Cytokinetics Inc (CYTK) 2012 Q1 法說會逐字稿

Good afternoon and welcome, ladies and gentlemen, to Cytokinetics first 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 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 the Cytokinetics' Senior Management Team on this conference call today. Also present during this call are Robert Blum, our President and Chief Executive Officer, and Dr. Andrew Wolff, Senior Vice President and Clinical -- of Clinical Research and Development and Chief Medical Officer. We are all joined together for this call, taking place from New Orleans, the site of this year's annual meeting of the American Academy of Neurology.

Following the forward-looking statement disclaimer, Robert will provide an overview of the past quarter, along with the recent highlights on the advancement of our clinical development pipeline. Andy will then provide details on the progress of the Company's clinical development programs, emphasizing our most recent developments in connection with CK-2017357, which we'll refer to as CK-357. I will provide some brief comments with respect to our cash position and our investment in research and development activities. Robert will then conclude the call with additional comments, including our next steps for our development stage programs relating to CK-357 and omecamtiv mecarbil, as well as a discussion of the projected company milestones for the remainder of 2012. We will then open the call for a brief question and answer session.

The following discussion, including our responses to questions, contain statements that constitute forward-looking statements for the 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 corporate partnering; 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 10K, our quarterly reports on Form 10Q, and our current reports on Form 8K. 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.

In the first quarter we continued to make progress in advancing both of our Phase II clinical trials programs. With respect to our skeletal muscle activator program, we have made especially significant progress. In March we received notification that CK-357, our lead drug candidate for the potential treatment of ALS, had received orphan medicinal product designation by the European Medicines Agency, or EMA. And just last week we received notification that CK-357 has received fast-track designation from the US Food and Drug Administration, or FDA.

These designations, along with the orphan drug designation from the FDA that we received in 2011 for CK-357, affords Cytokinetics certain potential advantages which may improve both the speed and quality of our development program for CK-357 and should facilitate our future interactions with FDA and EMA, consistent with our interest to further evaluate the safety and efficacy of CK-357 in patients confronting ALS.

Moreover, yesterday here in New Orleans at the American Academy of Neurology annual meeting we announced additional safety and tolerability data regarding CK-357 from two recently completed Phase II clinical trials in patients with ALS. The results from these trials inform our plans for a potential registration program that we plan to further refine through interactions with regulatory authorities over the remainder of this year. Andy will elaborate on these most recent clinical trials data and their relevance to the potential treatment of ALS in a moment.

In parallel with our progressing CK-357, you will also hear from Andy about recent progress in the development of omecamtiv mecarbil, our novel cardiac myosin activator for the potential treatment of heart failure. Under our collaboration with Amgen, the first cohort of the Phase IIb ATOMIC-AHF clinical trial completed enrollment recently with over 200 patients enrolled. We look forward soon to a decision from the trial's data monitoring committee regarding potential dose escalation into the next cohort of this large international trial.

Alongside this progress, in the last quarter Amgen also initiated a Phase I safety and tolerability study designed to evaluate multiple oral formulations of omecamtiv mecarbil in healthy volunteers. Andy will also discuss that trial and its goals.

And with that introduction, I'll turn the call over to Andy to elaborate on the specific progress that we have achieved in both our clinical development programs since our last teleconference.

Thank you, Robert.

Yesterday in an oral presentation at the American Academy of Neurology annual meeting Dr. Jeremy Shefner presented data from the second part -- or second cohort or Part B of CY 4024, our two-part Phase IIa randomized double-blind, placebo-controlled multiple-dose safety, tolerability, pharmacokinetic and pharmacodynamic clinical trial of CK-357 in patients with ALS.

To remind you, in Part A of this trial patients did not receive riluzole while, in Part B, patients received riluzole at a reduced dose of 50 milligrams daily during 14 days of treatment with CK-357 or matching placebo. Part B of the study was otherwise identical in design to Part A.

Between Parts A and B, a total of 49 patients were randomized to treatment, 13 of whom received placebo, while 12 patients were treated in each of the three active treatment arms receiving once-daily doses of CK-357 at 125 milligrams, 250 milligrams or 375 milligrams.

