Good morning. My name is Robert Blum, and it's my pleasure to welcome you to the Cytokinetics webcast to discuss the results of the FORTITUDE ALS trial that were announced here yesterday at the American Academy of Neurology Annual Meeting in Philadelphia. This meeting is convening here in Philadelphia, but is also being webcast and we welcome those people who are dialed into the webcast. Today, we're going to elaborate on some very important data that were presented yesterday at the AAN relating to the development of reldesemtiv for the potential treatment of ALS. I'll be making and others will be making some forward looking statements.
We will refer you to our SEC filings with regard to caveats to those statements. We do not undertake any obligations to update those statements. As you know and to set some context, Cytokinetics is a pioneer in developing a new pharmacology relating to modulators of the contractility of muscle, different types of muscle. Today, we're going to be in particular talking about reldesemtiv, a next generation activator of troponin found specifically in fast skeletal muscle. And as we are advancing our pipeline, we're aiming towards the treatment of severe diseases of muscle dysfunction and weakness.
Today, I'll be joined by colleagues Doctor. Fady Malik, who leads our research and development and has been with Cytokinetics since we founded the company in 1998 and it's his vision around these modulators of muscle biology that we've been prosecuting as we advance our pipeline. You'll hear from him relating to the underlying biology and mechanism of reldesemtiv that sets the table for the discussion of the results to follow. I'm also joined by Andy Wolf, our Chief Medical Officer. Andy Wolf has been with us 15 years and like Fady is a physician and has overseen the conduct of most of the clinical trials that we've conducted at Cytokinetics.
He'll be moderating a Q and A session to follow. I'm especially pleased to be joined by 2 leading ALS treatment physicians and clinical research investigators, people who have pioneered the advancement of new medicines in ALS for decades. Jeremy Scheffner, who is Lead Investigator of FORTITUDE ALS, Professor and Chair of Neurology at the Barrows Neurologic Institute and Professor, Chair of Neurology, University of Arizona in Phoenix, Jeremy, a founder of the Neal's ARO and principal investigator of this study will be in a position to provide context for these data not only with respect to this mechanism, but also in particular as it relates to the development of investigative medicines for ALS for many years. So to Angela Genge, a member of the steering committee for the FORTITUDE ALS trial, Director of the Clinical Research Unit in Montreal overseeing the Neurologic Institute there and I should point out one of the lead enrollers of patients not only in this trial but also for the benefit ALS and vitality ALS trials having a lot of experience with this mechanism over quite a long period of time. Thank you both for joining us on the panel here this morning.
I'm going to make some brief introductory comments and then Fady will join me in a discussion of our pipeline and how it's advancing. But first, may I underscore that this is a picture of the sarcomere. It's the fundamental unit of muscle contractility around which we've been focusing our drug discovery and development activities for many years. And as you may know, we are advancing now a broader portfolio of compounds that are all directed to this structure, activators and inhibitors that we divide into 2 verticals, those that pertain to cardiac muscle like omecamtiv mecarbil in Phase III for the development of heart failure, but also other compounds like AMG 594, a cardiac troponin activator and CK-two seventy four, a cardiac myosin inhibitor. I'll have more to say about these later in the morning.
Today, we're going to primarily focus to reldesemtiv, a small molecule activator of troponin. And as you'll hear from Fady, that gives rise to a therapeutic hypothesis that we were testing in FORTITUDE ALS. Putting that into another context, here's our pipeline. We are advancing, as you can see here, in mid stage and late stage clinical trials, investigative medicines, all of which have been discovered and optimized and characterized by scientists at Cytokinetics in our laboratories and now in advanced clinical trials. We've conducted over 50 clinical trials over these many years, thousands and thousands of patients enrolled in published peer reviewed placebo controlled clinical trials and FORTITUDE ALS ranks amongst those as yet another study as you'll hear that serves to represent opportunity moving forward.
I'm going to set the table a little bit now in terms of the discussion of FORTITUDE ALS and I'll come back and make some other comments. But what I'll say is, as we go through the program this morning, please keep in mind that we do Phase II clinical trials for a reason. We do Phase II clinical trials in order to understand the potential for consistency of effect across doses, time points, endpoints and subgroups in order to be able to properly design a Phase 3 trial that could have the robustness with a statistical significance of p less than 0.05 in order to support potential registration. And I would put forward as you'll hear now in further detail that FORTITUDE ALS most definitely accomplished the objectives that we established and in that way lend support for progression of reldesemtiv into further clinical trials. With that, I'm going to turn the podium over to Fady.
He'll walk you through more of what we understand for the mechanistic biology and then he'll turn it over to Jeremy to present not only those slides that he presented yesterday to the audience at the AAN, but also elaborate on those with additional data and as he will then be joined in conversation led by Andy and together with Angelo.
Great. Thank you, Robert. And I'll just remind you of the work we've done in pioneering the discovery and development of modulators of the sarcomere muscles. Sarcomere being that fundamental engine that drives muscle contractility. It's an elegant biological machine whose components can be taken apart and reconstituted in ways that facilitate drug discovery and faithfully are replicate it from biochemical to intact muscle to the activity at the level of an intact organ or intact muscle.
