Cytokinetics Inc (CYTK) 2013 Q4 法說會逐字稿

Good afternoon and welcome, ladies and gentlemen, to Cytokinetics' fourth-quarter 2013 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 company's request, 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. After Robert's opening remarks, Dr. Andrew Wolff, our Senior Vice President of Clinical Research and Development and Chief Medical Officer, will provide an update on the clinical development of tirasemtiv for the potential treatment of ALS and also will provide an update on the phase 1 clinical trials of CK-2127107, or CK-107, in healthy volunteers. Next, Dr. Fady Malik, our Senior Vice President of Research and Early Development, will update you regarding recent progress in the clinical development of omecamtiv mecarbil for the potential treatment of heart failure. I will then provide a financial overview for the quarter. Robert will then conclude the call with additional comments regarding how the 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 now turn the call over to Robert.

Thank you and good afternoon. Thanks to everyone on the line for joining us on this call today.

2013 was a successful year for Cytokinetics. In 2013, Cytokinetics delivered on key objectives in research and development and in other areas relating to business development and overall across the Company. Taken altogether, our company's solid execution in 2013 now positions us well in 2014.

In R&D, we progressed each of our clinical development programs through important milestones. That progress was accompanied by our new alliance with Astellas and our expanded strategic alliance with Amgen.

I am proud of the progress Cytokinetics made last year. Looking forward, we are focused on the continued development of our three clinical-stage programs as well as further corporate development initiatives that we expect to position the company to deliver on our mission and result in potential returns for all our stakeholders.

Starting with a look at the progress made during 2013 in our skeletal-muscle contractility program, in the fourth quarter, we completed the enrollment of BENEFIT-ALS with 711 patients. We are now focused to the completion of the trial and look forward to the potential presentation of results from BENEFIT-ALS in April at the annual meeting of the American Academy of Neurology. This large international Phase IIb clinical trial of tirasemtiv is designed to inform our global registration planned for this promising drug candidate and we are evaluating strategic scenarios for the further development and the potential commercialization of tirasemtiv. In addition, in 2013, we made progress under our new collaboration with Astellas for the development of CK-2127107 or CK-107 and in the context of joint research to identify next-generation skeletal sarcomere activators.

During the last quarter, we reported results from our first time in humans Phase I clinical trial of CY 5011, as Andy will elaborate in a moment. More recently, we completed dosing in another Phase I trial, CY 5014, evaluating the relative bioavailability of two different liquid oral forms of CK-107. Both of these trials are part of an agreed development plan with Astellas that is focused to the characterization of CK-107 for potential evaluation as a treatment for non-neuromuscular diseases in Phase II trials.

In our cardiac muscle contractility program, together with Amgen, in the last quarter, we prepared for the continuation of COSMIC-HF and progression of this ongoing Phase II clinical trial of oral omecamtiv mecarbil to the expansion phase. We recently reported on changes to the trial design of COSMIC-HF that are included in the protocol amendment agreed with Amgen. We believe that implementing these changes in COSMIC-HF enables us to evaluate a plasma concentration-guided dose titration strategy in Phase II that we anticipate implementing in the potential Phase III development of omecamtiv mecarbil and that may better reflect real-world clinical practice. Fady will describe the recent changes to the protocol of COSMIC-HF in more detail later in this call.

Looking forward in 2014, we are focused to preparations for the commencement of enrollment in the expansion phase of COSMIC-HF and a Phase I study to compare the safety, tolerability and pharmacokinetics of omecamtiv mecarbil in healthy volunteers of Japanese ancestry with Caucasian counterparts. We are also collaborating with Amgen on a number of other work streams intended to inform potential progression to Phase III.

So with that introduction, I will turn the call over to Andy for an update on the progress of our skeletal muscle contractility program.

Thank you, Robert. I am pleased to provide an update on recent developments in our skeletal muscle program, especially because we can report that we have concluded enrollment in BENEFIT-ALS with 711 patients enrolled in over 75 centers in eight countries. Over 400 of those patients now have completed the 12 weeks of double-blind treatment. As you know, BENEFIT-ALS is 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.

In December, the study's lead investigator, Dr. Jeremy Shefner, provided an update on BENEFIT-ALS during a platform presentation at the international symposium on ALS MND. Dr. Shefner's presentation included double-blind aggregate data that were well received by conference attendees and that underscored the ALS communiques enthusiasm for results from this trial.