In Part B of this trial, CK-357 appeared to be at least as well tolerated in patients receiving riluzole as in those who did not receive riluzole in Part A. This is an important observation, suggesting that riluzole at this reduced dose can be safety coadministered with CK-357. As has been observed in previous clinical trials of CK-357, including in Part A of this study, lightheaded or dizziness was the most frequently reported adverse event.

Again, as was also observed in Part A of the study, this dizziness was mostly mild. It generally began early after the initiation of treatment and resolved with continued dosing, usually within the first few days of continued treatment. No patients in Part B reported severe dizziness and only one on 250 milligrams daily reported moderate dizziness. Furthermore, there were no patients in Part B who discontinued the study prematurely for any reason. In other words, all 25 of those patients completed all 14 days of dosing.

CY 4024 was too small to have sufficient statistical power to robustly evaluate the effects of CK-357 on the various outcome measures that were assessed during the study. However, we are encouraged by trends that appear dose related and potentially clinically meaningful in magnitude in the ALS Functional Rating Scale in its revised format, or the ALSFRS-R, and in maximum voluntary ventilation, or MVV.

To remind you, the ALSFRS-R is a clinically validated instrument designed to measure disease progression and changes in functional status in ALS patients. The average change in the ALSFRS-R score is approximately minus 0.9 points per month; about a point per month. In this trial the ALSFRS-R was evaluated twice, on days 8 and 15.

MVV is a clinical assessment of pulmonary function and endurance that measures the maximum volume of air that patients can repeatedly inhale and exhale, expressed in units of liters per minute. In this trial MVV was also evaluated on days 8 and 15.

I can refer you to Cytokinetics' press release from yesterday and I am pleased to say that our investigators were encouraged by the trends toward functional improvements in these clinically important efficacy assessments, as well as by the magnitude of the potential effects. Importantly, there was no evidence for any differences in these outcome measures between patients in Part A who did not receive riluzole and those in Part B who did receive riluzole.

Given what we know about the predictable and progressive rate of functional decline in ALS patients, as measured by the ALSFRS-R and the similarly expected decline in pulmonary function, the fact that increases were observed in these measures in some ALS patients in the trial after only one and two weeks of treatment with CK-357 gives us reason to be optimistic regarding what we may observe in longer and larger trials.

In addition to the data from CY 4024, a poster was presented yesterday at AAN that contained data from CY 4025, another randomized, double-blind, placebo-controlled Phase IIa clinical trial of CK-357 in patients with ALS. In this trial CK-357 was administered for 21 days in ascending multiple doses of 7 days each using a twice-daily regimen. All these patients also took the reduced dose of 50 milligrams of riluzole per day.

Patients were randomized three to one to the twice-daily oral dose titration regimen with CK-357 or placebo. The primary objective of CY 4025 was to assess the safety and tolerability of CK-357 when administered using this twice-daily dose titration regimen to patients with ALS, and to determine if the total daily dose of CK-357 could be increased from the 375 milligrams once-daily dose evaluated in CY 4024 to a target of 250 milligrams twice daily or a total daily dose of 500 milligrams in CY 4025.

27 patients were treated in CY 4025. All 6 randomized to placebo completed three weeks of dosing. Of the 21 patients randomized to CK-357, 14 were escalated to the highest dose of 250 milligrams twice daily and completed three weeks of dosing. The authors concluded that the twice-daily dose titration regimen evaluated in the trial was generally safe and well tolerated, and that the majority of patients could be titrated successfully to 250 milligrams twice daily.

As was observed in CY 4024, dizziness was the most frequently reported adverse event in CY 4025. None of the 6 patients who received placebo in CY 4025 reported dizziness, while 12 of 21 patients experienced dizziness during dose titration with CK-357. In 10 of these patients dizziness was mild. The other 2 patients experienced moderate dizziness.

Like CY 4024, CY 4025 was not powered to evaluate statistically the effects of CK-357 on the various outcome measures that were assessed during the study. Nevertheless, the authors concluded that encouraging trends in the ALSFRS-R and MVV were observed on CK-357 relative to placebo that were similar in both direction and magnitude to those we observed in CY 4024.

