Cytokinetics Inc (CYTK) 2014 Q1 法說會逐字稿

Good afternoon and welcome, ladies and gentlemen, to Cytokinetics' first quarter 2014 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 us on this conference call today. Leading today's call is Robert Blum, our President and Chief Executive Officer. Robert will be making opening remarks regarding recent corporate highlights. Following Robert's initial comments, Andy Wolff, our Senior Vice President of Clinical Research and Development and Chief Medical Officer, will provide comments relating to the clinical development of Tirasemtiv, which will include a summary of recently reported results from BENEFIT-ALS, our completed Phase IIb trial, which evaluated Tirasemtiv for the potential treatment of ALS. Afterwards, Robert will provide additional comments and perspectives on our Company's plans in light of the results of BENEFIT-ALS.

Following those remarks, Fady, our Senior Vice President of Research and Early Development, will provide you with an update on the clinical development of omecamtiv mecarbil for the potential treatment of heart failure. In addition, he will also provide an update on progress with Phase I clinical trial of CK2127107 or CK-107 in healthy volunteers.

I will then provide a financial overview for the quarter. Robert will then conclude the call with comments regarding how Company activities align with our corporate strategy and projected milestones for 2014. We will then open the call for questions.

Please note that the following discussion, including our responses to questions, contains statements that constitute forward-looking statements for purposes of the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995, including but not limited to statements relating to our financial guidance and collaborations with Amgen and Astellas, 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 is 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.

I will now turn the call over to Robert.

Thank you, Sharon and thank you to everyone on the line for joining us for this call today.

The first quarter of 2014 was an important one for Cytokinetics, but that does not diminish our disappointment that, as we recently reported, BENEFIT-ALS did not meet its primary endpoint. Andy will elaborate on the results from BENEFIT-ALS that were reported on April 29 at the annual meeting of the American Academy of Neurology or AAN, and again, during our investor webcast on April 30.

On behalf of all of my colleagues at Cytokinetics, I would like to express our gratitude to the BENEFIT-ALS investigators and their evaluators and coordinators, as well as to the patients who participated and their families and caregivers, all of whom dedicated so meaningfully to the conduct of this important clinical trial. While BENEFIT-ALS did not meet its primary efficacy endpoint, that result appears to be confounded by tolerability issues related to Tirasemtiv in this trial. Extensive analyses of the data from BENEFIT-ALS are underway in order for us to understand the relationships between tolerability and the results of Tirasemtiv on the ALS functional rating scale in the trial.

Results from BENEFIT-ALS on certain pre-specified secondary endpoints show effects of Tirasemtiv that we believe to be potentially clinically meaningful and that we believe are unprecedented in a clinical trial of patients with ALS. These effects are not on subgroups of patients in BENEFIT-ALS, nor are they as determined post hoc, but rather as prospectively defined and deemed important in the design of the trial and in accordance with its pre-specified statistical analysis plan. We believe that we owe it to patients living with ALS who are in such dire need of a therapy that can impact the loss of motor -- muscle function, to understand as thoroughly as possible the results we have from BENEFIT-ALS. We understand the challenges in front of us. Cytokinetics may be wrestling with these issues for weeks to months, while at the same time we intend to continue to execute on key objectives across our other research and development programs.

In the first quarter, while our organization was engrossed in completing BENEFIT-ALS, we demonstrated progress with respect to each of omecamtiv mecarbil, our cardiac muscle activator, which is partnered with Amgen, and CK-107, our follow-on fast skeletal muscle activator, which is patterned with Astellas.

In the quarter, we announced that the expansion phase of COSMIC-HF open to enrollment, and Fady will elaborate more on progress in that trial later in this call. In parallel, we progressed our ongoing Phase I studies of CK-107 with the initiation of CY5012. On multiple ascending dose Phase I trials of CK-107 in healthy volunteers, we earned a $2 million milestone payment from Astellas.

