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One last remark, if you would like to follow the presented slides on your end as well, please feel free to go to roche.com/investors to download the presentation. At this time, it's our pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.
Thanks Henrik. Could I have the agenda slide, please? Welcome to our third IR event in 2026, focusing on the phase III FENhance 1 and 2 results for Fenebrutinib in RMS, which just got presented yesterday at AAN in Chicago. Today's call is scheduled for 60 minutes, and we will have our Roche team dialing in from Chicago.
Let me quickly take you through today's agenda. We have two speakers with us. Following my opening, the first speaker for today will be Alexandra Goodyear. She is an MD and our Lifecycle Leader for Fenebrutinib.
Alexandra will provide a quick introduction to Fenebrutinib and how this molecule truly differentiates from other BTKs who have been in late-stage development for MS. She will also highlight again the positive phase III FENtrepid results for Fenebrutinib in PPMS, which have been presented earlier this year at ECTRIMS.
Our second speaker for today will be then Jiwon Oh. Jiwon is an MD and PhD, FRCPC, a medical director of the Barlo Multiple Sclerosis Program, an associate professor and staff neurologist at the Division of Neurology at St. Michael's Hospital at the University of Toronto, and a scientist at the Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute.
She is the lead author for FENhance 1 and 2 and has been sitting on the study's steering committee. Jiwon will take us again through the positive phase III FENhance 1 and 2 results for Fenebrutinib in RMS, which she presented yesterday at AAN. Afterwards, we will have a Q&A session.
In addition to our two speakers, we will be joined for the Q&A session by Hideki Garren, a senior vice president and our Global Head of Product Development for Neurology, and by Levi Garraway, our Executive Vice President and Head of Product Development and our Chief Medical Officer. With that, over to you, Alexandra.
Thank you very much. I will take us through an overview of Fenebrutinib's development program. Next slide. With the positive phase III study data in RMS and primary progressive MS, Fenebrutinib has the potential for both first and best in class.
Fenebrutinib has the potential to be acting on B cells and macrophages in the periphery, as well as B cells and microglia within the central nervous system. With this ability, we're hoping that Fenebrutinib, as seen in the phase III that Dr. Garraway will take us through, is decreasing relapsing biology as well as progressive biology, and these two together are leading to overall decrease in disability accumulation.
With this, Fenebrutinib has the potential to be the first and only high-efficacy oral treatment for both RMS and PPMS, and with this has the opportunity to increase high-efficacy treatments for patients, as well as expand the Roche MS and neuroscience footprint.
On the right-hand side, you see the Fenebrutinib development program, where we have now had four positive trials in MS, including the phase II RMS trial, the FENtrepid primary progressive MS trial, and the two nearly identical relapsing MS trials. Fenebrutinib's been studied in a large number of patients across the entire development program, and data will be submitted for filing mid-year.
Next slide. Here is the primary progressive MS data that Bruno alluded to that was presented earlier this year. On the left-hand side, we're looking at the Kaplan-Meier curve for disability progression that was analyzed by the composite endpoint of cCDP.
Here you can see that the treatment curves separate already at week 24, Fenebrutinib being the blue line on the bottom. That separation in curves is maintained throughout the study duration. With this, Fenebrutinib achieved non-inferiority versus ocrelizumab in the only head-to-head trial of any MS therapy versus ocrelizumab.
On the right-hand side, you can see the breakdown in the composite disability progression endpoint. The makeup was EDSS, Timed 25-Foot Walk, and 9-Hole Peg Test. You can see that the most profound treatment effect was seen with 9-Hole Peg Test, which is an upper limb mobility test, very important for patients for them to be able to maintain independence throughout their lives.
Second, followed by the effect on EDSS, and then Timed 25-Foot Walk. Notably, in a post-hoc analysis that looked at the same composite endpoint that was used in ORATORIO-HAND, which was a contemporaneous phase III study of ocrelizumab versus placebo, which used the endpoint of EDSS and 9-Hole Peg Test. When we look at that endpoint in the FENtrepid study, we saw a 22% reduction versus ocrelizumab.
Next slide. This differentiated data that we have been showing, we think it really stems from the unique structure and binding mechanism of Fenebrutinib. On the left-hand side, we show the chemical structures of Fenebrutinib, as well as some of the other BTK inhibitors being explored in late-stage development for MS.
You can see that Fenebrutinib's structure is very unique, with highlighted portions that get into both the H2 and H3 pockets of the Bruton's tyrosine kinase and allow it to bind non-covalently and very selectively.
On the right-hand side, we see that we were able to achieve the selectivity that we were aiming for when designing this molecule. What you're looking at on the right-hand side is a panel of very similar kinases to BTK. BTK is the first row right at the top. We can see that Fenebrutinib binds to BTK at a low concentration, and then really no other off-target kinases until you get to very high concentrations.
This compares very favorably to some of the other covalent inhibitors, which we can see are hitting multiple kinases. We're hoping with this, that this helps improve long-term safety outcomes with Fenebrutinib. Next slide. On this, Fenebrutinib has high systemic exposure as well as CNS penetration.
On the left-hand side, we're looking at free plasma concentration curves, and Fenebrutinib being the red line at the top, you can see it achieves much higher concentrations over the whole 24-hour dosing period. This really reflects the different strategies of having a non-covalent drug versus covalent drugs, and then optimizing the non-covalent drug to have high exposure.
This is important because the free plasma fraction is the part that is able to cross the blood-brain barrier in order to bind with microglia and B cells within the central nervous system. On the right-hand side, we are showing the data that Fenebrutinib is able to achieve that.