We're very pleased with the data from each of CY 4024 and CY 4025. Data from these two trials, together with data from earlier trials conducted with CK-357, will help us optimize dosing regimens for CK-357 in ALS patients and set the stage for further interactions with regulatory authorities.

As Robert mentioned, we recently received fast-track designation for CK-357 for the potential treatment of ALS. As you may know, the fast-track process was designed to facilitate the development and expedite the review of drug candidates intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. A potential drug that receives fast-track designation is also eligible for accelerated approval and a rolling review, as well as possibly a priority review.

Importantly, fast-track designation for a potential drug may allow more frequent meetings between the sponsor and FDA to discuss the development plan and ensure collection of appropriate data needed to support approval, as well as possibly more frequent written correspondence from FDA about such matters as the suitability of designs for proposed clinical trials.

We look forward to engaging FDA in connection with our plans for CK-357 over the next several months. We believe that the fast-track designation for CK-357 from FDA is important. And together with the fact that both FDA and EMA have granted orphan drug designations to CK-357 for the potential treatment of ALS underscores the potential value that regulatory authorities see in our novel mechanism compound for this grievous and ultimately fatal disease.

Lastly, as we have emphasized, our interest for CK-357 are not limited to its potential for the treatment of ALS. As evidence, we continue to enroll patients in our Phase IIa evidence of effect clinical trial of CK-357 in patients with generalized myasthenia gravis.

To remind you, this is a Phase IIa double-blind randomized placebo-controlled three-period crossover pharmacokinetic and pharmacodynamic evidence of effect study. Up to 36 patients may be enrolled at approximately 15 study centers in the United States. Patients enrolled in the trial receive single oral doses of placebo and a CK-357 at 250 and 500 milligrams in random order. This clinical trial and additional preclinical research related to myasthenia gravis are funded by a $2.8 million grant from the National Institute of Neurological Disorders and Stroke.

Turning now to our cardiac muscle contractility program. Together with Amgen we made substantial progress in the first quarter for this program as well. I am pleased to report that we have completed enrollment in cohort one with over 200 patients enrolled in our international randomized double-blind, placebo-controlled Phase IIb clinical trial of intravenous omecamtiv mecarbil in patients hospitalized with acute heart failure.

This trial, known as ATOMIC-AHF, which stands for Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure, is designed to enroll three successive ascending-dose cohorts, each of which will enroll approximately 200 patients randomized one-to-one to omecamtiv mecarbil versus placebo.

The dose of omecamtiv mecarbil in cohort one targeted a peak plasma concentration of omecamtiv mecarbil of approximately 115 nanograms per mL. Cohort two is designed to target a peak concentration of approximately 230 nanograms per mL, and cohort three to target 310 nanograms per mL. Now that cohort one has completed enrollment, an independent data monitoring committee will review the data and determine whether it is appropriate to open the next cohort.

Alongside the progress in our Phase IIb trial, in the most recent quarter Amgen initiated a Phase I randomized open-label 4-way crossover study designed to evaluate multiple formulations of omecamtiv mecarbil in healthy subjects. That's multiple oral formulations. Approximately 60 subjects will be enrolled in this study. Each will receive 2 of the 6 oral formulations included in the study, each administered as a single dose under both fasted and fed conditions.

The primary objective of this study is to determine the effect of food on the bioavailability of omecamtiv mecarbil when administered in these multiple oral formulations. The secondary objectives are to evaluate the bioavailability, safety, tolerability and pharmacokinetic profiles of omecamtiv mecarbil when administered in these multiple oral formulations. Results from this clinical trial are expected to guide selection of one or more oral formulations of omecamtiv mecarbil for later stage clinical trials in patients with heart failure.

Advancing both the intravenous and the oral program in parallel is a priority as we prepare to study them together in a combined regimen of omecamtiv mecarbil for the potential treatment of heart failure. As always, additional information about all our Phase II trials can be found at www.clinicaltrials.gov.

And with that update on our clinical development activities in the first quarter, I'll turn the call back over to Sharon.

Thank you, Andy.

As our press release contains detailed financial results for the first quarter of 2012, I'll refer you to that public statement for the details on our P&L and balance sheet.

