Investor Breakfast and Webcast Following Presentation of Results from BENEFIT-ALS Conference Call
April 30, 2014 7:00 PM ET
Robert I. Blum – President, Chief Executive Officer & Director
Fady I. Malik – Senior Vice President-Research & Early Development
Andrew A. Wolff – Chief Medical Officer & Senior Vice President
Jeremy M. Shefner – Professor and Chair, Department of Neurology, Upstate Medical University, State University of New York and Lead Investigator of BENEFIT-ALS
Jinsy Andrews – Director of Clinical Research and Medical Monitor of BENEFIT-ALS
Merit Cudkowicz – Professor of Neurology, Harvard Medical School and Chief of Neurology Service at Massachusetts General Hospital and Director of the ALS Clinic at MGH
Robert I. Blum
Good morning. My name is Robert Blum. I’m president and CEO of Cytokinetics. Thank you for joining us at this Investor Breakfast and Webcast held here in conjunction with the American Academy of Neurology. We’re pleased to be able to welcome you to this meeting, and also those of you who are dialed into the webcast, we welcome you. Today we’re going to be talking about BENEFIT-ALS.
BENEFIT-ALS is a Phase IIb clinical trial of Tirasemtiv in the treatment of ALS. Today, I’ll be making forward-looking statements. We’ll be talking about BENEFIT-ALS and their implications. We’ll be looking at scientific data, and we’ll be talking about what our plans are with respect to best understanding those data. I’ll be making forward-looking statements, and I’ll refer you to our SEC filings and the risk factors associated with those filings. We don’t undertake any obligation to update those statements.
Here’s our meeting agenda for today. I’ll be making just a few introductory remarks. I’ll then turn over the podium to my colleague, Fady Malik. Fady is Cytokinetics’ first scientist, first employee. He’s built our Muscle Biology programs under his vision and supervision, and he’ll talk about the muscle biology platform that’s been guiding Cytokinetics for now over 15 years. I’ll then turn the podium over to my colleague, Dr. Andrew Wolff. Andy is our Chief Medical Officer. He has been responsible for the clinical development of Tirasemtiv, including the design and overseeing the conduct of BENEFIT-ALS.
Andy has been with Cytokinetics for over 10 years. Andy will turn the podium over to Jeremy Shefner. Jeremy Shefner’s the Lead Investigator of BENEFIT-ALS. Jeremy is the founder of the NEALS Organization and has been responsible for oversight and conduct of clinical trials for over 20 years for the potential treatment of ALS. He’ll then turn the podium over to Jinsey Andrews.
Jinsey Andrews is a former investigator of Tirasemtiv, having worked for many years as a neurologist at clinics here in the Northeast before joining Cytokinetics over a year ago to be a member of the team at the Company conducting this trial. And she served as the Medical Monitor of BENEFIT-ALS. Jinsey will turn the podium back to Jeremy, as well as Bob Miller and Merit Cudkowicz, who will speak about these results in the context of their experience, all of them together, having led clinical trials in ALS for so many years and for seeing patients and understanding these data in the implications of patient care.
We’ll then open up the program for questions and answers from all of you. I’ll make then a few concluding remarks. Here are the people that will be on the panel. I’ve described them as they’re also now listed here, so you can put names and faces with titles. A few slides to set a context for our discussion of Tirasemtiv and BENEFIT-ALS.
This slide describes Cytokinetics’ development pipeline in this year 2014. There you see highlighted in the yellow box Tirasemtiv. Tirasemtiv is a compound that Cytokinetics has been developing independently. We developed it in Phase I and Phase IIa studies, Phase IIa studies in ALS, and also other indications, and a Phase IIb study, BENEFIT-ALS, that you’ll be hearing more about today. This compound is a fast skeletal troponin activator. We have another fast skeletal troponin activator.
It’s called CK2127107, CK107 for short. CK107 acts by the same mechanism of action, very different chemistry, and has been engineered to remove certain potential liabilities associated with Tirasemtiv that have been known for sometime. CK107 is the subject of an alliance we have with Astellas. With Astellas, we’re developing CK107 for other indications, as you’ll soon see in another slide.
We also have a cardiac muscle program. Omecamtiv mecarbil is a first-in-class cardiac myosin activator. It comes in two forms, an intravenous form and an oral form. Those two forms, that compound, are being developed in collaboration with Amgen in a collaboration that dates back to 2006. We are doing together clinical trials. We’ve done Phase I and Phase IIa studies. We’ve done a Phase IIb study. We’re now in the process of doing other studies, as the next slide will show, moving that program forward with the goal of that being in Phase III.
Here is the slide referencing omecamtiv. Omecamtiv has been the subject of a study called ATOMIC, a Phase IIb study of this cardiac muscle activator in acutely ill decompensated hospitalized heart failure patients. That study read out results last year, 2013, that we believe support the progression to Phase III. We’ve also recently conducted an additional Phase I study and are now conducting an additional Phase II study, called COSMIC, each with oral forms of omecamtiv mecarbil.
We and Amgen have selected one oral form. We’re proceeding with that one oral form in an ongoing Phase II study called COSMIC, the goal to complete enrollment in that study this year and have that program be teed up to move into Phase III to occur next year. Coming back to our skeletal muscle program, which will be where we emphasize this content of program today, skeletal muscle troponin activators come in forms that allow for development broadly.
Tirasemtiv is being developed for neuromuscular indications, and you’ll hear more about that today, ALS and other neuromuscular indications, CK107 in non-neuromuscular indications partnered with Astellas. Both compounds, Tirasemtiv and CK107, amplify response to motor neuron input, increase muscle power, slow the onset and reduce the extent of muscle fatigue, but that has application in different clinical areas and areas associated with muscle weakness and conditions associated with muscle dysfunction
We’ve been developing Tirasemtiv independent of our partner, Astellas, for ALS and neuromuscular indications, and CK107 we are developing in Phase I under Astellas’ sponsorship, with the goal to have that compound be Phase II ready by the end of this year and proceed together with our partner, Astellas, in multiple Phase II indications currently focused to non-neuromuscular applications.
A few additional opening comments, and then I’ll turn it over to Fady. Since the Company’s founding in 1997, and we commenced operations in 1998, Cytokinetics has been focused to an area of biology called the cytoskeleton. Since 2005, 2006, we’ve focused that effort to muscle biology-directed programs, of which those compounds I just mentioned form the cornerstone of our research and development activities. We have two partnered and fully funded programs with each of Amgen and Astellas. What we’re going to be talking to you about today is in addition to those, and Tirasemtiv in BENEFIT-ALS. To be clear, as I believe all of you may already know, we announced the top line results of BENEFIT-ALS last Friday.
BENEFIT-ALS missed on its pre-specified primary efficacy endpoint of ALSFRS. You’ll hear more about that today. However, these data are very fresh, and in pre-specified analyses of secondary endpoints, we have already observed that Tirasemtiv in BENEFIT-ALS did demonstrate increases in pulmonary function, in particular slow vital capacity and measures of muscle strength. In fact, it’s the first trial in patients with ALS to increase pulmonary function and muscle strength, and represents a significant step forward for the science and our understanding of this mechanism and its potential for the treatment of ALS.