What we're looking at on that side is human CSF concentrations of these drugs, Fenebrutinib being the blue bar all the way on the left. Each drug has its own IC90, the concentration needed to inhibit 90% of the target.
We can see that Fenebrutinib is able to cross the blood-brain barrier and be in concentrations within the CSF well above the IC90, which is really differentiated compared to the other BTK inhibitors, as shown here. Next slide. I think that brings us to Dr. Oh's presentation of our phase III data in RMS. Dr. Oh.
Thank you Alexandra. I will now, with that background, take you through the very recently reported results from FENhance 1 and 2, which were two nearly identical phase III clinical trials evaluating the efficacy and safety of Fenebrutinib in comparison to an active comparator, teriflunomide, in people with relapsing BARLO MS Program.
Next slide. Alexandra has already very nicely outlined this, but BTK inhibitors are of very high interest in the MS field, because we know that BTK signaling is crucial to activation of both B cells and myeloid cells in the periphery and the central nervous system.
We know that inhibiting BTK has the potential to address both relapsing and progressive disease biologies across the entire MS disease spectrum. As you've already heard, Fenebrutinib is a BTK inhibitor that was uniquely, purposefully designed.
It is CNS penetrant, which is very important because when we're talking about modulating both relapsing and progressive disease biologies, we want to ensure that a drug that is active in the periphery can easily get into the central nervous system, which Fenebrutinib can clearly do.
It's non-covalent, it's highly selective, and importantly, it has an optimized PK/PD profile, which is likely in large part of the reason we see a clear effect of Fenebrutinib on relapsing disease biology that I'll tell you about in a second.
Already in a phase II clinical trial, the FENopta study, Fenebrutinib demonstrated near-complete suppression of disease activity in people with relapsing MS. As you heard, in the phase III FENtrepid study that evaluated Fenebrutinib versus ocrelizumab in people with primary progressive MS, Fenebrutinib demonstrated efficacy in that it was non-inferior in reducing the risk of composite confirmed disability progression.
In that post-hoc analysis that Alexandra presented, where there was a modified composite endpoint, Fenebrutinib demonstrated superiority in this post-hoc analysis in comparison to ocrelizumab. Today, right now, we'll be focusing on the FENhance 1 and 2 trial results, and the objective of these two trials was to evaluate the efficacy and safety of Fenebrutinib in comparison to teriflunomide in people with relapsing MS.
Next slide. This was the study design of FENhance 1 and 2, which were two largely identical phase III multi-center randomized trials. As you can see, the inclusion criteria were quite typical for what we usually see in contemporary relapsing MS clinical trials.
People with relapsing MS were randomized in a 1:1 ratio to either Fenebrutinib at 200 mg twice daily, or the active comparator of teriflunomide at 14 mg once daily, which is a very commonly used first-line oral disease-modifying treatment in relapsing MS.
At the end of the study, they were given the option to continue in the open-label extension period. The trial went for a minimum of 96 weeks for each participant because it was an event-driven trial. As you can see, study visits were done periodically, as is expected with most contemporary relapsing MS trials, and there were MRIs performed as well. Of course, safety was evaluated for the duration of the study.
Next slide. The primary endpoint, as expected, because these were trials looking at relapsing MS, was the annualized relapse rate. For key secondary endpoints, the key clinical disability progression endpoint, again, a composite confirmed disability progression was used. This is an endpoint that consists of either EDSS progression, which is the typical global neurological disability scale that we use in really every MS clinical trial.
However, a participant was deemed to have progressed if they showed progression in either the EDSS or the Nine-Hole Peg Test, which is a test of manual dexterity, or the Timed 25-Foot Walk, which is a semi-quantitative measure that measures ambulatory speed. In addition, key MRI endpoints were evaluated as well, which included T1 gadolinium-enhancing lesions and the development of new or enlarging T2 lesions.
I wanted to note as well that, as with any clinical trial, there was a statistical hierarchy. Each of the endpoints that we discussed, it was pre-specified that in this statistical hierarchy, they would be evaluated in each individual FENhance clinical trial separately.
However, there was a planned pre-specified pooled analysis of the Composite Confirmed Disability Progression endpoint. This is relevant when we discuss what was observed with respect to these secondary clinical endpoints. Next slide.
When we look at baseline characteristics across FENhance 1 and 2, as you can see, clinical characteristics were quite well-matched between treatment arms across the two FENhance studies. Also just wanted to note when you look at the time since MS diagnosis, and I'm just going to draw your attention to the fourth row down, and I know it's a very busy table.
It's very clear that this was a really early group of people with relapsing MS because the median time since diagnosis was one year. Really, a lot of these participants were newly diagnosed. Similarly, when you look at the proportion of people who had previously been on disease-modifying treatment, which is row five, as you can see, only about 15%-20% of participants were previously treated.
The majority of these participants were within a year of diagnosis as well as treatment naive. These points just illustrate that this was a very early population of people with relapsing MS. Next slide. When the primary endpoint was evaluated, as you can see, Fenebrutinib very clearly substantially reduced the annualized relapse rate versus teriflunomide in both FENhance 1 and 2, and it was a substantial reduction.
As you can see, the relative reduction was 51% and 58% in FENhance 1 and 2 respectively. Next slide. When you look at different subgroups, as you can see, generally the treatment effect was consistent across different subgroups.
