Cytokinetics Inc (CYTK) 2017 Q4 法說會逐字稿

Good afternoon, and welcome, ladies and gentlemen, to the Cytokinetics Fourth Quarter 2017 Conference Call. At this time, I would like to inform you that this call is being recorded. (Operator Instructions) I will now turn the call over to Diane Weiser, Cytokinetics' Vice President of Corporate Communications and Investor Relations. Please go ahead.

Good afternoon, everyone, and thank you for joining us today. Robert Blum, our President and Chief Executive Officer, will kick off the call with a few introductory comments about the current state of our business. Then, Fady Malik, our EVP of Research and Development, will provide updates on the Phase III department program for omecamtiv mecarbil. Andy Wolff, our SVP and Chief Medical Officer, will then share some insights following further analysis of results from VITALITY-ALS and key lessons learned that may be applicable to the ongoing development of CK-2127107 or CK-107. Andy will also provide an update on FORTITUDE-ALS, the Phase II clinical trial of CK-107 in patients with ALS. Fady will then provide updates on the other clinical trials in the development program for CK-107 and speak to our expanding pipeline emerging out of research. Pete Roddy, our SVP and Chief Accounting Officer, will provide the financial overview for the quarter; and Ching Jaw, our SVP and Chief Financial Officer, will share our 2018 financial guidance as well as strategies to extend our cash runway before Robert concludes with additional perspectives on our company outlook and expected 2018 corporate milestones before we open the call for questions.

Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements for purposes of the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. Examples of forward-looking statements may include statements relating to our financial guidance and goals, our strategic initiatives, our collaborations with Amgen and Astellas, clinical trials and the potential for eventual regulatory approval of our drug candidates. 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 8-K. We undertake no obligation to update any forward-looking statements after this call.

And now I will turn the call over to Robert.

Thanks, Diane, and thanks again to everyone for joining us on the call today. We begin 2018 with a bright outlook for Cytokinetics despite the disappointing results last year from VITALITY-ALS. While we had prepared the company to progress rapidly to regulatory filings and the potential commercialization of tirasemtiv had the outcome of VITALITY-ALS positive, we are not in that position today, having suspended development of tirasemtiv. However, as we have stated many times, it is in times like these when our R&D and business strategies architected to create a diversified pipeline in the pharmacology of muscle biology matters most.

Cytokinetics was built from our first day to not pivot on the outcome of a single program or clinical trial but instead to push forward a diversified portfolio of novel mechanism drug candidates. We maintain an agile business model which enables us to pivot quickly and refocus the company in response to scientific and clinical data and to allocate resources where they offer the best opportunity to monetize our progress and advance investigational medicines to the benefit of patients and to maximize shareholder return.

As we have previously outlined, we prepared for the current scenario strategically, operationally and financially. Now the combination of a late-stage pipeline, including 2 first-in-class muscle activators, productive collaborations with Amgen and Astellas, a growing pipeline of next-generation and novel compounds and a strong balance sheet, altogether provide a solid foundation on which we are building our future.

On this call, we will report on expected milestones for clinical trial programs underway with both omecamtiv mecarbil, under our collaboration with Amgen; and CK-107, under our collaboration with Astellas.

Regarding CK-107, we recently gained approval for use of reldesemtiv, as the international nonproprietary name from the World Health Organization and the United States Adopted Name Council. Therefore, we will start using that generic name, reldesemtiv, for CK-107 on this call. We will also point to exciting compounds emerging from research and elaborate on our financial outlook as we continue to execute well in our R&D programs.

There is much to be optimistic about as we continue to execute our multipronged research and development strategy at Cytokinetics. 2018 promises to be an important year as we further elucidate the potential of reldesemtiv, as it may inform a potential Phase III clinical development program in 2019 and as we advance the Phase III clinical program for omecamtiv mecarbil while also beginning to unlock the potential of newer compounds emerging from research.

Now let me turn the call over to Fady so he can update you on omecamtiv mecarbil.

Thanks, Robert. GALACTIC-HF, the Phase III cardiovascular outcomes clinical trial being conducted by Amgen under our collaboration, is proceeding well with regulatory approvals for the trial secured in all 35 countries and significantly having achieved the activation of over 700 sites that are currently enrolling patients.

