that are used for urinary incontinence. So if you put an elder patient on product like this and what does it do? It makes urination painful. It causes urination to be hesitant, etcetera and if you could imagine if you are an older man, that just isn’t what you need. So it’s not a happy product for frail and elderly patients to be taking and what physicians do to try to overcome this problem is they under-dose midodrine. They put it at lower doses or they do the dosing less infrequently, trying to get the patient to tolerate it and as we have done our market research, we have heard many times that physicians tell us, they simply can’t get the efficacy that they know the product is probably capable of giving, because the patients can’t tolerate the dose or can’t tolerate the product nature of the adverse events.

Dr. Simon Pedder

And just the kind of follow up for the supine hypotension question you said Jonathan, I would just recall to you that the difference that we saw in our placebo components of the trial was 3% of patients on Droxidopa having supine hypertension over a 180 versus 1.5 on placebo. So the difference was really 1.5% greater than 180.

The midodrine label states at 13% will get supine hypertension but over 200. So there is a real difference that back and forth that we would have with the FDA and the labeling, we would want a more descriptive detail that would fully demonstrate what the difference was seen in our studies compared to what's been seen in midodrine.

Jonathan Eckard - Leerink Swann

That’s all very helpful. Just the question was really summed around just where our comparator would be if there was a black box warning and you guys are lined up very well. If I can give another question on a potential label is 306 would be in Parkinson’s; with regards to what the FDA then appears to be looking for is durability, maybe it doesn’t seem to be an issue. The fact that 306 is only in Parkinson’s, in your initial kind of a gut feel, how would that impact the potential patient if that could be included in a label if 306 was allowed to be used. Do you think you will be able….?

Dr. Simon Pedder

I don’t think it would and the reason why John is that the MSA and PAF, the other two big patient group were both typically significant when we combined 301, 302 together independently. Parkinson’s was closed. In 302, PD patients had the best response; in 301 they had the least response. But combined, they show a similar like benefit on the OHP of about one year improvement across the board. So I don’t think there is any concern, I think PAF as in MSA, the data speaks for itself, it very clearly shows us physical significance when you combine 301 and 302.

Jonathan Eckard - Leerink Swann

That’s helpful. I guess the last question which, I guess, is probably just looking at this point but, the 306b result at least in the magnitude, the benefit that we saw in 306a was repeated, is a trial in itself as a utility, as a standalone for its own NDA approval?

Dr. Simon Pedder

We would give 306b in conjunctions with the present filing for a future filing for NOH.

Operator

Our next question is from [Anatolia Avodarmal of Carnie]. You question please?

Unidentified Analyst

Simon and Bill I wanted to ask if you guys can comment on the timeline of separation in respect to item one in OHQ that we saw in the eight week study, 306A and is there any implication if any, for thinking about 306 B giving the same end points. I think the question is, it does seem like we see some compression of a benefit over time that would be starting at week four. Perhaps less so for item 1 and OHQ? And if we did see, I guess the specific question is, if we did see that kind of benefit compression what would your revised power calculation before 306 B achieving significance in those end points.

Dr. Simon Pedder

Well, I will start off and let Bill jump in. My only comment is, please remember there is only 51 patients in 306A, 27 are on placebo and 24. It was a smaller data set. That being said, the range for the benefit on item one went from a 1.5 unit at week one to a 0.9 unit difference at week eight. So although it did compress a little bit, they would still be what we see at 0.9 is what was reported in 301 and I will point back to that at obviously a range of benefits. And as we demonstrated at the Advisory Committee that a lot of these patients that were having benefit were the patients who were having robust benefit of two units, three units, four units, five units, six units improvement on dizziness. So we feel relatively comfortable that 306b will show the same outcome. Bill?

Bill Schwieterman

Yeah, I don’t have much to add to that. I think you know what we saw in 306b was more numbers of patients to begin with, so it’s really difficult to make any firm conclusions regarding the temporal effects and so forth. But you are right it went from 1.5 to nine and that was largely driven by placebo effects in some of the patients coming out.

I think overall it is also fairly consistent over the long-term and we remain pretty confident that the 306b data especially when you look at the falls data in that study where you see a 60% reduction in all and really a small number of patients, but we also think that that's an objective out to measure and that’s going to be helpful in allowing FDA for the long-term.

Operator

Thank you. Our next question is a follow-up from Scott Henry of Roth Capital.

Scott Henry - Roth Capital

Just a couple of follow-ups. I guess first with regard to meeting with the FDA, do you have any sense of the timeline for that; is that something that could occur in the second quarter or do you have any sense on the calendar there?