However, in people who were younger, and had a lower time since symptom onset, as well as in those who had gadolinium-enhancing lesions and those who had less disability, it seemed that the treatment effect was accentuated.
Overall, it seems that the treatment effect is consistent, but not really surprisingly, in those who were earlier along in the disease course, the treatment effect seems to be accentuated. Next slide. Moving on, when key secondary MRI endpoints were evaluated, as you can see with T1 gadolinium-enhancing lesions, Fenebrutinib very clearly decreased T1 gad lesions versus teriflunomide at 70% as well as 77% in FENhance 1 and 2 respectively.
Not surprisingly, when new or enlarging T2 lesions were evaluated as well, as you can see, Fenebrutinib very clearly reduced the formation of new or enlarging T2 lesions in comparison to teriflunomide by 76% and 82% in FENhance 1 and 2 respectively. Next slide.
Now, when the composite confirmed disability endpoint was evaluated, in each individual trial, as you can see, although there was a consistent trend towards favoring Fenebrutinib in FENhance 1 and in FENhance 2, the confidence interval still slightly overlapped 1.
However, when the pooled cCDP endpoint was evaluated across both FENhance 1 and 2, as you can see, the confidence interval did not overlap 1 and disfavored teriflunomide. Similarly, in that post-hoc modified cCDP analysis, which included only EDSS and Nine Hole Peg Test, just as a reminder, as Alexandra said, this was the endpoint that was actually recently used in the ORATORIO-HAND trial. As you can see, you see similar trends.
Consistently, there is a trend favoring Fenebrutinib with this modified cCDP endpoint as well. When you look at the pooled analysis, you can see that there is a clear treatment effect with the confidence interval not overlapping one. Next slide.
Moving on. When you look at the treatment effect of the individual components of the cCDP measure, so this composite measure. As you can see first, the greatest number of events was related to changes in the Timed 25-Foot Walk.
However, when you look at the treatment effect of individual components of the cCDP score, it really was the 9-Hole Peg Test that seemed to have the strongest treatment effect of Fenebrutinib versus teriflunomide. This is interesting and probably informative about the cCDP measure because it seems that the treatment effect is greatest with the 9-Hole Peg Test, but the most frequent events that were observed were with the Timed 25-Foot Walk. Next slide.
Moving on to safety. When you look at the overall safety profiles, these were generally comparable between Fenebrutinib and teriflunomide, with similar rates of any adverse events, as well as serious adverse events and adverse events leading to withdrawal from treatment.
However, there was an imbalance in fatal adverse events, with seven fatalities observed in Fenebrutinib-treated participants and a single fatality observed in teriflunomide-treated participants.
However, when you break down and take a look at each of these individual fatalities, and we'll do that on the next slide, it's reassuring because there was no clustering of causes that seem to suggest that there is some signal related to fatalities and Fenebrutinib. We'll look at that in detail on the next slide.
Also wanted to highlight, obviously with any immunomodulatory treatment, there is a concern about infections and particularly serious infections. It was reassuring because in the FENhance 1 and 2 clinical trials, the proportion of people who had any infection was similar between treatment arms.
Importantly, the proportion of people who had any serious infections was similar across treatment arms between Fenebrutinib and teriflunomide, which was reassuring to see. Getting back to the fatalities. This is a table that summarizes all of the fatalities seen across the FENhance 1 and 2 clinical trials.
The first seven cases are fatalities of participants who are on Fenebrutinib. That final case listed here is the fatality that was observed in a participant who was on teriflunomide. A couple of things. First of all, it's reassuring that there is no clear clustering of events that's related to something that potentially could be related to a mechanism of action that we know of Fenebrutinib, which is a BTK inhibitor.
Of the seven fatalities that were observed among Fenebrutinib-treated participants, most of them were considered to be not relevant to Fenebrutinib, but two of the cases were deemed to be likely relevant to Fenebrutinib. These were the two infectious cases, which included a participant who had pneumonia as well as a participant who had neurocryptococcosis.
However, with both of these infectious cases, it's important to note that there were complicating other contributing factors. With the case of pneumonia, the family actually declined hospitalization despite the physician recommending this.
With the neurocryptococcosis case, probably some people may not be familiar with this bug, but this is a bug that is endemic to some regions in Latin America, often related to occupational exposure, which was the case in this particular participant. This is a bug that can actually cause, even in immunocompetent individuals, serious infections.
As you can see with the other fatalities that were observed in the Venetoclax treatment arm, there was a case of intestinal ischemia, a case of hemorrhagic stroke, a case of death, a case of suicide, multiple injuries, and another case of suicide. Overall, these other deaths were not considered to be relevant by the study site PI to Venetoclax.
Generally, it seems that when you look at these individual cases, it's reassuring that there is no clustering of events that raise any red flags, that this might be related directly to Venetoclax. Next slide. Liver safety, as you know, is a signal that we need to pay attention to with BTK inhibitors because a number of BTK inhibitors have shown that they can cause liver enzyme elevation.
When we look at this in FENhance 1 and 2, as you can see with any liver enzyme elevations three times or more the upper limit of normal, the proportion of individuals that had this looked similar across treatment arms and was in keeping with what has been seen with other BTK inhibitors that have been evaluated in phase III clinical trials.
Of note, there was only a single Hy's Law case in a Fenebrutinib-treated participant, as confirmed by the Hepatic Adjudication Committee. There was also a single Hy's Law case in the teriflunomide treatment arm that was confirmed by the Hepatic Adjudication Committee. It's important to note that with all of these liver enzyme elevations, these were all reversed. Next slide.
