Theravance Announces Positive Results From a Phase 2 Study of TD-9855 in Patients With Fibromyalgia (Transcript)

May. 1.14 | About: Innoviva, Inc. (INVA)

Theravance Inc. (THRX) Special Call April 30, 2014 5:00 PM ET


Mike Aguiar - SVP and CFO

Mathai Mammen - SVP, Research and Early Clinical Development


Steve Byrne - Bank of America

David Friedman - Morgan Stanley


Ladies and gentlemen, good afternoon. At this time I would 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 completed 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 afternoon everyone -- afternoon everyone and thank you for joining us as we discuss the positive top line clinical results in a multi-dose six week placebo controlled Phase II safety and efficacy study of TD-9855 and investigational norepinephrine serotonin and reuptake inhibitor that we studied in patients with fibromyalgia.

With me on the call today is Mathai Mammen, Senior Vice President of Research and Development. We prepared a few brief remarks for today’s call and then we’ll open 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-K filed with the SEC.

Before I turn the call over to Mathai Mammen, I would like to remind you that the slide presentation can be accessed from our web site and the slide number referenced during the discussion can be located at the lower right corner of each slide.

I’ll now turn the call over to Mathai Mammen, Mathai?

Mathai Mammen

Good afternoon everyone and thank you for joining us. I’m quite excited to tell you about the recent results from the Phase II study with TD-9855, a novel norepinephrine serotonin and reuptake inhibitor or NSRI that emerged from our internal discovery program.

Let’s turn to Slide 1. First by way of background the overarching goal of our program is to create an NSRI with a unique balance of activity between norepinephrine and serotonin with the potential to treat a range of central nervous system conditions including chronic pain. Theravance’s research group used our proprietary approach to design TD-9855 to be brain-penetrant and inhibit reuptake of both norepinephrine and serotonin, with some selectivity for norepinephrine. Through a Phase I development program we have established that TD-9855 is generally well tolerated, notably with trial participants experiencing no significant nausea or vomiting. In addition, through a Positron Emission Tomography or PET study, conducted in partnership with a major university, we have confirmed that TD-9855 is a highly centrally penetrant compound in humans and inhibits norepinephrine reuptake more potently than serotonin reuptake in a dose range of 4 to 20 milligram.

Additionally TD-9855 has a relatively long half-life of approximately 35 hours. The immediate focus of our program is to test TD-9855 in the management of chronic pain disorders. We have chosen to initially study the compound in patients with fibromyalgia, a condition that affects predominantly women and is characterized by complex often difficult to treat symptoms, including wide spread pain as well as a consolation of other symptoms. Despite the availability of several approved medicines, many patients with fibromyalgia remain dissatisfied with the alternatives that are available to them and end up cycling through multiple medications in search for an acceptable efficacy and tolerability. We believe that there is a significant opportunity for a well-tolerated product that improves the overall functioning of patients with fibromyalgia.

TD-9855, with its unique transporter profile has the potential to provide pain relief and beneficially impact other symptoms important to patients with fibromyalgia such as fatigue. TD-9855 also has the potential to offer these benefits with fewer putatively serotonergic side effects such as nausea and [indiscernible]. Such side effects are frequently observed with current SNRI medications. To support these objectives we designed a statistically rigorous Phase II study in a fibromyalgia patient population.

On Slide 2 is a reminder that we will be making forward looking statements. So let’s turn now to Slide 3 for an overview of the design of our Phase II study. 392 patients were enrolled in the study with moderate to severe fibromyalgia. These patients had base line pain scores ranging from four to nine on an 11 point pain numerical rating scale also known as a pain NRS. They were randomized to placebo or one of two doses of 9855 5 milligram and 20 milligram. These doses were selected based on an evaluation of our Phase I safety data, in conjunction with data from the PET imaging study we conducted in healthy volunteers to measure targeting data of the TD-9855 at both norepinephrine and serotonin transporters. The Phase II study consisted of a one week placebo run in, a six week treatment phase and two weeks of washout. Subjects received either a 2.5 milligram or 10 milligram dose of TD-9855 for one week before dose escalation to 5 milligram and 20 milligram respectively. For simplicity I will refer to the active treatment arms as 5 milligram and 20 milligram. Based on the half-life of TD-9855, we predicted that steady state drug levels for the target doses would be achieved in approximately a week.

