BOSTON -- Researchers thinking about how to evaluate drugs aimed at progressive forms of multiple sclerosis have developed a new standard for judging quasi-remission and floated it here this week to the general neurology community.
Jerry Wolinsky, MD, of the University of Texas Health Science Center in Houston, presented a poster at the American Academy of Neurology's annual meeting here on NEPAD -- "no evidence of progression or active disease" -- as applied to data from the ORATORIO study of ocrelizumab (Ocrevus) in primary progressive MS.
As defined in the poster, NEPAD is an enhancement to the NEDA (no evidence of disease activity) endpoint that, in just a couple of years, has entered common use in clinical trials and to some extent in clinical practice. NEDA is defined as lack of active MRI lesion activity, no relapses, and no confirmed disability progression on the Expanded Disability Status Scale (EDSS).
This measure has been criticized for its reliance on the relatively coarse EDSS, which is a largely subjective categorical scale. In response, Wolinsky and colleagues have added scores on the 9-hole peg test and timed 25-foot walk to EDSS in proposing NEPAD as a better definition of a remission-like state. (MS specialists have studiously avoided using the word "remission" because they think it exaggerates patients' actual freedom from disease.)
In particular, NEPAD as applied to the ocrelizumab data was defined as follows:
- No protocol-defined relapses on treatment
- No 12-week disability progression on EDSS
- No confirmed disability progression of 20% or more in 9-hole peg test score
- No confirmed disability progression of 20% or more in 25-foot walk times
- No new or enlarging T2 MRI lesions and no gadolinium-enhancing T1 lesions
The primary results from ORATORIO, presented last June, were that risks of both 12- and 24-week confirmed disability progression on EDSS were each reduced by 24% with ocrelizumab versus placebo.
NEPAD was achieved by 29.9% of ocrelizumab patients in the trial, compared with 9.4% of the placebo group, Wolinsky said here. The drug's effect on MRI activity appeared to drive most of the difference versus placebo, with 70.3% versus 26.5% meeting the no-activity standard.
By contrast, the placebo group did nearly as well as those receiving ocrelizumab when it came to prevention of relapses and disability progression. No relapses were seen through week 120 in 82.9% of the placebo group versus 92.7% of the active-drug group. And, under the relatively stringent three-part standard for no progression, it was met by 30.3% of the placebo group versus 43.2% of those on ocrelizumab.
On the other hand, the difference of 13 percentage points between the trial arms on this measure of disability progression was greater than in EDSS-measured progression alone, for which the gap was only 5.5 percentage points.
Wolinsky told 鶹ý that, in relapsing MS, the relapses are the most significant event for clinicians to track because they are what will guide treatment decisions.
In progressive forms, relapses can still occur but it's the disability progression that becomes the chief clinical concern. That's where the first part of NEPAD -- NEP (Wolinsky pronounced it "neep"), the three components measuring progression -- comes in.
Setting a threshold of 20% decline in function on the 9-hole peg test and 25-foot walk is "reproducible and clinically meaningful," he said.
Earlier in the meeting, a study was presented indicating that many individuals meeting the NEDA and NEPAD criteria for lack of MRI activity still showed activity on more sensitive scans, such as diffusion tensor imaging. Wolinsky said such quantitative scans provide useful information but are easier to interpret when pooled and analyzed for groups than for individual patients "because of noise" and other factors.
The flip side of the 30% of ocrelizumab patients achieving NEPAD, of course, is that 70% were still showing some type of disease activity -- including 57% with continuing disability progression by the three-part standard. That raises a question of what else can be done to bring those numbers down. Combining existing disease-modifying drugs is considered too risky, as many of the individual drugs exert some type of immune suppression and a double hit may raise the infection risk unacceptably. Also, the one major trial to test a combination -- interferon-beta-1a (Avonex) plus glatiramer acetate (Copaxone) -- showed no increase in efficacy beyond what was seen with the individual agents.
Wolinsky speculated that a more feasible combination could be an anti-inflammatory drug plus one with an entirely different agent that does not adversely affect immune function. He mentioned biotin as one possibility -- earlier studies have shown it reduces disability progression. Another would be so-called remyelinating agents that repair the nerve damage in MS, which is currently a lively area for research.