We ended the first quarter with approximately $43.1 million in cash, cash equivalents and investments, excluding restricted cash, which represents approximately 13 months of going-forward net cash burn based on our 2012 financial guidance.

Our first quarter 2012 R&D expenditures totaled $8.7 million. From a program perspective, for the first quarter approximately 67% of our R&D expenses were attributable to our skeletal muscle contractility research and development activities, 13% to our cardiac muscle contractility activities, 9% to our smooth muscle contractility activities, and 11% to our other research activities.

We continue to focus our financial resources largely on the progression of our skeletal muscle contractility research and development program. We believe that this program, together with our cardiac muscle contractility program which is partnered with Amgen, represents opportunities for the nearest-term value generation for the Company, as Robert will outline in a moment with the milestones for the remainder of 2012.

In the first quarter of 2012 we continued to close corporate partnering transactions that we believe can contribute to an extension of our cash resources. In recent weeks we extended our collaboration with Global Blood Therapeutics, a Third Rock Ventures company. This transaction affords us sponsored research through the remainder of the year.

Moreover, together with previously announced continuation of our joint research program with Amgen, in which they also are supporting scientists at Cytokinetics, we are moving us closer to our objective of having a significant portion of our research expenses sponsored by third parties at a time when our expenses in development are expected to increase.

We believe that our taking these creative steps forward ensures that we can be both financially prudent and strategically thoughtful about how we mature our R&D organization and retain the expertise and knowhow that has contributed to our uncommon excellence in R&D.

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

Thank you, Sharon.

This has been an exciting week for Cytokinetics and it punctuates a similarly very exciting quarter. The data presented this week here at AAN relating to CK-357 represents the culmination of hard work and has set the stage for our potential progression into registration studies.

In addition, enrollment in the ATOMIC-AHF trial has steadily increased and we look forward to the safety data review by the independent data monitoring committee, which may enable that clinical trial to progress to the next stage.

It is nice to see both of these novel mechanism muscle biology programs maturing in such a way as can provide meaningful hope to ALS and heart failure patients, respectively. All -- as is well documented, both populations are in need of new therapies to address unacceptably high morbidities and mortality.

In the last quarter we also continued to demonstrate that our continued commitment to ongoing research at Cytokinetics could deliver important returns on investment and that we could monetize that commitment in transactions that offset certain costs and affords a fiscally prudent path forward.

As evidence of the value of our persistent dedication to muscle biology research, our scientists presented important preclinical data yesterday at each of the American Academy of Neurology and Experimental Biology meetings. At AAN Cytokinetics' scientists presented a poster containing data from a preclinical study designed to examine the effects of CK-357 in SOD1 mutant transgenic mice, a model of ALS in humans.

The authors concluded that mice treated with CK-357 maintained hind-limb grip strength during disease progression and that CK-357 increased muscle strength of a nerve muscle pair in situ. In addition, the results evidenced a delay in the time to a pre-specified humane endpoint in the CK-357-treated mice compared to the age-match control, SOD1.

At the Experimental Biology meeting Cytokinetics' scientists presented results from a preclinical study designed to assess the effects of CK-357 in two models of running fatigue, one aerobic and the other anaerobic. The authors concluded that skeletal muscle troponin activators such as CK-357 improved performance in an endurance-type fatigue assay and an assay that tests motor coordination under moderately fatiguing and increasingly difficult conditions. These data suggest a role for CK-357 and other skeletal muscle troponin activators in reducing muscle-related fatigue that may have utility in disease conditions in which muscle-related fatigue may lead to disability.

I believe our determined commitment to ongoing translational research at Cytokinetics is informing potential clinical development strategies for CK-357, and also may benefit our potential partnering strategies.

Now, with respect to partnering strategies, I'm often asked to comment on potential progress in connection with the partnering of our skeletal muscle program. Obviously, I must be careful as most of the relevant details of our ongoing discussions remain highly confidential.

