No sweat for BioMarin at Vimizim panel; well, maybe a little
This article was originally published in Scrip
If the members of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) are as placid as the agency seemingly appeared to be in briefing documents released ahead of the 19 November meeting of the outside advisers, BioMarin Pharmaceutical won't have much to sweat over, although that doesn't mean regulators didn’t raise some issues for the panel to sink its teeth into in mulling over the data for Vimizim (elosulfase alfa), an enzyme replacement treatment (ERT).
Indeed, the FDA wants the EMDAC to opine on whether the six-minute walk test (6MWT) is an appropriate measure to adequately evaluate the treatment benefit of Vimizim in patients with Mucopolysaccharidosis Type IVA (MPS IVA), a rare lysosomal storage disorder, and if the "modest" 22.5-meter improvement observed in walking distance represents a clinically meaningful benefit.
The FDA also wants the committee to weigh whether Vimizim should be approved for all MPS IVA patients or a subgroup based on an exploratory analysis, which suggested the drug might be more effective in patients with more severe disease at baseline.
The FDA also pointed out that about 8% of patients treated with Vimizim experienced anaphylaxis – a reaction often experienced by patients given ERTs.
Regulators said, however, most patients given Vimizim developed antidrug and neutralizing antibodies, and suggested further studies may be needed to better understand the role of antibody development on long-term efficacy and safety – an issue most analysts expected to get some play at the 19 November meeting.
Investors, nonetheless, appeared more than comfortable with the FDA's preview documents, with shares of San Rafael, California-based BioMarin rising as high as 9% on 15 November, before closing at $69.29, a gain of $4.96, or 7.71%.
BioMarin's biologics license application for Vimizim included the firm's 24-week, randomized, double-blind, placebo-controlled Phase III clinical trial, known as MOR-004, to support the effectiveness of the experimental drug as a treatment for patients with MPS IVA (scripintelligence.com, 30 May 2013).
MOR-004 evaluated two dosing regimens of Vimizim: 2mg/kg/dose once weekly – the proposed dosage – and 2mg/kg/dose once every other week versus placebo in patients with MPS IVA, a disease that is characterized by deficient activity of Nacetylgalactosamine-6-sulfatase (GALNS) causing excessive lysosomal storage of glycosaminoglycans, such as keratan sulfate and chondroitin sulfate. The excessive storage causes a systemic skeletal dysplasia, short stature and joint abnormalities, which limit mobility and endurance.
Malformation of the chest impairs respiratory function, and looseness of joints in the neck cause spinal instability and potentially spinal cord compression.
Other symptoms of MPS IVA, also sometimes called Morquio A syndrome, may include hearing loss, corneal clouding, and heart disease.
Initial symptoms often become evident in the first five years of life. The disease substantially limits both the quality and length of life of those affected.
The primary efficacy endpoint of BioMarin's study was defined as the change in distance walked in the 6MWT from baseline to week 24.
While the FDA agreed the 6MWT could be used as a primary efficacy measure, BioMarin was advised to analyze it using a responder analysis, in which a responder was defined as a score change in a measure experienced by a patient over a predetermined period that has been demonstrated in the target population to represent treatment benefit.
But due to the heterogeneity in disease presentations, BioMarin reported difficulty defining a responder that could be used as a primary endpoint, regulators noted.
Therefore, the pre-specified primary endpoint remained as change in 6MWT from baseline to week 24.
While patients in the elosulfase alfa 2mg/kg QW treatment group demonstrated a statistically significant change in the 6MWT versus placebo at week 24 based on the prespecified Analysis of Covariance model, with a mean difference of 22.5 meters, whereas those in the 2mg/kg QOW treatment group performed similarly to those in the placebo group, with a mean difference of 0.5 meters.
The real question for the EMDAC is whether Vimizim should be approved for the subgroup population or all MPS IVA patients.
Based on the FDA's exploratory subgroup analysis, regulators said the improvement in 6MWT was more pronounced among patients who walked shorter distances at baseline – an observation that suggests Vimizim may be more efficacious in a subgroup of patients who have more limitations in mobility, regulators said.
Long-term uncontrolled data indicated no further improvement on the 6MWT with continued therapy, but showed stabilization in walking ability over time, the agency said.
"Although the FDA views the efficacy benefit of GALNS therapy as modest and greater in a more severe subgroup, this is not surprising based on previously reported data and the character of MPS IVA disease, which is more skeletal," said analyst Leerink Swann analyst Joseph Schwartz.
He said he expected the physicians on the EMDAC to recognize that most trials show greater separation for drugs versus placebo in more severe subgroups, and that Vimizim's benefit is maximized by administering it as early as possible in the course of disease, "rendering this finding less relevant."
Deutsche Bank analyst Dr Robyn Karnauskas said she strongly believed the drug will be approved in all patients.
Given the lack of alternative treatment options in MPS IVA and the significant morbidity and mortality associated with the disease, RW Baird analyst Christopher Raymond predicted the FDA and its advisory committee "are likely to give a thumbs-up for Vimizim."
Sagient Research's BioMedTracker, an affiliate of Scrip, put the chances of Vimizim gaining the FDA's nod in MPS IVA at 84%, which is 3% above the average probability of US approval for the same indication based on the historical performance of medicines in the same development phase.
But the BioMedTracker analysts thought there was room to question efficacy of the drug, since the improvement on 6MWT was driven by a smaller group of high performers, placebo patients who switched over to treatment did not improve and there was no improvement on the secondary endpoint stair climb test.