Unscripted - Duchenne Muscular Dystrophy: What Truly Matters to Patients and Caregivers

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Welcome to Unscripted The AMCP podcast, a look inside managed care pharmacy. Listen in as experts explore the challenges, innovations and opportunities shaping health care for millions of patients. Welcome to this episode of Unscripted The AMCP podcast. I'm your host, Fred Goldstein. This episode kicks off a series of four podcasts, each focusing on a different rare disease. Today's rare disease is Duchenne muscular dystrophy, and I'm looking forward to discussing how payers can identify and prioritize what matters most to patients and their families. 

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This program is supported by an independent medical education grant from ITF Therapeutics. Make sure to check the show notes for additional information. It is now my pleasure to introduce our faculty for today's program. Steve Kheloussi, principal consultant at Kheloussi Consulting. Welcome, Steve. Thanks so much, Fred. Very happy to be here. Yeah. It's fantastic to get you on. So why don't we begin give our audience a little background on the disease itself? 

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Absolutely. So Duchenne muscular dystrophy also goes by Duchenne. And it's the most common childhood onset form of muscular dystrophy. It is a rare disease affecting about one in every 3500 male births worldwide. But notably, it's one of the most common genetic disorders. And so it's an excellent genetic disorder. It leads to mutations in the DMD gene. And what then happens is there is an absence of dystrophin, which is going to lead to muscle fiber degeneration. 

00:01:52:14 - 00:02:16:03 

And so these patients are initially going to present with muscle weakness in the upper arms and shoulders. And the upper legs and the pelvic region. And eventually it's going to progress to leg braces around the ages of 8 to 9 years old. And eventually these patients are going to be wheelchair bound. And later on in the disease, they're going to lose their function of their arms and so on. 

00:02:16:05 - 00:02:34:14 

But it gets really severe when they begin to lose the muscle strength in their ribs. And so it leads to respiratory problems. You see a lot of bone. Yeah. And difficulty coughing and all of that. But then on top of it it can also lead to cardiomyopathy. And so it is a fatal disease in all of these patients. 

00:02:34:18 - 00:02:58:03 

But with the advent of medications, quality of life has been improved over time as well. So very serious disease, very common as far as genetic diseases go, but still a rare disorder altogether. So you touched on for just mentioning treatments. Can we talk about the evolving treatment landscape and where we're at today? Yeah, absolutely. So we have a few different classes of medications that can be used for DMD. 

00:02:58:03 - 00:03:21:10 

The cornerstone of therapy is corticosteroids. So there are two FDA approved corticosteroids. The FISA court the more alone and we see a lot of off label use of prednisone as well. And so as I mentioned those are the cornerstone. We also see Calvinists. And it's a histone. Do you see the Ace inhibitor that's also used. And that's going to be used in combination not as a replacement to corticosteroids. 

00:03:21:10 - 00:03:42:23 

The problems with the corticosteroids and given is that they do have side effects associated with them, especially corticosteroids with long term use. You know, all of the corticosteroid associated symptoms that we've all come to to learn about. So we have to be aware of those. And these patients are going to be on these for extended periods of time, thereby increasing the risk of these long term adverse events as well. 

00:03:43:02 - 00:04:12:19 

After that, we have the Exxon skipping therapies, which are our antisense oligo nucleotides. There are four of those available. These basically work by skipping over the mutation in the DMD gene that is causing that absence of dystrophin. And so there are some target regions that are the primary targets of these Exxon skippers. But there's still a lot of work that needs to be done, because even with all of our therapies, we're still targeting only a small proportion of the population with DMD. 

00:04:12:21 - 00:04:40:03 

So the Exxon skippers are all FDA approved through the accelerated approval pathway. Therefore, they need ongoing studies to confirm their effect. And these medications approval is all based on the ability to improve dystrophin levels, which we'll talk about the importance of that hopefully later on. But really, I think the most important thing is that we're still waiting for confirmatory trials on one of the therapies that was FDA approved in the mid 20 tens. 