This is an area of biology that we've used as an engine for drug discovery at Cytokinetics for nearly 20 years now. The assay that underlies most of our drug discovery is this high throughput screening assay of a functional sarcomere where we can replicate the activity of muscle in a test tube, so to speak, or a a plate of compounds, 384 well plate of compounds that whose activity can be whose activity may modulate that of this reconstituted sarcomere, taking it apart into its fundamental components act in the roadway, the S1 head of myosin, which is the motor domain and then the regulatory domains of troponin tropomyosin that regulate that actin myosin interaction in a way that's faithfully replicated in this biochemical assay. Over the years, we've conducted nearly 20,000,000 screens of this system in cardiac, skeletal, smooth muscle of various different types. And this fundamental biological assays led to discovery of compounds that and the development of the compounds that Robert introduced at the beginning of the session here. Now a fast skeletal muscle troponin activator is a small molecule that binds to troponin.
Troponin is fundamentally the transmission in the sarcomere. Once it binds to calcium, the myosin is allowed to engage the active filament and for muscle contraction thereby to ensue. And reldesemtiv binds to troponin in a way that increases its affinity for calcium. So it changes the gearing ratio in the sarcomere and fundamentally we can show that in this assay that's shown on the slide here where the affinity for calcium is demonstrated. Now the consequences of increasing the affinity of calcium within the sarcomere is sensitizing the sarcomere mirror threefold.
1st, skeletal muscle troponin activators amplify the response to motor neuron input. This is important for what we'll be talking today given that ALS is a neuromuscular disease. 2nd, they increase muscle power. And third, they improve muscle fatigue ability by reducing the requirement of both nerve and calcium in order to drive muscle contractility. We've shown this in a number of preclinical models across a number of different disease conditions including ALS, SMA, myasthenia gravis, models of heart failure and so forth.
Much of that work has been published. But importantly, what we're able to show and we've shown now both with the first compound in this field, which is tirasemtiv and now with the second reldesemtiv is that the fundamental mechanism of action translates from the preclinical setting to the human setting. And in his case, what we're looking at is a what is a force frequency relationship of muscle. So in an intact animal or in an intact human, if you stimulate the nerve to muscle, the muscle is activated. The faster you stimulate the nerve, the greater muscle is activated and you see more force is developed.
And if you dose in the presence of reldesemtiv, a troponin activator, you see that curve shift to the left because the muscles now more sensitive to nerve input and generates more force. So either the muscle at the same stimulation frequencies, the muscle generates more force or for the same amount of force, it requires less nerve input. And on the right, you see the human translation there where in an assay that where you stimulate nerve on the outside of the knee, you see an activation of the muscle in the front of the leg and a concentration exposure dependent increase in the force that's developed there as you stimulate the nerve. So this certainly shows that the mechanism of action is active in humans and also describes its exposure response relationship. And in going from our 1st compound in this area, tirasemtiv to our 2nd reldesemtiv, which you can see in the two graphs on the right both conducted in humans that reldesemtiv provides a greater pharmacodynamic response, so an increase in the force that is produced in response to nerve input to a greater extent than we saw with tirasemtiv.
Reldesemtiv was also better tolerated in Phase 1 studies and tirasemtiv was and fundamentally these results supported progress of reldesemtiv into Phase 2 program. Now we have an extensive experience in trials in ALS as you probably know. We've conducted several trials with tirasemtiv that gave us experience with this mechanism of action and also provided fundamentally the belief that there was a biological activity of this mechanism of action in patients with ALS. And now FORTITUDE ALS, which I think builds upon those, it confirms that this mechanism of action is relevant to ALS as Jeremy will go over with you. But almost 2,000 patients have been enrolled from a network of 80 sites in over in a dozen countries in the U.
S, North America and Europe. So with that, I'll turn it over to Jeremy Scheffner, who will walk you through the results of our latest study FORTITUDE ALS. Thank you,
Gerry. Good morning. So just to dive right into what the study looked like, this was a large Phase 2 trial with a duration of 12 weeks of active treatment and inclusion criteria that were fairly typical of many ALS trials, but somewhat less restrictive than has been the case for a few Phase III trials and in particular more restrictive than the Adaravone study, which led to approval using a group of patients that were quite early in their disease, but had diffuse disease and were rapidly progressive. We took a broader approach. We did allow both videravone to be used as well as riluzole, but patients had to be stable on either or both.
And the primary efficacy endpoint was slow vital capacity and the analysis was changed from baseline to mega score, which is a quantitative measurement of muscle strength using a handheld dynamometer and with individual muscles normalized so that you could create an average strength. We also looked at safety markers as well as 2 pharmacokinetic days and I'll show those data as well. The study was predominantly enrolled in North America and more than half of the patients came from the United States. Approximately 100 patients came from Canada and small numbers of patients came from the Netherlands and Ireland, slightly more from Spain and then Australia had 5 sites and contributed 20 patients. This is the study schematic.