To conclude, the results of FENhance 1 and 2 demonstrate that Fenebrutinib is clearly superior to teriflunomide in significantly reducing relapses as well as disease activity on MRI, demonstrating that there is likely a substantial impact of Fenebrutinib on relapsing disease biology in MS.
With respect to the disability measures, there was a consistent trend favoring Fenebrutinib over teriflunomide, which together when you keep in mind the results of FENtrepid suggest that Fenebrutinib has also an impact on progressive disease biology in MS.
For safety, the rates of adverse events were comparable, including hepatic transaminase level elevations as well as infections. There was an imbalance observed in fatal AEs, but we've gone over each of these in detail. Overall, it seems to be reassuring that again, there is no clustering of causes of fatalities that seem to be relevant to the known mechanism of action of Fenebrutinib.
Taken together, these results demonstrate that Fenebrutinib is the first BTK inhibitor to show clear efficacy on relapsing disease biology versus an active comparator. Again, when we bring into this the results that we've seen with FENtrepid, Fenebrutinib is the first and only oral treatment option to demonstrate efficacy across the entire MS disease. Thank you very much, and I will just hand back over to-
Yeah. Thanks. Thanks, Dr. Oh, for the presentation. With that, I think we open the Q&A. The first questions go to Luisa Hector from Berenberg. Luisa, please.
Great. Thank you, Bruno, and thank you very much for the call. I would love to hear from Dr. Oh just in terms of now that we've got all of the data in for Fenebrutinib, who are the patients that you feel should be on Fenebrutinib, where you're positioning it both in the relapsing and the progressive group? Thank you.
Sure. I think FENhance 1 and 2 very clearly demonstrate that even in very early active relapsing MS patients, this is a drug that has a very profound effect on clinical and MRI measures of relapsing disease activity.
In fact, the effect that we see is akin to our currently available highest efficacy therapies. Definitely an agent that is suitable in early relapsing MS, which was the trial population of FENhance 1 and 2.
However, based on what we see in FENtrepid, it's also clear that it is non-inferior, and there's good suggestion that based on what we know about the drug and the mechanism of action, and the fact that it gets into the central nervous system, and the magnitude of benefit that was seen across FENtrepid, that this is a drug that is at least non-inferior, maybe even better than our only available agent in PPMS.
Taking together all of this and the fact that in the field as clinicians, when we think about relapsing MS, we know that both relapsing and progressive disease biologies are at play across the spectrum of the disease, which includes PPMS, but also many different stages, if you will, of relapsing MS.
This is to say that based on what we see across the entire Fenebrutinib clinical development program, as well as what we as clinicians and scientists are thinking in the field right now about MS, it seems that this is a drug that is likely will be useful across the entire spectrum of MS, even people with relapsing MS who are clearly having progressive components of disease because of what we see in FENtrepid.
Luisa, did this answer your question or do you have a follow-on question?
Yes. Can I then ask, do you see yourself choosing whether to start a patient on Fenebrutinib or Ocrevus, or is there a sort of sequencing that seems obvious to you now the data's in hand?
Treatment decisions are always pretty individual. In certain people, there's always kind of a preference often that patients have for mode of administration and frequency of therapy. However, in the end, as with most cases, it all depends on the individual patient.
The benefit that Fenebrutinib may have over a drug like ocrelizumab, which is a very commonly used drug, as you know, in the MS field, is that it may have a clearer effect on progressive disease biology. Although with the pure relapsing component of disease, I think we would use both drugs in a similar fashion.
If there is a relapsing MS patient that clearly has evidence of progressive disease, which we see in the majority of people with relapsing MS, even in the earlier stages of disease, it may make sense to use a drug like Fenebrutinib because we know that it has an effect on relapsing as well as progressive disease biologies.
Brilliant. Thank you.
Very good. Next questions go to James Gordon from Barclays. James, please.
Hello. James Gordon, Barclays. A couple of questions, please. First question was assuming Fenebrutinib does get approved for RMS and PPMS, how do you think the label might capture any potential liver infection or suicide profile of the drug? How would that impact uptake?
Also, are there precedents for other drugs which you could think about which had similar profiles in any of these attributes, and how did that impact uptake? Maybe just squeezing in one other one. I've been asked by some people, in terms of suicides, could there be a mechanistic explanation, or do you think it would be noise? How to think about that, please.
Maybe I'll start just high level on the label. You might expect this, but it's too early to comment. In fact, as you know, we'll be submitting the entire data package as a composite package to the FDA by mid-year, and we'll go through the process thereafter. It's too early to speculate on what the label might or might not say. For some of the other aspects, I'll turn to either Jiwon Oh or others.
Bruno, would you mind repeating some of the key aspects there? It was a bit hard to hear here on what aspects you might want Dr. Oh or myself to elaborate on.
James, can you? Sorry.
Assuming you can still hear me.
We can hear you, yes.
Great. Thank you.
You might want to repeat the question.
I've been asked about a couple of attributes. One was about the liver profile, one was about a potential increased risk of infection, and then whether it's connected or not, but in terms of suicide profile. There are other MS drugs that also have some of these things.
If some of those were, we'll see if they are, but if some of those were reflected on the label, how would that impact how a doctor might go about using a drug which had a profile in terms of liver infection or suicide?
Perhaps, Doctor Oh, you'd like to start on how you would use the drug and how would that impact using-
Sure
using the drug in patients.