Cytokinetics is purposely developing a pipeline of novel mechanism drug candidates with strategic partners to enable the Company to manage risk inherent in the pursuit of innovation. Our conviction remains strong and we believe our Company remains on solid footing.

As you will hear now in more detail from my colleagues, we have constructed a portfolio of development stage programs that enable multiple paths to potential successes. Let's begin with a summary of what we know and still must learn from BENEFIT-ALS and Tirasemtiv.

I'll now turn the call over to Andy.

Thank you, Robert. In the first quarter, we concluded dosing and follow-up of patients in BENEFIT-ALS. More recently, we completed the data collection, database lock, and analyses to inform the presentation by Jeremy Shefner, the trial's lead investigator at AAN.

As you know, BENEFIT-ALS was a Phase IIb multinational, double blind, randomized, placebo controlled clinical trial designed to evaluate the safety, tolerability, and potential efficacy of Tirasemtiv in patients with ALS. BENEFIT-ALS enrolled 711 patients from 73 centers and eight countries. 605 patients were randomized to double-blind treatment (inaudible) 302 were randomized to placebo and 303 to Tirasemtiv.

We had previously reported that a programming error committed by our data management vendor caused 58 patients, initially randomized to and treated with Tirasemtiv, to be subsequently dispensed and treated with placebo. To preserve the scientific integrity of the trial, a protocol amendment excluded from the primary efficacy analysis all 156 patients who are randomized in blocks that included any of the 58 effected patients.

The primary efficacy analysis of BENEFIT-ALS compared the change in the ALS functional ratings scale in its revised form, or the ALSFRS-R from baseline to the average score after eight and 12 weeks of double-blind treatment on Tirasemtiv versus placebo. BENEFIT-ALS did not achieve its primary endpoint. The ALSFRS-R declined to 2.98 on Tirasemtiv versus 2.40 points on placebo, a key value of 0.11. Consequently, BENEFIT-ALS joins a long list of clinical trials that have failed to demonstrate an effect on the ALSFRS-R.

While Tirasemtiv did not affect the ALSFRS-R in BENEFIT-ALS, several clinically important measures of respiratory performance and other measures of cell to muscle function and fatigability were protocol specified secondary endpoint. While the effect of Tirasemtiv on these secondary endpoints was inconsistent, statistically significant and potentially clinically important increases versus placebo in slow vital capacity and muscle strength were observed on Tirasemtiv. Slow vital capacity, or SVC, is the most routinely performed measure of pulmonary function in patients with ALS. It measures the maximum volume of air, which can be exhaled in a slow and steady manner. SVC is generally viewed as a clinically useful measure of disease progression and its rate of decline has an important predictor of survival.

In BENEFIT-ALS, SVC declined more than twice as quickly in patients on placebo as on Tirasemtiv. Specifically, 2.7 percentage points per 30 days on placebo versus 1.2 on Tirasemtiv. While we believe this reduction in the rate of decline in SVC on Tirasemtiv versus placebo may be clinically meaningful, it is definitely statistically significant, with a P value of 0.0006. In addition, the rate of decline in muscle strength as reflected by the percent change from baseline and the Mega Score of muscle strength was also statistically significantly lower on Tirasemtiv versus placebo. The Mega Score is a composite measure of strength of five muscle groups on each side. To our knowledge, no prior clinical trial in patients with ALS has demonstrated statistically significant and potentially clinically meaningful effects on measures of respiratory performance and skeletal muscle function.

These findings are encouraging, but do not explain why treatment with Tirasemtiv and BENEFIT-ALS did not demonstrate an effect on other measures of pulmonary function and the ALSFRS-R. However, we have begun to understand what may be confounding the results of BENEFIT-ALS in connection with the effect of Tirasemtiv on ALSFRS-R.

We observed issues with the tolerability of the Tirasemtiv dosing regimen employed in BENEFIT-ALS. For example, 99 patients terminated treatment prematurely after randomization to Tirasemtiv versus 33 on placebo. The majority of adverse events observed on Tirasemtiv were mild. However, patients with gastrointestinal adverse events lost significantly more weight than those who did not report them and such adverse events were reported more often on Tirasemtiv than on placebo. Specifically, 44% of patients on Tirasemtiv versus 26% on placebo.