More recently, in January, the Data Safety Monitoring Board, or DSMB, for BENEFIT-ALS convened and reviewed data relating to the potential safety, tolerability, and efficacy of tirasemtiv from the trial. We are pleased to report that the DSMB recommended that BENEFIT-ALS proceed to completion without any changes to the protocol.

I'm also happy to confirm that an abstract intended to include the first public announcement of the results from BENEFIT-ALS has been accepted by the American Academy of Neurology, or AAN, for presentation by Dr. Shefner during a platform session at their annual meeting in Philadelphia at the end of April. At that meeting, we expect Dr. Shefner will present the major efficacy, safety and tolerability measures from BENEFIT-ALS.

Given that the last patient visit in the trial is not expected to occur until the end of March, we realize that it is an aggressive goal for us to resolve all outstanding data queries, lock the trial database and complete the required statistical analyses in time for a presentation of results from BENEFIT-ALS at AAN, but we will be working diligently to try to achieve that objective. If we are not able to complete the analyses in time to make the first presentation of the BENEFIT-ALS data at AAN, we hope to do so approximately a month later in Istanbul at the Joint Congress of European Neurology organized by the European Federation of Neurological Societies in collaboration with the European Neurological Society. Between now and those upcoming meetings, Cytokinetics' priorities are also focused on preparations for the further development of tirasemtiv as may follow the reporting of results, including the conduct of manufacturing and related activities and other initiatives consistent with Phase III planning.

Turning now to the development of CK-107, in the last quarter, we reported data from CY 5011, a Phase I first time in humans clinical trial of CK-107 in healthy male volunteers conducted by Cytokinetics under our collaboration with Astellas. CY 5011 was a double-blind randomized placebo-controlled study designed to assess the safety, tolerability and pharmacokinetics of single ascending oral doses of CK-107 administered to healthy adult males in the three-period dose-escalating crossover design.

The primary objective of this trial was to evaluate the safety and tolerability of single doses of CK-107 administered orally to healthy male volunteers. The secondary objective was to evaluate the pharmacokinetic profile of single doses of CK-107.

Planned single doses of CK-107 up to 4000 milligrams, the highest dose administered in this trial, were well-tolerated. Therefore, a maximum tolerated dose could not be defined. The pharmacokinetic profile of CK-107 was linear and dose proportional across the dose range studied with a mean terminal half-life compatible with once or twice-daily dosing.

Also during the quarter, we completed dosing in CY 5014, a Phase I clinical trial of CK-107 in healthy male volunteers. This trial is a randomized open-label two-period crossover study to assess the relative bioavailability, pharmacokinetics, safety and tolerability of two forms of CK-107 when administered orally in a liquid suspension. We are compiling the data from CK-5014 and look forward to reporting the results later in 2014.

I am pleased with the results from the ongoing development of CK-107, which suggests an encouraging tolerability and pharmacokinetic profile for this novel activator of skeletal muscle. Results from CY 5011 along with the results from other ongoing and planned Phase I clinical trials and related nonclinical development activities will inform plans for the further potential clinical development of this drug candidate. As we continue to collaborate with Astellas for the readying of Phase II development, we look forward to providing further updates regarding CK-107.

With that update on our skeletal sarcomere activators, I will turn the call over to Fady for an update on our cardiac contractility program.

Thank you, Andy. As reported with our Q3 earnings, Cytokinetics and Amgen selected an oral formulation of omecamtiv mecarbil based on the results of the ascending dose cohorts in COSMIC-HF and agreed to proceed to the expansion phase in the ongoing clinical trial. Last year, we also announced that Cytokinetics and Amgen agreed to amend the protocol for COSMIC-HF before proceeding. More recently, we announced the details of the protocol amendment.

Under the protocol amendment, three key changes to the expansion phase of the trial are being implemented. First, we revised one of the three treatment arms of the trial to include a dose titration step. Originally, one arm was to receive 25 milligrams twice daily, another was to receive 50 milligrams twice daily, and a third was to receive placebo. The amendment now implements a dose titration step in the 50 milligram arm. And the other two arms are unchanged.

