Staff neurologist, Cleveland Clinic; Hôtel-Dieu de France Hospital, Lebanon

Gabrielle Macaron, MD

This study shows that ozanimod treatment is associated with positive outcomes on clinical and regenological measures of disease activity. This was seen in patients who were treatment naïve or in patients who were already on another disease-modifying therapy at baseline. This effect was maintained over the duration of the study period, which was 4 years. The clinical implication of this result is that patients with relapsing or remitting MS [multiple sclerosis] can benefit from ozanimod as a first- or second-line therapy. It’s important, however, to have a direct and long-term comparison of outcomes between these groups to see if treatment-naïve patients will benefit more in the long term. This would be in line with the first- line high-efficacy treatment approach in MS, which has been increasingly used in practice in the past few years.

In summary, significant recent data show that early treatment with a high-efficacy medication seems to be a good approach for many of our patients with MS, and delaying treatments is associated with poor outcomes in the long term, based on several recent studies evaluating this. My main advice is for every patient to always individualize treatment decisions based on the course and characteristics of the disease, such as the MRI lesion burden, the severity, and the frequency of relapses. It’s also based on patient characteristics: their age, family plans, and comorbidities but also their preferences. It takes into account the dynamic and continuous process of MS pathology throughout the life of a patient. Especially when we interpret data from randomized control trials, which aren’t necessarily generalizable to all our patients. When we pick a treatment according to randomized control trials, always think of the individual patient and how generalizable the data are and applicable they are and to our patients.

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Dr Macaron shares her interpretation of the data and importance of individualizing treatment for patients with multiple sclerosis.

Clinical Pearls for MS Management in Everyday Practice

The latest data on ozanimod was recently presented at EAN [European Academy of Neurology Congress]. But before we discuss those data, let’s go over the 2 pivotal phase 3 randomized control trials, RADIANCE and SUNBEAM, which evaluated ozanimod and compared ozanimod at 2 different doses: 0.5 mg and 1 mg of ozanimod hydrochloride vs interferon beta-1a. Both studies were in Nansen Neuroscience [Lecture] in 2019, and both studies have similar results in favor of ozanimod.

The main difference between the 2 trials is duration. RADIANCE was done over 24 months, whereas SUNBEAM was done over 20 months. In both studies, over 1300 patients with relapsing MS [multiple sclerosis], aged between 18 and 55, and with an EDSS [Expanded Disability Status Scale] less than 5 were enrolled. The primary outcome measure was to analyze relapse rate, and this was significantly lower in both ozanimod groups compared with the interferon group. This result was seen in both trials. The secondary outcome measures, such as the mean number of new or enlarging T2 lesions and the number of gadolinium-enhancing lesions, were significantly lower in both ozanimod groups, but more so in the 1-mg group, so the higher ozanimod dose, compared with interferon.

Although both studies were not designed to compare doses, the number of relapses and the number of new lesions on MRIs were lower in the higher dosage of ozanimod. That’s what led to the approval of the higher dose. Ozanimod was also more effective than interferon in decreasing measures: loss of whole-brain volume, loss of cortical gray matter volume, and loss of thalamic volume. SUNBEAM and RADIANCE are the first phase 3 studies to report this reduction in cortical gray matter and thalamic volume loss in MS. That suggests that ozanimod might have an effect on the neurodegenerative component of the disease. This idea is also supported in SUNBEAM, where ozanimod at the higher dosage also had an efficacy or a positive effect on cognitive measures in the trial. Another important result of these trials is that the pooled analysis of RADIANCE and SUNBEAM data on disability progression did not truly show a difference between groups over the study period. That’s important to mention. Maybe we need more time to see this difference.

Another important study that’s directly relevant to the abstract presented at EAN is the DAYBREAK study. This is a single-arm, open-label extension study in patients with relapsing MS who completed any phase 1 through 3 trial of ozanimod. Almost 2500 patients were included and treated with ozanimod at the higher dosage, which is 0.92 mg. That’s the approved dose, which is equivalent to 1 mg of ozanimod hydrochloride, which was evaluated in the phase 3 trials. This open-label extension study had a mean duration of 4 years. For patients who were on ozanimod in the parent trial and then were included in DAYBREAK, it was was around 5 years. In this study, the adjusted annualized reduction rate remained low throughout the study, and 71% of patients remained relapse-free. The number of new or gadolinium-enhancing lesions was also low throughout the treatment period and across the different initial groups. Based on which parent trial they were in and which treatment arm patients were on and regardless of the number, the radiological activity remained low. After switching from interferon to ozanimod, patients had numerically lower annualized relapse rates and a decreasing lesion count during the duration of the extension study.

Now we can move on to the ozanimod data presented at EAN. This conference was held in Vienna, Austria. The abstract is titled, “Efficacy of Ozanimod in Disease-Modifying Treatment, Naïve vs Experienced Patient With Relapsing Multiple Sclerosis

This was an exploratory analysis. The others evaluated the efficacy of ozanimod in patients who were treatment naïve before enrolling in the pivotal trials vs those who were previously treated with another disease-modifying therapy and who received interferon during the parent trial or the higher dose of ozanimod, whether it was SUNBEAM or RADIANCE, and then received ozanimod in DAYBREAK. Fifteen hundred patients were included in this open-label extension study. Those were patients who initially entered RADIANCE or SUNBEAM, not patients who were in the phase 1 or 2 trials. Of those enrolled patients, less than a third were previously treated with another disease-modifying therapy. Mostly that was interferon and glatiramer acetate—platform therapies and the rest—and more than two-thirds were treatment naïve. In both groups, ozanimod was effective in maintaining a low annualized relapse rate and a low mean number of new T2- enhancing lesions.