These data are literally days old. We have had a team sequestered for about two weeks where they only were being able to generate results in the last week, with tables, listings and figures that would allow us to put these data into some sort of synthesized package, and we raced to get these results presented here at the AAN. We have a statistical analysis plan that looks like a dissertation. We have done 100 pre-specified analyses and other analyses with a database that exceeds over 2 billion data points. We have quite a lot more work to do to understand these data, try to knit them together and connect the dots, and synthesize them in order to assimilate them to know what may be the proper next steps. We intend to do that.
That’s our responsibility, and that will be what we focus on, going forward. There may be an additional path here, but we don’t know it, and we aren’t yet committed to any next steps other than to understand what the data from BENEFIT-ALS can tell us. We want to understand issues relating to tolerability and how that can be improved while maintaining activity. You’ll hear more about that in these next several slides. And I’ll come back later, and I’ll make some additional comments to wrap up the presentation.
With that introduction, I’d like to turn it over to my colleague, Fady Malik.
Fady I. Malik
Thank you, Robert, and welcome, everybody. Thank you for coming this morning. I just intend to give some brief comments and an overview of our biology platform and its translation to humans before we transition into a discussion of BENEFIT-ALS. So for the last – over a dozen years, we’ve been focused on this biological target, the sarcomere, which is shown here in this movie. Target is the fundamental unit of muscle contraction and works with a motor called myosin, shown there in the orange filaments, with the motor heads reaching to the blue actin filament, pulling the actin filaments together, which is the basis for muscle contraction.
Now, that interaction between actin and myosin is regulated by the troponin-tropomyosin complex, which is there in green on this filament, and that complex binds calcium, and in binding calcium, moves the tropomyosin out of the way. When troponin binds calcium, tropomyosin moves out of the way and enables myosin to interact with the actin filament. And both skeletal muscle and cardiac muscle have the same fundamental structure.
However, the component proteins are, for the most part, unique in cardiac and skeletal muscle, which has enabled us to develop selective activators of each of those muscle types. Targeting the tropomyosin complex are what we call our fast skeletal troponin activators. Because these troponin activators are selective for the troponin complex that is present in fast skeletal muscle, troponin complex is the calcium sensor that I just mentioned.
Targeting the motor protein, myosin, is omecamtiv mecarbil, a cardiac myosin activator, and again, that molecule is selective for the cardiac form of myosin and is being developed for its use in heart failure. Both of these molecules have evidence of pharmacodynamic translation into humans, and here is shown the evidence for omecamtiv mecarbil, cardiac myosin activator, in these echos taken from a patient with heart failure.
The echos on the left represent how this poorly functioning heart at baseline, and the echos on the right represent this better functioning heart after an infusion of omecamtiv mecarbil for 24 hours. And I like to show these, because cardiac muscle, we have nice visual indicators of improvements in muscle function different from what we – the tools we have available to us in skeletal muscle. What you can see on the right is that the heart is now rounded and is contracting to a greater extent. What you see on the bottom right is that the pumping chamber up there towards the top of the triangular figure is a little smaller, pumping more vigorously, that the valves separating the pumping chamber and the left atrium at the bottom is opening much more widely, because there is more blood flow from the left atrium to the left ventricle. And in fact, the left atrium itself has gotten substantially smaller as its function, as well, has improved.
These data in heart failure patients have been published extensively and form the basis for this program’s proceeding forward in the development of the drug in both acute and chronic heart failure. Tirasemtiv now, a fast skeletal troponin activator, it’s the subject of our discussion today, has been looked at in a number of pre-clinical models.
As Robert mentioned, it has the properties of amplifying the muscle’s response to neuromuscular input, increasing muscle power, and decreasing muscle fatigability. And here’s a set of data that I’ve selected from mice that have a – over-expression of a mutated form of the SOD-1 protein, the protein which is responsible for some of the cases of familial ALS. These mice develop weakness over time. And as we’ve investigated here, if you dose these mice with Tirasemtiv at a point in their disease course, using assays of muscle function, including grip strength, hang time, and running time, you can see that in each case there is evidence for a functional effect of Tirasemtiv to improve their performance in each of those assays. And that’s after a single dose of Tirasemtiv.
The mechanism of action has been translated into humans as well, similar to what we did with our cardiac myosin activator. Here we developed a unique assay to investigate one of the properties of this mechanism, which is to amplify the muscle’s response to neuromuscular input. And that’s done by stimulating the nerve on the outside of the knee, called the peroneal nerve, diperoneal nerve. It activates a muscle group in the front of the leg called the anterior tibialis, and that causes your foot to pull upwards, and you can measure that force using a foot plate.
And what’s shown here in this graph is that, if we stimulate that nerve at increasing rates of frequency, so five hertz, seven hertz, 10 hertz, so forth, the muscle works by the nerve firing faster and faster in order to generate more force, and we – and look at each time we do that look at the plasma concentration at that particular time point across several doses of the drug that were administered, including a placebo treatment, you could see that the placebo-corrected changes from baseline increase in a dose-dependent or rather concentration-dependent fashion, the light green to the darker green bars going left to right, and also on a frequency-dependent fashion, amplifying to a greater extent the muscle’s response at lower frequencies of nerve stimulation, which is typically where most of our activities of daily living occur.
So, both mechanisms of action have clear pharmacodynamic evidence of their function in humans, and what’s been the next journey, if you will, for this molecule has been to now demonstrate its potential clinical efficacy and specific disease.
And with that, I’ll turn it over to Andy Wolff, who will describe our work in that area.
Andrew A. Wolff
Thank you, Fady. So, prior to BENEFIT-ALS, we conducted three earlier Phase IIa studies of Tirasemtiv in patients with ALS, which went by the numbers of 4021, 4024, and 4025. And in a few slides, I’ll briefly summarize the major upshot of them. But we took the learnings from those trials and, after discussions with FDA and EMA, designed BENEFIT-ALS in order to more definitely evaluate the potential utility of Tirasemtiv in patients with ALS.
This slide really summarizes what we learned from those three earlier clinical trials. When we did a meta-analysis, when we looked at the relationship between various pharmacodynamic parameters and the effect of Tirasemtiv on them versus the plasma concentration of Tirasemtiv, we saw highly statistically significant associations between increases in these measures of pulmonary function and muscle strength, and Tirasemtiv plasma concentration.
And so, going into BENEFIT-ALS, I used to say fairly frequently that everything that occurs with Tirasemtiv, the things that we like and the things that don’t, appear to be very highly dependent upon the plasma concentration. So we have now completed BENEFIT-ALS, as you know, and as our colleague, Dr. Jeremy Shefner, will describe shortly, we owe a great debt to the investigators in our 75 centers distributed across eight countries, and an even greater one to the 711 patients that participated in this study.
The design of BENEFIT-ALS is summarized on this slide here. After a screening period of up to three weeks, during which we determined that patients met the eligibility criteria, patients were enrolled into an open-label treatment period of one week. And during that one week, they received Tirasemtiv at 125 milligrams twice a day. And we did that for two reasons. One was we knew that there would be a certain percentage of patients that would not tolerate even that intended starting dose of 125 milligrams twice daily, and it was better for them, if they were going to drop out of treatment, to do so before randomization.