Dr. Simon Pedder

Yeah, we will be requesting meeting right away and then it would be within 60 days and we’ll remind them that this is an orphan status drug and that it’s supposed to be more open transparent dialogue with orphan diseases and that we would appreciate if they could meet with us as soon as possible.

Scott Henry - Roth Capital

And then the bigger picture question is and obviously you’ve got the benefit of greater dialogue with the FDA than we do; when you think about 306 confirming 301, they have different endpoints. So to me, that’s obviously not a simple confirmation. Do you think that falls data can confirm the composite endpoint or do you think that the composite endpoint would have to confirm the composite endpoint?

Dr. Simon Pedder

Well, at the Advisory Panel what Dr. Temple mentioned is that you can look at all the endpoints if your primary meets fiscal significance, then you can decide what’s really important based on looking at all the data. And clearly from the analysis that the same group did at the FDA, they highlighted instruments that, dizziness was clearly the most cardinal symptom of NOH in their research and it was pointed out by our own research and they seemed to have highlighted the fact that improvement on dizziness is what really key for these patients.

And so although we look at the OHQ as a group and works basically significant with them, there was the fact about directing what they felt was more clinically meaningful and ambiguous with these patients and that is improvement on dizziness which obviously had a FDA point towards 301.

And because of that I think that again as an education and learning experience going forward we learned from these trial, that clearly maybe Item 1 is the most robust and the more appropriate and that’s good for us because, in the biggest study we ever did, we had a 1.3 unit improvement and patients had typically significant improvements to the patients who had a two, three, four, five, six unit improvements compared to placebo.

So I think what they are learning and what we’re learning is that dizziness maybe the key thing to look at and we think that’s probably a big win for us. Bill, Art can you sum that?

Bill Schwieterman

The only thing I’ll add to that, FDA actually has a long history of using complementary trials upon in different endpoints to collaborate and show consistency as a fact. So I don’t think its vast replication. It has never really been amended at the FDA what they wanted an efficacy data that are convincing, showing them data.

And I think one of the advantages of our program and our drug actually is that it shows benefits across a range of our company; it is a hard questionnaire which showed significant it could be, one that they pointed out at the advisory committee, it’s also important business. We also showed a real significance; we have early data showing that shows benefit in 306, efficacy data on 301 (inaudible).

Operator

Thank you. Our final question is from [Michael Hagen of Winston Patrick Securities]. Your question please.

Unidentified Analyst

I am wondering if and apologies if I am repeating constant here, but I am wondering if the black box would be due to an inclusion of 300 milligram dose and if so, how important that 300 milligram dose is to you?

Dr. Simon Pedder

No, I don’t think we saw any dose response when it came to supine hypertension. So it’s not really a dose issue. Even with small amount was droxidopa, if these patients have complete lack of (inaudible) they can have a blood pressure response in the low dosages. So it’s really independent of doses and that’s patient-by-patient and that’s why we really key on that slow, but steady titration to benefit, so that they can bounce off the benefit of the drug versus potential issue such as attention.

Unidentified Analyst

And a follow-up class expansion, you’ve got the question earlier and do you think that this would be Class I or Class II review considering the 3 milligram dosing and can you repeat that would you think the 3 milligram is worth go to the Class II and including the data would you be more apt to leave that on the side and hope for a Class I review considering the orphan status?

Bill Schwieterman

I think I don’t want to speculate too much until to speak to FDA and so I think we need to get some ideas about what they really want specifically. So we think about the actual. But I looked at that and I think the 3 milligram dose issue is not really the one that FDA is going to focus on, and certainly not the one that we go into a response but we really have to do more with the 306b data.

And the Class II responses are generally are reserved for those; I was reviewing it last night again, you know with the involvement sort of we’re in discussion and so forth. And so if the FDA once go out and (inaudible) 306b then it would be a Class II. It’s conceivable and we might view it differently that as Class I but I don’t really want to get into that.

Dr. Simon Pedder

And with that, we appreciate the questions and I think that all we can do is once we’ve met and talked to the FDA we are obviously going to update you people accordingly.

Operator

Thank you. That concludes our question and answer session for today. I would now like to turn the conference back over to Dr. Simon Pedder for any closing remarks.

Dr. Simon Pedder

I just like to summarize by thanking you all for your interest and your support. Obviously, we’ve got a very important meeting with the FDA and we look forward to updating you on our plans and moving forward to this very important drug and treating this unmet medical need so (inaudible). Thank you.

Operator

Ladies and gentlemen, thank you for your participation. That concludes the presentation. You may disconnect and have a wonderful day.

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