We're pleased to note that the trial is on track in enrolling patients that have the intended risk profile consistent with the trial design. We also continued protocol development, feasibility assessments, regulatory interactions and other readiness activities for a second Phase III clinical trial of omecamtiv mecarbil that is planned to be conducted by Cytokinetics in collaboration with Amgen. After consideration of the specifics related to the design and feasibility, we've decided to focus this trial on the potential of omecamtiv mecarbil to increase exercise performance in patients with heart failure which could distinguish omecamtiv mecarbil from other medicines used for the treatment of heart failure. The goal is to complete this trial and report results at the same time with GALACTIC-HF.

Our shared objective with Amgen is to consider additional clinical research, for example, as we've stated previously, related to the potential for omecamtiv mecarbil to reverse the progressive enlargement of the heart in patients with heart failure. Our objective in the overall clinical program is to elucidate how the novelty of mechanism for this first-in-class cardiac myosin activator and translate the clinical evidence that supports a meaningfully differentiated product profile.

And now I'll turn the call over to Andy to discuss perspectives and lessons learned from VITALITY-ALS as well as to update you on the progress of FORTITUDE-ALS.

Thanks, Fady. We reviewed results from VITALITY-ALS back in November. So today, I'd like to reflect on our continuing analyses that may apply to our ongoing development program for reldesemtiv. As you know, despite our actions to improve upon the tolerability challenges we observed in BENEFIT-ALS by extending the open-label lead-in phase from 1 week to 2 weeks and prolonging the dose titration steps in VITALITY-ALS, we unfortunately saw that the percentage of patients treated with tirasemtiv who discontinued double-blind treatment prematurely was still nearly 3x higher than on placebo.

Interestingly, in VITALITY-ALS, the rate of decline in slow vital capacity, or SVC, among the placebo patients was slower than what has been observed in previous trials, including BENEFIT-ALS, EMPOWER and those contributing to the PRO-ACT database. Based on those trials, we expect that the average decrease in SVC over 24 weeks to be approximately 16.2 percentage points. In VITALITY-ALS, SVC declined by 14.4 percentage points during 24 weeks on placebo, less than expected and the smallest decline from baseline to 24 weeks observed in a recent major controlled clinical trial in patients with ALS. In addition, mortality at 48 weeks was less than half of what was observed in the Phase III EMPOWER trial of dexpramipexole, the most recent large clinical trial in patients with ALS. These observations occurred despite the fact that baseline characteristics from these recent studies were similar to those in VITALITY-ALS. Whatever may underlie it, this apparent change in the rate of ALS disease progression in patients enrolled in VITALITY-ALS, despite using typical inclusion criteria, will need to be considered carefully as we plan for a potential Phase III trial with reldesemtiv in 2019.

Importantly, unlike BENEFIT-ALS in which the primary analysis was essentially an on-treatment analysis, in VITALITY-ALS, we conducted an intent-to-treat analysis. In order to reduce the amount of missing data in the primary analysis, we focused on keeping patients in the trial, whether or not they remained on double-blind study drug. This contributed to our inability to demonstrate a clear benefit of tirasemtiv versus placebo because the primary efficacy analysis included many patients randomized to tirasemtiv who contributed an SVC measurement to the primary endpoint at 24 weeks despite having terminated treatment often months earlier. Despite all of this, the results presented at ALS/MND in December as well as the results from several additional analyses that we have conducted reaffirm our belief that there was a biological effect observed in VITALITY-ALS, which supports the continued development of reldesemtiv. Our ongoing analysis of VITALITY-ALS will inform our statistical analysis planned for FORTITUDE-ALS, and our experience conducting our first Phase III clinical trial will surely inform the design of a potential next Phase III trial for reldesemtiv in ALS.

I also want to comment on the status of VIGOR-ALS, the open-label extension clinical trial for patients who completed VITALITY-ALS. There are over 100 patients continuing treatment with tirasemtiv in this trial. And earlier this week, we convened an expert panel of ethicists, ALS patient advocates, clinicians and other experts in pre-approval access to advise us regarding how best to continue to provide access to tirasemtiv for these patients. We plan to make a decision regarding continued access to tirasemtiv in the current quarter.