And Dr. Shefner will show you how well that worked, or didn’t work. The other thing was it helped us to preserve the blind, because at the time we began BENEFIT-ALS, the most prominent adverse event occurring on Tirasemtiv was a mild dizziness, mostly mild, that generally resolved within about a week of treatment. So, by doing this open-label period upfront, if patients did become dizzy, but only mildly so and were able to tolerate that dizziness, and then went on to be randomized, if the dizziness resolved in the first week or so of double-blind treatment, it would be impossible to distinguish whether that was because the patient was randomized to placebo or they were randomized to Tirasemtiv and the dizziness just went away, because it usually does.
The primary outcome measure was the change from baseline in the ALSFRS-R, and maybe I’ll go back and just make the point that, after patients were randomized, the ALSFRS-R was assessed at four weeks, eight weeks, and 12 weeks of treatment, which corresponds to visits five, six and seven, and the changes from the baseline value obtained at screening. Other measures of pulmonary function and muscle strength were also assessed at those visits.
This slide summarizes briefly the ALSFRS-R. Many of you are familiar with it. It consists of 12 different assessments of activities of daily living and function, each of which is scored four to zero, four if there is absolutely no impairment and zero was the patient cannot perform it at all. As you’ll see, our patients at baseline came in with a score right around 36, so you could tend to think of it as threes across the board, but the disease is so heterogeneous, that was really not the case. And so, patients had scores of four in some places and zero in others. But the average was around 36.
We pre-specified a number of secondary endpoints, and that’s an important point to make. When you see the data on the secondary endpoints, those were endpoints that we intended to examine from the very beginning. They’re not something that we looked at in a post-hoc manner. And they include slow vital capacity, the change – all of these changes, maximum voluntary ventilation, and we’ll describe each of these in somewhat more detail, going forward.
The Sniff Nasal Inspiratory Pressure, all of these are measures of pulmonary function, and then muscle strength endpoints by handheld dynamometry, where we measured limb muscle strength, and then also hand grip strength. The slow vital capacity, as you’ll hear in more detail later on, is probably the most important measure of pulmonary function in patients with ALS. Its absolute value is a very strong measure of disease progression, and the rate at which it changes is also a very strong predictor of their eventual outcome and allows physicians, patients, and families actually to plan around the end of these unfortunate patients’ lives.
It consists of asking the patients to take as deep a breath they can, and then to exhale as completely as they can. It’s not a matter of how fast they can do it. It’s a matter of how completely they can do it. MVV is different. In that case, the patients are asked to inhale and exhale, over and over, as quickly and as deeply as they can to see how much air they can move in a preset period of time, and those units are liters per minute. Being a repeated activity, it’s subject to fatigue in a way that slow vital capacity wouldn’t be.
And the Sniff Nasal Inspiratory Pressure is now a maximal effort in which the patients are asked in this case now to inhale as forcefully and deeply as they can, and the measure is in the negative pressure, or the amount of suction, if you will, that they can generate in that effort to inhale. The muscle mega-score is done by handheld dynamometry. The little guy you see right there, it’s – there is no perspective to know, but it fits in the palm of one’s hand, and the evaluator holds it against the patient, and the patient then pushes against it with their knee extensor or with their arm, whichever muscle group is being measured, and this records the force in pounds that the patients can generate.
And then, finally, grip strength is measured with another special dynamometer tailored specifically to measure grip. And the one that we used was a nice one that the patients could actually see what they were able to generate as they looked at the dynamometer. So, those are the assessments and an overview of the design of the study, and how we got there and the rationale for it.
And with that, I’ll turn it over to my colleague, Dr. Shefner to describe the results.
Good morning. So, Andy described the design of the study, and this is the description of where patients ended up in the study. We enrolled 711 patients. 106 of those 711, or about 14%, were lead-in failures. So as intended, there were a certain number of patients that didn’t tolerate the drug at the lowest dose used and ultimately we are not randomized. Of the remaining 600, they were equally randomized to placebo and Tirasemtiv, and you can see right away that Tirasemtiv had a differential effect on dropout. Three times as many patients dropped out of the study on the Tirasemtiv arm as in the placebo arm.
And essentially, all of those dropouts were accounted for by nonfatal adverse events, and you can see in the light blue boxes on the most lateral columns that there were 78 nonfatal AEs in the Tirasemtiv arm as compared to 12 in the placebo arm. The data set that we used for all of the efficacy analyses was called the Modified Full Analysis Set. And this data set consists of all of the patients who received at least one dose of double-blind medication, who had at least one efficacy assessment after being randomized to active treatment, which means that they made it to at least week four of the treatment Phase, and they did not – they were not in the randomization groups that contained 58 patients that were randomized in error in the middle of the study from active treatment to placebo.
For many of you know that there was this drug assignment error in the middle of the study where 58 patients were mistakenly switched from active treatment to placebo. Those patients in the analysis were excluded from further analysis, as were all of the placebo patients that were in the randomization blocks that accompanied these patients. And so, you can see in the red ovals – the second red ovals, 75 patients on placebo were excluded for this reason, and 63 on Tirasemtiv. Because of differential dropout, we ended up with a slightly asymmetric data set to analyze in terms of efficacy, with 178 Tirasemtiv patients and 210 placebo patients.
In terms of baseline demographics, this was a well-matched group on all of these measures. The only mild caveat to that was that there was a small but statistically significant difference in – of starting slow vital capacity. The Tirasemtiv Group had an average vital capacity of 85.7% of predictive and the placebo group had an average vital capacity of 889.7%.
This is – this slide shows both the number of patients completing over time, as well as the doses they achieved. And you can see that, on the placebo side, unsurprisingly, patients were able to get to the full dose of the placebo, and the dropouts were quite marginal.
On the Tirasemtiv side, there were far more dropouts. You can see that those occurred in the early weeks of the study far more than the later weeks. And slightly more than half of the patients achieved the maximum intended dose of 500 milligrams a day, with about a quarter ending up at 375 per day, and a quarter at 125 b.i.d., or 250 a day. And these data represent the primary efficacy – endpoint, which is the ALSFRS average between visit six and seven compared to the baseline value. And you can see that both groups dropped, as anticipated, for ALS. The placebo dropped 2.4 points over three months, and the Tirasemtiv group dropped 2.98.
So, there was a numerical difference that actually favored placebo in this initial analysis. This difference, however, was not statistically significant. And in the rest of the slides, what I’m going to show you are the – this ALSFRS data and all of the other secondary endpoints expressed as scatter plots, and with the statistics looking at the change in slope. And so, here’s the ALSFRS data plotted as a scatter plot. There is a difference in slope favoring placebo that is also not statistically significant. The P value is about 0.16.
If you look at all of the slopes for the pre- specified endpoints that Andy talked about, there are six of them, and you can see where they fall with respect to favoring placebo versus Tirasemtiv and their level of significance here. The ALSFRS, as noted previously, changed slightly more in the – in a way that favored placebo, but it was not statistically significant. Of the others, slow vital capacity, which Andy described and which is an important predictor of disability and mortality in ALS, that change strongly favored Tirasemtiv. And so, just in terms of the magnitude of that change, the slope of the decline in vital capacity in the treatment group, in the Tirasemtiv group, was one-third as great as the slope in the placebo group.