As a result, patients on Tirasemtiv lost 0.9 kilograms more weight over 12 weeks of double-blind treatments than patients on placebo. While weight loss is a concern in patients with ALS, it may also be the key to understanding a lack of an effect from Tirasemtiv on the ALSFRS-R in BENEFIT-ALS.

Patients who lost than the medium weight loss on Tirasemtiv during the trial did moderately better on Tirasemtiv and placebo, reflecting a statistically significant interaction between the amount of weight lost and the effect of Tirasemtiv on the ALSFRS-R. This could mean that Tirasemtiv may benefit those ALS patients who can tolerate it.

As a result, we are working to understand better the relationships between the tolerability and the potential efficacy of Tirasemtiv and we'll need to consider the findings from these additional analyses in the context of our broader skeletal muscle development program.

Additional presentation of BENEFIT-ALS data, are planned to occur during the annual meeting of the European network for the Cure of ALS, or ENCALS in Leuven, Belgium May 22 to May 24, and the European Federation of Neurological Societies, European Neurological Society, Joint Congress of European Neurology 2014 in Istanbul, Turkey from May 31 to June 3. Having shared these results from BENEFIT-ALS and our perspective on them, I will now turn the call back to Robert.

Thank you, Andy. These findings are still coming together and do not change the primary efficacy analysis of BENEFIT-ALS. However, in light of the fact that BENEFIT-ALS was a Phase IIb trial and did demonstrate statistically significant effects on certain important pre-specified secondary measures, it is entirely legitimate and frankly imperative to explore these questions of the data and consider their implications on the further potential development of Tirasemtiv.

Considering the Tirasemtiv is a new chemical entity with a novel mechanism of action, and ALS is a disease for which no drug is available to improve function for desperate patients who suffer progressive loss of muscle function, it is incumbent on us to delve deeply into the data, underlying the results of BENEFIT-ALS. This landmark trial will be the subject of extensive data analyses and reporting for some time.

It was the largest Phase II trial ever conducted in patients with ALS, and to our knowledge, the only clinical trial to show an impact on measures of vital capacity and muscle strength.

BENEFIT-ALS evaluated pre-specified measures of muscle function that we believe reflect the well-characterized mechanism of action of Tirasemtiv. A trial such as BENEFIT-ALS can be very informative to the ALS community. We believe that fast skeletal troponin activation by Tirasemtiv may have conferred clinical benefit to certain patients, and we look forward to diligently working through these matters.

The last patient, last visit in BENEFIT-ALS, occurred only a little more than a month ago and we moved swiftly to collect the data from this large international trial, lock the database, and analyze and report the topline findings as promptly as we could. Our team at Cytokinetics, and all of the study site personnel, and our CROs did an extraordinary job making sure that happened less than two weeks after database lock. Reporting results as soon as they were available was the proper thing to do for patients with ALS who urgently require new treatment options.

The complete results from BENEFIT-ALS will not be more fully appreciated for what may be months to follow. What we know now is that we have a biologically active compound and we need to understand whether it may be possible to dose Tirasemtiv to better tolerability to optimize its treatment potential in patients with this devastating disease.

Please know that we will do the right thing and investigate the results of BENEFIT-ALS thoroughly before we determine our next steps in connection with Tirasemtiv.

I'd now like to ask Fady Malik to provide an update on activities in connection with our other clinical development programs and I'll return later in the call to speak to all of our corporate priorities.

Thank you, Robert. Firstly, turning to the development of omecamtiv mecarbil, in the first quarter, Cytokinetics announced that the expansion phase of COSMIC-HF opened to enrollment. So to remind you, omecamtiv mecarbil is a first-in-class cardiac myosin activator that we're developing for the potential treatment of heart failure in collaboration with Amgen.