Because we were aware of tolerability challenges with tirasemtiv early in its development, we designed a next-generation fast skeletal muscle troponin activator, which is reldesemtiv, from a distinct chemical scaffold to eliminate the off-target effects and drug-drug interaction seen with tirasemtiv and to improve potency. As Fady will elaborate, we have demonstrated these intended improvements in recently published Phase I studies in healthy volunteers.

Moving to FORTITUDE-ALS, our ongoing Phase II study of reldesemtiv in patients with ALS. Site activation and enrollment activities are progressing well. We believe that FORTITUDE-ALS offers us the opportunity to test the therapeutic hypothesis of skeletal muscle activation in ALS without the compounding tolerability issues we faced with tirasemtiv. In addition, in FORTITUDE-ALS, we have included novel functional measures of speech and handwriting and measurement of SVC at home. To date, 45 sites are activated, over 120 patients have been screened and nearly 90 had been enrolled, so we are well on our way to completing enrollment in the first half of 2018, with results expected in the second half of the year.

During this first quarter, senior members of our team will visit essentially all the sites participating in FORTITUDE-ALS to engage our investigators, review with them the results from VITALITY-ALS and remind them of the critical differences between reldesemtiv and tirasemtiv. In general, our investigators remain optimistic regarding the potential application of reldesemtiv in ALS, view FORTITUDE-ALS as one of the most important trials they are conducting and don't foresee any issues enrolling FORTITUDE-ALS in the context of the results of VITALITY-ALS. Those that are enrolling patients have observed significantly better tolerability with reldesemtiv compared to tirasemtiv. We appreciate that our investigators continue to share our belief in the potential therapeutic benefit of fast skeletal muscle troponin activation in ALS and are grateful for their efforts to conduct FORTITUDE-ALS. We look forward to completing this clinical trial and reporting results before the end of the year.

Now I'll turn the call back over to Fady to provide additional updates on reldesemtiv as well as developments in research.

Thanks, Andy. In parallel with bringing VITALITY-ALS to a close, we're busy in the fourth quarter advancing the 4 mid-stage clinical trials of reldesemtiv in both neuromuscular and non-neuromuscular diseases or conditions in which impaired muscle function and weakness play a meaningful role.

As you know, in addition to ALS, these include clinical trials in spinal muscular atrophy, chronic obstructive pulmonary disease and frailty. Cytokinetics is conducting the neuromuscular trials, while Astellas is conducting the non-neuromuscular trials. We're proceeding with urgency and hope to result -- report results from all of these clinical trials in 2018.

I'd like now to update you on how these additional clinical trials are progressing toward this goal as well as to elaborate on the recently published Phase I studies pointing towards potential greater potency and tolerability of reldesemtiv compared to tirasemtiv.

We expect to report results from the Phase II clinical trial in patients with SMA first. As you know, we've worked diligently now for nearly a year to enroll a second cohort of CY 5021 which opened in March 2017. It's been slow-going for several reasons. First, the availability of nusinersen in 2017 led many eligible patients to seek treatment with this novel therapy, and many of them are not interested in participating in another clinical trial while they go through the approval process to obtain it. The screen failure rate continues to sit at approximately 50% due in most part to patients being either too functional or not functional enough as we have said before. Sites have exhausted their pools of potential patients based on their clinic rosters. And since many of these older patients are not connected to a clinic on an ongoing basis, they're now more dependent on identifying new patients outside their practice.

On the plus side, after enrolling 75% of the patients in Cohort 2, we've conducted a blinded analysis of variability for the change from baseline of several of our efficacy measures. In short, based on this analysis, CY 5021 appears to have sufficient statistical power to check differences versus placebo in the efficacy endpoints that are less than that which represents generally accepted clinically meaningful differences. Therefore, in consultation with our partners at Astellas, we have recently elected to inform sites of our plans to conclude enrollment in Q1. We will then proceed to a final analysis of the data once the patients conclude dosing. We believe moving forward expeditiously to understand if there's a potential effect of reldesemtiv on a function of patients with SMA is critical given the evolving therapeutic landscape in SMA. And we look forward to sharing the data from this clinical trial with the SMA community during Q2. It's an interesting time in SMA patient care, and we're beginning to see an evolution within the community akin to what we have recently seen in ALS, that is greater urgency and attention by the community to better inform our understanding and definition of endpoints using clinical research. The Cure SMA consortium, in which we participate, is leading such activities to evaluate clinic effects for patients beyond just the technical point score of the Hammersmith scale, for instance. For example, a small increase in the strength and stamina of a thumb movement could lead to more independent control of a motorized wheelchair that could be immensely meaningful to these patients living with SMA.