So, patients changed three times faster in the negative direction in the placebo group as compared to the Tirasemtiv group. Maximum voluntary ventilation and hand grip fatigue both changed in ways that marginally favored Tirasemtiv but were not significant. SNIP, which is Sniff Nasal Inspiratory Pressure, change in the negative direction, also not statistically significant. And then, muscle strength in the extremities, which is expressed by mega-score – this is an average strength of 10 muscle groups measured on both sides of the body. That also changed in a way that strongly favored Tirasemtiv.
And again, the point estimate of effect is that the slope of decline in this mega- score was three times greater, approximately, in the placebo group as compared to the Tirasemtiv group. And that difference was significant at the.0158 level. Just briefly, here’s what those data look like in scatter plots. This is the slow vital capacity, and again, the slopes are noted at the bottom, and the difference is significant at the.0006 level, highly significant.
And strength, similarly, the slope for treatment is almost three times greater for placebo than Tirasemtiv, and that P value is.0158. Those – these curves don’t look like they diverge as much, but that’s because of the axis that we need to use – we needed to use to plot this because of the relatively few outliers that you can see at the top. Not only were dropouts asymmetric in this study favoring Tirasemtiv as having more dropouts, there were also more frequent AEs in the Tirasemtiv arm as compared to placebo.
Now, AEs in ALS studies are very frequent, and you can see that 87.5% of the placebo group had adverse events, but 97%, or 96.7% of the Tirasemtiv group did, as well, representing a difference in AEs of almost 10%. The AEs are listed in order of frequency. The colored AEs are the ones that have a difference of greater than 5% in their incidence between Tirasemtiv and placebo, and you can see that there were number of them. The blue are AEs that had that same difference but were related to the GI system, and that will be important in my comments just coming up.
This plot is a Kaplan-Meier curve that shows the rate of dropout in the two arms, in the placebo arm and in the Tirasemtiv arm. And you can see that the dropout in the placebo arm is fairly consistent. It’s fairly linear. There’s a – sort of a steady number of dropouts, which reflect the general health of this population being studied. But then, on the Tirasemtiv arm, there was a fairly stark and dramatic early termination rate so that, by four weeks, the majority of people who terminated on Tirasemtiv had already done so.
And then, after that, there was an asymptote of this – of termination, and so in the – patients were able to stay in the study at about the same rate as the placebo-treated patients. So, obviously the ALSFRS data were puzzling and initially discouraging to us, and so we tried to figure out what could have made this happen. It was a surprise to see. And one thing we looked at, because it has been a problem with – in previous ALS studies, is whether the active treatment had an impact on rate of weight loss.
And we found that, at every week, the average weight loss in the Tirasemtiv treated patients was slightly more than twice as great as in the placebo group, and that’s the graph on the left. And you can see that the difference between placebo and treated patients – and Tirasemtiv-treated patients increases over time. This weight loss is directly related to GI side effects. And so, on the right-hand side, you can see the weight loss in patients on placebo and on Tirasemtiv who had GI side effects, or GI adverse effects, as compared to those who did not.
And unsurprisingly, people with GI adverse events lost more weight in placebo versus Tirasemtiv, and in placebo and Tirasemtiv. But it was more dramatic on Tirasemtiv, and the ends are much greater. Far more patients had GI side effects on Tirasemtiv, and they are the group that lost the bulk of the weight. And just for context, the average weight loss in patients that did not have GI AEs in the Tirasemtiv group matched almost exactly the average weight loss in the placebo group.
So how did the weight loss relate to ALSFRS? This is a bit of a complicated slide. All of the bars reflect a comparison between Tirasemtiv and placebo. Down favors placebo, up favors Tirasemtiv. And what we did is we cut the treatment group by their median and plotted the group of people who lost more than the median amount of weight, which are plotted in blue, versus above the median weight loss. So the people who lost less weight are in the pink.
And so, at week four, those who lost more weight did clearly worse on ALSFRS compared to Tirasemtiv. That’s the blue bar down. And the people who lost less than the median basically performed identically. You can see that there’s virtually no bar at week four. At week eight and week 12, the same pattern is seen except that there is a slight numeric advantage that favors Tirasemtiv in the group of patients that lost less than the median amount of weight. This interaction is – has a significant value of.052, suggesting that the Tirasemtiv – the treatment-weight loss interaction is important, and it suggests a small positive benefit of Tirasemtiv in those patients that did not lose the median amount of weight or more.
So, what can we conclude from this study, and Andy said several times, and I certainly completely agree, that we’re not finished with this. The data are not fully analyzed. But from what we know so far, there are several questions that I think we can answer. And the first is, did Tirasemtiv have an effect that is potentially biologically important in this disease group? And my view is that the answer is a clear yes. This is the only ALS study that has been performed since (indiscernible) to show this amount of positive effects. And it’s the only study that has ever been performed in ALS that has shown a statistically significant and potentially clinically meaningful effect on both strength and breathing.
With respect to tolerability, it’s equally clear that the drug was not well tolerated. That’s made evident by the three times greater number of dropouts in the Tirasemtiv group as compared to the placebo group, the fact that more AEs were noted in the Tirasemtiv group than the AE group, and that weight loss was significantly greater in the Tirasemtiv and the – as compared to the AE – to the placebo group.
With respect to ALSFRS, the primarily endpoint was not met. Tirasemtiv did not positively impact ALSFRS in the primary analysis. It appears that that difference is largely accounted for by differential weight loss. And that if one does statistical things to account for that, there’s at least a hint that the ALSFRS may have been impacted in a mildly positive way in those patients who lost less weight. But, those analyses can be – need to be refined and looked at further.
And so, now Jinsey Andrews will discuss a little bit about the results in context.
Okay. Thank you. Good morning. So as part of the team that had what felt like moments just to reflect on what we were looking at, so Dr. Shefner gave us the data. The data was large volume of data points that we had to synthesize very quickly. And once we had the results, we had to look and see what we had and what we’ve seen in other trials.
So Tirasemtiv, as Dr. Shefner explained, missed the primary endpoint, but we did see statistically significant benefits on Tirasemtiv on our pre-specified secondary endpoints. And so, reflecting back – and I should say that I have been an investigator for many of the trials that are listed, as well as our panelists. And looking back at the trials, it was something very different that we see with Tirasemtiv.
And so, we’ve been given, and we’ve discussed this morning, what we’ve seen pre-clinically and the translation into the clinics early in our phase I and phase II trials, but clearly this is something very new and very exciting. And the points that we did see as we reflected on the data is that we saw an improvement in slow vital capacity. And as a clinician who treats ALS, breathing is critically important. So we know that the nerves are dying, and, as a result, they affect the breathing and the diaphragm, and this is what ALS patients usually die from.
And we know that survival has been correlated with vital capacity. It is a measure. And, unfortunately, unlike cardiology where they have the echocardiogram to look at heart function, as a neurologist treating ALS, we don’t really have objective measures. So we use the vital capacity as one of our objective measures in clinics to measure disease progression and help to give prognosis to our patients. It also is a measure that reflects diaphragm dysfunction, and of course in practice parameters that are published for ALS treatment, we use the vital capacity to make some vital clinical decisions for our patients.
