FDA-Approved Medications: New Data on Previously Approved Medications
Company: Genentech and Roche Pharma AG
- Starting dose: 300 mg given via IV infusion, followed two weeks later by a second 300-mg infusion
- Subsequent doses: 600 mg given via IV infusion every six months
- Approved in 2017 for RMS and PPMS
Ocrevus® (ocrelizumab) is an anti-CD20 monoclonal antibody. Humanized monoclonal antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans.
In 2017, the FDA approved Ocrevus for use in both relapsing forms of MS (RMS) and primary-progressive MS (PPMS). Approval was based largely on the results of three important studies announced in 2015. In relapsing MS, Ocrevus 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 combined enrollment for both studies was 1,656 individuals with relapsing forms of MS.
In the OPERA studies, individuals received either 600 mg of Ocrevus via intravenous (IV) infusion every six months, or the approved 44 mcg dose of Rebif ® (interferon beta-1a) via subcutaneous injection three times weekly. In both studies, participants receiving Ocrevus had reductions in annualized relapse rates (ARRs) of 46 and 47 percent over a two-year period versus the interferon groups. Additionally, in the Ocrevus treatment 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.
Recent data from an open-label extension of OPERA suggest that Ocrevus slows disease progression among patients with RMS who switched from another diseasemodifying therapy. Patients who received Ocrevus or interferon beta-1a during the OPERA trial either continued or were switched to Ocrevus at the start of the trial’s open-label extension phase. The mean ARR in the interferon-to-Ocrevus group fell from 0.20 in the year before the patients switched agents to 0.10, 0.08, and 0.07 in years 1, 2, and 3 of the open-label phase, respectively. Patients who continued Ocrevus maintained low mean ARRs throughout the latter stages of the core study and the extension phase.
Notably, the Ocrevus continuation group had a significantly lower proportion of patients with 24-week confirmed disability progression at all points of the open-label extension, suggesting that the interferon-to-Ocrevus group would have benefited from earlier Ocrevus initiation.25
Rates of T1 enhancing lesions and new or enlarging T2 lesion development were lower among the continuous Ocrevus group, compared with the interferon-to-Ocrevus group. Rates of brain atrophy likewise were significantly lower in the continuous Ocrevus group, again suggesting strong benefits of early Ocrevus initiation. Whole brain volume, cortical gray matter volume, and white matter volume were analyzed.26
Recently released data also provide new details on the ORATORIO study, which assessed the effectiveness and safety of Ocrevus in people with PPMS. Prior to this study, no Phase III studies in PPMS had been successful. ORATORIO, which was published in 2015, was a double-blind, global, multicenter trial involving 732 people with PPMS. Participants were randomized to receive either placebo or Ocrevus, which was administered every six months in two 300 mg doses given two weeks apart. The primary endpoint of the study was time to onset of confirmed disability progression, defined as an increase in EDSS sustained for at least 12 weeks.
The ORATORIO study met its primary endpoint, showing that treatment with Ocrevus significantly reduced the progression of sustained clinical disability by 24 percent compared with placebo. Walking speed, as measured by the timed 25-foot walk, was improved by 29 percent. Hyperintense T2 lesions on MRI actually were reduced among patients taking Ocrevus, and brain-volume loss as viewed on MRI was reduced by 17.5 percent. The incidence of adverse events associated with Ocrevus in ORATORIO was similar to placebo; the most common adverse events were mild-tomoderate infusion-related reactions.
New data from the ORATORIO open-label extension suggest that starting Ocrevus therapy sooner than later in the course of MS may slow disability progression. Seventy-two percent of patients who participated in the double-blind portion of the ORATORIO trial entered the study’s open-label extension phase between 156 and 240 weeks after the core trial started. Depending on which study arm they had been in during the doubleblind phase, participants were either switched to Ocrevus from placebo or continued Ocrevus through the extension phase. During the extension period, researchers assessed the prevalence of disability progression at 24 weeks by means of Expanded Disability Status Scale (EDSS) and 9-hole peg test scores.
Throughout the core trial, Ocrevus had reduced the risk of EDSS-scored disability progression by 25 percent and peg testscored disability progression by 45 percent. In the open-label extension, overall confirmed disability at 24 weeks was significantly less prevalent in the continuous Ocrevus group, compared with the placeboto-Ocrevus group.9
Researchers also recently released pooled safety data from seven Phase III trials and a Phase II trial that followed a total of 3,811 Ocrevus-treated individuals with MS. The researchers reported that per 100 patient years of use (a measurement of medication benefits and risk based on study participation) the rates of adverse events were: any adverse events, 242; serious adverse events, 7.23; infections, 74.5; serious infections, 2.00; malignancies, 0.45. They noted that those statistics are consistent with the adverse event rates reported among patients with PPMS and RRMS who have been taking Ocrevus outside of clinical trials in the time since the medication was approved for use.27