Liver enzyme monitoring is something that most MS neurologists are very familiar with. With probably almost all of our existing drugs, there's different schedules that we use for liver enzyme monitoring. Even going back to the days of the old interferon beta agents, this is something that we're quite accustomed to doing.
The liver enzyme monitoring protocol in FENhance 1 and 2 was every two weeks after initiation of the study drug. It seems like with all of the cases that were observed, it's really within the first 20 weeks that you may see liver enzyme elevation.
Overall, I'm not sure exactly what the label will say, and obviously these discussions will be had in the next little while, but it is probably expected that there will be a requirement for liver enzyme monitoring somewhat frequently. This will be time-limited.
As a clinician, you don't ever want to be doing some sort of intense monitoring forever. Every two weeks, it is relatively frequent. However, I think this will be very manageable in clinical practice because it's time-limited.
Again, this issue of liver enzyme monitoring is something that we do with almost all of our current MS therapies. Something that is pretty familiar and that many MS neurologists are quite accustomed to. With respect to the question about infection, I think the results from the Fenebrutinib clinical development program are actually quite reassuring.
In FENhance 1 and 2, when you look at any infections, and particularly any serious infections, there really wasn't a difference between Fenebrutinib and teriflunomide, which is reassuring, but obviously this will continue to be monitored in the open label extension.
Finally, with respect to the cases of suicide that were observed, many of these cases did have some confounding factors, but obviously this is something that we will need to pay attention to. There have been precedents for this with respect to MS disease-modifying treatments.
Again, back in the days of the Interferon beta agents, Betaseron actually did have a signal for this, and so this is something that obviously clinicians will have to keep in mind, and probably will have to have some counseling with patients about this beforehand.
I think we also need to keep in mind that with these cases that were observed, there isn't really a biologically plausible mechanism by which Fenebrutinib or BTK inhibitors in general might do this.
Really need to delve deeper into the cases and to continue to monitor to understand this, but also need to keep in mind that in MS, depression is very, very common and seen in 50%-80% of people, even at the very beginning of disease.
There are a number of complicating factors here that make it unclear really if this is related to Fenebrutinib. Then there's other reassuring pieces of data, including the fact that Fenebrutinib has been studied in other autoimmune conditions, and there really wasn't any sort of suicide signal that was observed.
In the phase II FENopta trial as well, which was obviously a smaller study, there really weren't any cases observed here. This is something that we'll need to continue to monitor and not take lightly. However, it's really not clear whether these cases were really related to Fenebrutinib.
Yeah, if I can just.
Thanks a lot.
If I can just jump in, just to say that for Roche and Genentech, patient safety is extremely important. It's the number one concern we have. Of course, we want to work with regulators to make sure the patients are safe while getting this drug to patients as quickly as possible.
I do want to add that in these two studies and in the PPMS study as well, patients with suicide risk were not excluded as part of the study. As Dr. Garraway mentioned, in other studies outside of MS with Fenebrutinib, we have over 650 patients where that suicide risk was not seen.
James, did this answer your questions on the potential safety profile and how you would manage it in practice?
That's great. Thanks a lot .
Yep.
We move on. Next questions go to Alex Ebeling from UBS.
Hi. Thanks for taking my questions. Two, please. First, on liver enzyme elevations. So here they were lower, in the FENhance 1-2 RMS studies relative to the FENtrepid PPMS study. I'm wondering, what do you believe is the reason behind this? Do you think it's related to the age of the patients enrolled or anything else?
Second question on one of the deaths. I was just wondering if you could provide any more color on the fatality from neurocryptococcosis gattii. The slides state that the pathogen, and you said that it can cause serious infection even in an immunocompetent patient, but the death was related to Fenebrutinib. So what gives you confidence it's not a signal of excessive immunosuppression? Thank you.
Do you want me to take that one?
Sure. I'll address the neurocryptococcosis issue. I think it's always difficult in study settings to know definitively what is related to a study drug or not. Because of what we know about the mechanism of action of BTK inhibitors, they are immunomodulatory agents, and this is the case for all MS disease-modifying treatments because you need to modulate the immune system to show an effect in the disease.
If there is an adverse event that plausibly is related to the mechanism of action of a drug, this is when it's deemed, by the study site investigator usually, that it is likely relevant. It's not surprising that the fatalities that were related to infections because of exactly what we know about the mechanism of action of the drug was deemed to be likely related to Fenebrutinib.
Of course, there's a lot of rationale behind why this would be the case. With neurocryptococcosis, we talked about how it's endemic, and it can, even in immunocompetent hosts, cause serious infections. I think that's one piece of information that's reassuring that Fenebrutinib is not a drug that causes substantial immunosuppression so that you'll see these somewhat wacky infections.
However, I think it's reassuring that there aren't other opportunistic infections that have cropped up in this pretty large clinical development program. In addition, I think we need to keep in mind, also when you look at the totality of infections, and particularly serious infections across the Fenebrutinib clinical development program, which also included older patients with PPMS, there really wasn't a difference seen with respect to serious infections.
Although it's a rare infection and potentially can be related, when you look at the totality of what was observed with respect to infections, which is obviously the adverse event that we tend to pay most attention to, it doesn't seem like there is some signal for severe immunocompromisation as well as opportunistic infections.
Thanks Dr. Oh. I'm happy to take the question on PPMS liver enzyme data versus RMS. You are correct that there is a big difference in age of the populations that we studied in the RMS study versus the PPMS study. In the RMS population, the average age was approximately 35, 36, versus in the primary progressive MS trial in which we enrolled patients up to age 65, and the average age was 49. You're correct that age does play a factor.
