Ocrelizumab Effect on PPMS Upper Extremity Function to be Evaluated in ORATORIO-HAND Trial


The Group Medical Director for Neuroscience at Genentech discussed the ORATORIO trial findings, as well as what the upcoming ORATORIO-HAND trial will evaluate.

Dr Peter Chin

Peter Chin, MD, MSHS

In recent years, the advancement of therapeutics for multiple sclerosis (MS) has moved forward to the point that treatments for more progressive forms of the disease have begun to surface and show promise. Additionally, clinical trials have begun to read out results for treatments in progressive MS, with one of the more impressive candidates being the only approved treatment for progressive MS, ocrelizumab (Ocrevus, Genentech).

One of the trials of ocrelizumab that has shown some of the more encapsulating data was the ORATORIO trial, which suggested that ocrelizumab was capable of impacting disease progression in progressive MS. Peter Chin, MD, MSHS, the Group Medical Director for Neuroscience at Genentech, told NeurologyLive that he was particularly impressed with the therapy’s performance on the 9-hole peg test (9HPT) outcome measure, implying a treatment effect on upper extremity ability in these patients.

Now, a trial using the 9HPT as its main outcome has been planned, dubbed the ORATORIO-HAND trial (NCT03562975), in order to more fully elucidate the therapy’s impact on upper extremity movement in patients with progressive disease. It is set to begin in the first half of 2019 and will seek to enroll 1000 patients with Expanded Disability Status Scale (EDSS) scores between 3 and 8.

To further discuss the ORATORIO trial’s findings, as well as what the upcoming ORATORIO-HAND trial will seek to discover, Chin spoke with NeurologyLive in an interview.

What are the key takeaways for the clinician community from the ORATORIO study?

Peter Chin, MD, MSHS: ORATORIO is the first positive phase 3 trial in patients with primary progressive MS (PPMS). This is a less common form of MS that is relentless and debilitating, and up until very recently, there have been no approved therapies for PPMS.

Ocrelizumab represents the first and only therapy approved in both relapsing and primary progressive forms of MS. That’s an important milestone that the field of MS has sort of crossed over in the last year and a half. Now, the main results of ORATORIO were published at the beginning of 2017 in the New England Journal of Medicine, and these are all the sort of pre-specified end points from the protocol. The main end point was showing a 24% reduction in time to confirmed disability progression (CDP), confirmed after 3 months. That’s measured by the standard disability measure, if you will, and that’s the EDSS, or the expanded disability scale.

The most recent data that had been published are data showing that, from the same study, ocrelizumab reduces the progression of upward extremity impairment or arm function in patients with PPMS. This is a really important set of data because arm function in patients with progressive MS, or advanced MS—it becomes really critical, particularly for people who have other disability from their MS. Many patients with PPMS have impaired ambulation, or impaired walking, and preserving arm function becomes really critical for maintaining independence and quality of life in the more advanced phases of the disease. So, these data that show that ocrelizumab can slow the progression are very meaningful.

What does this add to what’s already known about ocrelizumab, and in the context of the upcoming ORATORIO-HAND study?

These analyses that have just been published related to arm function or upper extremity function and the outcome measure—or the end point that was used—was a 20% worsening in 9HPT. The 9HPT is a standard clinical outcome in MS clinical trials where a patient has to use 1 hand to place pegs into a block that has 9 holes, and then remove them again as quickly as possible. Then, that whole thing gets timed. The time is what we measure, and in the ORATORIO study, these analyses looked at the proportion of patients that were progressing on placebo versus ocrelizumab.

The time to progression was the formal analysis, and what it showed was that of the patients with PPMS in the ORATORIO study, those that were treated with ocrelizumab had less progression on this test of arm function on this than patients on placebo. That’s already an important finding, to show that you can delay the progression or the worsening of arm function. There were a number of analyses that were presented in this particular paper that were looking at patients who had lower disability scores and higher disability scores and patients who showed upward extremity impairment when they entered the study versus those who were functioning with normal times when they entered the study. Long story short, across these different sub-groups within the study, ocrelizumab showed evidence of treatment effects, and that’s the analysis from the study that’s already been completed. There’s a lot of data in that paper.

