Cytokinetics Inc (CYTK) 2012 Q4 法說會逐字稿

Good afternoon, and welcome, ladies and gentlemen to the Cytokinetics fourth quarter 2012 conference call. At this time, I would like to inform you that this call is being recorded, and that all participants are in a listen-only mode. At the request of the company, we will open the call for questions and answers after the presentation. I will now turn the call over to Sharon Barbari, Cytokinetics Executive Vice President of Finance and CFO. Please go ahead.

Good afternoon, and thank you for joining the Cytokinetics senior management team on this conference call today. Also present during this call are Robert Blum, our President and Chief Executive Officer; Dr. Andrew Wolff, Senior Vice President of Clinical Research and Development and Chief Medical Officer; and Dr. Fady Malik, Senior Vice President of Research and Early Development. Following the forward-looking statement disclaimer, Robert will provide an overview of the past quarter highlighting advancements in our clinical development programs. Andy will then detail recent progress in our clinical development of tirasemtiv for the potential treatment of ALS. And Fady will update you regarding recent progress in our clinical development of omecamtiv mecarbil for the potential treatment of heart failure. I will then provide a financial overview and comments with respect to our cash position, details on our investments and research and development activities, and our 2013 financial guidance. Robert will then conclude the call with additional comments regarding recent activities and expected next steps in projected milestones for 2013 for our development programs. We'll then open the call for questions.

The following discussion including our responses to questions contain statements that constitute forward-looking statements for purposes of the Safe Harbor provisions of the Private Securities Litigation Act of 1995. Including but not limited to statements relating to our financial guidance, to the initiation, enrollment, design, conduct, and results of clinical trials and to other research and development activities. Our actual results might differ materially from those projected in these forward-looking statements. Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements in contained in our SEC filings including our most recent annual report on Form 10-K, our quarterly reports on Form 10-Q, and our current reports on Form 8-K. Copies of these documents may be obtained from the SEC or by visiting the Investor Relations section of our website. These forward-looking statements speak only as of today. You should not rely on them as representing our views in the future. We undertake no obligation to update these statements after this call. Now I'll turn the call over to Robert.

Thank you, Sharon. 2012 was an important year for Cytokinetics and the progress we made in both of our clinical development programs during the fourth quarter is very exciting. We focused our activities to key deliverables in 2012 from our cardiac and skeletal muscle programs that would lay the foundation for what we believe may prove to be a pivotal year for Cytokinetics in 2013. The initiation of our Phase IIb clinical trial evaluating tirasemtiv in ALS, now known as BENEFIT-ALS, was one of those key deliverables. BENEFIT-ALS, which stands for Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS, is enrolling patients in North America, and we expect very soon will be open to enroll independent Europe, as well. In January, we hosted the European investigators meeting for BENEFIT-ALS, and Andy will elaborate on that meeting and we'll also provide other details regarding BENEFIT-ALS in a moment. Until then, I will just say that the enthusiasm of the clinical investigators and other study personnel at both the North American and European meetings is encouraging. We are optimistic about our enrollment timelines for BENEFIT-ALS, which is expected to enroll 400 patients with ALS from over 70 sites throughout the US, Canada, and Europe.

In November, we announced positive data from our Phase IIa Evidence of Effect clinical trial known as CY4023. That trial evaluated tirasemtiv in patients with generalized myasthenia gravis. Andy will elaborate more on this trial in a moment. In brief however, we are encouraged by these data because they demonstrate pharmacodynamic activity of the novel mechanism of tirasemtiv in another distinct population of patients with neuromuscular disease. In addition to our recent progress with tirasemtiv, in the last quarter the clinical trials program for omecamtiv mecarbil also advanced to a key milestone. In November, we announced the opening of the third and final cohort of the ongoing Phase IIb clinical trial known as ATOMIC-AHF, which stands for Acute Treatment of Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure. Enrollment momentum underscores the continued interest in omecamtiv mecarbil in the approximately 140 international centers participating in this trial.

Alongside that progress, Cytokinetics and Amgen have been busily collaborating in preparations to launch another Phase IIb clinical trial designed to evaluate modified release oral formulations of omecamtiv mecarbil. This next trial is named COSMIC-HF, which stands for Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure, and enrolling patients in heart failure and left ventricular systolic dysfunction is the goal. This Phase IIb trial is expected to inform the selection of one of these oral formulations for advancement into the Phase III clinical program. We are pleased to share this progress with our shareholders and remain optimistic as we are nearing the completion of ATOMIC-AHF and preparing for the start of COSMIC-HF. Fady Malik will elaborate on the omecamtiv mecarbil clinical trials program later in this call.

And with that introduction, I will now turn the call over to Andy to elaborate on the progress that we recently achieved in our program for tirasemtiv. Later in the call, I will return to provide additional perspectives relating to our future plans.

Thank you, Robert. As Robert mentioned, last month Cytokinetics hosted a meeting for our European BENEFIT-ALS investigators. Robert has already mentioned the enthusiasm for the trial we experienced among the study personnel at that meeting. I continue to believe that the excitement we witnessed at both this recent meeting and the earlier North American investigators meeting last September will likely result in enrollment rates that should enable us to maintain our timeline and will hopefully allow us to close enrollment, analyze data, and present results from BENEFIT-ALS at the ALS/MND meeting in December 2013. To remind you, BENEFIT-ALS is a Phase IIb multinational, double-blind, randomized placebo-controlled clinical trial designed to evaluate safety, tolerability, and potential efficacy of our fast skeletal muscle troponin activator, tirasemtiv, in patients with ALS.