The primary efficacy measure for pain was the weekly average of a daily pain score during the sixth and last week on study medication. In addition, we pre-specified two secondary end points to measure overall functioning and treatment response. The fibromyalgia impact questionnaire, which I’ll refer to as the FIQ and the patient global impression of chain scale, also known as PGIC. The FIQ and the PGIC have both previously been used in pivotal trials and are broadly accepted as meaningful end points in addition to pain for a fibromyalgia population.

The PGIC is a measure of a patient’s overall assessment of treatment effect. The FIQ is a questionnaire that asks the patient about a wide range of symptoms that she might experience, including questions related to fatigue as well as about her ability to participate in activities of daily life. Both secondary end points were measured on Day 43 immediately following the last day of medication.

Statistical significance was determined with the one sided P value of less than 0.25 for primary and secondary end points directed from a duplicity [ph]. We applied a hierarchal data analysis scheme in which secondary end points were analyzed only if the primary end point was met. We also assessed safety and tolerability.

Please turn now to Slide 4, where I summarize the efficacy data from the primary end point of pain. I’m pleased to report that patients receiving the 20 milligram dose of TD-9855 experienced a statistically significant reduction in average pain score from base line at week six relative to placebo.

The plot on Slide 4 shows the weekly average pain score on the Y axis and the week of therapy on the X axis. The red box on the right highlights the data on week six, our primary end point. The lower red curve represents the 20 milligram dose, the blue curve the 5 milligram dose, and the green curve placebo.

As evident on the graph, the 5 milligram dose of TD-9855 was not significantly different from placebo. This figure on Slide 4 also shows the time course of improvement in pain score. The 20 milligram TD-9855 treatment group began to separate from placebo by week two coinciding with reaching steady state levels of the drug in the blood. We note that the beneficial impact on pain persisted and remains statistically significant for the duration of the active treatment phase. I am also happy to report that we met both pre-specified secondary end points of 20 milligram dose.

Turning now to Slide 5, we summarize the results of the first of the Study 2 secondary endpoint, the fibromyalgia impact questionnaire or FIQ. TD-9855 demonstrated a significant and meaningful 5.8 point improvement on the FIQ on day 43, compared to placebo with a P value equal to 0.010. We observed a similar temporal pattern of improvement as with the primary end point, namely a separation from placebo after two weeks of treatment that was sustained for the duration of the study.

Please turn now to Slide 6. This slide depicts our other secondary end point, the PGIC, which as a reminder is a measure of the patients overall evaluation of treatment response. Here we show the percentage of patients who reported being very much improved or much improved by the end of the study relative to base line. The 20 milligram dose achieved its pre specified end point as a statistically significant greater portion of responders compared to placebo, 48% versus 32% with a P value of 0.015.

Turning to the graph, one can see in the placebo arm a modest increase in the percentage of patients reporting very much improved or much improved. However these response rates plateau at about 30%, whereas in the 5 milligram dose group and certainly the 20 milligram dose group, the proportion of patients exceed 40%. We note that 47% or 48% of patients receiving 20 milligrams report feeling very much improved or much improved at days 29 and 43 respectively. Taking together the positive treatment effects on both the primary and the secondary end point are consistent with a clinically meaningful improvement in pain and the overall function of the patient with fibromyalgia.