So, that includes deciding when a patient needs non-invasive ventilation, deciding when they need a feeding tube, and deciding when they need hospice and palliative care. And of course, as many of you are aware, the vital capacity is typical eligibility criteria for ALS clinical trial participation. The second point that we saw was the muscle strength mega-score. And so, it is the main – muscle weakness is the main symptom of nerves dying.
So, motor neuron degeneration leads to muscle weakness. And despite how a patient presents to the clinic, it could be hand weakness, it could be leg weakness, it could be speech problems, they’re all – result from the muscle weakness that’s caused by the disease. So, our muscle mega-score is an integrated measure of several muscle groups, because patients do look different, and in this study we specifically looked at elbow flexion, wrist and knee extension, ankle dorsiflexion and grip strength. And we commonly measure, so, another way we can evaluate our patients in our clinic is to measure muscle weakness.
So, I think – I hope that you have had a good chance to look at the data and understand some of the clinical context and the historical context of what we’re dealing with at this point with Tirasemtiv. So, before I open the floor up for our questions and answers, I wanted to invite our panelists, which we’re very grateful that you could join us, Dr. Robert Miller, who is the Clinical Professor of Neurology and Neurological Science at Stanford University Medical School and Director of the Forbes North ALS Research Center at the California Pacific Medical Center, and also Dr. Merit Cudkowicz, who is a Professor of Neurology at Harvard Medical School, Chair of Neurology Service at Mass General Hospital, and Director of the ALS Clinical Center at MGH. So, I’d like to invite both of you to join the conversation and give us some brief comments about what your thoughts may be on this.
Well, good morning. I run a large ALS clinic in San Francisco and have for the last 25 years or so. And I want to underscore how desperate this disease is. ALS is the Grim Reaper of neuromuscular diseases, and our patients are dying within two to five years. For the past 20 years, we’ve seen a very long series of negative clinical trials, as you heard summarized in a slide a moment ago. I’m having a little bit of a deja vu, because 20 years ago when we first saw the data on riluzole, the primary, that is mortality, was hit, although in a very modest way, with two to three months prolongation of survival, and none of the secondarys were positive, including breathing function and also a functional rating scale.
In the ensuing 20 years, all of the trials that have been done in ALS have been negative. And now, we have a drug who, in the lead-up small studies, has consistently showed some beneficial impact on measures of strength and breathing. Unfortunately, the issues of tolerability cloud the data that we’re seeing now in the current trial, and it was a surprise, led to a large number of dropouts, and clearly obfuscated the interpretation of the ALSFRS-R. The ALSFRS-R is a great global measure of functional impairment in ALS, but to me it’s a very high bar, and no trial has yet – no compound in any trial in ALS has yet shown a positive impact on that scale.
To me, the great excitement about Tirasemtiv is that it actually can make patients stronger and improve breathing function, not just slow the decline of these things. So, it’s a very promising drug. In the ALS, we say we don’t want to miss a drug that’s positive, and here we have a signal, I think, both in the two measures that you’ve seen, breathing, very important signal and also in the change in strength, and that in spite of some very significant issues with weight loss and tolerability and adverse events.
So, I continue to feel there’s something here that’s very important, and so do my patients.
Thank you. I want to just echo my thanks to Jeremy and Cytokinetics for really conducting a very well-done study. I’ve been in the ALS field since the mid-’90s, have led many of those trials you saw on that list that – what I would really call are failed trials. And I think here with this drug, with Tirasemtiv, if you have a successful study, and the first one since riluzole. Some of the core teaching I had when I was learning how to do trials is to try to avoid a failed trial. A failed trial is when you haven’t learned anything about your drug or the disease at the end. And we’re really quite at the opposite end here.
We have a drug that we know the mechanism. We’ve seen a biological effect, and really an important one on symptoms that are critical for patients. When we see our patients and we ask them what their main problem are, or what they want a drug for they say it’s their weakness, and here we have evidence, really for the first time, of a drug that has an effect on strength. They haven’t had any drug like that. And strength in two ways – on the limb strength, which is really critical for the patients, as well as the breathing.
The patients went to the FDA maybe two years ago, had a all-day conference with the FDA. And what they said loud and clear is that they want access to drugs quickly. They want to be able to take risks. They don’t want to be treated like patients who have non-fatal illnesses, like migraine, and that they’re willing to enroll in these studies and to try things to get drugs that might be helpful. I really compare it to oncology, where some drugs, unfortunately, do make people sick at first, but then have huge successes. And I think what we’ve learned in this study, we’ve learned the side effect profile, and they’re all manageable.
We have ways to manage weight loss and nausea and dizziness, and actually knowing what might happen is a huge advantage for planning the next study and how to move this drug forward. So, I do think we have to listen to the patients and their needs. And a drug that could give them a few extra months even, if not longer, of breathing better would be huge. It would mean that they’d be less tired. They’d be able to do more. They’d have more time before they have to make some of their critical decisions about feeding tube or breathing support. It really could mean a lot to their quality of life. So, I’m very excited about this. I know drug development’s a long haul, but I think we’ve learned a lot from this trial about how we can move forward to get this fully on the market for our patients.
Thank you very much, Dr. Miller and Dr. Cudkowicz. I’m going to open up the floor now for questions-and-answers. So if you have a question, come up to the microphone. And I’ll invite all the panelists, and Dr. Shefner, to join in on answering the questions.
Hi, this is for the experts, Drs. Miller, Cudkowicz, and Shefner. As you look at the strength measures and the lung function measures, you’ve got slow vital capacity, but you also have MVV. How do you sort of reconcile one respiratory measure working, the other one not? And how – what is that relative value, in your mind, across the sort of four?
Sure. So, it would be much easier to have all outcome measures changing in the same direction. Vital capacity is the clearly best-known measure in ALS, and we know quite a bit about the natural history of vital capacity changes in ALS, changes in study after study by about 3% per month. MVV and SNIP are measures that are not uncommon in the pulmonary world but are relatively new to us. And the knowledge of how ALS patients change on those measures is much less known, so I would classify those much more as exploratory measures.
How does SNIP change in ALS? Well, there was a recent study in 2012, a small study that compared SNIP ALSFRS and vital capacity, and in four months ALSFRS and vital capacity changed exactly as we expected to, and SNIP at the end of four months was absolutely no different. It was higher one month, lower the next month. The relationship to disease is much less clear. With respect to MVV, there is very little known about the expected changes over time in ALS. Just in terms of how it’s done, it’s a hard test. You work for 12 seconds breathing and rapidly as you can. It’s not so easy for me. It’s a lot harder for an ALS patient, and it’s even harder for an ALS patient who may be having adverse events and doesn’t feel at the top of their game.
So, I think both of those were interesting things to measure. I think the reasons why we didn’t see big changes is something yet to be fully determined. But, I know a lot about SVC, and so I can interpret that. I don’t know that much about how either SNIP or MVV change in ALS.