The trial is designed to enroll approximately 400 patients who will be randomized one-to-one to receive 12 weeks of double-blind treatment with tirasemtiv or placebo. All enrolled patients will complete one week of treatment with open label tirasemtiv at 125 milligrams twice daily prior to randomization, in order to ensure that randomized patients will tolerate that dose of tirasemtiv and also to minimize the potential for unblinding treatment to a general to mild adverse events that tend to occur early during tirasemtiv treatment and that usually resolve by the second week of continued treatment. Clinical assessments will take place monthly during the course of treatment. Patients will also participate in follow-up evaluation FO7 and 28 days after the final dose. The primary endpoint of BENEFIT-ALS is the change from base line in the ALS functional ratings scale in its revised form, or the ALSFRS-R. Secondary endpoints will include maximum voluntary ventilation, or MVV, and other measures of skeletal muscle function.

I am also pleased to report that in the last quarter, we announced positive data from our Phase IIa Evidence of Effect clinical trial of tirasemtiv in patients with generalized myasthenia gravis, or MG. This phase is known as CY 4023. This Phase IIa clinical trial was a double-blind, randomized, placebo-controlled, three-period crossover, pharmacokinetic and pharmacodynamic study of tirasemtiv in patients with generalized MG. Patients enrolled in CY 4023 received single or double doses of placebo, 250 milligrams and 500 milligrams of tirasemtiv in random order approximately one week apart. At six hours after dosing, decreases which reflect improvements in the quantitative MG score, or acute MG, were statistically significantly related to the dose of tirasemtiv declining by 0.49 QMG points per each 250 milligrams of study drug with a P value of 0.02. To remind you, acute MG is a validated index of disease severity that is often employed as a primary endpoint in clinical trials of patients with MG.

Also, at six hours after dosing in CY 4023, increases which reflect improvements in the percent predicted forced final capacity or statistically significantly related to the dose of tirasemtiv, increasing by 2.2 percentage points, for 250 milligrams of study drug with a P value of 0.04. Both the 250 milligram and 500 milligram single oral doses of tirasemtiv studied in this Phase IIa clinical trial were well tolerated by the 32 patients enrolled in CY 4023. There were no premature terminations and no serious adverse events were reported. The most commonly reported adverse event in CY 4023 was dizziness, which increased in frequency with dose and was reported as mild in all but one case that was classified as moderate. As always, additional information about our completed or ongoing Phase II trials can be found at www.clinicaltrials.gov. With that update on our tirasemtiv clinical development activities in the third quarter, I'll turn the call over to Fady for an update on our cardiac muscle contractility program.

Thank you, Andy. Much as Andy described the development progress in our skeletal muscle activator program, I also have good news to share regarding the development of omecamtiv mecarbil. Together with Amgen, we've made import progress this past quarter with the development of the intravenous form of omecamtiv mecarbil in Phase IIb as well as the oral forms moving into Phase IIb. We are pleased with the progression of ATOMIC-AHF, which moved into the third and final cohort in the past quarter. To remind you, ATOMIC-AHF is an ongoing, international, randomized, double-blind, placebo-controlled, Phase IIb clinical trial of an intravenous formulation of omecamtiv mecarbil in patients hospitalized with acutely decompensated heart failure. ATOMIC-AHF initiated enrollment of the final cohort in late November. With nearly 140 sites enrolling patients, the trial is progressing rapidly and has enrolled over 500 patients to date. Again, additional information on our Phase II trials can be found at www.clinicaltrials.gov.

In addition to the progress in ATOMIC-AHF, as Robert mentioned, Cytokinetics and Amgen have been working together to initiate COSMIC-HF, a Phase IIb, double-blind, randomized, placebo-controlled, multi-centered dose escalation study designed to evaluate modified release oral formulations of omecamtiv mecarbil in patients with heart failure and left ventricular systolic dysfunction. When this trial is open to enrollment and is posted on clinicaltrials.gov, we will elaborate on its design, but until then we can iterate that it is designed to inform the potential selection of one of these oral formulations for advancement into later phase clinical trials. The trial will be conducted in two stages. An initial stage which will compare the oral formulations in heart failure patients receiving daily doses of omecamtiv mecarbil for a shorter duration, and then a second stage in which an expanded cohort of heart failure patients will receive daily doses of one oral form of omecamtiv mecarbil for a longer duration. This international trial is expected to importantly inform our understanding of the longer term safety and tolerability of omecamtiv mecarbil administered orally to heart failure patients. In addition, we'll have the opportunity to evaluate the potential for sustained pharmocodynamic effects and the relationship to the pharmacokinetics of our drug candidate. With that update on our clinical development activities, I'll turn the call over to Sharon.

Thank you, Fady. Our press release contains detailed financial results for the fourth quarter 2012, so I'll refer you to that public statement for the details on our P&L and balance sheet. Over the past quarter, we've been focused on deploying the funds from our June 2012 financing to the manufacturing start-up and initiation activity associated with our BENEFIT-ALS trial. We ended the fourth quarter with approximately $74 million in cash and cash equivalents and investments which represent over 16 months of going forward net cash burn based on our 2013 financial guidance. Our fourth quarter 2012 R&D expenditures totaled $9.2 million. From a program perspective, for the fourth quarter, approximately 73% of our R&D expenses were attributable to our skeletal muscle contractility research and development activities, 12% to our cardiac muscle contractility activities, and 15% to our other research activities.

