Choosing the Right MS Treatment by Customizing Therapy to the Individual

With more multiple sclerosis (MS) treatments becoming available, it is now possible to better personalize approaches, explained speakers during a session at MSVirtual 2020: 8th Joint ACTRIMS-ECTRIMS Meeting.

Customizing effective treatments

A policy initiative was set up 5 years ago with the goal of spreading the adoption of a therapeutic strategy to maximize the brain health of every person with MS. The principle idea was that MS should be treated as effectively as early as possible, said Gavin Giovannoni, MBBCh, PhD, FCP (Neurol., SA), FRCP, FRCPath, chair of neurology at the Blizard Institute in the Barts and The London School of Medicine and Dentistry at Queen Mary University of London.

This means intervening early and effectively to affect the trajectory of MS over time. “I’m convinced we are doing this now,” he said.

In the pre–disease-modifying therapy (DMT) era, by age 65, more than 80% of patients with MS needed a walking stick¹. However, by the era of low-efficacy DMTs, that proportion was down to 60%, and now, in the high-efficacy era of DMTs, that proportion has fallen further, to 20% to 30% of patients needing a walking stick by the age of 65.

“So, there’s no doubt that by adopting this early, effective treatment approach, we have a major impact on the overall outcome,” Giovannoni explained.

However, the challenge remains: how do we determine which patients with MS will respond to treatments? If there are 100 patients, it’s not clear who will or won’t respond to therapy, and the only real option is to use statistical modeling.

• If 100 patients are on tier 1 or low-efficacy DMTs, there is going to be a 20% response rate
• If 100 patients are on tier 2 or moderate-efficacy DMTs, there may be a 40% to 50% response rate, but the majority will still be nonresponders or suboptimal responders
• If 100 patients are on tier 3 or high-efficacy DMTs, 80% of patients will have no evidence of disease activity

Providers have to decide if they want to gamble on low- or high-efficacy therapies when they initiate treatment. Should they start with low-efficacy and move through the tiers or go right to the top tier from the outset?

Research has shown that early access to high-efficacy DMTs results in better outcomes. For fingolimod, natalizumab, and alemtuzumab the response rates are much higher, and they are associated with a lower risk of conversion to secondary progressive MS compared with therapies like interferon beta or glatiramer acetate.² In addition, patients who started on high-efficacy therapies within 2 years of disease onset had less disability after 6 to 10 years than patients who started high-efficacy therapy later in the disease course.³

“There’s little doubt in my mind…early access is what’s important,” Giovannoni said. “Early access not late access.”

However, treatment is not only about efficacy—patients are going to be exposed to serious adverse events on these therapies. This is when patient choice becomes important. Providers will need to take into account issues like family planning and pregnancy when personalizing treatments.

“That’s why safety comes into it,” Giovannoni said. “We always worry about the serious adverse event when we are customizing treatment strategies for patients with multiple sclerosis.”

At baseline, the provider needs to look for ways to de-risk the high-efficacy DMTs to make them more palatable for patients to try as a first-line therapy.

Understanding the individual’s disease is crucial, including profiling the patient in terms of understanding their risk aversion, adherence, comorbidities, and other factors before customizing treatment However, once that is done, it must be layered onto the health system and economic factors, he pointed out.

“So, there is not a simple solution to the customized medicine in relation to our disease-modifying therapy,” Giovannoni said.

Subgroup analyses to understand response rates

Predicting a better response to treatments is very important in MS now that there are multiple treatment options to choose from, said Maria Pia Sormani, professor of biostatistics at the University of Genoa, Italy.

However, it is not easy to define response to treatment in MS. For instance, in solid tumors, a reduction in the tumor mass after chemotherapy is defined as a response to treatment because there is no spontaneous mass reduction without treatment. In relapsing-remitting MS, simply having no relapses after an immunomodulatory drug cannot be defined as having a response to treatment, because in the disease, patients can have stable disease course even without treatment.

A subgroup analysis can help better understand patients who are responders to therapy, she explained. One study of cladribine tablets showed that while the overall risk reduction versus placebo was 50%, there were differences in response depending on disease activity.⁴ In patients with high disease activity, the probability of disease progression was reduced by more than 80% among patients who took cladribine; the reduction was less than 20% in patients without high disease activity.

Sometimes, when many subgroups are tested, researchers will find by chance that some subgroups have a higher response to treatment, but that finding might not be confirmed in a follow-up study, Sormani noted.

Another analysis showed that in the DEFINE study,5 patients with no prior MS treatment had a relapse risk reduction of 67% when treated with oral BG-12 (dimethyl fumarate), but in the CONFIRM study,⁶ the opposite was true: the reduction was only 36% in patients with no MS treatment, and the risk reduction was larger in patients who had previous treatment (54%).

A new approach that Sormani and her colleagues crafted would create a personalized profile of patients who respond better using a patient-specific continuous score.⁷ They applied the analysis to 3 trials: ALLEGRO was used to define the score; BRAVO was used to test the score; and CONCERTO was used to externally validate the findings.

The score was able to define responders and nonresponders, and Sormani provided an example of how it might be applied in clinical practice. First instance, take a patient with MS with 1 relapse in the previous year, 1 gadolinium-enhancing lesion on the baseline scan, and a normalized brain volume of 1600 cm3:

1. If the patient is a 30-year-old man, his score is 0.32, which labels him as a nonresponder
2. If the patient is a 52-year-old woman, her score is –0.71, which labels her as a responder

In conclusion, Sormani noted that there are now statistical techniques based on post-hoc analyses of clinical trials that can help identify which patients will benefit the most from which treatments in order to choose the best MS therapy for them.

“We must try to push on pharmaceutical companies to allow re-analysis of their clinical trials to identify subgroup responders to every drug,” she said.

References

1. Capra R, Cordioli C, Rasia S, Gallo F, Signori A, Sormani MP. Assessing long-term prognosis improvement as a consequence of treatment pattern changes in MS. Mult Scler. 2017;23(13):1757-1761. doi:10.1177/1352458516687402

2. Brown JWL, Coles A, Horakova D, et al. Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA. 2019;321(2):175-187. doi:10.1001/jama.2018.20588

3. He A, Merkel B, Brown JWL, et al. Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. Lancet Neurol. 2020;19(4):307-316. doi:10.1016/S1474-4422(20)30067-3

4. Giovannoni G, Soelberg Sorensen P, Cook S, et al. Efficacy of cladribine tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: a post hoc analysis of the CLARITY study. Mult Scler. 2019;25(6):819-827. doi:10.1177/1352458518771875

5. Bar-Or A, Gold R, Kappos L, et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study. J Neurol. 2013;260(9):2297-305. doi:10.1007/s00415-013-6954-7

6. Hutchinson M, Fox RJ, Miller DH, et al. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol. 2013;260(9):2286-96. doi:10.1007/s00415-013-6968-1

7. Pellegrini F, Copetti M, Bovis F, et al. A proof-of-concept application of a novel scoring approach for personalized medicine in multiple sclerosis. Mult Scler. 2020;26(9):1064-1073. doi:10.1177/1352458519849513