After screening patients were randomized equally to 1 of 3 doses of reldesemtiv and placebo, they were studied on active treatment for 12 weeks, withdrawn from drug and then studied again 4 weeks later. And outcome measures were assessed at baseline, at screening and then approximately every 4 weeks after that except for the 2 week period as well. This is the description of the baseline demographics and it's a very busy slide. The things to note are that average age, most of the sort of baseline characteristics of rating scale value at entry was about 37. Rating scale value at entry was about 37 and the average vital capacity slow vital capacity was about 85% predicted.
About 25% of patients were on Adaravone at the time of their study enrollment. And this shows the patient disposition. It's quite a busy slide, but there's some important points here. First, 606 patients were screened to randomized 458 patients, 457 of them ultimately went on drug divided equally into the 4 groups. If you look at the red bars, you can see that early terminations from study treatment were actually quite well balanced across groups.
There was not a tendency for more patients to drop out over time in the treating groups versus placebo. On the other hand, if you look at the bars below that, the blue bars, you can see that the dropouts due to early terminations from study treatment due to adverse events did have somewhat of a dose dependent pattern, although the numbers were still quite small. And then finally, the purple bars below that, there was an increased number of dropouts to proceed progressive disease in the placebo group as compared to the other treatment groups, small numbers, but still interesting. This slide shows the pattern of when patients terminated early. And if you were have seen the tirasemtiv data, you know that this is a markedly different pattern where for the prior drug, there was very significant dose related early terminations from study treatment.
Here, the groups are all quite similar and the drug tolerability is quite good. The pharmacokinetic data at week 2 week 12 is presented here. And you can see that reldesemtiv has increased serum concentrations in a dose dependent fashion and that if you look at the differences between week 2 week 12, there really aren't any, so there's no tendency for the drug to accumulate over time. And so looking at these concentrations and relating them to one of the figures that Fady showed, the pharmacodynamic demonstration of force in normal human volunteers, This shows the increase in force that tirasemtiv is associated with the different stimulation frequencies of the nerve. And again, you can see approximately where the different dose levels take you on the pharmacodynamic pattern.
And you see that there's a they're at the point where you should see a signal for all doses and the 2 higher doses are actually fairly close to each other in terms of what you might expect to see based on the concentration relationships to increases in muscle force. So here is the primary endpoint, which is change from baseline to 12 weeks in slow because this measure is expressed in percent baseline. And this is somewhat slower than what we expected and what it was seen in many previous ALS trials. Clinically and experimentally, we usually think that vital capacity drops by about 3% per month. And in this study, it dropped by a little bit more than 2.15.
So a slower decline in these patients with regard to this measure. There was a dose dependent effect of this drug towards reducing the decline further. The primary analysis which was a mixed model for repeated measures weighting of placebo and the lowest dose to a smaller extent versus the 2 higher doses, that analysis reached a significance of 0.11 approaching but not meeting a 0.0 5 level. If you look at the pattern of responses over time in the 3 groups and in the placebo group, you can see the gray bar is the placebo group drop. And you can see that at all time points and all dose levels, there is a tendency for the treated patients to do relatively better than the placebo patients.
The effect is largest at 12 weeks and actually is maintained for the most part for 4 weeks after that even though patients were off drug. We did an analysis where we combined all patients on drug and compared them to placebo. And here's a graph depicting that. The P value for the comparison of drop at 12 weeks is 0.1, but the relative risk reduction in rate of progression in somatic capacity is 27%, which is I think if verified would be thought of as a clearly clinically significant change in ALS progression. ALSFRS looked very similar at virtually all time points and all dose levels at all dose levels, patients progressed less quickly on the ALS functional rating scale than placebo.
The mixed measures analysis showed a P value of 0.09. And again, there was a tendency for the difference to be maintained 4 weeks after withdrawing from study treatment. Comparing all three doses together in the same way we did previously for vital capacity, the difference seemed to get larger with time. And the comparison at 12 weeks comparing all three groups to placebo was quite highly statistically significant. It was significant at the one level.
And again, you can see the persistence of the effect. And if you're ALSFRS aficionados, you know that it's basically 12 questions and you can divide them into 4 domains: a fine motor domain, a gross motor domain, a bulbar function or facial and tongue domain and a respiratory domain. The last two actually change much less over time and so contribute less in the total score to the drop than both fine motor and gross motor. And you can see that in terms of the effect of tirasemtiv, the effect is primarily seen in those two domains and gross motor more than fine motor. There are P values for each comparison.
There are many of them and it's probably not worth taking them too literally, but they do suggest quite a prominent effect. And this is the strength evaluation. And again, you can see it's the same pattern that for, in this case, most time points and all doses, there is a tendency for patients to lose strength less rapidly than patients on placebo. There are 2 P values here, one for a comparison of slope, which had a P value of 0.3 and then the other is change from baseline to week 12 similar to the other analyses and that had a P value of 0.13. That's there.
