A few steps stand between BioMarin Pharmaceutical Inc. and another rare disease drug approval.
The San Rafael-based drug developer (NASDAQ: BMRN) believes improvements in a six-minute walking test by young patients with a crippling and deforming genetic disease, known as MPS IVA, is enough to secure Food and Drug Administration approval of its drug. But the agency, which is bringing together a panel Tuesday to recommend a course of action, may want additional data and another measure of the drug’s effectiveness.
In the middle are patients and their families, who today must rely on pain medication and hip replacement and other surgeries as temporary respites from a potentially fatal disease. There are no approved drug therapies.
“We would like to have a cure, but we don’t have that option,” said Stephanie Bozarth, whose 7-year-old daughter Annabelle in Alexandria, Va., was one of 176 MPS IVA patients participating in a Phase III trial of BioMarin’s drug. “We have no option. This is all we’ve got.”
Bozarth will be one of a handful of parents of MPS IVA patients — along with BioMarin executives and rare disease treatment advocates — expected to address the FDA panel Tuesday. The committee’s recommendation isn’t binding, but the agency typically follows the group’s direction.
This much is sure: MPS IVA, also known as mucopolysaccharidosis Type IVA or Morquio A syndrome, is one of a nasty family of so-called lysosomal storage diseases. It is caused when both parents contribute a mutation, which occurs in one in every 200,000 to 300,000 live births, that causes a deficiency in a complicated-sounding enzyme, called N-acetylgalactosamine-6-sulfate sulfatase.
The enzyme normally clears out long chains of sugar molecules known as mucopolysaccharides, but because the enzyme is mutated and can’t do its job, those molecules accumulate.
The disease deforms bones, compresses the spine, damages heart valves, clouds vision and kills patients with the most severe form by the time they turn 30.
There are 500 to 800 patients with MPS IVA today. About one-third of patients who walk require a walking aid, and the severest cases will be wheelchair-bound by the time they are teenagers.
BioMarin’s drug, an enzyme replacement therapy called Vimizim, also known as elosulfase alfa, is infused once a week — more or less than that doesn’t appear to be effective.
In BioMarin’s late-stage trial, conducted at 31 sites in 17 countries, patients were given a six-minute walk test at the beginning and end of the 24-week study. Patients given the once-a-week formulation walked nearly 25 yards further at the end of the test.
By comparison, patients given Vimizim every other week and those given a placebo could walk little more than 1-1/2 feet further.
Before the trial, Annabelle Bozarth, who was diagnosed with MPS IVA at two months after her mother noticed a lump on her back, couldn’t walk from a parking lot into a grocery store without being exhausted and in pain. She had hip reconstruction surgery when she was 4 years old.
After six week’s in the Vimizim trial, beginning in September 2011, her parents noticed a surge in her energy. Now 7, she rides her bike, walks to the park with her younger disease-free sisters and plays for hours.
Still, Annabelle likely won’t grow taller than 3-1/2 feet tall, her mother said.
“Most kids of her severity are in wheelchairs by this point,” Stephanie Bozarth said.
Annabelle, who is in second grade, receives a fresh infusion of Vimizim into her arm during a five-hour appointment every Wednesday.
“We absolutely could be buying a lot of time for her,” Stephanie Bozarth said.
Anecdotal evidence, however, holds little sway with FDA advisory panels. Its 22 voting members will look closely at the walking test, which helped BioMarin and Genzyme win approval of Aldurazyme in 2003, which is a treatment for MPS I, and aided BioMarin when it secured approval alone in 2005 of the MPS VI treatment Naglazyme.
The key question for the panel’s member is quite basic: Is a statistically significant improvement in walking distance clinically meaningful?
There is big money at stake in the answer. Naglazyme, for example, costs more than $350,000 a year, and Vimizim at least would cross the six-figure threshold.
A Thomson Reuters survey of eight analysts estimated that it would generate annual sales of $532 million by 2018 for BioMarin, which is led by CEO Jean-Jacques Bienaimé.
Perhaps more closely, the panel also will weigh a so-called secondary endpoint of the Phase III trial: a three-minute stair-climbing exercise. Patients on either dose of Vimizim didn’t perform well, and the difference between the doses was only 1.1 stairs per minute.
What’s more, an extended study of the drug over 48 weeks did not show additional improvement by patients in the walking test. Their ability, however, seemed to stabilize and overall remained better than prior to starting therapy.
Interestingly, patients who were given the placebo in the 24-week trial but were switched to the drug in the 48-week study did not improve, but they did stabilize.
"It is not clear whether enzyme replacement therapies are able to reverse preexisting skeletal damage," FDA staff said in a report released last week. "If skeletal dysplasia is already severe when initiating therapy, it is possible that treatment with enzyme replacement therapy may only allow prevention of further progression."
FDA staff said Vimizim provides a “modest” benefit.
That's enough for Stephanie Bozarth.
“It’s not just about one kid,” she said. “It affects aunts, uncles, cousins, grandparents. We’re all affected by it, and we all want it to get approved.”