For the 12 months ended December 31, 2012, our R&D expenditures totaled $35 million. From a program perspective for the 12 months, approximately 70% of our R&D expenses were attributable to our skeletal muscle contractility activities, 13% to our cardiac muscle contractility activities, and 5% to our smooth muscle contractility program, and 12% to our other research activities. As a reminder, Cytokinetics was awarded $3.5 million in grants from the NIH or NINDS to fund research and development of tirasemtiv in MG. Through December 31, 2012, Cytokinetics incurred $4.5 million in research and development expense associated with our MG program, and has received $3.2 million, or 70% of the programs funding from NINDS.

Today we are announcing our financial guidance for 2013. We anticipate our 2013 revenue to be in the range of $1 million to $3 million. Our cash R&D expenses are expected to be in the range of $40 million to $44 million, and our G&A expenses are expected to be in the range of $12 million to $13 million. This financial guidance is on a cash basis and does not include an estimated $4.8 million in non-cash related operating expenses, primarily related to stock compensation expense. In addition, this guidance does not reflect potential revenue from any potential new collaboration.

This past quarter and year, we have delivered on key objectives in both of our first-in-class development programs. In 2013, our financial resources are planned to largely be focused on the progression of our skeletal muscle contractility research and development program and the BENEFIT-ALS trial in particular. We believe that this program, together with our cardiac muscle contractility program that is partnered with Amgen represents opportunities for the nearest term value generation for the Company as both are expected to generate results in 2013. That concludes the financial portion of today's call. With that, I'll turn the call back over to Robert.

Thank you, Sharon. So we are pleased to report on Cytokinetics' important progress in 2012. In the last year, Cytokinetics executed on those key deliverables that now position us to potentially achieve transformative outcomes in connection with our lead programs directed to activating each of cardiac and skeletal muscle. On one such example relates to a new addition to our clinical development pipeline. During the last quarter, Cytokinetics filed an investigational new drug, or IND application, for CK-2127107, which has recently cleared review by the US Food and Drug Administration, or FDA. CK-107, a selective fast skeletal muscle troponin activator is a drug candidate that was discovered during Cytokinetics' optimization of a different chemical series in that which produced tirasemtiv.

Now stepping back a bit, over the last several years we've embarked on a bold mission to define an entirely novel pharmacology rooted in the mechanics of muscle contractility and function. In total, Cytokinetics cardiac and skeletal muscle activators have now been the subject of 20 human clinical trials that have investigated safety and tolerability, pharmacokinetics and pharmacodynamics, drug-drug interactions, and both single and multiple dose regimens. These trials have yielded evidence supporting our hypothesis that activating cardiac muscle myosin can improve systolic function reflected by increases in ejection fraction and stroke volume in heart failure patients. Similarly, we've observed that activating skeletal muscle troponin results in increased muscle force and power and endurance that may preserve or prolong the independence and quality of life in patients with ALS. In 2013, we proudly assumed the leadership for what we hope can prove to be the next key advance in the care of ALS patients, especially in light of recent disappointments associated with other once promising development programs at other companies.

In everything we do, we hear the urgent call to action for better medicines for patients who suffer from this grievous illness. Last week, the FDA announced that it will hold a public hearing on February 25th to obtain input from stakeholders on matters relating to the needs and preferences of ALS patients and their caregivers. We are encouraged that FDA has solicited input on the scientific evaluation, marketing, authorization, and post-marketing surveillance of potential products to diagnosis or treat ALS. Cytokinetics will be attending that public hearing much in the same way as we last year responded to the European medicines agency invitation for public comment regarding potential revisions to their guidelines for the evaluation of new drugs for ALS. We believe that to date, our proposals to develop tirasemtiv for the potential treatment of ALS have been well received by both FDA and EMA, and we look forward to participating in constructive dialogue with the agencies regarding the development of potential new therapies for ALS.

To that point, I will remind you that in December, Cytokinetics hosted our second investor R&D day, at which we provided an update on recent Company activities and the future for our potential therapeutics in heart failure and ALS. Following the Company update, we moderated a panel that delved into the integrated care of ALS patients. The panel was comprised of medical professionals who described what it means to live and with to provide care for patients living with this devastating disease. The webcast of both the Company presentations and the panel discussions may be viewed on our website under Investor Relations. I encourage everyone on this call to view that broadcast with particular attention to the ALS panel discussion because it provides an important context for what we are doing at Cytokinetics, and also illustrates the challenges confronting patients and their caregivers, all of whom we aim to serve.

Now with 2012 behind us, let me turn to our expected milestones for 2013. For tirasemtiv, by mid-year 2013, Cytokinetics anticipates completion of enrollment in BENEFIT-ALS. By the end of the year, Cytokinetics expects to report data from BENEFIT-ALS. Also in our skeletal muscle program in the first half of 2013, Cytokinetics anticipates initiating a Phase I clinical trial evaluating CK-107 in healthy volunteers.

Turning now to omecamtiv mecarbil. In the first quarter of 2013, Cytokinetics anticipates the opening to enrollment of COSMIC-HF. In the first half of 2013 Cytokinetics anticipates the completion of enrollment in ATOMIC-AHF, and in mid-year 2013, Cytokinetics expects results from ATOMIC-AHF to be reported. So thank you for joining us today for the formal portion of our call. Operator, with that, I would now like to open the call up to questions, please.