How that relates to ORATORIO-HAND—it relates in 2 ways. No. 1, the findings from the original ORATORIO study are important, because they show that you can actually have a treatment effect on arm function—in other words, delay the worsening of arm function—which is really important for preserving independence and quality of life and the ability to do day-to-day activities that use the abilities of your arms and hands. The second implication of this data is that we learn a lot about how the 9HPT end point performs as an outcome measure. In other words, we learned a lot about how to actually do studies using the 9HPT as a clinical outcome.

In this paper, there were all kinds of different analyses looking at different thresholds of worsening and the 20% to 30%, so there are a lot of numbers in there. The relevance of all that is that the data help the community understand how best to measure arm function and how best to implement this outcome measure as an end point in future clinical studies. It’s particularly important in PPMS because the traditional measures, especially in the more advanced stages of disease, rely heavily on walking. That’s something you can’t really measure in patients who have severe ambulatory impairment.

From an innovation and clinical trial standpoint, the relevance in these data also enabled the field to better study PPMS in the future. The first example of that is the ORATORIO-HAND study. This is a study that will investigate the efficacy and safety of ocrelizumab in patients with PPMS—including patients that have a higher disability score, patients who are non-ambulatory, patients who are using a wheelchair—where you can’t measure how well someone walks as a clinical trial outcome. That’s a significant innovation in the field. It’s also going to address major questions that are really important, clinically, about whether or not intervening with ocrelizumab will slow the progression of disease in patients who are even more advanced then the patients who have been studied to date. This is the first phase 3 trial using 9HPT as a primary end point and it unlocks the field’s potential to study patients that we couldn’t really study before using traditional methods.

Were any of the findings surprising or unexpected in any way?

Nothing particularly surprising. The first thing I’d say is the magnitude of the effect is important. When we look at the overall result, the first analysis that was reported is the time to confirmed progression, defined as a 20% or more increase in 9HPT time, and the magnitude of the effect is substantial.

There are 2 different end points that we looked at—time to CDP and 24-week progression—and they’re very similar end points. But the main result shows that a 44% to 45% reduction on those 2 end points in the risk of progressing on this upward extremity end point. That’s a pretty substantial treatment effect over the course of a couple of years, and it’s very meaningful. The 20% change is sort of what’s commonly accepted in the field as a clinically meaningful change, and so inherent to the end point is the clinical meaningfulness, and then the magnitude of the reduction and risk is rather substantial, so that stands out to me.

The other thing that stands out to me is the various subgroups analyses. The consistency of the effect is pretty clear when you look at the results presented. The authors looked at a lot of different outcomes in different ways, and they all suggest, very consistently, that there is evidence of a treatment effect. Whether you’re looking at the hand that has better performance versus the hand that has worse performance, they all show evidence of a treatment benefit. Same with some of the subgroup data that I alluded to earlier.

Patients with a baseline EDSS less than 6—those are folks that are still able to walk without assistance, without a cane—they showed benefits. But, so did also the patients who had an EDSS greater than or equal to 6—these are folks who have impaired ambulation and require the assistance of 1 or 2 canes to walk.

At a high level, the consistency of the effect across the subgroups and whichever way you look at it, the results still suggest ocrelizumab has the slowest progression. The 3 takeaways for me are No. 1, the magnitude of the effect in slowing worsening of arm function. No. 2, the consistency across these different subgroups that are presented, and then No. 3, the consistency of the treatment effect, no matter the perspective of how you define worsening based on all these different analytical methods, those are all very powerful results, from my perspective.


Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376:209-220. doi: 10.1056/NEJMoa1606468

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