Moving now to the other ongoing trials with reldesemtiv conducted by Astellas under our collaboration. At the end of 2017, we are nearly 80% enrolled in the Phase II clinical trial of reldesemtiv in patients with COPD. Furthermore, in terms of the Phase Ib study of reldesemtiv in elderly adults with limited mobility, we have 6 clinical trial sites activated and screening with 15 subjects enrolled in 2017 towards a goal to enroll a total of 60 subjects. Also during the quarter, as Andy mentioned, 3 Phase I studies of reldesemtiv are published in the journal Muscle & Nerve that highlight some key differences this compound has from tirasemtiv with respect to potency and tolerability. The most telling Phase I study looked at pharmacodynamic effects in healthy volunteers and was similar to a previous study conducted with tirasemtiv. In this study, we stimulated the deep tibial nerve which runs on the outside of the knee and controls the tibialis anterior muscle in the front of the leg. The force produced during stimulation of the nerve was measured before and at several points in time after subjects received single doses of reldesemtiv. We found that the magnitude of response was twice as large over a range of plasma concentrations that was approximately half that which we observed with tirasemtiv. This is largely because reldesemtiv is less protein-bound and, therefore, penetrates the muscle more effectively, producing a larger effect. Additionally, the tolerability issues observed with tirasemtiv in Phase I were not observed with reldesemtiv. As we look to results of our fourth mid-stage clinical trials, we hope to see these results translating to improvement in muscle force, power and stamina in the 4 diseases or conditions of muscle weakness or impairments.

Finally, as we announced at the start of the year, we have been especially diligent and productive in our collaborative and independent research programs. As we mark Cytokinetics' 20th anniversary, we celebrate nearly a dozen development compounds that have emerged from our research with a primary focus on skeletal and cardiac muscle contractility. We recently announced 3 new development compounds, one each under our collaborations with Amgen and Astellas and another independently. We are proud that our pioneering leadership and innovation in muscle biology continue to flourish.

Firstly, we're advancing another next-generation skeletal muscle activator under our collaboration with Astellas. Our strategy is to develop a flexible portfolio and franchise approach in which reldesemtiv may be developed for certain indications whereas the next-generation compound may be more appropriate for other indications. Our research collaboration was recently extended through 2019, and discovery will focus on both fast skeletal muscle troponin activators and other novel mechanism skeletal muscle activators. Additionally, we're also advancing a next-generation cardiac muscle activator under our collaboration with Amgen. We expect to have more to say about this first-in-class compound as it approaches its Phase I study. Additionally, we're advancing a cardiac sarcomere directed compound from our independent muscle biology research. And we plan to elaborate on both of these exciting new compounds later this year at a company R&D day.

With those updates, I will now turn the call over to Pete to provide an update to our financials.

Thank you, Fady. After I make several comments on our cash, our revenue and spending on research and development, Ching will provide guidance for 2018 and related financial strategies. More details are included in the press release itself.

We ended the fourth quarter with $285 million in cash, cash equivalents and investments. Milestone revenue in Q4 included $1 million earned under our strategic alliance with Amgen related to the nomination of a next-generation cardiac muscle activator development candidate. Other license and R&D revenue in Q4 came primarily from our strategic alliance with Astellas.

Our revenue in Q4 was reduced by $6.3 million and, for all of 2017, by $20 million as we continue to co-fund GALACTIC-HF, increasing potential royalties on future sales of omecamtiv mecarbil. We have 3 more quarterly payments of $6.3 million for a total of about $19 million until we have completed our co-funding commitment of $40 million.

Our fourth quarter 2017 R&D expense totaled just over $26 million. About 82% of our R&D expenses were attributable to our skeletal muscle contractility programs, which include both expenses associated with the development and clinical trials for tirasemtiv and reldesemtiv, 13% to our cardiac muscle contractility programs and 5% to our other research activities. These percentages approximate what we've seen in prior quarters with an as-expected increase for reldesemtiv and an appropriate decrease in expenses for tirasemtiv.