(Operator Instructions)

Simos Simeonidis, Cowen & Company.

Thanks for taking the questions. First with omecamtiv mecarbil, I'm not sure if you're going to be able to talk about this because I think you may want to wait till more details can become available, but in terms of COSMIC, can you talk about how many different formulations you're going to be testing and how they're different from what you tested so far? Secondly, are you going to be able to tell us something about the length of treatment and whether this is going to be the same patient population you're going to be testing in the chronic part of the treatment in the potential Phase III trial with this drug?

So I'll start and answer the first part of that question. I may turn to Fady to help me with the second part to the extent that we can provide some general guidance about what Phase III might look like. With respect to your question on the design, we have not spoken publicly about the number of oral formulations that are going to be studied in COSMIC. What I can say is that it's several, and that we will reasonably soon, in this first quarter of 2013, be in a position to elaborate with much more specificity, meaning it's going to posted to clinicaltrials.gov and then we can elaborate on that design. But we are going to be selecting several oral formulations from a larger number that we profiled as you may remember last year in healthy volunteers.

So those subjects received healthy oral formulations, and from that we've selected a subset of those that we are gong to be studying together with Amgen in collaboration in COSMIC-HF. The duration of treatment will also be specified once we've got that information publicly disclosed and posted to clinicaltrials.gov. The next part of your question I think related to will these patients be of a profile similar to those that would be enrolled in Phase III and I'll turn to Fady to help us with that.

I think the patient population will be similar to what we enroll in Phase III. In Phase III, we might pick a somewhat higher risk patient population just in order to ensure we have a sufficient event rate. But in general, they are pretty similar patient populations. And just to remind you, ATOMIC-AHF and the acutely ill population sort of book-ends the spectrum of patients that we would tend to enroll in Phase III. So from the most acutely ill to these more stable heart failure patients.

And assuming in the Phase III and again I am speculating, I assume all of the patients in Phase III will be hospitalized in the beginning of the trial, and then when they go home, they'll take the oral formulation. Correct?

Not absolutely. I think while we haven't finalized details of the Phase III program, we anticipate certainly that there will be patients that will be enrolled on the drug as outpatients. Perhaps they would have been hospitalized in the last couple of months, or they had other features that would make them at higher risk, but they might not necessarily be in the hospital.

To that point, Simos, I think the way we've been thinking about this, and as Fady points out, a lot still has to be defined and together with Amgen, but our expectation is that the Phase III program will be enrolling patients who are at high risk of death or readmission, meaning they are in hospital, or have recently been discharged, such that they would be expected to be at higher risk for those key morbidity and mortality events. So that's still to be pinned down, but that's the way we and Amgen have been thinking about it to this point.

Okay. Then about the open label Phase I single dose trial with omecamtiv mecarbil you disclosed, can you tell us a little bit about the reasoning behind this trial? What you're hoping to see and when you're going to have this data?

Yes, the open label Phase I study was to compare the pharmacokinetic profile of a panel of oral formulations that were developed in order to modify the absorption of omecamtiv mecarbil. So really it's a fairly straightforward oral pharmacokinetic cross-over trial that was completed last year, and that gave us a way to prioritize which of the several oral formulations we would further study in heart failure patients.

So Simos, I just want to clarify. Are you referring to that Phase I study or the one that's contained within our press release today in renal patients?

I was referring to the trial in patients in renal insufficiency and patients undergoing haemodialysis, actually.

I'm sorry. So that particular trial is meant to inform us as to whether renal dysfunction changes the pharmacokinetics of the drug. As you know in heart failure, patients have variable renal function, and so it's important to understand the impact of renal function on omecamtiv mecarbil pharmacokinetics. We haven't really given any specific guidance in terms of how that trial would report out, but it would certainly inform going forward the development program.

Okay. And then a couple quick ones on tirasemtiv. Can you clarify what happens after the first week of dosing in BENEFIT-ALS? I know the first week is open label, and everyone -- all of the patients will get tirasemtiv. But what happens if somebody cannot really tolerate the drug? Do they drop out? I know that really hasn't happened in the trial so far but if somebody has a tolerability issue, would they drop out, or can you walk us through the mechanistically what happens, and then secondly, when you're into the second week, how does the dose escalation happen?

The dosing begins, as you mentioned, at 125 milligrams twice daily. Which was the way we started dosing in one of the earlier Phase IIa studies, which is also where patients continue if they're randomized to receive active tirasemtiv, rather than placebo. So there's a week of open label treatment with 125 twice daily. Patients don't tolerate that initial starting dose, then they do drop out of the study and they're not eligible to be randomized, so that ensures, or at least it helps to ensure that patients are actually randomized on the double-blind treatment to tolerate at least the starting dose, and we would expect that most will. The other benefit, as we mentioned during the call, is that there is a relatively high incidence of mild adverse events, commonly dizziness, that tend to occur early right after the initiation of treatment but that we've shown tends to go away even as treatment continues usually by the second week of treatment.