00:04:40:03 - 00:05:06:05 

And, you know, it's been almost a decade since that was approved and we still don't have that data. So that's one of the problems, I think, with with this disease area is it's extremely challenging to study, especially given the fact that these patients are diagnosed relatively early on and their bodies just naturally get stronger over time, which leads to even placebo treated patients seeing benefit, potentially just because their bodies are naturally getting stronger. 

00:05:06:05 - 00:05:26:01 

And so it's a very challenging disorder to to study. And that leads to a lot of data gaps. And then our final therapy that we have at the moment is the planned estrogen mix. Apart from that, which is much easier stated as evidence, which is just for educational purposes, I'll continue to refer to it through its brand name. 

00:05:26:06 - 00:05:53:18 

11. This is a one time gene therapy and fully FDA approved for ambulatory patients with DMD. However, it only has accelerated approval currently for non ambulatory patients. Also. Unfortunately, recently there were two acute liver failure deaths in patients with DMD who were non ambulatory who were treated with the limited s. And so there's much more of that information that's going to be needed about that before we know if we can safely use that medication. 

00:05:53:18 - 00:06:15:21 

And then now the ambulatory population. But for right now it does have full approval in the ambulatory population. So you talk about this approval in a biological measure. What about the patients. What are they looking for. Yeah that's a really good question. One thing that I've come to appreciate about rare disease is the value of the patient voice in just letting us know what matters to them. 

00:06:15:21 - 00:06:37:17 

There is some data in DMD that says that dystrophin levels a biomarker, or a surrogate endpoint that the FDA is relying on for accelerated approval does not matter to patients. What patients care about it really depends if they are ambulatory or non ambulatory. But the ambulatory population cares about maintaining their quality of life and their function, reducing the fatigue that they feel. 

00:06:37:21 - 00:06:57:13 

And then the non ambulatory population really cares about just maintaining upper body strength because they need that to move their wheelchairs effectively and so forth that they're not motorized. And so it's interesting to see the FDA rely on these biomarkers. It's sort of the best that we can do when it comes to rare disease, because we just don't have enough patients to study. 

00:06:57:13 - 00:07:22:08 

And the studies take quite a lot of time. And we're looking at data where active, treated patients are being compared to external controls. So there's just a number of different challenges with studying this. And so it makes sense that the FDA has provided that guidance that manufacturers can rely on dystrophin levels for accelerated approval. But there is a little bit of a data gap between what actually matters to patients. 

00:07:22:08 - 00:07:47:23 

And there's also a data gap of how effective is dystrophin as a biomarker in determining the relationship to meaningful outcomes in these patients. It has not been consistently shown, according to a few of the clinical trials related to ambulation and placebo controlled patients for a few of their medications one exon skipper and then, however, this as well that they consistently improve dystrophin levels and ambulation measures as well. 

00:07:47:23 - 00:08:07:07 

And so there's some question about the relationship, at least in my mind. And I think that's giving some payers a little bit of pause on uncovering these medications. And unfortunately, it's giving some patients a little bit of pause, I would imagine as well in, you know, using something that's going to improve a biomarker and not necessarily something that they actually care about, like ambulatory measures. 

00:08:07:11 - 00:08:29:12 

And lest I forget, could you touch upon the issue because obviously it has a profound impact on the caregivers or their families, etc.. Yeah, absolutely. And so this disease takes an incredible toll, not just on the patient, but also on the caregivers from the patient side. These patients have significant quality of life declines compared to non DMD controlled patients. 

00:08:29:14 - 00:08:52:15 

And it gets worse as the disease gets worse. It's not just the physical aspects of it but also the mental health component. And they have a harder time acclimating to school. They have more sick days and or missed school time as well. But on top of that, even when they get into the workplace, they have a hard time acclimating to the workplace based on difficulties with wheelchair access and workplace accommodations and so forth. 