And if you average all groups together and look at the difference, it looks very similar. The magnitude effect is slightly smaller. It's 0.221 and the P value for that difference between all treated patients versus placebo at 12 weeks is 0.2. We did a variety of subgroup analyses and these are disease entered the study at greater or less than a given value of ALSFRS, greater or less than a 2 year symptom onset, site of onset and a pre study evaluation of how fast people were progressing with respect to ALSFRS. And this is a forest plot where every point to the right of the line, which is a 0 effect line, suggests a benefit of the study drug right of the no effect line.
It's the effect was really quite All of the points are to the right of the no effect line. The effect was really quite consistent about across all of these subgroups. And that's true for vital capacity shown here. It also is true for the LS Functional Rating Scale shown here. And it was also true for Muscle MEG score.
So again, quite, I think, amazing consistency of the data. With regard to safety, mortality was very rare in this study. There was one death in patient on active treatment and that patient was on placebo. There were 2 deaths in the 4 week follow-up period, 1 was on placebo and 1 on the highest dose, so very rare occurrences. And serious adverse events were quite evenly distributed across the spectrum of placebo to all dose groups.
So rare and not significant not higher in treated patients. With respect to adverse events, both fatigue and nausea, although rare, had a dose dependent increase in being reported as compared to placebo. The other clinical adverse events listed here don't have a clear trend like that. In particular, it's probably worth pointing out dizziness, was a big problem with tirasemtiv and seems to be not a problem at all with this drug. There were some laboratory events to be aware of.
Cystatin C increased in a dose dependent fashion and since we calculated GFR based on cystatin C, GFR decreased in a dose dependent fashion as well. And there was some tendency for transaminases to be increased a dose dependent fashion as well. And looking at those data in a little bit more detail, here's the average changes in GFR based on cystatin C over time for all three groups versus placebo. You can see there's no change in the gray bars. And there is a dose dependent decline in GFR that reaches its maximum level quickly by 2 weeks, stays very constant during the course of the study.
And then when you withdraw the drug comes back towards normal. The maximum in the group and so the biggest changes on the order of a 15% drop. And so this was noted. It doesn't seem to be severe. It wasn't associated with signs of renal toxicity as Andy will discuss.
So the GFR dropped, but other renal markers didn't change. And although it's something to be aware of and was the biggest reason for withdrawal from study seems to be a modest effect. Transaminase elevations were more than 5 times the upper limit of normal for a few patients. I think there are 6 patients displayed here. And you could see that they could happen at various times during the study, but then when study drug was withdrawn, the transaminases returned towards normal.
So our summary is that the pre specified analysis for the primary and secondary endpoints were not statistically significant at the criterion we set. The P values approached significance for the first two, but not for strength. But the patients on reldesemtiv declined in all measures less than placebo and that there was a trend towards the differences getting larger with time for both SVC and ALSFRS revised. Reldesemtiv in terms of the estimate of the size of effect showed clinically meaningful effects in reducing the decline of vital capacity 27% in 3 months ALSFRS, 25% in 3 months and in strength as well, which is 21%, when you combine the groups and compare them to placebo, the incidence of early treatment discontinuation, serious AEs and clinical AEs were overall similar between the 4 groups, but that there were elevations in transaminases and declines in eGFR that were dose related and the GFR change was the leading cause of termination from study treatment. And so it's our view that these results support the continued investigation of reldesentiv into a pivotal Phase III trial.
Here are the investigators and members of the steering committee and the data safety monitoring committee. Thanks. So I think
we're going to open it up now for Q and A and this can be moderated by Andy. Some questions have already come in, that I think Andy you're going to maybe start with or then maybe we'll come to the questions here in the audience as well. Is that okay?
Yes, I'll start with a question maybe each to our 2 panelists and then open it up to the audience and I'll continue to ask questions to our panelists, but it's intended to be interactive. So let me start with you, Jeremy. How can you put this data into context of Phase 2 studies in patients with ALS that we've seen in the past 10, 20, even 30 years?
Well, so my involvement in ALS trial started with the arylazole study. And I think this is the most positive and consistent demonstration of potential benefit that has been shown in any Phase II study for any drug in ALS. So that may be superseded by results that are going to be presented tomorrow for antisense treatment of a very small number of ALS treatments with a specific mutation. But for sporadic ALS, the consistency and magnitude of these effects is greater in Phase II than any other study that I'm aware of.
So and I'd like to bring people's attention to the fact that this was a broad population, some of whom had had ALS for up to 4 years and that would speak to the fact that they are slow progressors. So they met criteria after 4 years of ALS. So we've actually in this study expanded dramatically. We've done the other end of the spectrum from the development of several other drugs and yet we have such strong results.
Angela, we've already heard from a few people who see the P value of 0.11 on the primary endpoint and they don't seem to look any further. What do you have to say to them?
Look further. It's a very basic concept. This is a Phase 2 study in which we didn't control for a slow progressors in the placebo arm. We didn't control for a lot of other details. We wanted maximum exposure for ALS patients to this drug across the disease state and yet we still saw this benefit and I would draw your eyes to both having moved the bar on the SVC and also to have moved the bar on the gross motor subset of the ALSFRS for patients this is a critical, critical change or response.