COSMIC-HF is the Phase II, double blind, randomized, placebo-controlled, multicenter clinical trial designed to assess the pharmacokinetics and tolerability of omecamtiv mecarbil in patients with left heart failure and left ventricular systolic dysfunction.

The secondary objectives are to assess the changes from baseline in systolic ejection time, stroke volume, left ventricular end systolic diameter, left ventricular end diastolic diameter, heart rate, and N-terminal pro-brain natriuretic peptide, which is a biomarker associated with the severity of heart failure, all during the 20 weeks of treatment with omecamtiv mecarbil.

The expansion phase of COSMIC-HF is expected to enroll heart failure patients from approximately 100 clinical sites internationally and this trial is being conducted by Amgen in collaboration with Cytokinetics. Also during the first quarter, Cytokinetics began preparations for the initiation of CY 1211, following the review of the protocol for the trial with the FDA.

CY 1211 is the Phase I single center placebo-controlled double-blind study, comparing the pharmacokinetics of omecamtiv mecarbil between healthy Japanese and Caucasian volunteers. CY 1211 will be conducted by Cytokinetics in collaboration with Amgen.

I'll now provide an update relating to CK-107, our next generation skeletal muscle troponin activator that is partnered with Astellas. During the quarter, we completed CY 5014, a Phase I study of CK-107 in healthy male volunteers. CY-5014 was a randomized open label two period crossover study designed to assess the relative bioavailability, pharmacokinetics, safety and tolerability of two forms of CK-107, when administered orally in a liquid suspension.

Also in the quarter, Cytokinetics initiated enrollment in CY-5012, a double blind, randomized, placebo-controlled, parallel group study in which the primary objective is to assess the safety, tolerability, and pharmacokinetics of CK-107 following multiple ascending doses in healthy volunteers.

With that update on our cardiac and skeletal sarcomere activators, I'll turn the call over to Sharon to update our financials.

Thank you, Fady. As our press release contains detailed financial results for the first quarter of 2014, I will refer you to that public statement for the details of our P&L and balance sheet.

In the past quarter, as you heard on today's call, we have largely been focused on the completion of BENEFIT-ALS.

We ended the first quarter with approximately $101 million in cash, cash equivalents, and investments, which represents approximately 20 to 22 months of going-forward net cash burn based on our current 2014 financial guidance.

Revenues for the first quarter of 2014 were $8 million. This revenue included the recognition of $2.1 million of license revenues and $5.2 million of research and development revenues from our collaboration with Astellas, along with $0.7 million of research and development revenues from our collaboration with Amgen.

Our first-quarter 2014 R&D expenditures totaled $12.5 million. From a program perspective for the first quarter, over 80% of our R&D expenses were attributable to our skeletal muscle contractility program activities. This includes both the development of Tirasemtiv, which we are performing independently, and research and development activities that we are performing under a collaboration with Astellas, which includes the development of CK-107. Astellas reimburses us our agreed costs under our agreed research and development plan. In addition, approximately 10% of our R&D expenditures were attributable to our cardiac muscle contractility activities. Amgen reimburses us for certain agreed research costs performed in connection with our agreed research plan directed to next generation sarcomere activators. The remainder of our research costs are attributable to our other research activities.

For the 12 months ended December 31, 2014, our R&D expenditures totaled $49.5 million. From a program perspective for those 12 months, approximately 82% of our total R&D expenses were attributable to our skeletal muscle contractility activities, 7% to our cardiac muscle contractility program, and 11% to our other research activity.

At this time, we are reiterating our cash based financial guidance for 2014 of cash revenue in the range of approximately $19 million to $21 million, cash R&D expenses in the range of $50 million to $53 million and cash G&A expenses in the range of $15 million to $17 million. This financial guidance is on a cash basis and does not include approximately $10 million in revenue deferred from 2013 into 2014 under generally accepted accounting principles, and an estimated $3 million in non-cash related operating expenses, primarily related to stock compensation expense.