So patients who tolerate that initial week will then be randomized. If they go on to placebo, they go on to placebo for the remaining 12 weeks of the study. If they are randomized to receive tirasemtiv, they get another week of treatment at that same dose of 125 milligrams twice a day. And potentially, part of the benefit of the design is that if dizziness goes away then in the second week or so of double-blind treatment, it's not going to be clear to the investigator and the patient whether the reason the dizziness or whatever resolved is because they were withdrawn from active open label treatment on to placebo, or because those mild side effects generally do resolve with continued treatment. So it helps preserve the blind.

After the first week of double-blind treatment, patients randomized to receive active tirasemtiv are titrated up to 125 milligrams in the morning, and 250 in the evening, and then at the beginning of the third week, they go up to 250 milligrams in the morning, and 250 milligrams in the evening. There's a great deal of flexibility about that titration. That's the way titration is intended to go forward in patients who have no problems tolerating the drug, but titration could be done more slowly, there can be dosing interruptions, there can be down titration, and then attempts to go back up again.

The big difference between what happens during the open label phase and the double-blind phase is that during the open label phase, if the patient cannot really tolerate the treatment, they should be discontinued from the study. Once they are randomized, however, if the patient is having adverse events, we need to keep them on the highest dose that they can truly tolerate, and if that's not 250 milligrams twice a day, then whatever dose lower than that they can tolerate, we need to keep them on, because the study is designed as an intention to treat trial, so we want to keep each patient on some study drugs rather than lose them altogether.

Does that answer the questions, Simos?

Absolutely. That's very helpful. Thank you. Robert, final question for you. Can you comment on the status of partnerships for tirasemtiv? Namely, are you hoping, or do you intend to have a partnership before you read out BENEFIT-ALS, or do you think you may want to wait for the data before you sign on a partner?

So there's nothing about having the data from BENEFIT-ALS that would suggest that that will be required or is our intention alongside of trying to get a partnership deal done. What's more important is, can we get the deal done that we're striving to do, which relates to maintaining an active leadership role in the development and commercialization of tirasemtiv in North America as we've discussed publicly many times. That's very important to Cytokinetics. So getting a deal done is not predicated on having data from BENEFIT-ALS. I should make that very clear. Getting a deal done is not predicated on having data from BENEFIT-ALS, and it is still very much our priority to get a deal done and that's where I'm spending quite substantial amounts of my time.

Okay. Yes, that answers the question. Thank you for taking the questions.

Charles Duncan, Piper Jaffray.

Hi, guys, thanks for taking my question. It's related to this upcoming February meeting. It just seems curious that that was announced recently, after the failure of dex, and I'm just kind of wondering what you think the agenda items are for that meeting.

You know, we were also surprised by that announcement. It was not something that had been telegraphed, at least not such that we understood that to be scheduled, but now that we know about it, we are preparing for it, and I don't know that we can point to any precedence other than to say that we expect it will be a very packed agenda with lots of patients and their caregivers, and also sponsors making short statements, so I think other than that, we don't really have much insight. We know what you know in terms of what's been posted publicly.

Okay. And then maybe on the subject of endpoints in ALS, we've done a lot of diligence on this, but it seems like it may be a little bit of a moving target. Are there are any takeaways that you can -- that you make from the recent failure of Dexpramipexole and in terms of the design of your, not only BENEFIT-ALS, I don't expect you to change that, but perhaps the way that you look at that trial and then the path forward?

So it's a very good question, and so I'll start, and maybe Andy will also want to add. We don't know anything more than what has been stated publicly about the performance of Dexpramipexole in that empower study other than it did not seem to meet any of the pre-specified endpoints. We are expecting to hopefully within the next few months see results from that study, and as Biogen Idec has implied, there are learnings from that study that can inform the future drug development activities in ALS. We have been, not unlike Biogen Idec, I suspect, we have been the beneficiary of many clinical trials that have preceded us, many of which have been conducted by the Northeastern ALS Consortium, in terms of understanding how best to design a large international clinical trial.

And we are informed by the databases that have been generated in the course of those studies to understand what might be the event rate and how to design the inclusion and exclusion criteria, and also how to pick the best centers that might be in the best position not only to enroll a study like this rapidly, but also where the site personnel are well trained to conduct the assessments that have the right kind of test-retest reliability for the purposes of a clinical trial. We, as you know, have done a fairly extensive number of Phase II and Phase IIa studies to understand the pharmacodynamics of tirasemtiv and in ALS patients so that we've selected some of those assessments and we've rejected others based on where we think we might have the best opportunity to demonstrate a statistically relevant signal of activity. So we'll learn alongside of you and others from the Biogen Idec experience, but we think we have got as good a handle on what might be the tirasemtiv activity in ALS as can be knowable based on the studies we've done to this point.

I agree with all of that. I would just say I don't think the unfortunate results in the empower study here will impair our likelihood of success or failure. It's an entirely different mechanism. I don't think it bears at all on the applicability of the ALSFRS-R endpoint either, which has become quite the standard endpoint for use in studies in patients with ALS. So I think we were disappointed by the news, as was the entire ALS community, and it's difficult to say too much more than I already have, absent a fuller presentation of the data. There's not been that much that's been made public yet. But from what we do know, I don't see any reason to be concerned about the design of our trial, or our primary endpoint.

That's helpful, Andy. And my last question is related to a comment you made on the European investigator meeting that you conducted recently. You said there's a fair amount of enthusiasm. I'm wondering if you could provide us a little bit of -- a bit more color on that, and if it differed from the US investigators, and if you believe there is any variability in the enrollment of ALS patients in Europe versus the states that could confound the results in any way, or change the timelines of enrollment.

