Le Hua, MD

I wouldn’t just limit this to siponimod (Mayzent; Novartis), but all of our therapies need to improve. We need to find a better way to figure out when that transition happens from purely a primarily inflammatory stage to just the leftover, underlying process. We know that starts from the very beginning, but we don’t have a good sense of what happens during that sweet spot of when patients transition.

The diagnostic accuracy of secondary progressive MS can take up to 2 to 3 years. As with everything, time is brain. The better we can accurately capture that transition point, the better we can target therapies. I do like the therapies that have a 2-compartment approach, having both peripheral inflammatory effects, as well as neurodegenerative effects because we know that neurodegeneration starts early on and continues as patients age. I do see in the future maybe having more neurodegenerative targets that might not necessarily have an anti-inflammatory component.

As the disease progresses, we should focus more on the actual processes that underlie neurodegeneration, with either reparative strategies, myelination strategies, or neuroprotective strategies.

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An expert provides the necessary steps needed to bolster accuracy of prescribed disease-modifying therapies for MS and do away with outdated trial-and-error approaches. 

Research to Further Improve Treatment Optimization in MS

We know a lot about older patients and we’re starting to just scratch the surface. Because we have a lot of therapies that do a significant job of stopping relapses, which is the part of the disease we know we control well. However, we still see disability progression. Now we’re starting to coin the phrase progression independent of relapse activity, or PURA.

Because we’re seeing PURA, we still want to get a better understanding of what drives that process. Aging is part of that, immunosenescence is part of that, different changes happening in the brain, different aging processes, reduced ability to remyelinate, reduced ability to utilize energy, clear debris, and help with oxygenation species are all part of that change in older patients.

On the flip side, because of immunosenescence, safety also becomes a concern for older patients, particularly because of increased infection risks. Knowing all that, we need to start to approach our older patients differently. One of the unfortunate things we don’t have is that most trials have not enrolled older patients. Without enrollment of older patients, we don’t have high quality, prospective data. In terms of efficacy and safety, we’re doing the best we can with retrospective data, large control studies, and subgroup analyses, but formal studies in older patients is what’s needed. As we better understand the underlying disease processes and safety concerns, we can then better design drugs to drive at slowing down progression and disability in MS.

Le Hua, MD, provided insight on the current knowns and unknowns about older patients with multiple sclerosis, how their disease progresses, and the need for additional research.

Understanding Disease Progression in Older Patients With MS

The original EXPAND study had been presented, so we wanted to look at a subgroup analysis of those who were younger than 50 [years] and older than 50 [years]. This is a follow-up study. We’ve looked at young age differences before, using 45 [years] as the cutoff point. The reason we focused on 50 [years] is because we’re learning more about progressive disease.

As you can see from CMSC and ECTRIMS, there’s a lot of focus on older patients. We wanted to see if there’s a difference when we separate those patients out into younger and older. Thankfully, in our study, we were able to see that confirmed disability progression was also reduced in both the under 50 and over 50 age groups. In those less than 50 [years], 3-month confirmed disability progression was reduced by 31%. In those over 50, the 3-month confirmed disability progression was reduced by 38%.

Again, what’s nice about this data is that EXPAND really focused on the secondary progressive patients. Even when we separate out the older patients versus the younger patients, we still see an effect in the older age group. Of course, the caution is that when we separate out and do the subgroup analysis, the numbers become smaller. Any post-hoc analysis always has the standard limitations we’re aware of; however, those results are still instructive and give us an idea of what to expect.

An expert provided context on a subanalysis of the EXPAND study that evaluated the effect of baseline age on the efficacy and safety of siponimod (Mayzent; Novartis) in secondary progressive multiple sclerosis. 

Siponimod’s Efficacy on Secondary Progressive MS

“We can extract from animal models that, yes, it might have this effect, it might have neuroprotective effects, but we never really know 100%. But, it’s reassuring because the whole story is that we probably need to treat both the peripheral immune components as well as the CNS component.”

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) forum

, February 27-29, 2020, in West Palm Beach, Florida, Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health, and colleagues presented data from a subanalysis of the EXPAND study of siponimod in patients with secondary progressive multiple sclerosis (SPMS).

The analysis stratified patients by their ages, under and over the age of 45 years, at baseline. In total, the cohort consisted of 779 patients, of which 473 were ≥45 years old (siponimod, n = 213; placebo, n = 93) and 306 were <45 years old (siponimod, n = 303; placebo, n = 170). Those younger than 45 years experienced a reduced risk of 3-month confirmed disease progression (CDP) by 31.9% compared with placebo (hazard ratio [HR], 0.68; 95% CI, 0.45—1.04; 

= .0734), and 6 month CDP risk by 39.5% (HR, 0.61; 95% CI, 0.38—0.96; 

 = .0339). Those 45 years and older reduced the risk of 3-month and 6-month CDP by 31.5% (HR, 0.69; 95% CI, 0.48—0.97; 

 = .0340) and 33.1% (HR, 0.67; 95% CI, 0.45—1.0; 

The aim of the assessment was to further explore some of the complexities which surface when treating patients with MS as they age, particularly when their chronological and immunological ages can be so different. To find out more about what these data mean and what still needs to be elucidated, 

1. Hua L, Bar-Or A, Lublin FD, Meng X, Su W, Cree BA, Fox R. Analyses Of The Effect Of Baseline Age On The Efficacy And Safety Of Siponimod In Patients With Active SPMS From The Expand Study. Presented at 2020 ACTRIMS Forum. February 27-29, 2020; West Palm Beach, FL. Abstract P029.