In addition, this guidance does not reflect potential revenues from milestone payments that we were or may be achieved in partner programs. Once we more fully understand the implications of the BENEFIT-ALS data on the potential future development of Tirasemtiv, we will provide updated financial guidance.

We believe that we have sufficient financial resources to enable our focus to be on the further analysis of data from BENEFIT-ALS, as well as to advance our other research and development programs.

This concludes the financial portion of today's call. With that, I'll now turn the call back to Robert.

Thank you, Sharon. Cytokinetics is committed to pursuing a portfolio approach to our research and development. With the continued advancement of the development program for omecamtiv mecarbil, we are optimistic about the potential of this novel mechanism compound to address unmet needs in the treatment of heart failure.

We believe that omecamtiv mecarbil in both intravenous and oral forms may demonstrate a clinical profile that can represent significant innovation for both acutely ill and chronic care patients. We look forward to updating you on the progress of this promising program.

As you also heard today, we continue to make progress in the development of CK-107. We have completed two Phase I trials and recently initiated a third. We are executing well on Phase II readiness activities in accordance with agreed plans and under the joint oversight of Cytokinetics and Astellas.

Together we are setting the stage for the investigation of CK-107 in non-neuromuscular disease indications. We believe CK-107 offers promise to address high unmet needs in an array of syndromes and conditions associated with muscle fatigue and weakness. We look forward to sharing future updates throughout the year.

Not only do our partnered programs represent meaningful upside in therapeutic categories with high commercial potential, but they also provide risk diversification, balance, and funding. We believe Cytokinetics is well positioned operationally, financially and programmatically to return value.

We have a job to do with respect to Tirasemtiv and BENEFIT-ALS. We must understand the results especially if they may inform a next potential trial. Candidly, the results we know now represent both a stepping-stone and a potential hurdle to what lies ahead. We are encouraged by certain results and confounded by others. That is not at all an expected for a Phase II trial in a disease for which no precedent exists for what we're trying to do.

We will need to consult with experts in the field and engage directly with regulatory authorities to understand what a registration program for Tirasemtiv in ALS could look like. We already know we have the support of ALS investigators, patients with ALS, and ALS advocacy groups to proceed. How that may occur is still to be determined.

We have received feedback from them that underscores their belief that the effects on pulmonary function and muscle strength observed in BENEFIT-ALS are potentially clinically meaningful. Can they form the basis for registration if confirmed? That is to be determined. We believe there may be relevant precedents that we must better understand. Could we dose Tirasemtiv to greater tolerability in ALS patients? We have preliminary ideas on how that may be possible, but there is still much to be learned from our data.

How might we approach funding a potential next trial and could that be done with a partner? That depends on several factors that includes scope, and timing, and cost and must be still determined. We will update you as we obtain clarity on these issues that can inform our potential plans. We intend to do right by patients who can benefit from medicines like Tirasemtiv, as well as our other first-in-class compounds that we believe are uniquely positioned to push forward.

Now, let me turn back to our expected milestones for 2014. Firstly, for Tirasemtiv, Cytokinetics expects to continue to analyze the data from BENEFIT-ALS to inform potential further development in ALS. Next, for CK-107, Cytokinetics expects to conduct additional Phase I studies and certain Phase II readiness activities in 2014, pursuant to our collaboration agreement with Astellas. And next for omecamtiv mecarbil, Cytokinetics anticipates commencement of patient enrollment in CY 1211 to occur by mid-year 2014 and Cytokinetics expects both the enrollment of patients in the expansion phase of COSMIC-HF, as well as the conduct of CY 1211 to be completed in 2014.

In conclusion, we remain optimistic about the future development of Tirasemtiv. However, further analyses of data from BENEFIT-ALS will be critical to informing decisions with respect to the potential further development of Tirasemtiv.

In addition, we are pleased with Cytokinetics' progress and execution in the last quarter in the development programs for omecamtiv mecarbil and CK-107, and we're looking forward to the planned progress for these programs in 2014. As a Company, we are on solid footing with over $100 million in cash and we are resolute in our commitment to maintain multiple paths for potential successes.