What I can say is this, that we continue to explore the possibility of partnering; but to be clear, on terms that we believe are important to ensure that CK-357 is developed intelligently and swiftly for ALS patients and their families. Recent clinical and preclinical data support Cytokinetics' views towards potential deal terms. As mentioned previously, we have made it a corporate priority to ensure that any deal we may do is one that we can confidently believe aligns with the urgency and quality of the drug development program and is consistent with the progress we ourselves have demonstrated to date.

Can we do a deal on those terms? Yes, we believe that we can. If not, however, we may explore other ways to ensure that our program can be funded, even as we may require our taking another look at cost structures, other revenue possibilities and other strategic and financing possibilities. We remain open to an array of these options to ensure we can continue to execute on what we believe to be the best path forward for these programs and for Cytokinetics.

Now, let me turn to the milestones for the remainder of 2012. Turning firstly to our skeletal muscle contractility program for CK-357. In the second half of 2012 we anticipate that data will be available from our ongoing Phase IIa Evidence of Effect Clinical Trial of CK-357 in patients with generalized myasthenia gravis.

In 2012 we anticipate interactions with regulatory authorities to discuss the development of CK-357 as a potential treatment for patients with ALS, including potential registration strategies. And for CK-20127107, or CK-107, by the end of 2012 we anticipate filing an IND for this potential drug candidate, CK-107.

Next, turning to omecamtiv mecarbil. In the second quarter of 2012 we anticipate a decision regarding the potential progression to the second cohort of the ATOMIC-AHF clinical trial following review of data from cohort one by the independent data monitoring committee.

Also in the second half of 2012, we anticipate that safety, tolerability and pharmacokinetic data from the ongoing Phase I clinical trial of oral formulations of omecamtiv mecarbil in healthy volunteers will be evaluated. These data are expected to enable selection of one or more of those oral formulations to be evaluated in potential studies to follow in stable heart failure patients.

As you can see, we expect continued progress in our leading clinical stage muscle biology programs through the remainder of the year and I look forward to providing future updates.

And with that, Operator, that concludes the formal portion of our call today and I'd now like to open up the call for questions.

(Operator Instructions). Our first question comes from the line of Charles Dunkin with JMP Securities.

Good afternoon.

Hi, guys. This is Roy in for Charles. Thanks for taking the question. Just one quick question. I wonder if you could discuss possibly some of the options that you see for a capital efficient approach to further development of 357 in ALS. We noted that the survival trials in the past have generally gone over a year.

That's a very good question and I'll start and see if Andy has anything he wants to add.

To be clear, based on conversations we've had with regulatory authorities, we don't assume that we're going to need to demonstrate a survival advantage, although that will certainly be something that will be assessed over time in order to be getting a first approval for CK-357.

We do believe that already data from multiple clinical trials of CK-357 in ALS patients are demonstrating improvements in functional status parameters, even after the first dose, and continuing now over two and three weeks evaluated. And that, if we see a persistence of improved functional status or even a change in the rate of decline of functional status as measured by validated instruments like ALSFRS-R, that we believe that would warrant a potential registration approval. So, we think that will be a more capital efficient approach to garnering registration for CK-357.

Okay. Thank you, Robert. Very helpful. Congratulations on the progress.

Sure thing.

Our next question comes from the line of Mike King with Rodman & Renshaw.

Hi, Mike.

Hey, good afternoon, Robert and team. Thanks for taking the question. I -- a little bit frustrated because I hate to see your stock react so badly to what otherwise looks like very good news today. And just wondering if you might speak to, well, a couple of aspects of the 357 results.

Andy, can you just help us understand a little bit better that -- it seemed like the prognostic factors were sort of skewed against 357 in various patient cohorts. I just wonder how one can take that into account when considering -- even beyond the numbers, I mean -- so, the numbers in the context of the underlying patient characteristics rather than just sort of treated versus placebo. Is that -- does that make sense?

I'm not quite sure if I'm clear on what you're asking. These are two small studies, so you don't really have a whole lot of data to ensure a balanced distribution across treatment groups. But, I mean, really, in this -- in the 4024 study where the patients received two weeks of dosing without titration, the MVV was significantly higher in patients on placebo.

Right.