Our fourth quarter G&A expenses include investments -- included investments in commercial readiness through the availability of results from VITALITY-ALS, which were effectively truncated thereafter. Our commercial planning colleagues went to great lengths to, where possible, make planning commitments contingent on the potential positive results of VITALITY-ALS.

Lastly, I'll note that accounting for the Q1 2017 sale of Q2 royalties to Royalty Pharma gave rise to a noncash interest expense in 2017 of $14.0 million.

I'll stop there, and Ching will share our guidance for 2018 cash needs and related strategies.

Thanks, Pete. Today, we announce our financial guidance for 2018. The company anticipates cash revenue will be in the range of $17 million to $23 million, operating expenses will be in the range of $105 million to $115 million and net cash utilization will be approximately $100 million. With current cash of $285 million, this represents over 24 months of cash runway given our 2018 guidance.

Cash revenue guidance excludes the $19 million contra revenue from our co-funding of the Phase III development program for omecamtiv mecarbil, partially offset by other cash payments that we expect to receive but won't recognize as revenue in 2018. Our estimate of net cash utilization in 2018 of approximately $100 million takes these 2 items into consideration. Compared to 2017, we will be reducing the net cash utilization by 15% to 20% year-over-year. Immediately following the results of VITALITY-ALS, we froze headcount and quickly moved to wind down clinical site activities and contracts associated with potential commercialization of tirasemtiv, such as commercial API supply contracts, with no penalties. We will also significantly reduce our clinical costs in the near term as part of our current clinical trials are reimbursed by our collaboration partners.

While we move forward to multiple data readouts for reldesemtiv this year, we recognize that our most valued catalyst in the pipeline are expected results from GALACTIC-HF in 2020 or 2021. Our goal is to manage our current $285 million cash through this important milestone without relying on dilutive financing. As has been our practice, we will look for opportunities to raise non-dilutive capital through potential collaboration deals and our unpartnered cardiac sarcomere directed program, which we expect to advance to Phase I later this year.

We also are eligible to receive milestone payments from our existing collaborators over this time period. As always, we will take a strategic and risk-mitigated approach to our financials, and we are pleased to begin and hope to end 2018 with a strong cash position while we advance our expanded pipeline.

With that summary, I will now turn the call back over to Robert.

Thank you, Ching. So as we begin our 20th year of company operations, we do so with the same ingenuity, perseverance and conviction as we had on day 1. We remain on track to execute against our Vision 2020 strategy to advance and expand our pipeline with the addition of 3 new potential drug candidates moving into development as well as expected results from 4 mid-stage clinical trials of reldesemtiv as well as the continued enrollment of GALACTIC-HF.

It is especially gratifying to note that while our powerful research engine continues to drive innovation as evidenced by 3 novel mechanistic compounds moving forward for diseases and conditions associated with muscle weakness and impaired muscle function, we are also exploring additional research platforms for potential clinical applications that extend beyond muscle contractility and include muscle growth, energetics and metabolism. Along the way, we remain authentically patient-centric and purpose- and values-driven. 2018 is off to a productive start, and I'm optimistic about all we'll accomplish of this year.

Now let me recap our expected milestones for 2018. For omecamtiv mecarbil, we expect to complete enrollment of patients with chronic heart failure in GALACTIC-HF in approximately 1 year. We also expect to finalize plans for the second Phase III trial of omecamtiv mecarbil, which is intended to evaluate its potential to increase exercise performance in patients with heart failure.

For reldesemtiv, we expect results from a Phase II clinical trial of reldesemtiv in patients with SMA in Q2 of 2018. We expect results from a Phase II clinical trial of reldesemtiv in patients with ALS in the second half of 2018. We expect results from a Phase II clinical trial of reldesemtiv in patients with COPD also in the second half of 2018. And we expect results from a Phase Ib clinical trial of reldesemtiv in adults with limited mobility also in the second half of 2018.

For our preclinical research. We expect to advance 2 development compounds, 1 with Amgen, 1 with Astellas, into IND-enabling studies in 2018, one of which may proceed to Phase I this year. We also expect to advance in unpartnered cardiac sarcomere directed compound through IND-enabling studies in 2018 to enable initiation of Phase I in 2018. And we expect to continue research activities under our joint venture research program with Astellas directed to the discovery of next-generation skeletal muscle activators.

Operator, with that, we can now open the call up to questions, please.

(Operator Instructions) Our first question is from the line of Mara Goldstein from Cantor Fitzgerald.