Operator, that concludes the formal portion of our call today. I'd now like to open the call to questions please.

(Operator Instructions) And your first question comes from Charles Duncan from Piper Jaffray.

Hi, Charles.

Hi, it's Roy in for Charles actually. Thanks for taking the question.

Hi, Roy.

Hi, just I guess the first question is, if you could speculate maybe if you think there might be an easy fix for the GI adverse events?

Your question is, do we think there may be an easy fix for the GI adverse events. I'll tell you it's too premature for us to speculate on that, recognizing these data are still just days old, but I will ask Andy to comment.

I think it is hard to know at this point. What we have been able to find out, and there's more to do, is that they tend to be mild for the most part. And it would appear they have an onset that maybe is a little later than the types of adverse events that tend to be most associated with early termination, particularly from open-label treatment.

So I don't think these GI adverse events actually got a lot of attention from the investigators during the study, because the great majority of them really were not intolerable. But in another trial with more perspective focus on them, I think it may be possible to manage them better. But I can't really say that right now.

What I might add to Andy's comments is, for those of you who haven't yet had an opportunity, I would encourage you to listen to the webcast from our presentations on April 30, where investigators and non-investigators with BENEFIT-ALS commented on just that and other data, and in particular, the adverse effects.

We know that the tolerability profile of tirasemtiv in this trial was not as anticipated in some respects, and that is in particular, with regard to GIAEs based on what we know today. But as you'll hear on that webcast, there was a strong sentiment that these kinds of GIAEs are able to be managed well in clinic. And that with the concomitant administration of other meds, or just simply as Andy pointed out, knowing about them in advance may contribute to more favorable tolerability in the next study. That's still something that we need to understand and we need to delve much more deeply into the data in order to inform what could be the design of a potential next study.

Okay, helpful. Thanks. And patients on Tirasemtiv had their (inaudible) dose limited to 50 milligrams, correct? Was that also the case in prior studies?

In small earlier Phase II studies, yes. In patients who received (inaudible) Tirasemtiv, their (inaudible) dose was reduced to 50 milligrams once daily.

Okay. And can you remind me if we know what the source of the dizziness signal might be, if there's a mechanistic basis there?

Your question relates to, do we know what might be contributing to the dizziness signal associated with Tirasemtiv and I do think we have a decent handle on that based on both preclinical and other earlier clinical work. I'll turn it to my colleague, Fady Malik, to address that.

We know that Tirasemtiv crosses the blood-brain barrier. So it enters the brain where it might have an effect on receptors in the CNS. I think it's difficult to pin one specific receptor down, but the --- we have noted an effect of Tirasemtiv on gabaergic receptors that can be implicated in feelings of dizziness and things like that.

So we've obviously looked at that as a potential target. But there is no -- there probably are a lot of CNS receptors that can cause dizziness and in our other program, in follow-on molecule, we've taken an approach there of potentially just trying to keep it out of the CNS so that we wouldn't encounter this in a future molecule.

So based on what we knew from the Phase IIa studies, we knew to look for lightheadedness and dizziness. That was information conveyed to investigators and also patients, and we did see, as expected, that when dizziness did occur, it tended to abate, as we would have expected after roughly about a week. The reason you do clinical trials is to learn things about the tolerability of the drug before you might advance them forward. And certainly, in this Phase II study, we learned more about tolerability of Tirasemtiv over longer duration treatment. And that is information that can inform the potential path forward, were that to be our choice to proceed to next steps and certainly in order to know that we have to dive much deeper into these data.

Thank you. I'll turn back in queue.

Thank you.

(Operator Instructions) And we do have a question for Chad Messer from Needham and Company.

Hi, Chad.

Hi, thanks for taking my question. I know, as you mentioned, you still have quite a bit of review to do with your data. I wondered if it was possible to share with us, even in general terms, the kinds of additional analyses you think are important to query the database, whether it be sort of subset analyses, looking at different patients by what dose they received or what kind of questions do you still have to ask of the data? And then just a second quick follow-up, any update, or idea, or thoughts on timing with getting in front of the FDA with this data? thanks.