Let’s now turn to Slide 7. In addition to pain we were very interested in understanding the potential of TD-9855 to offer clinical benefit on other symptoms. To do this we selected several assessments of symptoms commonly seen in patients with fibromyalgia that are often sub-optimally impacted by medicines available to them today. Two of these are particularly important are fatigue and general physical functioning. Slide 7 summarizes the effects of the 20 milligram dose of TD-9855 on some of these exploratory end points.

While we believe that these end points are important for understanding the potential clinical utility of TD-9855 and in forming future development strategy, I would like to underscore that these were exploratory. So the P value should be interpreted disruptive.

Although there were a number of exploratory assessments, let me start with the fatigue. We observed the beneficial impact on fatigue measured by different tools in different ways with a high level of consistency in our data set. We evaluated fatigue using the multi-dimensional assessment of fatigue and the DSF fibro scale, which is under development as a fit for purpose patient reported outcome for fatigue in fibromyalgia.

A beneficial impact was seen both on global and cognitive fatigue domain. In addition to fatigue we made other assessments of overall impact to the patient. One is the positive effect as measured by the composite responder analysis. This measurement captures not only reduction in pain but also overall treatment response and physical function. Specifically, a responder is defined as a subject with a reduction of pain of greater than or equal 30%, a PGIC of very much improved or much improved and a greater than six point improvement on the physical component summary as assessed with the 36 item short form health service known as the FS36 [ph].

In summary, we observed a consistent pattern of improvement on fatigue and physical functions as assessed by multiple care, providing us with the confidence that TD-9855 helped our patients beyond providing pain relief.

Now please turn to Slide 8 for a discussion of the safety and tolerability of TD-9855. Both doses of TD-9855 were generally well tolerated. I will first discuss SAE, then continue with other safety findings including a tabulated summary of common SAEs reported in this file. There were two SAEs reported in the study, one in the 20 milligram dose which was assessed by the investigators not treatment related and one in the 5 milligram dose which was assessed as possibly treatment related.

The patient on 5 milligram is a 57 year old female that suffered transient neurological symptoms and was hospitalized for evaluation. She was found to have clinically significantly high blood glucose levels of 396 milligrams. On further investigation the subject had pre-existing histories of uncontrolled, unmanaged diabetes and past episodes of transient ischemic attack. The patient was discontinued from the study and improved as her diabetes was managed. The discontinuation rate was approximately 20% and was similar across [indiscernible].

Norepinephrine potentiating medicine such as SNRIs are well known to have effects on heart rate and blood pressure. As a result we paid particularly close attention to these effects. We concluded that the changes in heart rate and blood pressure that were observed on TD-9855 arms were well within the range of those seen with approved drugs in this class. There were no significant changes in mean body weights at either 5 or 20 milligram and there were no treatment related clinically significant abnormal lavatory front.

Now let’s turn to Slide 9 for a tabulated summary of AE. This table lists treatment emergent AEs that were reported in more than 5% of patients in the 20 milligram treatment groups, our primary group of interest. These are listed by descending order of frequency. The most common treatment emergent adverse events reported were headache, dizziness, constipation, insomnia, nausea, fatigue, pharyngitis, increased appetite and [indiscernible]. And as Jeff discussed, norepinephrine potentiating medicines are known to increase heart rate. Therefore we paid particularly close attention AE related to these known effects. In our study, the rate effected cardio observed were within the range observed in approved drug. Of some note, rates of nausea in 20 milligram for TD-9855 were slight comparable to placebo.

Now let’s turn to Slide 10, our final slide. In summary, we’re very pleased with the positive results of our Phase III study of TD-9855. The 20 milligram dose is significant for the primary end point which is pain and the two pre-specified secondary end point and exhibited positive treatment effects across a range of relevant exploratory end points including fatigue.

Furthermore TD-9855, was generally well tolerated, including low rates of nausea consistent with other studies in this program. Patients with fibromyalgia required treatment options for the management of complex symptoms including pain and consolation of other symptoms. Patients today often end up trying different medicines in search of one that manages their various symptoms and is well tolerated. We believe that TD-9855 has the potential to offer what this patient needs a medicine with a potential to produce the pain of fibromyalgia and the improved symptoms important to these patients, such as fatigue.