Also it's a signifier of also the increased comorbidities that you see in the PPMS population and polypharmacy that you see in the PPMS population. It's an older population. It's probably those three things together, age, comorbidities, and co-meds, that are really contributing to that. We found that unsurprising to see that difference between the RMS and PPMS populations.
Alex, did we answer all your questions?
Yes. Great. Thank you.
Yep. Let's move on. Next questions go to Sachin Jain from Bank of America. Sachin, please.
Hi there. Thanks for taking my questions. A couple more on safety from the Roche side, and then one for Dr. Garraway. Wonder if you could just provide any color on your FDA interactions around safety. As you can tell from the call, investors are clearly worried by the safety profile and approvability. Just wonder how you would frame your dialogue with the regulator, I'm assuming ongoing around the safety issues that have come up.
The second question is, as we think about what questions the FDA may ask in a potential adcom, just wondering what additional work you can do prior to submission to address what questions you think they may ask on suicide and infection. Would you present that data? Because obviously we've only got limited information on the infection and suicidality so far.
How you're thinking about post-marketing commitments as you put the package together. Those are the questions for the Roche folks. Just one simple one for Dr. Oh. The PPMS data will be unique to Fenebrutinib within the BTK. To what extent does that data influence your potential adoption in RRMS? Thank you.
Would you like to start?
Sure. In the MS field, as clinicians, we're recognizing more and more that the current classifications that we have of MS are not adequate nowadays. Just because, when we designate someone as relapsing MS, we often simultaneously, very early on in disease, see clinical, and when you have the tools, imaging evidence of progressive disease biology.
Then in progressive MS, and PPMS is considered to be probably the most purely progressive form of MS, we often see evidence of relapsing disease biology as well. Because of this, we know that MS is a disease continuum.
Having the totality of the data available from Fenebrutinib, where it really has gone from really early relapsing MS all the way to the most purely progressive form of MS, which is PPMS, and to demonstrate a clear effect across that spectrum, that is what gives us reassurance that this is a drug that probably will be beneficial from the beginning to the very later progressive stages of disease.
From a clinical standpoint, it gives us reassurance that individuals will likely benefit from Fenebrutinib, probably for different reasons across the entire spectrum of disease. The issue though, of course, is that in the real world, usually medications are approved for specific indications.
When you have an indication both for PPMS as well as relapsing forms of MS, and within relapsing forms of MS, we, as clinicians, tend to be pretty liberal with what we designate as relapsing forms of MS, because again, we know that relapsing disease biology happens across the spectrum, as does progressive disease biology. This just gives us flexibility to use the drug, again, pretty liberally across the spectrum of MS.
Thanks, Dr. Oh. We appreciate the interest in how things are going with the FDA. Of course, we are following the typical processes for interactions with the FDA and health authorities. We are very early in that process. As we've shared previously, we did share the top-line data with the FDA right away following our data readouts.
Currently, we are in the process of putting together our filing dossier. We're in contact, but it is early to comment on that before we are formally in the filing process. Levi, was there anything you would like to add to that?
Sachin, did this help?
I guess the second question was just what additional work do you plan on doing around the suicidality, infection, and would you present that at some point?
Thank you. We, of course, have an ongoing open label extension study in which we are following the patients from the original phase II FENopta study, as well as the relapsing studies and the primary progressive study.
We are following all of those patients in an open label extension study, including patients that were originally on the active comparator and have now switched to Fenebrutinib. We think that will be very enlightening on confirming or refuting the signals that we're seeing in the double-blind treatment period.
Whether or not we need to do post-approval commitment studies will be something determined in filing. That would, of course, be very typical for MS drugs, most, if not all of whom, have post-approval commitment studies. What those will be will come out during the filing process.
Thank you very much.
Let's move on, and the next questions go to Peter Verdult from BNP Paribas.
Yeah, thanks, Bruno. Peter Verdult here from BNP. Thanks for the call, everyone. Two questions for Alexandra or Levi. Look, I know you're focused right now on the filings, but if you allow me just to look ahead, is there any future clinical development that you want to do with Fenebrutinib, in SPMS, within MS, or any indications beyond MS? That's question one.
Dr. Oh, forgive me. Just returning to the first question, but pushing you for maybe a little bit of numbers. Assuming Fenebrutinib is approved end of the year, can you give us some ballpark numbers in relapsing remitting MS and PPMS in terms of what proportion of new or current patients would you consider starting on Fenebrutinib or switching? If I could push you with some numbers, that would be appreciated. Thank you.
I'm happy to start talking about the future Fenebrutinib development program. We are exploring different opportunities because, of course, Bruton's tyrosine kinase is an excellent target for many autoimmune diseases. We are exploring where that could fit well with the Roche portfolio.
Within MS specifically, we at Roche feel very much like Dr. Oh, that MS is one disease, and there is relapsing and progressive biology in all patients starting from the very beginning. Medically and clinically, we think we have the data necessary already to really guide physicians on use of Fenebrutinib in clinic.
At the moment, there are no plans for a SPMS study.
I can echo that. I think Dr. Garraway and Alexandra have said this very well. That certainly there may be additional studies that we would do. For example, here at AAN, there have been conversations about can one refine understanding of the difference between the inflammatory component and the progressive component.
There may be other things we can do to fully elaborate that and the mechanisms that are happening, and that may help inform, in practice, the conversation about whether to use for example. From the standpoint of additional studies and subtypes, fully agree that we don't think that would be indicated.