Chad, very good questions, and I'm not sure I can give you satisfactory answers yet, but I'll try. With regard to your first question, there are many hundreds of analyses that are pre-specified and still need to be performed, as well as others that these data now suggest need to be done. And there are things relating to correlations between adverse effects and also with dose and exposure, and what we can learn through the course of the study in connection with riluzole and also patients not on riluzole. There are subgroups that we want to better understand.

There's a tremendous amount that was prioritized to occur after the presentation at AAN, in order to ensure we had data as soon as we could for presentation, but where now it makes sense to spend the time, the necessary weeks at least, and potentially months to understand these data in their full meaning. And as such, I think it's premature to even speculate on when that's going to be completed and what we'll then have in terms of a timeline for discussion with the FDA. I understand why you asked the question, but we're going to be very careful to do a deliberately careful job of analyses, in order to then be next informed as to what would be timelines and plans from that point. And I guess I'll just have to ask for your patience and understanding as we go deep into these data.

All right, well thank you and good luck with the analysis.

Thank you. Chad.

Your next question comes from Charles Duncan and Roy Buchanan.

Good morning.

Hi, guys, just a couple of follow-ups. Was anything done in the protocols to coach the patients through the dizziness and was that, I guess, maybe ineffective in preventing dropouts and what happened there?

Andy, I'll turn to you. The question relates to, was anything done to coach the patients regarding dizziness and were we successful at that with regard to the early terminations and those that continued.

Well, certainly patients knew that and we had known that dizziness did tend to abate with continued treatment in most patients. But that did not prevent dizziness from being the most common reason for early termination from both the open-label phase, as well as the double-blind phase. So they have the information, but it still resulted in --- it still was the single adverse event that resulted in the most early terminations.

And we knew that would likely be the case, and as such, as Andy has spoken before, the efficacy analyses were really driven by those patients who tolerated the open-label titration and had at least one efficacy visit, the first one occurring at week four following randomization. So I do think that we have enough experience with the lightheadedness that we know how to manage that for clinical trials, and now we need to understand some of these other issues. We also need to understand what might have contributed to the weight loss and how that confounded the results on ALSFRS. We don't believe that weight loss had effect to any of the other effects and certainly, we think it stands independent of Slow Vital Capacity. So these are things that we want to go much deeper into understand.

Okay great. Then I had one last question. I guess on the confusional state, could you guys could characterize that a little bit more, how severe it was and what's that actually look like?

Most of these adverse events were reported as mild. A minority were moderate. Very few were severe. Patients were -- and I'll tell you what, I'm not sure that the confusional state is different from the dizziness. I think, it depends a lot on how -- what word the patients choose to describe it and then it maps differently. So some patients felt lightheaded and if they used the term lightheaded that complaint maps to the standard adverse event term of dizziness. Others might have said they felt buzz. We've heard that before. That goes to euphoric mood. And others might have said they were having difficulty thinking and that would go to confusional state. All of them appear to be related to the presence of drug in the central nervous system.

Maybe just to add to that, what we also know is that these same terms and adverse effects are not uncommon in ALS, and were also observed in placebo treated patients, albeit, it is an issue that we think is more common amongst those treated with Tirasemtiv. So again, we just need to be able to understand its correlation with plasma exposure, with dose, with time, things that might have contributed to other ways that certain patients responded and others did not. That's not straightforward, but important to do.

Thanks guys.

Your next question comes from Larry Smith from SmithOnStocks.

Hi, Larry.

Hi Robert. Robert, moving onto COSMIC-HF, when I look at the secondary end points, those are very important measures of heart function, but we're only looking at 20 weeks of treatment. I wonder what we should be expecting in terms of data. Are we going to be looking at trends or could some of these measures revise to the level of statistical significance?

