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Although the FDA has delayed making a final decision on ocrelizumab for multiple sclerosis (MS), full findings from three randomized controlled trials of the drug have been published -- and the results are in line with what has been previously reported at several meetings, researchers said.

In the ORATORIO study, progressive MS patients were 24% less likely to have 12-week confirmed disability progression (CDP) if they were on the drug rather than on placebo (HR 0.76, 95% CI 0.59 to 0.98, P=0.03), according to , director of the Multiple Sclerosis Research Group at the University of Texas Health Science Center at Houston, and colleagues.

In the OPERA I and OPERA II trials, patients with relapsing multiple sclerosis had 46% and 47% lower annualized relapse rates, respectively, than those on interferon, according to , of the University of Basel in Switzerland, and colleagues.

But the trials, , also reported additional details about neoplasms. As of June 30, 2016, the overall incidence rate of first neoplasm among patients treated with ocrelizumab across all studies was 0.40 per 100 patient-years of exposure, compared with 0.20 per 100 patient-years in pooled comparator groups.

These findings "warrant ongoing evaluation in the context of the epidemiology of neoplasms in the population of patients with MS and long-term experience with ocrelizumab and other anti-CD20 treatments," the researchers wrote.

In a press release about the changed Food and Drug Administration Prescription Drug User Fee Act date, Genentech was quick to note that the delay was not due to safety or efficacy concerns -- rather, it had to do with manufacturing processes, the company said.

The researchers noted that the findings suggest a role for B-cell targeting therapies in MS, and while most immunologic therapies in the condition focus on T cells, these results suggest that B cells also play a role in the condition.

Ocrelizumab in Progressive Disease

The ORATORIO study enrolled 732 patients randomized to either 600 mg ocrelizumab every 24 weeks or to placebo for at least 120 weeks.

In addition to better results for the primary endpoint of 12-week disability progression (32.9% versus 39.3%), those on ocrelizumab also had better 24-week CDP (29.6% versus 35.7%; HR 0.75, 95% CI 0.58 to 0.98, P=0.04), Wolinsky and colleagues reported.

By the end of the study, performance on the timed 25-foot walk test (T25FW) worsened by 38.9% with ocrelizumab compared with 55.1% for placebo (P=0.04).

The total volume of brain lesions on T₂-weighted MRI fell 3.4% with ocrelizumab, but rose by 7.4% with placebo (P<0.001), and the percentage of brain volume loss was lower with the drug (0.90% versus 1.09%, P=0.02), the researchers reported.

However, there was no significant difference in terms of changes on the Physical Component Summary score of the 36-Item Short-Form Health Survey.

Some adverse events occurred more frequently in the ocrelizumab group, including infusion-related reactions (39.9% versus 25.5%), upper respiratory tract infections (10.9% versus 5.9%), and oral herpes infections (2.3% versus 0.4%).

Serious adverse events occurred at similar rates (20.4% for ocrelizumab and 22.2% for placebo), but there were more neoplasms in the drug group (2.3% versus 0.8%), and more deaths occurred in the ocrelizumab group (0.8% versus 0.4%).

Among those on ocrelizumab, the four deaths were due to pulmonary embolism, pneumonia, pancreatic carcinoma, and aspiration pneumonia. The one death in the placebo group was due to a road traffic accident.

Wolinsky and colleagues concluded that there is a need for an extended observation period to determine the long-term safety and efficacy of ocrelizumab.

Relapsing Disease

OPERA I enrolled 821 patients and OPERA II enrolled 835 patients with relapsing MS. They were randomized to 600 mg of ocrelizumab every 24 weeks, or to 44 mcg of interferon beta-1a three times a week, for a total of 96 weeks.

In both studies, patients on ocrelizumab had lower annualized relapse rates than those on interferon (0.16 versus 0.29, 46% lower rate, P<0.001; and 0.16 versus 0.29, 47% lower rate, P<0.001).

In prespecified pooled analyses, the percentage of patients with 12-week confirmed disability progression was significantly lower with ocrelizumab (9.1% versus 13.6%; HR 0.60, 95% CI 0.45 to 0.81, P<0.001), and the same was seen for 24-week CDP (6.9% versus 10.5%, HR 0.60, 95% CI 0.43 to 0.84, P=0.003).

The mean number of gadolinium-enhancing lesions per T₁-weighted MRI was lower with ocrelizumab in both trials (0.02 versus 0.29 and 0.02 versus 0.42), they reported.

The change in MS functional composite score favored ocrelizumab in one trial, but not in the other.

In terms of adverse events, serious infections occurred in fewer ocrelizumab patients (1.3% versus 2.9%), but more herpesvirus infection was seen with the investigational drug (5.9% versus 3.4%).

And again, there were more neoplasms with ocrelizumab (0.5% versus 0.2%). During an open-label phase of the study, five additional cases of neoplasm occurred: two breast cancers, two basal-cell skin carcinomas, and one malignant melanoma.

The researchers similarly concluded that larger and longer safety studies are needed.

In an accompanying editorial, , director of the Division of Neuroimmunology at Johns Hopkins Hospital in Baltimore, praised ocrelizumab for being "the first drug to show a significant effect in slowing disability progression in a phase III trial in primary progressive multiple sclerosis, and that the trial therefore represents a landmark study in the field."

Calabresi said the mechanisms by which B-cell depletion achieves these effects is not fully understood, but may be multi-functional, given that B cells have important roles in antibody secretion, antigen presentation, and the release of effector cytokines.

However, one possible explanation for the positive effects of ocrelizumab in ORATORIO is that the patient population was younger (mean age of 45), and had more active MRI scans (more than 25% had gadolinium-enhancing lesions) -- "allowing for a measurable anti-inflammatory effect in those who had some inflammation and an early reversible stage of the disease," he said.

Indeed, the OLYMPUS trial of rituximab, also an anti-CD20 B-cell targeting therapy, in progressive disease did not meet its primary efficacy endpoint, but a subgroup analysis showed delayed progression of disability in younger patients (age 50 and under) who had evidence of increased inflammatory disease activity.

Still, Calabresi said the continued separation of disability progression curves beyond 52 weeks, "when anti-inflammatory effects have been maximized, and the success in the relatively non-inflammatory disorder of primary progressive MS suggest that additional mechanisms of action may be operational, and further study is warranted."

He warned that immune suppression could render patients susceptible to infections, as well as impaired immune surveillance of new cancer cells, which can increase the risk of neoplasms.

Although progressive multifocal leukoencephalopathy has not yet been seen with B-cell depletion in MS, there does appear to be a "higher than normal risk of herpes reactivation and of neoplasms, especially breast cancer," he wrote, adding that these effects will need to be studied in future trials and in phase 4 monitoring to better understand the extent of the risk.

"Clinicians are urged to carefully consider which patients might benefit the most from ocrelizumab and to stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early," he concluded.