Natalizumab Beneficial in Secondary Progressive MS?

November 21, 2017

A new post hoc analysis of the ASCEND trial in secondary progressive multiple sclerosis (MS) suggests that natalizumab (Tysabri, Biogen) is effective in this population, particularly for upper limb function.

In the latest "area under the curve" (AUC) analysis, natalizumab was associated with a 77% reduction in the 9 Hole Peg Test time score, reflecting improved finger dexterity.    

ASCEND investigator Gavin Giovannoni, MD, Barts and the London School of Medicine and Dentistry, London, United Kingdom, commented: "There is much more capacity to see a treatment effect in upper limb function than lower limb function in patients with more advanced secondary progressive MS.  

"The EDSS [Expanded Disability Status Scale] — the main disability endpoint used in MS trials — is really not fit for purpose at this level of disability. We need new trials focusing on different endpoints, particularly upper limb function in patients with more advanced secondary progressive MS. I challenge Biogen to learn from our latest analysis and do an ASCEND-2 trial."

Dr Giovannoni presented this new AUC analysis of the ASCEND data at the recent 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting. 

He argued that this type of analysis takes into account both improvement and worsening of disability and therefore gives a more reliable picture of a drug's

Area Under the Curve

ASCEND was a randomized trial of natalizumab vs placebo in secondary progressive MS. It had a fixed duration of 2 years, followed by an open-label extension phase.

Natalizumab did not meet the primary endpoint — delayed disability progression, as assessed by a multicomponent endpoint consisting of EDSS, timed 25 Foot Walk Test (which measures lower limb function), and the 9 Hole Peg Test (9HPT; which measures upper limb function) — during the 2-year randomized phase. 

However, in the open-label extension phase, a benefit was seen in the natalizumab group on the multicomponent endpoint and in upper limb disability progression, Dr Giovannoni said. 

He explained that the new AUC analysis was conducted to investigate both improvements and worsening in disease with treatment; improvement was more likely to be seen in upper limb function in patients with advanced disease because the upper limbs had more neuronal reserve available for longer.

 

He noted that in progressive MS, neuronal reserve decreases and the patients generally become less responsive to anti-inflammatory therapy, leading to reduced treatment effects and a therapeutic lag (ie, longer time required to show a treatment effect).  

"It is now becoming apparent that MS is a length-dependent axonopathy — in other words, the length of the nerve fiber dictates which systems become affected first in more advanced disease. So as the lower limbs have longer fibers, they acquire more hits over time and are more likely to degenerate early and patients are more likely to present with progressive disease in the lower limbs first.  

"This also means that pathways to the upper limbs have more reserve capacity and a greater ability to recover and repair function, and this will be missed in an endpoint that only tracks worsening of disability. This has very important implications for the design of new trials."

Dr Giovannoni also pointed out that the ASCEND trial included more advanced patients than some of the other secondary progressive trials. "The majority of patients (71%) had not experienced a relapse in the prior 2 years, so they were 'as pure a progressive population as possible,' and over 60% had lost a lot of lower limb function (EDSS score of 6 or higher) so they were needing walking aids."    

"As the arms are thought to have a greater neuronal reserve than the legs, earlier and greater treatment effects may be shown on upper limb function compared with lower limb function, and this is exactly what we have shown in the current analysis," he added.

Fixed-Duration Design

Dr Giovannoni also noted that another disadvantage for ASCEND was its fixed-duration design.

"It probably takes longer than 2 years to see an effect in patients who have little or no reserve. And some of the other trials in secondary progressive MS which have been successful were event driven rather than time driven," he said.

In the current AUC analysis, trapezoidal analysis was used to compare changes from baseline in EDSS scores and percentage changes from baseline in the Timed 25 Foot Walk and the 9HPT for natalizumab-treated vs placebo-treated patients.
Results showed significant improvements from baseline to week 96 with natalizumab relative to placebo in both tests. The median AUCs of the Timed 25 Foot Walk were 19.18 for natalizumab vs 24.5 for placebo, a 28% reduction (P = .020), and for the 9HPT scores were –1.59 for natalizumab vs 2.58 for placebo, a 77% reduction (P = .006).

The negative median AUC for natalizumab patients on the 9HPT suggests that most natalizumab-treated patients experienced an overall favorable disability experience relative to baseline on upper limb function, Dr Giovannoni noted.

Natalizumab patients were less likely to reach thresholds of increased AUC disability (indicating a net worsening of disability from baseline) and more likely to reach thresholds of deceased AUC disability (indicating a net improvement in disability from baseline).

No significant difference was seen in the EDSS score.

"These results are consistent with the primary ASCEND results, showing the greatest effect in upper limb function, where there is more reserve capacity," Dr Giovannoni said.

"These results give us insights as to how we should be doing trials in more advanced disease. We should be developing outcome measures that capture both improving and worsening disease with more focus on upper limb function that has more reserve than lower limb function.

"They also tell us that the EDSS is a flawed outcome measure for more advanced disease. It is much less sensitive to change and does not capture sufficient change over a period of time. For us to be able to do reasonably powered, relatively quick trials in advanced disease, we need to get rid of the EDSS from the primary outcome and focus on more responsive measures, particularly upper limb function," he said.  

Suggesting Some Benefit

Commenting on the findings for Medscape Medical News, Edward Fox, MD, Multiple Sclerosis Clinic of Central Texas, Round Rock, who presented a post hoc analysis of the ORATORIO trial suggesting that ocrelizumab also improves upper limb function in primary progressive MS, noted the 9HPT is a good single marker of upper limb function.

"It really picks up whether a person can use a keyboard or a cell phone — important daily activities," he said.

Dr Fox agreed that after a certain point the EDSS was not a good marker of upper limb function and noted the 9HPT is "vastly more sensitive."

However, he added that currently the EDSS is required as the disability outcome in MS trials.

"But it is my hope that other ways to evaluate patents should be allowed, such as the 9 Hole Peg Test. This is a very easy way to measure progression of upper extremity function," he said.

Also commenting for Medscape Medical News, Jeff Cohen MD, Cleveland Clinic, Ohio, said many were surprised that ASCEND was negative because natalizumab is a potent medication and some of the other new drugs have shown benefit in the secondary progressive population. 

"Probably the main difference between the results of the various progressive trials was more to do with differences in the populations included. Earlier patients seem to do better," he said.

Discussing the current post hoc analysis, he said, "You always have to be careful with post hoc analyses but this does suggest some benefit."   

Dr Giovannoni sits on steering committees for AbbVie, Atara Bio, Biogen, Novartis, Roche, and Teva and receives consultancy fees from Biogen, Canbex, Genzyme-Sanofi, GlaxoSmithKline, Merck Serono, Novartis, Roche and Synthon.

7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017. Parallel Session 6. Oral presentation 131.  Presented October 26, 2017.

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