I don't know that that necessarily skewed things against 357. Actually, you could argue it might have gone the other way, that the 357 patients, having lower maximal voluntary ventilation, had more room to improve than the placebo patients, and yet still the improvements were better on 357 than on placebo in that study, as well as in the other trial.

Right.

I think they're too small to try to read too much into them. I think the bottom line is things are certainly lining up in the right direction and they're doing it at about the same magnitude sort of every time we do it, even though there are different groups of patients and the doses may be a little different and so forth.

Okay. And then, just to turn to the topic of dizziness for a bit, I'm just wondering -- your thoughts about it, both from a kind of a pharmacologic point of view, as well as a clinical point of view. So from a pharmacologic, is it a -- do you understand if it -- is it PK -- was it Tmax, Cmax or some other metric related to that or --? And then, from a clinical standpoint, how important do you believe it is to reduce or eliminate the dizziness in order to prevent unblinding in registration trials?

So, we have not completed a full pharmacokinetic-pharmacodynamic analysis of these trials that we just presented yesterday. But in the past, what we have seen is that the likelihood of dizziness does appear to be related to higher Cmaxs and shorter Tmaxs. And that's why we went to the twice-daily dosing regimen in the study that we did do and -- to reduce the Cmax and also to raise the trough.

You raise an interesting point that we've discussed before about the dizziness being potentially unblinded -- unblinding. I don't know that there's too much we can do, but I would point out that not every patient gets dizzy. And in fact, I think we did achieve our goal in the dose titration study of actually reducing the overall occurrence of dizziness even as we got to a higher total daily dose. So, it was only 12 of 41 who got dizzy at all; and of those 12, 6 of them really had very transient episodes of dizziness.

So in the end, I don't know how particularly unblinding it will be. It is true that we almost never see it on placebo and we see it only on 357, but we are now to the point where we're sort of seeing it really in a -- on a prolonged sustained basis, really even only in the minority of the 357 patients.

Maybe, Mike, just to add to that, and also to your point about the stock price, I can't comment on the stock price, but what I can say is that here in New Orleans, amongst the investigators who shared in the presentation of the data and then afterwards, I think there's a general consensus that we hopefully put that issue to bed in terms of lightheadedness or dizziness. That while it is reported as the most common, most frequently cited AE, it is mostly mild and, even when not, it tends to abate with multiple dosing.

So, that was a key question coming out of a study that we conducted about a year ago. And now, with these two studies, one fixed oral dose, the other ascending-dose titration oral dose, I think it's fair to say that we've asked and answered that question and we've demonstrated with these data in these patients in these studies that the drug seems safe and well tolerated.

Okay. Maybe just -- not to press the point, but is it possible to start low and go slow, start at a lower dose and increase the dose over some period of time, whether it's days or weeks, to see if that also might help?

Well, that's what we did in 4025. We started at 125 milligrams twice a day and a week there, and then a week at 125 in the morning and 250 in the afternoon, and then a third week at 250 in the morning and 250 in the evening. And as I say, among the patients who received that regimen, only a little over half of them complained of dizziness.

Yes.

I don't know that I'd want to start much lower and go too much slower because we do want to get the therapeutic concentrations in a reasonable period of time.

Yes.

And -- but, it did -- it certainly did decrease the occurrence of dizziness and it mostly resolves.

And it shouldn't be lost in this conversation that, by doing that, by splitting the dose and dose titrating, we got a majority of patients to an even higher dosing level than we had ever achieved before on single oral doses, but now on multiple oral doses. So, you would expect that we're getting to even higher plasma concentrations and more patients are above the threshold plasma concentrations that we targeted. So, I think that's also very good news.

Okay. I appreciate the color. Do you think you've got -- I mean, are you satisfied now that you've got the right Phase II dose for 357?

I'll want to look at the plasma concentration data in more detail. We haven't had the opportunity to do that yet. But, my gut tells me that we wouldn't be well advised to try to push too much higher than where we've got, to 250 twice a day.

I do think we can probably be more successful in getting most patients up there. I think we found that in Part B of 4024 there were a couple of patients who had a very minimal dose interruption; one one day and another two days due to adverse events that may well have been due to the drug, but they then were able to go back onto treatment and complete the study normally.

