Biotech Values

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For MS, Merck's trial might be the first of many trials incorporating cancer drugs.

Phase 2 Study

At the meeting here, Dr. Hauser presented results of a randomized, double-blind, placebo-controlled 48-week trial conducted at 38 sites in North America. The phase 2 trial randomized 104 patients with relatively early RRMS in a 2:1 fashion to receive either 1000 mg of intravenous rituximab or placebo on study days 1 and 15.

Eligible patients had experienced at least 1 relapse in the year prior to enrollment. There was 1 baseline imbalance, Dr. Hauser noted, in that the rituximab group had more gadolinium-enhancing lesions than the placebo group.

The primary end point was the total cumulative number of gadolinium-enhancing T1 lesions seen on 4 brain MRI scans at weeks 12, 16, 20, and 24. There was a data lock as of June 2006, so full 48-week follow-up data were not yet available for this presentation.

"The study met its primary end point, achieving a significant decline in the number of gadolinium-enhancing lesions cumulatively found at the 12-, 16-, 20-, and 24-week scans," Dr. Hauser said. All subgroup analyses showed treatment effects that were "quite robust" favoring rituximab, and the effect size appeared larger in patients under 40 years.

This result can also be expressed as a statistically significant 91% relative reduction in the total cumulative mean number of gadolinium-enhancing lesions per patient, he noted.

Total Cumulative Mean Gadolinium-Enhancing Lesion Count per Patient at Weeks 12, 16, 20, 24
End Point Placebo, n=35 Rituximab, n=69 P
Mean + SD 5.5 + 15.0 0.5 + 2.0 < .0001


Secondary end points, including the total number of new MS lesions at any time and total amount of MS disease — that is, both old and new lesions combined — were also statistically significantly improved in the treated group.

The proportion of patients with clinical relapses during 24 weeks, another secondary end point, was also significantly reduced, by 58%, with rituximab treatment. "All of these data were quite robust," he noted.

Proportion of Patients With Relapses During 24-Week Follow-up
End Point Placebo, n=35 Rituximab, n=69 P
Proportion of patients with relapses, n (%) 12 (34.3) 10 (14.5) .0238


Rituximab was generally well tolerated, Dr. Hauser said; with the exception of infusion-associated events, the rates of adverse and serious adverse events were comparable between groups. There were 2 grade-4 disabling adverse events in the rituximab group, but these were considered unrelated to the infusion: 1 myocardial infarction and 1 thyroid neoplasm. Infection-associated adverse events were moderate and also comparable; serious infections were not seen preferentially in the rituximab group, he added.

There were also analyses done to see whether rituximab, which is part murine and part human antibody, caused the development of human antichimeric antibodies (HACA). At week 24, they were not able to measure HACA in any of the treated patients, but in the group that had reached week 48 at the data cutoff in June 2006, they had access to 21 serum samples, one third of which were HACA-positive.

"It is possible that this difference could relate to the blocking effect of rituximab on our ability to measure these antibodies by ELISA [enzyme-linked immunosorbent assay]," he said. "Importantly, there was no clear relationship between HACA positivity and efficacy or safety, although clearly longer analyses will be required."

Dr. Hauser noted that it has not yet been decided whether a phase 3 trial will proceed with this chimeric antibody or if they will use a fully human antibody being developed by Genentech, currently called 2H7. Another large phase 2/3 trial is ongoing using rituximab in primary progressive MS, with results expected early next year.