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RealTalk MS
Episode 461: A New Disease-Modifying Therapy Has Been Submitted for FDA Approval with Dr. Jiwon Oh
00:34:04
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- [00:01]
A
I'm john strum and this is real talk, mississippi. It's June 30th and we have a lot to talk about. A short while ago, we shared some very positive results of the phase 3 clinical trials for phenibrutinib in both relapsing remitting and primary progressive Ms. Those clinical trial results have been submitted to the FDA for approval. And this week my guest is Dr. Jiwon oh, the principal investigator in one of the phase 3 trials for phenobrutinib. Dr. O is here to walk us through these positive results and to discuss what makes phenobrutinib a different kind of disease modifying therapy and who might benefit most from phenobrutinib. But before we get to my conversation with Dr. O, there are a few other things that you should know about. The EMA is the European Medicines Agency. It's the European counterpart to the FDA in the United States. And last week the EMA approved Tolebrutinib, now known by its trade name Senrify, for the treatment of non relapsing secondary progressive Ms. That's secondary progressive Ms. Without relapses. Over the prior two years in its phase 3 clinical trial, Sanrifke was shown to significantly delay disability progression among people with non relapsing secondary progressive Ms. And while the trade name Sanrifke is new, if you're a regular listener, you may recall hearing about Tolebrutinib this past December. The FDA chose not to approve the drug in the United States. Instead, the FDA called into question characteristics of the tolebrutinib clinical trial that the FDA itself had provided guidance on in the past. The FDA voiced concerns about the drug's safety profile. And if I can insert a mini rant here, as someone whose wife lived with non relapsing secondary progressive ms, I can categorically say that she would have welcomed this therapy. Is there some risk involved? There's risk getting out of bed in the morning, but we weigh the risks and most of us determine that it's still worth getting out of bed. There isn't another approved treatment that's been shown to be effective in slowing disability progression for people with non relapsing secondary progressive Ms. Today in the United States, that means those people just get worse. Dear fda, let someone in that situation determine their risk tolerance. Patients do that every time they consider a new medication. I remain hopeful that Sanofi, the manufacturer of Senrifke, can find a way to work through things with the FDA and that the FDA sharpens its own focus if it has an opportunity to revisit and reconsider this medicine. I'll end this short but deeply felt rant by mentioning that Sanrifkey has also been approved in Australia, making the US the outlier rather than the global leader in providing the most effective disease modifying therapies to people who are living with Ms. Sanofi has announced that Sanrifke will be available in Germany this year with a detailed risk management program and patient support program in place. We'll keep you updated on what may be next for Senrifke. Meanwhile, if you'd like to review the results of the Phase 3 clinical trial for Senrifke in people with non relapsing secondary progressive ms, you'll find that link in today's show notes. And if you'd like to watch my interview with Dr. Robert Fox, the principal investigator of that phase three clinical trial, you'll also find that link in today's show notes. Women represent about two thirds of the Ms. Population, yet there hasn't been nearly enough research focused on the intersection of Ms. And women's health issues. Well, I'm glad to say that situation is rapidly changing, and the National Ms. Society has announced funding for two important studies that will try to better understand the impact of Ms. On menopause and the impact of menopause on Ms. The first study is a deep dive into the actual biology of aging, co led by Dr. Li Hua at the Cleveland Clinic and Dr. Jennifer Graves at UC San Diego. Historically, studies on menopause relied on women trying to remember exactly when their last period was. As you can imagine, during perimenopause, when things can be wildly irregular, that memory can be a bit fuzzy. So rather than relying on memory, the researchers are measuring something called AMH that's anti mullerian hormone. Think of AMH as a snapshot of a woman's ovarian reserve or how many eggs they have left, and lower AMH means more advanced reproductive aging. Earlier data has already showed that lower AMH levels track with faster disability accumulation and more loss of gray matter brain, completely independent of how old the person is or how long they've had Ms. The researchers are also looking at telomeres. Those are the protective caps on the ends of chromosomes that shorten as our cells age. And they're also looking at blood proteins that reveal nerve damage. By studying 400 women with Ms. And 100 healthy controls, the research team wants to see if ovarian aging acts as a specific accelerator for M. If it does. It means that as a woman hits perimenopause, doctors might need to pivot to more aggressive disease modifying therapies or targeted hormone interventions. It's one more path toward a more personalized approach to Ms. Treatment. While this first study focuses on analyzing blood and brain scans, the second study being funded focuses on the daily reality of living with Ms. That study is being co led by Dr. Amber Salter and Dr. Robert Fox and it involves analyzing over 20 years of data from the Narcoms Registry. Using detailed menopause questionnaires, the research team is going to compare how women's symptoms, their disability level and overall quality of life change before, during and after menopause. The goal here is shared decision making. If a doctor can look at a patient and say, here's the typical trajectory of Ms. During menopause, here are the overlap symptoms to watch out for. It takes away the guesswork. It opens a door for early lifestyle changes or perhaps hormone therapy to mitigate some of those changes. And once again, it leads to a more personalized approach to Ms. Care. What I like most about this news is that it represents a significant shift toward personalized sex specific medicine. For decades, clinical trials have treated everyone's biology as being mostly uniform. Now we're recognizing that the unique biological milestones of a woman's life, like menopause, may