Overall functioning of patients represents a unique opportunity within the spectrum of agents for fibromyalgia. We’re very pleased with the results report today which support continued clinical development of TD-9855.

And now I’d like to turn the call over to the conference facilitator to open the call for questions.

Question-And-Answer Session


Thank you sir. (Operator instructions). Our first question comes from the line of Steve Byrne from Bank of America.

Steve Byrne - Bank of America

Maybe you went over this earlier in the call. I missed the very beginning. But it’s my understanding that the causes of fibromyalgia are not very well understood and if you got into the biology of it early in the call then my apologies but if that is the case, how did you design a molecule to address symptoms that the biology is not very well understood?

Mathai Mammen

So the biology is how fibro -- you’re right, that the task [ph] completely understood but there is a sense that this generalized pain condition is due to potentially a deficit in descending sensory fibers. So allowing too much signal through basically from the periphery. So the thought here with the norepinephrine meaning NSRI is that at that level of the spinal cord, we could reintroduce normal levels of that inhibitory signal. And thereby like impact the disease. I think we’ve talked about this in other calls but that mechanism, that’s the mechanism by which we think an NSRI is an analgesic, should be useful in other pain conditions as well, maybe not for all comers but for those that also suffer from this particular deficit in so called DNIC.

Mike Aguiar

Steve, its Mike. As we started the program, the initial intention was not a narrow fibro product but rather something that had applicability and potentially pain and other CNS conditions. One of the problems that we were trying to solve with the NSRI are some of the serotonergic side effects and so we designed a molecule that was more norepinephrine leaning than serotonin leaning. And at least the date in the Phase I or Phase II is that we have run we really have not seen any significant serotonergic side effects. So we had this study readout and I would say it was really a homerun from our perspective. It takes little more work here to figure out what the next steps are but I think we are quite pleased with one the profile of the molecule and how it behaves in patient pain in particular the very specific results that we got out of the study.

Mathai Mammen

And one point, -- I can elaborate one point further is that fatigue is one of the core symptoms that fibromyalgia patients suffer and there is a logic to why a norepinephrine potentiating medicine might help there. And so we were especially happy to see the multiple measurements that we made in this study against the fatigue come through with some consistency.

Steve Byrne - Bank of America

And do you expect to meet with the agency before you give any idea on how you would pursue for Phase III on this?

Mathai Mammen

I think right now we just opened up the dataset. So we’re actively looking through and studying our data beyond the top line data reported today. But yes, obviously at some point when we’re ready, we would want to talk with regulators about the dataset.

Steve Byrne - Bank of America

And Mike, I assume you are listening to the GSK call this morning. It sounds like somebody out there is getting a little aggressive on pricing, presumably with BREO and Anoro entering the market. Do you -- are you particularly concerned about it as a potential impact on the launch of these two drugs?

Mike Aguiar

Yes, thanks for the question Steve. So we’ve certainly been aware that there being competitive threats out there for a while and competitive responses. If you were to look all the way back to -- the announcement at express scripts didn’t cover BREO for example, there was one of their early examples of where that was coming from as it was fairly aggressively in that particular situation. So are we concerned that the competition is aware that we’re out there? No, not particularly. And we expected that in total.

So I think sitting here today we are continuing to maintain the guidance we’ve had out there for a while from about a year ago to expect an initial launch that is on the shallower end of the launch curve and then continue to move up over time. But again at least from our perspective there really wasn’t a big surprise out there from the pricing perspective because again we’ve been seeing competition react to the BREO launch out there for a period of time.

