Yesterday, a group of experts presented “Changing lives: Long-term outcomes of MPS IVA & VI patients” at the Satellite Symposium sponsored by BioMarin.
The program began with insights on the natural progression from Paul R. Harmatz, MD, from UCSF Benioff Children’s Hospital, who introuced the two related diseases, mucopolsaccharidosis syndrome (MPS) IVA (Morquio A syndrome) and MPS VI (Maroteaux-Lamy syndrome).
Both are rare genetic lysosomal storage disorders that result from a deficiency in lysosomal enzymes that are involved in breaking down glycoaminoglycins (GAGs). The build up leads to dysfunction throughout different organs, including musculoskeletal and joint problems, shortened stature, respiratory, cardiac, neurological, and abdominal system impairment, and vision and and hearing loss. Patients may present these symptoms differently. To read more about MPS IV and MPS VI, click here and here.
Although these conditions have many similarities, there are several differences between the disorders, which are caused by deficiencies in different enzymes. MPS IV causes joint laxity and hypermobility, whereas MPS VI causes joint stiffness. MPS VI patients are also more likely to have coarse facial features.
Harmatz stressed that it’s important for physicians to discern the subtle differences and find the correct diagnosis, so that a patient receives correct enzyme therapy. He clarified that whether a patient presents classical or non-classical, slowly progressing symptoms, no cases are considered mild. Harmatz also emphasized that maintaining mobility is key to preserving quality of life.
He explained, “When I think of treating these patients, I think of two areas. One is supportive care, and the other is specific therapy.” A wide range of specialists may be needed to manage the patient’s symptoms.
Treatment impact is assessed by evaluating untreated patients, and measuring outcomes at baseline and during follow up after enzyme replacement therapy (ERT). The clinical outcome measures most commonly used are respiratory function, endurance growth, and urinary GAG (uGAG) levels. Patient reported outcomes are also clinically meaningful measures.
Harmatz ended the introduction with questions about which patients benefit most from ERT: Is it generally beneficial to start ERT in patients with classical disease presentation and high uGAG levels? Is ERT beneficial in non-classical patients, or those with low uGAG levels? Is starting ERT earlier in life preferable to patient outcomes?
Anna Jovanovic, MD, MRCP, FRCPath from Salford Royal NHS Foundation Trust and Christina Lampe, MD, vice director of the Center for Rare Diseases of the Derpartment of Pediatric and Adolescent Medicine at the Helios Dr. Horst Schmidt Kliniken GmbH in Wiesbaden, Germany shared insight on these questions.
Jovanovic reported on MPS IVA patient response to long-term treatment, using recombinant human GANS (elosulfase alfa, Vimizim), which gained FDA approval four years ago. The phase 3 study followed 176 patients, which is a large number in the small patient population. These patients improved significantly in the six minute walk test, and showed less significant significant decreases in uKS, and improvements in respiratory function and three-minute stair climb tests compared to the placebo. Respiratory outcomes, as well as improvements in mobility and self-care, showed greatest levels of improvement in patients who received continuous treatment for two years. Analysis comparing treated and untreated adults showed that treated patients continued to improve in various measures compared to untreated patients, who declined or did not improve. The treatment was deemed safe, although side effects such as vomiting, nausea, abdominal pain, headache, and fatigue were commonly experienced. Anaphylactic events and hematuria were also less commonly reported.
Jovanovic shared a case study of a female patient who exhibited symptoms of MPS IVA at age eight. The patient had attended university, held a job, and wanted to maintain an independent life. She began ERT at age 38. Her six-minute walk test improved, respiratory function remained stable, and self-care and mobility looked positive. Although she still experiences physical limitations including joint pain and mobility restraints, she felt physically better, experienced less fatigue, joint stiffness, and was more able to work and maintain a social life.
Next, Christina Lampe discussed the long-term outcomes of the MPS VI ERT clinical trial program. This ERT uses recombinant human ARSB (galsulfase, Naglazyme), which has been available for 10 years.
The 10 year study followed 55 patients, with average ages of 11-14 years. The safety profile was similar to other ERTs, and though adverse events were common, most were manageable.
The study showed sustained improvement in the six-minute walk test throughout patients of all ages, although patients with lower baseline uGAG showed the greatest improvement. There was also improvement in respiratory function, which was greatest in young patients and patients with lower baseline uGAG. The treatment resulted in sustained growth in patients who were under the age of 18, especially in young patients and those with high baseline uGAG.
Lampe discussed sub-analyses in older patients, addressing the question: is ERT helpful to all MPS VI patients or only certain groups?
Patients starting ERT after the age of 16 found long-term stabilization results compared to untreated patients. In a progressive disorder like MPS VI, stabilization is a positive result.
When comparing patients with low and high baseline uGAGs, both groups showed a decrease in uGAG levels, an improvement in the six mile walk test, and similar pulmonary function. The safety profiles were similar, although slightly more adverse events occurred in patients with high baseline uGAGs.
Research implied that beginning treatment earlier leads to greater results. Patients who start ERT before the age of six experience the most benefit in terms of growth. Lampe discussed a study of two siblings with MPS VI. The brother began treatment at age five, while the sister began at six weeks. Their case was followed for ten years, and researchers found that the sister had less characteristic coarse facial features, better hearing, and less symptoms exhibited overall compared to her brother.
Lampe also shared a case report of a patient with non-classical MPS VI. The patient’s symptoms began at age six At age 13, she experienced hip dysplasia and cardiac symptoms, which led to a diagnosis. After university, she began a career teaching children with special needs. At 24, she started ERT. Since then, she has experienced minimal changes in respiratory function, and her heart is stable. She spent her early life worried about her final height, independence, lifespan, and future. In adulthood, she still experiences pain while walking long distances, and initially found it difficult to manage working full time while undergoing ERT. However, much has changed, and her health has largely stabilized. When she goes to a parties, everyone knows to expect her on a scooter, and she’s currently getting ready to marry her boyfriend in the spring.