Ocrelizumab gets first-ever FDA approval for primary progressive MS


The humanized monoclonal antibody ocrelizumab became the first drug to receive approval from the Food and Drug Administration for the treatment of primary progressive multiple sclerosis in adults, according to a March 29 announcement from the agency that also said it is approved for relapsing-remitting disease in adults.

The drug has a mechanism of action similar to rituximab (Rituxan) through its selective targeting of CD20-positive B cells, which depletes them from circulation. CD20-positive B cells are thought to be a key contributor to myelin and axonal damage.

Dr. Fred Lublin

Dr. Fred Lublin

Ocrelizumab will be marketed under the brand name Ocrevus and is expected to be available to people in the United States within 2 weeks, according to an announcement from its manufacturer, Genentech. The first dose is given as two 300-mg infusions administered 2 weeks apart. Subsequent doses are given as single 600-mg infusions. The biologic was granted breakthrough-therapy, fast-track status by the FDA because of its promising results in the phase III ORATORIO trial for primary progressive MS.

Although the effect of ocrelizumab on primary progressive MS patients was modest, its stature as the only drug approved for the indication represents “a start for being able to treat progressive MS,” Fred Lublin, MD, a member of the steering committee that designed and monitored the phase III ocrelizumab trials, said in an interview.

In the ORATORIO trial that randomized 732 patients with primary progressive MS in a 2:1 ratio to infusions of either 600 mg ocrelizumab or placebo every 24 weeks for 120 weeks, ocrelizumab reduced the risk of progression in clinical disability by 24% at 12 weeks (the primary end point), 25% at 24 weeks, and 24% at 120 weeks, compared with placebo (N Engl J Med. 2017 Jan 19;376[3]:209-20).

Over 120 weeks, the antibody also reduced the volume of hyperintense T2 lesions by 3.4%, whereas patients taking placebo experienced a 7.4% increase. The rate of whole brain volume loss was also significantly reduced from week 24 to 120 (–0.9% with ocrelizumab vs. –1.1% for placebo).

The group of patients who participated in ORATORIO was younger and had more activity on MRI, but it’s unclear if there is a progressive MS patient population who will respond best to the biologic, said Dr. Lublin, director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Hospital in New York.

Ocrelizumab joins a growing list of available drugs for treating relapsing-remitting MS, “but I think it will be a popular one because the efficacy was exceptionally good,” especially when considering that it was compared against high-dose interferon, Dr. Lublin said.

“The safety was acceptable, and so I think it will get a lot of use. There are always some who like to wait until a drug has been out for a while, but there is considerable experience with this type of drug based on off-label use of rituximab” in relapsing-remitting patients, including phase II trial data (but not phase III), he said. There’s potential for ocrelizumab to be used as a first-line treatment for relapsing-remitting disease to the same extent as natalizumab (Tysabri), he added.

In two identical phase III trials, OPERA I and OPERA II, investigators randomized 1,656 relapsing-remitting MS patients to intravenous ocrelizumab 600 mg every 24 weeks plus placebo subcutaneous injections three times weekly or to subcutaneous interferon beta-1a 44 mcg (Rebif) three times weekly plus placebo IV infusions every 24 weeks over 96 weeks (N Engl J Med. 2017 Jan 19;376[3]:221-34).

Compared with interferon beta-1a, ocrelizumab reduced the annualized relapse rate by 46% in OPERA 1 and 47% in OPERA 2. In a pooled analysis of both trials, the risk of confirmed disability progression was 40% lower for ocrelizumab at both 12 and 24 weeks. Ocrelizumab conferred a 94% and 95% reduction in the total number of T1 gadolinium-enhancing lesions and a 77% and 83% reduction in the total number of new and/or enlarging hyperintense T2 lesions. An exploratory analysis also suggested that the drug reduced the rate of whole brain volume loss, compared with interferon beta-1a.

At 96 weeks, 47.9% and 47.5% of ocrelizumab patients versus 29.2% and 25.1% of interferon patients had no evidence of disease activity (NEDA) in the two studies. NEDA is a composite score defined as no relapses, no confirmed disability progression, and no new or enlarging T2 or gadolinium-enhancing T1 lesions.

Across both studies, relapses occurred in about 20% of ocrelizumab patients versus about 35% of interferon patients. About 10% of ocrelizumab patients had clinical disease progression, compared with about 15% of interferon patients. Similarly, about 10% of ocrelizumab patients developed new gadolinium-enhancing lesions, compared with about 35% in the interferon groups. New or enlarging T2 lesions were found in about 40% in the ocrelizumab groups but in more than 60% in the interferon arms.

Safety results at 24 weeks in the OPERA trials showed that infusion reactions were significantly more common with ocrelizumab than with interferon beta-1a (34% vs. 9.7%), and most of these were mild to moderate in severity. Otherwise, there were similar rates of serious adverse events, including serious infections.

In ORATORIO, infusion reaction occurred in 40% of ocrelizumab patients and 26% of placebo patients. Most of the reactions were mild to moderate in severity. Among all patients in ORATORIO, 13 malignancies occurred over 3 years, and they occurred more than twice as often in the ocrelizumab arm than in the placebo arm (2.3% vs. 0.8%). These included four breast cancers in the active arm and none in the placebo arm.

No cases of progressive multifocal leukoencephalopathy (PML) have been reported in association with ocrelizumab, although the risk of PML with long-term use is unknown.

The FDA said in its announcement that ocrelizumab should not be used in patients with hepatitis B infection or a history of life-threatening infusion-related reactions to the drug. Ocrelizumab is required to be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. The agency also advised that vaccination with live or live attenuated vaccines is not recommended in patients receiving the drug.

Genentech says it plans to offer patient assistance programs through Genentech Access Solutions.

Dr. Lublin reported receiving fees for serving on an advisory board from Genentech/Roche and from many other companies investigating or marketing drugs for MS.

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