Executives
Mike Aguiar - SVP & CFO
Mathai Mammen - SVP, Research & Early Clinical Development
Rick Winningham - CEO
Analyst
Anant Padmanabhan - Cowen and Company
Steve Byrne - Bank of America
Howard Liang - Leerink Swann
Stephen Willey - Stifel Nicolaus
Theravance, Inc. (THRX) Phase 2b Study 0091 with its LAMA Candidate TD-4208 Results Call September 4, 2013 8:30 AM ET
Operator
Ladies and gentlemen, good afternoon. At this time, I'd like to welcome everyone to the Theravance Conference Call. During the presentation, all participants will be in a listen-only mode. A question-and-answer session will follow the company's formal remarks. (Operator Instructions)
I will repeat these instructions after management completes their prepared remarks. Today's conference call is being recorded. And now, I would like to turn the call over to Mike Aguiar, Senior Vice President and Chief Financial Officer. Please go ahead, sir.
Mike Aguiar
Good morning, everyone, and thanks for joining us. As we discussed the positive top-line Phase 2b study results from a dose ranging 7 day crossover design Phase 2b study of TD-4208. An investigational long-acting muscarinic antagonist administered once-a-day as a nebulized aqueous solution in patients with moderate to severe chronic obstructive pulmonary disease.
With me on the call today is, Rick Winningham, our Chief Executive Officer, and Mathai Mammen, Senior Vice President of Research & Early Clinical Development. We've prepared a few brief remarks for today's call and then we'll open it up for questions.
A copy of the press release and slide presentation can be downloaded from our website or you can call Investor Relations at (650) 808-4100 and we will be happy to assist you.
Before we get started, we would like to remind you that this conference call contains forward-looking statements regarding future events and the future performance of Theravance.
Forward-looking statements include anticipated results and other statements regarding Theravance's goals, expectations, strategies and beliefs. These statements are based upon the information available to the company today and Theravance assumes no obligation to update these statements as circumstances change.
Future events and actual results could differ materially from those projected in the company's forward-looking statements. Additional information concerning factors that could cause results to differ materially from our forward-looking statements are described in greater detail in the company's Form 10-Q filed with the SEC.
Before I turn the call over to Mathai, I would like to remind you that this slide presentation can be accessed from our website and the slide number referenced during the discussion can be located at the lower right corner of each slides. Additionally, we will not be answering any questions on the call today regarding next week's Advisory Committee Meetings on ANORO ELLIPTA as the briefing documents will be posted by the FDA in the next few days.
I'll now turn the call over to Mathai Mammen. Mathai?
Mathai Mammen
Thanks Mike. Good morning everyone and thank you for joining us. I'm very excited to review the results from the Phase 2b study with TD-4208. First by way of background TD-4208 was discovered as part of a major effort we had internally with the multivalent antagonist of the muscarinic receptor family with long receptor half lives. Beta antagonists were intend to have long-action in the lungs and be suitable for inhalation delivery.
The current goal of our LAMA program is to develop a once-a-day inhaled medicine in a nebulizer that offers improved efficacy and tolerability relative to current therapy. And that provides the bases for combination nebulized products with other medicines such as an inhaled corticosteroid. We believe the opportunity for nebulized product is significant and complementary to that addressed by the GSK Theravance collaboration products.
For some COPD patients current handheld devices are simply not suitable. For instance, some patients may lack the physical or mental dexterity to coordinate a single-breadth inhalation. Nebulization may be the preferred delivery mode for such patients. A strict requirement of the LAMA intended for nebulization is chemical stability in aqueous solutions a feature not common to many LAMA.
TD-4208 is a non-esters non-quaternary nitrogen compound that is chemically stable in aqueous solutions. We announced the results last year the single dose study in COPD patients with TD-4208 and ipratropium as an active comparator. As a reminder in that study TD-4208 was fast acting with the speed of onset comparable to ipratropium and demonstrated a significance and durable bronchodilator response using doses of 350 microgram and 700 microgram.
In the study we are reporting today 0091 we have replicated the evaluation of the original dose range together with lower doses in order to better understand the dose response relationship for TD-4208. For this reason we've included six doses over a 30 fold range from 22 microgram to 700 microgram delivered to patients using a well established standard PARI nebulizer device delivering a simple aqueous formulation.