I'm hoping you could maybe just give us a little bit more color on the exercise performance study that you spoke about in terms of what are the broad parameters that you used to design the trial base on and what's the delta that you'll be looking at.

Sure. Just to be clear, you're referring to the second Phase III trial of omecamtiv mecarbil.

Yes, that is correct.

I'll turn it to Fady to answer your question.

I think I'm going to -- it's still a little early to give you specifics with regards to the exact endpoints and how we're designing the study. We'll certainly be prepared to describe that in a lot more detail later in this year as we lock those details down. But I think, as you know, in heart failure, there are several types of ways of assessing exercise performance. We are leaning towards one specific mean, but also we're interested in incorporating other measures of assessing patient activity, more modern techniques such as actigraphy and activity monitoring as potentially secondary exploratory endpoints. But the size of the trial will certainly be much smaller than GALACTIC, it'll encompass hundreds of patients and also its duration of treatment will be limited, more in the range of what we did, say, for COSMIC than being open-ended as it is for GALACTIC. I'm sorry I can't be more specific, but I think it's still a little early to speak into details of the protocol.

Okay. And then if I could just ask, switching gears for a second to reldesemtiv, on the SMA trial that you'll read out and the discussion around looking at the data in a blinded fashion and being able to maintain power. So when you report those results -- and again, there was no primary endpoint, correct? So is there a hierarchy of, if you will, sort of power that's distributed amongst those endpoints that you'll look at? And so how should we think about that when you report those results out?

Yes. There is no hierarchy of endpoints. All the endpoints are treated equally basically. And being an exploratory study, we haven't adjusted for multiplicity either. So each endpoint is evaluated independently. We'll look at it basically on the same level of each -- each endpoint will be sitting on the same platform as we evaluate them. And all of the p-values that describe them will be nominal.

And our next question is from the line of Jason Butler from JMP securities.

Just one on, I guess, broadly the reldesemtiv program in ALS. Can you talk a little bit about what you learned from the control arm in VITALITY, how it compared with historical studies and how it compared with what you would have expected and if there are any learnings that flowed through there and to the reldesemtiv Phase II program?

Yes. I'll admit that this has been somewhat unsatisfying to this part because we are still in the process of trying to glean and crystallize some learnings from the VITALITY-ALS experience. We've been somewhat surprised by some of the things that we learned including, as Andy mentioned, the slower-than-expected decline in the placebo-treated patients compared to other recently conducted trials despite the fact that baseline characteristics look very similar. But we are still digging into that. And maybe I'll turn it to you, Andy, to share some of your thoughts about things that we've done and things we still may be doing.

Well, we've -- I mean we've looked at a lot of different things. Mainly, we've looked at baseline characteristics, et cetera, in terms of how the patients were being treated at the primary endpoint of 24 weeks, whether they were on their target dose level, whether they were still being treated but after down-titration or whether they discontinued. We also looked at a calculated rate of prestudy disease progression where you can assume that the ALSFRS-R total score was 48 at the time of first symptoms. And then you know what it is, and they come into the trial -- you can divide the population into tertiles, and you can look at your faster progressors, your middle progressors and your slower ones. I have to tell you, none of that really has informed us why this population seem to progress more slowly than what we have seen in earlier trials. We mentioned the much lower mortality, we mentioned the smaller decline in vital capacity. And we've shown slides, although we haven't really pointed to it that much, that the ALSFRS-R total score, which you would have thought would come down around 12 points in 48 weeks, only came down about 9. So there's nothing clear that explains it.

I think what we can say is that it doesn't appear to be driven by site variability, site to site, or things that you might immediately question nor other issues with study conduct. The VITALITY-ALS study is confounded, as you know, by the tolerability issues with tirasemtiv. But we are still digging into this, and we have some other things still that we intend to do. You may remember that we entered into a collaboration with a company called Origent Data Sciences as provided by grant funding received by the ALS Association. And this is a company developing machine learning tools that enable us maybe to dig a little deeper into patient characteristics and rate of disease progression beyond that which is otherwise obvious from the things that we've looked at previously like baseline characteristics and rate of disease progression. So we're hopeful that this may inform some other lessons and learnings. I think the bottom line, however, is that despite the fact that we saw a slower-than-expected placebo event decline, we don't think that should affect the way we conduct FORTITUDE-ALS. Based on what we know today, we believe we're adequately powered in order to be able to see the effect size that we expect with reldesemtiv in that trial and, therefore, there's nothing then that we've learned or, frankly, thought we might learn and didn't learn that prompts us at this time to consider altering the design or conduct of FORTITUDE-ALS.