Very good question. So as you know well, having followed the Company for a long time, omecamtiv mecarbil as has been dosed for hours and days has demonstrated effects that are measurable and statistically relevant on echocardiographic parameters. And the goal COSMIC-HF is to understand in a less ill population, but as dosed chronically over weeks of treatment if some of those effects are also durable. I'll turn it to Fady Malik to elaborate.

Hi Larry, I think it's good question. I think the answer lies in how large of a magnitude set does one think is clinically relevant. And in terms of remodeling and things like that, really quite small changes are thought to be meaningful, especially if you're only dosing for 20 weeks. A conundrum there is that the smaller the change, obviously the harder it is to achieve statistical significant.

And so I think again just speaking for ourselves, I can't really speak on behalf of our partners at Amgen, if we were to see trends in a number of echocardiographic variables that are heading in the right direction, not necessarily achieving statistical significance, but where physiological picture all kind of make sense, I think that is sufficient really for us to conclude that we're having a desired effect on cardiac function.

And to that point, there is no predefined primary efficacy endpoint in COSMIC, no specific hurdle for efficacy that we have to hit, in order for that to be deemed a positive study. So to Fady's point, our goal is to ensure safety, tolerability, and PK and PD that are within the range of expected values during this longer-term treatment with omecamtiv.

I have one other question on Tirasemtiv. I believe if I heard you correctly, I think it was on the call on BENEFIT-ALS, you mentioned that in myasthenia gravis the patients were younger and the side effects were more benign. I don't know if that's correct or not. But if it is correct, why haven't you put more emphasis on myasthenia gravis either paralleling with ALS or possibly even going before ALS?

So I'll answer your second question after Andy addresses the point about age in the MG study.

They were in general younger, and they were overall less debilitated. And we have seen over the course of now looking at patients with three different diseases, claudication were the oldest, myasthenia gravis were on average the youngest, and ALS patients were in the middle, that the tolerability and in particular these CNS adverse events are correlated with age. I don't know that I can give you a good mechanistic explanation for that, but it's unsurprising to me, especially the CNS AEs. We haven't really had time to look into the gastrointestinal one to that level yet.

And to your question about strategy, we had to make choices and prioritizations, and based on what we know about ALS, what we knew then and we still know now, it's an areas of higher urgent unmet need with a more concentrated clinical trials network, highly motivated patients that would participate in clinical research. And we thought from a return on investment standpoint and an urgency that would be an area where we could make a bigger impact sooner, and also that would be an area where we thought the regulatory construct was more well defined.

The mechanism of action of fast skeletal muscle activation is something that extends as you know broadly to ALS and other neuromuscular diseases, as well as to non-neuromuscular diseases associated with muscle weaknesses and fatigue. And we have to make certain choices given our limited access to capital and other resources. And now together with ALS experts, together with a broader audience of neuromuscular experts, we can think about Tirasemtiv. But also we can consult with our partners at Astellas about non-neuromuscular indications given the focus of that deal and CK-107's development program. And I think we'll have a lot more to say after we've had time to digest these data and have these consultations.

And one final question, when do you think we could see topline data on COSMIC-HF.

So, it's too early to say. Enrollment is proceeding well in the expansion phase, but it's too early to point to when that may occur. Certainly, we're intending that that could be in 2015 and when in 2015 will depend on the enrollment rate. Maybe we'll have more to say about that I hope with our next earnings call, based on the rate of enrollment at that time.

Okay. Thank you.

Thank you.

There are no further questions at this time. I would now like to turn the call back over to you, Robert Blum, President and CEO.

So thank you everyone for your participation in today's call. We've had a number of press releases in recent days and also the webcast on Wednesday last week, this earnings call and webcast today. So I do believe there's extensive information out there regarding Cytokinetics, our priorities, and our plans. We do look forward to updating you as those continue to evolve. And with that we'll conclude the call and look forward to the next opportunity once we have more that we can share.

Ladies and gentlemen, this does conclude today's conference call. You may now disconnect.