I can answer the kind of ballpark numbers for treatment cases. These are really, really ballpark numbers. When it comes to choice of treatment, when a patient is treatment-naive, so newly diagnosed, I think very clearly the field is evolving, to start with high efficacy treatment in almost everybody, with a new diagnosis of relapsing MS from the beginning.
What we currently have now that is probably the most widely used treatment in general are the anti-CD20 agents, and there's a number of them.
Fenebrutinib would very clearly be a choice that patients would make from amongst these high efficacy treatments against relapsing disease biology, and that choice is often made by patients, to be honest, just because people have very kind of strong preferences about mode of administration and how frequently they need to take therapy.
Some people just really want to be on oral therapies and don't want to think about having to go into an infusion center and needles and all of this. Then some people like the freedom of just having to go somewhere once every six months and not having to think about it.
Probably in a decent proportion of newly diagnosed people with MS, Fenebrutinib would be a very good drug because it has high efficacy against relapsing disease, and we have excellent evidence in the field demonstrating how important it is for most people from the very beginning of the disease to start treatment with high efficacy against relapsing disease activity, which tends to be the dominant driver of disease in very early stages.
I wanted to add to that, though, in people who, even from the beginning of disease, clearly have evidence of some progressive components of disease, Fenebrutinib would then be the treatment of choice because you have the benefit of having an agent that has very high efficacy against relapsing disease but also has an effect on progressive disease mechanisms.
Particularly when we take into account what we know about the drug, which is that it easily gets into the central nervous system, and what we know from the FENtrepid trial, where it was non-inferior to ocrelizumab, but there is clear suggestion that there was a benefit on these progressive disease processes in the FENtrepid trial. With respect to patients who are switching, reasons for switching vary quite a bit.
Again, given what we are understanding in the field that currently we have many people on high efficacy treatments, and they demonstrate clear evidence of slow progression over time. Fenebrutinib would probably be the first treatment option in that setting.
For treatment sequencing, because we're reassured that it is very potent against relapsing disease activity, but again, has that benefit of targeting progressive disease mechanisms that many of our current therapies cannot really do in a meaningful way.
Ballpark figures, I'd say in treatment naive, probably 30%-50% of people would consider starting on a drug like Fenebrutinib, so long as the safety profile is similar to what we use with the current high efficacy treatment options. In many switches, obviously, not necessarily switches related to family planning or tolerability, things like that. Many switches can be related to efficacy.
In fact, I'd say probably 50%-60% of switches tend to be related to efficacy. This would be a very natural, probably one of the top choices. I would say over 50% of people in a first switch setting would probably consider a drug like Fenebrutinib, given what we've seen with the clinical trial data as well as what we know about the mechanism.
Very helpful. Thank you.
Bruno, I think you're muted.
Bruno, you're on mute.
Sorry. I mentioned you got a lot of ballpark numbers here for your model, Peter. Any additional questions or
Well, I could try my luck and say, do it again through PPMS, but that would be cheeky. I'll refrain and let the next person ask that question or do something else. Thank you.
Okay, very good. Let's move on. Next questions go to James Quigley from Goldman Sachs.
Great. Thanks, Bruno. I've got a couple of follow-ups as well here. On the suicides, you've been pretty clear you don't think there is a biologic rationale for BTK in driving potential suicide ideation. Did you take any measurements of mood changes or changes in depression levels as part of the adverse events monitoring for FENhance or FENtrepid? Did that data give you any more confidence that there is no or very low suicidality risk?
The second question for Dr. Oh. How do you compare the disability progression data across trials? Obviously taking into account the limitations of cross-trial comparison, but in the Kesimpta trials versus Aubagio, there was a 34% benefit in CDP EDSS score off of Fenebrutinib. When we look at the CDP EDSS, the benefit was around 19%-23% across both the trials.
In PPMS, you had the numerically higher reduction versus Ocrevus, as you said. How do you extrapolate these data through to the RMS population when you're thinking about disease and disability progression? Thank you.
I can start with the question about mood in the trials. As was stated earlier, we did not have this previewed as there had not been any signal about depression or suicidality in our early phases of studies. The phase III study was not set up in order to evaluate mood. We did not have a mood scale there.
Going forward, there was a question earlier about whether or not we would be doing future studies to evaluate this. If we were to do so, perhaps including a mood scale to be able to evaluate depression, and evaluate whether it gets worse would be something that we would consider. That is not being planned now, but throughout our funding processes, if such a study came forward, including a mood scale would be very appropriate.
We did have the C-SSRS scale as is recommended by the FDA for any neuro treatment that's in development. There we saw. It's not a depression scale. There is suicidal ideation to evaluate that. In the C-SSRS scale, we did not see any clear trend in suicidal ideation.
You would kind of think mechanistically that if there was a biologic reason for this, that you would see patients would worsen in ideation, patients would worsen in behavior, and this we didn't see. We have these rare events, but we don't have a clear signal on suicidal ideation. To us, this shows that there are gaps, and so perhaps we would include, as you suggest, perhaps mood indicators in future studies, but we don't have that data today.
I can address comparing disability progression across clinical trials. We're always taught in school to never compare across clinical trials, and particularly with disability progression, it's tough because there really is a period effect related to clinical trials these days. When you look back simply at relapse rates in placebo arms of relapsing MS clinical trials in the past two decades, you see a dramatic decline over time.
This is directly related to the fact that our diagnostic criteria have continued to evolve over time, more widespread availability of MRI and kind of loosening of MRI criteria required to come to a diagnosis of MS. Overall, this has really resulted in the face of MS being completely different from what it was actually two decades ago.
