FDA cleared BioMarin Pharmaceutical Inc.’s Morquio A syndrome treatment Vimizim (elosulfase alfa) Feb. 14 with a broad label that places no limits on the enzyme replacement therapy’s use either by baseline disease severity or age – despite agency questions about efficacy in patients with better mobility and a lack of efficacy and safety data in very young children.

Two weeks ahead of its Feb. 28 PDUFA deadline, FDA approved Vimizim, a hydrolytic lysosomal glycosaminoglycan-specific enzyme, as for the first treatment indicated for patients with Morquio A syndrome, also known as Mucopolysaccharidosis type IVA (MPS IVA).

The average annual cost for Vimizim therapy is expected to be approximately $380,000 for a typical patient.

MPS IVA is thought to affect up to 800 people in the U.S. As with other treatments for very rare diseases, Vimizim will carry a premium price tag.

The drug is to be given once weekly as an intravenous infusion over a minimum of 3.5 to 4.5 hours. During a Feb. 18 conference call, BioMarin Chief Commercial Officer Jeff Ajer said the list price per vial is $1,068. A typical patient weighing 22.5 kg will require nine vials per weekly infusion, bringing the average annual cost of therapy to approximately $380,000, which is “consistent with the other enzyme replacement therapies to treat ultra rare disorders,” Ajer said.

BioMarin has identified approximately 1,500 MPS IVA patients globally, about 15% of whom are in the U.S., Ajer said. Product is available to ship to hospitals immediately.

Patient Subgroups A Non-Issue In Labeling

MPS IVA is an autosomal recessive lysosomal storage disease caused by a deficiency in N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Missing or insufficient enzyme activity results in impaired catabolism of glycosaminoglycans (GAGs), and accumulation of GAGs in multiple organs and tissues leads to significant morbidities and multisystem clinical impairments. Patients experience progressive skeletal dysplasia, valvular heart disease, reduced respiratory function and eye problems, among other issues. Elosulfase alfa is intended to provide the GALNS enzyme that is taken up into the lysosomes, increasing catabolism of GAGs.

Although FDA staff raised concerns about Vimizim’s efficacy, the therapy was favorably received by the agency’s Endocrinologic and Metabolic Drugs Advisory Committee at a Nov. 19 meeting.

Agency reviewers had questioned whether the lone pivotal study’s primary endpoint – the six-minute walk test – was adequate to evaluate treatment benefit in MPS IVA patients. They also wondered whether the 22.5-meter benefit seen with elosulfase alfa was clinically meaningful, particularly since a secondary endpoint, the three-minute stair climb test, did not demonstrate a similar efficacy advantage Also see "Efficacy Endpoint For BioMarin’s Vimizim Faces FDA Panel Scrutiny" - Pink Sheet, 15 November, 2013..

An FDA exploratory analysis suggested that patients who walked shorter distances at baseline – and were thus more physically impaired – showed greater improvement than those who were able to walk longer distances before the trial began. As a result, FDA asked the committee to consider whether approval would be appropriate for all patients or only a subgroup of patients.

Eighteen of 21 advisory committee members voted for approval for all MPS IVA patients, while two panelists favored approval in only a subgroup of patients based upon FDA’s exploratory analysis of baseline disease severity. In a separate, earlier vote, 12 committee members said effectiveness had been shown in all patients, while eight said data supported effectiveness only in a subgroup Also see "FDA Panel Backs Efficacy Of BioMarin’s Rare Disease Drug Vimizim" - Pink Sheet, 20 November, 2013..

One committee member said labeling should reflect that efficacy was not as good in those patients who were able to walk more than 200 meters at baseline. However, the Clinical Studies section of Vimizim labeling makes no mention of the greater efficacy seen with more severe disease at baseline, and the Indication statement merely says that Vimizim is approved for patients with MPS IVA.

“We are very pleased to receive the broadest possible label,” BioMarin Chief Medical Officer Henry Fuchs said on the call.

The indication also does not distinguish by age even though the pivotal trial enrolled patients ages 5 to 57 years old. The Pediatric Use section of labeling states that safety and effectiveness in patients younger than five years old have not been established.

BioMarin is conducting a Phase II study in MPS IVA patients younger than age five; the study was due to complete in January, according to ClinicalTrials.gov.

The company does not believe the absence of safety and efficacy data in patients under five years old will be a hurdle to use and reimbursement in this subpopulation.

“I don’t anticipate a barrier with zero to four year olds and, shortly, we’ll have the data to fully address that,” BioMarin’s Ajer said, noting that the pediatric trial will conclude shortly.

“The general expectation on the part of our geneticist prescribers is that enzyme replacement therapies work best when patients are treated earlier, so there is a natural tendency to want to treat as early as possible,” Ajer said. “That said, it will be helpful to have clinical trial experience demonstrating the relative safety and effectiveness in zero to four year olds.”

Post-Marketing Registry

Completion of the pediatric trial and an extension study of the pivotal trial are among BioMarin’s post-marketing study plans for Vimizim.

In addition, “BioMarin has agreed to conduct a post-approval registry in order to further understand Vimizim’s long-term safety and effectiveness,” Fuchs said. “Investigators will follow patients for a period of 10 years. This registry is voluntary, but patients who are treated with Vimizim in the commercial setting will be encouraged to participate.”

Fuchs pointed to the company’s experience with a similar long-term registry for its MPS VI treatment Naglazyme (galsufase), which was approved in 2005.

“Data from the Naglazyme registry combined with that from our clinical trial program have provided important efficacy and safety information on the effects of long-term treatment with Naglazyme in MPS VI patients,” he said, noting that improved growth outcomes have been associated with longer treatment with the enzyme replacement therapy.

He said the company also has agreed to evaluate immunogenicity and the potential to modify outcomes of immune responses with Vimizim. In its briefing document for the advisory committee meeting, FDA raised concerns about the high percentage of Vimizim-treated patients who developed neutralizing antibodies and suggested further studies were needed on the relationship between antibody development, therapeutic response and occurrence of anaphylaxis or other hypersensitivity reactions.

Vimizim labeling includes a boxed warning about the potential for life-threatening anaphylactic reactions and the need to closely observe patients during and after infusion and to be prepared to manage anaphylaxis. Pretreatment with antihistamines, with or without antipyretics, is recommended prior to the start of infusion.

The approval makes BioMarin the first recipient of a rare pediatric disease priority review voucher pursuant to an incentive program created by the FDA Safety and Innovation Act of 2012. As with the tropical disease priority review voucher program created through the FDA Amendments Act of 2007, the voucher may be redeemed for priority review of a future application that would not otherwise qualify for the shorter regulatory timeline, or it may be transferred or sold to another sponsor.

With FDA approval now in its pocket, BioMarin is turning its regulatory sites to Europe, where EMEA’s Committee for Medicinal Products for Human Use could make an approval recommendation for elosulfase alfa this week.

BioMarin’s Vimizim Secures Broad Label In Morquio A Syndrome

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