The one other thing I would like to add is as you think about all the various components of marketing and sales, GSK has continued to make significant progress on the reimbursement side and they announced today that they expect to be over 70% on Part D reimbursement here by 1st of March. As you recall we entered the year at very low single digit. So we have made tremendous progress on that front. So while I always want to beat my guidance, I would say that we are continuing to understand where the market is and where we are today and expect to continue to see growth going forward.


Thank you. Our next question comes from the line of David Friedman from Morgan Stanley.

David Friedman - Morgan Stanley

Thanks for taking the question. Just one on fibromyalgia. I am having some difficulty finding the spots in the efficacy that are differentiated versus something like Savella. So is it possible just if you could highlight the areas where you guys expect your drug could have potential differentiation in that regard or something that you’ve seen in the trial that you think is different than some of the other drugs out there? And then just a question for Mike. Just off your last comment, you talked about sort of guidance. I wasn't aware, is there specific guidance that you guys have out for the respiratory products or are you just saying, in general the way that you have been talking? Thanks.

Mike Aguiar

So let me address your second question first. I’ll let Mathai take that. So we have never given specific dollar guidance but for probably the last year we have been very consistent with the guidance that these types of products have a fairly shallow initial launch and it’s for a variety of reasons, it takes time to build reimbursement. This is a primary care market, so there is a significant amount of physician education that happens. Clearly the timing of the launch had an impact on the reimbursement as we were late in the year. It does take a little bit of time to build reimbursement and talking to various payers late in the year, it’s a little tougher to get onto 2000 formulary -- sorry 2013 formulary when you’re talking to them in November as eyes are on 2014 at that point.

So I would say that there were a variety of reasons we have that guidance. We were very consistent with it throughout and are still maintaining that guidance today, but again there has not been a single piece of guidance out there that we’ve given, we’ve had numbers on it. With that, Mathai?

Mathai Mammen

Yeah thanks David, I’ll address the question on competitors in this space. So what we saw on this trial as primary and secondary was solid effect on pain. The patient felt, in general, half the patients felt that they very significantly improved on treatment and a really nice score in the FIQ where the overall impact on the patient disease was significantly impacted. Additionally, and I think that this is quite interesting, we saw an impact of albeit an exploratory measurement on a number of measurements we saw on impact on fatigue. And I think we trace this back to the particulars of the norepinephrine serotonin balance that I alluded to in the beginning of the call.

In addition the compound, as we reported before has a very nice long half-life 35sh hours. And I think that kind of [indiscernible] trial as well as the transport profile makes for a well-tolerated medicine. So through the Phase I program, through other studies that we’ve done, we’ve seen this -- we’ve been -- it's been quite remarkable that how well tolerated this TD-9855 is, very, very low rates of nausea. You’d look at the labels for Savella for instance and you can get an idea of that being quite a different picture than what we’ve seen so far for 9855. Savella dosed twice a day. We dose once a day because of our long half-life. So I think what we have is a broadly effective agent in 9855 with a potential to be useful as broad efficacy, broadly defined for fibromyalgia patients. That is in itself differentiating and we have a drug that so far has been really well tolerated. And so holistically, I think that this is an agent that potentially has value for fibro patient.

David Friedman - Morgan Stanley

And then just last question to be clear. Will you guys run Phase IIIs on your own or is this is a program that will only move forward with a partner?

Mathai Mammen

I think it’s little too early to determine that David. We’re again very early into the data here and in the process of further discussions. So I would just say stay tuned on that. As a general strategy we’ve historically looked to partner. It is an important component of our overall business strategy. So that is certainly after the business objective but with regard to 9855 that may or may not be the path we ultimately choose to follow. I think today we’re just quite excited that we hit on the end points we wanted to do and had a fairly clean tolerability profile.


Thank you. (Operator instructions). And I see no further question from the phones. I would like to turn the conference back to Mike Aguiar for any concluding comments.

Mike Aguiar

Thank you very much operator and thanks everyone for participating in our call today. Have a great day.


This does conclude today’s conference call. We thank you for your participation. You may now disconnect.

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