I wouldn't expect that there are significant variations and practice patterns between North America and Europe that would likely confound the results. That's not something that's been seen to date in international clinical trials of ALS. Drugs that have not succeeded have not succeeded fairly similarly across in the geographies in which they've been studied. What we do know from past studies is that centers of excellence, or at least that's what we would call them here in the United States, are even more centralized in European countries than they are here, so the centers tend to have much larger [cash man] areas and enroll very quickly once initiated. So the number of patients per center that we might anticipate from the European centers could be expected to be even greater than the very encouraging enrollment we've seen very early on now from our North American centers.

Maybe just to give an anecdote in terms of the enthusiasm, despite the fact that we have only really just begun enrolling in the last quarter of 2012, nevertheless, one serious concern of our European site personnel was that the study would be finished enrolling before they could even get started, and we reassured them that 400 patients, even with the enthusiasm that we're seeing in the North American centers, they're going to have a chance to enroll. What I will say, and this is a repetition of what we said during the call, is I am extremely confident in our timelines, given what we've heard. What we've seen so far to date and what we're hearing from the sites that are soon to be initiated.

To add a little color commentary to that, even as we don't have all of the North American centers up and running yet, and the Europeans will follow, we are impressed by, for those centers that are enrolling patients, how many they were ready to screen at the time they got their IRB approvals and their budgets and everything was put in place. So I think this study is well-positioned given the absence of other competing clinical trials, but also given, I think, the enthusiasm for this mechanism and the motivation amongst patients and investigators, I think this study is well-positioned to enroll rapidly.

Thanks Robert and Andy for the added information.

Thanks, Charles.

Ritu Baral, Cannaccord.

Thanks guys for taking the question. As you guys went through the BENEFIT-ALS design, there was no mention of riluzole. Is that correct, you're not allowing background riluzole in this trial?

No, patients that are taking riluzole, when they come into this study, stay on riluzole and patients that are not taking riluzole should not be given riluzole for the duration of the study. If it should so happen that a patient is relatively newly diagnosed and hasn't had the opportunity to get on riluzole, they should take it, they should begin that first and be stabilized on riluzole before coming into trial. But there is no requirement for patients to be on riluzole, nor is there an exclusion. We would expect the majority of the patients will be taking it, but there will be some few that will not be on it.

And Ritu, as you know, one of the things we did before committing to this trial was a drug-drug interaction study, tirasemtiv with riluzole, so we understand the PK effects of co-administering them so I think we have got a good handle on that going into this trial.

Got it. Will you allow any dose adjustments of the riluzole?

Well, there is a protocol dose adjustment. So as you may recall, the drug-drug interaction that Robert mentioned results in about a doubling of riluzole levels when it's ministered in the presence of tirasemtiv. So when patients are randomized to tirasemtiv, their riluzole dose is cut in half in a double-blind fashion. They only receive the normal label dosage 50 milligrams twice daily. Patients on placebo continue to receive that and patients with randomized with tirasemtiv receive 50 milligrams once daily in a manner that preserves the blinded study.

Got it. That's helpful. And then, you know, that being said, the background of riluzole, what would you expect to see after three months of treatment in the ALSFRS-R? If I remember correctly, most patients see a decline of I think one point on scale per month. What sort of magnitude of effect in a perfect world and a perfect trial, which, of course, never happens, what magnitude effect might you see?

Well, you're correct, on average in recent trials, the placebo group tends to decline actually so far, unfortunately, all patients tend to decline at about 0.9, to be more precise, points on a scale per month. So at the end of three months, you would expect untreated patients to decline by 2.7 points. Since you asked the question the way you did, I'll take advantage of it. You said it's not a perfect world. In a perfect world, a patient treated with tirasemtiv will not have declined at all, and on average their ALSFRS-Rs will be higher than they were at baseline. So we're not assuming that. That's not our conservative assumption. I wouldn't put it completely outside of the realm of possibility that that would truly be the home run scenario. What we have powered this study to be able to detect is a difference of 1.18 points from placebo. So if the placebo folks have declined by an average of 2.7 points, and patients treated with tirasemtiv have gone down by 1.52 points or less, than we have 80% power or more to detect that difference with an alpha 0.05 or P value of 0.05.

Got it. That's very helpful. And what percentage of patients would you expect to come from Europe, despite the fact that I believe you said there's no real treatment difference or natural history progression difference between US and Europeans.

I think it's premature to speculate on that. What I can tell you is there is no quota. We've not set aside X numbers for different numbers. We know the importance of enrolling the study as quickly as we can, and we will enroll it from whichever of our sites can enroll as quickly as they can.

What we can say, Ritu, is that a significant majority of the centers that we're targeting are North American centers, and they will likely be coming online sooner, but the European centers will certainly be coming online and can contribute meaningfully. So if you think about the fact that we said we've got over 70 centers that will be enrolling here and as they come online, we'll be posting them to clinicaltrials.gov. You can imagine doing the math that we're going to end up seeing probably at least half the patients if not more coming from North American centers.

Great. And last question for Sharon. Your revenue guidance goes down meaningfully in the coming year. What is essentially driving that, given that I think to the Amgen relationship hasn't changed?

So every year we go through a process with our collaborators so one global [blood] ended at the end of 2012, so that collaboration is not continuing into 2013, and then every year we look at the research plan with Amgen and determine what resources we can provide to that research program. So the revenue projections are including revenue from myacardia so that relationship continues through August of this year at least based on the current collaboration agreement, and then our proposed revenue with Amgen.