(Operator Instructions) Our next question is from the line of Chad Messer from Needham.

In SMA, I know it's exploratory, but assuming we have something interesting and it's worth going on and doing another study, perhaps a pivotal study, do you guys have in mind ways of getting a larger study enrolled faster? Or do you think just sort of the maturity of nusinersen in the marketplace will sort of have that take care of itself?

Yes. It's a very good question and one that we've been spending a lot of time on here. So firstly, keep in mind that the study that we are conducting of reldesemtiv in SMA, which we refer to as CY 5021, is a study that has already enrolled over 75% of its intended 72 patients and, therefore, it's not a small study. It's, in fact, quite a bit larger than most studies that you're seeing conducted in SMA and, therefore, we think it stands on its own for what will be the data arising from this clinical research. But we are encouraged by the fact that the variability appears to be less than what we intended. There's not a lot of history that one can point to, to conduct studies in adolescents and adults with SMA. So we made certain assumptions with regard to what would be the variability around the endpoint, and we are very pleased that the variability appears to be less than what we initially assumed. But I think to your point, it's not practical to go into a Phase III planning process with what would be expectations of a 50% screen failure rate nor the kind of rate of enrollment that has been the case with this Phase II study. So we're looking at other geographies and also ways we might alter the inclusion and exclusion criteria in order to be able to tease apart a signal from the noise in the way of what we think could be clinically meaningful and registrable. And maybe I'll turn it to you, Fady, to see if there's anything I left out of it, anything else you want to add.

Yes. I mean, I just think the next study, obviously, we will be including nusinersen-treated patients. And so nusinersen came online in the middle of this study, and making that change would have been pretty disruptive to the conduct of this study. As you said, people are initiating treatment, and it's hard to know when they reach a plateau. When we get to Phase III, I expect more likely most of the patients in this age range that wanted to be on nusinersen would be on nusinersen and would have reached some sort of steady-state. We also look at the entry criteria critically in the context of the results that we get and it may be that we can modify them so that we can increase the entry of patients into the trial based on the results that we see emerging out of this trial. So -- and you definitely point to a key issue and something we'll be focused on as we think about a Phase III program.

It's another reason why we're excited to see these results as soon as we can in Q2 and engage the SMA community around what would be appropriately our focus for the design and conduct of a potential Phase III trial. The landscape, as you know well, is rapidly evolving not only with nusinersen but also with gene therapy and other potential new medicines. And what I think continues to be our belief is that reldesemtiv should prove complement to any and potentially all of those investigational medicines. And therefore, a Phase III study design should take into consideration the advent of new therapies and how we might stratify around them but not exclude them. And that's truly where I think reldesemtiv may ultimately have its best positioning as a complement to SMN-directed therapies.

And our next question is from the line of Charles Duncan from Piper Jaffray.

I had a couple of questions. One is FORTITUDE with 107 or reldesemtiv. I'm wondering if perhaps I missed this is because of the noise, timing of data. And then I believe that Andy mentioned, he's seen significant better tolerability. And I'm just wondering if he could provide some additional color on what that means.

Also, the data should be available before the end of the year, I think we did say that, but I know you're in a noisy place. And we can just look at the blinded data and see that we're not having nearly the number of early terminations as we did in BENEFIT-ALS. And frankly, also of the few there have been, they've not been for adverse events, they tended to be associated more with the disease progression in ALS. So -- and we've also mentioned that we've gone to visit essentially every one of our investigators. I was with one on Tuesday and another on Wednesday, and they both talked about how, night and day, the tolerability is in this trial relative to the data with tirasemtiv.

Very good. Let me ask you a question on VITALITY or VIGOR. And kind of appreciate the stories told there but interested to know a little bit more about this patient population. And so I'm wondering, first of all, when would you anticipate some of the data and analyses that you pointed to, to be presented in a peer-reviewed form? And then also, do you have any additional information on those roughly 100 patients that have decided to persist on tirasemtiv? Those appear to be an interesting cohort.