Patients in the 50 milligram arm will receive 25 milligrams twice daily for eight weeks and then titrate up to 50 milligrams twice daily for the remaining 12 weeks, if eligible to do so, based on a trough plasma concentration of omecamtiv mecarbil measured in week 2. Patients not eligible to titrate upwards will continue on 25 milligrams twice daily for the rest of the study.

The second revision to the protocol is to increase the duration of the expansion phase from 12 weeks to 20 weeks. The purpose of this change is to allow time to conduct the bioanalyses of the trough plasma sample taken at two weeks and have the data available for a decision regarding dose titration at eight weeks. Extending the duration to 20 weeks in total allows for patients in the titration arm to stay at the 50 milligram dose for the full 12 weeks as well as increases the overall duration of exposure to omecamtiv mecarbil in all active dose groups. We believe that the implementation of this dose titration strategy may maximize the number of patients who achieve targeted plasma concentrations of omecamtiv mecarbil while reducing the number of patients who might experience excessive exposures. We also believe that the strategy may yield important information that may guide and simplify our planning for Phase III.

The third revision to the protocol is that we increased the number of patients enrolled in the expansion phase from 300 to 450 patients. We believe that this change will increase the statistical power to detect differences in the echocardiographic endpoints that we are evaluating and provide for a larger pharmacokinetic and safety data set.

Recently, Cytokinetics and Amgen have been collaborating to respond to information requests received from regulatory authorities relating to their ongoing review of the protocol amendment submitted for COSMIC-HF. And while COSMIC-HF continues to progress towards initiation of the expansion cohort, our companies are working together to plan for potential Phase III activities.

In parallel, we have begun making preparations for the Phase I clinical trial of omecamtiv mecarbil known as CY 1211. This trial is a single-center placebo-controlled double-blind study comparing the pharmacokinetics of omecamtiv mecarbil between healthy Japanese and Caucasian volunteers. This trial is being conducted by Cytokinetics in collaboration with Amgen and is provided for under our recently expanded alliance with Amgen.

CY 1211 is the first step towards the potential inclusion of Japanese patients in a global registration trial and dossier. We expect to share more details relating to this trial in the coming months. In the meantime, we are collaborating with Amgen to respond to information requests from regulatory authorities relating to their ongoing review of the protocol for CY 1211 as well.

So with that update, I will turn the call over to Sharon.

Thank you, Fady. As our press release contains detailed financial results for the fourth quarter of 2013, I will refer you to that public statement for the details of our P&L and balance sheet.

In the past quarter, we were focused on completing the enrollment of BENEFIT-ALS and executing on the development and research plans associated with the Astellas collaboration. While we reported a profitable quarter with net income of $6.5 million, we do not expect this to continue in the future, as it is largely reflective of the recognition of license revenue of $17.2 million from our Amgen collaboration, which is not recurring.

We ended the fourth quarter with approximately $80.2 million in cash, cash equivalents and investments, which represents approximately 16 to 18 months of going-forward net cash burn based on our 2014 financial guidance, which I will cover in a moment.

Revenues for the fourth quarter of 2013 were $24.3 million. This revenue included the recognition of $2.4 million of the $16 million Astellas license fee and $4.1 million in program expense reimbursements and other revenues. Revenues for the fourth quarter also included license revenues from our collaboration with Amgen of $17.2 million and $0.6 million from program expense reimbursements.

Revenues for the 12 months ended December 31 were $30.6 million. This revenue included the recognition of $3.9 million of the $16 million Astellas license fee and $6.4 million in program expense reimbursements in other revenues, as well as the $17.2 million in license revenue from our Amgen collaboration along with the $2 million from program expense reimbursement. In addition, $1 million in revenue from our myocardium collaboration which ended in August 2013.

Our fourth-quarter 2013 R&D expenditures total $13.8 million. From a program perspective for the fourth quarter, approximately 88% of our R&D expenses were attributable to our skeletal muscle contractility program activities. These include 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 will reimburse our agreed costs under the research and development plan and will be primarily responsible for the conduct of Phase II development and commercialization activities. In addition, 7% of our R&D expenses were attributable to our cardiac muscle contractility activities and 5% to our other research activities.

For the 12 months ended December 31, 2013, 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 activities.