Thanks. Are there questions from the floor? I think there yes. So there's a microphone coming your way.
Jeremy, can you comment on the maintenance or the potential maintenance of the SVC after drug withdrawal? How should we be thinking about that mechanistically?
It's very interesting. It wasn't just for SVT, it was for strength in OSFRs as well. And it's not a new observation. So this was seen in the signal that we saw in BENEFIT ALS where there was a strong SVC effect of the drug, it was also maintained after 28 days. And so it's not a pharmacologic effect in the sense that it's not due to maintenance of the drug or its metabolite in the system.
And so I think there's 2 choices. It has to be some sort of long term effect on muscle or nerve. And with respect to muscle, I think it's possible that if you make your muscles more useful, you use them more. And so there may very well be a conditioning effect that outlasts the actual drug that's in the body. Alternatively, if you're not having to fire motor neurons as fast to get the level of activation that you need to make the movements that you require, you may be stressing them less.
And so that may have an effect on long term motor neuron survival as well. We don't have assays for either of those possibilities right now, but you could if you think of ways that you might look at there are some potential ways to look at it in the future.
And I'll just add that not only have we seen this persistence of effect on vital capacity with tirasemtiv and now here vital capacity and ALSFRS R with reldesemtiv in patients with ALS, But recently we presented data from a study of reldesemtiv in older children and adults with spinal muscular atrophy and there the improvement in 6 minute walk distance that was evident after 4 8 weeks was also persistent 4 weeks after the last dose of study drug. So we've seen it now in 2 different disease populations on at least 2 or possibly 3 different endpoints.
Thank you. Joe Pantginis from H. C. Wainwright. Thank you very much for all the additional information.
My question is really looking at 2 layers of perspective from the panel. Number 1 and Doctor. Schefter, you certainly touched on one of them. Number 1 is, for example, when you look at the 27% rate or slowing of the rate of decline, can you put this into real world perspective about why this is meaningful to a patient? How does it help them?
And then secondly, as part of this perspective, you talked about comparing these data to other Phase IIs in the past, but how does it compare to the Adaravone data that led to its approval based on how broad this is?
1st, with respect to what do percentage points mean in terms of patients? And you can ask that for any of these outcomes. And I guess it's probably easiest to discuss it with Vital Capacity because respiratory failure is the main cause of death. So if in fact you can slow the rate of progression in vital capacity by a quarter or more because it does seem to increase with time, But even 25% means that you require non invasive ventilation 25% less frequently, which for a survival disease with a survival of on the order of 4 years is up to a year later. You potentially prolong survival by about that same amount.
And I think that level of prolongation of disease, If true, if we were speaking to a group of hematologists, oncologists about a cancer chemotherapy, that would be a home run. So with respect to predictors of death, biocapacity is the strongest. With respect to ALSFRS, it's an imperfect scale. But if you look at the individual values, changes of one point, many of them are incredibly significant. And so going from intelligible speech to unintelligible speech is a one point change.
And so the scale drops by on average about 1 point per month overall. If you can take away a loss of 1 point every year, for example, that's a 10% chance, that's important. If you can change the level of blood disability by 3 points at the end of the year, that depending on which particular points they are, can be incredibly meaningful. So I think just I think these are things that make a difference to ALS patients. With respect to what's the perspective with compared to Indaravone?
So remember, Indarabone is 6 months and it was a 33% change in rate of progression in ALSFS. We had a 25% change at 3 months. And if you compare apples to apples, looking at theoderaone data at 3 months, there is about an 8% change in ALSFRS at that point. So in terms of magnitude at that time, it's clearly greater. Is it likely that the effect will continue to diverge from placebo in as a longer study progresses?
That's something we'd have to see. But even at 25%, it's the same order of magnitude. And to me, if you start adding 25% effects on to 25% effects, at some point you get a drug combination of real meaning for patients.
So the other important issues to highlight when you attempt to compare apples to oranges is that the edaravone study took only the most ideal patients. They didn't take all comers in the Phase III. They took a subset of patients who were 2 things. They were very early in the disease and they had proven progression rates. They couldn't stay in that study unless they were actively progressing.
With this particular program we took everyone not everyone but 4 years is a lot of everyone and so because of the way patients are entered into studies we therefore took slower progressors And even in the placebo arm we took slower progressors and they progress more slowly than in other studies. So, if you actually look at what patients will be taking a drug like this, we actually mirrored what patients will be most interested in taking a drug like this. The other thing to remember is edaravone was allowed in this study. So this is in addition to real world use of edaravone. It is not an Adaravone naive or restricted population.
So we're not actually comparing to only placebo or placebo and riluzole. Patients were allowed at Darabone as well. So I think that makes it a more complete perspective.
Hi. I'm Dave Leibowitz from Morgan Stanley here for Jeff Hung. Specifically, given the results of this trial and the results of the tirasemtiv Phase 3 from the past, when you look forward and envision a Phase 3 trial for this program, what is this trial going to look like? What will the patients be? How might they be different?
