Conference Coverage
HILTON HEAD, SC—Managing patient expectations is important when discussing new and pending treatments for multiple sclerosis (MS), according to a lecture given at the 39th Annual Contemporary Clinical Neurology Symposium. The FDA’s recent approval of daclizumab and ongoing priority review of ocrelizumab mean that neurologists likely will be discussing these therapies with patients in their clinics. Conversations may revolve around efficacy, laboratory monitoring, and risk of adverse events.
In the case of daclizumab (Zinbryta), which was approved in May 2016, patient counseling may focus on monthly laboratory monitoring requirements that are part of the drug’s risk evaluation and mitigation strategy (REMS) program and the potential for adverse events at any time during treatment, said Harold Moses Jr, MD, Associate Professor of Neurology at Vanderbilt University in Nashville.
Harold Moses Jr, MD
Ocrelizumab (Ocrevus) could be the first drug approved for primary progressive MS and a new treatment option for patients with relapsing MS. Neurologists may need to temper patients’ expectations regarding the drug’s efficacy in patients with more advanced progressive disease.
“If this drug gets approved for progressive MS, you are going to have a number of patients coming to your clinics to ask for this drug,” he said. It is unclear, however, how beneficial the treatment might be for patients with advanced disease, based on the clinical trial conducted in primary progressive MS. “In my opinion, if someone is 65 to 70 years old and has had primary progressive MS for 15 to 20 years and has been wheelchair-confined for five or more years, it is unlikely that this drug is going to be very meaningful for them. Although, I do not know that for a fact. Therefore, my plan is to offer this [treatment], probably for approximately a year, and see what happens. We will continue to follow them and make a decision together about continuing therapy or stopping.”
“Remember, half the people in the world who have MS have progressive disease,” Dr. Moses said. “They have seen more than 20 years of therapies [approved] for relapsing MS, so they have a lot of pent-up expectations about a treatment option, and rightfully so. I just think this potential treatment has to be discussed in a broader context of how the study was done.”
Daclizumab
Daclizumab is an interleukin-2 receptor blocking humanized monoclonal antibody approved for use in relapsing forms of MS. It is self-administered as a subcutaneous injection once per month at a dose of 150 mg/mL. The drug’s label notes, “Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.” This FDA guidance is similar to that for alemtuzumab. “With more than a dozen drugs for MS, it is not too surprising we are seeing this,” Dr. Moses said.
The efficacy of the drug was demonstrated in two randomized, double-blind studies. One study compared daclizumab with interferon beta-1a. The other study compared daclizumab and placebo.
In the active comparator study, 919 patients received daclizumab and 922 received interferon beta-1a. Compared with interferon beta-1a, daclizumab had a statistically significant effect on annualized relapse rate (0.393 vs 0.216; relative reduction, 45%) and on the number of new or newly enlarging T2 hyperintense lesions. Treatment did not significantly affect 12-week confirmed disability progression.
In some patients, daclizumab has a significant impact on the liver. As a result, physicians are asked to assess transaminase levels and total bilirubin monthly during treatment and for six months after stopping therapy, Dr. Moses said.
Autoimmune hepatitis and other immune-mediated disorders, including lymphadenopathy, noninfectious colitis, and cutaneous adverse events, were seen with daclizumab treatment.
Dermatologic reactions to daclizumab can range from mild rashes to serious reactions, and can include psoriasiform nail changes, erythematous changes and swelling, and desquamation and erythema of the palms. Neurologists should advise patients that these reactions “could happen at any point while they are taking this medication,” Dr. Moses said. Some patients experienced reactions after receiving the therapy for nearly three years.Patients also experienced adverse events related to infection, including nasopharyngitis, bronchitis, and tonsillitis. “Daclizumab is the newest approved drug for relapsing MS,” Dr. Moses said. “It has a unique mechanism of action and a favorable dosing schedule. Challenges exist with monitoring requirements and potential serious adverse events.”
Ocrelizumab
Ocrelizumab is a humanized monoclonal antibody that depletes CD20+ B cells.
Two identical studies, OPERA I and II, evaluated ocrelizumab in patients with relapsing MS. Another trial, ORATORIO, assessed ocrelizumab in patients with primary progressive MS. In the trials, patients received 600 mg of ocrelizumab by IV infusion every 24 weeks.
In OPERA I and II, treatment with ocrelizumab resulted in a 46% and 47% reduction in annualized relapse rate, respectively, compared with interferon beta-1a. In addition, ocrelizumab reduced the risk of confirmed disability progression for 12 weeks by 43% and 37%, respectively. Ocrelizumab also dramatically reduced the number of T1 gadolinium-enhancing lesions and the number of new or enlarging T2 hyperintense lesions, compared with interferon beta-1a.
The ORATORIO study included 732 patients with primary progressive MS who received ocrelizumab or placebo. Patients were ages 18 to 55, had an Expanded Disability Status Scale score of 3.0 to 6.5, and had abnormal CSF. Patients were treated for at least 120 weeks. Investigators measured slowing of disability progression as the primary outcome. There was a 24% reduction in clinical disability sustained for at least 12 weeks, compared with placebo.
Ocrelizumab generally was well tolerated. In the clinical trials, a similar proportion of patients treated with ocrelizumab and controls experienced adverse events. In OPERA I and II, the most common adverse event associated with ocrelizumab was infusion-related reactions, which occurred in 34.3% of patients in the ocrelizumab arm, compared with 9.7% of patients in the interferon beta-1a arm.
In ORATORIO, more malignancies were reported in patients treated with ocrelizumab, compared with patients who received placebo (11 vs 2). The implications of that finding are unclear. “We will see how that plays out in terms of what the FDA thinks about that,” Dr. Moses said.
The FDA has granted a priority review designation to ocrelizumab, with a targeted action date of December 28, 2016. “Ocrelizumab remains on the horizon with a potential role in both relapsing and progressive MS,” Dr. Moses said.
—Jake Remaly