Yes. Yes.

So, I mean, I think with a few additional strategies like that, allowing a day or two at a time of dose interruption if necessary and maybe suggesting or even having a protocol written to require that, there needs to be at least a second attempt to up-titrate in the event of a first failure. I'll bet you we'll do better than getting two-thirds of the patients to that dose. I mean, can I prove it yet? No, but I believe that we can probably be more successful in elevating almost all the patients to that dose and have them stay there.

Right. Okay. Listen, let me jump back in queue and let someone else take a shot. Thank you.

Thanks, Mike.

Our next question comes from the line of Brian Klein with Lazard Capital Markets.

Good afternoon, Brian.

Hi, guys. Thanks for taking the questions and congrats on the data.

Thank you.

So, a couple questions here. Andy, maybe you can help me understand. In the lowest dose in both trials, does the data suggest that the patients did worse than placebo?

No, I don't think you could really say that.

Because you're seeing, at least in the ALSFRS scores, that it continues to go negative as opposed to turning positive. So, I'm just trying to understand what the significance of that is.

So, I mean, we -- that would -- you're probably looking at data from the combination of Parts A and B of 4024?

Yes.

So, I don't see that. If you look at the scatter plot that was presented yesterday, the biggest decreases in the study in ALSFRS-R were on placebo. No patient on 125 had a decrease that was as big as what was observed on placebo. And at 250 the largest decrease was even less than on 125 and certainly less than on 250. So, I mean, I think there's a fairly clear dose-related trend to seeing the ALSFRS-R go up. What I would say is I just don't think 125 milligrams a day is probably enough to really do anything. So, it's probably essentially like placebo, but I don't see any suggestion that it's making anybody any worse, really.

Okay. Building on that, then, what would you anticipate would be a primary endpoint for your Phase III trial? Would it be looking at the reduction in -- or demonstrating that the decline in ALSFRS is reduced with your treatment, or you're looking at an absolute benefit?

Well, I don't think we would need to show an absolute benefit; in other words, to say that at the end of the study patients on average are actually better than they were at baseline. That would be a wonderful outcome, but more optimistic than I think we even need to hope for. What we really need to show is just that the ALSFRS-R score is higher than in patients treated with placebo. And as long as it is statistically significantly higher after however long we run the study, I think that will be received very favorably.

Okay. And so I would assume that you would power that based on the historical rate of decline, which you mentioned was 0.9 per month?

Yes --.

And then -- go ahead.

That's right. I'm sorry to interrupt, I didn't mean to, but yes. I mean, basically, people will generally tend to accept somewhere in the range of a 20% reduction in that decline. So I mean, if you ran a study for three months and you said that the patients were likely to have had a decline of on average 2.7 points on placebo, 20% of that is not a whole lot. So, a difference from placebo of on the order of 0.5 or 0.6 points would be in that range. And the studies that we contemplate would be powered to detect that kind of a difference.

Great. How many patients do you think you'd have to enroll for that kind of trial?

It does depend on how many groups and so forth and so on, but I would say that in each treatment group that you wanted to study -- okay, it would probably be around at least 150 patients. It depends on how much power you want to have and so forth. But, the next study that we will do will this time be hundreds of patients, not dozens of patients.

Got it. And do you also plan to treat for longer periods of time?

Certainly longer. How much longer is still an item of very active discussion at Cytokinetics. Longer would be better. We're very aware of that. But, it also comes down to under what scenario and what we can afford if we're doing it on our own.

Got it. And then maybe just a question for Sharon. Your guidance at the end of the fourth quarter looking at 2012 for revenue was somewhere in the range between $4 million and $5 million. It looks like you're almost halfway there. Just wondering if you could give some insight into your expectations for Amgen reimbursement and whether that guidance has changed?

So, the Amgen reimbursements were included in our original guidance. What was not included in our original guidance, and is a very recent development for us, is the extension of the Global Blood Therapeutics transaction. So, that doesn't have as much associated with it. So right now, the range that we've provided for guidance is going to stand.

Great. Thanks so much for answering my questions.

Thanks, Brian.

Your next question comes from the line of George Zavoico with MLV & Co.

