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Biomarin’s Vimizim: FDA Panel Says Yes to Morquio A


By Randy Osborne
Staff Writer

As expected, Biomarin Pharmaceutical Inc.’s Vimizim (elosulfase alfa), an enzyme replacement therapy for mucopolysaccharidosis (MPS) Type IVA, also called Morquio A syndrome, sailed through an FDA advisory panel with positive voting.

The Endocrinologic and Metabolic Drugs Advisory Committee posed three questions for panelist balloting. Number one asked whether or not “the totality of clinical data support the effectiveness of Vimizim” for Morquio A, with three possible answers: “A. Yes, the data support effectiveness; B. Yes, however, the data only support effectiveness in a subgroup of [Morquio A] patients with worse baseline walking abilities; C. No, the data do not support effectiveness.”

Twelve panelists voted “A” and eight voted “B,” though one mistakenly voted “B” and had intended to vote “A.” One panelist, David Cooke, clinical director of pediatric endocrinology at Johns Hopkins University School of Medicine in Baltimore, voted “C.”

Cooke said he “did that because I’m bothered by that convergence of effect at the endpoint of the extension study of all the treatment arms, such that there was no difference in treatment whether it was 24 weeks or 72 weeks. A lot of that appears to be driven by the placebo effects seen in the initial 24 weeks. It’s unexplained, given the expected decline in function within this group, but nonetheless, that does bother me in terms of being confident of evidence of efficacy.”

Even so, Cooke said he was “very suspicious that there really is a treatment effect here. I would just like to see a little bit more, and I would say something like the change in tissue accumulation of the MPS’s would really strengthen efficacy of this medication over the long term, but given the data that we have now, I don’t see that efficacy.”

Question number two asked whether the Vimizim data raised safety concerns. Sixteen panelists voted no and five yes. The third question asked whether Vimizim should be approved, and if so, whether the label should be limited to a subset. Voting came out 18 yes, two yes for a subset, and one voted no.

The panel exhaustively discussed the six-minute walk test (6MWT) as a trial endpoint used by San Rafael, Calif.-based Biomarin, which stopped trading of its stock (NASDAQ:BMRN) Tuesday as the meeting was in session.

Correlating 6MWT improvements into clinically meaningful benefit turned out to be a tricky matter, in the view of panelists and of the FDA, which anyway called the degree of benefit in the 6MWT as “modest” on Vimizim.

The matter emerged as more important early in the meeting, given that no statistically significant effect was observed in the secondary endpoint, three-minute stair climb, to support the 6MWT.

Another question that arose involved whether blinding the study in the lysosomal storage disorder was compromised by injection-related reactions such as anaphylaxis, which turned up more often in the treatment arms of the study. But no clear connection was found between those reactions and 6MWT improvements, according to data provided by Biomarin.

The development of neutralizing antibodies came up, as some panelists wondered if the plateau of the 6MWT at week 36 could have been traced to that cause. Data came to the rescue there, too, as the company showed hardly any proven relation between antibodies and the 6MWT, using the urine biomarker keratan sulfate (KS), though Biomarin said it needed to do follow-up work.

Morquio A is characterized by excessive storage of KS and can lead to systemic skeletal dysplasia, short stature and joint abnormalities. No specific therapy for the condition exists, but spinal fusion may prevent permanent spinal cord injury in persons whose neck bones fail to grow properly.

Positive Phase III data with Vimizim, then known as N-acetylgalactosamine-6 sulfatase, were disclosed about a year ago. Data from the pivotal trial called MOR-004, which enrolled 176 patients, showed that the compound given at 2 mg/kg once weekly hit the primary endpoint, demonstrating statistically significant improvement over placebo in 6MWT over 24 weeks. Patients in the once-weekly treatment group had a mean increase of 22.5 meters, for a “p” value of 0.0174. (See BioWorld Today, Nov. 6, 2012.)

Panelist John Loeser, professor of neurological surgery at the University of Washington in Seattle, said “the overwhelming evidence we have seen today says this drug should be approved.”

William Gahl, clinical director of the National Human Genome Research Institute in Bethesda, Md., said “the evidence supported effectiveness only in a subgroup, but I believe that approval should be for all. Why is that? It’s because we don’t really know who among these individuals will respond – I don’t think that was absolutely delineated very well – and I think that if we approve for all, we’re going to find that out.”

The FDA is not bound to the advisory committee’s recommendation, though it generally follows suit. Vimizim’s PDUFA date is Feb. 28, 2014.