demand their own unique playbook. If you or a loved one are managing Ms. And hitting that midlife transition, take this as your sign to start the conversation with your neurologist early. You don't have to just white knuckle it through the overlap of hot flashes and Ms. Fatigue. Meanwhile, we'll keep a close eye on these studies and share results as they become available. On this podcast, we often talk about having access to quality, affordable healthcare. Well, it turns out that isn't just a challenge for Americans living with Ms. According to one of the most respected polling organizations in the world, being able to afford health care is a challenge for the majority of Americans with or without Ms. Last week, the Gallup organization shared the results of a poll that was taken last year. Now, that was before we were even hit with the current level of rising inflation. And Last year only 49% of Americans felt they could afford access to quality care and pay for their doctor's visits and prescriptions. That 49% is down from a peak of 61% in 2022, making it the lowest level since Gallup began tracking this metric in 2021, 51% of the poll respondents indicated that they were concerned about paying for medical services in the next year, and 42% they were worried about prescription drug costs, maybe a bit. Surprisingly, these concerns span income levels and generations. About a third of the households earning between $120,000 and $179,999 a year, and 20% of the households earning $180,000 or more a year indicated they either lacked quality coverage or struggled to afford prescription drug. Every age group in this Gallup Poll, except those adults between the ages of 50 and 65, showed a decline in the percentage of people who could afford health care from 2023 to 2025, and only a third of the adults between the ages of 18 and 29 felt secure in their ability to afford health care costs. Now, we've been talking about numbers from 2025, and they're concerning. But let's look at 2026, when Congress passed deep cuts and burdensome restrictions to Medicaid and chose to let tax subsidies expire for health insurance purchased through the Affordable Care act marketplace, which, as we've often discussed, has caused health insurance premiums to skyrocket. Since June 2025, Medicaid has lost an estimated 3.8 million enrollees, and the Affordable Care act has seen declines in people who are insured in 41 states. Nonprofit health policy and research organization KFF estimates that nearly 5 million fewer people will enroll in Affordable Care act health insurance plans this year. So the challenge of accessing quality affordable health care is not limited to people affected by chronic illness. It's become a problem for the majority of Americans. And because I believe that advocacy starts with each one of us, it's my hope that everyone carries their worry and their concern into the voting booth with them when our midterm elections roll around. Because whether you're living with Ms. Or not, everyone should be casting their vote for those candidates who are going to best represent their interests and their concerns. Now, if you'd like to review that Gallup Poll in greater detail, you'll find that link in today's show. Notes. Last week, the US House of Representatives Appropriations Committee gave us a small win on the way to what we hope is a more important, more meaningful win. The House Appropriations Committee approved $20 million in funding for the Ms. Research program at the Department of Defense. This program, better known as the msrp, represents the only federal funding that is specifically earmarked for Ms. Research. Since its start in 2009, the MSRP has received a total of $153.3 million in congressional appropriations, and it's funded 208 research awards. These investments have led to 395 publications, 102 follow on grants, 4 patents, additional 3 patent applications, and 13 clinical trials. Now you may remember that Congress appropriated $20 million for the Ms. Research Program in 2025. And then, without warning, that funding was completely eliminated. Thanks to the efforts of Ms. Activists across the country, $15 million in congressional funding for the MSRP was restored for fiscal year 2026. Now the House Appropriations Committee has at least begun the process of funding the MSRP at $20 million for fiscal year 2027. The funding bill will move to the House floor for a vote and meanwhile the Senate will go through a similar committee and floor vote process. And if the House and Senate bills are not identical, the bills will go through the reconciliation process before that funding can be included in fiscal year 2027. This is all a way of saying the process is off to a great start, but we haven't crossed the finish line and this is where you can take less than five minutes to make a big difference. The next time you look down and notice that you're holding your phone in your hand, stop scrolling for just a minute and call area code 202-224-3121. That's the number for the House of Representatives switchboard operator. They can connect you to your Congressional Representative's office and you don't even have to speak to your representative. When the office receptionist answers the phone, identify yourself as a constituent and let them know that you're asking your Congressman or Congresswoman to advocate for the Ms. Research program to be included in that final funding bill. Every office keeps careful track of those calls and they can absolutely make a difference when it comes time to vote. So please take just a couple of minutes. Call area code 202-224-3121 and let them know that the Ms. Research Program is important to you and ask for their support. Research makes a difference because it leads to breakthrough treatments Phenobrutinib is a breakthrough treatment that, based upon very positive outcomes in phase 3 clinical trials, is currently under FDA review for treating, relapsing, remitting Ms. And primary progr progressive Ms. My guest this week is Dr. Jiwon oh, a principal investigator in one of those Phase 3 clinical trials. And in a moment, Dr. Oh is going to explain what makes phenobrutinib special and who might benefit most from this disease modifying therapy. Doctor Jiwon oh is a clinician, scientist and medical director of the Barlow Multiple sclerosis program at St. Michael's Hospital at the University of Toronto. And Dr. O was a principal investigator in the clinical trial for afenobrutinib, a BTK inhibitor that's been submitted for regulatory approval. Welcome back to the podcast, Dr. O.