Which of the endpoints would you choose to select for that Phase 3 program? And is 12 weeks the ideal duration? Or might you
give one quick comment and let them talk about the planned study. The most striking thing about the tirasemtiv trial as compared to the reldesemtiv was a side effect profile and therefore dropouts due to side effects. That difference is not inconsequential. In fact, it was very consequential with terasemtiv. And the fact that reldesemtiv has an incredibly strong retention rate for an ALS trial.
They stayed in the duration really speaks to the tolerability of this drug and that we were able to actually see the benefit in all comers. We didn't have that big dropout that adversely affected the analysis of the terasemtiv study. There are still people who take terasemtiv which speaks to if you could tolerate it. If you didn't have side effects, people are still very much invested in that drug as well. Although reldesemtiv has a much more interesting and more tolerable profile.
In terms of design, I think we met in late April to look at these data for the first time. So I think we've been more focused on looking at these data than designing the next study, but I think clearly it's going to be longer. 6 months is was the time for the primary outcome measure in vitality. And I think that's probably an appropriate time for that, although duration of effect beyond that is going to be important to look at as well. We chose vital capacity for the vitality study based on what we saw with tirasemtiv, not necessarily because of our expectation that something is special about the diaphragm and couldn't be seen more generally with extremity function.
And since and I think the real difference of this drug versus tirasumab is that we can really get a better picture of the range of effects not colored by tolerability. And since we saw a strong signal in ALSFRS and it's already been an approval endpoint, my tendency would be to go there first, but it's not something that we've decided. Beyond that, Angel has mentioned the sort of inclusivity of this patient population. And there my own view is that you learn more if you look at a broader group of patients, but I think we might want to be more careful to make sure that the patients that we select are less likely to be very slow progressors. And so there's a variety of ways to do that.
Angela, you've already spoken to the much better tolerability of reldesemtiv compared to tirasemtiv and now we've touched on the fact that in this trial now for the first time we've seen a pretty clear effect on ALSFRS R and vital capacity whereas with tirasemtiv, we really saw only effects on vital capacity and ALSFRS R was not so positively impacted. How could you explain that?
Well, certainly the ability of the patients to take the drug helps in your assessment long term. That's obvious. If you lose a significant number of patients to a non secondary side effect, you struggle. What we see with this data and is reported by the patients is that they have a very clear feeling of their ability to continue to do their activities. So activities of daily living and the ALSFRS is a reflection of the ability to not lose ability.
So they maintain their activity. In many cases, they maintain their work schedule. They maintain their life schedule. The one thing that has evolved between the terasemtiv development and this relasemtiv trial is an evolution in our trial design really drilling down on the subscores of the ALSFRS and even some other subscores that are relevant to the regulators and the patients and an improvement or a lack of decline of your gross motor function has a huge impact. So I think that we've got some very positive results to build on here.
So if I were to summarize, you're saying that better tolerability probably underlies an ability to see an effect on the ALSFRS R that we didn't see before? Absolutely.
Jason Butler, JMP Securities. First question, obviously, you've only had the data for a short period of time, but have you had a chance to look at any responder analyses yet? Are there any subpopulations other than that you showed there that you thought about that, for example, patients on edavron, whether they're showing the same response, different responses? And then second question just on the renal safety, both from mechanism of action and clearance perspective for the drug, any explanations for what might be happening there? Have you seen this previously in practicing perspective, what would this kind of magnitude of change matter to patients or earlier this patients have more risk of having renal insufficiency?
Thanks.
So I'll start with what we know about what is and isn't happening and then I'll ask our panelists to comment on what they think the implications of that are for future studies. As we said several times, we've only had the data for a little while, but we have had the opportunity to consult a couple of expert nephrologists and we will consult more. To answer one of your questions, we have seen this across different populations in healthy volunteers, and older kids and adults with SMA and ALS, and it seems to be a very consistent pattern. The input that we've gotten from our experts tells us more about what they think it's not than what they think it is, but what they think it's not is pretty reassuring. They point to the fairly rapid evolution, the fact that this effect on GFR appears to be fully evolved after 2 weeks is faster than one might expect for a drug induced nephritis.
And another thing that is very impressive to them and we didn't show you the data, but the urine analyses are very clean. There were no casts in the urine and at 457 patients, the only casts in any of the urinalysis were a baseline and none after treatment. That's a clear marker of renal injury, cellular death, sediment in the urine. Also red cells, white cells, very infrequent. So that's very impressive to them and I always reflect upon the fact that I think we look at your analyses in clinical trials often sort of that, or do we really need to do that, but it was very important to us here in this trial.
So it does not appear to be a true toxicity. There is no evidence of inflammation. It doesn't appear to be renal damage and the fact that it recovers if we follow patients or volunteers long enough that it essentially recovers completely also suggests that this isn't a toxicity to the kidney, but some pharmacodynamic effect that to be honest, we don't understand, but there are other drugs notably ACE inhibitors that disrupt intraglomerular hemodynamic such that they really do affect the decline in glomerular filtration, but it recovers when you withdraw the drug. And that might be what's happening here. That's one thing that's been hypothesized is that we have some effect on the intraglomerular pressures so that, the filtration fraction falls, eGFR falls, but it recovers when you stop the drug.