Moving on to our financial guidance for 2014, the company anticipates cash revenue will be in the range of approximately $19 million to $21 million, cash R&D expenses will be in the range of $50 million to $53 million, and cash G&A expenses will be 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 activities primarily related to stock compensation expense. In addition, this guidance does not reflect potential revenues from milestone payments that may be achieved in partnered programs.

We believe that our financial resources in the next 12 months will largely be focused on the completion of BENEFIT-ALS and the analysis of data from that trial as well as certain readiness activities necessary to support the potential further development and commercialization of tirasemtiv.

That concludes the financial portion of today's call. With that, I will turn the call over to Robert.

Thank you, Sharon. So, as you heard on our call today, we have been busy advancing our clinical stage programs. Our progress in 2013 positions Cytokinetics well for continued progress in 2014.

As a result of what we accomplished in 2013, this year has the potential to be a watershed year for Cytokinetics. In preparation for potentially positive results from BENEFIT-ALS, we have been engaged in planning for next steps relating to tirasemtiv and have been making preparations on multiple fronts across the company. Our base case scenario for tirasemtiv contemplates our proceeding to conduct a Phase III clinical trial, and we are conducting a series of readiness activities, including certain manufacturing and other nonclinical activities. In addition, we are engaging in regulatory and clinical development work streams to position the company to advance tirasemtiv into the expected final stages of an international registration program.

At the same time, we are poised to execute on next steps in connection with the more probable base case scenario. We also recognize the urgency associated with advancing new investigational medicines to patients with ALS and the important role we may play to address these high unmet needs. Therefore, we have also engaged in planning activities to inform practical and affordable strategies for the potential commercialization of tirasemtiv, both in North America and outside of North America. We believe that Cytokinetics is taking prudent but appropriately aggressive actions to position the company to respond to several potential outcomes related to BENEFIT-ALS in 2014.

For our omecamtiv mecarbil development program, we are looking forward to initiation of patient enrollment in the expansion cohort of COSMIC-HF. While administering to the protocol amendment has necessitated delays in the timeline to data from this ongoing Phase II trial, more importantly, taking these actions now provides for a larger and potentially more meaningful data set from COSMIC-HF. In preparing for the potential progression of omecamtiv mecarbil, we continue to engage heart failure experts to discuss ways we may design a Phase III program for omecamtiv mecarbil. We are optimistic about the continued development of our novel mechanism compound and are collaborating with Amgen on activities that anticipate potential progression of Phase III.

The unmet need in heart failure remains high and we believe that omecamtiv mecarbil in both intravenous and oral forms may demonstrate a clinical profile that can represent a significant innovation for both acutely ill and chronic care patients. We look forward to continued progress with regards to this promising program throughout 2014.

Lastly, as you have heard, we continue to make important progress under our collaboration with Astellas. We are pleased to have completed two Phase I trials of CK-107 in the six months since our collaboration was initiated. Under our collaboration agreement, we are responsible for Phase I studies and other Phase II readiness activities for CK-107. We are executing well, in accordance with an agreed development plan, and under the joint oversight of Cytokinetics and Astellas.

Together with our partner, we are setting the stage for the investigation of CK-107 and other skeletal muscle activators in non-neuromuscular disease indications. We believe CK-107 offers great promise to address high unmet needs in a wide array of syndromes and conditions associated with muscle fatigue and weakness. We look forward to sharing future updates throughout 2014.

Now, let me turn back to expected milestones for 2014. For tirasemtiv, Cytokinetics expects to report data from BENEFIT-ALS at the American Academy of Neurology annual meeting in Philadelphia in April. For CK-107, Cytokinetics expects to conduct additional Phase I studies and certain Phase II readiness activities in 2014 and pursuant to our collaboration agreement with Astellas.

For omecamtiv mecarbil, Cytokinetics expects commencement of patient enrollment in both the expansion phase of COSMIC-HF and in CY 1211 to occur in the first half of 2014, following regulatory authorities' review of responses relating to information requests provided in connection with the protocols submitted for the two trials. 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 concluding, we are pleased with Cytokinetics' progress and execution in the last quarter and in 2013. And we are hopeful for their implications for a bright future for our company and all shareholders.

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

(Operator Instructions). Ritu Baral with Canaccord.