And I could also add vital capacity is something that commonly done in clinics, and it’s our objective measure, so patients really know how to do it, and our ALS clinics know how to do it, and our ALS clinics know how to do it and have long years of experience performing it. And the MVV, I have – as a site investigator for the previous studies, MVV is very effort-dependent, and when doing it, that was one of the feedbacks I got from the sites, as being the medical monitor, that patients really were – it’s very effort-dependent, and it’s difficult. And remember, patients are coming for long periods of evaluation, so slow vital capacity is done first. And then, in the long list of evaluations, and we’re doing multiple pulmonary measures, so we still have to sort that out.
(inaudible) The mega-score versus the grip strength, as well, sort of how you look at – how you guys look at those.
One of the – so the question is how do we view the muscle strength and mega-score and grip strength?
Well, just to be clear, the mega-score includes the grip strength. So, that’s one of the – two of the 10 muscles that are – make up that score. And so, grip strength changed in a similar way to the rest of the other muscles.
So I guess I could just pose a question to you, how would you view the magnitude of changes s that you saw in the study, for muscle mega-score?
Well, so, in a short study, you always have to be careful estimating effect sizes. But, the point estimate of effects for both SCC and for grip is dramatic. It suggested that patients changed more than twice as much when they were on placebo as compared to treatment, which if confirmed is amazing. I mean, that – many of you may have followed the lithium study, the initial Italian study that suggested this near-miraculous effect of lithium on ALS. Well, the estimates of their effect, in terms of the change between placebo and lithium, was the same as this. It was a factor of three. And so, if that’s true, if that’s confirmed in succeeding studies, that’s a major difference
Fady Ibraham Malik
Maybe I’d just add a clarifying point, I think. When you look at hand grip on the slides that Jeremy presented that’s hand grip fatigue. So, that’s maybe something I should have clarified in my presentation. That’s a measure of how long patients can maintain a given grip. So, the way that’s done is we first ask the patients to do a maximal grip, and that value is what goes into the mega-score. But then, we set them a new target that’s only 30% of the maximum they just demonstrated, and we ask them to try to maintain that for as long as they can. And so, that is measured in seconds, and that is what did not change much, but the – but very, very variable. But, the grip strength did, and that contributes to the mega-score.
So I think in talking about our secondary endpoints, I wanted to reflect on something that Dr. Miller alluded to when he gave his brief comment. We – with BENEFIT-ALS, we missed our primary endpoint and we see the secondary endpoints that are significant. And Dr. Miller had mentioned a different experience when riluzole came along, where the survival endpoint was met but there was no functional benefit. So, I would pose to the panel what to ask what your perspective is on this finding, and how you the results. So, if anyone wants to
Merit E. Cudkowicz
I’ll add that full riluzole, because it had this kind of disconnection, it does leave a lot of patients I am not sure if they want to take it. They kind of say, well, I’m not sure I want to live longer if I’m not functioning any better so there’s really – since riluzole’s time, there’s been a real push to develop drugs that can have a noticeable change on people’s actual strength and function. So, I’m not worried about it not meeting the ALSFRS. I think for a drug like this that goes to work directly on your muscles, that the ALSFRS might really be too general of a kind of questionnaire.
And as Dr. Miller mentioned, we haven’t really seen any drug have an effect on that scale, so it might be more of a scale issue. And we have certainly seen that scale be sensitive to side effects in other trials, particularly one with Topiramate that I led in the late 90s, that had weight loss and had a similar effect on ALSFRS. So, I think it’s very dependent on how the patients feel the time you’re asking them those questions. Dr. Miller, did you have a comment?
Well, I just one other point and that is with riluzole, we really were unclear about how that drug was producing a beneficial impact. Here we have a mechanism. We have results in mice, and then in a mouse ALS model, and then in normal human subjects, all showing increased strength, and then trials in ALS patients showing that this muscle activator actually does make muscle stronger, both breathing muscles and limb muscles. So, it’s very much more satisfying than when we were listening to the listening to the data on riluzole.
So, I think Dr. Cudkowicz had mentioned patients’ willingness to take risks. And when we’re looking at the results and looking at the data from BENEFIT-ALS, we note that we had a lot of early terminations, and of course the weight loss issue and the adverse events. What is your take on how important adverse effect profile is in a fatal disease like ALS?
Merit E. Cudkowicz
I mean, of course we never want to make people feel bad, but I think in this illness that the patients and the physicians really feel like you can take a lot of risk just like you do in oncology and brain really serious fatal illness. It isn’t an illness we want to be treating kind of with vitamins. We really want to try to make a big impact. And again, we have to manage the side effects, because we don’t want them dropping out or not feeling well. But again, with knowledge, one can try different things, such as slowing the escalation of the drug, giving them medicines for nausea, giving them – making sure they’re eating more, or ways to keep their appetite up. So, I think it’s a – knowledge is really helpful on how to minimize these, but I think with a disease like this, if we have a drug that works, the patients will be very willing to accept some risks and adverse events, and also the physicians.
So, you mentioned the drug that works, right? I – someone has a question? Yes, go ahead
Yes. So, I know this is a bit of a speculative question, but given the depth of experience developing drugs for ALS, I can’t think of a better panel to pose it to. Given the data that we have, or we’ve looked at today, what do you think next possible steps might be? I mean, is a trial with a primary endpoint of SVC kind of on the table? Is that what we’re looking at? And if so, what secondary endpoints would you like to see also hit to support that? Or basically, where do we go from here, possibly? And I know it’s early days, but maybe you can each walk me through what you think your opinion of what it might look like.
Sure. We’ll start with Dr. Shefner, and then go down the line.
Well, I come back to my view that this is a positive study in terms of important outcomes. And so, I think there should be next steps, that’s the first question. I think that this is something that needs to be further evaluated. And I think all of what you said makes sense. I think the first question is, can we make this drug more tolerable to more patients at clinic – at meaningful dose levels, and there are a number of approaches, a slower titration, management of the symptoms that we already now know exist, potentially a lower maximum dose, although that’s yet to be clear whether that’s important.
So, those are all strategies to get more people on the drug. What the primary outcome measures should be, I think – I’m certainly not ready to say, and it’s probably not completely up to any of us at this table. It’s going to be a conversation with the FDA. The FDA has never said that ALSFRS is their only bar for approval, and in fact there was a study in the early 2000 of a drug called Xaliproden that was developed by Sanofi, and in their discussions with the FDA led to a primary endpoint that was a time-to-failure analysis based on a SVC. So, SVC has been an acceptable endpoint in the past to the FDA. It’s clinically very meaningful to us who take care of patients, and to the patients themselves. And when patients come into clinic, the two things they want to know is, well, my general impression, but what’s my vital capacity. That’s – they hang onto that number. It’s important to them. And so, I think one could design a trial with that as the primary endpoint.
Well, I would just say, as a clinician, the two positive secondary endpoints here, vital capacity and global strength score, are extremely meaningful to patients and to us as clinicians. We went through a phase in clinical trials in ALS where strength was our primary endpoint, multiple muscles, just as we saw here today. And we began to back away from that a little bit because it is not such a strong predictor of mortality as the vital capacity, as you’ve heard, a very strong predictor of mortality. But, when you put these two side-by-side, to me this is where the money is.