The director of the Multiple Sclerosis Program at Cleveland Clinic’s Lou Ruvo Center for Brain Health detailed what can currently be surmised about siponimod’s effect in treating patients with SPMS.

Le Hua, MD: Siponimod in Secondary Progressive Multiple Sclerosis

“It really does get into the question of, can we dichotomize our patients? We know there is a younger group and an older group, and we really wanted to look at if there was a difference in the drug working on one group or the other?”

 in patients with secondary progressive multiple sclerosis (SPMS) validated the oral, second-generation sphingosine 1-phosphate (S1P) receptor modulator versus placebo. At the 

, February 27-29, 2020, in West Palm Beach, Florida, more data were presented from the assessment, the main findings of which showed siponimod had significantly reduced risk of 3-month and 6-month confirmed disability progression (CDP) by 21% and 26%, respectively.

One of those datasets was presented by Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health. It evaluated the efficacy and safety of the therapy in patients under and over the age of 45 years at baseline. In total, the cohort consisted of 779 patients, of which 473 were ≥45 years old (siponimod, n = 213; placebo, n = 93) and 306 were <45 years old (siponimod, n = 303; placebo, n = 170).

All told, those younger than 45 years experienced a reduced risk of 3 month CDP by 31.9% compared with placebo (hazard ratio [HR], 0.68; 95% CI, 0.45—1.04; 

 = .0339). Those 45 years and older reduced the risk of 3-month and 6-month CDP by 31.5% (HR,0.69; 95% CI, 0.48—0.97; 

, Hua discussed the findings of this subanalysis of the EXPAND study and what it &shy;&shy;means for the understanding of older and younger groups of patients with MS.

1. Bar-Or A, Cohan SL, Coyle PK, Lublin FD, Meng X, Su W, Cree BA. Analysis of the effects of disease duration on the efficacy and safety of siponimod in patients with active SPMS from the Expand study. Presented at 2020 ACTRIMS Forum. February 27-29, 2020; West Palm Beach, FL. Abstract P030.

2. Hua L, Bar-Or A, Lublin FD, Meng X, Su W, Cree BA, Fox R. Analyses Of The Effect Of Baseline Age On The Efficacy And Safety Of Siponimod In Patients With Active SPMS From The Expand Study. Presented at 2020 ACTRIMS Forum. February 27-29, 2020; West Palm Beach, FL. Abstract P029.

The director of the Multiple Sclerosis Program at Cleveland Clinic’s Lou Ruvo Center for Brain Health discussed the findings of a subanalysis of the EXPAND study of siponimod in patients with secondary progressive multiple sclerosis.

Le Hua, MD: Subanalysis of the EXPAND Study of Siponimod in SPMS

“Our main focus [since the first MS approval] has been that we need to get therapies out there, we need to get stronger therapies—we haven’t really thought of age as a factor to consider.”

In the early 1990s, when the first therapies for multiple sclerosis (MS) treatment became widely available, physicians who were managing these patients had little on their minds outside of addressing the need for more therapies. As time went on, this focus shifted toward a need for higher efficacy therapies, but all the while, patients with MS were getting older.

Now, according to Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health, the prevalence of MS has altered to an older population. As treatment has improved, patients have begun to live longer with the disease—and are on disease-modifying therapies longer. This, she told 

, has required a parallel shift in thinking about age in MS.

, February 27-29, 2020, in West Palm Beach, Florida, Hua discussed the need to take age into consideration when managing a patient with MS, and how the approach to treating this population changes over time.

The director of the Multiple Sclerosis Program at Cleveland Clinic’s Lou Ruvo Center for Brain Health discussed the need to take age into consideration when managing a patient with MS, and how the thinking about the disease and age has shifted.

Le Hua, MD: Considering Age in Multiple Sclerosis Treatment

“A lot of the studies have shown that the older you get, the less relapses there are, the less MRI changes, the less activity. …[But,] we don’t have a really good idea as to if we should be treating older patients differently if what’s actually underlying the disease is different.”

Multiple sclerosis (MS) is a difficult disease for physicians to treat, even with the relatively vast arsenal of therapeutics available as treatment options. Additionally, a wide variety of factors, including a patient’s age at the time and at diagnosis as well as the duration of the disease, influence the physician’s approach to managing its progression.

, February 27-29, 2020, in West Palm Beach, Florida, a number of conversations around the topic of treatment in this sense sprung up. Currently, the disease-modifying therapies are designed to target the early phase disease course, which is characterized by lesion activity and inflammation, while treatments for progressive disease have required a modified approach.

To find out more about the questions facing MS specialists and the correlation between age, disease duration, and treatment in patients, 

 sat with Le Hua, MD, director, Multiple Sclerosis Program, Cleveland Clinic Lou Ruvo Center for Brain Health. Hua detailed the current thinking about how to address this challenge.

The director of the Multiple Sclerosis Program at Cleveland Clinic’s Lou Ruvo Center for Brain Health detailed the current thinking about the challenges of addressing multiple sclerosis in older patients.