In patients who were on interferon beta-1a during the parent trial, the annualized relapse rate decreased significantly after switching to ozanimod in the extension study. This happened in both groups, so those who were treatment naïve and those with disease-modifying therapy experienced prior to enrolling in the parent trial. This annualized relapse rate was numerically lower in the treatment-naïve group in both the parent trial and the open-label extension study, but it’s important to note a potential bias: treatment-naïve patients might have a milder and less active disease independently of treatment. In patients who were continuously on ozanimod since the beginning of the parent trial, the annualized relapse rate remained low in the open-label extension study and was numerically lower in disease-modifying therapy-naïve patients as well. The same bias applies here. The number of gadolinium-enhancing lesions was numerically higher in the treatment-experienced group at the end of the parent trials, but in the open-label extension study—after switching to ozanimod for patients who were on interferon, whether or not they were exposed to treatment at baseline—this number decreased significantly in both groups. This also applies to the mean number of new T2 lesions.

Dr Gabrielle Macaron reviews data with ozanimod in treatment naïve vs experienced patients with relapsing multiple sclerosis presented at EAN 2022. 

Ozanimod in DMT Naïve vs Experienced Patients with Relapsing Multiple Sclerosis

What factors lead to a change of disease-modifying therapy? In a nutshell, the answer is that patients with relapsing/remitting multiple sclerosis [MS] typically stay on their treatment if it’s working. Higher-efficacy disease-modifying therapies work better for most patients, and we typically don’t need to switch patients who are on this category of treatment based on efficacy. In practice, treatment response and efficacy are measured based on the presence or absence of clinical relapses; a worsening physical disability, which is most commonly measured by the EDSS [Expanded Disability Status Scale]; and new or enhancing lesions on follow-up MRIs. These 3 key criteria are grouped in a composite outcome measure, which is called NEDA, or no evidence of disease activity, which is commonly used in clinical research and practice. But defining treatment response isn’t as straightforward and several other factors might be necessary to take into account or take into consideration before we can decide if a patient should stay on a treatment or switch treatments. This area of the MS field is still a gray zone, and we don’t exactly know what factors are the most predictive of long-term positive treatment response.

A multiple sclerosis expert, Dr Gabrielle Macaron, discusses factors that can lead to a change of therapy for patients with multiple sclerosis.

Factors Necessitating Treatment Change in Multiple Sclerosis

"The escalation approach is becoming less and less popular over time, especially in recent years, and the early high efficacy approach is gaining more popularity, because we know the consequences long term in multiple sclerosis (MS). I'm hoping we can do the same in neuromyelitis optica spectrum disorders (NMOSD).”

Researchers from Cleveland Clinic have found that patients with an age of onset (AO) of under 21 years of NMOSD were 

more likely to experience severe residual visual loss

These patients were more likely to have SRVL, as well as blindness, binocular optic neuritis (ON), and recurrent optic neuritis when compared to patients with AO greater than or equal to 21 years. However, they were less likely to receive high-efficacy first-line oral therapy. After adjusting for race, sex and disease disruption, the odds of SRVL were 4.68 times greater in patients with an AO <21 years (95% CI, 1.53–14.34; 

 reached out to first author Gabrielle Macaron, MD, neurologist, Cleveland Clinic and Hôtel-Dieu de France Hospital, Lebanon, to learn more about NMOSD about the associations between NMOSD AO and vision loss. Macaron stressed that more research needs to be done to understand the differences between NMOSD in younger and older populations and that traditional approaches to treating NMOSD should shift according to these and previously reported data. She also discussed recent medications such as eculizumab being studied in NMOSD.

Macaron G, Khoury J, Bena J, et al. Early age of onset predicts severity of visual impairment in patients with neuromyelitis optica spectrum disorder. 

 Published online January 6, 2021. doi: 10.1177/1352458520981736

The neurologist from Cleveland Clinic discussed how her study reinforced previous findings that individuals with early onset neuromyelitis optica spectrum disorders are more likely to experience severe vision loss. 

Investigating Disability and Onset Age in NMOSD: Gabrielle Macaron, MD

“Younger individuals have worse visual outcomes... for this reason, maybe we should treat them with the efficacious medications early on in the disease course. We need more data to make sure that higher efficacy meds are safe in this population. We should start thinking about treating those patients more actively and early on, without using an escalation approach, which is what we traditionally do in multiple sclerosis.”

 suggest that patients with an age of onset (AO) of under 21 years with neuromyelitis spectrum disorders (NMOSD) were more likely to experiences severe residual visual loss (SRVL) independent of disease duration.

First author Gabrielle Macaron, MD, neurologist, Cleveland Clinic and Hôtel-Dieu de France Hospital, Lebanon, and colleagues found that patients with an AO of under 21 years of age were more likely to have SRVL, as well as blindness, binocular optic neuritis (ON), and recurrent optic neuritis when compared to patients with AO ≥21 years. These patients were also more likely to receive less effective first-line oral therapy. The odds of SRVL were 4.68 times greater in patients with an AO <21 years (95% CI, 1.53–14.34; 

 = .007) after adjusting for race, sex and disease disruption.

 reached out to Macaron to learn more about NMOSD and its available therapies. She discussed what steps should be taken next to help reduce debilitating attacks of NMOSD in younger patients.

The neurologist from Cleveland Clinic discussed how her team found that patients with AO ≤21 years old had worse visual outcomes than those >21 years old. 

Gabrielle Macaron, MD

Articles

Clinical Pearls for MS Management in Everyday Practice

Ozanimod in DMT Naïve vs Experienced Patients with Relapsing Multiple Sclerosis

Factors Necessitating Treatment Change in Multiple Sclerosis

Investigating Disability and Onset Age in NMOSD: Gabrielle Macaron, MD

Improving Outcomes in Patients With Early Onset NMOSD: Gabrielle Macaron, MD

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