So just to be clear, that's --

The grant piece, sorry, the MG grant, as well, the 4023 trial has now come to an end. We only have closeout activities that remain in 2013.

And as it relates to our Amgen derived sponsored research revenue, that's, as Sharon pointed out, somewhat fluid, as we each year negotiate for a research program, just to be clear, that's not related so much to joint development activities. That's all paid for by Amgen, but rather this is a research program.

Got it. Thanks so much for taking the question, guys.

Mike King, JMP Securities.

Good afternoon, guys. Thanks for taking the question. Just wanted to ask about COSMIC. Just wondering why -- two questions on COSMIC. Number one, why you don't think there will be a readout, or at least you're not guiding to a readout in 2013, and just to be clear on COSMIC, is there no clinical endpoint per se, or is this purely a PKPD study to ascertain the correct dosage formulation?

So it's principally a study, and this will become more clear once we can elaborate on its design. It's principally a study to inform the selection of an oral form, and whether that can occur in 2013 is going to certainly be a function of the enrollment rate, and hence we're not giving any guidance to when we might see data from either the first stage or the second stage until such time as we see enrollment and we discuss that with Amgen. So that's the answer to your question. It's not for not knowing that that would be relevant, but rather instead because until the study is initiated, it's premature to speculate on that, much like was for ATOMIC at that time.

But there will be opportunities to conduct assessments beyond safety and tolerability in PK, and again we'll elaborate more on that, but it won't be a study designed for a principal efficacy analysis as you might be thinking with clinical outcomes, in large part in order to do that in a population of stable heart failure patients you're talking about what ultimately might be thousands of patients, and hence we would reserve that for a Phase III program. Before then, in Phase IIb, we just want to make sure that we've got both as an intravenous form and as an oral form product that is well tolerated and that can be pharmacodynamically and pharmacokinetically predictable in a population of heart failure patients.

Okay. I understand. That's helpful. Just maybe a quick follow-up on that. Can you say -- I know you're loathe to give, you know, any information about number of doses and such, but I'm just wondering is there anything you can say about the PKPD that you would prefer? You just said -- you used the word predictable, Robert. I'm just wondering, is there sort of a dosing or a blood level profile that you guys are titrating to? Or some other type of?

Yes, we'll be titrating up with the goal of wanting to measure pharmacokinetics and exposure levels that would be consistent with what we've seen with this compound before, and making certainly that that's not any more variable or unpredictable in a heart failure population, a population with stable heart failure, and wanting to make sure we see trends, not necessarily P values, but trends that support pharmacodynamically the activities that we'll be wanting to see in Phase III and hopefully those translating into clinical benefit.

Right, but I'm saying is -- you know, do you try to look at minimal variability, or staying above a certain seam in, or anything else that you can say or would you rather keep that under wraps for now?

Yes, Mike, this is Fady. I think the key question, as we've continued to develop this drug, is to be able to dose the drug in a broad patient population in a range of concentrations that we've established are pharmacodynamically reactive and don't result in outliers that have excessive pharmacokinetic concentrations, drug concentration. So in a lot of ways, the study is designed to give us confidence that we can -- that the doses that we select will result in that is range of exposures and are safe and well tolerated.

Okay. I think I get it. Thanks. I'll get back in queue.

Jason Butler, JMP Securities.

Just a couple of quick follow ups to my questions. The first one on the BENEFIT-ALS trial, you talked about expecting or hoping to get data in at the ALS/MND meeting in December. Would you expect to press release the data much before that, or the topline data much before that conference, or is the first disclosure we should expect actually right around the date of that conference?

It's a little early right now to speculate, but I will try to answer your question as best I can. It has been our precedent to topline results by press release before they would be presented in a medical congress. So that's certainly what we would want to do in this case, if we can, keeping in mind that the last patient, last visit would be 12 weeks into the last patients having been enrolled, and then the last assessment 28 days after that. It could very well be that we're not in a position to lock the database until fourth quarter, and then once data is analyzed, we may not have a whole lot of time between then and that meeting, which this year is occurring in early December. But we will try.

Okay. Great. And then just a housekeeping question. Can you -- for Sharon. Could you talk about the use of your ATM facility in 4Q and so far in the first quarter of 2013?

I can talk. We haven't changed our balance with respect to the use of the ATM. We have not touched that in the fourth quarter or in the first quarter.

Okay. Great. Thanks for taking the questions.

George Zavoico, MLV.

Thanks for taking my questions. A couple of quick ones. You mentioned 400 patients in the ALS trial, one week run in potential drop out. The question relates to how many you might need to enroll to get to that 400. The first week, it wasn't that bad of a dizziness. I really don't expect too much of a -- I wouldn't expect too much of a dropout rate.

We're not expecting a high drop out rate from that open label stage either, so I wouldn't imagine the need to enroll too many more than the 400 in order to get to a complete 400.

Yes, that's what I figured, too. That's good. Good. And now the ALS community has a rather powerful social media network, and not to speak -- which added to the physician excitement with patients already getting ready to enroll, you know, typically how often does an ALS patient see their physician, and do you see social media within the ALS patients having them call physicians earlier than they might have ordinarily have gone to see them, or physicians actually calling their patients to come in and say look, we've got the trial starting, we've got to enroll you guys, or both.