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B
Thank you, John. It's always a pleasure to be here.
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A
There were two phase 3 trials for phenobrutinib, the phentropid trial and the Fenhance trial. And results from these trials were recently reported. In simple terms, what was the most important discovery from these studies for someone who's living with ms?
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B
So I'll just start in chronological order, John. So the fentrepid trial results were reported earlier. Actually, the high level results were reported at the end of last year and then very recently at the American Academy of Neurology, the results of Fenhance 1 and 2, which were two nearly identical phase 3 trials, were reported. So with Phentrepid, this was a phase three trial that looked at the effect of fenibrutinib in comparison to ocrelizumab in people with primary progressive Ms. And what this trial showed was that fenibrutinib is not inferior to ocrelizumab. So this is a very particular kind of trial design that doesn't really look for whether one treatment is better than another, but looks at whether they are relatively similar. And as you know, ocrelizumab right now is the only drug we have available for primary progressive ms, and we know that it is effective. So the Phentrepid trial showed very clearly that phenibrutinib is not inferior to ocrelizumab in people with pms, which is very exciting because it's another treatment for pms. But what was interesting was that in that trial, the magnitude of the benefit of fenibrutinib was greater than what was seen with ocrelizumab throughout the duration of the trial. However, because the trial was designed as a non inferiority trial, we don't necessarily know if phenibertinib was better than ocrelizumab. Regardless, it was non inferior, which is really great news because this means it's another treatment option for people with primary progressive Ms. And then moving on to the very recent trial results. So FeHance 1 and 2, which were two nearly identical phase 3 clinical trials that looked at the effect of phenibrutinib versus teriflunamide, a very commonly used first line disease modifying treatment, in people with relapsing Ms. So these two trials looked at the effect of phenobrutinib versus teraflunamide in people with relapsing ms, and then found very clearly that phenibrutinib was more effective than tariflunamide in reducing relapses, which was the primary endpoint of these two clinical trials. So this is also very exciting because very clearly, in phenhance 1 and 2, phenibrutinib showed that it was actually quite a bit better than teraflunamide at reducing relapses and new MRI lesions. So it's clear that it is another treatment option for people with relapsing Ms.
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A
The data suggests that patients on phenobrutinib in the Fenhance trial experienced a relapse rate equivalent to about one every 17 years, which is amazing. How does that compare to the treatments patients are using today?
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B
So, first of all, it is quite amazing and really shows us that these days some of these newer treatments can be extremely effective at reducing relapses. I would say, you know, in recent clinical trials, there have been other therapies that have been evaluated that have similarly shown extremely low relapse rates like this. So, for instance, recently reported clinical trial results include high dose ocrelizumab, for instance, the Musette and Gavotte trials that were reported last year, and then very recently the Ohand clinical trial as well. All of these trials have shown that with some of these highly effective therapies, relapse rates can be dramatically reduced to what we see with fenibrutinib as well in fenhan. So overall, I would say, first of all, it is a strikingly low annualized relapse rate, which is great news, and means that these therapies are really effective and that these days, with many contemporary clinical trials, with some of the therapies that we know are highly effective, like anti CD20 agents, fenobrutinib similarly seems to show a dramatic reduction in relapse rate.
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A
Well, as you mentioned, in the Phentrepid study, phenobrutinib was compared directly to ocrevus for primary progressive Ms. And you've explained the results. I'm curious, when it comes to drilling down a little bit, were there any specific areas where disability was delayed, like arm or hand function, something that really stood out?
