March 29, 2013

San Diego, California — Long-term follow-up of patients with multiple sclerosis (MS) in the phase 2 trial of ocrelizumab suggest that the drug continues to be effective for up to 18 months after the last dose, with no new safety concerns identified.

The latest data from the phase 2 study with the drug, a humanized monoclonal antibody targeted against CD20-expressing B cells, were presented by lead investigator Stephen Hauser, MD, here at the American Academy of Neurology (AAN) 65th Annual Meeting last week.

Results showed that patients having up to 4 treatment cycles of ocrelizumab and followed for as long as 18 months after the last dose had minimal new MRI activity and a low level of clinical disease activity. In addition, there were no new safety concerns and no reports of opportunistic infections.

"Major Blockbuster"?

Dr. Hauser commented to Medscape Medical News: "We are still seeing a remarkable suppression of disease activity a year after the last dose, with no safety signal and no serious adverse events. We are very hopeful about this agent. I think there is no question that it is going to work. If the safety profile seen in phase 2 can be extended to phase 3 and to post marketing studies, this will be a major blockbuster."

The phase 2 study randomly assigned 220 patients with relapsing-remitting MS to 1 of 4 treatment regimens. For the initial cycle patients received placebo, ocrelizumab 600 mg, ocrelizumab 2000 mg, or interferon-β. For the next 3 cycles, the placebo, ocrelizumab 600 mg, and interferon-β groups all received ocrelizumab 600 mg and the high-dose ocrelizumab group received 2 injections of ocrelizumab 1000 mg, followed by a final dose of ocrelizumab 600 mg.

Each cycle lasted 24 weeks, with ocrelizumab being given as a single injection at the start of each cycle.

Table 1. Phase 2 Study Design

Cycle Placebo/OCR Group Low-dose OCR Group High-dose OCR Group Interferon-β/OCR Group
Cycle 1: 0-24 weeks Placebo OCR 600 mg OCR 2000 mg Interferon-β
Cycle 2: 24-48 weeks OCR 600 mg OCR 600 mg OCR 1000 mg OCR 600 mg
Cycle 3: 48-72 weeks OCR 600 mg OCR 600 mg OCR 1000 mg OCR 600 mg
Cycle 4: 72-96 weeks OCR 600 mg OCR 600 mg OCR 600 mg OCR 600 mg

OCR, ocrelizumab.

Initial 24-week primary endpoint data published in The Lancet in November 2011 showed both doses of the drug significantly reduced the total number of gadolinium-enhancing lesions on MRI versus placebo. Clinical relapses were also reduced with the drug, with no apparent separation between doses, and extension data out to 48 weeks suggested sustained efficacy.

One patient died at week 4 in the high-dose ocrelizumab group after being hospitalized with systemic inflammatory response syndrome. Dr. Hauser said it was "uncertain" whether this was related to the drug.

The current report focuses on extended follow-up of the patients in this study out to 144 weeks (almost 3 years), with the last dose of the drug being given at 96 weeks.

Of 220 patients, about 90% entered the safety follow-up after 96 weeks, and 168 completed to 144 weeks, Dr. Hauser noted. He noted that the marked reduction in inflammation persisted through the 4 courses of drug therapy to 96 weeks and that no patient had a gadolinium-enhancing lesion by 96 weeks.

"Now with a longer period of follow up — up to 144 weeks — there continues to be nearly complete cessation of activity, with only 3 patients having had evidence of MRI activity," he said. "In the low-dose group (the dose being used in phase 3 trials) there has been no evidence of MRI activity 1 full year after completion of the fourth cycle."

Overall the annual relapse rate continues to be low in all 4 groups out to 144 weeks, Dr. Hauser reported.

Table 2. Adjusted Annual Relapse Rates

Week Placebo/OCR Group Low-Dose OCR Group High-Dose OCR Group Interferon-β/OCR Group
Weeks 0-24 0.557 0.127 0.213 0.364
Weeks 24-96 0.195 0.199 0.231 0.157
Weeks 96-144 (no drug given) 0.116 0.082 0.352 0.076

 

Adverse events were few in the long-term follow-up period, with 7 serious adverse events across the 4 groups.

Table 3. Adverse Events, Weeks 96 to 144

Endpoint Placebo/OCR Group Low-Dose OCR Group High-Dose OCR Group Interferon-β/OCR Group
Serious adverse events (n) Injury: 1 Salivary duct inflammation: 1

Muscle weakness: 1

Breast cancer: 1

Acute psychosis: 1

Suicidal ideation: 1

Drug-withdrawal syndrome: 1
Infections (n) 13 12 13 9

 

No serious infections occurred. "The safety overview continues to support an optimistic outlook," Dr. Hauser commented.

Phase 3 trials are now ongoing. These include the ORATORIO study in 630 patients with primary progressive MS and the OPERA I and II studies in patients with relapsing-remitting MS. All these studies have completed enrollment, with results expected in 2015.

In an interview with Medscape Medical News, Dr. Hauser said, "The current landscape for MS therapy is made up of not very effective drugs which are extremely safe and extremely effectively drugs which are not very safe. In the future we need extremely effective drugs which are also extremely safe and tolerable. Ocrelizumab looks like a very effective drug, and the safety profile is also extremely promising so far."

He added that giving the drug as an infusion once every 6 months also had adherence advantages. "It is more attractive than a twice-daily pill or a shot every other day. There is a huge problem with noncompliance in MS, especially in young people who think they are immortal."

On the mechanism of action, Dr. Hauser noted that it had been discovered that humoral immune mechanisms were involved in MS. "We found that autoantibodies were deposited on the myelin membrane. So we thought that maybe we could target the B cells. Contrary to the initial view, we found that B cells were actually central to MS. Ocrelizumab interferes with the presentation of autoantigens by B cells to T cells. The B cells are the messengers for the MS disease process."

Dr. Hauser also pointed out that ocrelizumab does not appear to cause a global suppression of immunity. "It is targeted against the CD20 molecule on the surface of B cells in the blood, so depletes the cells expressing this molecule. Other B cells do not have CD20 on their surface so are not affected by this therapy."

''Rebooting the Autoimmune Process"

And preliminary evidence suggests that when the affected B cells start to re-emerge, they are not as proinflammatory as the B cells that were present before depletion. "It may be that we are rebooting the autoimmune process, which could explain why the effect lasts for so long," Dr. Hauser suggested.

Commenting on the study for Medscape Medical News, Edward Fox, MD, director of the Multiple Sclerosis Clinic of Central Texas, Round Rock, said the results "looked good."

Dr. Fox, who is involved in clinical trials with a similar drug, alemtuzumab (Lemtrada, Genzyme/Sanofi), a monoclonal antibody that targets CD52, present on T and B cells, noted that B cells replete within 6 months, so B cell–depleting drugs might be expected to have a more temporary effect that drugs targeting both B and T cells. "But the B cell depleters are very exciting too," he added.

American Academy of Neurology (AAN) 65th Annual Meeting. Abstract S31.006. Presented March 20, 2013.

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