So, vital capacity, and possibly looking at some of the data from this study in terms of the amount of time to drop to drop to certain values of vital capacity – time to failure, we call it – focusing on the breathing muscles, the vital capacity, and on the mega-score, going forward, I think is the way I would want to do it.
I mean let Dr. Cudkowicz answer, and then we’ll take a question.
Merit E. Cudkowicz
Well, I agree with the two prior speakers. I think this drug works on the muscle and to impact strength, as we’ve seen. So, having either SVC or the mega-score the primary and the other as a secondary would be really important. Be nice at the end of the day to be able to tell patients this drug will give you X number of months at a better vital capacity, or a better strength. And then, secondary, we’re really trying to developing some patient-reported kind of outcomes on things like time to needing an assistive device. Can this drug give you more time without being in the wheelchair? Those kind of measures would be really important for interpreting the facts and helping patients.
Okay. And we have a question?
Thank you. I was wondering if you saw any patterns among the sub-components of the ALSFRS or amongst different types of patients, because the disease can be heterogeneous with the muscle groups that are affected. And if you can talk about that, whether you saw some things – more things improve, any patterns there, and similar patterns amongst things not improving, or maybe even getting worse on the – for the people on the drug. And then, can you talk a little bit about how the ALSFRS captures function versus strength, and how important that is and how this drug might impact one versus the other concept? Thanks
Well, there are a lot of questions here. Let’s see if I can remember it. So, with respect to individual components of the ALSFRS, there’s more to do in that regard in terms of the analysis. But, an initial look didn’t pull one out as being a single arbiter of decline or de-selectively improved. In terms of looking at patient subsets, we’ve done a bunch of them. Many of them were pre-specified. Many of them we thought of later when we saw the data. And most of them were uninformative with respect to ALSFRS. So, the finding was fairly robustly negative in terms not showing a subgroup that had a clear benefit, but there also wasn’t a subgroup that clearly carried the most decline except for the weight distinction.
We looked at the onset of disease, bulbar versus extremity. We looked at sex. We looked at age. We looked at the site – the geography. We looked at spasticity, whether that predicted a better or worse response. And with respect to ALSFRS, none of that seemed to make much difference. I think we haven’t had as good – had as much time to look at the secondaries in that in as exhaustive a way. So, that was the ALSFRS components of the subgroups. You had a third one. Oh, so how does the ALSFRS reflect strength versus other things? Well, clearly, if you look at the individual questions in the ALSFRS, one aspect about that scale is that it that’s amazingly crude. You go from normal to nothing in four points. And so, one can change very significantly in terms of one’s walking or one’s ability to turn in bed without changing – without changing even a single point on the ALSFRS. So, I think it – by being so global, it sacrifices a huge amount of precision. And just one issue about this drug, is that one would predict, I think, if it has a clear effect on muscle strength, everybody’s going to have a different sweet spot, coming in. So if your arm is just too weak to feed oneself, a little bit of extra strength could make you be able to feed yourself. If your leg is just too weak so that you no longer get out of the chair, a little extra strength could make that possible but everybody is going to be somewhat different, and try to collect that in a global perspective is pretty tough.
In the last couple of years of hearing these data of Tirasemtiv, probably the most striking single observation for me has been a couple of individual patients who during the earlier studies, the shorter-term studies that were more exploratory demonstrated very significant functional improvement within a very short period of starting the drug. So one of our patients, for example, who had arms that were just at her sides when she went into the study within a matter of a week or two was able to raise her hand up, and she came up to me and said look, and we – I was stunned, because it was a really a very dramatic change that she lost after she was transitioned off the drug.
Another patient wheeled up to me in his wheelchair to shake my hand, and I was struck by the force of his handshake, and he was mashing my hand. And this was a hand that had been quite weak prior to starting the study. Neither of us knew what they were taking at the time, but the striking observations were, for me, unparalleled. And I’ve been doing this for a very long time. So, the improvements in strength and in breathing that occur short-term may not be reflected in the global ALSFRS-R, and in its rate of decline over time. To me, the great strength of this drug is that it can, in the very short time produce noticeable increases, significant increases in strength and breathing and that’s I think something we’ve got to keep the focus on.
And I should add to your comment. So, I too was an investigator for the early Phase II, and both – had two patients that were walking with canes, and clearly within a week, had some improvements which declined after they discontinued the medication. So, clearly, there’s strength, and every patient is different in how they present and how they have weakness. So, it is hard to measure using a global ALSFRS functional scale when you have a whole group of patients that look different and are reflected differently on that scale. I will add – I’ll ask Dr. Miller, given your experience, and given how you’ve had experiencing many, many patients over the years in clinical trials, how would you think patients would feel about participating in another trial with Tirasemtiv? And I’ll pose this to the rest of the panel, as well.
I can say that my patients were very disappointed, that they couldn’t continue to receive the medication. My patients feel that there is something here. They definitely have expressed to me that they would be enthusiastic about participating in another trial to clarify the value of this drug and so would I.
Yes. Dr. Cudkowicz?
Merit E. Cudkowicz
Oh, I feel that, I mean, we’ve already heard from our patients in this current trial, that they thanking us for doing this, and also hoping that we’re going to continue and they’re ready to sign up. So, they’re very eager.
And Dr. Shefner, final thoughts
Oh, do we have questions? Yes?
Yes, hi. This is a question about the adverse events, the GI adverse events. Seems like it was taken as a bit of a surprise by most of you, what was the clues leading up to it? And – because you did three Phase II trials before. Did you have any evidence that you might see this sort of extra – higher frequency of GI events? And once the patients were in the trial and they started having these events, how effective were any measures that you to help alleviate the nausea and some of the other GI effects, and were they effective? Because it seems like, because of the dropout rate maybe it wasn’t as effective as maybe you would like it be?
Go ahead. Dr. Shefner?
So, I don’t think we had a hint, going in, that that would be so significant. And the big difference in this trial versus the previous ones is it’s the longest anybody had ever been exposed to Tirasemtiv was three weeks. And that three-week period was an escalation period, so those – they weren’t on 500 milligrams for the entire three weeks. So, that may be the reason for it. I don’t think we’ve carefully looked at the GI AEs in terms of timing in the study yet, so
Andrew A. Wolff
Yeah, I can answer that, I mean, the other thing is that goes along with what Jeremy just said, that we’ve never treated anybody before BENEFIT-ALS for more than three weeks is that, if you look at the average time to onset of these GI adverse events, it’s significantly longer than, for example, dizziness, which tends to occur very early, but also resolved very quickly in most patients. So this has – these events had a more insidious onset, and they weren’t that severe either. So, they wouldn’t have necessarily prompted any intervention because the great, great majority of them were classified as mild.
to reiterate that, I mean, so the weight loss difference was quite significant. It was twice as great. But, the total weight loss was about four pounds in three months. And so that’s – in terms of magnitude, without knowing this as being something to focus on, I think most investigators would not have pickup on that. And so, I mean, that something we can modulate, going forward, but the intensity of these symptoms and the amount of weight loss although clear is not dramatic.
But, just to reiterate, then, most of the patients that did drop out dropped out because of the GI events?