Thanks for taking the question. As we all look forward to BENEFIT-ALS data, can you give us a little more detail on these next step readiness activities that you mentioned and also walk us through what you are thinking as far as a scenario analysis? Positive data -- what would the next trial potentially look like? And what threshold of data do you think that you'd need to see in order to maybe contemplate early filing?

Okay. So, those are a series of questions we will try to tick off one at a time. So in terms of readiness activities, there are so many. I will start with what is going on in the CMC and nonclinical side. That's where we want to make sure that, to the best of our abilities, we are not in a position where supply would be rate limiting to the start of a Phase III program.

You know, our goal would be, data permitting and end of Phase II meetings with regulatory authorities permitting, that we would be in a position to progress tirasemtiv into Phase III by the end of the year. That's not part of our formal guidance right now because it's awaiting the data in those conversations. But in order to be able to make that timeline, there are things we have to be doing in terms of optimizing, manufacturing of drug substance and drug product, doing it at scale, making sure those scratches are validated and serving our longer-term potential interests as it relates to commercial quantities and quality. So there's a lot of things going on in the CMC and nonclinical side.

There are other nonclinical studies that we have to be geared up for. And there are regulatory conversations. There are conversations we have with disease and patient advocacy organizations. There's market research and forecasting. There's all sorts of planning that goes along side of the organization that would be required to conduct a Phase III study or other market access and other kinds of commercial development and planning work streams. So I just touched on it at a very high level, but hopefully that gives you a flavor.

I'm going to turn to Andy and talk about expectations for what we might see out of the data that could support Phase III, but I will remind you that our base case is that the data supports Phase III and would not be yet the subject of an accelerated registration. But at the same time, we need to be poised for that if the data would speak to that and also the regulatory conversations we have would render that more practical. So, we are preparing for both a base case and a best case, even as we recognize more prudently and practically we should be poised for Phase III.

So I think, if we see from BENEFIT-ALS a very clear separation of patients treated with tirasemtiv versus placebo in their ALS FRSR scores and especially if we have confirmatory data from the key secondary endpoints, the maximal ventilatory volume and the sniff nasal inspiratory pressure, etc., that we would probably proceed into a Phase III study even if we possibly missed a p-value less than 0.05. I think, in that situation, the magnitude of the difference between tirasemtiv and placebo and the consistent direction of the other secondary endpoints would drive our decision more than a bright line around 0.05, especially if it were very close. We would need another confirmatory trial, but it would appear to be rational to do one. And furthermore, we would have 711 patients' worth of data informing us better regarding sample size calculations, inclusion and exclusion criteria, etc.

For us to contemplate filing after a single study, clearly we would need to have a p-value less than 0.05 on the primary endpoint and probably more than just barely less than 0.05, significantly less than 0.05, and without any internal inconsistencies that might raise any questions, meaning we are not seeing all of the effects coming from one center or a small group of centers, the secondary endpoints are all lining up in the same direction and are confirmatory and no new emerging safety or tolerability concerns. So that would be the kind of result we would need to think we could go into regulators and propose an early approval.

So, I will remind you that the Phase IIb study is powered with 80% power to detect a lesser difference in treatment versus placebo at 12 weeks and with a p less than 0.05. And that's not uncommon that a Phase IIb study would have 80% power, where with a Phase III you expect to have higher power. As we think about Phase III, I will ask Andy to comment here in a minute, we would be looking for learnings from Phase IIb in the BENEFIT-ALS study, which is, as far as we know, is a largest Phase II study that has been done in a population of ALS patients. There's a lot that we can learn from that as we think about Phase III.

If we start to see in these data that patients are better than their own baseline, and at 12 weeks they are improved relative to when they came into the study and, as Andy points out, that's consistent across endpoints, I think we would certainly want to engage regulatory authorities to understand whether that would be effective and tolerable to submit for an accelerated review and potential approval. But I don't want to get too far out in front of our skis on this. We will wait and see what the data has in store for us, and then we'll set proper expectations afterwards.

So, then finally, you also asked what a Phase III would look like if that's what we were moving toward. And clearly, anything I'm about to say would need to be refined and re-examined up against things that would come out of BENEFIT-ALS, like the observed variability in the change from baseline in the ALS FRSR, as well as things that, with now this much larger data set, we may believe tend to predict better responders versus those who may not respond as well.