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B
Yes. So, you know, all of these clinical trials, interestingly, have been using as the disability endpoint, a composite endpoint. So this means that it's a combination of different neurological measures that we use to try to measure disability accurately. And so in Phentrepid, the Composite endpoint that was used was a combination of the EDSs, which is that you know, typical global disability status scale that we almost always use in clinical trials. But also a measure of walking speed was evaluated, which was the 25 foot timed walk. And in that composite measure, a measure of manual dexterity was included as well, which is the nine hole PEG test. And so when you look at the results with that composite endpoint, fenobrutinib was clearly non inferior to ocrelizumab. So but when you look at individual components of the composite endpoint, it became apparent that the treatment effect was greatest on the nine hole PEG test. And so this seems to show that there's kind of differential effects sometimes of drugs on different measures of disability. And particularly with this measure of manual dexterity, it seems to have a substantial effect.
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A
We often hear that Ms. Damage happens behind the blood brain barrier. How does phenibrutinib actually get into the brain? And why is that different from most current injectable or infusion therapies?
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B
So, you know, fenobrutinib belongs to a class of medication known as the BTK or Bruton's tyrosine kinase inhibitors. And these happen to be really small molecules that can easily cross the blood brain barrier. So that's a huge benefit that these molecules have because in contrast to many of our other highly effective therapies, like for instance, the monoclonal antibodies. So these are what ocrelizumab and ofatumumab and uglituximab and natalizumab. These are the therapies that many of us consider to be the highly effective therapies. And they are all monoclonal antibodies, which means that they're giant molecules that really cannot cross the blood brain barrier. So because of the small size of phenobrutinib and the fact that it achieves a very good therapeutic concentration in the blood, it can actually very easily cross the blood brain barrier. And then there have been studies looking at a subset of people that were evaluated in the phase 2 clinical trial of fenibrutinib. And when you actually measure CSF concentrations of fenobrutinib, it's clear that fenobrutinib not just crosses the blood brain barrier, but gets in there at a biologically relevant concentration, meaning that it's at a concentration that we know can beneficially modulate cells that we want to target behind that closed blood brain barrier, which include B cells and microglia. Because we know that these cells play a really important role in mediating progressive disease biology. So this is in contrast to those big monoclonal antibodies I just told you about, because they're such giant molecules that they really can't cross the blood brain barrier the way small molecules like phenobrutinib can.
- [24:10]
A
Most of our current high efficacy drugs focus on killing B cells. Can you explain how phenibrutinib quiets both B cells and the brain's resident immune cells called microglia, without completely deleting them?
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B
Sure. So because phenobrutinib is a BTK inhibitor, BTK happens to be an enzyme that's involved in many different processes relevant to B cell maturation and proliferation, which are the steps that are often needed in an autoimmune disease to create inflammation that we don't necessarily want to happen. And so because BTK inhibitors inhibit this enzyme, that helps B cells proliferate and mature and turn into kind of pathogenic B cells. And then we also know BTK happens to play a really important role in maturation and proliferation of microglia. This is how it beneficially modulates those pathways. So it inhibits key pathways that allow these cells to kind of differentiate into these pathologic versions that drive Ms. Disease processes. But it doesn't necessarily wipe out all of the b. C.E. the way, say, drugs like ocrelizumab or ofatumumab or ublatuximab do. So, you know, in the end, it's kind of targeting a cell of interest in a similar way, but it doesn't completely deplete them and wipe them out because it's affecting a pathway that is needed for these cells to differentiate and proliferate into these pathologic versions that we know drive disease processes.
- [25:52]
A
Do you think that translates to more resistance to infection?
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B
It's probably the case, John. And obviously, you know, theoretically that makes a lot of sense because you're not totally wiping out, you know, a key player in the normal immune response. However, I always say the proof is in the clinical trials pudding. So we'll have to see that, that what we think, you know, potentially is a benefit pans out in clinical trial settings. But yes, I think that theoretically is the potential benefit of not of having a class of molecule that targets a cell that we know is a driver of pathology, but doesn't necessarily wipe them all out, because we know that obviously we do need B cells to mount normal human response immune responses as well.
- [26:40]
A
The trials mentioned some elevations in liver enzymes for a patient considering this drug in the future. What does that mean in terms of monitoring.