00:08:52:15 - 00:09:17:14 

So the patients just will continue to struggle over time. But the caregiver aspect of this is, is massive as well, in that certain caregivers, you know, we'll have to spend over 50% of their day caring for these patients, and that's 50% less time that they have to do things that they enjoy, things that they want to do, etc. there is increased absenteeism for caregivers. 

00:09:17:14 - 00:09:37:06 

There's also decreased presenteeism, which is the idea that even when they are physically present, they are not mentally present because they're distracted. And so there's there's quite a number of different quality of life impacts for, for the caregivers as well. And one thing that really struck me when researching this disease is the idea that the caregiver is not just the parents. 

00:09:37:06 - 00:10:01:17 

It could also be the grandpa. It's it could be the aunts, the uncles. But what was really touching to me is the impact on siblings as well. So siblings as caregivers is a very important consideration in childhood disease like this. So the older siblings and sometimes even the younger siblings have to miss out on social events. They they have a hard time making friends because they are assuming the role of the caregiver as well. 

00:10:01:17 - 00:10:20:15 

And that has an impact on on them as well. Wow. It's really broad. So when the managed care takes a look at this, how are they looking to integrate some of these data sets or other information and think about the absenteeism and presenteeism from the sense of an employer obviously losing the access to a valuable employee because they may be worrying about it or not able to show up at work. 

00:10:20:15 - 00:11:00:18 

So how are they bringing that in? Yeah, that's a great question. I would love to say that they are frequently considering these sorts of things, but I think the truth is that Asian perspectives in general are not commonly incorporated into payor decision making. And this is not just the DMD issue. I think this is an overall issue. But in rare disease, we do hear from payers that they are more likely to incorporate the patient perspective into their decision making, basically because there's less evidence and there's there's less data to make population level decisions in the true traditional sense of the evidence, you know, the randomized, controlled, placebo, randomized, placebo controlled trials, etc.. 

00:11:00:20 - 00:11:33:05 

So it's it's interesting because DMD is one of those rare genetic disorders. But as I mentioned, there's a quite a number of different medications available. And so over time, we've seen as the data has filled out a little bit more, that pairs are more likely to cover these medications. But we are still seeing some payers considering those exon skipping therapies, for instance, as investigational or experimental, because we're just missing sort of that connection between dystrophin levels and those meaningful outcomes. 

00:11:33:05 - 00:11:58:17 

And so it leads to a little bit of a challenge for payers that they want to look for this hard, objective data without necessarily relying on some of that, that softer. And these are not my terms, softer subjective data of, you know, patient perspective and patient preference and so on. But in the absence of that hard objective data, you know, we do hear from payers that they are utilizing that a little bit more. 

00:11:58:17 - 00:12:25:12 

We're also seeing that the patient perspective is a focus of the FDA. And so there were programs like the patient focused Drug Development Program that really emphasize patient experience data in making sure that manufacturers are studying outcomes that matter to patients, and not just things that will get them an FDA approval. Something that is clinically meaningful as well as important to the patient is really the main goal. 

00:12:25:12 - 00:12:48:21 

So we're seeing movement in that direction. And and a lot of that's happening behind the scenes that I think there's just some gaps between the payer understanding of that and how that's being incorporated into drug development, as opposed to just assuming that the patient perspective is, again, that soft biased, potentially data IV just give me anything I need a drug to treat my child sort of perspective. 

00:12:49:02 - 00:13:06:09 

It's it's actual data. And it's important that payers are recognizing that. And we need to see that data a little bit more prominently spelled out in the DMD population. I think to really move the needle on this in this case, I agree with you completely on that. Bringing in that patient perspective is critical and beginning to listen to what matters to them. 

00:13:06:09 - 00:13:26:17 

So I want to thank you, Steve, for joining us. Yeah, thanks so much. I really appreciate being here. And thank you for listening to this episode of Unscripted, The AMCP podcast. Be sure to look out for and join us for our next episode in this series as we dive into another rare disease.