But based on what we know now and going in, we would imagine it would need to be of six months' duration. And now, because it would be a Phase III, we would want 90% power to see our treatment effect. Both of those things cause the study to need to be larger. So it would probably be something over 1000 patients, between 1000 and 1500, to be refined again based on what we see from BENEFIT-ALS. I think it wouldn't be a bad guess to say it would be somewhere right in the middle there, around 1200, 1300.

Great. Thanks for taking all the questions.

Sure. Did that get to all your questions?

Yes. That was all three (technical difficulty)

I think there were two.

Simos Simeonidis with Cowen and Company.

I'm going to shift to omecamtiv mecarbil, if I may. And for the expansion phase of COSMIC-HF, you mentioned that you expect to complete the trial by the end of the year. So my questions are the following -- do you have a rough estimate of when enrollment can start again after the new protocol?

The second one would be, so, with the trial, given guidance that it's going to end in 2014, we assume we are not going to have data until probably sometime in Q1 or Q2 2015.

And finally, how should we think about the scenarios where Amgen decides -- Amgen and you decide to go into a Phase III trial? Is this something that would happen after you have the data from COSMIC? Could it come at an earlier point? And so that's it.

Yes, so a couple of questions. I will take a few of those and then I will turn it over to Fady as well.

With respect to Phase III, I would not assume that we are going to get started with Phase III before we have completed COSMIC. Certainly, we are encouraged by the data from ATOMIC. We think it supports progression of Phase III, but we also want to see the results from COSMIC before we would engage in that final activity in support of a movement to Phase III. And I think that's consistent with comments we have been making and also Amgen has been making.

The start of commencement of enrollment in the expansion phase of COSMIC with this release we are saying would happen in the first half of the year. And that could be Q1, but in order to be conservative, we are suggesting that it's first half of the year. And when it happens, we will announce that.

And the enrollment could proceed very quickly. We saw, in the dose escalation phase of COSMIC, that with a number of centers enrolling, that those cohorts enrolled very, very rapidly. So we expect that we can enrolled the COSMIC study in the expansion phase probably not in a matter of weeks but certainly in a matter of months. And certainly we feel comfortable with our guidance that that's going to occur in 2014. That's not necessarily at the end of 2014; that could very well be much sooner.

But I will ask Fady maybe to comment on, given that patients are going to be getting treatment for longer periods of time, what that means in terms of possible data.

So, I think the objectives in terms of data in the trial still remain similar, that we are going to be examining the pharmacokinetics of the molecule in a large group of patients, looking at echocardiograms. I think the main thing that time gets us here is obviously a longer time to look at the impact of omecamtiv mecarbil on cardiac function and dimensions over time. And I wouldn't underestimate, as well, that now we are moving towards five months of continued treatment, if you think of what these patients eventually will be studied as is in a trial in Phase III that would put them on continuous treatment indefinitely. Having five months is substantially better, I think, than having three months of exposure data. So, safety data will also be expanded in that respect and more confidence given in that respect, too.

Given that it is an expansion phase that's getting started here in 2014 and not at the end of 2013, as was at one time our goal, it does mean that data from COSMIC is more likely to be coming in 2015. And when in 2015 will depend on how rapidly it enrolls and we will hopefully be able to point with some more guidance around that when we see enrollment completing.

Did that help?

I just have two very quick ones also on omecamtiv mecarbil. With the expansion of your partnership with Amgen to include Japan, could you also remind us or speak about the rationale or the significance of doing the Phase I trial in Japanese and non-Japanese patients, what is the role of that trial?

And the final question is, is there any updates on the -- you did a small trial in patients with renal insufficiency. Is there anything to report there? Are we going to see these data? Just provide us an update, if you could. Thank you.

So, let me start with the strategic implications. So when we announced in June of last year that we expanded our alliance with Amgen to include Japan, it was very much with the view that we wanted to be working together to enable the possibility that Japan could be included in a global registration program for omecamtiv mecarbil, which means the possibility of enrolling patients in Japan in a Phase III program. So there's obviously things that have to be done in between to enable that to happen. And we have been talking to Amgen about how best to do that. And it's nice for us at Cytokinetics to be able to ourselves be conducting this study, which will be conducted in patients of Japanese ancestry here in the United States comparing to Caucasian subjects. This is a very common approach to getting safety and tolerability but primarily PK data to support what may be conversations with regulatory authorities around what might else be required in order to be able to make that goal happen. So this is the first step, and this is a study that we will be doing under an agreed protocol with Amgen under their sponsorship, and it's a study that we ought to be able to start and finish this year.