Let's please turn to Slide 3 for a discussion of 0091. This Phase 2b study was a 7-day repeat dose study where every patient received placebo and four of the six dose group in an incomplete block design with a two week washout period between the five periods. The primary endpoint was predefined as a change from baseline in FEV1 trough after day seven dose. On day seven in all periods we collected serial spirometry from patients over the 24 hour period post-dose. The predefined primary endpoints was the change from base line in FEV1 trough on day seven. The key secondary endpoints were peak effect, area under the FEV1 curve or AUC and the weighted mean FEV1 again derived from the day seven spirometry. The weighted mean is an especially important secondary endpoint and is conceptually the average FEV1 change measured over the entire 24 hour period.
Please turn to Slide 4 where I'll summarize the efficacy data. Prior to doing that I first note that we analyzed the data very carefully for any evidences carryover effects from period-to-period and there were none. Now the data. I'm pleased to report that statistically significant effects were seen at all fixed doses studies from 22 micrograms to 700 micrograms. In other words the primary endpoint was reached for all doses study. The placebo adjusted FEV1 changes of trough ranged from 53 ml to 114 ml.
I'm equally pleased to report that we met all secondary endpoints for all six doses with weighted mean FEV1 ranging from 83 ml to 147 ml. We observed that the medium time to reach 100 milliliters improvement in FEV1 range from 30 milliliters to 60 milliliters.
Let's now look at Slide 5 for a deeper look at the bronchodilator responses over the range of doses study. Plotted on the left is the primary endpoint trough FEV1 on day seven verses dose. Plotted on the right is the key secondary endpoint weighted mean FEV1 on day seven versus dose. These two plots provide a comfortingly consistent picture. The placebo response was small. The two lowest doses of 22 micrograms and 44 micrograms provided a bronchodilator response but not likely to be a clinically meaningful one. The highest dose of 700 seem to offer no advantages over the next two highest doses. The dose of 175 microgram seems to be approaching the top of a dose response on these and multiple other measures. These doses are proprietary to rich information set from which we feel able to select the smaller range of doses for additional study.
Please turn to Slide 6. An additional objective of the study was to determine the likelihood that TD-4208 could be appropriately dosed once daily and not more frequently. All the preclinical data are consistent with the compound with an extended pharmacodynamic action in the lung as where the single dose clinical data reported earlier. The data from study 0091 continues to support once daily doses.
As stated previously we collected FEV1 at a number of time points distributed over the 24 hours at the last day of doses. It is instructed the first visually inspect the 24 hour placebo corrected serial FEV1 curves, which are shown here on Slide 6. One can see that the curves are generally flat across the 24 hour dosing in a row for all doses. One sensitive analysis is to look at the area under this FEV1 curve or AUC for the first 12 hours on day seven and compare this value to the AUC in the second 12 hours on day seven. For all doses study and is tabulated here the ratio of the two AUCs was very close to one for all doses meaning that almost all the treatment effects for the first half of the day was preserved in the second half of the day. There are multiple ways to analyze these data and to use data drawn from approved or late stage bronchodilator drugs at calibration. In general, the current data set provides further evidence that TD-4208 has the potential to be dosed once a day.
So in summary of the efficacy data 0091 we have first demonstrated a dose response for TD-4208; second, identified a dose range that is appropriate to include in future studies; and third, observed a constant bronchodilation response relative to placebo across the full 24-hour dosing interval, consistent with the compound that could be dosed once daily.
Now turning to Slide 7, I will summarize safety findings. As I will describe further in the slide to follow, treatment-related adverse events were comparable to placebo. There were no SAEs related to treatment and no discontinuations due to AEs related to treatment. A full review of all labs for all subjects in the study revealed no clinically significant signs. There were no increases in heart rate at any other time points for any of the doses studied related to placebo. There were no ECG changes including arrhythmias and QTc changes at any of the doses at any of the time point. All of these data are consistent with the very low plasma concentrations of TD-4208 measured in the study.
I will now elaborate on AEs on Slide 8. TD-4208 exhibited an AE profile at all doses that were comparable to placebo. Shown here are the tabulated treatment emergent AEs that occurred two or more times in the entire study. The overall percentages of patients reporting any AEs were about 18% on placebo and between 7% and 16% on TD-4208. The two most common AEs were headache and dyspnoea. Generally, TD-4208 was well tolerated in study 0091.
Now let's turn to the final slide. In summary, all doses in this Phase 2b program for TD-4208 met all primary and secondary endpoints providing significant and clinically meaningful bronchodilation at the higher doses. The 24 hour Serial FEV1 profiles are consistent with the once daily regimens. And finally the safety and tolerability of TD-4208 appeared comparable to placebo at the doses study. We look forward to continue to announce this for our new data set in planning next step.
I'd like to end by offering my sincere thanks to the Theravance team that conducted an excellent study and especially to the patients that participated.
