Treating primary progressive multiple sclerosis patients with Ocrevus (ocrelizumab) led to a three-fold increase in the proportion of those showing no evidence of disease progression and no signs of inflammatory disease activity over more than two years of treatment, results of a Phase 3 trial show, and support new measures that might better capture disability in PPMS patients.
The research, “Evaluation of No Evidence of Progression or Active Disease (NEPAD) in Patients With Primary Progressive Multiple Sclerosis in the ORATORIO Trial,” was published in the journal Annals of Neurology.
Measuring disease progression in clinical trials and clinical practice requires reliable and comprehensible measures. Although widely used, the Expanded Disability Status Scale (EDSS, range 0-10) cannot fully capture changes in walking speed and hand or arm function, which are key determinants of overall disability in progressive forms of MS.
No evidence of progression (NEP) is a newer measure that reflects the absence of disability progression, including upper limb function and walking speed.
Maintaining NEP status means stable disease with no worsening in EDSS, in walking ability (assessed by the Timed 25-Foot Walk (T25FW) test, or the time it takes to walk 25 feet as quickly and safely as possible), and in upper limb function (assessed by the 9-Hole Peg Test (9HPT), a test of arm and hand dexterity).
Patients with PPMS have less frequent signs of disease activity, which include relapses and brain lesions (assessed though magnetic resonance imaging or MRI).
So scientists proposed a new measure — called “no evidence of progression or active disease” (NEPAD) — to evaluate both NEP and clinical and MRI measures of active disease. The researchers believe that NEPAD may represent a more sensitive and comprehensive measure of disease control in PPMS patients.
The randomized, double-blind ORATORIO Phase 3 trial (NCT01194570) analyzed the efficacy and safety of Ocrevus — developed by Genentech, part of the Roche group — in 732 PPMS patients (age range 18–55).
Results showed that Ocrevus treatment delayed the relative risk of disability progression by 25% compared to placebo, while also reducing the volume of chronic brain lesions and total brain volume loss. As a result, Ocrevus became the first therapy approved by the U.S. Food and Drug Administration and the European Commission for both PPMS and relapsing MS.
Now, researchers assessed Ocrevus’ effect in PPMS patients included in the Roche-funded ORATORIO study using as trial goals changes in NEP and NEPAD.
These people received either 600 mg of Ocrevus or placebo by intravenous (IV) infusion every six months for a minimum of 120 weeks (about 2.3 years). The trial’s main goal was time to onset of clinical disability progression (CDP) sustained for at least 12 weeks. CDP was defined as a 1.0 point or greater increase in EDSS score from a baseline (study start) score of 5.5 or less, or a 0.5-point increase from a baseline score greater than 5.5.
NEP status, analyzed in 230 placebo- and 461 Ocrevus-treated patients, was defined as no evidence of CDP for 12 weeks, no 20% or more change in hand/arm function as measured by the 9HPT for 12 weeks, and no 20% or more change in walking ability as measured by the T25FW test for 12 weeks. “The 20% cut-off for progression on the T25FW test and the 9HPT has previously been shown to be a clinically meaningful magnitude of disease progression,” the study noted.
In turn, NEPAD — assessed in 234 placebo- and 465 Ocrevus-treated patients — included NEP, no brain MRI-measured disease activity, and no relapses. Relapses were defined as new or worsening neurological symptoms attributable to MS lasting longer than 24 hours and preceded by neurological stability for a minimum of 30 days.
Brain MRI scans were conducted at baseline, and weeks 24, 48, and 120; new or enlarging T2 lesions and/or T1 enhancing lesions were considered evidence of MRI disease activity (T1 MRI imaging offers information about current disease activity by highlighting areas of active inflammation, while a T2 MRI image provides information about disease burden or lesion load).
Overall, the majority of the PPMS patients analyzed experienced clinical disease progression or evidence of disease activity.
From baseline to week 120, Ocrevus-treated patients who achieved NEP (42.7% of 461 people) or NEPAD (29.9% of 465) — no disease activity or progression — were found to have lower T2 brain lesion volume and a lower EDSS score (lesser disability) compared to those with evidence of MS progression. They also had a slightly superior performance on the 9HPT and the T25FW test.
Patients who reached NEPAD also showed fewer T1 lesions than patients with progressing or active disease.
Compared to placebo treatment, the proportion of Ocrevus-treated PPMS patients maintaining NEP or NEPAD from baseline to week 120 was higher — for NEP, 42.7% versus 29.1% in the placebo group; for NEPAD, 29.9% versus 9.4% in the placebo group.
These results showed that Ocrevus treatment increased the proportion of PPMS patients with NEPAD throughout the 120 weeks of the study by three-fold.
“In conclusion, ocrelizumab (Ocrevus) increased the proportion of patients with PPMS with no evidence of progression and no clinical and subclinical disease activity compared with placebo,” the team wrote. “As such, NEPAD may represent a meaningful and comprehensive disease outcome in patients with PPMS.”
However, data from ORATORIO’s open-label extension and real-world data are needed to “determine whether NEPAD maintained throughout 120 weeks will translate into sustained NEPAD and enhanced protection against accrual of disability in patients with PPMS over the long term,” the researchers concluded.
Of note, five of the study’s 11 authors are employees and/or shareholders of Roche or Genentech.