With respect to its design, if you have any questions about that, maybe I'll turn to Fady, and also with respect to the renal study. But I will tell you that these are studies that we don't always communicate in scientific forums, being that they are Phase I and otherwise more in keeping with what would be typical for those medical meetings.

Yes, I think Robert summed up the Japanese bridging study well. The major -- I will just add that the major objective there in terms of initiating a development program in Japan is to ensure that the dose of the drug that you are using, that you have settled on by doing studies in non-Japanese patients, is the same that you would apply in a Japanese population, which is they certainly have precedent for lower doses being used in Japanese populations. So, this study is really meant to serve as a bridge and then to enable the selection and design of a proper dose to be used in subsequent studies in Japanese populations. And its design is fairly simple. It basically uses two arms to compare oral dosing and IV dosing in a Japanese population and a coincidently treated Caucasian population.

The renal study, we have previously summarized the results. And as far as the implications to development, the statement that we made, which is that there were no meaningful differences in the pharmacokinetics of omecamtiv mecarbil in patients that were dialysis dependent, meaning no renal function at all, and matched comparators that had normal renal function, that there were no differences between those two groups is the bottom line. And what that means for the development program is that we don't need to worry about dose adjusting omecamtiv mecarbil based on renal function. And in heart failure, that's relatively important because renal function can be impacted by the disease and also variable over the course of the disease. And it was one of the reasons we selected omecamtiv mecarbil in the first place, was because we didn't think its PK would be impacted by renal function. This study in this small, very select patient population confirms that.

Just to follow up on (technical difficulty) I think epidemiologic studies indicate that over half of patients with heart failure also have compromised renal function. So, it's an important thing to know and it's an advantage, we think, for omecamtiv that we wouldn't have to approach those patients differently.

That's great. That's very helpful. Thank you for taking all the questions.

Charles Duncan with Piper Jaffray.

It's actually Roy in for Charles. Thanks for taking the question. Just a very quick one, most have been answered. Have you guys disclosed if there are any discontinuations from the escalation phase in COSMIC?

Discontinuations from the escalation phase in COSMIC? Escalation phase?

The escalation phase -- we haven't really disclosed the details of that particular part of the trial.

Okay, good enough. Thank you.

Jason Butler with JMP Securities.

Thanks for taking my question. I Just wanted to stay on the titration in COSMIC-HF and maybe look forward more to clinical practice and commercialization. How feasible is this kind of plasma-directed titration going to be to incorporate into everyday clinical practice? How do you see this playing out with the physician?

I'm going to ask Andy to comment. Both Andy and Fady, as you know, is practicing clinical cardiology, I think will share with you why this is quite common for cardiovascular drugs.

And this is done all the time, and sometimes you have a more biological readout like blood pressure or heart rate, and you push the dose that way. But it's not uncommon at all, especially in cardiovascular medicine, to measure a plasma concentration and increase that way. And I think, once we are in clinical practice with this compound, there will be a point of care assay that will make this quite easy to do so that it's not something where you have to send it off to a lab in another state and wait days for your result; you will have it essentially immediately and can decide what to do next.

Yes, I will add there are large classes of drugs that are -- I think the important thing to focus on is that a blood test is potentially required. Blood tests are commonly used to titrate drugs, as Andy pointed out, not just on drug concentrations but whether you check renal function after you change the dose of an ACE inhibitor or cholesterol after you change the dose of a statin or liver clotting parameters and so forth.

So cardiologists are used to taking blood tests to monitor the effects of drug. I don't think it's really a difference to them whether that test is a biological parameter or a drug concentration. They do both.

That's great. Thanks for taking my question.

Paul Matteis, Leerink Swann.

I was just wondering how many patients now you have of evaluable data for benefit, not the number that's actually finished the trial thus far, but how many you anticipate to be part of the primary efficacy analysis? Because I know you said you have 711 enrolled but then there are some excluded from the CRO debacle. And then getting onto that just kind of wondering what that implies in terms of the powering of the study, because I know your 80% power assumption was also predicated on both an enrollment assumption and a standard deviation assumption in the primary endpoint. Thanks.