So
what do you
think this means for further development?
So I mean the kidneys are really far away from what I feel like I'm expert about. But I mean I think that it's a signal. I think that we're going to have to be careful and we're going to have to have a lower limit below which if somebody drops, they'll probably have to withdraw from study treatment in the future in a future study. But I think that if you look at that sort of a threshold that has been proposed to us, that would have been a very rare occurrence in this study.
I was just kind of and we had about 6 early terminations due to drop in eGFR.
And so with regard to your first question, which was any further subgroups, the one you mentioned, we did start to look at and the effect is seen both in patients who were taking a dervo and those who weren't. And the general magnitude of the effect were similar in both cases. I think responder analyses are very interesting to look at and we're going to do that, but beyond that, we haven't yet.
I'll just add again from our expert consultants. Their advice was that a 25% decline in GFR was probably too stringent when you're starting with the population whose average glomerular filtration rate is over 100, and they would be willing to treat patients until they fell below 60, especially because they're reassured that if you stop the drug, it will recover.
Yes. The change in GFR would have no effect on the clinicians' decision whether or not to start this drug unless you were dealing with a renally impaired patient. And as you know ALS patients are young, healthy, active and typically have no significant other medical problems. So they're the they would be the last group that you would worry about what we're seeing so far.
So thank you for all the updates. The baseline characteristics all look pretty balanced and I assume you controlled for some of them, the rest were handled by randomization. The one mismatch seemed to be a bulbar onset for the higher group, the 4 50 milligram dose group. And your own subgroup analysis showed that, that was the one group that didn't really respond at all. That makes sense, of course, clinically and other studies to bulbar onset progresses faster and so forth.
Wondered if there was a comment about the ability to measure the Balbaron set and the seal around the flow and things like that and if there is any qualitative quantitative measure of if that was, I guess, the sites look all very experienced and so forth, but if there was some comment around that. And the second question is, do you have a baseline trajectory such that in post hoc analysis, you can look at slow fast risk progressors? Or do you just have the inclusion criteria and cannot do subgroup it out going forward, at least in the post hoc?
So let me comment just on the technique and the problem with bulbar patients in clinical trials where you have an SVC. Patients can have trouble with the test and still be in good functional condition. So it's one of the tricks of actually dealing with vulvar onset patients in these ALS studies. We can't exclude them, but they really do struggle with the seal as you mentioned. So it is the reason why are the you really should never only focus on an SVC and an ALS trial because of these effects and it will be very difficult, a rapidly progressive bulbar would be very difficult to for any drug to change their ability to seal around the tool that we use.
Go ahead, Jim.
So with respect to that question, you're right. On SVC, there was less essentially no signal. But in terms of the other measurements, Bolivar side of onset didn't seem to have any effect on the subgroups. And so I mean, I would look at this in terms of consistency of subgroup changes. I'm not impressed by that.
But what my group does at Barrow is we manage the training for all for outcome measures for this study and lots of other studies. And so all of the points you made about difficulty in with that bolivar patients have in performing that test are certainly true and adds to the variability. But the variability around the decline in SVC in this study was quite small. So I think we did a good job of training sites. You had asked a question about, can we somehow look at rates of progression?
And so we have no interim look, but the way people have estimated rates of progression in prior studies is with this formula, you ask the patient what's the month of your first symptom, you look at their ALS functional rating scale at the time that you're examining them and you estimate the slope from 48, which is the highest value of the ALSFRS R at the date of their first symptom to what they are now and you can draw a slope between that. And so you can use that kind of calculation to estimate rate of progression. If you look at what that last set of comparisons of subgroups, that's exactly what we did.
So just to emphasize, these are not based on the rate of progression during the study, but the rate of progression prior to enrollment of the study and then that they're stratified into 3 tertiles. So you see it make sense if your ALSFRS, as Angel says, hasn't declined over the last 24 or 48 months by very much over the next 3 months in which there are no trials, it's not likely to decline very much and you wouldn't see much of a signal as a consequence.
All right. Gil Blum on for Chad Messer, Needham and Company. Just a quick question about the dose for Phase 3, giving the ongoing Phase 1 in healthy volunteers and the effects you guys seen on EGFR?
Well, I mean, we've got to figure that out. I mean, I think if for the most part, if you look
at the
efficacy and relative incidence of side effects in this study, you might be tempted to go with the middle dose. I'm actually also very interested in the fact that if you look at all of the doses that we use, we're nowhere near the top of the pharmacodynamic range. And if we could find a way to safely manage the adverse events, I think looking higher at some point in the development process of this drug would be pretty important.
It just begets to ask the question is looking at healthy volunteers relevant at this point?
I'm sorry.
Is looking at healthy volunteers still relevant at this point?