And with that I'll turn the call over to Rick. Rick?
Rick Winningham
Thanks, Mathai. In summary, we are very pleased with these study results for TD-4208 a compound discovered and developed by Theravance. Looking forward, Theravance has a number of important events coming out during the remainder of 2013. These include next week's FDA Advisory Committee for ANORO ELLIPTA; potential RELVAR ELLIPTA regulatory events in other regions; Phase 2 results in ADHD for our dual norepinephrine and serotonin reuptake inhibitor; the producer date for ANORO and ELLIPTA in December; and finally the separation of Theravance into two publicly traded entities either late this year or early in 2014.
And now I'd like to turn the call over to the conference facilitator and open the call for questions.
Question-and-Answer Session
Operator
Thank you. (Operator Instructions) We’ll have our first question from Anant Padmanabhan with Cowen and Company. Your line is open.
Anant Padmanabhan - Cowen and Company
I have a couple. First, I was wondering if you could discuss any market research you have and the demand for a nebulized LAMA. What percent of LAMA eligible patients do you think would need nebulized formulation? And then I have a follow-up.
Rick Winningham
Sure. It's a great question. Based on the research that we've conducted to-date in the current market that exist today in the United States, we would estimate between 5% and 10% of patients prefer a nebulized route of administration for the reasons that Mathai highlighted in his remarks.
Anant Padmanabhan - Cowen and Company
And then, could you discuss any plans to do a LABA/LAMA formulation as a nebulizer? And what would be the LABA in this case?
Rick Winningham
Yeah, no, not at this particular point in time I -- we don't have plans to do a LAMA/LABA combination. Yeah our LABA combination work is really focused with GSK. Mathai did highlight in a nebulizer work that we expect to do with an inhaled corticosteroid. So, I think there is an opportunity for that type of work but it's unlikely that we will take on LABA combination because of our agreement with GSK.
Operator
Our next question comes from Steve Byrne with Bank of America. Your line is open.
Steve Byrne - Bank of America
Mathai, can you talk about the dose response curve, is it logical to you that there could be a peak a dose response and that the higher doses some detrimental effect on FEV?
Mathai Mammen
No that wouldn't be physiologically expected or consistent with the behavior antagonist. My expectation is that if you look at from based on all of the published LAMA dose response type data that's out there that these antagonists have a quite a rough dose response curve. We're actually quite pleased that the very low doses as I said in the prepared statements have a minimal effect and the higher doses generally have or somewhere on a max effect. And I explained the kind of ups and downs of the higher doses as noise within the population relatively small set.
Mike Aguiar
Yeah, Steve, this is Mike. I think if you look at a lot of the data here and compare and see with the UMEC data for example it's just not typical to see a really robust very clear dose response curve with the muscarinic antagonist that's not necessarily the way they behave. So I just would reiterate what Mathai said which is we're awfully pleased to see lower doses where there with the level of efficacy albeit below clinical significance so that would clearly find the lower end of where would be looking and then to have several doses that were clinically relevant. So we did exactly what we want it but again I just would not expect the kind of your traditional a highly linear type dose response curve with these compounds that's not really what is seen in the clinics today.
Steve Byrne - Bank of America
Then can you comment on this 114 milliliters of trough FEV how would that compared to the say standard-of-care?
Mathai Mammen
I think the absolute efficacy is highly dependent on the population we see for example with Spiriva there is studies where Spiriva looks to have a 70 milliliters and other studies where it's about 140 milliliters, 150 milliliters. So my own contention is that LAMAs have an efficacy that's quite comparable among the LAMAs and where they actually play out the choice of therapeutic doses dictated by systemic, side effects, tolerability and safety. And so here we were pleased to see that even if the higher doses we had excellent safety and tolerability. So I think we'll be able to get to a place where we'll be able to get all one can out of this mechanism.
Steve Byrne - Bank of America
And Mathai, can you just talk about where you want to go from here with the clinical developments that you've need to do more dose ranging before you go into Phase 3?
Mathai Mammen
So I think that we're -- we've just uncovered the dataset right now and we're looking carefully at the full set of data. I think we've chosen to report top-line here. We need to discuss internally exactly what we would do next before Phase 3. And I'll also note on the previous question one of the features of this compound that we did note at all doses is a very flat dose response curve. So even at the low doses there is very flat dose response curve so that is especially appealing to that.
Operator
(Operator Instructions) Our next question comes from Howard Liang with Leerink Swann. Your line is open.
Howard Liang - Leerink Swann
Will you need to look at the BID dose to show that's split dose BID is the same as QD at twice-a-dose?