Well, we haven't said anything publicly about the patients in VIGOR-ALS. I believe we eventually will. There's -- they haven't been on treatment, in the aggregate, that long to draw, I think, any meaningful conclusions about them, but we'll clearly continue to follow them carefully. The design paper for VITALITY-ALS just was published, so it's available, and I think the results will be submitted shortly.

Here shortly, yes, we open them.

Yes. I expect you'll see data from the primary analysis pertaining to VITALITY-ALS, beyond that which is already presented in slides, in a published manuscript. I expect that to be this year. Secondary manuscripts, possibly also later this year. And certainly, there are medical meetings and scientific congresses where that could also be presented. This is a large Phase III study, VITALITY-ALS. And as such, there's a lot to learn regarding the conduct of clinical research in ALS in the modern era. So we intend to make those data available not only to help us understand what happened with tirasemtiv but, more importantly, to inform things that we may do with reldesemtiv and also to provide that information to the ALS community. Regarding VIGOR-ALS, as Andy points out, there's over 100 patients still remaining on tirasemtiv and VIGOR-ALS. Some of those have been patients that got not only 48 weeks of randomized double-blind placebo-controlled treatment with tirasemtiv but also may have been on tirasemtiv for upwards of 1 year, 2, in VIGOR-ALS. So you've got 1 to 2 years of experience with some of those patients. And it was very interesting that we were able to convene this meeting earlier this week with experts, as Andy pointed out. And there are, clearly, investigators and their patients who are quite insistent that they would be -- offer the opportunity to remain on tirasemtiv as we want to do the right thing by them and others. So we're still deciding how best to make that happen, and we'll have more to say about that later in this quarter.

Robert, are you collecting any, I won't call it efficacy, but call it activity data within Vigor and track -- and as you're tracking those patients?

Haven't really gotten any activity data per se in VIGOR. I mean we've look primarily at their progression by measuring, again, vital capacity and also the ALSFRS.

So some of the same efficacy endpoints that we are measuring in VITALITY-ALS, we are also measuring in VIGOR-ALS, alongside of collecting safety information.

So you are. Okay. That will be very interesting to look at. And then final question, I appreciate your patience with me in all this noise, back to reldesemtiv. When you consider SMA, and I think you kind of alluded to this, but it seems like it's tough to define good versus great in terms of what you're looking for, as it's primarily a signal-seeking study. But I'm wondering if you have any further color on that. And then finally, it seems like the drug should be or will be eventually used if it's approved in combination with these other agents. And so beyond a clinical study, what are you doing to enable future studies to look at in combination with, say, nusinersen?

I will take the second part of that first. I think the -- clearly, we'll end up studying the drug in combination with other potential therapies in Phase III. And that would, if you will, be enabling. I mean the SMA community now speaks of SMN-enhancing drugs, such as nusinersen or the AveXis drug or others that -- or the AveXis gene therapy that are aimed at increasing SMN protein levels. And then they speak of muscle-enhancing therapies now, of which CK-107 is really the lead in that pipeline. And so they do certainly expect them to be used in combination, and we'll have to investigate in that way eventually as well. With regards to your first question, which had to do with the endpoints and what might we see as most compelling. I think ultimately, it'll be looking across the endpoints and seeing that the endpoints, at least some of them, are moving in similar directions. The magnitude probably makes as much importance -- as important as the p-value. And we'll be looking also at a new PRO that's been developed, sort of an exploratory endpoint that was introduced into the second cohort. I think all of those things will give us a sense of how patients perceived they are doing as well as how they're functioning, and then we'll go from there.

It's great to see something like SMA see a big evolution in treatment paradigm. And it's a challenge for you guys, but eventually you'll be a contributor, I appreciate that.

Thank you, Charles.

Thank you, Charles.

And at this time, I'm showing we have no further questions over the phone. Presenters, I turn it back to you.

Thank you. And thank you to all the participants who joined us on our teleconference today. Thank you for your continued support and your interest in Cytokinetics. 2018 offers great promise, and we believe we're well funded to hopefully realize the potential for our novel mechanism muscle biology directed drug candidates. We look forward to providing you further updates through the course of 2018. Operator, with that, we can now conclude the call, please.

Ladies and gentlemen, this does conclude today's conference call. We think you greatly for your participation. You may now disconnect.