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B
So it's clear that not just with fenibrutinib, but a number of the other BTK inhibitors that it seems like this class of drug does have a signal of having liver enzyme elevation, particularly within the first couple months of starting the drug. And so within the clinical trials, frequent liver enzyme monitoring was implemented. And so when you do this and watch liver enzymes carefully, it's clearly a signal that we need to monitor for, for, you know, possibility of drug induced liver injury. But when you monitor very closely, particularly within a few months of initiation, it seemed clear, at least based on the fenobrutinib clinical trials, that, yes, you do observe some patients with liver enzyme elevation, but when you catch it early, it doesn't result in any cases of drug induced liver injury that is irreversible. And so overall, I think what this means for patients is that, yes, this is something that will need to be monitored when the drug is used in the real world, but it is a safety issue that can be observed and watched carefully and therefore managed. So shouldn't be necessarily some sort of difficult issue that prevents people from starting the drug.
- [28:08]
A
Phenobrutinib is an oral medication that's taken daily. For a patient who's used to going into a clinic for an infusion every six months, what are the pros and cons of switching to a daily pill?
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B
You know, it's interesting because people have such different preferences about this. You know, some people absolutely hate the thought of having to go into an infusion center. Booking an appointment that often takes like four to six hours. It means you have to take a whole day off of work. You know, you have to get needles and medications infused. And so some people really hate that. And the thought of just being able to take a pill a day is so much more attractive. However, there are some people who don't like the thought of having to have a daily reminder of disease. Some people forget to take daily pills, too. I can say I'm one of the people that if I was told to take a pill daily, I likely would forget frequently. And so it really is dependent on the patient. But I think some people really appreciate the convenience of having a pill that you can just take. You don't have to worry about scheduling things, getting needles, all of these things. So it offers a really nice option for people who really prefer that mode of administration.
- [29:21]
A
Is there a specific profile or type of Ms. Patient? I'm thinking perhaps someone who hasn't responded well to other drugs, or maybe someone who's very early in their Diagnosis, who would benefit most from this sort of treatment?
- [29:38]
B
Well, I think one of the most attractive parts of, you know, the results that we just talked about is that it's clear that fenabrutinib is a drug that is highly effective in people with relapsing ms, which is great and useful for many people with Ms. Because we know that relapsing disease biology plays a big role in many people, particularly in the early parts of the disease. But then the fact that it is also a treatment that very clearly has a benefit in progressive disease processes, as illustrated by Phentrepid, I think it makes it a really attractive option almost across the entire disease course because, you know, we're in ms, we're trying to figure out the best way to classify disease, but we now know more than ever that Ms. Is a disease spectrum, and both relapsing and progressive disease biologies are at play, even at the very beginning of the disease in many people and throughout the disease course. So if you have a treatment that we know is highly effective against relapsing disease processes, but also effective in progressive disease processes, it's almost like regardless of what part of the disease you're in, so long as you don't have any contraindications, it might be a really useful drug.
- [30:52]
A
Now, I have a bonus question. What are the next steps for the fda? I mean, realistically, when might an individual living with Ms. Be able to discuss fenobrutinib as an option with their neurologist?
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B
You know, it's so hard to predict these things, John, and I, you know, based on all of the kind of back and forth with, say, tolebrutinib, I think it's hard to predict exactly what will happen. But I think very clearly these three trials illustrate that fenobrutinib is an effective drug in many clear subtypes of Ms. And so there obviously are, you know, safety signals that need to be monitored. But hopefully, based on the exciting results of these clinical trials, it is clear that there is a benefit to the drug and that many people with Ms. Would likely appreciate another option in our treatment armamentarium. So I am very hopeful that regulators will see the value of, you know, these clinical trials and that this will be an option available to people living with Ms. In the near future.
- [32:04]
A
Dr. Chiwon. Oh, I want to thank you for all you do in the clinic and the lab to improve the lives of people who are living with Ms. Thanks so much for talking with me today.
- [32:13]
B
Thank you for having me, John.
- [32:15]
A
That's going to wrap up this episode of RealTalk Ms. Real Talk Ms. Is powered by the National Ms. Society, and you can share this episode of the podcast by letting your friends or family members know that all they have to do is point their web browser@realtalkms.com 461. You'll find that link in today's show notes, so you can easily copy and paste it right into an email or a text. As summer gets underway, graduating high school seniors and returning college students may not be ready to think about classes starting up in September. But if you're a student with a disability, that can be a physical disability or a cognitive disability, this is actually the ideal time to plan for and request accommodation in your classes or your campus housing. Next week, Britt Neff, an access specialist at the University of Washington School of Law, joins me to discuss how the process of accommodation works for college students. If you're a college student living with Ms. Or you know one, this is an episode you'll want to be sure to catch. I'm John Strum. Thanks for listening. Stay safe and make healthy choices.