FDA-Approved Medications: New Data
Company: Genentech and Roche Pharma AG
- 600 mg given via IV infusion every six months
- Approved in 2017 for RMS and PPMS
Ocrevus is an anti-CD20 monoclonal antibody. While it is similar to the medication Rituxan® (rituximab), Ocrevus has the potential advantage of being a more humanized antibody than Rituxan. Humanized monoclonal antibodies are antibodies from non-human species (such as mice) whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans.
In March 2017, Ocrevus won FDA approval for use in both RMS and PPMS. The approval was based largely on the results of three important studies announced in 2015. In relapsing MS, ocrelizumab met both the primary and major secondary endpoints in the Phase III, OPERA I and OPERA II studies. The OPERA studies had identical designs. The total combined enrollment for both studies was 1,656 individuals with relapsing forms of MS.
In the OPERA studies, individuals received either 600 mg of ocrelizumab via intravenous (IV) infusion every six months, or the approved 44 mcg dose of Rebif® (interferon beta-1a), given via subcutaneous injection three-times weekly. Participants receiving ocrelizumab had significant reductions in both studies in annualized relapse rate of 46 and 47 percent over a two-year period versus the interferon groups. Additionally, in the ocrelizumab groups, new MRI lesions were reduced by 94 and 95 percent, brain atrophy was decreased by 24 and 25 percent, and risk of progression of sustained clinical disability was decreased by 40 percent.
A further analysis of the OPERA trials’ data reported in February 2018 found that patients receiving Ocrevus fared better than those receiving interferon beta-1a on a composite measure that assessed absence of relapse, confirmed disability progression, and MRI disease activity. The endpoint is known as “no evidence of progression or active disease,” or NEPAD. The researchers found that 39.3 percent of the 740 patients who received Ocrevus had NEPAD at 96 weeks after study start, versus 21.5 percent of the 753 people receiving interferon beta-1a.6
The FDA’s approval of Ocrevus in PPMS was based in part on results from the ORATORIO study, which was published in 2015. Prior to this study, no Phase III studies in PPMS had been successful, despite multiple attempts. ORATORIO was a randomized, double-blind, and global multi-center trial that studied the effectiveness and safety of Ocrevus compared to placebo in 732 people with PPMS. Every six months, two 300 mg infusions (for a total of 600 mgs) were given two weeks apart. Members of the treatment group were compared to a placebo group. The study’s primary endpoint was time to the onset of confirmed disability progression, defined as an increase in the Expanded Disability Status Scale (EDSS) sustained for at least 12 weeks. (The EDSS scores function on a scale of 1 to 10; a higher score refers to more disability.)
The ORATORIO study met its primary endpoint, showing that ocrelizumab significantly reduced the progression of clinical disability (sustained for at least 12 weeks) by 24 percent compared with placebo. Walking speed, as measured by the timed 25-foot walk, was improved by 29 percent. MRI hyper-intense T2 lesions were actually reduced by Ocrevus, and brain-volume loss as viewed on MRI was reduced by 17.5 percent. The incidence of adverse events associated with Ocrevus was similar to placebo; the most common adverse events were mild-to-moderate infusion-related reactions.
In a post hoc set of analyses reported in February 2018, investigators found that Ocrevus reduced the risk of progression of severe upper extremity disability, a functional impairment that frequently occurs in PPMS. When patients entered the ORATORIO trial, and every 12 weeks thereafter throughout the study, participants completed a test that involves placing pegs in holes. Confirmed progression was measured by changes in the time required to perform the test. Compared to placebo, Ocrevus reduced the risk of confirmed significant progression (a 35-percent or greater increase in test time) in both hands by 49 percent at week 12 and by 41 percent at week 24. Ocrevus also reduced the risk of progression in terms of the patient’s self-identified best hand and worst hand.7
The period since the FDA’s approval of Ocrevus has also seen the first reported cases of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal brain infection, in patients taking the medication. Assessing what role, if any, Ocrevus may have played in the development of PML or other adverse events can be quite complicated, particularly when an individual had previously taken other DMTs known to be associated with risk for those events.
For example, the first person taking Ocrevus who was reported to have PML had taken Tysabri® (natalizumab) for three years prior to beginning Ocrevus. An increased risk for PML has previously been linked to Tysabri, which the FDA approved in 2004 for use in relapsing forms of MS. Also, as of December 2017, the post-marketing surveillance of Ocrevus had recorded 24 deaths among the 30,000 patients who have been treated with the medication worldwide (an additional eight people died during clinical trials that involved roughly 2,000 participants). The causes of death have been varied, and in some cases unknown, with no cancer deaths reported. While physicians, regulators, the medication’s manufacturers, and others are monitoring the post-approval efficacy and safety profile of Ocrevus, it is very difficult at this point to discern the significance, if any, of these data.
Meanwhile, in January 2018, the European Commission approved Ocrevus for use in treating both RMS and PPMS.8 Ongoing research into Ocrevus includes an open-label study of more than 600 people with RRMS, to assess the impact of the medication on these individuals who have had a suboptimal response to other DMTs.9