FDA's Rare Disease Program: A Rare Opportunity to Help Kids

Laura A. Stokowski, RN, MS,Anne Pariser, MD; Andrew Mulberg, MD


March 18, 2014

Editorial Collaboration

Medscape &

In This Article

Dual Challenges in Drug Development

Medscape: The disease that we are talking about today, MPS IVA, is part of the broad category of lysosomal storage disorders that may affect as many as 1 in 2315 newborns.[1] MPS IVA is much rarer and has been diagnosed in only about 800 people in the United States. In these patients, missing or insufficient enzyme activity impairs the catabolism of glycosaminoglycans (GAGs), including keratan sulfate and chondroitin-6-sulfate. The accumulation of GAGs in multiple organs and tissues eventually results in diminished functional capacity, reduced endurance, impaired quality of life, and early mortality. MPS IVA is a heterogeneous disease, characterized by severe short stature due to a progressive skeletal dysplasia along with pulmonary and cardiovascular disease. There is no cure for MPS IVA, but enzyme replacement with elosulfase alfa is intended to provide the exogenous enzyme GALNS that is taken up into the lysosomes and subsequently increases the catabolism of the GAGs.

Was it challenging to find enough patients for the trial to test this just-approved drug?

Dr. Pariser: Most of these genetic diseases are probably underdiagnosed, particularly at the more attenuated end of the spectrum, and there are some problems that we encounter with just about every rare disease program. It is correct that there are very few patients, but we have had good success with the development of many orphan drugs. A little more than 450 products have been approved in the United States. Most of these rely on small trials and small numbers of patients, so we do need to apply flexibility and judgment and make the most of the information that we have, but a lot of the time we are successful in moving these needs forward.

The bigger problem is that the diseases tend to be very poorly understood, and that factors into everything: How you are going to diagnose patients, find them, and describe their disease course? Can you build a clinical trial around this? What should that trial look like? What will we use for endpoints? There are many challenges here, but it's something that we have put a great deal of time and effort into working on.

Dr. Andrew Mulberg

Dr. Mulberg: This trial occurred in the context of a multinational landscape of 17 countries and 31 clinical sites. Compared with what happens in a larger study for a hypertension drug, for example, it underscores that a lot of sites are needed to find enough patients who are appropriately diagnosed with a rare disease. The recruitment effort that it takes is a problem that we have in pediatric drug development in general, not just for diseases of inborn errors of metabolism. It often requires a global program, depending on the prevalence of the disease under investigation. Although this trial involved both children and adults, aged 5 through 57 years, pediatric trials are often very difficult to enroll for many reasons, and clinical trials for rare diseases take a long time. It can take many years just to identify an adequate number of patients.

Medscape: In the randomized, placebo-controlled trial used for the approval of elosulfase alfa, the drug met one of its primary endpoints, which was an improvement of 22.5 meters in the 6-minute walk test (6MWT) from baseline to week 24. For such a wide age range of patients with MPS IVA, can you explain how this represents a clinically significant improvement?

Dr. Mulberg: We always struggle with trying to identify a primary endpoint that can allow us to assess a drug's efficacy. There was some discussion about whether 22 meters was indeed a clinical benefit in the 6MWT. Other drugs approved by the FDA for other indications had been approved using the same endpoint, although it is hard to compare treatment differences and benefit across different diseases. On November 19, 2013, the Division sought advice from the Endocrinologic and Metabolic Drugs Advisory Committee about the appropriateness of the 6MWT to assess treatment benefit in this patient population. Most of the committee members considered the 6MWT to be adequate for evaluating treatment benefit in MPS IVA patients because the 6MWT is an integrated measure that is able to show change in this heterogeneous patient population. Although 6MWT is an assessment of multiple organ systems involved in MPS IVA, the community is encouraged to identify a more appropriate functional measure specific to MPS IVA patients, especially in the younger than 5 years old age cohort. During the Advisory Committee meeting discussing elosulfase alfa, parents of children with MPS IVA spoke publically in favor of that endpoint.

The primary manifestations of MPS IVA are musculoskeletal. The 6MWT was originally developed to measure functional capacity and endurance in adult patients with cardiac or pulmonary diseases. The 6MWT has also been used to support the approval of ERTs for MPS 1, MPS II, MPS VI, and Pompe disease. The clinical manifestations and prognoses can vary between these different forms of MPS. Patients with Pompe disease and MPS I, II, and VI tend to have more extensive cardiopulmonary involvement that affects their endurance, whereas patients with MPS IVA experience difficulty ambulating, largely as a result of progressive skeletal dysplasia such as joint deformities and contractures.

Treatment with elosulfase alfa 2 mg/kg once weekly resulted in a modest improvement in the 6MWT but not in the 3-minute stair climb test. On exploratory subgroup analysis, the improvement in 6MWT was more pronounced in patients who walked shorter distances at baseline, suggesting that elosulfase alfa may be more efficacious in patients who have more limitations in mobility. Long-term uncontrolled data indicated no further improvement on the 6MWT with continued therapy but showed stabilization in walking ability over time. Thus, it is not clear whether ERT can reverse pre-existing skeletal damage. It is possible that it can only prevent further progression. These issues remain to be explored with further studies. It is especially important to understand the long-term efficacy of elosulfase alfa in providing clinical benefit to patients with MPS IVA.

Dr. Pariser: These genetic diseases are often progressive. What patients have told us in a variety of situations is that even slowing the rate of decline would be clinically important to them. They don't always have to see an improvement -- sometimes just seeing a slower rate of decline or maintaining function would be clinically meaningful to them as well.

Medscape: In some of the other forms of MPS that are being treated with ERT, it is said that the earlier the treatment, the better the outcomes; and in some cases, young infants are being treated with ERT.[2] What is the youngest age that elosulfase alfa is approved for, and what are the plans for evaluating the safety and efficacy in even younger patients so that treatment can begin as soon as the disease is diagnosed, at whatever age that is?

Dr. Mulberg: The clinical trial conduct was conducted in patients aged 5-57 years. Many congenital disorders present early in life, and others may take years to develop clinically. Ideally, therapies will be targeted to the age that patients can be diagnosed when the drugs are approved. In this case for elosulfase alfa, there is a postmarketing requirement for this company to explore the effects of elosulfase alfa in children younger than 5 years of age. BioMarin is already conducting a phase 2 multinational study of this drug in pediatric patients with MPS IVA from birth to age 5 years. We are very eager to see what those data demonstrate.

Dr. Pariser: Speaking collectively, many of these are progressive disorders. Enzyme replacement is not a reparative therapy. We are trying to slow the progression. There is no expectation that we are going to undo the damage that has already been done. Certainly we want to identify patients earlier, if we can, to prevent or attenuate that progression. That being said, this is an approved drug, so under the practice of medicine, physicians can prescribe it for their patients.

Dr. Mulberg: It would be considered off-label use in the younger pediatric population at this point. We have no data on any of the issues we have discussed, including the safety risks, the hypersensitivity risks, the development of allergic reactions, dosing, etc. It is a problem that we face with many drugs used in children today for which we don't have appropriate labeling.