No. And so, the penultimate slide that I showed, which actually showed the frequency of GI AEs, it was far less than half of the patients. If that those people are accounted for most of the average weight loss, but it was not it was far less than half of the patient. And it was not a common reason for termination at all.
So, I’ll just add that weight loss and looking at the change in weight was something that we’d planned to do ahead of time because weight change and rate of weight loss is well-known to affect disease progress in ALS. And so we have planned it, and we had seen a statistical difference between the placebo and Tirasemtiv groups, which led us to probe further. So – and the other thing, as Dr. Shefner and Dr. Wolff was saying, that dizziness was the leading cause for early terminations and nauseas were – nausea that was reported by patients were generally mild.
And in the context of a patient having ALS, it is one of many symptoms that they come into clinic reporting, and we already had been aware of the dizziness being an issue with the drug. And so, I think all of our investigators were very aware and proactive about asking, but nausea could have been something that has persisted and been in a whole complex picture, been something that patients may not have brought up, as well. They might have just felt it, reported it, but not asked for further treatment because they’ve got lot of other problems going on. Any other questions? Yes?
So I appreciate that there’s a lot of work that needs to be done so. But, is there any read-through from the myasthenia study? And I suspect you’re not prepare to discuss what you see, I’m sure you see AEs and those kinds of things already, but if there is Fady or Andy, if you can comment on if there’s way to recheck that to see if?
Andrew A. Wolff
They were really very different patients, I mean, not only – well, not only did they have different disease, but they were just much less debilitated. They were younger and they did actually tolerate the drug very well that was, the one study that that we’d done with Tirasemtiv where there were literally absolutely no early terminations, there is a three-period crossover designed study in every single patient completed all three periods. The single dose study two like one we did in at in the very first ALS study patients got a single dose Tirasemtiv on two different study days, and then placebo on a third. We did see however one thing that was very consistent between the myasthenia gravis patients and the ALS patients was a very significant increase in their slow vital capacity. It actually was a force vital capacity.
Thanks. Do you have additional comments, Dr. Malik?
Fady Ibraham Malik
I was just bring that point.
Okay, yes. Any other question? Yes?.
Unidentified Company Representative
I think you alluded that this is something you might do in the future, but can you talk about, at least anecdotally, any use of antiemetics in the trial, and to what extent patients try to manage the nausea in BENEFIT-ALS?
So, I can answer since I was the one having to handle the calls. The – so as I mentioned before the most majority of the complains that were nausea specifically nausea specifically nausea were mild and so generally they are classified as moderate or severe if they required treatment. We are still looking at the data to see how many patients required anti-nausea medication, and they are available, and it is something that we use in ALS patients so it is manageable, its just like I said, in the context of an ALS patient deteriorating, nausea falls on the bottom of the list because there’s so many other things that you have to deal with, including deteriorating respiratory function and muscle function that’s affecting their daily life.
So with that I’ll conclude the question-and-answer session and I will bring Robert Blum back up to give some conclusion.
Thank you Jinsey and thank you to my colleagues at Cytokinetics on this panel and also Jeremy Shefner and also Bob and Miller for their comments and perspectives. We have tremendous responsibilities for a company like Cytokinetics. To put this into some more context we are roughly about 90 people at a company in South San Francisco. And we are developing a scientific platform that’s given rise to many promising first-in-class muscle biology-directed programs. I started this program with some remarks about our partnered programs omecamtiv mecarbil with Amgen, CK107 with Astellas – to try to set a landscape for you in which we’re going to be evaluating these results relating to BENEFIT-ALS. There’s certain things we know with some certainty.
We had a last patient last visit in BENEFIT-ALS at the end of March. This was a study that was conducted around the world in 75 centers 73 of whom enrolled patients, and this is an extraordinary undertaking, the largest phase II study ever conducted in ALS patients. And as we seen there is a lot of data here, the database lock occurred in mid-April. That by itself was an extraordinary task, collecting and cleaning the data in order to enable it to be locked, for then analyses that only started within the last two weeks.
We had a team sequestered at Cytokinetics for those data analyses, and they brought me into the room only a few days ago and we felt it was our obligation both to shareholders, but also to patients and the investigators in the centers to report the results of the primary efficacy analysis as soon as they were known. And hence, we issued a top line press release last Friday morning.
We wanted to respect the integrity of the process and the ongoing analyses in order to allow the investigators to review data and to allow Jeremy to present the results at this meeting. So the investigators meeting occurred two days ago, Jeremy presented these results to the Scientific Congress yesterday, and we have an extraordinary amount of work still to do. There are specified analyses, and that’s what’s been shared with you, they were pre-specified as part of a statistical analysis plan. These are not post-hoc, these are not subgroups. These are as prospectively defined to be important and meaningful for patients and in context of clinical research, and we know unequivocally that this study didn’t hit on its primary efficacy analysis.
We also know that this study did hit on pre-specified secondary analyses that are deemed important, clinically meaningful, and predictive of disease progression and survival. With that, we have great responsibilities, as well. We operate with great responsibilities across this program and as a company. Next week, we’ll talk financially. Cytokinetics has an earnings call scheduled for Tuesday, May 6, and at that time we’ll update on the financial metrics of the Company, our cash, number of months of forward burn, expected milestone payments, and other things that read on financial measures of the companies viability and sustainability and especially we are please that the other programs are advancing to key milestone as fully funded by our partner.
But, now we have a job to do with respect to Tirasemtiv and BENEFIT-ALS, and we will do that job, and that a job that isn’t just about trial and data and P values. It’s not just about endpoints. It’s not about stock price. It’s not about puts and calls. It’s really about what are we going to do to understand how this science translates to potential therapeutic options in medicine for these patients.
Our business, let’s be very clear, is to do the right thing by patients who can benefit from medicines that we are uniquely positioned to discover, develop and advance and we have something important here in benefit ALS. We know we have a trial that stands out a amongst other studies, but all we also know we have great deal of work to understand these data in order to be able to construct potential plans, around which we could execute in a variety of ways and we are going to do that because that’s what the patients want us to do, that what our responsibility is to the patients who could best benefit from Tirasemtiv or some other way we might approach addressing the interest in ALS.
Our conviction remain strong. These results support the original plan for conducting BENEFIT-ALS, and now we understand enough to say that we need to delve more deeply into these data to know what we may do next. So please understand that this will take time before we’re going to be able to make commitments about what we’ll be able to do in the next phase of development of skeletal muscle activators for the potential treatment of ALS and other neuromuscular diseases.
We’re keenly aware of the urgent needs for patients with ALS. That was true before we had these results, and that’s more true today, and we’ll look forward to sharing with the investment community. We’ll look forward to sharing with ALS patients and their caregivers, with the investigators and other clinicians who treat ALS patients what we hope to be able to do, and we’ll also put that in a framework that makes sense from a business standpoint and would ensure the viability, sustainability, and growth and value in Cytokinetics, which is also our commitment to shareholders. So, with that, I will end the program. Thank you very much for your interest in what we are doing. Thank you for your understanding of where we are and we are still needing to go and we’ll look forward to giving you updates as we get more clarity. Thank you
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