Mathai Mammen
Currently the division in the U.S. regulators do ask for a formal QD BID study. So we're not able to say from the current dataset that we're definitively a QD dose drug but we're projecting that it looks pretty good. The flatness of our dose response curves we would project a reasonable chance in a formal QD BID study.
Rick Winningham
Yeah, Howard, it's a great question. I think because of the flatness of the curve over 24 hours that at multiple doses because of the ratio of effect of the second 12 hours to the first 12 hours approaching one, I think this would be a compound that I'm not too concerned about relative to on a twice-a-day versus once-a-day study. I mean, I think we'll have to get into more of the data but based on what we've seen today I think we are pretty confident in the once-a-day profile of this drug so much though that we would necessarily hold up any advance studies based on the completion of that type of a program we would likely do it concurrently with advanced studies.
Howard Liang - Leerink Swann
So and may be you can talk about strategically what you would intend to do with its compound do you eventually want to market it yourself and also and what the requirement of Phase 3 program for something like this to be similar to other COPD drugs in terms of the scope of the program?
Rick Winningham
Yeah. So I think the Phase 3 program likely for a nebulized compound would be similar to other single agent long-acting muscarinic antagonist. I think it's not the Phase 3 program is not overwhelmingly burdensome here for a nebulized product and we do see an opportunity in 5% to 10% of the COPD population that's very complementary to what we're doing with GSK. Where we go some here in terms of partnership I think we'll leave that open right now. I think we're very excited that we've got a drug here it's got a very good profile it behaved exactly as it was designed to do in the discovery program and I think whether we get a partnership whether we do further studies on our own that's sort of yet to be decided.
Operator
Our next question comes from Stephen Willey with Stifel. Your line is open.
Stephen Willey - Stifel Nicolaus
Yeah. Thanks and forgive me if you've already covered this in early part of the call. I think you had made some prior comments I think around once you had confirmed the TD profile of the drug that you would then potentially had some reformulation options as either DPI or an MDI. And I'm just trying to think about it whether or not you guys are bent on just going forward with nebulizer only or would you potentially explore some of these other administration opportunities?
Rick Winningham
No, Stephen, that's correct. The form of the product the physical characteristics of the product support development in nebulizer but also in a DPI or an MDI we have that work ongoing it needless to say it's not as advanced as a nebulized form but we have that work ongoing in the physical properties that compound supported. So overall 4208 were quite broadly excited about what about what this may mean for the future of the company.
Stephen Willey - Stifel Nicolaus
So would you potentially look to explore parallel development pathways whereby you could have both a nebulized formulation and a DPI formulation in development at the same time?
Rick Winningham
Well yeah I think we would explore that I think it's unlikely we would take simultaneous Phase 3 programs as an example and in both the DPI and a nebulizer. But as we gain more confidence with the product in this for me was a critical study in which to gain significant confidence. The work that we put into the DPI and the MDI will increase because of the confidence generated from the study.
Stephen Willey - Stifel Nicolaus
And then just in terms of commentarial opportunities on the collaborative of the strategic firm. I know that there is really not a whole lot of available once daily LABA assets that are out there. I know that you said you weren't going to pursue that well but may be just give us a little bit color in terms of the once daily ICS assets that would be out there strategically or at least that are out there in development?
Rick Winningham
Yeah, I mean I think the assets that are out there or I didn't really don't want to go into a lot of detail on them because I think that's somewhat of a competitive advantage for us in keeping some of that quite. But suffice to say albeit that there are and I think we've seen opportunity with the LAMAs to combine with the potential steroid of a similar duration.
Stephen Willey - Stifel Nicolaus
And then if I could just ask just one quick ANORO question if you don't mind. Have you guys been pretty to all that subpopulation data that I guess GSK claims is used to support the approval of the higher dose?
Mike Aguiar
Yeah, Stephen, this is Mike. I don't want to get too far up here right now with ANORO commentary just because we've got briefing docs that will be posted here in a sort of eminently. So I'm going to punt on any ANORO questions right now. I would just say we remain confident in our dataset and I really wouldn't want to go beyond that right now again the data will be out in a very short order and we'll get a chance to discuss this soon for public view on Tuesday of next week. So I'll punt on that question for now.
Operator
Thank you. It appears we have no further questions on the phone. I'd now like to turn the call back over to Mr. Winningham. Please go ahead, sir.
Rick Winningham
Yeah, thank you very much. I'd like to thank everyone for joining us this morning with us to share this important news and we look forward to providing further updates on Theravance as the year progresses. Have a great day.
Operator
This does conclude today's conference call. We thank you for your participation. You may now disconnect.
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