Yes, so I will be able to answer that question but maybe not with the precision that you might prefer. What I will say is we over-enrolled the study, as you know, not by a lot but by roughly 5% in connection with what had been an approximate 680, and we enrolled 711. With today's press release, we announced that over 400 patients have completed treatment. The number is higher than that 400, but we haven't been specific.

There are still patients on treatment. And as we are expecting most of those patients to complete all of their treatment, we are thinking that the last treatment period would potentially be this month and last patient, last visit, given that there's a seven-day and 28-day follow-up after last treatment, will be at the end of March.

So in recognition of those parameters, we do see data, albeit as blinded in aggregate. And we have a sense of standard deviation. We have a sense of early terminations. I guess what I can say is we are very comfortable that we have the statistical power we were intending in the design of this study. But I'm not sure there's much more than that I can say unless, Andy, you tell me that --

I think if you don't think you can say more than that, I don't think I can say more than that. But I would agree. And what I might do is just remind everyone the study was originally powered to have 80% power to be able to detect a 1.18 point difference from placebo in the change from baseline to the end in the ALS FRSR score. And I will just reiterate what Robert said. From everything we know and our best guess is, because it's still blind, I think we are right on that.

Okay, great. That's really helpful. And then just one more question about the 1.18 point difference. Where exactly does that come from? The scale, I think it's a 36-point scale, so it seems like a relatively small difference. Can you help us understand exactly what the clinical or practical implications of a 1.18 difference would be and how you think that could be viewed by physicians if it did generate a p-value below 0.05?

So, first of all, it's actually a 48-point scale, so that means that the 1.18 is even a smaller percentage than you were suggesting. But I think what is more instructive is the way in which we understand the scoring system to behave. So as you probably know, patients go down about 1 point per month, on average. And in fact, in the recent EMPOWER trial of Dexpramipexole, they went down even a little bit faster than that, about 1.1 points per month.

So, we would expect that, on placebo, patients would have a decrease overall of around 3 points from their baseline. So 1.18 -- I can't do the arithmetic in my head real fast, but it's probably around 35% or 40% improvement in that decline.

When ALS specialists have been surveyed as to what they thought would be meaningful in terms of a treatment effect on this endpoint, they always come out around 20% or 25%, so it would actually be a much more substantial treatment effect than what they have said in the past they would find to be clinically meaningful.

And then finally, just to try to personalize what it would mean to, say, be 1 point better than on placebo, if you've ever taken the time to actually look at the individual gradations in each one of the domains, 4 is perfect function, 0 is no function at all. But the key things are what does it mean to be a 3 rather than a 4 or a 2 rather than a 3?

And I think if you look at the scale, you will find that there's not any place where you would tell yourself, well, I don't care if I'm a 3 instead of a 4. It doesn't matter to me if I'm a 2 rather than a 3. Each one of those points lost is a very significant decrement in an area of critical importance to functional independence. So, I'm confident that, with both ALS patients and their caregivers and their clinicians, if we hit that, there will be very little question about its clinical relevance.

The other thing I will add is, if we hit that, it will be the first time that has ever occurred that a drug has demonstrated a statistically relevant effect like that against the ALS FRS.

So there's a poster on our website -- we can also send it to you, Paul -- that was presented back in 2011 by Cytokinetics at the International ALS MND meeting which traces the ALS FRS and its revision over 20 years. And there are citations in that poster that refer back to the publications Andy is referring to regarding surveys of clinicians and what they think to be clinically meaningful.

Yes, that sounds great. I would love to see that. And thanks for the clarity. I look forward to AAN and I'm sure we will see you there. Thanks a lot.

Looking forward to it.

That seems to be our last question for today. I will now hand the call back over for closing comment.

Okay. So thank you to all the participants on our teleconference today. Thank you for your continued support and your interest in Cytokinetics. We are looking forward to what we hope may be a very promising 2014. We look forward to keeping you informed of our progress. And with that, operator, we can now conclude the call.

Ladies and gentlemen, thank you for joining us today for our conference call. You may now disconnect.