So I'll try to take a stab at that. Firstly, the typical ALS patient is atypical meaning even that patient is not going to see his or her caregiver with the same regularity throughout the course of their disease. In the early times following diagnosis, those patients tend to be seen more often, and later the disease, less often. Depending on their location, if it's in close proximity to their center of excellence, or their treatment center, they may see them more often. Others less often, although there are some who persevere and drive long distances every four to six weeks. So we've seen that that's not so consistently predictable, but in the course of a clinical trial, ALS patients have demonstrated, as we have learned, to do some pretty remarkable things.

Some of them will travel very long distances in order to participate in a clinical trial, such as ours. So we're anticipating that that will be potentially the case here across many centers. Regarding your question around social media and the blogosphere, you're absolutely right. ALS patients are well known to be very active, communicating with one another, and in chatrooms, we are seeing an increased buzz relating to this clinical trial. We monitor that, and we see that already patients are speaking about their interest in this trial, or, in some cases, their experience in this trial already. So there have been recent reports in the media about ALS patients who have driven very rapid enrollment in certain clinical trials as a function of things that are shared in the blogosphere, and that is something that we are aware of. Whether that will happen in this clinical trial, it's to be determined.

Well, I guess it's a good sign. Past experience does sometimes predict future results. So hopefully that will help a lot in getting your trial enrolled rapidly. Thanks. One question about omecamtiv, then. Ultimately the strategy is to go from obviously IV in the hospital to oral at home, but there's also a portion or could also be used, obviously, without the initial IV in the acute phase, but starting with relatively stable congestive heart failure patients. Is that transition from IV to oral and an oral alone from a clinical trial planning perspective, is that going to be two separate trials, or how do you see that going forward to be able to marry the two formulations?

So it's -- it's not yet defined and clear. It's something that we'll be seeking inputs on this year, and I say we, meaning we together with Amgen, in order to best understand whether this should be one large Phase III study, or multiple Phase III studies, and I think you're asking the right questions. We'll want to get our arms around that, too.

Okay. That's great. Okay. That's it. Thank you very much.

Chad Messer, Needham & Company.

Hi. Thanks for taking my question. We've covered a lot of ground today, but I did want to ask one on your latest clinical stage asset, 107. You guys have went into three different indications with tirasemtiv, and I'm just wondering if there's anything you can share about your thoughts about where you might start exploring this compound once you get out of -- I know the first trial was in healthy volunteers, but once you're through that phase.

Yes, so, firstly, I'll say thanks for recognizing that achievement, and Fady leads an organization where CK-107 was brought forward from research, different chemical series, into nonclinical development, and he and Andy and their teams collaborated on following that idea at the end of last year, and I'm really pleased that we now have a green light to proceed into Phase I. The strategy with CK-107 is one that will be informed both by what we learn about 107 itself in Phase I, and also what we learn about tirasemtiv in Phase IIb. So we can imagine going in a couple of different directions with CK-107 based on what we'll know later this year. I'll ask Fady to comment on what we already know about CK-107. Some of these data you might remember we presented at our R&D day in December and how it is distinguished from tirasemtiv.

So CK-107 was really designed to address the ability to use it in a broader patient population than we might envision using tirasemtiv, and so along those lines at our R&D day, we showed its efficacy in improving running performance in a heart failure model that was produced by myocardial infarction in rodents. And so it bears all of the pharmacologic properties who characterize with tirasemtiv but it's other aspects of its profile potentially make it amenable to broader patient populations. There's no drug-drug interactions with this particular molecule, at least as far as we've characterized in vitro. It gets into the brain to a much lesser extent, and other data as well suggests we wouldn't see some of the light headedness that we see with tirasemtiv and so forth. So things are -- obviously that's what Phase I and beyond are meant to confirm, but that's where we're thinking of taking this different molecule.

I think from a strategy standpoint, the Company is very committed to pursuing this mechanism of action initially in ALS and some of these orphan rare diseases, so if tirasemtiv looks to be effective and well tolerated in that population, we'll pursue that strategy with tirasemtiv and CK-107 might be therefore more appropriately developed in other indications. However if we see something in tirasemtiv that suggests that the light headedness or some other aspect of its profile should be improved upon, and hence CK-107 may be able to, as engineered, be a better horse to ride in that setting, then we will do that, and we'll know that through the course of this year.

All right. Very good. So it's potentially both potentially a backup but also a way into other indications.

That's right. We're very enthusiastic about some of the data we generated in the last year, and I say we, I mean under Fady's leadership, he and his team. But especially as pertains to heart failure and the ability as we demonstrated preclinically to see increased endurance times there, and other ways that we might address fatiguability and a loss of muscle force and power, and even loss of muscle mass perhaps, in some other indications, it suggests that this mechanism of action can be exploited more broadly, then we'll do that in time, either with tirasemtiv, or CK-107, or perhaps another compound, but we'll know a lot more later this year.

All right, great. Thanks for that update.

At this time, there are no further questions, I would now like to turn the call back over to Robert Blum, President and CEO, for any closing comments.

So thank you, operator, and thank you to all of the participants on our teleconference today. Thank you for your continued interest in Cytokinetics. We will look forward to updating you on our continued progress in this very promising year, 2013. With that, operator, we can now conclude the call. Thanks so much.

Ladies and gentlemen, this concludes today's Cytokinetics conference call. We thank you for your participation. You may now disconnect.