What we know is that we're in clinical trials recruiting milder and milder populations of people with MS. This is reflected in the baseline characteristics of the FENhance clinical trials where generally the average age is similar, but clearly people have less disability and are really within a year of MS diagnosis in these clinical trials.
Already you have a milder MS population. With that, it becomes harder to detect disability progression when people are so early in their disease course. This is why it's challenging to compare disability progression, which is the harder measure by far in comparison to the clinical measure of relapses. It's very challenging to compare that across clinical trials.
I also wanted to note that in contemporary clinical trials, we do see this issue of problems detecting differences in disability progression, even though we know clearly these are drugs that have a profound effect on relapses and therefore should also have an effect on disability progression.
Take, for example, the ublituximab phase III clinical trials, which were the most recent anti-CD20 clinical trials, where very clearly there was an effect, a profound effect, on relapsing disease activity clinically. But you don't see that corresponding effect on disability progression.
And this is similar temporally to the study population of Fenebrutinib. All this to say, I think it's really challenging to look at numbers and try to compare across clinical trials because of this evolution of what MS looks like, the milder disease population.
It would be a disservice to draw conclusions based on just that magnitude of effect on disability progression, which is already a very challenging measure.
I just want to add that, yes, totally agree with Dr. Oh that cross-drug comparisons have lots of fallacies. It's important to note within our study, we compare. In the relapsing MS study, the comparator is teriflunomide, which has already shown a disability benefit of 30% over placebo in the past.
In our PPMS study, comparator is Ocrevus, where we have shown 24% disability improvement over placebo. Already in our studies we have raised the bar in terms of measuring disability progression.
Very good. James, did this answer all your questions?
Yes, it did. Thank you very much.
Yeah. We move on. Next questions go to Steve Scala from Cowen. Steve, please.
Thank you so much, and congratulations on the data. I do have two questions, but they are both on safety. First, Dr. Oh, I'm just curious, have you ever seen a trial in neurology with such a significant adverse skew in deaths and have it just be a random finding and that that drug was ultimately approved despite that finding?
The second question, perhaps for the Roche folks, was the liver monitoring instituted while the trial was already underway? And if yes, how many liver enzyme elevations were observed before that implementation, and how many were after that liver function monitoring implementation? Thank you.
I can start with that right away, if helpful. You're very astute in remembering that this was implemented during the clinical trial process. We started all three of the phase III studies with monthly monitoring, and at the time that we implemented the change to every two-week monitoring, we had well recruited the studies and were over 50% recruited.
The PPMS trial was probably over 70% recruited at that time, so that the data that we're looking at in terms of liver enzymes is predominantly collected with the monthly monitoring. Once we implemented the every two-week monitoring, we did see a shift in detecting the liver elevations earlier. Which also gives us the reassurance that our every two-week monitoring is working.
After we implemented the every two-week monitoring, we did not see any further high elevations, and of course, the single highest Hy's Law case occurred while the monthly monitoring was in place.
I can address the question about deaths. I don't know all the numbers by heart, but in recent memory, I don't think I have seen an MS phase III clinical trial with this significant imbalance, this magnitude of an imbalance in deaths.
However, I think these rare but serious events by chance can result in these imbalances that we see. This is why it is so important to tease apart each and every single case to see if there is some plausible mechanism that may be relevant to Fenebrutinib.
As you saw from the FENhance data as well as the FENtrepid data, there really isn't any sort of clustering of events. It is a little bit odd that there is this, just based on sheer numbers alone and imbalance.
I think the most responsible thing to do is to tease apart every single case, and overall, there didn't seem to be a signal that was relevant to what we know about the mechanism of BTK inhibitors. Obviously this will need to continue to be evaluated. The short answer is no. I have not seen any recent phase III trial with a similar magnitude of imbalance.
Steve? Chris?
Yes. Very helpful. Thank you.
We go to the final questions. Final questions go to Urban Fritsche from ZKB.
Yeah, thanks a lot for taking question. A question on the subgroup analysis. Do you have any idea why prior DMT use could be beneficial for Venetoclax treatment? Could this data be informative for the real-world sequencing of therapies, which indeed would be a bit contradicting to your prior comments that Venetoclax would be ideal for naive patients?
Perhaps I can just comment before handing this to Dr. Oh, that of course, as Dr. Oh described in the baseline characteristics, patients previously treated with DMTs was a very small proportion. Because of that, we have to be cautious when making inferences there that the confidence intervals around that group are large.
Just reminding us that that's actually a small data set, which we were not powered to make conclusions. Dr. Oh, any further comments there?
No. I think it was really only 15% of the entire study population that contributed to that subgroup. I completely agree. I think we just need to be cautious about which subgroup analyses are more meaningful than others, just based on numbers.
Okay. Thank you very much.
Excellent. I think with that, we are at the end of our call. I would like to thank again all our speakers for their time and their efforts exploring new treatment options for MS patients. Let me also thank the IR team members who worked on the slides and prepared the event, to call out here, Alexandre Mauron and Loren Kao, and also Celeste Lloyd for event organization.
I hope the event was helpful, providing a timely update of our MS franchise. If there are any remaining questions, please reach out to the Roche IR team. We will be happy to help. Otherwise, we might meet again soon at our Q1 results call tomorrow or on one of the roadshows on Friday. With that, we'll close the call. Have a good evening. Have a good day. Bye-bye.