NEW ORLEANS – On top of the first success with an investigational pharmaceutical agent for primary progressive multiple sclerosis reported last year, the otherwise negative results from recent clinical trials in progressive disease are at least informing the field of which direction to take in future research, Dr. Fred D. Lublin said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“The breaking news is that we are making headway. Two years ago we didn’t have a clue. Now we have clues,” said Dr. Lublin, professor of neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center, New York.

In the ORATORIO trial, the selective B-cell–targeting monoclonal antibody ocrelizumab (600 mg intravenous infused every 6 months as two 300-mg infusions given 2 weeks apart) was compared with placebo in 732 people with primary progressive MS (PPMS) in a 120-week blinded treatment continued for at least 120 weeks. After 24 weeks of treatment, ocrelizumab lessened the risk of progression in clinical disability by 25%, compared with placebo. Over the 2-year blinded treatment, the volume of hyperintense T2 lesions was reduced by 3.4% in the treatment arm, compared with a 7% increase in the placebo arm. Rate of whole brain volume loss was also reduced. A subgroup analysis presented at the ACTRIMS Forum revealed the influence of gadolinium-enhanced lesions on treatment efficacy.

“ORATORIO has opened the door to the problem of solving progressive MS”, said Dr. Lublin. Yet, considerable challenges remain. This was true even in the ORATORIO trial, where the treatment success was tempered by a 2.3% rate of malignancies in patients receiving ocrelizumab, which was more than double the 0.8% rate in the placebo arm.

Impact of trial design

The ORATORIO trial also highlighted another conundrum of trials to date, namely patient selection. The trial was designed to include young people with brain inflammation, a population that can respond well to treatment. But, in real life, patients with progressive MS can be older without signs of inflammation. For them, and for patients with a longer history of progressive MS, treatment might be less effective.

Other aspects of trial design that can bear on the outcome include the target (inflammation or degeneration), who to target, how to measure treatment outcome, and whether the endpoint is a confirmed decline that persists for a defined time or the more rigorous sustained decline, in which the decline is maintained for the course of the study. The disease phenotypes can also be important in trial design when it comes to screening patients. For example, one recognized MS phenotype is an active form that features clinical relapses and/or gadolinium-enhancing lesions on MRI, but which does not progress. Inclusion of this phenotype in a study can dilute the power of the study to detect a treatment effect if the progressive disease is in a nonprogressive phase during the study period.

Subgroup analysis of a trial with a failed primary outcome may reveal some patients who respond better to treatment, as in the OLYMPUS randomized, placebo-controlled trial. While the difference to confirmed disease progression in PPMS between rituximab and placebo was not significant overall, disease progression was significantly delayed in older patients.

Informative negative trials

With a solid trial design, a failed outcome can be informative, as it is likely because of a biological reason rather than a faulty trial design. The randomized, double-blind, phase III INFORMS trial of fingolimod versus placebo in PPMS is an example. While the primary and secondary outcomes involving delay to 3-month confirmed disease progression were not met, fingolimod treatment was associated with significantly fewer T2 and gadolinium-enhanced T1 lesions. Scrutiny of the study results could inform future trials.

A second example is the ASCEND trial of natalizumab in patients with secondary progressive MS. The trial’s failure likely reflected the very rigorous primary endpoint of a delay of confirmed disease progression at 3 months that was sustained up to 6 months or longer.

The MS-SPI randomized, multicenter, double-blind, placebo-controlled study that evaluated oral biotin in patients with PPMS or secondary progressive MS was especially noteworthy for its primary endpoint of improvement in disease at 1 year. The endpoint was met by 13% of those in the treatment arm versus 0% in the placebo arm (P = .0051).

“I wish I had more breaking news to report. But we are making progress with progressive disease. We learn from each study, and we are developing a clearer understanding of how to more effectively approach progression,” Dr. Lublin said.

Dr. Lublin reported receiving research support and/or serving as a consultant for many companies marketing MS drugs, including Biogen, Genentech, and Novartis.

Positive headway reported for progressive multiple sclerosis