Hi, George.

Hi, Robert, Sharon, Andy. Congratulations again on the data.

Thank you.

I have a quick question regarding the parallel development on omecamtiv regarding the oral and the IV. You've done a lot more studies in the IV than you've got the oral, so the oral's a little bit behind, I guess. First of all, Andy, is that a fair assessment? And --.

Oh, yes, I think that's a fair assessment. And IV is in a trial of around 600 patients of acutely ill folks. And all we've done with the oral to date is well compensated patients with heart failure and clear evidence of systolic dysfunction, but not decompensated and symptomatic at the time.

So, my question is then, is I imagine since it's essentially the same molecule you can use -- I imagine you could use a lot of the safety and tolerability data to move the oral formulation through maybe a little bit faster for have it catch up. What's your strategy then in getting the oral to catch up to the IV? And when -- because ultimately, I believe you still -- the overall strategy ultimately is to go hospital to home, IV to oral in sort of a smooth transition.

Well, I'll start with that, George. The strategy really is to, with the intravenous form of the drug, demonstrate whether we can translate pharmacodynamic benefits as measured by echocardiographic parameters. And as you've already seen those data, to potential clinical benefit in a population of acutely ill heart failure patients.

With the oral, we may end up ultimately targeting different plasma concentrations in the chronic patient outpatient setting. So, much of what we'll be doing in Phase II is not so much intended to assess for potential efficacy, but to ensure that the oral can be safely administered to those patients over weeks to months of therapy and, in that way, be in a position to do in Phase III a rigorous assessment of IV coupled with oral against clinically meaningful endpoints like death and hospital readmission. Otherwise, you'd be doing in Phase II with an oral form what ultimately you need to do in a Phase III study and there's no point in reproducing that. So, the goal is to get into Phase III, where we can properly interrogate that possibility.

So, is part of the strategy to seek approval for the IV formulation independent of the oral formulation? Is that part --?

That's not the strategy, no. In fact, that may ultimately prove to be a path forward, but that's not the primary strategy. The primary strategy, as we and Amgen have talked repeatedly, is that we think that there's a best opportunity to demonstrate potential clinical benefit by coupling IV and oral as part of a regimen and that's what I expect our base case will look like.

Yes. I didn't think that that strategy had changed. Okay, great. Thank you very much.

Sure thing, George.

And your next question comes from the line of Mike King with Rodman & Renshaw.

Hey, Mike.

Thanks for taking the follow up. I'm just wondering if you guys can comment about what you're looking for in the oral forms of omecamtiv. What -- are you looking for exactly the same profile as the IV or you're looking for something a little bit different? And if you can say it's different, what is it that's different that you're looking for?

Well, I mean, it can't be the same as the IV. Absorption will necessarily be slower and we're not going to be able to maintain a concentration sort of at a continuous rate at steady state like you can do with an IV infusion, although we don't get to steady state even with the IV over the 48 hours of treatment in ATOMIC-AHF.

But, I think what we're looking for in particular is consistency of plasma concentrations at a given dose. So, that's another way in which the oral is never going to be like the IV. The IV is always going to be far more predictable in the concentration that you generate because it's 100% bioavailable. All of it goes in rather with the oral to a greater or lesser degree. And to some extent, dependent upon the formulation, there will be more heterogeneity in how much of the compound is absorbed and how fast. And I think more than anything else, what we'd like to do is try to find the formulation that is most predictable in terms of the plasma concentration that it generates and produces the least variability from patient to patient.

You might remember that we had evaluated previously, prior to even Amgen exercising its option, two oral forms, one which we referred to as immediate release TID and the other a modified release BID. And the goal in evaluating certain of these modified release technologies is to see if we can blunt the more rapid absorption and bring peak and trough ratios closer together to, as Andy points out, have therefore a more predictable pharmacokinetic profile.

Okay. So, you want slow uptake, steady concentration and then a gradual decline.

I think that's right.

Fair enough? Okay. Thanks very much.

Sure.

And there are no further questions in the queue at this time.

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With that, Operator, we can conclude the call.

Thank you, ladies and gentlemen. This does conclude today's conference call. You may now disconnect.