I'm sorry. I think it's relevant in terms of bioavailability. We've seen no differences between what you can determine there and what you determine for the most part in patients with dialysis. It's a place to begin looking. It's a
lot faster and easier to study bioavailability of different
definitive experiment that is going to be in the
current study, it was intended to examine a range of doses and we 150, 300, 450 and was intended to inform selection of dose. And so, I think the selection of dose will be balanced by what we think of as the benefit versus potential safety of the doses that we examined. And probably in this particular study, the balance is in the middle there around 300, but as Jeremy said, there's rationale to think about at some point exploring higher dose if we can.
Any other questions from the floor? Any other thoughts from our 2 expert panelists that they want to say that they haven't had a chance to say it?
I mean, just that it should be clear, I mean, I think these are really exciting results. And I am anxious to see a Phase 3 study go forward that really tests the hypothesis
So this is an oral medication with impressive results that is well tolerated and that's those are the 3 distinguishing features and we've tried it in all comers So I think we have something to run with.
So I want to thank our panelists. I want to thank my colleagues for those presentations and that discussion. I'd like to now end the program by putting some more context around these data and our corporate outlook. I'll first start by coming back to one of the comments I made in my introductory comments. This is a webcast where primarily the audience is investors.
And admittedly, there's already being demonstrated some skepticism around these results in communications that have been put forward regarding this trial. And you will not hear Cytokinetics underscore this data as having met the pre specified efficacy analysis. We laid out a pre specified efficacy analysis around which we achieved not conventional statistical significance, but certainly approaching that and borderline statistical significance with a P equals 0.11. But however, I hope that what you've heard today would underscore that these are impressive data in the context of the development of medicines for ALS and especially as was intended by the conduct of a Phase 2 study to inform the potential progression to Phase 3. As I said, why do you do a Phase 2 study?
You do a Phase 2 study to understand whether you have a high probability of achieving success in a Phase 3 study where there the bar should be 0.05 or lower? And what do you learn from a Phase 2 study that enables you to enrich and amplify a response that would be observed in a Phase 3 trial as you apply learnings from the Phase 2 study. We do have learnings from the study. We learned that with reldesemtiv, we've advanced the field beyond that which we achieved with tirasemtiv most especially with regard to tolerability and underlying that is now evidence to support the mechanistic hypothesis that reldesemtiv is affecting not only slow vital capacity in a large clinically meaningful way that seems to be increasing over time and persistent, but also absent intolerable effects, we're seeing evidence of effect there too on ALSFRS, which is a registratable endpoint as demonstrated by a recent approval. So we see these data as I hope you've also heard from our panelists and as I can tell you was unanimous when these data were shared with investigators.
We see these data as positive and lending support for progression of reldesemtiv to a next level clinical trial. Certainly, there's more analysis we need to do. Certainly, we need to understand if there's ways maybe by eliminating slow progressors or otherwise taking a look at those subgroups, we may be able to augment the effect and certainly demonstrate durability of effect and that's a task upon us that we relish. So I look forward to being able to provide updates to how we may now move forward with reldesemtiv in next level clinical trials underscoring that that's a conversation we also need to have with our corporate partner at Astellas. We and Astellas have only had a matter of a few days to review these data and there's a lot more we need to do together and with regulatory authorities in terms of understanding around which these data may lend support for progression into a specific Phase 3 trial, underscoring that we need to then know what does that trial look like, endpoints, timelines and budget.
What I can say is that it's highly unlikely that any such Phase 3 trial would occur in 2019. 19, just knowing what the task in front of us are, it's more likely that that would be underway, we would hope in 2020. So given that and given the pipeline that I shared with you before, I think as we point forward to milestones in 2019, in February, we laid out for investors what would be those key milestones 2020. We're now 3 for 3 on those milestones. Earlier this year, we announced that the GALACTIC study of Omecamtiv mecarbil had successfully passed through an interim futility analysis enabling us to proceed to completing enrollment of that study.
We'll have our earnings call later this week and we'll provide updates with regard to GALACTIC, but suffice it to say that that study is proceeding to conclusion of enrollment as is the METEORIC study now enrolling patients and both of those trials would be expected to deliver data in 2021 or possibly sooner. Put these data into further context, I also had shared with you that we would be looking to CK-two seventy four, our cardiac myosin inhibitor in Phase 1 to inform potential progression to Phase 2. That Phase 1 study is concluding. We'll have more to say about it also later this week on our earnings call, but we are already proceeding to plan for the design of a Phase 2 program in patients with hypertrophic cardiomyopathy for CK-two seventy four and that's also occurring as we and Amgen are conducting a Phase 1 study with regard to AMG 594, our cardiac troponin activator for the potential treatment of heart failure. So I want to thank you all for your interest and attention to these data.
I hope we set a proper context for reldesemtiv in the development of a program directed to patients with ALS and also how that fits into the overall corporate picture and corporate development for Cytokinetics. With that, we'll conclude this program. Thank you for joining us either here in person or on the webcast and we invite you to ask us questions and also engage us in comments as we can further elaborate on this for your benefit. Thank you very much.